WO2010074764A1 - Synthesis of oligomeric neolignans and their use - Google Patents

Synthesis of oligomeric neolignans and their use Download PDF

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Publication number
WO2010074764A1
WO2010074764A1 PCT/US2009/006713 US2009006713W WO2010074764A1 WO 2010074764 A1 WO2010074764 A1 WO 2010074764A1 US 2009006713 W US2009006713 W US 2009006713W WO 2010074764 A1 WO2010074764 A1 WO 2010074764A1
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alkyl
alkenyl
unsubstituted
alkynyl
substituted aryl
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PCT/US2009/006713
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French (fr)
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Scott A. Snyder
Ferenc Kontes
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The Trustees Of Columbia University In The City Of New York
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C07D207/327—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/21—Radicals derived from sulfur analogues of carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/86—Ring systems containing bridged rings containing four rings

Definitions

  • Helicterins A and B (1 and 2), helisorin (3), and helisterculin A (4) are structurally unique natural products with the ability to combat the avian myeloblastosis virus (see Figure 1) . From a biogenetic perspective, their architectures are considered to be products of seemingly straightforward Diels-Alder, radical- based, or acid-induced dimerizations of common, simpler precursors. Yet, the pursuit of such blueprints in the laboratory has failed thus far in enabling their successful synthesis .
  • Tezuka and co-workers reported the isolation and structural characterization of helicterins A and B, helisorin, and helisterculin A (1-4) , four members of a family of structurally distinct neolignans from the Indonesian plant Helicteres isora that possess mild inhibitory activity against the avian myeloblastosis virus [1] .
  • This molecule could give rise to helisorin (3) via a Friedel-Crafts reaction of the pendant aromatic ring onto the proximal ketone, while changes in its oxidation state could provide pathways to helisterculin A (4) and intermediate 7, the likely precursor needed to forge the acetal-based core of helicterin A and B (1 and 2) .
  • critical intermediate 8 could also be envisioned to arise via a radical-based union of appropriate carbon-centered radicals (12a and 12b) followed by a C-C bond- forming event.
  • This invention provides a compound having the structure
  • ⁇ , Y, ⁇ and ⁇ are each, independently, present or absent;
  • Gi is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R 1 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 7 and R 8 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl ( C 1-10 ) alkyl; or -SO 2 R 1 O, wherein R 10 is C 1-10 alkyl, or unsubstituted or substituted aryl; R 9 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and when R 7 and R 8 are H and R 9 is CH 3 , then R 1 is
  • R 5 is absent and A is C-R 4 , wherein R 4 is H, halogen, or ORn, wherein Ru is H, C 1-10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • R 13 is S or 0; and R 14 is -SCH 3 , , O r
  • R 3 and R 4 are each, independently, H, halogen, or OR 16 ; wherein R 16 is H, C 1-10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • R 22 and each occurrence of R25 is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R 23 is S or 0; and R 24 is -SCH 3 , , O r
  • R 2 is H, 29 wherein R 25 , R26, R 27 , R 28 , and R 29 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR31, -SR 31 , -OSO 2 R 31 , or -NR3 1 R32, wherein R 31 and R 32 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; wherein G 2 is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 a1kyny1ene ; and R 30 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 33 and R 34 are each, independently, H, C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO2R36, wherein R 36 is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 35 is H, C 1-10 alkyl , C 2-10 alkenyl , or C 2-10 alkynyl ; and when R 33 and R 34 are H and R 3 5 is CH 3 , then R 30 is
  • R 38 and each occurrence of R41 is C 1-10 alkyl; or unsubstituted or substituted aryl; R 39 is S or O; and R4 0 is -SCH 3 ; -NH-aryl,
  • heteroaryl, heterocyclyl; or or R 5 when present and R 6 taken together form 0; or R 4 joined to R 6 form a 5-membered heterocyclic ring; and
  • R 6 is a direct bond or wherein X is a direct bond, , or C(OMe) 2 ;
  • Y is H or OR 42 ; or when ⁇ is present, Y is ; wherein R 42 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10
  • R 43 and R 44 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO 2 R 4 6, wherein R 46 is C 1-10 alkyl, or unsubstituted or substituted aryl; and R45 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and when R 43 and R 44 are H and R 45 is CH3,
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • Z is H, CN, or wherein R 3 is S or 0; R b is -0- (C 1 -C 10 ) alkyl, -0-(C 2 - C 10 ) alkenyl, heterocyclyl, or heteroaryl ; or
  • This invention provides a compound having the structure
  • ⁇ and ⁇ are present or absent; wherein R 54 and R 55 are present or absent; and when ⁇ is present; ⁇ and R 54 are absent, and R 55 is present; and when ⁇ is present; ⁇ and R 55 are absent, and R 54 is present;
  • G 3 and G 4 are each, independently, is C 1-10 alkylene, C 2 -Io alkenylene, or C 2-10 alkynylene; R 4 8, R49, R 5 0, and R 5i are each, independently, H, C 1 _ 10 alkyl,
  • R 57 and R 58 are independently H, C 1-10 alkyl, C 2 - 10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl( C 1-10 ) alkyl, or -SO 2 R 60 , wherein R 60 is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 59 is H, C 1 _ 10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and when R 57 and R 58 are H and R 59 is CH 3 , then
  • R48, R49, R 5 0, or R 5 1 is ; and wherein R 53 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -SO2R6I, wherein R 61 is C 1 - lo alkyl, or unsubstituted or substituted aryl;
  • R 47 and R 52 are each H, CN, or wherein R 62 , R ⁇ 3, R ⁇ 4, R 6 5, and R 66 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2 - lo alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR 67 , -SR 67 , -OSO 2 R 6 ?, or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1-10 alkyl, C 2 - lo alkenyl, C 2 - lo alkynyl, or unsubstituted or substituted aryl; and wherein R 54 when present, R 55 when present, and R 56 are each, independently, H or OR 69 , wherein R 69 is H or C 1-10 alkyl; or
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
  • This inventions further provides a compound having the structure
  • R 70 and R 7 1 are each, independently, H, OH, -CO 2 R 74 , wherein R 74 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10
  • R 75 and R 76 are independently H; C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO 2 R 7 S, wherein R 78 is C 1-10 alkyl; or unsubstituted or substituted aryl; and wherein R 77 is H; C 1-10 alkyl, C 2 - ⁇ 0 alkenyl, or C 2-10 alkynyl; and at least one of R 75 and R 7 6 is other than H; wherein R 72 and R 73 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -SO 2 R 7 9, or -Si (R 80 ) 3, wherein R 79 is C 1-10 alkyl, or unsubstituted or
  • This invention provides a process for preparing a compound having the structure
  • ⁇ , Y, ⁇ and ⁇ are each, independently, present or absent;
  • Gi is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R 1 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 7 and R 8 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl( C 1-10 ) alkyl; or -SO 2 R 10 , wherein R 10 is C 1-10 alkyl, or unsubstituted or substituted aryl; R 9 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and when R 7 and R 8 are H and R 9 is CH 3 , then R 1 is
  • R 5 is absent and A is C-R 4 , wherein R 4 is H, halogen, or ORn, wherein Rn is H, C 1 _ 10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • R 13 is S or 0; and R 14 is -SCH 3 , , or
  • R 3 and R 4 are each, independently, H, halogen, or OR 16 ; wherein R 16 is H, C 1-10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • R 17 and each occurrence of R 20 is C 1-10 alkyl, or unsubstituted or substituted aryl; and Ri 8 is S or 0; and R 19 is -SCH 3 , , or
  • R 22 and each occurrence of R 25 is Ci-io alkyl, or unsubstituted or substituted aryl;
  • R 23 is S or 0; and R 24 is -SCH 3 , , or
  • R 2 is H, wherein R 25 , R 26 , R 27 , R 28 , and R 29 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2 -I 0 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (Ci-io ) alkyl; -0R 31 , -SR 31 , -OSO 2 R 31 , or -NR 3x R 32 , wherein R 31 and R 32 are each, independently, Ci-io alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; wherein G 2 is C 1-10 alkylene , C 2-10 alkenylene , or C 2-10 alkynylene; and
  • R 30 is H , C 1-10 alkyl , C 2-10 alkenyl , C 2-10 alkynyl , or
  • R 33 and R 34 are each, independently, H, C 1 - io alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1 _ 10 ) alkyl; or -SO 2 R 3 6, wherein R 36 is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 35 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; and when R 33 and R 34 are H and R 35 is CH 3 , then R 30 is
  • R 38 and each occurrence of R 4 i is C 1-10 alkyl; or unsubstituted or substituted aryl; R 39 is S or 0; and R4 0 is -SCH 3 ; -NH-aryl,
  • R 5 ⁇ hen present and R 6 taken together form 0; or R 4 joined to R 6 form a 5-membered heterocyclic ring; and
  • X is a direct bond, ⁇ , or C(OMe) 2 ;
  • Y is H or OR 42 ; or when ⁇ is present, Y is s. wherein R 42 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2 _ 10
  • R 43 and R 44 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO 2 R 4 6, wherein R 46 is C 1-10 alkyl, or unsubstituted or substituted aryl; and
  • R 45 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and when R 43 and R 44 are H and R 45 is CH 3 ,
  • R 42 is ;
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • Z is H, CN, or V wherein R a is S or O;
  • R b is -0- (C 1 -C 10 ) alkyl, -0-(C 2 - C 1 ⁇ )alken ⁇ l, heterocyclyl, or heteroaryl; or
  • R 1 is other than methyl
  • Gi is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • step b) contacting the product of step a) with a compound having the structure
  • R 42 is H , C 1-10 alkyl , C 2-10 alkenyl , C 2-10
  • R 4 3 and R 44 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO2R46, wherein R 46 is C 1 _ 10 alkyl, or unsubstituted or substituted aryl; and
  • R45 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ;
  • R25, R26, R27, R28, and R29 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR 31 , - SR31, -OSO 2 R 3 I, or -NR31R32, wherein R3 1 and R3 2 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; and
  • R a is S or O;
  • R b is -0- (C 1 -C 10 ) alkyl, -0-(C 2 - C 10 ) alkenyl, heterocyclyl, or heteroaryl;
  • This invention further provides a process for preparing a compound having the structure
  • G 3 and G 4 are each, independently, is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene; R 48 , R 49 , R 50 , and R 51 are each, independently, H, C 1-10 alkyl,
  • R 57 and R 5 8 are independently H, C 1-10 alkyl, C 2 - 1 0 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl(C 1-10 ) alkyl, or -SO 2 R 60 , wherein R 60 is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 59 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; and wherein R 53 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -SO 2 R 6 i, wherein R 6i is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R 47 and R 52 are each H, CN, or wherein R 62 , R 53 , R 64 , R 65 , and R 66 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR 67 , -SR 67 , -OSO 2 R 67 , or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; and wherein R 54 when present, R 55 when present, and R 56 are each, independently, H or OR 69 , wherein R 69 is H or C 1-10 alkyl; or
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
  • G 3 is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R 47 is H, CN, or wherein R 62 , R 6 3 , R 64 , R 6 5, and R 66 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR 67 , -SR 67 , -OSO 2 R 67 , or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; R 4 S and R 49 are each, independently, H, C 1-10 alkyl , C 2-10
  • R 57 and R 58 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -SO 2 R60, wherein R 60 is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 59 is H, C 1 _ 10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; and wherein each occurrence of R 8 i is, independently, C 1-10 alkyl, or unsubstituted or substituted aryl; with tetra-n-butylammonium fluoride so as to form a compound having the structure
  • step b) contacting the product _of step a) with sodium hydride so as to form a compound having the structure
  • G 3 is C 1 _ 10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R 47 is H, CN, or wherein R 62 , R 63 , R 64 R 65 , and R 66 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl(C 1-10 ) alkyl; -OR 67 , -SR 67 , -OSO 2 R 67 , or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; R 48 and R 49 are each, independently, H, C 1-10 alkyl, C 2-10
  • R 57 and R 58 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -SO2R60, wherein R 6 o is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 59 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; and wherein each occurrence of R 81 is, independently, C 1-10 alkyl, or unsubstituted or substituted aryl; with a first suitable Bronsted acid in the presence of methanol so as to form a compound having the structure
  • step b') contacting the product of step b') with a second suitable Lewis acid so as to form a compound having the structure
  • This invention provides a process for preparing a compound having the structure
  • R 70 and R 7i are each, independently, H, OH, -C ⁇ 2 R 74 , wherein R 74 is H, C 1-10 alkyl, C 2-10 alkenyl , C 2-10
  • R 75 and R 76 are independently H; C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO 2 R 7 S, wherein R 78 is C 1-10 alkyl; or unsubstituted or substituted aryl; and wherein R 77 is H; C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; wherein R7 2 and R 73 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-1 o alkynyl; unsubstituted or substituted aryl(C 1-10 ) alkyl; -SO 2 R 79 , or -Si(R 80 ) 3 , wherein R 79 is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein each occurrence
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • step a) comprising: a) contacting rosmarinic acid with TMSCHN 2 ; b) contacting the product of step a) with a compound
  • step c) contacting the product of step c) with a compound having the structure
  • step d) contacting the product of step d) with tetra-n- butylammonium fluoride so as to form a compound having the structure
  • This invention further provides a process for preparing a compound having the structure
  • Gi is C 1- io alkylene, C 2-10 alkenylene, or C 2-10 alkynylene; R 1 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 7 and R 8 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl(C 1-10 ) alkyl; or -SO 2 R 1O/ wherein R 10 is C 1-10 alkyl, or unsubstituted or substituted aryl; R 9 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; R26, R27, R28, and R 29 are each, independently, H, halogen, - NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR 31 , -SR 31 , -OSO 2 R 31 , or NR 31 R 32 , wherein R 3x and R 32 are each, independently, C 1-10 alkyl, C 2 -Io alkeny
  • R 43 and R 44 are independently H, C 1- io alkyl, C 2 - io alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl(C 1-10 ) alkyl; or -SO2R 46 , wherein R 46 is C 1-10 alkyl, or unsubstituted or substituted aryl; and R 45 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl;
  • This invention yet further provides a process for preparing a compound having the structure
  • G3 and G 4 are each, independently, is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R48, R49, R 5 0, and R 51 are each, independently, H, C 1-10 alkyl
  • R 57 and R 58 are independently H, C 1-10 alkyl, C 2 - 1 0 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl(C 1-10 ) alkyl, or -SO 2 R 6 O, wherein R 6 o is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 59 is H, C 1 _ 10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; and wherein R 53 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -SO 2 R6 I , wherein R 6 i is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R 47 and R 52 are each H, CN, or wherein R 62 , R ⁇ 3, R ⁇ 4 , R 6 s, and R ⁇ are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl(C 1-10 )alkyl; -OR 67 , -SR 67 , -OSO 2 R 67 , or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; or
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
  • G 3 is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R 62 , R 63 , R 64 , R 65 , and R 66 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR 67 , -SR 67 , -OSO 2 R 67 , or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl;
  • R48 and R 49 are each, independently, H, C 1-10 alkyl, C 2-10
  • R 57 and R 5 8 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -SO 2 R 60 , wherein R ⁇ o is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 59 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; with a suitable Lewis acid so as to form the compound.
  • This invention provides a process for preparing a compound having the structure
  • G 3 and G 4 are each , independently, is C 1 _ 10 alkylene , C 2-10 alkenylene , or C 2-10 alkynylene ;
  • R48, R49, Rs 0 , and R 51 are each, independently, H , C 1-10 alkyl ,
  • R 57 and R 5 8 are independently H, C 1-10 alkyl, C 2 - 1 0 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl( C 1-10 ) alkyl, or -SO 2 R 6 O, wherein R 60 is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 59 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; and
  • R 47 and R 52 are each H, CN, or wherein R 62 , R 63 , R 64 , R 65 , and R 66 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl ( C 1-10 ) alkyl; -OR 67 , -SR 67 , -OSO 2 R 67 , or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; or
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
  • G3 is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R47 is H, CN, or wherein R 62 , R 6 3, R 64 , R 65 , and R 66 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl(C 1-10 ) alkyl; -OR 67 , -SR 67 , -OSO 2 R 67 , or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; R 48 and R49 are each, independently, H, C 1-10 alkyl, C 2-10
  • R 57 and R 58 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -SO2R 60 , wherein R 60 is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 59 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; with a suitable base so as to form the compound.
  • This invention further provides a process for preparing a compound having the structure
  • G3 is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R 62 , R 63 , R 64 , R 65 , and R 66 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl(C 1-10 ) alkyl; -OR 67 , -SR 67 , -OSO 2 R 67 , or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl;
  • R 48 and R 49 are each, independently, H, C 1-10 alkyl, C 2-10
  • R 57 and R 58 are independently H, C 1-10 alkyl, C 2 - 10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl ( C 1-10 ) alkyl, or -SO 2 R 60 , wherein R 60 is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 59 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; and wherein each occurrence of R 8 i is, independently, C 1-10 alkyl, or unsubstituted or substituted aryl;
  • step b) contacting the product of step a) with a suitable hydride reducing agent; c) contacting the product of step b) with a suitable silylating agent; d) contacting the product of step c) with a suitable oxidizing agent so as to form the compound.
  • R 82 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl;
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • compositions, free of plant extract, comprising a compound having the structure
  • ⁇ , Y, ⁇ and ⁇ are each, independently, present or absent;
  • Gi is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene
  • R 1 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or wherein R 7 and R 8 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl(C 1-10 ) alkyl; or -SO 2 R 10 , wherein R 10 is C 1 _ 10 alkyl, or unsubstituted or substituted aryl;
  • R 9 is H , C 1-10 alkyl , C 2-10 alkenyl , or C 2-10 alkynyl ; and when R 7 and R 8 are H and R 9 is CH 3 , then R 1 is
  • R 5 when Y is present; R 5 is absent and A is C-R 4 , wherein R 4 is H, halogen, or ORn, wherein Rn is H, C 1-10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • R 12 and each occurrence of R1 5 is C 1 _ 10 alkyl; or unsubstituted or substituted aryl; and
  • R 13 is S or 0; and R 14 is -SCH 3 , t O r
  • R 3 and R 4 are each, independently, H, halogen, or OR 16 ; wherein R 16 is H, C 1-10 alkyl , -CH 2 SH, -BHCH 2 CH 3 , -
  • R 18 is S or 0; and R 19 is -SCH 3 , , or
  • R 22 and each occurrence of R 25 is C 1 -I -0 alkyl, or unsubstituted or substituted aryl;
  • R 23 is S or 0; and R 24 is -SCH 3 , , or
  • R 2 is H , wherein R 25 , R 26 , R27, R 2 8, and R29 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2 .10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl(C 1-10 ) alkyl; -OR31, -SR31, -OSO 2 R 3 I, or -NR 31 R 32 , wherein R 3x and R 32 are each, independently, C 1- io alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; wherein G 2 is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 a1kyny1ene ; and R 30 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 33 and R 34 are each, independently, H, C 1 - io alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO 2 R 3 6, wherein R 36 is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; and when R 33 and R 34 are H and R 35 is CH 3 , then R 3 o is
  • R 38 and each occurrence of R 41 is C 1-10 alkyl; or unsubstituted or substituted aryl; R39 is S or 0; and R 40 is -SCH 3 ; -NH-aryl
  • heteroaryl, heterocyclyl ; or ; or R 5 when present and R 6 taken together form 0; or R 4 joined to Re form a 5-membered heterocyclic ring; and
  • R2 is and
  • X is a direct bond, , or C(OMe) 2 ;
  • Y is H or OR 42 ; or when ⁇ is present, Y i 1sO • wherein R 42 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10
  • R 43 and R 44 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO 2 R 4 S, wherein R 46 is C 1-10 alkyl, or unsubstituted or substituted aryl; and
  • R 45 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and when R 43 and R 44 are H and R 45 is CH 3 ,
  • R 42 is or wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • R a is S or 0;
  • R b is -0- (C 1 -C 10 ) alkyl, -0-(C 2 - C 10 ) alkenyl, heterocyclyl, or heteroaryl; or
  • R 1 is other than methyl
  • compositions, free of plant extract, comprising a compound having the structure
  • ⁇ and ⁇ are present or absent; wherein R 54 and R 55 are present or absent; and when ⁇ is present; ⁇ and R 54 are absent, and R 55 is present; and when ⁇ is present; ⁇ and R 55 are absent, and R 54 is present;
  • G3 and G 4 are each, independently, is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene; R 4 8, R 4 9, R 5 0, and R 5i are each, independently, H, C 1-10 alkyl,
  • R 57 and R 58 are independently H, C 1-10 alkyl, C 2 - 1 0 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -SO 2 R 6 O, wherein R 6 o is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 59 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; and wherein R 53 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -SO 2 R6I, wherein R 6i is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R 47 and R 52 are each H, CN, or wherein R 62 , R 63 , R 64 , R 6 s, and R 66 are each, independently, H, halogen, -NO 2 , C 1 _ 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR 67 , -SR 67 , -OSO 2 R 67 , or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; and wherein R 54 when present, R 5 5 when present, and R 56 are each, independently, H or 0R ⁇ 9, wherein R 69 is H or C 1-10 alkyl; or
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
  • This invention provides a method of treating a cell expressing a mutant human huntingtin gene, wherein the expression of the mutant huntingtin gene results in a huntingtin protein having a polyglutamine N-terminal, comprising contacting the cell with any of the compositions described herein so as to treat the cell .
  • This invention provides a method of treating a cell expressing a mutant human huntingtin gene, wherein the expression of the mutant huntingtin gene results in a huntingtin protein having a polyglutamine N-terminal, comprising contacting the cell with any of the compounds described herein so as to treat the cell .
  • This invention provides a method of reducing cell death in a population of cells expressing a mutant human huntingtin gene, wherein the expression of the mutant huntingtin gene results in a huntingtin protein having a polyglutamine N- terminal, comprising contacting the population of cells with any of the compositions described herein so as to reduce cell death in the population of cells.
  • This invention provides a method of reducing cell death in a population of cells expressing a mutant human huntingtin gene, wherein the expression of the mutant huntingtin gene results in a huntingtin protein having a polyglutamine N- terminal, comprising contacting the population of cells with any of the compounds described herein so as to reduce cell death in the population of cells.
  • FIG. 1 Structures of helicterin A and B (1 and 2) and related natural products (3-6) .
  • Figure 4 Proposed use of a unique dimeric form of rosmarinic acid to overcome laboratory issues of chemoselectivity as observed with Nature's starting material .
  • Figure 9 Model studies directed towards the synthesis of the helicterin core via attempted dimerizations of 40 and 42.
  • Reagents and conditions (a) HCl (g) , 100 0 C, 45 min, 99%; (b) 160 0 C, 4 h, 32% b.r .s.m. ; (c) KHMDS (0.5 M in toluene, 1.3 equiv) , Tf 2 NPh (2.6 equiv) , THF, -78 0 C, 10 min, 74%; (d) BF 3 ⁇ OEt 2 (4.0 equiv), CH 2 Cl 2 , 0 0 C, 30 min, 79%. (e) NaH (10 equiv), THF, 25 0 C, 20 min, 99%.
  • FIG. 11 Total synthesis of helisterculin A (4) .
  • Reagents and conditions (a) 28 (6.7 equiv), mesitylene, 220 °C, 30 min, 44% (78% b.r. s.m.); (b) NaBH 4 (1.5 equiv), MeOH:THF (4:1), 0 °C, 1 h, 79%; (c) 0.2 M HCl, MeCN:H 2 O (15:1), 25 °C, 2 h, 74%; (d) BBr 3 (1.0 M in CH 2 Cl 2 , 8.0 equiv), CH 2 Cl 2 , -78 °C, 30 min, 92%.
  • FIG. 14 Compound 51 suppressed cell death in PC12 cells that were transfected with the human huntingtin gene containing mutant polyglutamine repeats, flanked by EGFP. Protein expression was induced by tebufenozide and ecdysone analogs. Compound 51 had no effect on uninduced cells.
  • Figures 15-20 Results of compounds 64-80 screened against PC12 cells that were transfected with the human huntingtin gene containing mutant polyglutamine repeats.
  • This invention provides a compound having the structure
  • ⁇ , Y, ⁇ and ⁇ are each, independently, present or absent;
  • Gi is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R 1 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 7 and R 8 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl(C 1-10 ) alkyl; or -SO 2 R 1 O, wherein R 10 is C 1 _ 10 alkyl, or unsubstituted or substituted aryl;
  • R 9 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and when R 7 and R 8 are H and R 9 is CH 3 , then R 1 is
  • R 5 when Y is present; R 5 is absent and A is C-R 4 , wherein R 4 is H, halogen, or ORu, wherein Rn is H, C 1-10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • CH SH, , or -Si(R 15 J 3 ; wherein R12 and each occurrence of R 15 is C 1-10 alkyl; or unsubstituted or substituted aryl; and
  • R 13 is S or 0; and R 14 is -SCH 3 , , O r
  • R 3 and R 4 are each, independently, H, halogen, or OR 16 ; wherein R 16 is H, C 1-10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • R 1 8 is S or 0; and R 19 is -SCH 3 , , or
  • R 22 and each occurrence of R 25 is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R 23 is S or 0; and R 24 is -SCH 3 , , or
  • R 25 , R 2 6, R27, R28, and R 29 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2 _ 10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR31, -SR 31 , -OSO 2 R 31 , or -NR31R32, wherein R 3x and R 32 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2 _ 10 alkynyl, or unsubstituted or substituted aryl; wherein G 2 is C 1- io alkylene, C 2-10 alkenylene, or C 2-10 alkynylene; and R 30 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 33 and R 34 are each, independently, H, C 1 - 1 0 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO 2 R 36 , wherein R 36 is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 35 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; and when R 33 and R 34 are H and R 35 is CH 3 , then R30 is
  • R 38 and each occurrence of R41 is C 1-10 alkyl; or unsubstituted or substituted aryl; R 39 is S or 0; and R 40 is -SCH 3 ; -NH-aryl,
  • heteroaryl, heterocyclyl; or or R 5 when present and R 6 taken together form 0; or R 4 joined to R 6 form a 5-membered heterocyclic ring,- and
  • R 6 is a direct bond or wherein X is a direct bond, , or C(OMe) 2 ;
  • Y is H or OR 42 ; or when ⁇ is present , Y is wherein R 42 is H, C 1-10 alkyl , C 2 _io alk.enyl, C 2-10
  • R 43 and R 44 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO 2 R 4 6, wherein R 46 is C 1-10 alkyl, or unsubstituted or substituted aryl; and R 45 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and when R 43 and R 44 are H and R 45 is CH 3 ,
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • Z is H, CN, or , wherein R a is S or 0; R b is -O- (C 1 -C 10 ) alkyl, -0-(C 2 - C 10 ) alkenyl, heterocyclyl, or heteroaryl ; or
  • the compound has the structure
  • R 7 and R 6 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl(C 1-10 ) alkyl; or -SO 2 R 1 O, wherein R 10 is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R9 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and when R 7 and R 8 are H and R 9 is CH 3 , then R 1 is
  • R 5 when Y is present; R 5 is absent and A is C-R 4 , wherein R 4 is H, halogen, or ORn, wherein Rn is H, d_ 10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • CH SH, , or -Si(R 15 J 3 ; wherein R 12 and each occurrence of R 15 is C 1-10 alkyl; or unsubstituted or substituted aryl; and
  • R 13 is S or 0; and R 14 is -SCH 3 , , or
  • R 3 and R 4 are each, independently, H, halogen, or OR 16 ; wherein R 16 is H, C 1-10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • R 17 and each occurrence of R 20 is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R 18 is S or 0; and R 19 is -SCH 3 , , or
  • R 22 and each occurrence of R 25 is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R 23 is S or 0; and R 24 is -SCH 3 , , or
  • R 25 , R 26 , R 27 , R 28 , and R 29 are each, independently, H, halogen, -NO 2 , C 1- io alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR3 1 , -SR 31 , -OSO 2 R 31 , or -NR 3 iR 32/ wherein R 3x and R 32 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; wherein G 2 is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene; and
  • R 30 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 33 and R 34 are each, independently, H, C 1 - 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO2R36, wherein R 36 is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 35 is H , C 1-10 alkyl , C 2-10 alkenyl , or C 2-10 alkynyl ; and when R 33 and R 34 are H and R 35 is CH 3 , then R 30 is
  • R 38 and each occurrence of R 41 is C 1-10 alkyl; or unsubstituted or substituted aryl;
  • R 39 is S or 0; and R 40 is -SCH 3 ; ; or
  • R 4 joined to R 6 form a 5-membered heterocyclic ring
  • X is a direct bond, , or C(OMe) 2 ;
  • Y is H or OR 42 ; or when ⁇ is present , Y is ; wherein R 42 is H , C 1 _ 10 alkyl , C 2-10 alkenyl , C 2-10
  • R 43 and R 44 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO2R46, wherein R 46 is C 1-10 alkyl, or unsubstituted or substituted aryl; and
  • R 45 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 " alkynyl; and when R 43 and R 44 are H and R 45 is CH 3 ,
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • the compound has the structure
  • R 6 is OR 37 ;
  • R 37 is ; wherein R 39 is S or O; and R 40 is -NH-aryl, heteroaryl, heterocyclyl; or
  • X is a direct bond or .
  • Z is H, CN, or wherein R a is S or 0; R b is -0- (C 1 -C 10 ) alkyl, -0-(C 2 - C 1 ⁇ )alkenyl, heterocyclyl, or heteroaryl; or
  • the compound has the structure
  • Gi is C 1-10 alkylene, C 2 -1Q alkenylene, or C 2-10 alkynylene
  • R 1 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 7 and R 8 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl( C 1-10 ) alkyl; or -SO 2 R 10 , wherein R 10 is C 1 _ 10 alkyl, or unsubstituted or substituted aryl;
  • R 9 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and at least one of R 7 and R 8 is other than H; and when Y is present; R 5 is absent and A is C-R 4 , wherein R 4 is H, halogen, or ORn, wherein Ru is H, C 1 _ 10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • CH SH, , or -Si (R 15 J 3 ; wherein R 12 and each occurrence of R 1 5 is C 1-10 alkyl; or unsubstituted or substituted aryl; and
  • R 13 is S or 0; and R 14 is -SCH 3 , , or
  • R 3 and R 4 are each, independently, H, halogen, or OR 16 ; wherein R 16 is H, C 1-10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • R 1 8 is S or 0; and R 19 is -SCH 3 , , or
  • R 22 and each occurrence of R 25 is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R 23 is S or 0; and R 24 is -SCH 3 , or
  • R 25 , R 26 , R 2 7, R 28 , and R 29 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR3 1 , -SR 31 , -OSO 2 R 31 , or -NR 3 iR 32 , wherein R 31 and R 32 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; wherein G 2 is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene; and R 30 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 33 and R 34 are each, independently, H, C 1 - io alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO 2 R 36 , wherein R 36 is C 1-10 alkyl, or unsubstituted or substituted aryl; and at least one of R 33 and R 34 is other than H; and wherein R 35 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; and
  • R 38 and each occurrence of R 4i is C 1-10 alkyl; or unsubstituted or substituted aryl;
  • R 39 is S or O; and R 40 is -SCH 3 ; ; or
  • R 4 joined to R 6 form a 5-membered heterocyclic ring
  • R 2 is ; and R 6 is a direct bond or and wherein X is a direct bond, , or C(OMe) 2 ;
  • Y is H or OR 42 ; or when ⁇ is present, Y is wherein R42 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10
  • R 43 and R 44 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO2R46, wherein R 46 is C 1-10 alkyl, or unsubstituted or substituted aryl; and R 45 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and at least one of R4 3 and R 44 is other than H; or
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • R 1 when ⁇ is present, R 1 is other than methyl
  • the compound has the structure
  • oc, Y, and ⁇ are each, independently, present or absent;
  • Gi is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene; R 1 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 7 and R 8 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl( C 1-10 ) alkyl; or -SO 2 R 10 , wherein R 10 is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R 9 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and when Y is present; R 5 is absent and A is C-R 4 , wherein R 4 is H, halogen, or ORn, wherein Rn is H, C 1-10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • R 12 and each occurrence of R 1 5 is C 1-10 alkyl; or unsubstituted or substituted aryl; and R 13 is S or 0; and R 1 4 is -SCH 3 , , or
  • R 3 and R 4 are each, independently, H, halogen, or OR 16 ; wherein R 16 is H, C 1-10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • R 17 and each occurrence of R 20 is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R 18 is S or 0; and R 19 is -SCH 3 , , O r
  • R 22 and each occurrence of R 2 s is C 1-10 alkyl, or unsubstituted or substituted aryl; and R 23 is S or O; and R 24 is -SCH 3 , , O r
  • R25, R 2 6, R27, R28, and R29 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl ; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR31, -SR31, -OSO 2 R 3 I, or -NR 3x R 32 , wherein R 31 and R 32 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; wherein G 2 is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene; and
  • R 30 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 38 and each occurrence of R4 1 is C 1-10 alkyl; or unsubstituted or substituted aryl;
  • R 3 9 is S or 0; and R 40 is -SCH 3 ; ; or ; or
  • R 4 joined to R 6 form a 5-membered heterocyclic ring
  • R 2 is ; and R 6 is a direct bond or ;
  • Y is H or OR 42 ; or when ⁇ is present, Y is ; wherein R 42 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10
  • R 43 and R 44 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO2R46, wherein R 46 is C 1-10 alkyl, or unsubstituted or substituted aryl; and
  • R 45 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; or
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • R 1 when ⁇ is present, R 1 is other than methyl
  • the compound has the structure
  • Gi is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene; C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 7 and R 8 are independently H, C 1 _ 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl(C 1-10 ) alkyl; or -SO 2 R 10 , wherein R 10 is C 1-10 alkyl, or unsubstituted or substituted aryl; R 9 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and when R 7 and R 8 are H and R 9 is CH 3 , then R 1 is
  • R 3 and R 4 are each, independently, H, halogen, or OR 16 ; wherein R 16 is H, C 1 - O-0 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • R 17 and each occurrence of R 20 is C 1 _ 10 alkyl, or unsubstituted or substituted aryl;
  • R 18 is S or O; and R 19 is -SCH 3 , , O r
  • R 22 and each occurrence of R25 is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R 23 is S or 0; and R 24 is -SCH 3 , t O r
  • R25, R 2 6, R 2 7, R 2 8, and R 2 g are each, independently, H, halogen, -NO 2 , C 1 _ 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR31, -SR31, -OSO 2 R 3 I, or -NR31R32, wherein R 31 and R 32 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; wherein G 2 is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene; and
  • R 30 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 33 and R 34 are each, independently, H, C 1 - l o alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO 2 R 3 6, wherein R 36 is C ⁇ -10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C 1 _ 10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; and when R 33 and R 34 are H and R 35 is CH 3 , then R 30 is
  • R 38 and each occurrence of R41 is C 1-10 alkyl; or unsubstituted or substituted aryl;
  • R 39 is S or 0; and R 40 is -SCH 3 ; ;. or
  • R 5 when present and R 6 taken together form 0; or R 4 joined to R 6 form a 5-membered heterocyclic ring;
  • Y is H or OR 42 , wherein R 42 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10
  • R 43 and R44 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO2R46, wherein R 46 is C 1-10 alkyl, or unsubstituted or substituted aryl; and
  • R 45 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and when R 43 and R 44 are H and R 45 is CH 3 ,
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • Z is H or CN; or a salt thereof.
  • the compound has the structure
  • R 1 is H, CH 3 , or wherein R 7 and R 8 are p-trifluoromethylbenzyl; and R 9 is CH 3 ; and wherein R 3 is H, OCH 3 , Br, -OSO 2 CF 3 , or -OiPr; R 4 is H, OH, or OCH 3 ;
  • R 5 is H, OH, -OSO 2 CF 3 , or -OSi (CH 3 ) 2 (t-butyl) ; and R 6 is H or ORn,
  • R 13 is S or 0; and R 14 is -SCH 3 ;
  • R 2 is H, , or , wherein R 26 and R 27 are each, independently, -OCH 3 , 7
  • R 30 is CH 3 or
  • R 25 and R2 6 are each wherein R 27 is CH 3 ;
  • R 34 is CH 3 or
  • R 35 and R 36 are each ; and R 37 is CH 3 ;
  • Z is H or CN
  • the compound is selected from the group consisting of Compound 17, 21, 24, 26, 33,
  • the compound is selected from the group consisting of Compound 51.
  • the compound has the structure wherein
  • Gi is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene; R 1 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 7 and R 8 are independently H; C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -SO 2 R 10 , wherein R 1 o is C 1-10 alkyl, or unsubstituted or substituted aryl; and R 9 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and when R 7 and R 8 are H and R 9 is CH 3 , then R 1 is
  • A is a direct bond or wherein R 3 and R 4 are each, independently, H, halogen, or OR 16 ; wherein R 16 is H , C 1-10 alkyl , -CH 2 SH , -BHCH 2 CH 3 , -
  • R I8 is S or 0; and R 19 is -SCH 3 , , or
  • R 22 and each occurrence of R 25 is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R 23 is S or O; and R 24 is -SCH 3 , , or
  • R 6 is a direct bond or . anc j wherein R 2 6, R27, R2 8 , and R 29 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR 31 , -SR31, - OSO 2 R 31 , or -NR 3x R 32 , wherein R 31 and R 3 2 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; wherein R 42 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 43 and R44 are independently H, C 1-10 alkyl, C 2 - 1 0 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO 2 R 4 S, wherein R 46 is C 1-10 alkyl, or unsubstituted or substituted aryl; and
  • R45 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and when R 43 and R 44 are H and R 45 is CH 3 ,
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • the compound has the structure
  • R 1 is CH 3 or 8
  • R 7 and R 8 are ; and R 9 is CH 3 ;
  • Re is a direct bond or ;
  • R 27 and R28 are each -OCH 3 ; and wherein R 42 is CH 3 ; or a salt thereof.
  • the compound is selected from the group consisting of: Compound 23 and 25. In an embodiment, the compound has the structure
  • R 6 is OR 37 ;
  • R 39 is S; and R 40 is or
  • X is a direct bond
  • R a is S or 0;
  • R b is -0- (C 1 -C 10 )alkyl, -0-(C 2 - C 1 o)alkenyl, heterocyclyl, or heteroaryl; or or a salt thereof .
  • the compound has the structure
  • H 3 CO CO2CH3 R 1 is H, methyl or H 3 C O
  • R 2 is H or
  • R 3 and R 4 are each -OCH 3 ;
  • R 5 is H or OR 2I ,
  • R 2 i is I wherein R 2 3 is S; and R 24 is ;
  • R 6 is OR 37 ;
  • R 39 is S; and R 40 is or
  • X is a direct bond
  • Z is H, CN, or wherein R a is S or 0; R b is -OCH 3 , -OCH (CH 3 ) 2 , -
  • OCH 2 CH CH 2 , -OCH 2 CH 2 CH 2 CH 3 , or
  • the compound is selected from the group consisting of Compound 64, 65, 66, 67, 68, 73, 74, 75, 76, 77, 78, 79, 80, and a pharmaceutically acceptable salt thereof .
  • This invention provides a compound having the structure
  • ⁇ and ⁇ are present or absent; wherein R 54 and R 55 are present or absent; and when ⁇ is present; ⁇ and R 54 are absent, and R 55 is present; and when ⁇ is present; ⁇ and R 55 are absent, and R 54 is present;
  • G3 and G 4 are each, independently, is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R48, R49, R 5 0, and R 5 i are each, independently, H, C 1-10 alkyl
  • R 57 and R 58 are independently H, C 1-10 alkyl, C 2 - 1 0 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl( C 1-10 ) alkyl, or -SO 2 R 60 , wherein R 60 is C 1 _ 10 alkyl, or unsubstituted or substituted aryl; and wherein R 59 is H, C 1-10 alkyl , C 2 - 1 Q alkenyl , or C 2-10 alkynyl ; and when R 57 and R 58 are H and R 5 g is CH 3 , then
  • R48, R49, R ⁇ o, or R 5 i is ; and wherein R 53 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -SO 2 R 6 I, wherein R 61 is C 1 _ 10 alkyl, or unsubstituted or substituted aryl;
  • R 47 and R 52 are each H, CN, or wherein R 62 , R 63 , R 6 4, R ⁇ 5, and R 66 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR 67 , -SR 67 , -OSO 2 R 67 , or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1 _ 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; and wherein R 54 when present, R 55 when present, and R 56 are each, independently, H or OR 69 , wherein R 69 is H or C 1-10 alkyl; or
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
  • the compound has the structure
  • G 3 and G 4 are each, independently, is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R48, R 4 9, R 5 0, and R 5 i are each, independently, H, C 1-10 alkyl
  • R 53 is H, C 1 _ 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1 - ⁇ 0 ) alkyl, or -SO 2 R6i, wherein R 6 i is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R47 and R 52 are each H, CN, or wherein R 62 , R ⁇ 3, R ⁇ 4, R&5, and R 6 6 are each, independently, H, halogen, -NO2, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl( C 1-10 ) alkyl; -OR 67 , -SR 67 , -OSO 2 R 67 , or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1-10 alkyl, C 2-10 alkenyl,
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
  • the compound has the structure
  • G3 and G 4 are each, independently, is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R48, R49, R 5 0, and R 5 1 are each, independently, H, C 1-10 alkyl
  • R 57 and R 58 are independently H, C 1-10 alkyl, C 2 - 10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl(C 1-10 ) alkyl, or -SO 2 R 6 O, wherein R 60 is C 1 _ 10 alkyl, or unsubstituted or substituted aryl; and wherein R 59 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; and wherein R 53 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -SO 2 R6i, wherein R 6 i is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R 47 and R 52 are each H, CN, or wherein R 62 , R ⁇ 3, R 8 4, R 6 s, and R 66 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR 67 , -SR 67 , -OSO 2 R 6 V, or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; and wherein R 54 when present, R 55 when present, and R 56 are each, independently, H or OR 6 g, wherein R 6 g is H or Ci-io alkyl; or
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
  • the compound has the structure
  • ⁇ and ⁇ are present or absent; wherein R 54 and R 55 are present or absent; and when ⁇ is present; ⁇ and R 54 are absent, and R 55 is present; and when ⁇ is present; ⁇ and R 55 are absent, and R 54 is present; R 48 , R49, R 50 , and R 5 1 are each CH 3 ;
  • R 53 is H or CH 3 ;
  • R 47 and R 52 are each wherein R 63 and R 64 are each -OCH 3 ; and wherein R 54 when present, R 55 when present, and R 5 6 are each, independently, H or OR 6 g, wherein R 6 g is H or CH 3 ;
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
  • the compound is selected from the group consisting of: Compound 43 and 48.
  • This invention provides a compound having the structure
  • R 70 and R 7 1 are each, independently, H, OH, -CO 2 R 74 , wherein R 74 is H, C 1- io alkyl, C 2-10 alkenyl, C 2-10
  • R 75 and R 76 are independently H; C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO 2 R 7 S, wherein R 78 is C 1-10 alkyl; or unsubstituted or substituted aryl; and wherein R 77 is H; C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and at least one of R-7 5 and R 7 6 is other than H; wherein R 72 and R 73 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl( C 1-10 ) alkyl; -SO 2 R 79 , or -Si(R 8 o)3, wherein R 79 is C 1 _ 10 alkyl, or unsubstituted
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • the compound has the structure
  • R 70 and R 7 1 are each, independently, H, OH, -CO 2 R 74 , wherein R 74 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10
  • R 75 and R 7 6 are independently H; C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO 2 R 7 S, wherein R 78 is C 1-10 alkyl; or unsubstituted or substituted aryl; and wherein R 77 is H; C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and at least one of R 75 and R 76 is other than H; wherein R 72 and R 73 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -SO 2 R 7 g, or -Si (R 80 ) 3 , wherein R 7 g is C 1-10 alkyl, or unsubstituted
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • the compound has the structure
  • R 70 and R 7i are each, independently, H, OH , -CO 2 R 74 , wherein R 74 is H, C 1-10 alkyl , C 2-10 alkenyl , C 2-10
  • R 75 and R 76 are independently H; C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (Ci -10 ) alkyl; or -SO 2 R 7 S, wherein R 78 is C 1-10 alkyl; or unsubstituted or substituted aryl; and wherein R 77 is H; C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and at least one of R 75 and R 76 is other than H; wherein R 72 and R 73 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -SO 2 R 7 ⁇ or -Si (R 80 ) 3 , wherein R 79 is C 1-10 alkyl, or unsubstituted or
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • the compound has the structure R 73 O
  • R 70 and R 7 1 are each, independently, H, OH, -COaR 74 ,
  • R 74 is H, CH 3 , or
  • R 75 and R 76 are each and wherein R 77 is CH 3 ; wherein R 72 and R 73 are each, independently, H, CH 3 ,
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • the compound is selected from the group consisting of: Compound 14, 27, 28, 29, 31, and 32.
  • This invention provides a process for preparing a compound having the structure
  • ⁇ , Y, ⁇ and ⁇ are each, independently, present or absent;
  • Gi is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R 1 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 7 and R 8 are independently H, C 1 _ 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl(C 1-10 ) alkyl; or -SO 2 R 1O/ wherein R 10 is C 1-10 alkyl, or unsubstituted or substituted aryl,- R 9 is H , C 1-10 alkyl , C 2-10 alkenyl , or C 2-10 alkynyl ; and when R 7 and R 8 are H and R 9 is CH 3 , then R 1 is when Y is present; R 5 is absent and A is C-R 4 , wherein R 4 is H, halogen, or ORn, wherein Rn is H, C 1-10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • R 13 is S or 0 ; and R 14 is -SCH 3 , , O r when Y is absent; R 5 is present and A is a direct bond or
  • R 3 and R 4 are each, independently, H, halogen, or OR 16 ; wherein R 16 is H, C 1 _ 10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • R 17 and each occurrence of R 20 is C 1 _ 10 alkyl, or unsubstituted or substituted aryl; and R 18 is S or 0; and R 19 is -SCH 3 , , or
  • R 22 and each occurrence of R 25 is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R 23 is S or 0; and R 24 is -SCH 3 , # O r
  • R 2 is H, 29 28 , or ; wherein R 25 , R 26 , R 27 , R 2 s, and R 29 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR 31 , -SR3 1 , -OSO 2 R 31 , or -NR 3 iR 32 , wherein R 31 and R 32 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; wherein G 2 is C 1- io alkylene, C 2-10 alkenylene, or C 2-10 alkynylene; and
  • R 30 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 33 and R 34 are each, independently, H, C x -
  • R 30 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO 2 R36, wherein R36 is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 35 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; and when R 33 and R 34 are H and R 35 is CH 3 , then R 30 is
  • R 38 and each occurrence of R 4x is C X-10 alkyl; or unsubstituted or substituted aryl; R 3 9 is S or 0; and R 40 is -SCH 3 ; -NH-aryl,
  • heteroaryl , heterocyclyl; or ;
  • R 5 when present and Re taken together form 0; or R4 joined to R 6 form a 5-membered heterocyclic ring;
  • R 2 is ; and R 6 is a direct bond or ⁇ ;
  • X is a direct bond, ⁇ , or C(OMe) 2 ;
  • Y is H or OR 42 ; or when ⁇ is present , Y is ; wherein R 42 is H , C 1-10 alkyl , C 2-10 alkenyl , C 2-10 5
  • R 43 and R 44 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1 -X 0 ) alkyl; or -SO2R46, wherein R 46 is C 1-10 alkyl, or unsubstituted or substituted aryl; and
  • R 45 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and when R 43 and R44 are H and R45 is CH3,
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • Z is H, CN, or wherein R a is S or 0;
  • R b is -0- (C 1 -C 10 ) alkyl, -0-(C 2 - C 1O )alkenyl, heterocyclyl , or heteroaryl; or
  • R 1 is other than methyl
  • Gi is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R 1 is H , C 1-10 alkyl , C 2-10 alkenyl , C 2-10 alkynyl , or wherein R 7 and R 8 are independently H, C 1- io alkyl, C 2 -Io alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1 _ 10 ) alkyl; or -SO2R10, wherein R 1 o is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R 9 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; with a first suitable oxidizing agent in the presence of methanol so as to form the compound having the structure
  • step b) contacting the product of step a) with a compound having the structure
  • n R 42 is H , C 1-10 alkyl , C 2-10 alkenyl , C2 -10 alkynyl , or wherein R 43 and R 44 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO2R46, wherein R 46 is C 1-10 alkyl, or unsubstituted or substituted aryl; and
  • R45 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ;
  • R 2 5, R26, R27, R 2 8, and R 2 9 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR31, SR31, -OSO 2 R 3 I, or -NR 3x R 32 , wherein R 31 and R 32 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; and
  • R a is S or 0;
  • R b is -O- (C 1 -C 10 ) alkyl, -O- (C 2 - C 10 ) alkenyl, heterocyclyl, or heteroaryl;
  • the compound has the structure
  • ⁇ , Y, and ⁇ are each, independently, present or absent;
  • Gi is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene; H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 7 and R 8 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl( C 1-10 ) alkyl; or -SO 2 R 1 O, wherein R 10 is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R 9 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and when Y is present; R 5 is absent and A is C-R 4 , wherein R 4 is H, halogen, or ORn, wherein Rn is H, C 1-10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • R 13 is S or O; and R 14 is -SCH 3 , , O r ; and when Y is absent; R 5 is present and A is a direct bond or
  • R 3 and R 4 are each, independently, H, halogen, or 0R 1 6,- wherein R 16 is H, C 1-10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • R 17 and each rence of R 20 is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R 18 is S or 0; and R 19 is -SCH 3 , or ; or
  • R 25 is C 1 _ 10 alkyl, or unsubstituted or substituted aryl;
  • R 23 is S or 0; and R 24 is -SCH 3 , , or
  • E 2 is H, , or : wherein R 25 , R 26 , R 2 7, R 28 , and R29 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl(C 1-10 ) alkyl; -OR31, -SR31, -OSO 2 R 3 I, or -NR 3 iR 32 , wherein R 31 and R 32 are each, independently, C 1- io alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; wherein G 2 is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene; and R 30 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 38 , , or -Si(R 4I ) 3 wherein R 38 and each occurrence of R 41 is C 1-10 alkyl; or unsubstituted or substituted aryl; R 3 9 is S or 0; and R 40 is -SCH 3 ; or
  • R 5 when present and R 6 taken together form 0; or R 4 joined to R 6 form a 5-membered heterocyclic ring; and
  • R2 is and
  • X is a direct bond, , or C(OMe) 2 ;
  • Y is H or OR 4 2; or when ⁇ is present, Y is s ⁇ ; wherein R 42 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10
  • R 43 and R 44 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO 2 R 46 , wherein R 46 is C 1-10 alkyl, or unsubstituted or substituted aryl; and
  • R 45 is H, C 1 - K ) alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; or ' wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • R 1 when ⁇ is present, R 1 is other than methyl
  • Gi is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene; R 1 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 7 and R 8 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO 2 R 1 O, wherein R 10 is C 1-10 alkyl, or unsubstituted or substituted aryl; R 9 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; with a first suitable oxidizing agent in the presence of methanol so as to form the compound having the structure
  • step b) contacting the product of step a) with a compound having the structure
  • R 42 is H, C 1-10 alkyl, C 2-10 alkenyl , C 2-10
  • R 43 and R 44 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO 2 R 4 6, wherein R 46 is C 1-10 alkyl, or unsubstituted or substituted aryl; and R 45 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ;
  • R25, R26, R27, R28, and R 29 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 )alkyl; -OR 31 , -
  • R 31 and R 32 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; in the presence of a first suitable energy source so as to form the compound having the structure
  • R 1 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 7 and R 8 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -SO 2 R 1 O, wherein R 10 is C 1-10 alkyl, or unsubstituted or substituted aryl; and R 9 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl.
  • R 1 is H, C 1-10 alkyl , C 2-10 alkenyl , C 2-10 alkynyl , or
  • R 7 and R 8 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1 _ 10 ) alkyl, or -SO 2 R 1 O, - .. - wherein R 10 is C 1-10 alkyl, or unsubstituted or substituted aryl; and R 9 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl.
  • the process further comprises : c) contacting the product of step b) with BBr 3 so to form a compound having the structure
  • the process further comprises : c) contacting the product of step b) with a first suitable hydride reducing agent so as to form a compound having the structure
  • the process further comprises: d) exposing the product of step c) to a first suitable Bronsted acid so as to form a compound having the structure
  • the process further comprises : e) contacting the product of step d) having the structure with a second suitable hydride reducing agent; f) contacting the product of step e) with a suitable silylating agent; g) contacting the product of step f) with a second suitable oxidizing agent so as to form a compound having the structure
  • R 25 is C 1-10 alkyl; or unsubstituted or substituted aryl .
  • the process further comprises : h) exposing the product of step g) to tetra-n- butylammonium fluoride so as to form a compound having the structure
  • the process further comprises : h) exposing the product of step g) to a second suitable Bronsted acid in the presence of methanol so as to form a compound having the structure
  • the process further comprises : i) exposing the product of step h) to a second suitable energy source so as to form a compound having the structure
  • the process further comprises : i) exposing the product of step h) to a third suitable
  • the process further comprises: e) exposing the product of step d) to a first suitable Lewis acid so as to from a compound having the structure
  • the process further comprises: d) exposing the product of step c) to a compound
  • the process further comprises : e) contacting the product of step d) " having the structure with Et 3 _3 and nBU 3 SnH in the presence of O 2 so as to form a compound having the structure
  • the process further comprises : d) exposing the product of step c) to a base and carbon disulfide followed by methyl iodide so as to form a compound having the structure
  • the process further comprises : e) exposing the product of step d) to PhSeSePh in the presence of AIBN and nBu 3 SnH so as to form a compound having the structure
  • the process further comprises : f) exposing the product of step e) having the structure to HCl so as to form a compound having the structure
  • the process further comprises : e) contacting the product of step d) with Et 3 B in the presence of O 2 so as to form a compound having the structure
  • the process further comprises: c) contacting the product of step b) with 1-Bu 2 Al(OiPr) so as to form a compound having the structure
  • the process further comprises:
  • step b) exposing the product of step b) to a first suitable Lewis acid so as to form a compound having the structure
  • the process further comprises: d) contacting the product of step c) with a second suitable Lewis acid so as to form a compound having the structure
  • the process further comprises: d) contacting the product of step c) with a second suitable Lewis acid so as to form a compound having the structure
  • the compound prepared is selected from a group consisting of: Compound 3, 4, 21, 23, 24, 25, 26, 33, 34, 35, 36, 37, 39, 40, 42, 44, 45, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, and 63.
  • the process further comprises:
  • step b) contacting the product of step b) having the structure
  • ⁇ is present or absent; wherein when ⁇ is present, is present;
  • R a is S or 0;
  • R b is -0- (C 1 -C 10 ) alkyl , -0- (C 2 -C 10 ) alkenyl, heterocyclyl, or heteroaryl;
  • the process further comprises: d) exposing the product of step c) to a first suitable Bronsted acid so as to form a compound having the structure
  • the process further comprises: e) contacting the product of step d) with a second suitable hydride reducing agent; f) contacting the product of step e) with a suitable silylating agent; g) contacting the product of step f) with a second suitable oxidizing agent so as to form a compound having the structure
  • R 25 is C 1-10 alkyl; or unsubstituted or substituted aryl .
  • the process further comprises: h) exposing the product of step g) to a second suitable Bronsted acid in the presence of methanol so as to form a compound having the structure
  • the process further comprises: exposing the final product to a compound having the
  • This invention provides a process for preparing a compound having the structure
  • G3 and G 4 are each, independently, is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R48, R49, R 5 0, and R 51 are each, independently, H, C 1-10 alkyl
  • R 57 and R 58 are independently H, C 1-10 alkyl, C 2 -
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
  • G 3 is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R 47 is H, CN, or wherein R 62 , R 6 3, R 64 , R 6 s, and R 6 6 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl( C 1-10 ) alkyl; -OR 67 , -SR 67 , -OSO 2 R 6 7, or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl;
  • R 48 and R 49 are each, independently, H, C 1-10 alkyl, C 2-10
  • R 57 and R 58 are independently H, C 1 _ 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -SO 2 R 60 , wherein R 60 is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 59 is H, C 1 _ 10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; and wherein each occurrence of R 81 is, independently, C 1-10 alkyl, or unsubstituted or substituted aryl; with tetra-n-butylairnnonium fluoride so as to form a compound having the structure b) contacting the product of step a) with sodium hydride so as to form a compound having the structure
  • G3 is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R 47 is H, CN, Or wherein R 62 , R 6 3, R 6 4, R 6 5, and R 66 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl(C 1-10 ) alkyl; -OR 67 , -SR 67 , -OSO 2 R 67 , or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; R48 and R49 are each, independently, H, C 1-10 alkyl, C 2-10
  • R 57 and R 58 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -SO 2 R 6 O, wherein R 60 is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 59 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; and wherein each occurrence of R 81 is, independently, C 1-10 alkyl, or unsubstituted or substituted aryl; with a first suitable Bronsted acid in the presence of methanol so as to form a compound having the structure
  • step b') contacting the product of step b') with a second suitable Lewis acid so as to form a compound having the structure
  • R 4 S and R 4 g are each, independently, H, C 1-10 alkyl, C 2-10
  • R 57 and R 58 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -SO 2 R 60 , wherein R 60 is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 5 g is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl .
  • R 48 and R 49 are each, independently, H, C I _ I Q alkyl, C 2-10
  • R 57 and R 5 s are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -SO 2 R 60 , wherein R 60 is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 59 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl.
  • the process further comprises: a) contacting a compound having the structure
  • G 3 is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R 47 is H, CN, or wherein R 62 , R 63 , R64, R 6 s, and R 66 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl(C 1-10 ) alkyl; -OR 67 , -SR 67 , -OSO 2 R 67 , or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl;
  • R 48 and R 49 are each, independently, H, C 1-10 alkyl, C 2-10
  • R 57 and R 58 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -S0 2 R6o, wherein R 60 is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 5g is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and wherein each occurrence of R 8 i is, independently, C 1-10 alkyl, or unsubstituted or substituted aryl; with tetra-n-butylaitimonium fluoride so as to form a compound having the structure
  • step b) contacting the product of step a) with sodium hydride so as to form a compound having the structure
  • the process further comprises: a') contacting a compound having the structure
  • G3 is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R 47 is H, CN, or wherein R 62 , R 6 3, R 6 4, R 6 5, and R 66 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl( C 1-10 ) alkyl; -OR 67 , -SR 67 , -OSO 2 R 67 , or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; R 4 S and R 49 are each, independently, H, C 1-10 alkyl, C 2-10
  • R 57 and R 58 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -SO 2 R 6 O, wherein R 60 is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 59 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; and wherein each occurrence of R 8 i is, independently, C 1-10 alkyl, or unsubstituted or substituted aryl; with a first suitable Bronsted acid in the presence of methanol so as to form a compound having the structure
  • step b') contacting the product of step b') with a second suitable Lewis acid so as to form a compound having the structure
  • the compound prepared is selected from the group consisting of: Compound 2, 43, and 48.
  • This invention provides a process for preparing a compound having the structure
  • R 70 and R 71 are each, independently, H, OH, -CO 2 R 74 , wherein R 74 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10
  • R 75 and R 7 6 are independently H; C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO 2 R 7 S, wherein R 7 s is C 1-10 alkyl; or- unsubstituted or substituted aryl; and wherein R 77 is H; C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; wherein R 72 and R 73 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -SO 2 R 79 , or -Si(R 80 J 3 , wherein R 79 is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein each occurrence of Ra
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • step a) comprising: a) contacting rosmarinic acid with TMSCHN 2 ; b) contacting the product of step a) with a compound
  • the process further comprises: c) contacting the product of step b) with a second suitable base so as to form a compound having the structure
  • step c) contacting the product of step c) with a compound having the structure
  • step d) contacting the product of step d) with tetra-n- butylannnonium fluoride so as to form a compound having the structure
  • This invention provides a process for preparing a compound having the structure
  • d is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R 1 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 7 and R 8 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl(C 1-10 ) alkyl; or -SO 2 R 10 , wherein R 10 is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R 9 is H, C 1 lio alkyl, C 2-10 alkenyl, or C 2-10 alkynyl;
  • R26, R27, R28, and R29 are each, independently, H, halogen, - NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR 31 , -SR 31 , -OSO 2 R 31 , or NR 3x R 32 , wherein R 31 and R 32 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; and C 1-10 alkyl , C 2-10 alkenyl , C 2-10 alkynyl , or wherein R4 3 and R 44 are independently H, C 1-10 alkyl, C 2 - 10 alkenyl, C 2-10 alkyn
  • This invention further provides a process for preparing a compound having the structure
  • G 3 and G 4 are each, independently, is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R48, R49, R 5 0, and R 51 are each, independently, H, C 1-10 alkyl
  • R 57 and R 5 s are independently H, C 1-10 alkyl, C 2 -
  • R 47 and R 52 are each H, CN, or wherein R 62 , R 63 , R 64 , R 65 , and R 6 6 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl( C 1-10 )alkyl; -OR 67 , -SR 67 , -OSO 2 R 67 , or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; or
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
  • G 3 is C 1 _ 10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R 47 is H, CN, or wherein R 62 , R 63 , R 64 , R 55 , and R 66 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR 67 , -SR 67 , -OSO 2 R 67 , or -NR 67 R 68 , wherein R6 7 and R 68 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl;
  • R4 8 and R49 are each, independently, H, C 1-10 alkyl, C 2-10
  • R 57 and R 5 s are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -SO 2 R 60 , wherein R ⁇ o is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 59 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; with a suitable Lewis acid so as to form the compound.
  • This invention provides a process for preparing a compound having the structure
  • G 3 and G 4 are each, independently, is C 1-10 alkylene , C 2-10 alkenylene , or C 2-10 alkynyl ene ;
  • R48, R49, R 5 0, and R 5 i are each, independently, H , C 1-10 alkyl ,
  • R 5 7 and R 58 are independently H, C 1-10 alkyl, C 2 - 10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl( C 1-10 ) alkyl, or -SO 2 R 6 O, wherein R 60 is C 1-10 alkyl, or unsubstituted or substituted aryl; and wherein R 59 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; and
  • R47 and R 52 are each H, CN, or wherein R 62 , R 63 , R 64 , R 6 s, and R 66 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR 67 , -SR 67 , -OSO 2 R 67 , or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; or
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
  • G 3 is C 1-10 alkylene, C 2-10 alkenylene , or C 2-10 alkynylene ;
  • R 47 is H, CN, or wherein R 62 , R 63 , R 6 4, R ⁇ 5, and R 66 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl( C 1-10 ) alkyl; -OR 67 , -SR 67 , -OSO 2 R 67 , or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; R48 and R49 are each, independently, H, C 1-10 alkyl, C 2-10
  • R 57 and R 58 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -SO 2 R 60 , wherein R 60 is C 1 _ 10 alkyl, or unsubstituted or substituted aryl; and wherein R 59 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; with a suitable base so as to form the compound.
  • This invention provides a process for preparing a compound having the structure
  • G3 is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R 47 is H, CN, or wherein R 62 , R63, R ⁇ 4# R 6 s, and R 66 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl(C 1-10 ) alkyl; -OR 67 , -SR 67 , -OSO 2 R 67 , or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1-10 alkyl, C 2 _ 10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl;
  • R 4 8 and R 4 9 are each, independently, H, C 1-10 alkyl, C 2-10
  • R 57 and R 5 s are independently H, C 1-10 alkyl, C 2 - 1 0 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -SO 2 R 60 , wherein R 6 o is C 1 _ 10 alkyl, or unsubstituted or substituted aryl; and wherein R 59 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; and wherein each occurrence of R 8 i is, independently, C 1-10 alkyl, or unsubstituted or substituted aryl;
  • step b) contacting the product of step a) with a suitable hydride reducing agent; c) contacting the product of step b) with a suitable silylating agent; d) contacting the product of step c) with a suitable oxidizing agent so as to form the compound.
  • R 82 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl;
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • compositions, free of plant extract, comprising a compound having the structure
  • ⁇ , Y, ⁇ and ⁇ are each, independently, present or absent;
  • Gi is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R 1 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , or wherein R 7 and R 8 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl(C 1-10 ) alkyl; or -SO 2 R 1 O, wherein R 10 is C 1 _ 10 alkyl, or unsubstituted or substituted aryl; R 9 is H , C 1-10 alkyl , C 2-10 alkenyl , or C 2-10 alkynyl ; and when R 7 and R 9 are H and R 9 is CH 3 , then R 1 is
  • R 5 is absent and A is C-R4, wherein R 4 is H, halogen, or ORn, wherein Rn is H, C 1-10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • CH SH, or -Si (R 15 ) 3; wherein R 12 and each occurrence of R 15 is C 1-10 alkyl; or unsubstituted or substituted aryl; and
  • R 13 is S or 0; and R 14 is -SCH 3 , , O r
  • R 3 and R 4 are each, independently, H, halogen, or OR 16 ; wherein R 16 is H, C 1 _ 10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • R 18 is S or 0; and R 1 g is -SCH 3 , # or
  • R 22 and each occurrence of R 25 is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R 23 is S or 0; and R 24 is -SCH 3 , , or
  • R 2 is H, wherein R 25 , R26, R27, R28, and R 29 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl( C 1-10 ) alkyl; -OR31, -SR31, -OSO 2 R 3 I, or -NR3 1 R3 2 , wherein R 31 and R 32 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or .substituted aryl; wherein G 2 is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 a1kyny1ene ; and R30 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 33 and R 34 are each, independently, H, C 1 - 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO 2 R36, wherein R 36 is C 1 _ 10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; and when R 33 and R 34 are H and R 35 is CH 3 , then R 30 is
  • R 38 and each occurrence of R4 1 is C 1-10 alkyl; or unsubstituted or substituted aryl; R 39 is S or 0 ; and R 4 0 is -SCH 3 ; -NH-aryl ,
  • X is a direct bond, c , or C(OMe) 2 ;
  • Y is H or OR42; or when ⁇ is present, Y wherein R 42 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10
  • R 43 and R 44 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO 2 R 46 , wherein R 46 is C 1-10 alkyl, or unsubstituted or substituted aryl; and
  • R 45 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and when R 43 and R 44 are H and R 45 is CH 3 ,
  • R 42 is or wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • Z is H, CN, or wherein R a is S or 0; R b is -0- (C 1 -C 10 ) alkyl, -0-(C 2 - C 10 ) alkenyl, heterocyclyl, or heteroaryl; or
  • R 1 is other than methyl
  • the composition comprises a compound having the structure
  • Gi is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene; , C 2-10 alkenyl , C 2-10 alkynyl , or
  • R 7 and R 8 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted • aryl( C 1-10 ) alkyl; or -SO 2 R 1 O, wherein R 10 is C 1-10 alkyl, or unsubstituted or substituted aryl; R 9 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and when Y is present; R 5 is absent and A is C-R 4 , wherein R 4 is H, halogen, or ORn, wherein Ru is H, C 1-10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • R 1 3 is S or 0 ; and R 14 is -SCH 3 , ⁇ -> / , or ⁇ SyOH
  • R 4 wherein R3 and R 4 are each, independently, H, halogen, or OR 16 ; wherein R 16 is H, C 1-10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • R 18 is S or O; and R 19 is -SCH 3 , , O r ,OH
  • R 22 and each occurrence of R 25 is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R 23 is S or 0; and R 2 4 is -SCH 3 , or
  • R 2 is H, , or wherein R 2 5, R 2 6, R27, R28, and R29 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl(C 1-10 ) alkyl; -OR 3 I, -SR31, -OSO2R31, or -NR 3 iR 32 , wherein R 3 i and R 32 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 a1kyny1ene ; and R 3 o is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 38 and each occurrence of R 41 is C 1-10 alkyl; or unsubstituted or substituted aryl; ⁇ N ⁇ N,
  • R3 9 is S or O; and R 40 is -SCH 3 ; W N or
  • R 5 when present and R 6 taken together form 0; or R 4 joined to R 6 form a 5-membered heterocyclic ring;
  • X is a direct bond, or C(OMe) 2 ;
  • Y is H or OR 42 ; or when ⁇ is present, Y is . wherein R 42 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10
  • R 43 and R 44 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C3. -10 ) alkyl; or -SO 2 R 4 6, wherein R 46 is C 1-10 alkyl, or unsubstituted or substituted aryl; and
  • R45 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; or wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • R 1 when ⁇ is present, R 1 is other than methyl
  • composition comprises the compound has the structure
  • Gi is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene
  • R 1 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 7 and R 8 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl(C 1-10 ) alkyl; or -SO 2 R 10 , wherein R 10 is C 1-10 alkyl, or unsubstituted or substituted aryl; R 9 is H, C 1-10 alkyl, C 2 _ 10 alkenyl, or C 2-10 alkynyl; and when Y is present; R 5 is absent and A is C-R 4 , wherein R 4 is H, halogen, or ORn, wherein R 11 is H, C 1-10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • R 13 is S or 0; and R 14 is -SCH 3 , , or
  • R 4 wherein R 3 and R 4 are each, independently, H, halogen, or OR 16 ; wherein R 16 is H, C 1 _ 10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • R 17 and each occurrence of R 20 is C 1-10 alkyl, or unsubstituted or substituted aryl; and R 18 is S or 0 ; and R 1 g is -SCH 3 , # or
  • R 22 and each occurrence of R 25 is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R 23 is S or 0; and R 24 is -SCH 3 , , or
  • R 25 , R 26 , R 27 , R 2 s, and R 29 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR 3x , -SR31, -OSO 2 R 3 I, or -NR 3 iR 32 , wherein R 31 and R 32 are each, independently, C 1 _ 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; wherein G 2 is C 1-10 alkylene , C 2-10 alkenylene , or C 2 -10 alkynylene; and
  • R 30 is H , C 1-10 alkyl , C 2-10 alkenyl , C 2-10 alkynyl , or
  • R 33 and R 34 are each, independently, H, C 1 -
  • R 38 and each occurrence of R 4 1 is C 1-10 alkyl; or unsubstituted or substituted aryl;
  • R 39 is S or 0; and R 40 is -SCH 3 ; ; or
  • R 5 when present and R 6 taken together form 0; or R 4 joined to R 6 form a 5-membered heterocyclic ring;
  • Y is H or OR42 ; or when ⁇ is present , Y is wherein R 42 is H, C 1-10 alkyl , C 2-10 alkenyl , C 2-10
  • R 43 and R 44 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO2R46, wherein R 46 is C 1-10 alkyl, or unsubstituted or substituted aryl; and
  • R 45 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; or
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • R 1 when ⁇ is present, R 1 is other than methyl
  • composition comprises the compound has the structure
  • ⁇ , Y, and ⁇ are each, independently, present or absent;
  • Gi is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene; R 1 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 7 and R 8 are independently H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO2R10, wherein R 10 is C 1-10 alkyl, or unsubstituted or substituted aryl; R 9 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and when Y is present; R 5 is absent and A is C-R 4 , wherein R 4 is H, halogen, or ORn, wherein Ru is H, C 1 _ 10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • R 12 and each occurrence of R 1 5 is C 1-10 alkyl; or unsubstituted or substituted aryl; and R 13 is S or O; and R 14 is -SCH 3 , , or
  • R 3 and R 4 are each, independently, H, halogen, or OR 16 ; wherein R 16 is H, C 1-10 alkyl, -CH 2 SH, -BHCH 2 CH 3 , -
  • R 1 8 is S or 0; and R 19 is -SCH 3 , , or
  • R 22 and each occurrence of R 25 is C 1-10 alkyl, or unsubstituted or substituted aryl; and R2 3 is S or O; and R 2 4 is -SCH3, ⁇ C N or
  • R25, R 2 6, R 2 7, R28, and R29 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl ; unsubstituted or substituted aryl(C 1-10 ) alkyl; -OR3 1 , -SR 31 , -OSO 2 R 31 , or -NR 31 R 32 , wherein R 31 and R 32 are each, independently, C 1 _ 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; wherein G 2 is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene; and
  • R 30 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or
  • R 3 s and each occurrence of R 41 is C 1-10 alkyl; or unsubstituted or substituted aryl;
  • R 39 is S or O; and R 40 is -SCH 3 ; ; O r
  • X is a direct bond, or C(OMe) 2 ;
  • Y is H or OR42; or when ⁇ is present, Y is ; wherein R 42 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10
  • R 43 and R 44 are independently H, C 1 -m alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; or -SO2R46, wherein R 46 is C 1-10 alkyl, or unsubstituted or substituted aryl; and
  • R45 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; or
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
  • R 1 when ⁇ is present, R 1 is other than methyl
  • the composition comprises the compound selected from the group consisting of: Compound 3, 4, 21, 23, 24, 25, 26, 33, 34, 35, 36, 37, 39, 40, 42, 44, 45, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, and 63.
  • the composition comprises compound 51.
  • the composition comprises a compound having the structure
  • R 6 is OR3 7 ;
  • R 37 is t R 40 ; wherein R 39 is S or O; and R40 is -NH-aryl, heteroaryl, heterocyclyl; or
  • X is a direct bond or Ms.
  • R a is S or 0;
  • R b is -0- (C 1 -C 10 ) alkyl, -0-(C 2 - C 1 ⁇ )alkenyl, heterocyclyl, or heteroaryl; or
  • composition comprises a compound having the structure
  • R 6 is OR 37 ;
  • R3 9 is S; and R 40 is or
  • X is a direct bond or .
  • R a is S or 0;
  • R b is -0- (C 1 -C 10 )alkyl, -0-(C 2 - C 1 ⁇ )alkenyl, heterocyclyl, or heteroaryl; or or a salt thereof.
  • the composition comprises a compound having the structure
  • R 1 is H, methyl or
  • R 3 and R 4 are each -OCH 3 ;
  • R 5 is H or OR 2I ,
  • R 21 is wherein R 23 is S; and R 24 is ; anc j
  • R 6 is OR 37 ;
  • R 3 9 is S; and R 40 is
  • X is a direct bond or Ms.
  • R 3 is S or 0;
  • R b is -OCH 3 , -OCH(CH 3 ) 2 , -
  • OCH 2 CH CH 2 , -OCH 2 CH 2 CH 2 CH 3 , , or
  • the composition comprises a compound selected from the group consisting of Compound 64, 65, 66,
  • compositions, free of plant extract, comprising a compound having the structure
  • ⁇ and ⁇ are present or absent; wherein R 54 and R 55 are present or absent; and when ⁇ is present; ⁇ and R 54 are absent, and R 55 is present; and when ⁇ is present; ⁇ and R 55 are absent, and R 54 is present;
  • G 3 and G 4 are each, independently, is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R48, R49, R 5 0, and R 5 i are each, independently, H, C 1-10 alkyl
  • R 57 and R 5 8 are independently H, C 1-10 alkyl, C 2 - 1 0 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -S0 2 R6o, wherein R 60 is C 1 _ 10 alkyl, or unsubstituted or substituted aryl; and wherein R 5 9 is H, C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl ; and wherein R 53 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, unsubstituted or substituted aryl (C 1-10 ) alkyl, or -SO2R6I, wherein R 6 i is C 1-10 alkyl, or unsubstituted or substituted aryl;
  • R 47 and R 52 are each H, CN, or wherein R 6 2, R ⁇ 3, R ⁇ 4, R 6 s, and R 66 are each, independently, H, halogen, -NO 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR 67 , -SR 67 , -OSO 2 R 67 , or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; and wherein R 54 when present, R 55 when present, and R 56 are each, independently, H or OR 69 , wherein R 6 g is H or C 1-10 alkyl; or
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
  • the compound has the structure
  • G 3 and G 4 are each, independently, is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R48, R49, R 5 0, and R 5 i are each, independently, H, C 1-10 alkyl
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
  • the compound has the structure
  • G3 and G 4 are each, independently, is C 1-10 alkylene, C 2-10 alkenylene, or C 2-10 alkynylene;
  • R48, R49, R 5 0, and R 5I are each, independently, H, C 1-10 alkyl
  • R 57 and R 58 are independently H, C 1-10 alkyl, C 2 -
  • R 47 and R 52 are each H, CN, or wherein R 6 2, R 6 3, R ⁇ 4, R 6 5, and R ⁇ are each, independently, H, halogen, -NO 2 , C 1-10 . alkyl, C 2-10 alkenyl, C 2-10 alkynyl; unsubstituted or substituted aryl (C 1-10 ) alkyl; -OR 67 , -SR 67 , -OSO 2 R 6 7 , or -NR 67 R 68 , wherein R 67 and R 68 are each, independently, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or unsubstituted or substituted aryl; and wherein R 54 when present, R 55 when present, and R 56 are each, independently, H or OR6 9 , wherein R 69 is H or C 1-10 alkyl; or
  • alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
  • the compound is selected from the group consisting of: Compound 2, 43, and 48.
  • the composition further comprises a pharmaceutically acceptable carrier.
  • This invention provides a method of treating a cell expressing a mutant human huntingtin gene, wherein the expression of the mutant huntingtin gene results in a huntingtin protein having a polyglutamine N-terminal, comprising contacting the cell with any of the compositions described herein so as to treat the cell.
  • This invention provides a method of treating a cell expressing a mutant human huntingtin gene, wherein the expression of the mutant huntingtin gene results in a huntingtin protein having a polyglutamine N-terminal, comprising contacting the cell with any of the compounds described herein so as to treat the cell.
  • This invention provides a method of reducing cell death in a population of cells expressing a mutant human huntingtin gene, wherein the expression of the mutant huntingtin gene results in a huntingtin protein having a polyglutamine N- terminal, comprising contacting the population of cells with any of the compositions described herein so as to reduce cell death in the population of cells.
  • This invention provides a method of reducing cell death in a population of cells expressing a mutant human huntingtin gene, wherein the expression of the mutant huntingtin gene results in a huntingtin protein having a polyglutamine N- terminal, comprising contacting the population of cells with any of the compounds described herein so as to reduce cell death in the population of cells.
  • the cell is a mammalian nerve cell.
  • the composition comprises a compound having the structure
  • the population of cells is a population of mammalian nerve cells .
  • the compound has the structure
  • Free of plant extract with regard to a composition as used here means that the composition is ' absent any amount of neolignan containing-plant material or neolignan-based oligomer containing-plant material. Thus only synthetically produced compounds and compositions are free of plant extract. Any compound or compositions isolated from a plant would always contain at least some trace amount of plant material .
  • the compounds of the present invention include all hydrates, solvates, and complexes of the compounds used by this invention. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein.
  • Compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
  • the compounds described in the present invention are in racemic form or as individual enantiomers.
  • enantiomers can be separated using known techniques, such as those described in Pure and Applied Chemistry 69, 1469-1474, (1997) IUPAC. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
  • the structure of the compounds of this invention includes an asymmetric carbon atom and thus the compounds occur as racemates, racemic mixtures, and isolated single enantiomers. All such isomeric forms of these compounds are expressly included in this invention.
  • Each stereogenic carbon may be of the R or S configuration.
  • isomers arising from such asymmetry e.g., all enantiomers and diastereomers
  • Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemicalIy controlled synthesis, such as those described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981.
  • the resolution may be carried out by preparative chromatography on a chiral column.
  • the subject invention is also intended to include all isotopes of atoms occurring on the compounds disclosed herein.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • isotopes of carbon include C-13 and C-14.
  • any notation of a carbon in structures throughout this application when used without further notation, are intended to represent all isotopes of carbon, such as 12 C, 13 C, or 14 C.
  • any compounds containing 13 C or 14 C may specifically have the structure of any of the compounds disclosed herein.
  • any notation of a hydrogen in structures throughout this application when used without further notation, are intended to represent all isotopes of hydrogen, such as 1 H, 2 H, or 3 H.
  • any compounds containing 2 H or 3 H may specifically have the structure of any of the compounds disclosed herein.
  • Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples disclosed herein using an appropriate isotopically-labeled reagents in place of the non-labeled reagents employed.
  • alkyl includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and may be unsubstituted or substituted.
  • C 1 -C n as in “C 1 -C n alkyl” is defined to include groups having 1, 2, ...., n-1 or n carbons in a linear or branched arrangement.
  • C 1 -C 6 as in "C 1 -C 6 alkyl” is defined to include groups having 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, pentyl, hexyl, and octyl .
  • alkenyl refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non-aromatic carbon-carbon double bonds may be present, and may be unsubstituted or substituted.
  • C 2 -C 6 alkenyl means an alkenyl radical having 2 , 3 , 4 , 5 , or 6 carbon atoms , and up to 1 , 2 , 3 , 4 , or 5 carbon-carbon double bonds respectively.
  • Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
  • alkynyl refers to a hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present, and may be unsubstituted or substituted.
  • C 2 -C 6 alkynyl means an alkynyl radical having 2 or 3 carbon atoms and 1 carbon- carbon triple bond, or having 4 or 5 carbon atoms and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms and up to 3 carbon-carbon triple bonds.
  • Alkynyl groups include ethynyl , propynyl and butynyl .
  • Alkylene alkenylene and alkynylene shall mean, respectively, a divalent alkane, alkene and alkyne radical, respectively. It is understood that an alkylene, alkenylene, and alkynylene may be straight or branched. An alkylene, alkenylene, and alkynylene may be unsubstituted or substituted.
  • aryl is intended to mean any stable monocyclic, bicyclic or polycyclic carbon ring of up to 10 atoms in each ring, wherein at least one ring is aromatic, and may be unsubstituted or substituted.
  • aryl elements include phenyl, p-toluenyl (4-methylphenyl) , naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl .
  • the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
  • arylalkyl refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an aryl group as described above. It is understood that an "arylalkyl” group is connected to a core molecule through a bond from the alkyl group and that the aryl group acts as a substituent on the alkyl group.
  • arylalkyl moieties include, but are not limited to, benzyl (phenylmethyl) , p- trifluoromethylbenzyl (4-trifluoromethylphenylmethyl) , 1- phenylethyl, 2-phenylethyl, 3-phenylpropyl , 2-phenylpropyl and the like.
  • heteroaryl represents a stable monocyclic, bicyclic or polycyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of 0, N and S.
  • Bicyclic aromatic heteroaryl groups include phenyl, pyridine, pyrimidine or pyridizine rings that are (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom. selected from O, N or S.
  • Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl , benzotriazolyl, benzothiophenyl , benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl , oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl , pyridazinyl, pyridy
  • heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms , it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.
  • heterocycle refers to a mono- or poly-cyclic ring system which can be saturated or contains one or more degrees of unsaturation and contains one or more heteroatoms .
  • Preferred heteroatoms include N, 0, and/or S, including N-oxides, sulfur oxides, and dioxides.
  • the ring is three to ten-membered and is either saturated or has one or more degrees of unsaturation.
  • the heterocycle may be unsubstituted or substituted, with multiple degrees of substitution being allowed. Such rings may be optionally fused to one or more of another "heterocyclic" ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s).
  • heterocycles include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1, 3-oxathiolane, and the like.
  • alkyl, alkenyl, alkynyl , aryl, heteroaryl and heterocyclyl substituents may be substituted or unsubstituted, unless specifically defined otherwise.
  • alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl groups can be further substituted by replacing one or more hydrogen atoms be alternative non-hydrogen groups.
  • hydrogen atoms include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl .
  • substituted refers to a functional group as described above in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non- hydrogen or non-carbon atoms, provided that normal valencies are maintained and that the substitution results in a stable compound.
  • Substituted groups also include groups in which one or more bonds to a carbon (s) or hydrogen (s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom.
  • substituent groups include the functional groups described above, and, in particular, halogens (i.e., F, Cl, Br, and I); alkyl groups, such as methyl, ethyl, n-propyl, isopropryl, n-butyl , tert-butyl, and trifluoromethyl ; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n- propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) and p- trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy) ; heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl, methanesulfonyl, and p- toluenesulfonyl; nitro, nitrosyl; mercapto;
  • substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
  • independently substituted it is meant that the (two or more) substituents can be the same or different.
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • energy source refers to a source that provides energy suitable for activating a chemical reaction and enabling such a reaction to occur.
  • energy sources include, but are not limited to, electromagnetic radiation, such as microwave radiation, ultraviolet radiation, infrared radiation, or visible light; thermal sources, such as heat; and sonic sources, such as ultrasound.
  • acids refers to acids under both the Bronsted- Lowry and the Lewis definitions of acids. Under the Bronsted-Lowry definition, acids are defined as proton (H + ) donors.
  • Bronsted-Lowry acids include, but are not limited to, inorganic acids such as hydrofluoric, hydrochloric, hydrobromic, hydroiodic, perchloric, hypochlorous, sulfuric, sulfurous, sulfamic, phosphoric, phosphorous, nitric, nitrous, and the like; and organic acids such as formic, acetic, trifluoroacetic, p- toluenesulfonic, camphorsulfonic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic,
  • Lewis acids include, but are not limited to, metal salts such as AlCl 3 , FeCl 3 , FeCl 3 * SiO 2 , C 1 -Cl 2 , HgCl 2 , CuCl, TiCl 4 , Yb(OTf 3 ), InOTf, TiCl 2 (OiPr) 2 , and Ti(OiPr) 4 ; organometallic species such as trimethylaluminum and dimethylaluminum chloride; and boron species such as BH 3 , B(Et) 3 , BF 3 , BF 3 -OEt 2 , BBr 3 , B(OMe) 3 , and B(OiPr) 3 .
  • metal salts such as AlCl 3 , FeCl 3 , FeCl 3 * SiO 2 , C 1 -Cl 2 , HgCl 2 , CuCl, TiCl 4 , Yb(OTf 3 ), InOTf, TiCl
  • bases include, but are not limited to, alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, lithium methoxide; alkali metal hydrides, such as lithium hydride, sodium hydride, and potassium hydride; alkali metal bicarbonates and carbonates, such as sodium bicarbonate, sodium carbonate, lithium bicarbonate, lithium carbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, and cesium bicarbonate; organolithium bases, such as methyllithium, n-butyllithium, s-butyllithium, tert- butyllithium, isobutyllithium, phenyllithium, ethyllithium, n-hexyllithium, and isoprop
  • silylating agent refers to a reagent that, when reacted with a nucleophile, generates a silyl derivative of the nucleophile. For example, reaction of a free hydroxyl with a silylating agent generates a silyl ether.
  • silylating agents include, but are not limited to, trimethylsilyl chloride, trimethylsilyl triflate (trifluoromethanesulfonate) , triethylsilyl triflate, triisopropylsilyl chloride, triisopropylsilyl triflate, dimethylisopropylsiIyI chloride, dimethylthexylsilyl chloride, dimethylthexylsilyl triflate, t- butyldimethylsilyl chloride, t-butyldimethylsilyl triflate, t-butyldiphenylsilyl chloride, and the like.
  • hydride reducing agent refers to a reducing agent capable of providing hydride.
  • hydride reducing agents include, but are not limited to, aluminium hydrides, such as U-Bu) 2 AlH, U-Bu) 3 Al, LiAlH 4 , LiAlH(OMe) 3 , LiAlH(Ot-Bu) 3 , and NaAlH 2 (OCH 2 CH 2 OCH 3 ) 2 ; boron hydrides such as 9-BBN, NaBH 4 , NaBH 4 -CeCl 3 , LiBH 4 , LiEt 3 BH, Li(S-Bu) 3 BH, K(S-Bu) 3 BH, Na(S-Bu) 3 BH, KPh 3 BH, (Ph 3 P) 2 CuBH 4 , Zn(BH 4 J 2 , Ca(BH 4 J 2 , Li(n-Bu)BH 3 , NaBH(OMe) 3 , NaBH(OAc) 3 , NaBH 3 CN
  • oxidizing agent refers to a reagent that, when reacted with a molecule, increases the oxidation state of the molecule. For example, exposure of a primary alcohol to an oxidizing agent produces the corresponding aldehyde or carboxylic acid. Similarly, for example, reaction of an oxidizing agent with a secondary alcohol produces the corresponding ketone.
  • oxidizing agents include, but are not limited to, hypervalent iodine reagents, such as 1,1, 1-triacetoxy-l, 1-dihydro-l, 2-benziodoxol-3 (IH) -one (Dess-Martin Periodinane) , iodosobenzene diacetate, iodosobenzene bis (trifluoroacetate) , iodosylbenzene, 2- iodoxybenzoic acid (IBX) , and iodobenzene dichloride; chromium(VI) reagents, such as chromium trioxide, pyridinium chlorochromate (PCC), pyridinium dichromate (PDC) , potassium dichromate, and sodium dichromate; and heavy metal complexes, such as lead tetraacetate, tetrapropylammonium perruthenate, cerium (IV) ammonium nitrate,
  • EDC N-ethyl-N' - (3-dimethylaminopropyl) carbodiimide
  • TBAF tetra- ⁇ -butylammonium fluoride
  • TBS fcert-butyldimethylsilyl
  • TMS trimethylsilyl
  • Tf trifluoromethanesulfonyl
  • KHMDS potassium bis (trimethylsilyl) amide or potassium hexamethyldisilazide
  • AIBN 1, 1 ' -azobisisobutyronitrile
  • the compounds of the instant invention may be in a salt form.
  • a “salt” is salt of the instant compounds which has been modified by making acid or base, salts of the compounds.
  • the salt is pharmaceutically acceptable.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols.
  • the salts can be made using an organic or inorganic acid.
  • Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like.
  • Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium.
  • pharmaceutically acceptable salt in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention.
  • salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed.

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Abstract

Compounds having the structure formule (I) and their uses are described herein.

Description

SYNTHESIS OF OLIGOMERIC NEOLIGNAN3 AND THEIR USE
This application claims the benefit of U.S.. Provisional Application No. 61/203,737, filed December 23, 2008, the entire content of which is hereby incorporated by reference herein.
Throughout this application, certain publications are referenced in brackets. Full citations for these publications may be found immediately preceding the claims . The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to describe more fully the state of the art to which this invention relates .
Background of the Invention
Helicterins A and B (1 and 2), helisorin (3), and helisterculin A (4) are structurally unique natural products with the ability to combat the avian myeloblastosis virus (see Figure 1) . From a biogenetic perspective, their architectures are considered to be products of seemingly straightforward Diels-Alder, radical- based, or acid-induced dimerizations of common, simpler precursors. Yet, the pursuit of such blueprints in the laboratory has failed thus far in enabling their successful synthesis .
In late 1999 and early 2000, Tezuka and co-workers reported the isolation and structural characterization of helicterins A and B, helisorin, and helisterculin A (1-4) , four members of a family of structurally distinct neolignans from the Indonesian plant Helicteres isora that possess mild inhibitory activity against the avian myeloblastosis virus [1] . Similar to many plant-derived polyphenols, their architectural complexity likely derives from the oligomerization of a simpler building block, in this case either rosmarinic acid (5) [2] or its doubly methylated form, oresbiusin B (6) [3] , if one assumes that all of the unassigned stereogenic centers in these isolates possess the same absolute chirality. Indeed, as shown in Figure 2, a possible biosynthesis of these adducts could begin via oxidation of the conjugated aromatic ring within 5 (cf. Figure 1) to its corresponding o-quinone (10), followed by a Diels-Alder reaction with the olefinic domain of unoxidized 5 (shown here as 9) to provide key intermediate 8. This molecule, in turn, could give rise to helisorin (3) via a Friedel-Crafts reaction of the pendant aromatic ring onto the proximal ketone, while changes in its oxidation state could provide pathways to helisterculin A (4) and intermediate 7, the likely precursor needed to forge the acetal-based core of helicterin A and B (1 and 2) . Alternatively, critical intermediate 8 could also be envisioned to arise via a radical-based union of appropriate carbon-centered radicals (12a and 12b) followed by a C-C bond- forming event.
Yet, despite the elegance and apparent simplicity of these general sequences, ones proposed by the original isolation chemists [1] and mirrored by many [4] in assessing putative biosynthetic pathways to related polyphenol natural products, the challenge for synthetic chemistry is accomplishing them in the absence of the enzymes that Nature likely deploys to achieve the requisite chemoselectivity [5] . For instance, the proposed conversion of 8 into 7 requires the selective delivery of hydride from the more hindered face of the [2.2.2] -bicycle onto the less accessible of its two ketones, and ortho- quinones of the type postulated for the opening Diels-Alder reaction typically decompose prior to intermolecular cycloaddition [6] . How, then, to achieve a laboratory synthesis of these molecules? Herein, the first synthetic solution to this problem, an answer revealing that many of the general tenets of the proposed biosynthetic scheme can be reduced to practice, but only by utilizing a building block that is structurally distinct from Nature's presumed starting material in combination with carefully conceived reaction conditions that achieve appropriate control on sensitive frameworks, is described. It is demonstrated herein that a non-natural building block, highly complex retro Diels-Alder/Diels-Alder reaction cascades, an unconventional protecting group to achieve the proper balance of chemical reactivity on sensitive scaffolds, and several carefully developed reaction conditions that effectively balance competing reaction pathways are the keys to accomplishing the first total synthesis of three of these natural products, and also their analogs.
Summary of the Invention
This invention provides a compound having the structure
Figure imgf000006_0001
wherein α, Y, δ and σ are each, independently, present or absent;
wherein when δ is absent,
Figure imgf000006_0003
is absent;
Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000006_0002
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl ( C1-10) alkyl; or -SO2R1O, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl; R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when R7 and R8 are H and R9 is CH3, then R1 is
Figure imgf000006_0004
; and when γ is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORn, wherein Ru is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000007_0001
, or -Si(R15)3; wherein R12 and each occurrence of R15 is CI-IQ alkyl; or unsubstituted or substituted aryl; and
R13 is S or 0; and R14 is -SCH3,
Figure imgf000007_0002
, Or
Figure imgf000007_0006
; and when Y is absent; R5 is present and A is a direct bond or
Figure imgf000007_0007
wherein R3 and R4 are each, independently, H, halogen, or OR16; wherein R16 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000007_0003
, or -Si (R20) 3; wherein R17 and each occurrence of R20 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R18 is S or 0; and R19 is -SCH3,
Figure imgf000007_0004
, or
Figure imgf000007_0005
; or R3 and R4 taken together form =0; and wherein R5 is H, halogen, or OR21, wherein R21 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000008_0001
-SO2R22,
Figure imgf000008_0002
, or -Si(R25)3, wherein R22 and each occurrence of R25 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R23 is S or 0; and R24 is -SCH3,
Figure imgf000008_0004
, Or
Figure imgf000008_0003
R2 is H,
Figure imgf000008_0005
29
Figure imgf000008_0006
wherein R25, R26, R27, R28, and R29 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR31, -SR31, -OSO2R31, or -NR31R32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1-10 alkylene, C2-10 alkenylene, or C2-10 a1kyny1ene ; and R30 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000008_0007
wherein R33 and R34 are each, independently, H, C1- 10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R36, wherein R36 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C1-10 alkyl , C2-10 alkenyl , or C2-10 alkynyl ; and when R33 and R34 are H and R35 is CH3 , then R30 is
Figure imgf000009_0001
; and R6 is H, halogen, or OR37 ; wherein R37 is H, C1-10 alkyl , -CH2SH, -BHCH2CH3 , -CH=SH,
, -SO2R38,
Figure imgf000009_0003
Figure imgf000009_0002
, or -Si(R41)3; wherein R38 and each occurrence of R41 is C1-10 alkyl; or unsubstituted or substituted aryl; R39 is S or O; and R40 is -SCH3; -NH-aryl,
heteroaryl, heterocyclyl; or
Figure imgf000009_0004
or R5 when present and R6 taken together form =0; or R4 joined to R6 form a 5-membered heterocyclic ring; and
when σ is present;
Figure imgf000009_0005
; and R6 is a direct bond or
Figure imgf000009_0006
wherein X is a direct bond,
Figure imgf000010_0001
, or C(OMe)2;
Y is H or OR42; or when α is present, Y is
Figure imgf000010_0002
; wherein R42 is H, C1-10 alkyl, C2-10 alkenyl, C2-10
alkynyl, or
Figure imgf000010_0003
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when R43 and R44 are H and R45 is CH3,
then R42 is
Figure imgf000010_0004
; Or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Z is H, CN,
Figure imgf000010_0005
or
Figure imgf000010_0006
wherein R3 is S or 0; Rb is -0- (C1-C10) alkyl, -0-(C2- C10) alkenyl, heterocyclyl, or heteroaryl ; or
when α is present, Z is -CH=CH-; and when α is present, R1 is other than methyl;
or a salt thereof.
This invention provides a compound having the structure
Figure imgf000011_0001
wherein ε and δ are present or absent; wherein R54 and R55 are present or absent; and when ε is present; δ and R54 are absent, and R55 is present; and when δ is present; ε and R55 are absent, and R54 is present;
wherein G3 and G4 are each, independently, is C1-10 alkylene, C2-Io alkenylene, or C2-10 alkynylene; R48, R49, R50, and R5i are each, independently, H, C1_10 alkyl,
C2-10 alkenyl, C2-10 alkynyl; or
Figure imgf000011_0002
wherein R57 and R58 are independently H, C1-10 alkyl, C2- 10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl( C1-10) alkyl, or -SO2R60, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1_10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when R57 and R58 are H and R59 is CH3, then
R48, R49, R50, or R51 is
Figure imgf000012_0001
; and wherein R53 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6I, wherein R61 is C1-lo alkyl, or unsubstituted or substituted aryl;
R47 and R52 are each H, CN, or
Figure imgf000012_0002
wherein R62, Rβ3, Rβ4, R65, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-lo alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67, -OSO2R6?, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-lo alkenyl, C2-lo alkynyl, or unsubstituted or substituted aryl; and wherein R54 when present, R55 when present, and R56 are each, independently, H or OR69, wherein R69 is H or C1-10 alkyl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof. This inventions further provides a compound having the structure
Figure imgf000013_0001
wherein v is present or absent; wherein R70 and R71 are each, independently, H, OH, -CO2R74, wherein R74 is H, C1-10 alkyl, C2-10 alkenyl, C2-10
alkynyl, or
Figure imgf000013_0002
wherein R75 and R76 are independently H; C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R7S, wherein R78 is C1-10 alkyl; or unsubstituted or substituted aryl; and wherein R77 is H; C1-10 alkyl, C2-χ0 alkenyl, or C2-10 alkynyl; and at least one of R75 and R76 is other than H; wherein R72 and R73 are each, independently, H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -SO2R79, or -Si (R80) 3, wherein R79 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein each occurrence of R80 is, independently, C1-10 alkyl, or unsubstituted or substituted aryl; and when R74 is H or CH3, R73 is other than H or Me; and wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof.
This invention provides a process for preparing a compound having the structure
Figure imgf000014_0001
wherein α, Y, δ and σ are each, independently, present or absent;
wherein when δ is absent, is absent;
Figure imgf000014_0003
Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000014_0002
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl( C1-10) alkyl; or -SO2R10, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl; R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when R7 and R8 are H and R9 is CH3, then R1 is
Figure imgf000015_0001
; and when Y is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORn, wherein Rn is H, C1_10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000015_0002
, -SO2R12,
Figure imgf000015_0003
, or -Si(R15)3; wherein R12 and each occurrence of R15 is C1-10 alkyl; or unsubstituted or substituted aryl; and
R13 is S or 0; and R14 is -SCH3,
Figure imgf000015_0004
, or
Figure imgf000015_0005
; and when Y is absent; R5 is present and A is a direct bond or
Figure imgf000015_0006
; wherein R3 and R4 are each, independently, H, halogen, or OR16; wherein R16 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000015_0007
, -SO2R17,
Figure imgf000015_0008
, or -Si(R20)3; wherein R17 and each occurrence of R20 is C1-10 alkyl, or unsubstituted or substituted aryl; and Ri8 is S or 0; and R19 is -SCH3,
Figure imgf000016_0002
, or
Figure imgf000016_0001
; or
R3 and R4 taken together form =O; and wherein R5 is H, halogen, or OR2I, wherein R21 is H, Ci-io alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000016_0003
, -SO2R22,
Figure imgf000016_0004
, or -Si(R25)3, wherein R22 and each occurrence of R25 is Ci-io alkyl, or unsubstituted or substituted aryl; and
R23 is S or 0; and R24 is -SCH3,
Figure imgf000016_0005
, or
Figure imgf000016_0006
; and when σ is absent;
R2 is H,
Figure imgf000016_0007
Figure imgf000016_0008
wherein R25, R26, R27, R28, and R29 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-I0 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (Ci-io ) alkyl; -0R31, -SR31, -OSO2R31, or -NR3xR32, wherein R31 and R32 are each, independently, Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1-10 alkylene , C2-10 alkenylene , or C2-10 alkynylene; and
R30 is H , C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl , or
Figure imgf000017_0001
wherein R33 and R34 are each, independently, H, C1- io alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1_10) alkyl; or -SO2R36, wherein R36 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and when R33 and R34 are H and R35 is CH3, then R30 is
Figure imgf000017_0002
,. and
Re is H, halogen, or OR37; wherein R37 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000017_0003
, -SO2R38,
Figure imgf000017_0004
0, or -Si (R41) 3 ; wherein R38 and each occurrence of R4i is C1-10 alkyl; or unsubstituted or substituted aryl; R39 is S or 0; and R40 is -SCH3; -NH-aryl,
heteroaryl, heterocyclyl; or
Figure imgf000017_0005
; or
R5 §hen present and R6 taken together form =0; or R4 joined to R6 form a 5-membered heterocyclic ring; and
when σ is present; R2 is
Figure imgf000018_0001
Figure imgf000018_0002
and
wherein X is a direct bond,
Figure imgf000018_0003
^^, or C(OMe)2;
Y is H or OR42; or when α is present, Y is
Figure imgf000018_0004
s. wherein R42 is H, C1-10 alkyl, C2-10 alkenyl, C2_10
alkynyl, or
Figure imgf000018_0005
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when R43 and R44 are H and R45 is CH3,
then R42 is
Figure imgf000018_0006
; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted; Z is H, CN,
Figure imgf000019_0001
or V
Figure imgf000019_0002
wherein Ra is S or O; Rb is -0- (C1-C10) alkyl, -0-(C2- C1θ)alkenγl, heterocyclyl, or heteroaryl; or
when α is present, Z is -CH=CH-;
and when α is present, R1 is other than methyl;
comprising: a) contacting a compound having the structure
Figure imgf000019_0003
wherein
when δ is absent,
Figure imgf000019_0004
is absent;
Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or 9
Figure imgf000019_0005
wherein R7 and R8 are independently H, C1-io alkyl, C2-Io alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R10, wherein R10 is C1_10 alkyl, or unsubstituted or substituted aryl; R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; with a first suitable oxidizing agent in the presence of methanol so as to form the compound having the structure
Figure imgf000020_0001
b) contacting the product of step a) with a compound having the structure
Figure imgf000020_0002
wherein R42 is H , C1-10 alkyl , C2-10 alkenyl , C2-10
alkynyl , or
Figure imgf000020_0003
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1_10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ;
R25, R26, R27, R28, and R29 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR31, - SR31, -OSO2R3I, or -NR31R32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; and
wherein Ra is S or O; Rb is -0- (C1-C10) alkyl, -0-(C2- C10) alkenyl, heterocyclyl, or heteroaryl;
in the presence of a first suitable energy source so as to form the compound having the structure
Figure imgf000022_0001
This invention further provides a process for preparing a compound having the structure
Figure imgf000022_0002
wherein ε and δ are present or absent; wherein R54 and R55 are present or absent; and when ε is present; δ and R54 are absent, and R55 is present; and when δ is present; ε and R55 are absent, and R54 is present; wherein G3 and G4 are each, independently, is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; R48, R49, R50, and R51 are each, independently, H, C1-10 alkyl,
C2-10 alkenyl, C2-10 alkynyl; or
Figure imgf000023_0001
wherein R57 and R58 are independently H, C1-10 alkyl, C2- 10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl(C1-10) alkyl, or -SO2R60, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and wherein R53 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6i, wherein R6i is C1-10 alkyl, or unsubstituted or substituted aryl;
R47 and R52 are each H, CN, or
Figure imgf000023_0002
wherein R62, R53, R64, R65, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; and wherein R54 when present, R55 when present, and R56 are each, independently, H or OR69, wherein R69 is H or C1-10 alkyl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof;
comprising: a) contacting a compound having the structure
Figure imgf000024_0001
wherein G3 is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
R47 is H, CN, or
Figure imgf000024_0002
wherein R62, R63 , R64, R65, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; R4S and R49 are each, independently, H, C1-10 alkyl , C2-10
alkenyl, C2-10 alkynyl; or
Figure imgf000025_0001
wherein R57 and R58 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R60, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1_10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and wherein each occurrence of R8i is, independently, C1-10 alkyl, or unsubstituted or substituted aryl; with tetra-n-butylammonium fluoride so as to form a compound having the structure
Figure imgf000025_0002
b) contacting the product _of step a) with sodium hydride so as to form a compound having the structure
Figure imgf000025_0003
or
a') contacting a compound having the structure
^
Figure imgf000026_0001
wherein G3 is C1_10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
R47 is H, CN, or
Figure imgf000026_0002
wherein R62, R63, R64 R65, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl(C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; R48 and R49 are each, independently, H, C1-10 alkyl, C2-10
alkenyl, C2-10 alkynyl; or
Figure imgf000026_0003
wherein R57 and R58 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R60, wherein R6o is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and wherein each occurrence of R81 is, independently, C1-10 alkyl, or unsubstituted or substituted aryl; with a first suitable Bronsted acid in the presence of methanol so as to form a compound having the structure
Figure imgf000027_0001
b') contacting the product of a') with a first suitable Lewis acid so as to form a compound having the structure
Figure imgf000027_0002
c') contacting the product of step b') with a second suitable Lewis acid so as to form a compound having the structure
Figure imgf000028_0001
This invention provides a process for preparing a compound having the structure
Figure imgf000028_0002
wherein v is present or absent; wherein R70 and R7i are each, independently, H, OH, -Cθ2R74, wherein R74 is H, C1-10 alkyl, C2-10 alkenyl , C2-10
alkynyl, or
Figure imgf000028_0003
wherein R75 and R76 are independently H; C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R7S, wherein R78 is C1-10 alkyl; or unsubstituted or substituted aryl; and wherein R77 is H; C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; wherein R72 and R73 are each, independently, H, C1-10 alkyl, C2-10 alkenyl, C2-1o alkynyl; unsubstituted or substituted aryl(C1-10) alkyl; -SO2R79, or -Si(R80)3, wherein R79 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein each occurrence of R80 is, independently, C1-10 alkyl, or unsubstituted or substituted aryl; and
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof;
comprising: a) contacting rosmarinic acid with TMSCHN2; b) contacting the product of step a) with a compound
having the structure
Figure imgf000029_0001
in the presence of a first suitable base so as to form a compound having the structure
Figure imgf000029_0002
62 . The process of claim 61 further comprising: c) contacting the product of step b) with a second suitable base so as to form a compound having the structure
Figure imgf000030_0001
d) contacting the product of step c) with a compound having the structure
Figure imgf000030_0002
in the presence of N-ethyl-N' - (3-dimethylaminopropyl)carbodiimide and a third suitable base; e) contacting the product of step d) with tetra-n- butylammonium fluoride so as to form a compound having the structure
Figure imgf000030_0003
This invention further provides a process for preparing a compound having the structure
Figure imgf000031_0001
wherein Gi is C1-io alkylene, C2-10 alkenylene, or C2-10 alkynylene; R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000031_0002
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl(C1-10) alkyl; or -SO2R1O/ wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl; R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; R26, R27, R28, and R29 are each, independently, H, halogen, - NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR31, -SR31, -OSO2R31, or NR31R32, wherein R3x and R32 are each, independently, C1-10 alkyl, C2-Io alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; and , C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000032_0001
wherein R43 and R44 are independently H, C1-io alkyl, C2- io alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl(C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl;
comprising: a) exposing a compound having the structure
Figure imgf000032_0002
to a suitable Lewis acid so as to form the compound.
This invention yet further provides a process for preparing a compound having the structure
Figure imgf000033_0001
wherein G3 and G4 are each, independently, is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
R48, R49, R50, and R51 are each, independently, H, C1-10 alkyl,
C2-10 alkenyl, C2-10 alkynyl; or
Figure imgf000033_0002
wherein R57 and R58 are independently H, C1-10 alkyl, C2- 10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl(C1-10) alkyl, or -SO2R6O, wherein R6o is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1_10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and wherein R53 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6I, wherein R6i is C1-10 alkyl, or unsubstituted or substituted aryl;
R47 and R52 are each H, CN, or
Figure imgf000033_0003
wherein R62, Rβ3, Rβ4, R6s, and Rββ are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl(C1-10)alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof;
comprising: a) contacting a compound having the structure
Figure imgf000034_0001
wherein G3 is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
Figure imgf000034_0002
wherein R62, R63, R64, R65, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl;
R48 and R49 are each, independently, H, C1-10 alkyl, C2-10
alkenyl, C2-10 alkynyl; or
Figure imgf000035_0001
wherein R57 and R58 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R60, wherein Rβo is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; with a suitable Lewis acid so as to form the compound.
This invention provides a process for preparing a compound having the structure
Figure imgf000035_0002
wherein G3 and G4 are each , independently, is C1_10 alkylene , C2-10 alkenylene , or C2-10 alkynylene ;
R48, R49, Rs0, and R51 are each, independently, H , C1-10 alkyl ,
C2-10 alkenyl, C2-10 alkynyl; or
Figure imgf000035_0003
wherein R57 and R58 are independently H, C1-10 alkyl, C2- 10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl( C1-10) alkyl, or -SO2R6O, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and
R47 and R52 are each H, CN, or
Figure imgf000036_0001
wherein R62, R63, R64, R65, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl ( C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof;
comprising: a) contacting a compound having the structure
Figure imgf000037_0001
wherein G3 is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
R47 is H, CN, or
Figure imgf000037_0002
wherein R62, R63, R64, R65, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl(C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; R48 and R49 are each, independently, H, C1-10 alkyl, C2-10
alkenyl, C2-10 alkynyl; or
Figure imgf000037_0003
wherein R57 and R58 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R60, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; with a suitable base so as to form the compound.
This invention further provides a process for preparing a compound having the structure
Figure imgf000038_0001
wherein G3 is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
Figure imgf000038_0002
wherein R62, R63, R64, R65, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl(C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl;
R48 and R49 are each, independently, H, C1-10 alkyl, C2-10
alkenyl, C2-10 alkynyl; or
Figure imgf000038_0003
wherein R57 and R58 are independently H, C1-10 alkyl, C2- 10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl ( C1-10 ) alkyl, or -SO2R60, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and wherein each occurrence of R8i is, independently, C1-10 alkyl, or unsubstituted or substituted aryl;
comprising: a) contacting a compound having the structure
Figure imgf000039_0001
with a suitable Bronsted acid so as to form a compound having the structure
Figure imgf000039_0002
b) contacting the product of step a) with a suitable hydride reducing agent; c) contacting the product of step b) with a suitable silylating agent; d) contacting the product of step c) with a suitable oxidizing agent so as to form the compound. This invention provides a process for preparing a compound having the structure
Figure imgf000040_0001
wherein R82 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl;
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof;
comprising: a) contacting a compound having the structure
Figure imgf000040_0002
with a compound having the structure
Figure imgf000040_0003
wherein R83 is halogen, -OH,
Figure imgf000041_0001
,
Figure imgf000041_0002
in the presence of a suitable base so as to form the compound.
This invention provides a composition, free of plant extract, comprising a compound having the structure
Figure imgf000041_0003
wherein α, Y, δ and σ are each, independently, present or absent;
wherein when δ is absent, is absent;
Figure imgf000041_0005
Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000041_0004
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl(C1-10) alkyl; or -SO2R10, wherein R10 is C1_10 alkyl, or unsubstituted or substituted aryl;
R9 is H , C1-10 alkyl , C2-10 alkenyl , or C2-10 alkynyl ; and when R7 and R8 are H and R9 is CH3 , then R1 is
Figure imgf000042_0001
when Y is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORn, wherein Rn is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH, , , or -Si(R15)3;
Figure imgf000042_0002
wherein R12 and each occurrence of R15 is C1_10 alkyl; or unsubstituted or substituted aryl; and
R13 is S or 0; and R14 is -SCH3,
Figure imgf000042_0003
t Or
Figure imgf000042_0004
when Y is absent; R5 is present and A is a direct bond or
Figure imgf000042_0005
wherein R3 and R4 are each, independently, H, halogen, or OR16; wherein R16 is H, C1-10 alkyl , -CH2SH, -BHCH2CH3 , -
CH=SH, -SO2R17,
Figure imgf000043_0001
Figure imgf000043_0002
, or -Si (R20) 3; wherein R17 and each occurrence of R20 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R18 is S or 0; and R19 is -SCH3,
Figure imgf000043_0003
, or
or
R3 and R4 taken together form =0; and wherein R5 is H, halogen, or OR21, wherein R21 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000043_0004
wherein R22 and each occurrence of R25 is C1-I-0 alkyl, or unsubstituted or substituted aryl; and
R23 is S or 0; and R24 is -SCH3,
Figure imgf000043_0005
, or
Figure imgf000043_0006
when σ is absent ;
R2 is H ,
Figure imgf000043_0007
wherein R25, R26, R27, R28, and R29 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2.10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl(C1-10) alkyl; -OR31, -SR31, -OSO2R3I, or -NR31R32, wherein R3x and R32 are each, independently, C1-io alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1-10 alkylene, C2-10 alkenylene, or C2-10 a1kyny1ene ; and R30 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000044_0001
wherein R33 and R34 are each, independently, H, C1- io alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R36, wherein R36 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and when R33 and R34 are H and R35 is CH3, then R3o is
Figure imgf000044_0002
H, halogen, or OR37; wherein R37 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000044_0003
, or -Si(R4I)3; wherein R38 and each occurrence of R41 is C1-10 alkyl; or unsubstituted or substituted aryl; R39 is S or 0; and R40 is -SCH3; -NH-aryl
heteroaryl, heterocyclyl ; or
Figure imgf000045_0001
; or R5 when present and R6 taken together form =0; or R4 joined to Re form a 5-membered heterocyclic ring; and
when σ is present;
R2 is
Figure imgf000045_0002
and
Figure imgf000045_0003
wherein X is a direct bond,
Figure imgf000045_0004
, or C(OMe)2;
Y is H or OR42; or when α is present, Y i 1sO
Figure imgf000045_0005
• wherein R42 is H, C1-10 alkyl, C2-10 alkenyl, C2-10
alkynyl, or
Figure imgf000045_0006
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R4S, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when R43 and R44 are H and R45 is CH3,
then R42 is
Figure imgf000045_0007
or wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Figure imgf000046_0001
wherein Ra is S or 0; Rb is -0- (C1-C10) alkyl, -0-(C2- C10) alkenyl, heterocyclyl, or heteroaryl; or
when α is present, Z is -CH=CH-;
and when α is present, R1 is other than methyl;
or a salt thereof.
This invention provides a composition, free of plant extract, comprising a compound having the structure
Figure imgf000046_0002
wherein ε and δ are present or absent; wherein R54 and R55 are present or absent; and when ε is present; δ and R54 are absent, and R55 is present; and when δ is present; ε and R55 are absent, and R54 is present;
wherein G3 and G4 are each, independently, is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; R48, R49, R50, and R5i are each, independently, H, C1-10 alkyl,
C2-10 alkenyl, C2-10 alkynyl; or
Figure imgf000047_0001
wherein R57 and R58 are independently H, C1-10 alkyl, C2- 10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6O, wherein R6o is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and wherein R53 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6I, wherein R6i is C1-10 alkyl, or unsubstituted or substituted aryl;
R47 and R52 are each H, CN, or
Figure imgf000047_0002
wherein R62, R63, R64, R6s, and R66 are each, independently, H, halogen, -NO2, C1_10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; and wherein R54 when present, R55 when present, and R56 are each, independently, H or 0Rβ9, wherein R69 is H or C1-10 alkyl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof.
This invention provides a method of treating a cell expressing a mutant human huntingtin gene, wherein the expression of the mutant huntingtin gene results in a huntingtin protein having a polyglutamine N-terminal, comprising contacting the cell with any of the compositions described herein so as to treat the cell .
This invention provides a method of treating a cell expressing a mutant human huntingtin gene, wherein the expression of the mutant huntingtin gene results in a huntingtin protein having a polyglutamine N-terminal, comprising contacting the cell with any of the compounds described herein so as to treat the cell .
This invention provides a method of reducing cell death in a population of cells expressing a mutant human huntingtin gene, wherein the expression of the mutant huntingtin gene results in a huntingtin protein having a polyglutamine N- terminal, comprising contacting the population of cells with any of the compositions described herein so as to reduce cell death in the population of cells. This invention provides a method of reducing cell death in a population of cells expressing a mutant human huntingtin gene, wherein the expression of the mutant huntingtin gene results in a huntingtin protein having a polyglutamine N- terminal, comprising contacting the population of cells with any of the compounds described herein so as to reduce cell death in the population of cells.
Brief Description of the Figures
Figure 1. Structures of helicterin A and B (1 and 2) and related natural products (3-6) .
Figure 2. Proposed biogenetic routes to helicterin A and B (1 and 2) . "R" denotes a general functional group.
Figure 3. Preliminary efforts to achieve their core synthesis . Reagents and conditions: (a) PhI(OAc)2 (1.05 equiv) , MeOHrCH2Cl2 (6:1), 25 0C, 14 h, 87%; (b) PhI(OAc)2 (1.1 equiv), MeOHrCH2Cl2 (5:1), 25 0C, 14 h, 97%; (c) acrylonitrile (100 equiv), toluene, 80 0C, 48 h, 43%; (d) AgOAc (1.1 equiv), toluene, 60 0C, 20 h, 20%.
Figure 4. Proposed use of a unique dimeric form of rosmarinic acid to overcome laboratory issues of chemoselectivity as observed with Nature's starting material .
Figure 5. Model studies to create the helisorin core. Reagents and conditions: (a) 13 (6.7 equiv) , mesitylene, 220 °C, 83% b.r.s.m. ; (b) BBr3 (1.0 M in CH2Cl2, 6.0 equiv) , -78 °C, 1 h, 86%; (c) BF3»OEt2 (6.0 equiv) , CH2Cl2, 0->25 °C, 16 h, 82%; (d) BF3OEt2 (20 equiv) , CH2Cl2, 25 °C, 16 h, 80%; (e) BF3-OEt2 (6.0 equiv) , CH2Cl2, 0->25 °C, 16 h, 53%.
Figure 6. Synthesis of building blocks 27, 28, and 32 from rosmarinic acid (5) . Reagents and conditions: (a) TMSCHN2 (0.95 equiv) , THF:MeOH (10:1) , -78 °C, 1 h; (b) p-CF3-BnBr (6.0 equiv) , K2CO3 (6.0 equiv) , KI (catalytic) , 60 °C, 8 h, 84% overall; (c) NaOMe (1.0 equiv) , MeOH:CH2Cl2 (1:1) , 25 °C, 2 h, 92% 28, 90% 29;
(d) 31 (2.0 equiv) , EDOHCl (2.0 equiv) , 4-DMAP (1.0 equiv) , CH2Cl2, 25 °C, 3 h; (e) TBAF (2.0 equiv) , AcOH, THF, 0 °C, 10 min, 94% overall; (f) TBSCl (2.5 equiv) , i- Pr2NEt (3.0 equiv) , CH2Cl2, 25 °C, 14 h, then K2CO3 (excess) , H2O, THF, 25 °C, 2 h, 99%.
Figure 7. Total synthesis of helisorin (3).
Reagents and conditions: (a) PhI(OAc)2 (1.05 equiv) , MeOH:CH2Cl2 (5:1) , 25 °C, 14 h, 99%; (b) 27 (6.7 equiv) , mesitylene, 220 °C, 30 min, 71% b.r.s.m. ; (c) BF3-OEt2 (30 equiv) , H2O (5.0 equiv) , C6H6, 0->25 °C, 16 h, 82% b.r.s.m. ;
(d) BBr3 (1.0 M in CH2Cl2, 20 equiv) , CH2Cl2, -78 °C, 30 min,
77%.
Figure 8. Synthesis of model dimerization percursors 40 and
42 from Diels-Alder product 21.
Reagents and conditions: (a) NaBH4 (excess), MeOH: CH2Cl2, 0
0C, 1 h, 99%; (b) 0.2 M HCl, H2O, toluene, 0 0C, 20 h, 86%; (c) 0.5 M HCl, H2O, THF, 25 0C, 14 h, 84%; (d) Me4NBH(OAc) 3
(5.0 equiv), MeCN:AcOH (10:1), 25 0C, 5 h, 75%; (e) TBSOTf
(1.0 equiv), Et3N (5.0 equiv), CH2Cl2, -78->25 0C, I h; (f)
Dess-Martin periodinane (1.5 equiv), NaHCO3 (10 equiv),
CH2Cl2, 25 0C, 1 h, 94% over 2 steps; (g) TBAF (1.0 M in THF, 2.0 equiv), AcOH (2.0 equiv), THF, 25 0C, 2 h, 76% b.r.s.m.; (h) 0.4 M HCl, MeOH : CH (OMe) 3 (4:1), 25 0C, 14 h,
93%.
Figure 9. Model studies directed towards the synthesis of the helicterin core via attempted dimerizations of 40 and 42. Reagents and conditions: (a) HCl (g) , 100 0C, 45 min, 99%; (b) 160 0C, 4 h, 32% b.r .s.m. ; (c) KHMDS (0.5 M in toluene, 1.3 equiv) , Tf2NPh (2.6 equiv) , THF, -78 0C, 10 min, 74%; (d) BF3^OEt2 (4.0 equiv), CH2Cl2, 0 0C, 30 min, 79%. (e) NaH (10 equiv), THF, 25 0C, 20 min, 99%.
Figure 10. Total synthesis of helicterin B (2) .
Reagents and conditions: (a) NaBH4 (1.5 equiv), MeOH:THF
(4:1), -30 0C, 1 h; (b) 0.5 M HCl, MeCN:H20 (100:1), 25 0C, 14 h, 56% overall; (c) Me4NBH(OAc)3 (5.0 equiv), MeCN:AcOH (80:1), 25 °C, 28 h; (d) TBSOTf (1.05 equiv), Et3N (5.0 equiv) , CH2Cl2, -78 °C, 1 h; (e) Dess-Martin periodinane (1.5 equiv), NaHCO3 (excess), CH2Cl2, 25 °C, 1 h; (f) 0.4 M HCl MeOH:CH(OMe)3 (4:1), 25 °C, 14 h, 43% overall; (g) BF3^OEt2 (8.0 equiv), CH2Cl2, 0 °C, 30 min, 67%; (h) BBr3 (1.0 M in CH2Cl2, 20 equiv), CH2Cl2, -78 °C, 45 min, 76%.
Figure 11. Total synthesis of helisterculin A (4) . Reagents and conditions: (a) 28 (6.7 equiv), mesitylene, 220 °C, 30 min, 44% (78% b.r. s.m.); (b) NaBH4 (1.5 equiv), MeOH:THF (4:1), 0 °C, 1 h, 79%; (c) 0.2 M HCl, MeCN:H2O (15:1), 25 °C, 2 h, 74%; (d) BBr3 (1.0 M in CH2Cl2, 8.0 equiv), CH2Cl2, -78 °C, 30 min, 92%.
Figure 12. Functionalization of the C(4') alcohol.
Reagents and conditions: (a) thiocarbonyl diimidazole (6.0 equiv), 4-DMAP (1.5 equiv), CH2Cl2, 40 °C, 48 h, 91%; (b) Et3B (1.0 M in hexanes, 5.0 equiv), n-Bu3SnH (5.0 equiv), O2 (excess), CH2Cl2, 0 °C, 2 h, 72%; (c) NaH (5.0 equiv), THF:CS2:MeI (4:1:1), 40 °C, 15 h, 94%; (d) AIBN (4.0 equiv), n-Bu3SnH (6.0 equiv), PhSeSePh (4.0 equiv), toluene, 80 °C, 15 min., 84%; (e) 0.7 M HCl, THF, 25 °C, 3 h, 66%; (f) AIBN (1.2 equiv) , n-Bu3SnH (3.0 equiv) , PhSeSePh (2.0 equiv) , toluene, 80 0C, 3 h, 72% b.r.s.m.; (g) Et3B (6.0 equiv), 02 (excess), CH2Cl2, 25 0C, 48 h, 75% b.r.s.m.
Figure 13. Further functionalization of the C(4') alcohol and other products .
Reagents and conditions: (a) Cl(PO)Ph2 (5.0 equiv) , Et3N (5.0 equiv), DCE:THF (1:1), 60 0C, 48 h, 89%; (b) MsCl (20 equiv), Et3N (15 equiv), THF, 25 0C, 6 h, 20 %; (c) oxalyl chloride (2.0 equiv), Et3N (2.0 equiv), 4-DMAP (catalytic), CH2Cl2, 2 h, then 5% HCl, H2O, 1 h, 25 0C, 98%; (d) Tf2O (4.0 equiv), pyridine, 0->35 0C, 2 h, 22% 61 and 46% 62 b.r.s.m.; (e) DIBAOi-Pr (0.93 M in toluene, 1.1 equiv), toluene, 60 0C, 48 h, 46% b.r.s.m.
Figure 14. Compound 51 suppressed cell death in PC12 cells that were transfected with the human huntingtin gene containing mutant polyglutamine repeats, flanked by EGFP. Protein expression was induced by tebufenozide and ecdysone analogs. Compound 51 had no effect on uninduced cells.
Figures 15-20. Results of compounds 64-80 screened against PC12 cells that were transfected with the human huntingtin gene containing mutant polyglutamine repeats.
Figure 21. Biomek setup for triplicate addition of compound and cell media to assay plates Detailed Description of the Invention
This invention provides a compound having the structure
Figure imgf000054_0001
wherein α, Y, δ and σ are each, independently, present or absent;
wherein when δ is absent,
Figure imgf000054_0002
is absent;
Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000054_0003
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl(C1-10) alkyl; or -SO2R1O, wherein R10 is C1_10 alkyl, or unsubstituted or substituted aryl;
R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when R7 and R8 are H and R9 is CH3, then R1 is
Figure imgf000054_0004
when Y is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORu, wherein Rn is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000055_0001
, or -Si(R15J3; wherein R12 and each occurrence of R15 is C1-10 alkyl; or unsubstituted or substituted aryl; and
R13 is S or 0; and R14 is -SCH3,
Figure imgf000055_0002
, Or
Figure imgf000055_0007
; and when Y is absent; R5 is present and A is a direct bond or
Figure imgf000055_0003
wherein R3 and R4 are each, independently, H, halogen, or OR16; wherein R16 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000055_0004
, or -Si (R20) 3; wherein R17 and each occurrence of R20 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R18 is S or 0; and R19 is -SCH3,
Figure imgf000055_0005
, or
Figure imgf000055_0006
R3 and R4 taken together form =0; and wherein R5 is H, halogen, or OR21, wherein R2x is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000056_0001
, -SO2R22, , or -Si(R25)3, wherein R22 and each occurrence of R25 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R23 is S or 0; and R24 is -SCH3,
Figure imgf000056_0002
, or
Figure imgf000056_0003
when σ is absent;
Figure imgf000056_0004
wherein R25, R26, R27, R28, and R29 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2_10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR31, -SR31, -OSO2R31, or -NR31R32, wherein R3x and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2_10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1-io alkylene, C2-10 alkenylene, or C2-10 alkynylene; and R30 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000056_0005
wherein R33 and R34 are each, independently, H, C1- 10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R36, wherein R36 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and when R33 and R34 are H and R35 is CH3, then R30 is
Figure imgf000057_0001
; and R6 is H, halogen, or OR37 ; wherein R37 is H, d-10 alkyl , -CH2SH, -BHCH2CH3 , -CH=SH,
Figure imgf000057_0002
, -SO2R38,
Figure imgf000057_0003
, or -Si(R4J3; wherein R38 and each occurrence of R41 is C1-10 alkyl; or unsubstituted or substituted aryl; R39 is S or 0; and R40 is -SCH3; -NH-aryl,
heteroaryl, heterocyclyl; or
Figure imgf000057_0004
or R5 when present and R6 taken together form =0; or R4 joined to R6 form a 5-membered heterocyclic ring,- and
when σ is present;
Figure imgf000057_0005
and R6 is a direct bond or
Figure imgf000057_0006
wherein X is a direct bond,
Figure imgf000058_0001
, or C(OMe)2;
Y is H or OR42 ; or when α is present , Y is
Figure imgf000058_0002
wherein R42 is H, C1-10 alkyl , C2_io alk.enyl, C2-10
alkynyl, or
Figure imgf000058_0003
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when R43 and R44 are H and R45 is CH3,
then R42 is
Figure imgf000058_0004
; Or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Z is H, CN,
Figure imgf000058_0005
or
Figure imgf000058_0006
, wherein Ra is S or 0; Rb is -O- (C1-C10) alkyl, -0-(C2- C10) alkenyl, heterocyclyl, or heteroaryl ; or
when α is present, Z is -CH=CH-; and when α is present, R1 is other than methyl;
or a salt thereof.
In an embodiment, the compound has the structure
Figure imgf000059_0001
wherein ex, γ, and σ are each, independently, present or absent; Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl , or
Figure imgf000059_0002
wherein R7 and R6 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl(C1-10) alkyl; or -SO2R1O, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl;
R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when R7 and R8 are H and R9 is CH3, then R1 is
Figure imgf000059_0003
when Y is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORn, wherein Rn is H, d_10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000060_0001
, or -Si(R15J3; wherein R12 and each occurrence of R15 is C1-10 alkyl; or unsubstituted or substituted aryl; and
R13 is S or 0; and R14 is -SCH3,
Figure imgf000060_0002
, or
when Y is absent; R5 is present and A is a direct bond or
Figure imgf000060_0004
wherein R3 and R4 are each, independently, H, halogen, or OR16; wherein R16 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000060_0005
, or -Si(R20)3; wherein R17 and each occurrence of R20 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R18 is S or 0; and R19 is -SCH3,
Figure imgf000060_0006
, or
Figure imgf000060_0007
; or
R3 and R4 taken together form =0; and wherein R5 is H, halogen, or OR2I, wherein R2x is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000061_0001
, or -Si(R25)3, wherein R22 and each occurrence of R25 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R23 is S or 0; and R24 is -SCH3,
Figure imgf000061_0002
, or
Figure imgf000061_0003
when σ is absent;
Figure imgf000061_0004
wherein R25, R26, R27, R28, and R29 are each, independently, H, halogen, -NO2, C1-io alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10 ) alkyl; -OR31, -SR31, -OSO2R31, or -NR3iR32/ wherein R3x and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; and
R30 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000061_0005
wherein R33 and R34 are each, independently, H, C1- 10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R36, wherein R36 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H , C1-10 alkyl , C2-10 alkenyl , or C2-10 alkynyl ; and when R33 and R34 are H and R35 is CH3 , then R30 is
Figure imgf000062_0001
R6 is H, halogen , or OR37 ; wherein R37 is H, C1-10 alkyl , -CH2SH , -BHCH2CH3 , -CH=SH ,
or -Si(R4I)3;
Figure imgf000062_0002
wherein R38 and each occurrence of R41 is C1-10 alkyl; or unsubstituted or substituted aryl;
R39 is S or 0; and R40 is -SCH3;
Figure imgf000062_0003
; or
Figure imgf000062_0004
R5 when present and R6 taken together form =0; or
R4 joined to R6 form a 5-membered heterocyclic ring; and
when σ is present; O
Figure imgf000063_0001
Figure imgf000063_0002
and
wherein X is a direct bond,
Figure imgf000063_0003
, or C(OMe)2;
Y is H or OR42 ; or when α is present , Y is ;
Figure imgf000063_0004
wherein R42 is H , C1_10 alkyl , C2-10 alkenyl , C2-10
alkynyl, or
Figure imgf000063_0005
44 wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 " alkynyl; and when R43 and R44 are H and R45 is CH3,
then R42 is
Figure imgf000063_0006
; Or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Z is H or CN; or when α is present, Z is -CH=CH-; and when α is present, R1 is other than methyl;
or a salt thereof.
In an embodiment, the compound has the structure
R
Figure imgf000064_0001
wherein δ is present or absent;
wherein when δ is absent,
Figure imgf000064_0004
is absent;
R6 is OR37;
wherein R37 is
Figure imgf000064_0002
; wherein R39 is S or O; and R40 is -NH-aryl, heteroaryl, heterocyclyl; or
X is a direct bond or
Figure imgf000064_0005
.
Z is H, CN,
Figure imgf000064_0003
or wherein Ra is S or 0; Rb is -0- (C1-C10) alkyl, -0-(C2- C1θ)alkenyl, heterocyclyl, or heteroaryl; or
or a salt thereof .
In an embodiment, the compound has the structure
Figure imgf000065_0001
wherein α, Y, and σ are each, independently, present or absent; Gi is C1-10 alkylene, C2-1Q alkenylene, or C2-10 alkynylene; R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000065_0002
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl( C1-10) alkyl; or -SO2R10, wherein R10 is C1_10 alkyl, or unsubstituted or substituted aryl;
R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and at least one of R7 and R8 is other than H; and when Y is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORn, wherein Ru is H, C1_10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000066_0001
, or -Si (R15J3; wherein R12 and each occurrence of R15 is C1-10 alkyl; or unsubstituted or substituted aryl; and
R13 is S or 0; and R14 is -SCH3,
Figure imgf000066_0002
, or
Figure imgf000066_0003
when Y is absent; R5 is present and A is a direct bond or
Figure imgf000066_0007
; wherein R3 and R4 are each, independently, H, halogen, or OR16; wherein R16 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000066_0004
, or -Si (R20) 3; wherein R17 and each occurrence of R20 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R18 is S or 0; and R19 is -SCH3,
Figure imgf000066_0005
, or
Figure imgf000066_0006
R3 and R4 taken together form =0; and wherein R5 is H, halogen, or OR21, wherein R2x is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000067_0001
, or -Si(R25)3, wherein R22 and each occurrence of R25 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R23 is S or 0; and R24 is -SCH3,
Figure imgf000067_0002
or
Figure imgf000067_0003
when σ is absent;
Figure imgf000067_0004
wherein R25, R26, R27, R28, and R29 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR31, -SR31, -OSO2R31, or -NR3iR32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; and R30 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000067_0005
wherein R33 and R34 are each, independently, H, C1- io alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R36, wherein R36 is C1-10 alkyl, or unsubstituted or substituted aryl; and at least one of R33 and R34 is other than H; and wherein R35 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and
R6 is H, halogen, or OR37; wherein R37 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000068_0001
, -SO2R38, or -Si (R41) 3;
Figure imgf000068_0002
wherein R38 and each occurrence of R4i is C1-10 alkyl; or unsubstituted or substituted aryl;
R39 is S or O; and R40 is -SCH3;
Figure imgf000068_0004
; or
Figure imgf000068_0003
or
R5 when present and R6 taken together form =0; or
R4 joined to R6 form a 5-membered heterocyclic ring; and
when σ is present;
R2 is
Figure imgf000068_0005
; and R6 is a direct bond or
Figure imgf000068_0006
and wherein X is a direct bond,
Figure imgf000069_0003
, or C(OMe)2;
Y is H or OR42; or when α is present, Y is
Figure imgf000069_0001
wherein R42 is H, C1-10 alkyl, C2-10 alkenyl, C2-10
alkynyl, or
Figure imgf000069_0002
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and at least one of R43 and R44 is other than H; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Z is H or CN; or when α is present, Z is -CH=CH-; and
when α is present, R1 is other than methyl;
or a salt thereof.
In an embodiment, the compound has the structure
Figure imgf000070_0001
wherein oc, Y, and σ are each, independently, present or absent;
Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000070_0002
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl( C1-10) alkyl; or -SO2R10, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl;
R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when Y is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORn, wherein Rn is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000070_0003
, or -Si(R15J3; wherein R12 and each occurrence of R15 is C1-10 alkyl; or unsubstituted or substituted aryl; and R13 is S or 0; and R14 is -SCH3,
Figure imgf000071_0001
, or
Figure imgf000071_0002
when Y is absent; R5 is present and A is a direct bond or
Figure imgf000071_0007
wherein R3 and R4 are each, independently, H, halogen, or OR16; wherein R16 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
Figure imgf000071_0003
, or -Si (R20) 3; wherein R17 and each occurrence of R20 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R18 is S or 0; and R19 is -SCH3,
Figure imgf000071_0004
, Or
Figure imgf000071_0005
R3 and R4 taken together form =0; and wherein R5 is H, halogen, or 0R2i, wherein R21 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000071_0006
, or -Si(R25)3, wherein R22 and each occurrence of R2s is C1-10 alkyl, or unsubstituted or substituted aryl; and R23 is S or O; and R24 is -SCH3,
Figure imgf000072_0001
, Or
Figure imgf000072_0002
when σ is absent;
Figure imgf000072_0003
wherein R25, R26, R27, R28, and R29 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl ; unsubstituted or substituted aryl (C1-10) alkyl; -OR31, -SR31, -OSO2R3I, or -NR3xR32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; and
R30 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000072_0004
wherein R33 and R34 are each, independently, H, C1. 10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R36, wherein R36 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C1-1o alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and R6 is H, halogen, or OR37; wherein R37 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000073_0001
, or -Si (R41) 3;
Figure imgf000073_0002
wherein R38 and each occurrence of R41 is C1-10 alkyl; or unsubstituted or substituted aryl;
R39 is S or 0; and R40 is -SCH3;
Figure imgf000073_0004
; or
Figure imgf000073_0003
; or
R5 when present and R6 taken together form =0; or
R4 joined to R6 form a 5-membered heterocyclic ring; and
when σ is present;
R2 is
Figure imgf000073_0005
; and R6 is a direct bond or ;
Figure imgf000073_0006
and
O wherein X is a direct bond,
Figure imgf000073_0007
, or C(OMe)2;
Y is H or OR42; or when α is present, Y is
Figure imgf000073_0008
; wherein R42 is H, C1-10 alkyl, C2-10 alkenyl, C2-10
alkynyl, or
Figure imgf000073_0009
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Z is H or CN; or when α is present, Z is -CH=CH-; and
when α is present, R1 is other than methyl;
or a salt thereof.
In any of the above embodiments, the compound has the structure
Figure imgf000074_0001
wherein
Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
wherein R7 and R8 are independently H, C1_10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl(C1-10) alkyl; or -SO2R10, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl; R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when R7 and R8 are H and R9 is CH3, then R1 is
Figure imgf000075_0002
. and wherein R3 and R4 are each, independently, H, halogen, or OR16; wherein R16 is H, C1-O-0 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000075_0003
, -SO2R17,
Figure imgf000075_0004
, or -Si (R20) 3; wherein R17 and each occurrence of R20 is C1_10 alkyl, or unsubstituted or substituted aryl; and
R18 is S or O; and R19 is -SCH3,
Figure imgf000075_0005
, Or
Figure imgf000075_0006
; or R3 and R4 taken together form =0; and wherein R5 is H, halogen, or 0R2i, wherein R2i is H, C1_10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000076_0001
, -SO2R22, , or -Si(R25)3, wherein R22 and each occurrence of R25 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R23 is S or 0; and R24 is -SCH3,
Figure imgf000076_0002
t Or
Figure imgf000076_0003
wherein R25, R26, R27, R28, and R2g are each, independently, H, halogen, -NO2, C1_10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR31, -SR31, -OSO2R3I, or -NR31R32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; and
R30 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000076_0004
wherein R33 and R34 are each, independently, H, C1- lo alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R36, wherein R36 is Cχ-10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C1_10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and when R33 and R34 are H and R35 is CH3, then R30 is
Figure imgf000077_0001
; and
R6 is H, halogen, or OR37; wherein R37 is H, Cx-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000077_0002
, -SO2R38,
Figure imgf000077_0003
, or -Si(R4I)3; wherein R38 and each occurrence of R41 is C1-10 alkyl; or unsubstituted or substituted aryl;
R39 is S or 0; and R40 is -SCH3;
Figure imgf000077_0004
;. or
or
Figure imgf000077_0005
R5 when present and R6 taken together form =0; or R4 joined to R6 form a 5-membered heterocyclic ring; and
wherein X is a direct bond or
Figure imgf000077_0006
; and
Y is H or OR42, wherein R42 is H, C1-10 alkyl, C2-10 alkenyl, C2-10
alkynyl , or
Figure imgf000077_0007
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when R43 and R44 are H and R45 is CH3,
then R42 is
Figure imgf000078_0001
or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Z is H or CN; or a salt thereof.
In any of the above embodiments, the compound has the structure
Figure imgf000078_0002
wherein
R1 is H, CH3, or
Figure imgf000078_0003
wherein R7 and R8 are p-trifluoromethylbenzyl; and R9 is CH3; and wherein R3 is H, OCH3, Br, -OSO2CF3, or -OiPr; R4 is H, OH, or OCH3;
R5 is H, OH, -OSO2CF3, or -OSi (CH3) 2 (t-butyl) ; and R6 is H or ORn,
wherein Rn is H, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000079_0001
Figure imgf000079_0002
wherein R12 is CH3 or CF3;
R13 is S or 0; and R14 is -SCH3;
Figure imgf000079_0003
Figure imgf000079_0004
R5 and R6 together form =0; or R3 and R4 together form =0; or R4 joined to R6 form a 5-membered heterocyclic ring; and
wherein R2 is H,
Figure imgf000079_0005
, or , wherein R26 and R27 are each, independently, -OCH3 ,
Figure imgf000079_0006
7
wherein R30 is CH3 or
Figure imgf000080_0001
wherein R25 and R26 are each
Figure imgf000080_0002
wherein R27 is CH3; and
wherein X is a direct bond,
Figure imgf000080_0003
Y is H or OR34,
wherein R34 is CH3 or
Figure imgf000080_0004
wherein R35 and R36 are each
Figure imgf000080_0005
; and R37 is CH3 ; and
Z is H or CN;
or a salt thereof.
In any of the above embodiments, the compound is selected from the group consisting of Compound 17, 21, 24, 26, 33,
34, 36, 36, 37, 39, 40, 42, 44, 45, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63.
In any of the above embodiments, the compound is selected from the group consisting of Compound 51.
In any of the above embodiments, the compound has the structure
Figure imgf000081_0001
wherein
Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000081_0002
wherein R7 and R8 are independently H; C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R10, wherein R1o is C1-10 alkyl, or unsubstituted or substituted aryl; and R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when R7 and R8 are H and R9 is CH3, then R1 is
Figure imgf000081_0003
A is a direct bond or
Figure imgf000081_0004
wherein R3 and R4 are each, independently, H, halogen, or OR16; wherein R16 is H , C1-10 alkyl , -CH2SH , -BHCH2CH3 , -
CH=SH,
Figure imgf000082_0001
Figure imgf000082_0002
, or -Si ( R2Oh ; wherein R17 and each occurrence of R20 is C1-10 alkyl, or unsubstituted or substituted aryl; and
RI8 is S or 0; and R19 is -SCH3,
Figure imgf000082_0003
, or
Figure imgf000082_0004
; or
R3 and R4 taken together form =0; and wherein R5 is H, halogen, or OR2I, wherein R21 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
O
Figure imgf000082_0005
, -SO2R22,
Figure imgf000082_0006
, or -Si(R25)3, wherein R22 and each occurrence of R25 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R23 is S or O; and R24 is -SCH3,
Figure imgf000082_0007
, or
Figure imgf000082_0008
; and
wherein R6 is a direct bond or . ancj wherein R26, R27, R28, and R29 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR31, -SR31, - OSO2R31, or -NR3xR32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein R42 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000083_0001
wherein R43 and R44 are independently H, C1-10 alkyl, C2- 10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R4S, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when R43 and R44 are H and R45 is CH3,
then R42 is
Figure imgf000083_0002
; Or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof.
In any of the above embodiments, the compound has the structure
Figure imgf000084_0001
wherein
R1 is CH3 or
Figure imgf000084_0002
8
wherein R7 and R8 are
Figure imgf000084_0003
; and R9 is CH3 ;
A is a direct bond or
Figure imgf000084_0004
• wherein R3 and R4 taken together form =0; R5 is H or OH;
Re is a direct bond or
Figure imgf000084_0005
; R27 and R28 are each -OCH3; and wherein R42 is CH3; or a salt thereof.
In an embodiment, the compound is selected from the group consisting of: Compound 23 and 25. In an embodiment, the compound has the structure
Figure imgf000085_0001
wherein δ is present or absent;
wherein when δ is absent,
Figure imgf000085_0002
is absent;
R6 is OR37;
wherein R37 is
Figure imgf000085_0003
wherein R39 is S; and R40 is
Figure imgf000085_0004
or
Figure imgf000085_0005
X is a direct bond or
Figure imgf000085_0006
Z iSH. CN,
Figure imgf000085_0007
^
Figure imgf000085_0008
wherein Ra is S or 0; Rb is -0- (C1-C10)alkyl, -0-(C2- C1o)alkenyl, heterocyclyl, or heteroaryl; or or a salt thereof .
In an embodiment, the compound has the structure
Figure imgf000086_0001
wherein δ is present or absent;
wherein when δ is absent,
Figure imgf000086_0003
is absent;
H3CO CO2CH3 R1 is H, methyl or
Figure imgf000086_0002
H3CO
R2 is H or
Figure imgf000086_0005
R3 and R4 are each -OCH3; R5 is H or OR2I,
wherein R2i is
Figure imgf000086_0004
I wherein R23 is S; and R24 is
Figure imgf000087_0001
; and
R6 is OR37;
wherein R37 is
Figure imgf000087_0002
wherein R39 is S; and R40 is
Figure imgf000087_0003
or
Figure imgf000087_0004
X is a direct bond or
Figure imgf000087_0005
Y is H or OR42; wherein R42 is methyl, -CH2CH=CH2 or 3
Figure imgf000087_0006
Z is H, CN,
Figure imgf000087_0007
or
Figure imgf000087_0008
wherein Ra is S or 0; Rb is -OCH3, -OCH (CH3) 2, -
OCH2CH=CH2 , -OCH2CH2CH2CH3,
Figure imgf000087_0009
or
Figure imgf000087_0010
or a salt thereof. In an embodiment, the compound is selected from the group consisting of Compound 64, 65, 66, 67, 68, 73, 74, 75, 76, 77, 78, 79, 80, and a pharmaceutically acceptable salt thereof .
This invention provides a compound having the structure
Figure imgf000088_0001
wherein ε and δ are present or absent; wherein R54 and R55 are present or absent; and when ε is present; δ and R54 are absent, and R55 is present; and when δ is present; ε and R55 are absent, and R54 is present;
wherein G3 and G4 are each, independently, is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
R48, R49, R50, and R5i are each, independently, H, C1-10 alkyl,
C2-10 alkenyl, C2-10 alkynyl; or
Figure imgf000088_0002
wherein R57 and R58 are independently H, C1-10 alkyl, C2- 10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl( C1-10) alkyl, or -SO2R60, wherein R60 is C1_10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl , C2-1Q alkenyl , or C2-10 alkynyl ; and when R57 and R58 are H and R5g is CH3 , then
R48, R49, Rδo, or R5i is
Figure imgf000089_0001
; and wherein R53 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6I, wherein R61 is C1_10 alkyl, or unsubstituted or substituted aryl;
R47 and R52 are each H, CN, or
Figure imgf000089_0002
wherein R62, R63, R64, Rδ5, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1_10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; and wherein R54 when present, R55 when present, and R56 are each, independently, H or OR69, wherein R69 is H or C1-10 alkyl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof .
In an embodiment, the compound has the structure
Figure imgf000090_0001
wherein ε and δ are present or absent; wherein R54 and R55 are present or absent; and when ε is present; δ and R54 are absent, and R55 is present; and when δ is present; ε and R55 are absent, and R54 is present; wherein G3 and G4 are each, independently, is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
R48, R49, R50, and R5i are each, independently, H, C1-10 alkyl,
C2-IQ alkenyl, C2-10 alkynyl; or
Figure imgf000090_0002
wherein R57 and R5β are independently H, C1-10 alkyl, C2-
10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl ( C1-10) alkyl, or -S02R6o, wherein R6o is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and at least one of R57 and R5s is other than
H; and wherein R53 is H, C1_10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-χ0) alkyl, or -SO2R6i, wherein R6i is C1-10 alkyl, or unsubstituted or substituted aryl; R47 and R52 are each H, CN, or
Figure imgf000091_0001
wherein R62, Rβ3, Rβ4, R&5, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl( C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; and wherein R54 when present, R55 when present, and R56 are each, independently, H or OR6g, wherein R69 is H or C1-10 alkyl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof.
In an embodiment, the compound has the structure
Figure imgf000091_0002
wherein ε and δ are present or absent; wherein R54 and R55 are present or absent; and when ε is present; δ and R54 are absent, and R55 is present; and when δ is present; ε and R55 are absent, and R54 is present; wherein G3 and G4 are each, independently, is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
R48, R49, R50, and R51 are each, independently, H, C1-10 alkyl,
C2-10 alkenyl, C2-10 alkynyl; or
Figure imgf000092_0001
wherein R57 and R58 are independently H, C1-10 alkyl, C2- 10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl(C1-10) alkyl, or -SO2R6O, wherein R60 is C1_10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and wherein R53 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6i, wherein R6i is C1-10 alkyl, or unsubstituted or substituted aryl;
R47 and R52 are each H, CN, or
Figure imgf000092_0002
wherein R62, Rβ3, R84, R6s, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67, -OSO2R6V, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; and wherein R54 when present, R55 when present, and R56 are each, independently, H or OR6g, wherein R6g is H or Ci-io alkyl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof .
In any of the above embodiments, the compound has the structure
Figure imgf000093_0001
wherein ε and δ are present or absent; wherein R54 and R55 are present or absent; and when ε is present; δ and R54 are absent, and R55 is present; and when δ is present; ε and R55 are absent, and R54 is present; R48, R49, R50, and R51 are each CH3;
R53 is H or CH3;
R47 and R52 are each
Figure imgf000093_0002
wherein R63 and R64 are each -OCH3 ; and wherein R54 when present, R55 when present, and R56 are each, independently, H or OR6g, wherein R6g is H or CH3;
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof .
In an embodiment, the compound is selected from the group consisting of: Compound 43 and 48.
This invention provides a compound having the structure
Figure imgf000094_0001
wherein v . is present or absent; wherein R70 and R71 are each, independently, H, OH, -CO2R74, wherein R74 is H, C1-io alkyl, C2-10 alkenyl, C2-10
alkynyl, or
Figure imgf000094_0002
wherein R75 and R76 are independently H; C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R7S, wherein R78 is C1-10 alkyl; or unsubstituted or substituted aryl; and wherein R77 is H; C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and at least one of R-75 and R76 is other than H; wherein R72 and R73 are each, independently, H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl( C1-10) alkyl; -SO2R79, or -Si(R8o)3, wherein R79 is C1_10 alkyl, or unsubstituted or substituted aryl; and wherein each occurrence of R8o is, independently, C1-10 alkyl, or unsubstituted or substituted aryl; and when R74 is H or CH3, R73 is other than H or Me; and
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof.
In an embodiment, the compound has the structure
Figure imgf000095_0001
wherein v is present or absent; wherein R70 and R71 are each, independently, H, OH, -CO2R74, wherein R74 is H, C1-10 alkyl, C2-10 alkenyl, C2-10
alkynyl, or
Figure imgf000095_0002
wherein R75 and R76 are independently H; C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R7S, wherein R78 is C1-10 alkyl; or unsubstituted or substituted aryl; and wherein R77 is H; C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and at least one of R75 and R76 is other than H; wherein R72 and R73 are each, independently, H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -SO2R7g, or -Si (R80) 3 , wherein R7g is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein each occurrence of R80 is, independently, C1-10 alkyl, or unsubstituted or substituted aryl; and when R74 is H or CH3, R73 is other than H or Me; and
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof .
In an embodiment, the compound has the structure
Figure imgf000096_0001
wherein v is present or absent; wherein R70 and R7i are each, independently, H, OH , -CO2R74 , wherein R74 is H, C1-10 alkyl , C2-10 alkenyl , C2-10
alkynyl, or
Figure imgf000097_0001
wherein R75 and R76 are independently H; C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (Ci-10) alkyl; or -SO2R7S, wherein R78 is C1-10 alkyl; or unsubstituted or substituted aryl; and wherein R77 is H; C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and at least one of R75 and R76 is other than H; wherein R72 and R73 are each, independently, H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -SO2R7^ or -Si (R80) 3 , wherein R79 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein each occurrence of R80 is, independently, C1-10 alkyl, or unsubstituted or substituted aryl; and when R74 is H or CH3, R73 is other than H or Me; and
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof.
In any of the above embodiments, the compound has the structure R73O
Figure imgf000098_0001
wherein v is present or absent; wherein R70 and R71 are each, independently, H, OH, -COaR74,
wherein R74 is H, CH3, or
Figure imgf000098_0004
wherein R75 and R76 are each and wherein R77 is CH3; wherein R72 and R73 are each, independently, H, CH3,
Figure imgf000098_0002
, -SO2R79, or -Si(R80)3,
wherein R79 is
Figure imgf000098_0003
N=/ ; and wherein each occurrence of Rβo is, independently, CH3 or t-butyl; and
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof. In an embodiment, the compound is selected from the group consisting of: Compound 14, 27, 28, 29, 31, and 32.
This invention provides a process for preparing a compound having the structure
O R1O-A,
Figure imgf000099_0001
wherein α, Y, δ and σ are each, independently, present or absent;
wherein when δ is absent,
Figure imgf000099_0003
is absent;
Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000099_0002
wherein R7 and R8 are independently H, C1_10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl(C1-10) alkyl; or -SO2R1O/ wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl,- R9 is H , C1-10 alkyl , C2-10 alkenyl , or C2-10 alkynyl ; and when R7 and R8 are H and R9 is CH3 , then R1 is
Figure imgf000100_0001
when Y is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORn, wherein Rn is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000100_0002
, or -Si(R15)3; wherein R12 and each occurrence of R15 is C1-10 alkyl; or unsubstituted or substituted aryl; and
R13 is S or 0 ; and R14 is -SCH3 ,
Figure imgf000100_0003
, Or
Figure imgf000100_0004
when Y is absent; R5 is present and A is a direct bond or
Figure imgf000100_0005
wherein R3 and R4 are each, independently, H, halogen, or OR16; wherein R16 is H, C1_10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000100_0006
, or -Si (R20) 3; wherein R17 and each occurrence of R20 is C1_10 alkyl, or unsubstituted or substituted aryl; and R18 is S or 0; and R19 is -SCH3,
Figure imgf000101_0005
, or
Figure imgf000101_0001
r
R3 and R4 taken together form =0; and wherein R5 is H, halogen, or OR21, wherein R21 is H, Cx-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000101_0002
4, or -Si(R25)S, wherein R22 and each occurrence of R25 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R23 is S or 0; and R24 is -SCH3,
Figure imgf000101_0003
# Or
Figure imgf000101_0004
when σ is absent;
R2 is H,
Figure imgf000101_0006
29 28 , or
Figure imgf000101_0007
; wherein R25, R26, R27, R2s, and R29 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR31, -SR31, -OSO2R31, or -NR3iR32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1-io alkylene, C2-10 alkenylene, or C2-10 alkynylene; and
R30 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000102_0001
wherein R33 and R34 are each, independently, H, Cx-
I0 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R36, wherein R36 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and when R33 and R34 are H and R35 is CH3 , then R30 is
Figure imgf000102_0002
R6 is H, halogen, or OR37; wherein R37 is H, Cx-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000102_0003
, -SO2R38, , or -Si (R41) 3; wherein R38 and each occurrence of R4x is CX-10 alkyl; or unsubstituted or substituted aryl; R39 is S or 0; and R40 is -SCH3; -NH-aryl,
heteroaryl , heterocyclyl; or
Figure imgf000102_0004
; or
R5 when present and Re taken together form =0; or R4 joined to R6 form a 5-membered heterocyclic ring; and
when σ is present; R2 is
Figure imgf000103_0001
; and R6 is a direct bond or ^
Figure imgf000103_0002
; and
wherein X is a direct bond,
Figure imgf000103_0003
^, or C(OMe)2;
Y is H or OR42 ; or when α is present , Y is
Figure imgf000103_0004
; wherein R42 is H , C1-10 alkyl , C2-10 alkenyl , C2-10 5
alkynyl, or
Figure imgf000103_0005
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-X0) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when R43 and R44 are H and R45 is CH3,
then R42 is
Figure imgf000103_0006
; Or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted; Z is H, CN, or
Figure imgf000104_0001
Figure imgf000104_0002
wherein Ra is S or 0; Rb is -0- (C1-C10) alkyl, -0-(C2- C1O)alkenyl, heterocyclyl , or heteroaryl; or
when α is present, Z is -CH=CH-;
and when α is present, R1 is other than methyl;
comprising: a) contacting a compound having the structure
Figure imgf000104_0003
wherein
when δ is absent,
Figure imgf000104_0004
is absent;
Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; R1 is H , C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl , or
Figure imgf000104_0005
wherein R7 and R8 are independently H, C1-io alkyl, C2-Io alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1_10) alkyl; or -SO2R10, wherein R1o is C1-10 alkyl, or unsubstituted or substituted aryl;
R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; with a first suitable oxidizing agent in the presence of methanol so as to form the compound having the structure
Figure imgf000105_0001
b) contacting the product of step a) with a compound having the structure
Figure imgf000105_0002
where n R42 is H , C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl , or
Figure imgf000105_0003
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ;
R25, R26, R27, R28, and R29 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR31, SR31, -OSO2R3I, or -NR3xR32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; and
wherein Ra is S or 0; Rb is -O- (C1-C10) alkyl, -O- (C2- C10) alkenyl, heterocyclyl, or heteroaryl;
in the presence of a first suitable energy source so as to form the compound having the structure
Figure imgf000107_0001
In an embodiment, the compound has the structure
Figure imgf000107_0002
wherein α, Y, and σ are each, independently, present or absent;
Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
R
Figure imgf000108_0001
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl( C1-10) alkyl; or -SO2R1O, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl;
R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when Y is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORn, wherein Rn is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000108_0002
, -SO2R12,
Figure imgf000108_0003
, or -Si (R15) 3; wherein R12 and each occurrence of R15 is C1-10 alkyl; or unsubstituted or substituted aryl; and
R13 is S or O; and R14 is -SCH3,
Figure imgf000108_0005
, Or
Figure imgf000108_0004
; and when Y is absent; R5 is present and A is a direct bond or
Figure imgf000108_0006
wherein R3 and R4 are each, independently, H, halogen, or 0R16,- wherein R16 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH, ,
Figure imgf000109_0010
Figure imgf000109_0001
or -Si (R20) 3 ; wherein R17 and each rence of R20 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R18 is S or 0; and R19 is -SCH3, or
Figure imgf000109_0003
Figure imgf000109_0002
; or
R3 and R4 taken together form =0; and wherein R5 is H, halogen, or OR21, wherein R21 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000109_0004
Figure imgf000109_0005
, or -Si(R25)3, whe 22 nd each occurrence of R25 is C1_10 alkyl, or unsubstituted or substituted aryl; and
R23 is S or 0; and R24 is -SCH3,
Figure imgf000109_0006
, or
; and
Figure imgf000109_0007
when σ is absent;
E2 is H,
Figure imgf000109_0008
, or
Figure imgf000109_0009
: wherein R25, R26, R27, R28, and R29 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl(C1-10) alkyl; -OR31, -SR31, -OSO2R3I, or -NR3iR32, wherein R31 and R32 are each, independently, C1-io alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; and R30 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000110_0001
wherein R33 and R34 are each, independently, H, C1- 10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R36, wherein R36 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and H, halogen, or OR37; wherein R37 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000110_0002
R38, , or -Si(R4I)3; wherein R38 and each occurrence of R41 is C1-10 alkyl; or unsubstituted or substituted aryl; R39 is S or 0; and R40 is -SCH3;
Figure imgf000111_0001
or
Figure imgf000111_0002
; or R5 when present and R6 taken together form =0; or R4 joined to R6 form a 5-membered heterocyclic ring; and
when σ is present;
R2 is
Figure imgf000111_0003
Figure imgf000111_0004
and
wherein X is a direct bond,
Figure imgf000111_0005
, or C(OMe)2;
Y is H or OR42; or when α is present, Y is
Figure imgf000111_0006
s^ ; wherein R42 is H, C1-10 alkyl, C2-10 alkenyl, C2-10
alkynyl, or
Figure imgf000111_0007
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-K) alkyl, C2-10 alkenyl, or C2-10 alkynyl ; or ' wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Z is H or CN; or when α is present, Z is -CH=CH-; and
when α is present, R1 is other than methyl;
or a salt thereof;
comprising: a) contacting a compound having the structure
Figure imgf000112_0001
wherein
Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000112_0002
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R1O, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl; R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; with a first suitable oxidizing agent in the presence of methanol so as to form the compound having the structure
Figure imgf000113_0001
b) contacting the product of step a) with a compound having the structure
Figure imgf000113_0002
wherein R42 is H, C1-10 alkyl, C2-10 alkenyl , C2-10
alkynyl, or
Figure imgf000113_0003
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ;
R25, R26, R27, R28, and R29 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10)alkyl; -OR31, -
SR3I, -OSO2R31, or -NR31R32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; in the presence of a first suitable energy source so as to form the compound having the structure
Figure imgf000114_0001
In an embodiment of the process, R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000114_0002
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R1O, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl; and R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl.
In an embodiment of the process, R1 is H, C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl , or
Figure imgf000115_0001
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1_10) alkyl, or -SO2R1O, - .. - wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl; and R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl.
In any of the above embodiments, the process further comprises : c) contacting the product of step b) with BBr3 so to form a compound having the structure
Figure imgf000115_0002
In any of the above embodiments, the process further comprises : c) contacting the product of step b) with a first suitable hydride reducing agent so as to form a compound having the structure
Figure imgf000116_0001
In any of the above embodiments, the process further comprises: d) exposing the product of step c) to a first suitable Bronsted acid so as to form a compound having the structure
Figure imgf000116_0002
In any of the above embodiments, the process further comprises : e) contacting the product of step d) having the structure
Figure imgf000117_0001
with a second suitable hydride reducing agent; f) contacting the product of step e) with a suitable silylating agent; g) contacting the product of step f) with a second suitable oxidizing agent so as to form a compound having the structure
Figure imgf000117_0002
, wherein each occurrence of R25 is C1-10 alkyl; or unsubstituted or substituted aryl .
In any of the above embodiments, the process further comprises : h) exposing the product of step g) to tetra-n- butylammonium fluoride so as to form a compound having the structure
Figure imgf000118_0001
In any of the above embodiments, the process further comprises : h) exposing the product of step g) to a second suitable Bronsted acid in the presence of methanol so as to form a compound having the structure
Figure imgf000118_0002
In any of the above embodiments, the process further comprises : i) exposing the product of step h) to a second suitable energy source so as to form a compound having the structure
Figure imgf000119_0001
In any of the above embodiments, the process further comprises : i) exposing the product of step h) to a third suitable
Bronsted acid; j) contacting the product of step i) with Tf2NPh in the presence of a base so as to form a compound having the structure
Figure imgf000120_0001
In any of the above embodiments, the process further comprises: e) exposing the product of step d) to a first suitable Lewis acid so as to from a compound having the structure
Figure imgf000120_0002
In an embodiment, the process further comprises: d) exposing the product of step c) to a compound
having the structure R21-L, wherein Rχ6 is
Figure imgf000121_0001
Figure imgf000121_0002
is Cl,
Figure imgf000121_0003
in the presence of a base so as to form a compound having the structure
Figure imgf000121_0004
In any of the above embodiments, the process further comprises : e) contacting the product of step d) " having the structure
Figure imgf000122_0001
with Et3_3 and nBU3SnH in the presence of O2 so as to form a compound having the structure
Figure imgf000122_0002
In any of the above embodiments, the process further comprises : d) exposing the product of step c) to a base and carbon disulfide followed by methyl iodide so as to form a compound having the structure
Figure imgf000123_0001
In any of the above embodiments, the process further comprises : e) exposing the product of step d) to PhSeSePh in the presence of AIBN and nBu3SnH so as to form a compound having the structure
Figure imgf000123_0002
In any of the above embodiments, the process further comprises : f) exposing the product of step e) having the structure
Figure imgf000124_0001
to HCl so as to form a compound having the structure
Figure imgf000124_0002
In any of the above embodiments, the process further comprises : e) contacting the product of step d) with Et3B in the presence of O2 so as to form a compound having the structure
Figure imgf000125_0001
In an embodiment, the process further comprises: c) contacting the product of step b) with 1-Bu2Al(OiPr) so as to form a compound having the structure
Figure imgf000125_0002
In an embodiment, the process further comprises:
c) exposing the product of step b) to a first suitable Lewis acid so as to form a compound having the structure
Figure imgf000126_0001
In an embodiment, the process further comprises: d) contacting the product of step c) with a second suitable Lewis acid so as to form a compound having the structure
Figure imgf000126_0002
In an embodiment, the process further comprises: d) contacting the product of step c) with a second suitable Lewis acid so as to form a compound having the structure
Figure imgf000127_0001
In any of the above embodiments of the process, the compound prepared is selected from a group consisting of: Compound 3, 4, 21, 23, 24, 25, 26, 33, 34, 35, 36, 37, 39, 40, 42, 44, 45, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, and 63.
In an embodiment, the process further comprises:
c) contacting the product of step b) having the structure
Figure imgf000127_0002
wherein δ is present or absent; wherein when δ is present,
Figure imgf000128_0001
is present;
Ra is S or 0; Rb is -0- (C1-C10) alkyl , -0- (C2-C10) alkenyl, heterocyclyl, or heteroaryl;
with a first suitable hydride reducing agent so as to form a compound having the structure
Figure imgf000128_0002
In an embodiment, the process further comprises: d) exposing the product of step c) to a first suitable Bronsted acid so as to form a compound having the structure
Figure imgf000128_0003
In an embodiment, the process further comprises: e) contacting the product of step d) with a second suitable hydride reducing agent; f) contacting the product of step e) with a suitable silylating agent; g) contacting the product of step f) with a second suitable oxidizing agent so as to form a compound having the structure
Figure imgf000129_0001
wherein each occurrence of R25 is C1-10 alkyl; or unsubstituted or substituted aryl .
In an embodiment, the process further comprises: h) exposing the product of step g) to a second suitable Bronsted acid in the presence of methanol so as to form a compound having the structure
Figure imgf000129_0002
In an embodiment, the process further comprises: exposing the final product to a compound having the
structure R2i~L, wherein R16 is
Figure imgf000130_0001
Figure imgf000130_0002
or
Figure imgf000130_0003
and L is Cl,
Figure imgf000130_0004
or
Figure imgf000130_0005
; in the presence o as to form a compound having the structure
Figure imgf000130_0006
This invention provides a process for preparing a compound having the structure
Figure imgf000131_0001
wherein ε and δ are present or absent; wherein R54 and R55 are present or absent; and when ε is present; δ and R54 are absent, and R55 is present; and when δ is present; ε and R55 are absent, and R54 is present; wherein G3 and G4 are each, independently, is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
R48, R49, R50, and R51 are each, independently, H, C1-10 alkyl,
C2-10 alkenyl, C2-10 alkynyl; or
Figure imgf000131_0002
wherein R57 and R58 are independently H, C1-10 alkyl, C2-
10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl(C1-10) alkyl, or -SO2R60, wherein R6o is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and wherein R53 is H, C1-10 alkyl, C2_10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6I, wherein R61 is C1-10 alkyl, or unsubstituted or substituted aryl; R47 and R52 are each H, CN, or
Figure imgf000132_0001
wherein R62, R63, Rβ4, Rβ5, and R66 are each, independently, H, halogen, " -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl( C1-10) alkyl; -OR67, -SR67, -OSO2R6?, or -NR67R68, wherein R67 and R6β are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; and wherein R54 when present, R55 when present, and R56 are each, independently, H or OR69, wherein R69 is H or C1-10 alkyl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof;
comprising: a) contacting a compound having the structure
Figure imgf000132_0002
wherein G3 is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
R47 is H, CN, or
Figure imgf000133_0001
wherein R62, R63, R64, R6s, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl( C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl;
R48 and R49 are each, independently, H, C1-10 alkyl, C2-10
alkenyl, C2-10 alkynyl; or
Figure imgf000133_0002
wherein R57 and R58 are independently H, C1_10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R60, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1_10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and wherein each occurrence of R81 is, independently, C1-10 alkyl, or unsubstituted or substituted aryl; with tetra-n-butylairnnonium fluoride so as to form a compound having the structure
Figure imgf000134_0001
b) contacting the product of step a) with sodium hydride so as to form a compound having the structure
Figure imgf000134_0002
or
a') contacting a compound having the structure
Figure imgf000134_0003
wherein G3 is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; R47 is H, CN, Or
Figure imgf000135_0001
wherein R62, R63, R64, R65, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl(C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; R48 and R49 are each, independently, H, C1-10 alkyl, C2-10
alkenyl, C2-10 alkynyl; or
Figure imgf000135_0002
wherein R57 and R58 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6O, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and wherein each occurrence of R81 is, independently, C1-10 alkyl, or unsubstituted or substituted aryl; with a first suitable Bronsted acid in the presence of methanol so as to form a compound having the structure
Figure imgf000136_0001
b') contacting the product of a') with a first suitable Lewis acid so as to form a compound having the structure
Figure imgf000136_0002
C) contacting the product of step b') with a second suitable Lewis acid so as to form a compound having the structure
Figure imgf000136_0003
embodiment of the process , R4S and R4g are each, independently, H, C1-10 alkyl, C2-10
alkenyl, C2-10 alkynyl; or
Figure imgf000137_0001
wherein R57 and R58 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R60, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R5g is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl .
In an embodiment of the process,
R48 and R49 are each, independently, H, CI_IQ alkyl, C2-10
alkenyl, C2-10 alkynyl; or
Figure imgf000137_0002
wherein R57 and R5s are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R60, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl.
In an embodiment, the process further comprises: a) contacting a compound having the structure
Figure imgf000138_0001
7 wherein G3 is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
R47 is H, CN, or
Figure imgf000138_0002
wherein R62, R63, R64, R6s, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl(C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl;
R48 and R49 are each, independently, H, C1-10 alkyl, C2-10
alkenyl, C2-10 alkynyl; or
Figure imgf000138_0003
wherein R57 and R58 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -S02R6o, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R5g is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and wherein each occurrence of R8i is, independently, C1-10 alkyl, or unsubstituted or substituted aryl; with tetra-n-butylaitimonium fluoride so as to form a compound having the structure
Figure imgf000139_0001
b) contacting the product of step a) with sodium hydride so as to form a compound having the structure
Figure imgf000139_0002
embodiment, the process further comprises: a') contacting a compound having the structure
Figure imgf000139_0003
wherein G3 is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; R47 is H, CN, or
Figure imgf000140_0001
wherein R62, R63, R64, R65, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl( C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; R4S and R49 are each, independently, H, C1-10 alkyl, C2-10
alkenyl, C2-10 alkynyl; or
Figure imgf000140_0002
wherein R57 and R58 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6O, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and wherein each occurrence of R8i is, independently, C1-10 alkyl, or unsubstituted or substituted aryl; with a first suitable Bronsted acid in the presence of methanol so as to form a compound having the structure
Figure imgf000141_0001
b' ) contacting the product of a') with a first suitable Lewis acid so as to form a compound having the structure
Figure imgf000141_0002
C) contacting the product of step b') with a second suitable Lewis acid so as to form a compound having the structure
Figure imgf000141_0003
In an embodiment of the process, the compound prepared is selected from the group consisting of: Compound 2, 43, and 48.
This invention provides a process for preparing a compound having the structure
Figure imgf000142_0001
wherein v is present or absent; wherein R70 and R71 are each, independently, H, OH, -CO2R74, wherein R74 is H, C1-10 alkyl, C2-10 alkenyl, C2-10
alkynyl, or
Figure imgf000142_0002
wherein R75 and R76 are independently H; C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R7S, wherein R7s is C1-10 alkyl; or- unsubstituted or substituted aryl; and wherein R77 is H; C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; wherein R72 and R73 are each, independently, H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -SO2R79, or -Si(R80J3, wherein R79 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein each occurrence of Rao is, independently, C1-10 alkyl, or unsubstituted or substituted aryl; and
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof;
comprising: a) contacting rosmarinic acid with TMSCHN2; b) contacting the product of step a) with a compound
having the structure
Figure imgf000143_0001
in the presence of a first suitable base so as to form a compound having the structure
Figure imgf000143_0002
In an embodiment, the process further comprises: c) contacting the product of step b) with a second suitable base so as to form a compound having the structure
Figure imgf000144_0001
d) contacting the product of step c) with a compound having the structure
Figure imgf000144_0002
in the presence of N-ethyl-N'- (3-dimethylaminopropyl)carbodiimide and a third suitable base; e) contacting the product of step d) with tetra-n- butylannnonium fluoride so as to form a compound having the structure
Figure imgf000144_0003
This invention provides a process for preparing a compound having the structure
Figure imgf000145_0001
wherein d is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000145_0002
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl(C1-10) alkyl; or -SO2R10, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl;
R9 is H, C1lio alkyl, C2-10 alkenyl, or C2-10 alkynyl; R26, R27, R28, and R29 are each, independently, H, halogen, - NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR31, -SR31, -OSO2R31, or NR3xR32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; and C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl , or
Figure imgf000146_0001
wherein R43 and R44 are independently H, C1-10 alkyl, C2- 10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl( C1-10) alkyl; or -SO2R4S, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl;
comprising: a) exposing a compound having the structure
Figure imgf000146_0002
to a suitable Lewis acid so as to form the compound.
This invention further provides a process for preparing a compound having the structure
Figure imgf000147_0001
wherein G3 and G4 are each, independently, is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
R48, R49, R50, and R51 are each, independently, H, C1-10 alkyl,
C2-10 alkenyl, C2-10 alkynyl; or
Figure imgf000147_0002
wherein R57 and R5s are independently H, C1-10 alkyl, C2-
10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl(C1-10) alkyl, or -SO2R60, wherein R6o is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and wherein R53 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6i, wherein R6x is C1-10 alkyl, or unsubstituted or substituted aryl;
R47 and R52 are each H, CN, or
Figure imgf000147_0003
wherein R62, R63, R64, R65, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl( C1-10)alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof;
comprising: a) contacting a compound having the structure
R
Figure imgf000148_0001
wherein G3 is C1_10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
R47 is H, CN, or
Figure imgf000148_0002
wherein R62, R63, R64, R55, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl;
R48 and R49 are each, independently, H, C1-10 alkyl, C2-10
alkenyl, C2-10 alkynyl; or
Figure imgf000149_0001
wherein R57 and R5s are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R60, wherein Rβo is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; with a suitable Lewis acid so as to form the compound.
This invention provides a process for preparing a compound having the structure
Figure imgf000149_0002
wherein G3 and G4 are each, independently, is C1-10 alkylene , C2-10 alkenylene , or C2-10 alkynyl ene ;
R48, R49, R50, and R5i are each, independently, H , C1-10 alkyl ,
C2-10 alkenyl , C2-10 alkynyl ; or
Figure imgf000149_0003
wherein R57 and R58 are independently H, C1-10 alkyl, C2- 10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl( C1-10) alkyl, or -SO2R6O, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and
R47 and R52 are each H, CN, or
Figure imgf000150_0001
wherein R62, R63, R64, R6s, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof;
comprising: a) contacting a compound having the structure
Figure imgf000151_0001
wherein G3 is C1-10 alkylene, C2-10 alkenylene , or C2-10 alkynylene ;
R47 is H, CN, or
Figure imgf000151_0002
wherein R62, R63, R64, Rβ5, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl( C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; R48 and R49 are each, independently, H, C1-10 alkyl, C2-10
alkenyl, C2-10 alkynyl; or
Figure imgf000151_0003
wherein R57 and R58 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R60, wherein R60 is C1_10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; with a suitable base so as to form the compound.
This invention provides a process for preparing a compound having the structure
Figure imgf000152_0001
wherein G3 is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
R47 is H, CN, or
Figure imgf000152_0002
wherein R62, R63, Rβ4# R6s, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl(C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2_10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl;
R48 and R49 are each, independently, H, C1-10 alkyl, C2-10
alkenyl, C2-10 alkynyl; or
Figure imgf000152_0003
wherein R57 and R5s are independently H, C1-10 alkyl, C2- 10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R60, wherein R6o is C1_10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and wherein each occurrence of R8i is, independently, C1-10 alkyl, or unsubstituted or substituted aryl;
comprising: a) contacting a compound having the structure
Figure imgf000153_0001
with a suitable Bronsted acid so as to form a compound having the structure
Figure imgf000153_0002
b) contacting the product of step a) with a suitable hydride reducing agent; c) contacting the product of step b) with a suitable silylating agent; d) contacting the product of step c) with a suitable oxidizing agent so as to form the compound. This invention provides a process for preparing a compound having the structure
Figure imgf000154_0001
wherein R82 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl;
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof;
comprising: a) contacting a compound having the structure
Figure imgf000154_0002
with a compound having the structure
Figure imgf000154_0003
wherein Rβ3 is halogen, -OH,
Figure imgf000155_0001
Figure imgf000155_0002
in the presence of a suitable base so as to form the compound .
This invention provides a composition, free of plant extract, comprising a compound having the structure
Figure imgf000155_0003
wherein α, Y, δ and σ are each, independently, present or absent;
O wherein when δ is absent, R|θΛ Gi iis absent;
Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl , or
Figure imgf000155_0004
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl(C1-10) alkyl; or -SO2R1O, wherein R10 is C1_10 alkyl, or unsubstituted or substituted aryl; R9 is H , C1-10 alkyl , C2-10 alkenyl , or C2-10 alkynyl ; and when R7 and R9 are H and R9 is CH3 , then R1 is
Figure imgf000156_0005
; and when Y is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORn, wherein Rn is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000156_0001
or -Si (R15) 3; wherein R12 and each occurrence of R15 is C1-10 alkyl; or unsubstituted or substituted aryl; and
R13 is S or 0; and R14 is -SCH3,
Figure imgf000156_0003
, Or
Figure imgf000156_0002
when Y is absent; R5 is present and A is a direct bond or
Figure imgf000156_0004
wherein R3 and R4 are each, independently, H, halogen, or OR16; wherein R16 is H, C1_10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000157_0001
or -Si(R20)3; wherein R17 and each occurrence of R20 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R18 is S or 0; and R1g is -SCH3,
Figure imgf000157_0006
# or
Figure imgf000157_0002
R3 and R4 taken together form =0; and wherein R5 is H, halogen, or OR2I, wherein R21 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000157_0003
, or -Si(R25)3, wherein R22 and each occurrence of R25 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R23 is S or 0; and R24 is -SCH3,
Figure imgf000157_0004
, or
Figure imgf000157_0007
,. and when σ is absent;
R2 is H,
Figure imgf000157_0005
wherein R25, R26, R27, R28, and R29 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl( C1-10) alkyl; -OR31, -SR31, -OSO2R3I, or -NR31R32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or .substituted aryl; wherein G2 is C1-10 alkylene, C2-10 alkenylene, or C2-10 a1kyny1ene ; and R30 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000158_0001
wherein R33 and R34 are each, independently, H, C1- 10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R36, wherein R36 is C1_10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and when R33 and R34 are H and R35 is CH3, then R30 is
Figure imgf000158_0002
H, halogen, or OR37; wherein R37 is H, C1_10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000158_0003
, or -Si(R4I)3; wherein R38 and each occurrence of R41 is C1-10 alkyl; or unsubstituted or substituted aryl; R39 is S or 0 ; and R40 is -SCH3 ; -NH-aryl ,
heteroaryl, heterocyclyl; or
Figure imgf000159_0005
; or R5 when present and R6 taken together form =0; or R4 joined to R6 form a 5-membered heterocyclic ring; and
when σ is present;
Figure imgf000159_0001
and
wherein X is a direct bond, c
Figure imgf000159_0006
, or C(OMe)2;
Y is H or OR42; or when α is present, Y
Figure imgf000159_0002
wherein R42 is H, C1-10 alkyl, C2-10 alkenyl, C2-10
alkynyl, or
Figure imgf000159_0003
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when R43 and R44 are H and R45 is CH3,
then R42 is
Figure imgf000159_0004
or wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Z is H, CN,
Figure imgf000160_0001
or
Figure imgf000160_0002
wherein Ra is S or 0; Rb is -0- (C1-C10) alkyl, -0-(C2- C10) alkenyl, heterocyclyl, or heteroaryl; or
when ex is present, Z is -CH=CH-;
and when α is present, R1 is other than methyl;
or a salt thereof.
In an embodiment, the composition comprises a compound having the structure
Figure imgf000160_0003
wherein α, Y, and σ are each, independently, present or absent; Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; , C2-10 alkenyl , C2-10 alkynyl , or
Figure imgf000161_0001
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted • aryl( C1-10) alkyl; or -SO2R1O, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl; R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when Y is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORn, wherein Ru is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000161_0002
, -SO2R12, , or -Si(R15)3; wherein R12 and each occurrence of R15 is C1-10 alkyl; or unsubstituted or substituted aryl; and
R13 is S or 0 ; and R14 is -SCH3 , ^->/ , or ςSyOH
O ; and when Y is absent; R5 is present and A is a direct bond or
R4 ; wherein R3 and R4 are each, independently, H, halogen, or OR16; wherein R16 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000162_0001
, or -Si(R20J3; wherein R17 and each occurrence of R20 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R18 is S or O; and R19 is -SCH3,
Figure imgf000162_0002
, Or ,OH
O ; or
R3 and R4 taken together form =0; and wherein R5 is H, halogen, or OR21, wherein R2i is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000162_0003
, -SO2R22, , or -Si(R25J3, wherein R22 and each occurrence of R25 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R23 is S or 0; and R24 is -SCH3,
Figure imgf000162_0004
or
Figure imgf000162_0005
when σ is absent;
R2 is H,
Figure imgf000162_0006
, or wherein R25, R26, R27, R28, and R29 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl(C1-10) alkyl; -OR3I, -SR31, -OSO2R31, or -NR3iR32, wherein R3i and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1-10 alkylene, C2-10 alkenylene, or C2-10 a1kyny1ene ; and R3o is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000163_0001
wherein R33 and R34 are each, independently, H, C1- 10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R36, wherein R36 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and H, halogen, or OR37; wherein R37 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000163_0002
, or -Si(R4I)3; wherein R38 and each occurrence of R41 is C1-10 alkyl; or unsubstituted or substituted aryl; ς^N^N,
R39 is S or O; and R40 is -SCH3; W N or
Figure imgf000164_0001
R5 when present and R6 taken together form =0; or R4 joined to R6 form a 5-membered heterocyclic ring; and
when σ is present;
Figure imgf000164_0002
and
wherein X is a direct bond,
Figure imgf000164_0003
or C(OMe)2;
Y is H or OR42; or when α is present, Y is
Figure imgf000164_0004
. wherein R42 is H, C1-10 alkyl, C2-10 alkenyl, C2-10
alkynyl, or
Figure imgf000164_0005
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C3.-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; or wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Z is H or CN; or when α is present, Z is -CH=CH-; and
when α is present, R1 is other than methyl;
or a salt thereof.
In an embodiment, the composition comprises the compound has the structure
Figure imgf000165_0001
wherein α, Y, and σ are each, independently, present or absent; Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000165_0002
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl(C1-10) alkyl; or -SO2R10, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl; R9 is H, C1-10 alkyl, C2_10 alkenyl, or C2-10 alkynyl; and when Y is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORn, wherein R11 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000166_0001
, -SO2R12, , or -Si (R15) 3; wherein R12 and each occurrence of R15 is CI-1Q alkyl; or unsubstituted or substituted aryl; and
R13 is S or 0; and R14 is -SCH3,
Figure imgf000166_0002
, or
OH ; and when Y is absent; R5 is present and A is a direct bond or
R4 ; wherein R3 and R4 are each, independently, H, halogen, or OR16; wherein R16 is H, C1_10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000166_0003
, or -Si (R20) 3; wherein R17 and each occurrence of R20 is C1-10 alkyl, or unsubstituted or substituted aryl; and R18 is S or 0 ; and R1g is -SCH3 ,
Figure imgf000167_0001
# or
Figure imgf000167_0002
R3 and R4 taken together form =0 ; and wherein R5 is H, halogen, or OR2I, wherein R21 is H, C1-10 alkyl , -CH2SH , -BHCH2CH3 , -CH=SH ,
Figure imgf000167_0003
, or -Si(R25)3, wherein R22 and each occurrence of R25 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R23 is S or 0; and R24 is -SCH3,
Figure imgf000167_0004
, or
Figure imgf000167_0005
when σ is absent;
Figure imgf000167_0006
wherein R25, R26, R27, R2s, and R29 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR3x, -SR31, -OSO2R3I, or -NR3iR32, wherein R31 and R32 are each, independently, C1_10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1-10 alkylene , C2-10 alkenylene , or C2 -10 alkynylene; and
R30 is H , C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl , or
Figure imgf000168_0001
wherein R33 and R34 are each, independently, H, C1-
10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R36, wherein R36 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and
R6 is H, halogen, or OR37; wherein R37 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000168_0002
, -SO2R38, , or -Si(R4I)3; wherein R38 and each occurrence of R41 is C1-10 alkyl; or unsubstituted or substituted aryl;
R39 is S or 0; and R40 is -SCH3;
Figure imgf000168_0003
; or
Figure imgf000168_0004
R5 when present and R6 taken together form =0; or R4 joined to R6 form a 5-membered heterocyclic ring; and
when σ is present;
Figure imgf000169_0001
and
O wherein X is a direct bond, , or C (OMe ) 2 ; O
Y is H or OR42 ; or when α is present , Y is wherein R42 is H, C1-10 alkyl , C2-10 alkenyl , C2-10
alkynyl, or
Figure imgf000169_0002
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Z is H or CN; or when α is present, Z is -CH=CH-; and
when α is present, R1 is other than methyl;
or a salt thereof. In an embodiment, the composition comprises the compound has the structure
Figure imgf000170_0001
wherein α, Y, and σ are each, independently, present or absent;
Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000170_0002
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R10, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl; R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when Y is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORn, wherein Ru is H, C1_10 alkyl, -CH2SH, -BHCH2CH3, -
CH-SH,
Figure imgf000170_0003
, or -Si(R15J3; wherein R12 and each occurrence of R15 is C1-10 alkyl; or unsubstituted or substituted aryl; and R13 is S or O; and R14 is -SCH3,
Figure imgf000171_0001
, or
Figure imgf000171_0002
when Y is absent; R5 is present and A is a direct bond or
Figure imgf000171_0003
wherein R3 and R4 are each, independently, H, halogen, or OR16; wherein R16 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000171_0004
, or -Si (R20) 3; wherein R17 and each occurrence of R20 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R18 is S or 0; and R19 is -SCH3,
Figure imgf000171_0005
, or
Figure imgf000171_0006
R3 and R4 taken together form =0; and wherein R5 is H, halogen, or OR2x, wherein R21 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000171_0007
, or -Si (R25) 3, wherein R22 and each occurrence of R25 is C1-10 alkyl, or unsubstituted or substituted aryl; and R23 is S or O; and R24 is -SCH3, ^CN or
Figure imgf000172_0001
when σ is absent;
Figure imgf000172_0002
wherein R25, R26, R27, R28, and R29 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl ; unsubstituted or substituted aryl(C1-10) alkyl; -OR31, -SR31, -OSO2R31, or -NR31R32, wherein R31 and R32 are each, independently, C1_10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; and
R30 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000172_0003
wherein R33 and R34 are each, independently, H, C1- io alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R36, wherein R36 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and R6 is H, halogen, or OR37; wherein R37 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000173_0001
, -SO2R38, , or -Si(R4I)3; wherein R3s and each occurrence of R41 is C1-10 alkyl; or unsubstituted or substituted aryl;
R39 is S or O; and R40 is -SCH3;
Figure imgf000173_0002
; Or
Figure imgf000173_0003
R5 when present and Rs taken together form =0; or R4 joined to Re form a 5-membered heterocyclic ring; and
when σ is present;
Figure imgf000173_0004
and
wherein X is a direct bond,
Figure imgf000173_0005
or C(OMe)2;
Y is H or OR42; or when α is present, Y is
Figure imgf000173_0006
; wherein R42 is H, C1-10 alkyl, C2-10 alkenyl, C2-10
alkynyl , or
Figure imgf000173_0007
wherein R43 and R44 are independently H, C1-m alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Z is H or CN; or when α is present, Z is -CH=CH-; and
when α is present, R1 is other than methyl;
or a salt thereof.
In an embodiment, the composition comprises the compound selected from the group consisting of: Compound 3, 4, 21, 23, 24, 25, 26, 33, 34, 35, 36, 37, 39, 40, 42, 44, 45, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, and 63.
In an embodiment, the composition comprises compound 51.
In an embodiment, the composition comprises a compound having the structure
Figure imgf000175_0001
wherein δ is present or absent;
O
wherein when δ is absent, 1 is absent;
R6 is OR37;
wherein R37 is tR 40 ; wherein R39 is S or O; and R40 is -NH-aryl, heteroaryl, heterocyclyl; or
O
X is a direct bond or Ms.
Figure imgf000175_0002
wherein Ra is S or 0; Rb is -0- (C1-C10) alkyl, -0-(C2- C1θ)alkenyl, heterocyclyl, or heteroaryl; or
or a salt thereof. In an embodiment, the composition comprises a compound having the structure
Figure imgf000176_0001
wherein δ is present or absent;
wherein when δ is absent,
Figure imgf000176_0002
is absent;
R6 is OR37;
wherein R37 is
wherein R3
Figure imgf000176_0003
9 is S; and R40 is or
X is a direct bond or
Figure imgf000176_0004
.
Figure imgf000176_0005
wherein Ra is S or 0; Rb is -0- (C1-C10 )alkyl, -0-(C2- C1θ)alkenyl, heterocyclyl, or heteroaryl; or or a salt thereof.
In an embodiment, the composition comprises a compound having the structure
Figure imgf000177_0001
wherein δ is present or absent;
wherein when δ is absent,
Figure imgf000177_0002
is absent;
R1 is H, methyl or
Figure imgf000177_0003
Figure imgf000177_0004
R3 and R4 are each -OCH3;
R5 is H or OR2I,
wherein R21 is
Figure imgf000177_0005
wherein R23 is S; and R24 is
Figure imgf000178_0001
; ancj
R6 is OR37;
wherein R37 is
wherein R3
Figure imgf000178_0002
9 is S; and R40 is
O
X is a direct bond or Ms.
Y is H or OR42; wherein R42 is methyl, -CH2CH=CH2 or
Figure imgf000178_0003
Figure imgf000178_0004
wherein R3 is S or 0; Rb is -OCH3, -OCH(CH3) 2, -
OCH2CH=CH2 , -OCH2CH2CH2CH3,
Figure imgf000178_0005
, or
or a salt thereof. In an embodiment, the composition comprises a compound selected from the group consisting of Compound 64, 65, 66,
67, 68, 73, 74, 75, 76, 77, 78, 79, 80, and a pharmaceutically acceptable salt thereof .
This invention provides a composition, free of plant extract, comprising a compound having the structure
Figure imgf000179_0001
wherein ε and δ are present or absent; wherein R54 and R55 are present or absent; and when ε is present; δ and R54 are absent, and R55 is present; and when δ is present; ε and R55 are absent, and R54 is present;
wherein G3 and G4 are each, independently, is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
R48, R49, R50, and R5i are each, independently, H, C1-10 alkyl,
C2-10 alkenyl, C2-10 alkynyl; or
Figure imgf000179_0002
wherein R57 and R58 are independently H, C1-10 alkyl, C2- 10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -S02R6o, wherein R60 is C1_10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and wherein R53 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6I, wherein R6i is C1-10 alkyl, or unsubstituted or substituted aryl;
R47 and R52 are each H, CN, or
Figure imgf000180_0001
wherein R62, Rβ3, Rβ4, R6s, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; and wherein R54 when present, R55 when present, and R56 are each, independently, H or OR69, wherein R6g is H or C1-10 alkyl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof.
In an embodiment of the composition, the compound has the structure
Figure imgf000181_0001
wherein ε and δ are present or absent; wherein R54 and R55 are present or absent; and when ε is present; δ and R54 are absent, and R55 is present; and when δ is present; ε and R55 are absent, and R54 is present; wherein G3 and G4 are each, independently, is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
R48, R49, R50, and R5i are each, independently, H, C1-10 alkyl,
C2-1Q alkenyl, C2-10 alkynyl; or
Figure imgf000181_0002
wherein R57 and R58 are independently H, C1-10 alkyl, C2-
I0 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl(C1-10) alkyl, or -SO2R60, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and wherein R53 is H, C1-10 alkyl, C2_10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6i, wherein R61 is C1-10 alkyl, or unsubstituted or substituted aryl; FU7 and R52 are each H, CN, or
Figure imgf000182_0001
wherein R62, R63, R64, R6s, and R66 are each, independently, H, halogen, -NO2, C1-io alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl( C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; and wherein R54 when present, R55 when present, and R56 are each, independently, H or OR6g, wherein R69 is H or C1-10 alkyl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof.
In an embodiment of the composition, the compound has the structure
Figure imgf000182_0002
wherein ε and δ are present or absent; wherein R54 and R55 are present or absent; and when ε is present; δ and R54 are absent, and R55 is present; and when δ is present; ε and R55 are absent, and R54 is present; wherein G3 and G4 are each, independently, is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
R48, R49, R50, and R5I are each, independently, H, C1-10 alkyl,
C2-10 alkenyl, C2-10 alkynyl; or
Figure imgf000183_0001
wherein R57 and R58 are independently H, C1-10 alkyl, C2-
10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl(C1-10) alkyl, or -S02R6o, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and wherein R53 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6I, wherein R61 is C1-10 alkyl, or unsubstituted or substituted aryl;
R47 and R52 are each H, CN, or
Figure imgf000183_0002
wherein R62, R63, Rβ4, R65, and Rββ are each, independently, H, halogen, -NO2, C1-10. alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67, -OSO2R67 , or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; and wherein R54 when present, R55 when present, and R56 are each, independently, H or OR69, wherein R69 is H or C1-10 alkyl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof.
In an embodiment of the composition, the compound is selected from the group consisting of: Compound 2, 43, and 48.
In an embodiment, the composition further comprises a pharmaceutically acceptable carrier.
This invention provides a method of treating a cell expressing a mutant human huntingtin gene, wherein the expression of the mutant huntingtin gene results in a huntingtin protein having a polyglutamine N-terminal, comprising contacting the cell with any of the compositions described herein so as to treat the cell.
This invention provides a method of treating a cell expressing a mutant human huntingtin gene, wherein the expression of the mutant huntingtin gene results in a huntingtin protein having a polyglutamine N-terminal, comprising contacting the cell with any of the compounds described herein so as to treat the cell.
This invention provides a method of reducing cell death in a population of cells expressing a mutant human huntingtin gene, wherein the expression of the mutant huntingtin gene results in a huntingtin protein having a polyglutamine N- terminal, comprising contacting the population of cells with any of the compositions described herein so as to reduce cell death in the population of cells.
This invention provides a method of reducing cell death in a population of cells expressing a mutant human huntingtin gene, wherein the expression of the mutant huntingtin gene results in a huntingtin protein having a polyglutamine N- terminal, comprising contacting the population of cells with any of the compounds described herein so as to reduce cell death in the population of cells.
In an embodiment, the cell is a mammalian nerve cell.
In an embodiment of the method, the composition comprises a compound having the structure
Figure imgf000186_0001
In any of the above embodiments, the population of cells is a population of mammalian nerve cells .
In any of the above embodiments of the method, the compound has the structure
Figure imgf000186_0002
"Free of plant extract" with regard to a composition as used here means that the composition is ' absent any amount of neolignan containing-plant material or neolignan-based oligomer containing-plant material. Thus only synthetically produced compounds and compositions are free of plant extract. Any compound or compositions isolated from a plant would always contain at least some trace amount of plant material .
The compounds of the present invention include all hydrates, solvates, and complexes of the compounds used by this invention. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. The compounds described in the present invention are in racemic form or as individual enantiomers. The enantiomers can be separated using known techniques, such as those described in Pure and Applied Chemistry 69, 1469-1474, (1997) IUPAC. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
It will be noted that the structure of the compounds of this invention includes an asymmetric carbon atom and thus the compounds occur as racemates, racemic mixtures, and isolated single enantiomers. All such isomeric forms of these compounds are expressly included in this invention. Each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemicalIy controlled synthesis, such as those described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981. For example, the resolution may be carried out by preparative chromatography on a chiral column.
The subject invention is also intended to include all isotopes of atoms occurring on the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
It will be noted that any notation of a carbon in structures throughout this application, when used without further notation, are intended to represent all isotopes of carbon, such as 12C, 13C, or 14C. Furthermore, any compounds containing 13C or 14C may specifically have the structure of any of the compounds disclosed herein.
It will also be noted that any notation of a hydrogen in structures throughout this application, when used without further notation, are intended to represent all isotopes of hydrogen, such as 1H, 2H, or 3H. Furthermore, any compounds containing 2H or 3H may specifically have the structure of any of the compounds disclosed herein. Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples disclosed herein using an appropriate isotopically-labeled reagents in place of the non-labeled reagents employed.
As used herein, "alkyl" includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and may be unsubstituted or substituted. Thus, C1-Cn as in "C1-Cn alkyl" is defined to include groups having 1, 2, ...., n-1 or n carbons in a linear or branched arrangement. For example, C1-C6, as in "C1-C6 alkyl" is defined to include groups having 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, pentyl, hexyl, and octyl .
As used herein, "alkenyl" refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non-aromatic carbon-carbon double bonds may be present, and may be unsubstituted or substituted. For example, "C2-C6 alkenyl" means an alkenyl radical having 2 , 3 , 4 , 5 , or 6 carbon atoms , and up to 1 , 2 , 3 , 4 , or 5 carbon-carbon double bonds respectively. Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
The term "alkynyl" refers to a hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present, and may be unsubstituted or substituted. Thus, "C2-C6 alkynyl" means an alkynyl radical having 2 or 3 carbon atoms and 1 carbon- carbon triple bond, or having 4 or 5 carbon atoms and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms and up to 3 carbon-carbon triple bonds. Alkynyl groups include ethynyl , propynyl and butynyl .
"Alkylene", "alkenylene" and "alkynylene" shall mean, respectively, a divalent alkane, alkene and alkyne radical, respectively. It is understood that an alkylene, alkenylene, and alkynylene may be straight or branched. An alkylene, alkenylene, and alkynylene may be unsubstituted or substituted.
As used herein, "aryl" is intended to mean any stable monocyclic, bicyclic or polycyclic carbon ring of up to 10 atoms in each ring, wherein at least one ring is aromatic, and may be unsubstituted or substituted. Examples of such aryl elements include phenyl, p-toluenyl (4-methylphenyl) , naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl . In cases where the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
The term "arylalkyl" refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an aryl group as described above. It is understood that an "arylalkyl" group is connected to a core molecule through a bond from the alkyl group and that the aryl group acts as a substituent on the alkyl group. Examples of arylalkyl moieties include, but are not limited to, benzyl (phenylmethyl) , p- trifluoromethylbenzyl (4-trifluoromethylphenylmethyl) , 1- phenylethyl, 2-phenylethyl, 3-phenylpropyl , 2-phenylpropyl and the like.
The term "heteroaryl" , as used herein, represents a stable monocyclic, bicyclic or polycyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of 0, N and S. Bicyclic aromatic heteroaryl groups include phenyl, pyridine, pyrimidine or pyridizine rings that are (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom. selected from O, N or S. Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl , benzotriazolyl, benzothiophenyl , benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl , oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl , pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1,4- dioxanyl, hexahydroazepinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl , dihydrobenzothiophenyl , dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindoIyI, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl , dihydropyriinidinyl , dihydropyrroIyI , dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl , tetrahydrofuranyl, tetrahydrothienyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl , pyrrolyl, tetra-hydroquinoline. In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms , it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.
The term "heterocycle" or "heterocyclyl" refers to a mono- or poly-cyclic ring system which can be saturated or contains one or more degrees of unsaturation and contains one or more heteroatoms . Preferred heteroatoms include N, 0, and/or S, including N-oxides, sulfur oxides, and dioxides. Preferably the ring is three to ten-membered and is either saturated or has one or more degrees of unsaturation. The heterocycle may be unsubstituted or substituted, with multiple degrees of substitution being allowed. Such rings may be optionally fused to one or more of another "heterocyclic" ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s). Examples of heterocycles include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1, 3-oxathiolane, and the like.
The alkyl, alkenyl, alkynyl , aryl, heteroaryl and heterocyclyl substituents may be substituted or unsubstituted, unless specifically defined otherwise.
In the compounds of the present invention, alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl groups can be further substituted by replacing one or more hydrogen atoms be alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl .
The term "substituted" refers to a functional group as described above in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non- hydrogen or non-carbon atoms, provided that normal valencies are maintained and that the substitution results in a stable compound. Substituted groups also include groups in which one or more bonds to a carbon (s) or hydrogen (s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Examples of substituent groups include the functional groups described above, and, in particular, halogens (i.e., F, Cl, Br, and I); alkyl groups, such as methyl, ethyl, n-propyl, isopropryl, n-butyl , tert-butyl, and trifluoromethyl ; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n- propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) and p- trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy) ; heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl, methanesulfonyl, and p- toluenesulfonyl; nitro, nitrosyl; mercapto; sulfanyl groups, such as methylsulfanyl, ethylsulfanyl and propylsulfanyl; cyano; amino groups, such as amino, methylamino, dimethylamino, ethylamino, and diethylamino ; and carboxyl . Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.
It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
The term "energy source" refers to a source that provides energy suitable for activating a chemical reaction and enabling such a reaction to occur. Examples of energy sources include, but are not limited to, electromagnetic radiation, such as microwave radiation, ultraviolet radiation, infrared radiation, or visible light; thermal sources, such as heat; and sonic sources, such as ultrasound.
The term "acid" refers to acids under both the Bronsted- Lowry and the Lewis definitions of acids. Under the Bronsted-Lowry definition, acids are defined as proton (H+) donors. Examples of Bronsted-Lowry acids include, but are not limited to, inorganic acids such as hydrofluoric, hydrochloric, hydrobromic, hydroiodic, perchloric, hypochlorous, sulfuric, sulfurous, sulfamic, phosphoric, phosphorous, nitric, nitrous, and the like; and organic acids such as formic, acetic, trifluoroacetic, p- toluenesulfonic, camphorsulfonic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. Under the Lewis definition, an acid is an electron acceptor capable of accepting electron density by virtue of possessing unoccupied orbitals. Examples of Lewis acids include, but are not limited to, metal salts such as AlCl3, FeCl3, FeCl3* SiO2, C1-Cl2, HgCl2, CuCl, TiCl4, Yb(OTf3), InOTf, TiCl2(OiPr)2, and Ti(OiPr)4; organometallic species such as trimethylaluminum and dimethylaluminum chloride; and boron species such as BH3, B(Et)3, BF3, BF3-OEt2, BBr3, B(OMe)3, and B(OiPr)3. Examples of bases include, but are not limited to, alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, lithium methoxide; alkali metal hydrides, such as lithium hydride, sodium hydride, and potassium hydride; alkali metal bicarbonates and carbonates, such as sodium bicarbonate, sodium carbonate, lithium bicarbonate, lithium carbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, and cesium bicarbonate; organolithium bases, such as methyllithium, n-butyllithium, s-butyllithium, tert- butyllithium, isobutyllithium, phenyllithium, ethyllithium, n-hexyllithium, and isopropyllithium; amide bases, such as lithium amide, sodium amide, potassium amide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, lithium diethylamide, lithium dicyclohexylamide, and lithium 2 , 2 , 6 , 6-tetramethylpiperidide; and amine bases, such as pyridine, 4- (dimethylamino) pyridine, trimethylamine, diethylamine, triethylamine, diisopropylethylamine, 1 , 8-diazabicyclo [5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4- diazabicyclo[2.2.2]octane (DABCO), and the like.
The term "silylating agent" refers to a reagent that, when reacted with a nucleophile, generates a silyl derivative of the nucleophile. For example, reaction of a free hydroxyl with a silylating agent generates a silyl ether. Examples of silylating agents include, but are not limited to, trimethylsilyl chloride, trimethylsilyl triflate (trifluoromethanesulfonate) , triethylsilyl triflate, triisopropylsilyl chloride, triisopropylsilyl triflate, dimethylisopropylsiIyI chloride, dimethylthexylsilyl chloride, dimethylthexylsilyl triflate, t- butyldimethylsilyl chloride, t-butyldimethylsilyl triflate, t-butyldiphenylsilyl chloride, and the like.
The term "hydride reducing agent" refers to a reducing agent capable of providing hydride. Examples of hydride reducing agents include, but are not limited to, aluminium hydrides, such as U-Bu)2AlH, U-Bu)3Al, LiAlH4, LiAlH(OMe)3, LiAlH(Ot-Bu)3, and NaAlH2 (OCH2CH2OCH3 ) 2 ; boron hydrides such as 9-BBN, NaBH4, NaBH4-CeCl3, LiBH4, LiEt3BH, Li(S-Bu)3BH, K(S-Bu)3BH, Na(S-Bu)3BH, KPh3BH, (Ph3P)2CuBH4, Zn(BH4J2, Ca(BH4J2, Li(n-Bu)BH3, NaBH(OMe)3, NaBH(OAc)3, NaBH3CN, Et4NBH4, Me4NBH(OAc)3, (n-Bu) 4NBH3CN, and (n-Bu) 4NBH (OAc) 3 ; and (3) silicon hydrides such as Et3SiH, PhMe2SiH, Ph2SiH2, and PhSiH3-Mo(CO)6.
The term "oxidizing agent" refers to a reagent that, when reacted with a molecule, increases the oxidation state of the molecule. For example, exposure of a primary alcohol to an oxidizing agent produces the corresponding aldehyde or carboxylic acid. Similarly, for example, reaction of an oxidizing agent with a secondary alcohol produces the corresponding ketone. Examples of oxidizing agents include, but are not limited to, hypervalent iodine reagents, such as 1,1, 1-triacetoxy-l, 1-dihydro-l, 2-benziodoxol-3 (IH) -one (Dess-Martin Periodinane) , iodosobenzene diacetate, iodosobenzene bis (trifluoroacetate) , iodosylbenzene, 2- iodoxybenzoic acid (IBX) , and iodobenzene dichloride; chromium(VI) reagents, such as chromium trioxide, pyridinium chlorochromate (PCC), pyridinium dichromate (PDC) , potassium dichromate, and sodium dichromate; and heavy metal complexes, such as lead tetraacetate, tetrapropylammonium perruthenate, cerium (IV) ammonium nitrate, and the like.
As used herein, abbreviations are defined as follows:
Ac = acetyl
4-DMAP = 4- (dimethylamino) pyridine DMF = N, iV-dimethylformamide
EDC = N-ethyl-N' - (3-dimethylaminopropyl) carbodiimide
TBAF = tetra-π-butylammonium fluoride
TBS = fcert-butyldimethylsilyl
TMS = trimethylsilyl Tf = trifluoromethanesulfonyl
KHMDS = potassium bis (trimethylsilyl) amide or potassium hexamethyldisilazide
AIBN = 1, 1 ' -azobisisobutyronitrile
9-BBN = 9-borabicyclo[3.3. ljnonane DIBA = diisobutylaluminum
THF = tetrahydrofuran
MeOH = methanol
DCE = 1, 2-dichloroethane
Ph = phenyl Me = methyl
Et = ethyl iPr = isopropyl n-Bu = n-butyl i-Bu = isobutyl s-Bu = sec-butyl t-Bu = tert-butyl
Ms = methanesulfonyl Ts = p-toluenesulfonyl
SET = single electron transfer
In choosing the compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. R1, R2, etc. are to be chosen in conformity with well-known principles of chemical structure connectivity.
The various R groups attached to the aromatic rings of the compounds disclosed herein may be added to the rings by standard procedures, for example those set forth in Advanced Organic Chemistry: Part B: Reaction and Synthesis, Francis Carey and Richard Sundberg, (Springer) 5th ed. Edition. (2007), the content of which is hereby incoporated by reference.
The compounds of the instant invention may be in a salt form. As used herein, a "salt" is salt of the instant compounds which has been modified by making acid or base, salts of the compounds. In the case of compounds used for treatment of cancer, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols. The salts can be made using an organic or inorganic acid. Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium. The term "pharmaceutically acceptable salt" in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide , hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J". Pharm. Sci . 66:1-19).
The compositions of this invention may be administered in various forms, including those detailed herein. The treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e. the subject or patient in need of the drug is treated or given another drug for the disease in conjunction with one or more* of the instant compounds. This combination therapy can be sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed.
As used herein, a "pharmaceutically acceptable carrier" is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also a pharmaceutically acceptable carrier.
The dosage of the compounds administered in treatment will vary depending upon factors such as the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect.
A dosage unit of the compounds may comprise a single compound or mixtures thereof with anti-cancer compounds, or tumor growth inhibiting compounds, or with other compounds also used to treat neurite damage. The compounds can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds may also be administered in intravenous (bolus or infusion) , intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by injection or other methods, into the cancer, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.
The compounds can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, rectal, topical, intravenous or direct injection or parenteral administration. The compounds can be administered alone but are generally mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. In one embodiment the carrier can be a monoclonal antibody. The active agent can be coadministered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorants and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
Specific examples of pharmaceutical acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described in U. S. Pat. No. 3,903,297 to Robert, issued Sept. 2, 1975. Techniques and compositions for making dosage forms useful in the present invention are described-in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al . , 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences VoI 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, VoI 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, VoI 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). All of the aforementioned publications are incorporated by reference herein. Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
The compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. The compounds may be administered as components of tissue-targeted emulsions.
The compounds may also be coupled to soluble polymers as targetable drug carriers or as a prodrug. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylasparta-midephenol, or polyethyleneoxide- polylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans , polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels .
The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parentally, in sterile liquid dosage forms .
Gelatin capsules may contain the active ingredient compounds and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets . Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
For oral administration in liquid dosage form, the oral drug components are combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol . Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. The compounds of the instant invention may also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen.
Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
The compounds and compositions of the invention can be coated onto stents for temporary or permanent implantation into the cardiovascular system of a subject.
The compounds and compositions of the invention are useful in reducing cell death in cells expressing a mutant human huntingtin gene, wherein the expression of the mutant huntingtin gene results in a huntingtin protein having a polyglutamine N-terminal.
This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter. Experimental Details
General Procedures. All reactions were carried out under an argon atmosphere with dry solvents under anhydrous conditions, unless otherwise noted. Dry tetrahydrofuran (THF) , acetonitrile (MeCN) , toluene, benzene, diethyl ether (Et2O) and methylene chloride (CH2Cl2) were obtained by passing commercially available pre-dried, oxygen-free formulations through activated alumina columns . Yields refer to chromatographically and spectroscopically (1H and 13C NMR) homogeneous materials, unless otherwise stated. Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Reactions were magnetically stirred and monitored by thin-layer chromatography (TLC) carried out on 0.25 mm E. Merck silica gel plates (60F-254) using UV light as visualizing agent and an ethanolic solution of phosphomolybdic acid and cerium sulfate, and heat as developing agents. SiliCycle silica gel (60, academic grade, particle size 0.040-0.063 mm) was used for flash column chromatography. Preparative thin-layer chromatography (PTLC) separations were carried out on 0.50 mm E. Merck silica gel plates (60F-254) . NMR spectra were recorded on Bruker DRX-300, DRX-400 and DMX-500 instruments and calibrated using residual undeuterated solvent as an internal reference. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, br = broad, app = apparent. IR spectra were recorded on a Perkin-Elmer 1000 series FT-IR spectrometer. Melting points were taken on a Mettler Toledo Type FP62 instrument, and are uncorrected. Microwave experiments were performed in a CEM Corporation MARS 1200W reactor. High- resolution mass spectra (HRMS) were recorded in the Columbia University Mass Spectral Core facility on a JOEL HXlIO mass spectrometer using FAB (fast atom bombardment), MALDI (matrix-assisted laser desorption/ionization) and APCI (atmospheric pressure chemical ionization) techniques.
Diθls-Aldβr dimβr (15). PhI(OAc)2 (8.58 g, 26.6 mmol, 1.05 equiv) was added to a solution of trans-3-methoxy-4- hydroxycinnamic acid methyl ester (14, 5.28 g, 25.4 mmol, 1.0 equiv) in MeOHiCH2Cl2 (6:1, 35 mL) at 25 0C, and the resultant light yellow solution was stirred at 25 0C for 14 h. Upon completion, the reaction contents were concentrated directly and the resultant crude yellow oil was purified by flash column chromatography (silica gel, hexanes : EtOAc , 3:2) to give Diels-Alder adduct 15 (5.26 g, 87% yield) as a yellow amorphous solid. 15: Rf = 0.22 (silica gel, hexanes : EtOAc , 1:1); IR (film) \max 2950, 1710, 1650, 1635, 1436, 1313, 1196, 1174, 1132, 1050, 733 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 16.0 Hz, 1 H), 6.97 (d, J = 16.0 Hz, 1 H), 6.19 (dd, J = 7.2, 2.0 Hz, 1 H), 6.17 (d, J = 10.0 Hz, 1 H), 6.06 (d, J = 15.6 Hz, 1 H), 6.01 (d, J = 10.0 Hz, 1 H), 6.00 (d, J" = 16.4 Hz, 1 H), 3.76 (s, 3 H), 3.74 (s, 3 H), 3.44 (s, 3 H), 3.43 (s, 3 H), 3.40 (app t, J" = 1.6 Hz, 1 H), 3.35 (s, 1 H), 3.30 (d, J = 6.4 Hz, 1 H), 3.22 (s, 3 H), 3.05 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 198.9, 191.2, 166.7, 166.1, 147.7, 146.1, 141.0, 140.2, 132.4, 128.2, 121.7, 119.8, 97.6, 94.1, 58.2, 51.7, 51.6, 50.6, 50.5, 50.2, 50.0, 48.7, 43.3, 40.6; HRMS (FAB) calcd for C24H28O10 + [M+] 476.1682, found 476.1613.
3-Mθthoxy-4-Hydroxydihydrocinnamic Acid Methyl Ester (16).
Concentrated HCl (2 drops) was added to a solution of 3- methoxy-4-hydroxydihydrocinnamic acid (0.225 g, 1.15 iranol, 1.0 equiv) in anhydrous MeOH (10 mL) at 25 0C, and the resultant solution was stirred at 25 0C for 20 h. Upon completion, the reaction contents were concentrated directly and the resultant crude yellow oil was purified by flash column chromatography (silica gel, hexanes : EtOAc , 3:2) to afford 16 (0.231 g, 96% yield) as a colorless oil. 16: Rf = 0.63 (silica gel, hexanes : EtOAc , 1:1); IR (film) {max 3445, 2951, 1731, 1606, 1515, 1434, 1364, 1290, 1234,. 1202, 1152, 1121, 1033, 818, 791, 732 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.83 (d, J = 8.0 Hz, 1 H), 6.70 (s, 1 H), 6.69 (d, J = 9.6 Hz, 1 H), 5.51 (s, 1 H), 3.87 (s, 3 H), 3.67 (s, 3 H), 2.88 (t, J" = 7.8 Hz, 2 H), 2.60 (t, J" = 7.8 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 173.4, 146.4, 144.0, 132.4, 120.8, 114.3, 110.9, 55.8, 51.6, 36.1, 30.7; HRMS (FAB) calcd for CuHi4O4 + [M+] 210.0892, found 210.0905.
Diels-Alder adduct 17. PhI(OAc)2 (0.384 g, 1.19 mmol, 1.1 equiv) was added to a solution of 16 (0.228 g, 1.08 mmol, 1.0 equiv) in MeOH: CH2Cl2 (5:1, 12 mL) at 25 0C, and the resultant yellow solution was stirred at 25 0C for 1 h. Upon completion, the reaction contents were concentrated directly and the resultant crude yellow oil was purified by flash column chromatography (silica gel, hexanes : EtOAc , 7:3) to afford the desired orthoquinone monoketal intermediate (0.253 g, 97% yield) as a bright yellow oil. [Note: this product was stored as a 0.2 M solution in toluene at 4 0C to prevent its dimerization] . Acrylonitrile (7.60 mL, 116 mmol, 100 equiv) was then added to a solution of this newly formed orthoquinone monoketal (0.2 M in toluene, 5.8 mL, 1.16 mmol, 1.0 equiv) and the reaction mixture was stirred in a sealed tube at 80 0C for 2 days. Upon completion, the reaction contents were concentrated directly and the resultant crude yellow oil was purified by flash column chromatography (silica gel, hexanes : EtOAc , 7:3) to afford 17 (0.148 g, 43% yield) as a colorless oil. 17: Rf = 0.41 (silica gel, hexanes : EtOAc , 1:1); IR (film)
\max 3004, 2969, 2921, 2139, 1740, 1713, 1445, 1422, 1365, 1222, 1091, 1069, 894 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.90 (d, J = 6.4 Hz, 1 H), 3.70 (s, 3 H), 3.35 (dd, J = 6.4, 2.0 Hz, 1 H), 3.32 (s, 3 H), 3.28 (s, 3 H), 3.13 (ddd, J = 10.0, 5.6, 2.0 Hz, 1 H), 3.04 (dd, J" = 4.8, 2.8 Hz, 1 H), 2.62-2.53 (m, 4 H), 3.13 (ddd, J" = 13.2, 10.0, 3.0 Hz, 1 H), 1.65 (ddd, J" = 13.2, 5.2, 3.2 Hz, 1 H); 13C ISIMR (75 MHz, CDCl3) δ 198.8, 172.9, 149.7, 120.7, 117.3, 93.4, 51.9, 50.9, 49.8, 49.2, 42.5, 31.5, 30.0, 26.2, 25.3; HRMS (FAB) calcd for C15H20O5N+ [M + H+] 294.1341, found 294.1356.
Dihydrofuran 18. AgOAc (0.452 g, 2.71 mmol, 1.1 equiv) was added to a solution of traπs-3-methoxy-4- hydroxydihydrocinnamic acid methyl ester (14, 0.513 g, 2.46 mmol) in toluene (8 mL) at 25 0C. The reaction mixture was then warmed to 60 0C and stirred for 20 h. Upon completion, the reaction contents were filtered through CeIite, concentrated, and purified by flash column chromatography (silica gel, hexanes : EtOAc , 7:3) to afford dihydrobenzofuran 18 (0.105 g, 20% yield) as a white amorphous solid. 18: Rf = 0.36 (silica gel, hexanes : EtOAc , 7:3); IR (film) imax 3444, 2952, 1736, 1705, 1634, 1601, 1518, 1496, 1435, 1171, 1145, 1033, 980, 846 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 16.0 Hz, 1 H), 7.26 (s, 1 H), 7.18 (s, 1 H), 6.91-6.86 (m, 3 H), 6.31 (d, J = 16.0 Hz, 1 H), 6.10 (d, J = 8.4 Hz, 1 H), 5.79 (br s, 1 H), 4.34 (d, J" = 8.4 Hz, 1 H), 3.90 (s, 3 H), 3.85 (s, 3 H), 3.82 (s, 3 H), 3.79 (S, 3 H); 13C NMR (75 MHz, CDCl3) δ 170.6, 167.5, 149.8, 146.7, 146.0, 144.6, 144.6, 131.2, 128.4, 125.6, 119.2, 117.8, 115.3, 114.5, 112.0, 108.7, 87.3, 56.0, 55.8, 55.3, 52.7, 51.5; HRMS (FAB) calcd for C22H22O8 + [M+] 414.1315, found 414.1331.
Mixed Diels-Alder Adduct 21. A solution of 15 (1.21 g, 2.54 πunol, 1.0 equiv) and dienophile 13 (3.78 g, 17.0 mmol, 6.7 equiv) in mesitylene (3.0 mL) was carefully degassed 3 times using the freeze-pump-thaw method, and then sealed under argon in a tube equipped with a magnetic stir bar.
The reaction solution was stirred at 220 0C (oil bath) for 30 min. After cooling to 25 0C, the reaction contents were purified directly by flash column chromatography (silica gel, hexanses: EtOAc, 4:1→1:1) to afford recovered 13 (3.20 g) alongside a light yellow solid which was recrystallized from Et2O to provide Diels-Alder adduct 21 (1.00 g, 43% yield, 83% yield based on recovered starting material) as a crystalline white solid. 21: Rf = 0.36 (silica gel, hexanes : EtOAc , 3:2); m.p. 143.0-143.5 0C; IR (film) {max 2951, 1735, 1719, 1632, 1519, 1436, 1311, 1287, 1269, 1239, 1195, 1172, 1146, 1062, 1027 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J" = 15.6 Hz, 1 H), 6.82-6.77 (m, 3 H), 6.62 (dd, J" = 6.8, 2.4 Hz, 1 H), 6.11 (d, J" = 15.6 Hz, 1 H), 3.92 (app t, J" = 0.2 Hz, 1 H), 3.85 (s, 3 H), 3.84 (s, 3 H), 3.78 (s, 3 H), 3.67 (s, 3 H), 3.58 (dd, J" = 6.8, 2.8 Hz, 1 H), 3.48 (s, 3 H), 3.44 (dd, J = 6.8, 2.0 Hz, 1 H), 3.34 (s, 3 H), 3.30 (dd, J = 6.8, 2.4 Hz, 1 H) ; 13C NMR (75 MHz, CDCl3) δ 200.9, 173.3, 167.2, 149.0, 148.1, 141.7, 140.0, 134.3, 133.1, 119.7, 118.2, 111.2, 111.08, 93.8, 56.3, 55.8, 52.4, 51.8, 51.0, 49.9, 47.0, 44.5, 42.4; HRMS (FAB) calcd for C24H28θ9 + [M+] 460.1733, found 460.1759.
Helisorin Core 23. BF3«OEt2 (0.016 mL, 0.130 itimol, 6.0 equiv) was added to a solution of Diels-Alder adduct 21 (0.010 g, 0.022 πunol, 1.0 equiv) in CH2Cl2 (0.5 mL) at 0 0C, and the reaction was slowly warmed to 25 0C and stirred from an additional 16 h. Upon completion, the reaction was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (2 x 10 mL) . The combined organic layers were then washed with saturated aqueous NaHCO3 (10 mL) , brine (10 mL) , dried (MgSO4) and concentrated. The resultant thick orange oil was purified by flash column chromatography (silica gel, hexanes : EtOAc, 1:1) to afford compound 23 (7.5 mg, 82% yield) as a colorless solid. 23: Rf = 0.24 (silica gel, hexanes : EtOAc , 3:7); IR (film) imax 3462, 2952, 1725, 1631, 1499, 1437, 1306, 1221,- 1167, 1116, 1003 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 15.6 Hz, 1 H), 6.82 (app s, 2 H), 6.74 (d, J = 5.2 Hz, 1 H), 6.05 (d, J = 15.6 Hz, 1 H), 4.14 (d, J = 3.6 Hz, 1 H), 3.88 (s, 3 H), 3.88 (s, 3 H), 3.88-3.85 (m, 2 H), 3.77 (s, 3 H), 3.62 (s, 3 H), 3.25 (s, 1 H), 3.09 (d, J = 3.6 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 204.6, 170.6, 167.0, 150.5, 149.5, 139.9, 138.7, 136.7, 136.4, 132.9, 118.5, 106.6, 105.8, 81.2, 56.1, 56.1, 55.9, 52.2, 51.8, 51.6, 51.4, 42.4; HRMS (FAB) calcd for C22H23O8 + [M+H+] 415.1393, found 415.1401.
Diketone 24. Solid NaHCO3 (0.040 g, 0.480 mmol, 10 equiv) and Dess-Martin periodinane (0.041 g, 0.096 mmol, 2.0 equiv) were added sequentially in single portions to a solution of hydroxyketone 37 (0.040 g, 0.048 mmol, 1.0 equiv) in CH2Cl2 (1 mL) at 25 0C. The resultant suspension was stirred at 25 0C for 1 h. Upon completion, saturated aqueous Na2SO3 (2 mL) was added and the resultant biphasic mixture was stirred vigorously for 1 h to quench any remaining oxidizing agents. The reaction contents were then poured into water (10 mL) , and extracted with EtOAc (3 x 10 mL) . The combined organic layers were washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL) , dried (MgSO4), and concentrated to afford crude diketone 24 (0.037 g, 93% yield) as a thick yellow oil, which was used immediately without further purification. 24: Rf = 0.15 (silica gel, hexanes : EtOAc, 3:2); IR (film) imax 2925, 1733, 1717, 1630, 1518, 1437, 1312, 1264, 1196, 1172, 1146, 1025, 809 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.38 (d, J" = 16.0 Hz, 1 H), 6.78 (app d, J = 8.5 Hz, 2 H), 6.58-6.57 (m, 2 H), 6.16 (d, J = 15.5 Hz, 1 H), 4.27 (t, J = 2.0 Hz, 1 H), 3.87-3.83 (m, 7 H), 3.84 (s, 3 H), 3.83 (s, 3 H), 3.80 (s, 3 H), 3.80-3.78 (m, 1 H), 3.72 (s, 3 H), 3.43 (dd, J = 6.0, 2.0 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 187.8, 187.8, 171.4, 166.5, 149.4, 148.6, 139.5, 137.7, 135.2, 131.8, 120.5, 119.2, 111.6, 110.8, 56.5, 55.9, 55.8, 52.9, 52.0, 50.7, 46.8, 45.3; LRMS (FAB) calcd for C22H22O8 + [M+] 414.13, found 414.14.
Rearragement Product 25. BF3-OEt2 (0.054 mL, 0.434 mmol, 20 equiv) was added to a solution of Diels-Alder adduct 21 (0.010 g, 0.022 mmol, 1.0 equiv) in CH2Cl2 (0.5 mL) at 25 0C, and the reaction was stirred at 25 0C for 12 h. Upon completion, the reaction contents were quenched with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (2 x 10 mL) . The combined organic layers were then washed with saturated aqueous NaHCO3 (10 mL) , brine (10 mL) , dried (MgSCU) and concentrated. The resultant thick orange oil was purified by flash column chromatography (silica gel, hexanes : EtOAc , 1:1) to afford a thick yellow oil which was recrystallized from Et2O to afford 25 (7.5 mg, 88% yield from 21) as a white crystalline solid. Compound 25 was also obtained from helisorin core 23 under identical reaction conditions (80% yield) and from diketone 24 using 6.0 equiv of BF3.OEt2 (53% yield) . 25: Rf = 0.26 (silica gel, hexanes : EtOAc , 3:7); m.p. = 105.8-106.4 0C; IR (film) imax 3463, 2924, 1734, 1717, 1596, 1308, 1264, 1209, 1114 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.50 (s, 1 H), 7.43 (d, J = 16.0 Hz, 1 H), 6.82 (d, J = 3.0 Hz, 1 H), 6.62 (d, J" = 3.0 Hz, 1 H), 5.95 (d, J = 16.0 Hz, 1 H), 3.97 (s, 3 H), 3.93 (s, 3 H), 3.90 (s, 1 H), 3.76 (s, 3 H), 3.52 (s, 3 H), 3.52 (s, 3 H), 3.40 (s, 1 H), 3.35 (d, J = 4.5 Hz, 1 H), 3.29 (d, J = 2.0 Hz, 1 H), 2.90 (dd, J = 4.5, 1.5 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 196.1, 171.5, 167.2, 154.9, 148.6, 145.3, 143.7, 138.6, 138.3, 122.6, 119.3, 109.7, 108.4, 95.9, 61.7, 56.3, 56.2, 54.2, 51.6, 50.1, 42.9; HRMS (FAB) calcd for C22H23O8 + [M+H+] 415.1393, found 415.1401.
Bromoketal 26. BBr3 (1.0 M in CH2Cl2, 0.365 mL, 0.365 mmol, 6.0 equiv) was added to a solution of Diels-Alder adduct 21 (0.028 g, 0.061 mmol, 1.0 equiv) in CH2Cl2 (1 mL) at -78 0C, and the reaction was stirred at -78 0C for 1 h. Upon completion, the reaction contents were poured into saturated aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (2 x 10 mL) . The combined organic layers were then washed with brine (10 mL) , dried (MgSO4), and concentrated. The resultant crude material was purified by flash column chromatography (silica gel, hexanes : EtOAc , 2:1) to afford bromoketal 26 (0.027 g, 86% yield) as a thick colorless oil. 26: Rf = 0.47 (silica gel, hexanes : EtOAc , 1:1); IR (film) {max 2951, 1735, 1718, 1635, 1519, 1437, 1313, 1247, 1196, 1173, 1148, 1027, 669 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 16.0 Hz, 1 H), 6.79-6.73 (m, 3 H), 6.70 (dd, J = 6.8, 1.6 Hz, 1 H), 6.15 (d, J" = 16.0 Hz, 1 H), 4.40 (t, J = 0.2 Hz, 1 H), 3.85 (s, 3 H), 3.84 (s, 3 H), 3.80 (s, 3 H), 3.68 (s, 3 H), 3.68 (s, 3 H), 3.68-3.67 (m, 1 H), 3.52 (dd, J = 6.6, 2.2 Hz, 1 H), 3.46 (dd, J = 6.8, 2.4 Hz, 1 H); LRMS (APCI) calcd for C23H25BrO8 + [M+] 508.1, found 508.2.
Dienophile 27. TMS-diazomethane (2.0 M in Et2O, 7.9 mL, 15.8 mmol, 0.95 equiv) was added in small portions over 1 h to a solution of rosmarinic acid (5, 6.00 g, 16.7 mmol, 1.0 equiv) in THF:MeOH (10:1, 110 mL) at -78 0C. Upon completion, the reaction contents were allowed to warm to 25 0C over 1 h, concentrated directly, and filtered through a short plug of silica gel (CH2Cl2:Me0H, 19:1) . The resultant thick brown oil was dried thoroughly under high vacuum to provide the desired ester intermediate that was carried forward without any additional purification. Next, p-trifluoromethylbenzyl bromide (7.40 mL, 48.0 mmol, 6.0 equiv), K2CO3 (6.60 g, 48.0 mmol, 6.0 equiv), and KI (catalytic) were added sequentially and in single portions to a solution of half of the crude ester just prepared (8.0 mmol, 1.0 equiv) in DMF (30 mL) at 25 0C. The resultant reaction mixture was then stirred at 60 0C for 8 h, and at 25 0C for 16 h. Upon completion, the reaction contents were carefully quenched by the addition of 1 M aqueous HCl (until gas evolution ceased), poured into water (50 mL) , and extracted with EtOAc (2 x 100 itiL) . The combined organic layers were then washed with 1 M aqueous HCl (50 mL) , saturated aqueous NaHCO3 (50 mL) and brine (50 mL) , dried (MgSO4), and concentrated. The resultant crude material was purified by flash column chromatography (silica gel, hexanes: EtOAc: CH2Cl2, 17 : 1 :2→5 :4 : 1) to afford dienophile 27 (6.00 g, 84% yield over 2 steps) as a white amorphous solid. 27: Rf = 0.45 (silica gel, hexanes : EtOAc : CH2Cl2, 3:1:1); IR (film) {max 1751, 1715, 1625, 1598, 1511, 1324, 1265, 1160, 1120, 1065, 1016, 824, 736 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.66-7.49 (m, 17 H), 7.11-7.08 (m, 2 H), 6.92- 6.81 (m, 4 H), 6.29 (d, J = 16.0 Hz, 1 H), 5.36 (dd, J = 8.0, 4.8 Hz, 1 H), 5.23 (s, 2 H), 5.19 (s, 2 H), 5.17 (s, 2 H), 5.16 (s, 2 H), 3.71 (s, 3 H), 3.18 (dd, J" = 14.4, 5.0 Hz, 1 H), 3.11 (dd, J = 14.4, 8.4 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 170.1, 166.0, 150.8, 148.6, 148.5, 147.7, 145.5, 141.2, 141.1, 140.7, 140.5, 127.9, 127.2, 127.2, 127.1, 125.8, 125.4, 125.3, 125.3, 123.3, 122.7, 122.2, 116.2, 115.2, 114.9, 114.0, 113.5, 72.8, 70.5, 70.3, 69.9, 52.2, 36.9; HRMS (FAB) calcd for C5IH38Fi2O8 + [M+] 1006.2375, found 1006.2424.
Dienophile 28 and Chiral Alcohol 29. Solid NaOMe (0.057 g, 1.05 mmol, 1 equiv) was added in a single portion to a solution of 27 (1.06 g, 1.05 mmol) in methanol : CH2Cl2 (1:1, 16 mL) at 25 0C, and the reaction was stirred at 25 0C for 2 h. Upon completion, the reaction contents were quenched with 1 M aqueous HCl (10 mL) , poured into water (10 mL) , and extracted with EtOAc (2 x 20 mL) . The combined organic layers were then washed with saturated aqueous NH4Cl (20 mL) and brine (20 mL) , dried (MgSO4) , and concentrated. The resultant crude yellow solid was purified by flash column chromatography (silica gel, hexanes : EtOAc , 7:3) to afford the desired dienophile 28 (0.493 g, 92% yield) as a white amorphous solid alongside chiral alcohol 29 (0.498 g, 90% yield) as a white amorphous solid. 28: Rf = 0.66 (silica gel, hexanes : EtOAc , 3:2); IR (film) {max 3004, 2918, 1713, 1422, 1363, 1222, 1126, 665 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.66-7.47 (m, 9 H), 7.13-7.09 (m, 2 H), 6.91 (d, J" = 8.8 Hz, 1 H), 6.27 (d, J" = 16.2 Hz, 1 H), 5.24 (s, 2 H), 5.22 (S, 2 H), 3.79 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 167.4,
150.4, 148.5, 144.1, 140.8, 140.6, 128.2, 127.2, 127.2, 127.1, 127.1, 127.1, 125.5, 125.5, 125.4, 125.4, 123.0, 116.1, 114.0, 113.4, 70.3, 70.0, 51.5; HRMS (FAB) calcd for C26H20F6O4 + [M+] 510.1266, found 510.1261.
29: Rf = 0.34 (silica gel, hexanes : EtOAc , 3:2); [α]22 D = +11.0° (c = 0.79, CHCl3); IR (film) <|max 3417, 1720, 1632, 1519, 1421, 1330, 1271, 1239, 1217, 1159, 1142, 1115, 1105, 1068, 1037, 1021, 823 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.64- 7.53 (m, 8 H), 6.85 (d, J = 8.4 Hz, 1 H), 6.84 (s, 1 H), 6.75 (dd, J = 8.4, 2.0 Hz, 1 H), 5.19 (s, 2 H), 5.17 (s, 2 H), 4.40 (dd, J" = 6.6, 4.2 Hz, 1 H), 3.73 (s, 3 H), 3.04 (dd, J = 14.2, 4.2 Hz, 1 H), 2.87 (dd, J = 14.0, 6.4 Hz, 1 H), 2.69 (br S, 1 H); 13C NMR (75 MHz, CDCl3) δ 174.4, 148.4, 147.6, 141.3, 141.2, 130.2, 129.8, 127.3, 127.2, 125.9,
125.5, 125.4, 122.8, 116.5, 115.0, 71.2, 70.5, 70.5, 52.4, 39.9; HRMS (FAB) calcd for C26H22F6O5 + [M+] 528.1371, found 528.1392.
Phenol 32. EDC-HCl (1.41 g, 7.34 mmol, 2.0 equiv) and 4- DMAP (0.448 g, 3.67 mmol, 1.0 equiv) were added sequentially in single portions to a solution of TBS- protected acid 31 (2.26 g, 7.34 inmol, 2.0 equiv) and chiral alcohol 29 (1.94 g, 3.67 mmol, 1.0 equiv) in CH2Cl2 (20 mL) at 25 0C, and the resulting mixture was stirred at 25 0C for 3 h. Upon completion, the reaction contents were diluted with EtOAc (30 mL) , poured into water (40 mL) , and extracted with EtOAc (2 x 50 mL) . The combined organic layers were then washed with 1 M aqueous HCl (3 x 30 mL) and brine (30 mL) , dried (MgSO4) , and concentrated to afford the desired ester as a yellow oil which was carried forward without any additional purification. Next, AcOH (0.6 mL) and TBAF (1.0 M in THF, 7.34 mL, 7.34 mmol, 2.0 equiv) were added sequentially and dropwise over the course of several minutes to a solution of the newly formed ester in THF (20 mL) at 0 0C. After 5 min of stirring at 0 0C, the reaction contents were poured into 1 M aqueous HCl (30 mL) and extracted with EtOAc (2 x 30 mL) . The combined organic layers were then washed with brine (30 mL) , dried (MgSO4) , and concentrated. The resultant crude yellow solid was purified by flash column chromatography (silica gel, hexanes : EtOAc , 7:3) to afford phenol 32 (2.43 g, 94% yield over 2 steps) as a white amorphous solid. 32: Rf = 0.35 (silica gel, hexanes : EtOAc , 3:2); [α]23 D = +36.2° (c = 0.65, CHCl3); IR (film) imax 3413, 3004, 1716, 1422, 1366, 1218, 1092, 902 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 16.4 Hz, 1 H), 7.62-7.58 (m, 4 H), 7.54-7.49 (m, 4 H), 7.06 (dd, J" = 8.0, 1.6 Hz, 1 H), 7.00 (d, J = 1.6 Hz, 1 H) 6.92-6.82 (m, 4 H), 6.31 (d, J" = 16.0 Hz, 1 H), 5.95 (s, 1 H), 5.37 (ddd, J = 8.0, 4.8, 1.2 Hz, 1 H) 5.16 (s, 2 H), 5.15 (s, 2 H), 3.93 (s, 3 H), 3.87 (s, 3 H), 3.18 (dd, J" = 14.4, 4.8 Hz, 1 H), 3.12 (dd, J" = 14.4, 8.4 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 170.2, 166.2, 148.4, 148.4, 147.6, 146.8, 146.2,
141.1, 141.0, 129.7, 127.2, 127.1, 126.5, 125.3, 125.2,
125.2, 123.2, 122.7, 116.1, 114.9, 114.7, 114.0, 109.4, 72.7, 70.4, 70.3, 55.6, 52.2, 36.9; HRMS (FAB) calcd for C36H30F6O8 + [M+] 704.1845, found 704.1864.
Carboxylic Acid 31. 1-Pr2NEt (8.07 mL, 46.3 mmol, 3.0 equiv) and TBSCl (5.82 g, 38.6 mmol, 2.5 equiv) were added sequentially in single portions to a solution of 3-methoxy- 4-hydroxydihydrocinnamic acid (30, 3.00 g, 15.4 mmol, 1.0 equiv) in CH2Cl2 (20 mL) at 25 0C, and the reaction mixture was stirred at 25 0C for 14 h. Upon completion, the reaction contents were diluted with EtOAc (60 mL) , poured into water (15 mL) , washed with 1 M aqueous HCl (2 x 30 mL) and brine (30 mL) , dried (MgSO4) and concentrated to afford the desired bis-silylated product as a light yellow oil which was carried forward without any additional purification. Next, the newly formed intermediate was taken up in wet THF (20 mL) , solid K2CO3 (2.00 g, excess) was added at 25 0C in a single portion, and the resultant slurry was stirred vigourously for 2 h at 25 0C. Upon completion, the reaction contents were diluted with EtOAc (60 mL) , poured into water (40 mL) , washed with 1 M aqueous HCl (30 mL) and brine (30 mL) , dried (MgSO4), and concentrated. The resultant white solid was then dried under high vacuum in a 60 0C oil bath for 3 h to drive off TBSOH and afford the desired carboxylic acid 31 (4.74 g, 99% yield) as a white amorphous solid. 31: Rf = 0.40 (silica gel, hexanes : EtOAc , 3:2); IR (film) imax 2956, 2931, 2858, 1679, 1625, 1509, 1418, 1283, 1265, 1205, 1160, 1123, 906, 839, 824, 783 cm-1; 1H NMR (400 MHz, CDCl3) δ 11.4 (br s, 1 H), 7.72 (d, J = 16.0 Hz, 1 H), 7.07-7.04 (m, 2 H), 6.86 (d, J = 8.8 Hz, 1 H), 6.31 (d, J = 16.0 Hz, 1 H), 3.85 (s, 3 H), 1.00 (s, 9 H), 0.18 (s, 6 H); 13C NMR (75 MHz, CDCl3) δ 173.0, 151.2, 148.0, 147.1, 127.9, 122.7, 121.1, 115.0, 111.1, 55.4, 25.6, 18.5, -4.6; HRMS (FAB) calcd for C16H25O4Si+ [M + H+] 309.1522 and C16H23O3Si+ [M - OH+] 291.1416, found 309.1503 and 291.1424.
Diels-Alder Dimer 33.' MeOH (10 mL) and PhI(OAc)2 (0.444 g, 1.38 iranol, 1.05 equiv) were added sequentially to a solution of phenol 32 (0.925 g, 1.31 mmol, 1.0 equiv) in CH2Cl2 (2 mL) at 0 0C. The resulting yellow solution was allowed to slowly warm to 25 0C, and then stirred for 14 h. Upon completion, the reaction contents were concentrated directly and purified by flash column chromatography (silica gel, hexanes : EtOAc , 7:3) to afford a 1:1 mixture of diastereomeric 33 (0.959 g, 99% yield) as a light yellow amorphous solid. 33: Rf = 0.22 (silica gel, hexanes : EtOAc , 3:2); IR (film) <imax 3059, 1731, 1718, 1631, 1512, 1421, 1326, 1267, 1220, 1165, 1126, 1065, 1018, 825 cm-1; 1H NMR (400 MHz, CDCl3, 1:1 mixture of diastereomers) δ 7.63-7.52 (m, 32 H), 7.24 (d, J = 14.0 Hz, 1 H), 7.21 (d, J = 15.2 Hz, 1 H), 7.03 (d, J" = 16.0 Hz, 1 H), 6.97 (d, J = 15.6 Hz, 1 H), 6.91-6.84 (m, 8 H), 6.80-6.76 (m, 4 H), 6.17 (app dt, J = 6.8, 3.4 Hz, 2 H), 6.13-5.96 (m, 7 H), 5.92 (d, J = 10.4 Hz, 1 H), 5.30-5.18 (m, 20 H), 3.70 (s, 3 H), 3.69 (s, 3 H), 3.66 (s, 3 H), 3.63 (s, 3 H), 3.40 (m, 10 H), 3.37 (br s, 1 H), 3.32 (m, 5 H), 3.30 (s, 1 H), 3.23 (d, J = 6.8 Hz, 1 H), 3.21 (s, 3 H), 3.17 (s, 3 H), 3.15-3.08 (m, 8 H), 3.02 (S, 3 H), 2.98 (s, 3 H); 13C NMR (75 MHz, CDCl3, 1:1 mixture of diastereomers) δ 198.8, 191.1, 170.1, 169.8, 165.6, 165.3, 164.9, 149.2, 149.1, 148.5, 147.7, 145.7,
133.1, 132.8, 130.7, 130.3, 129.9, 129.6, 129.5, 128.7,
128.4, 127.3, 127.2, 125.9, 125.5, 122.9, 122.8, 122.3,
121.0, 120.9, 119.4, 119.0, 116.3, 116.1, 115.1, 97.7, 94.3, 94.2, 77.2, 73.3, 70.5, 58.3, 57.9, 52.3, 52.2, 50.7,
50.6, 50.4, 50.1, 50.0, 49.9, 49.0, 48.9, 43.5, 43.3, 40.7,
36.9; LRMS (MALDI) calcd for C74H63Fi2Oi8Na+ [M - H + Na+] 1490.37, found 1490.46.
Mixed Diβls-Alder Product 34. A solution of 33 (1.07 g, 0.728 mmol, 1.0 equiv) and dienophile 27 (4.90 g, 4.87 iranol, 6.7 equiv) in mesitylene (3.0 mL) was carefully- degassed 3 times using the freeze-pump-thaw method, and then sealed under argon in a tube equipped with a magnetic stir bar. The reaction mixture was then stirred at 220 0C (oil bath) for 35 min. After cooling the reaction contents to 25 0C, the reaction mixture was purified directly by flash column chromatography (silica gel, hexanes: EtOAc: CH2Cl2, 8:1:1→5:4:1) to provide recovered 27 (4.12 g) along with 34 (0.960 g, 38% yield, 71% yield based on recovered starting material) as a light yellow solid.
[Note: compound 34 is produced as a 1:1 mixture of chromatographically separable diastereomers; only data pertaining to the diastereomer which leads to the final natural products is provided here] . 34: Rf = 0.24 (silica gel, hexanes: EtOAc: CH2Cl2, 3:1:1); [a] 25 D = +63.5° (c = 0.45, CHCl3); IR (film) {max 1740, 1435, 1367, 1325, 1228, 1246, 1112, 1065, 824 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.55-7.43 (m, 24 H), 7.34 (d, J = 16.0 Hz, 1 H), 6.87-6.69 (m, 8 H), 6.58-6.55 (m, 2 H), 6.18 (d, J = 15.6 Hz, 1 H), 5.29 (dd, J = 7.6, 5.2 Hz, 1 H), 5.18-5.02 (m, 13 H), 4.97 (app s, 2 H), 3.66 (s, 3 H), 3.57 (s, 3 H), 3.37 (app s, 2 H), 3.30 (s, 3 H), 3.28 (s, 3 H), 3.13 (dd, J = 14.4, 5.2 Hz, 1 H), 3.08 (dd, J = 14.2, 7.8 Hz, 1 H), 3.02 (dd, J = 14.2, 4.6 Hz, 1 H), 2.92 (dd, J = 14.8, 8.0 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 200.5, 172.2, 169.3, 165.9, 148.6, 148.5, 148.3, 147.8, 147.8, 142.4, 141.2, 141.0, 140.4, 134.3, 134.1,
130.4, 129.9, 129.5, 127.4, 127.3, 127.2, 127.1, 125.8,
125.5, 122.7, 122.6, 122.3, 120.7, 118.3, 116.1, 114.9, 114.7, 93.9, 77.2, 73.3, 73.0, 70.5, 70.4, 70.3, 55.3, 52.3, ^52.3, 51.0, 49.7, 46.7, 44.9, 42.1, 40.0, 36.7; HRMS (FAB) calcd for C88H70F18Oi7 + [M+] 1740.43, found 1739.98.
Helisorin (3). Water (0.012 mL, 0.645 mmol, 5.0 equiv) and BF3«OEt2 (0.487 mL, 3.88 iranol, 30 equiv) were added in single portions to a solution of Diels-Alder adduct 34 (0.225 g, 0.129 mmol, 1.0 equiv) in benzene (6 mL) at 0 0C. The resulting yellow solution was then warmed slowly to 25 0C and stirred for an additional 16 h. Upon completion, the reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL) , poured into water (10 mL) , and extracted with EtOAc (3 x 20 mL) . The combined organic layers were then washed with brine (10 mL) , dried (MgSO4), and concentrated. The crude orange solid was purified by flash column chromatography (silica gel, toluene: acetone, 19:1) to afford recovered 34 (0.080 g) alongside the protected natural product (0.116 g, 53% yield, 82% yield based on recovered starting material) as a colorless glass. Next, BBr3 (1.0 M in CH2Cl2, 0.283 mL, 0.283 mmol, 20 equiv) was added in a single portion to a solution of this newly formed intermediate (0.024 g, 0.014 mmol, 1.0 equiv) in CH2Cl2 (1 mL) at -78 0C, and the reaction was stirred at -78 0C for 30 min. Upon completion, the reaction mixture was quenched at -78 0C with saturated aqueous NaHCO3 (1 mL) , re- acidified with 1.0 M HCl (1 mL) , warmed to 25 0C, poured into water (10 mL) , and extracted with EtOAc (2 x 10 mL) . The combined organic layers were washed with brine (10 mL) , dried (MgSO4) , and concentrated. The resultant crude yellow solid was triturated with CH2Cl2 (3 X l mL) to afford helisorin (3, 9.2 mg, 89% yield) as a white solid. [Note: significant decomposition of helisorin (3) was observed following its application to silica gel, exposure to air, and/or temperatures above 25 0C] . 3: Rf = 0.13 (silica gel, CH2Cl2 :MeOH, 9:1); [α]25 D = +28.3° (C = 0.15, MeOH); IR (film) imax 3415, 1728, 1631, 1515, 1444, 1261, 1160, 1044 cm-1; 1H NMR (500 MHz, acetone-d6) δ 7.71 (br s, 4 H), 7.25 (d, J = 16.0 Hz, 1 H), 6.80 (s, 1 H), 6.74 (br s, 2 H), 6.72 (d, J" = 9.0 Hz, 1 H), 6.72 (d, J = 3.5 Hz, 1 H), 6.71 (br s, 1 H), 6.68 (d, J = 8.0 Hz, 1 H), 6.57 (dd, J" = 8.0, 2.0 Hz, 1 H), 6.56 (dd, J = 8.0, 2.0 Hz, 1 H), 6.04 (d, J = 16.0 Hz, 1 H), 5.15 (dd, J" = 9.2, 6.8 Hz, 1 H), 4.97 (dd, J = 9.2, 4.3 Hz, 1 H), 3.97 (br s, 1 H), 3.62 (s, 3 H), 3.64- 3.59 (m, 1 H), 3.55 (s, 3 H), 3.51 (d, J = 5.0 Hz, 1 H), 6.57 (dd, J" = 8.0, 2.0 Hz, 1 H), 3.57 (s, 3 H), 3.37 (app s, 2 H), 3.30 (s, 3 H), 3.28 (s, 3 H), 3.05 (dd, J = 13.7, 4.3 Hz, 1 H), 3.01 (br s, 1 H), 2.98 (dd, J = 14.7, 6.7 Hz, 1 H) , 2.97 (dd, J = 14.5, 4.5 Hz, 1 H) , 2.82 (dd, J- = 14.0, 9.5 Hz, 1 H) ; 13C NMR (125 MHz, acetone-d6) δ 204.7, 170.9, 170.7, 170.3, 166.7, 147.3, 145.9, 145.9, 145.8, 145.0, 145.1, 142.8, 140.7, 138.0, 137.6, 134.8, 128.7, 128.7, 121.9, 121.8, 118.2, 117.4, 117.4, 116.3, 116.2, 111.4, 111.0, 82.0, 75.0, 74.3, 57.5, 53.0, 52.9, 52.7, 52.5, 43.7, 37.6, 37.6; HRMS (FAB) calcd for C3SH35Oi6 + [M + H+] 747.4531, found 747.4528. All spectroscopic data for this synthetic material match those reported by Tezuka and co- workers for natural helisorin (3); see Table Sl at the end of this section for a direct comparison [Ia] .
Hydroxykβtal 35. NaBH4 (0.090 g, 2.38 mmol, 2.0 equiv) was added in a single portion to a solution of bicyclic ketone 21 (0.550 g, 1.19 mmol, 1.0 equiv) in MeOH : CH2Cl2 (5:1, 6 mL) at 0 0C, and the resultant mixture was stirred at 0 0C for 1 h. Upon completion, the reaction contents were diluted with EtOAc (20 mL) , poured into water (20 mL) , washed with 1 M aqueous HCl (20 mL) , saturated aqueous NaHCO3 (20 mL) , and brine (20 mL) , dried (MgSO4), and concentrated to afford hydroxyketal 35 (0.551 g, 99% yield) as a white amorphous solid. 35: Rf = 0.51 (silica gel, hexanes : EtOAc , 3:7); IR (film) {max 3548, 2949, 1717, 1630, 1517, 1436, 1310, 1237, 1194, 1119, 1086, 1056, 911, 868 cm- \- 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 15.6 Hz, 1 H), 6.94-6.92 (m, 2 H), 6.80 (d, J = 8.8 Hz, 1 H), 6.68 (d, J = 6.8 Hz, 1 H), 6.01 (d, J" = 16.0 Hz, 1 H), 3.89 (s, 3 H), 3.84 (s, 3 H), 3.75 (s, 3 H), 3.70 (d, J = 1.2 Hz, 1 H), 3.61 (s, 3 H), 3.58 (ddd, J = 8.8, 3.2, 1.2 Hz, 1 H), 3.55 (s, 3 H), 3.42 (dd, J" = 6.2, 2.2 Hz, 1 H), 3.39 (app d, J = 7.6 Hz, 1 H), 3.21 (dt, J = 6.8, 0.2 Hz, 1 H), 3.12 (s, 3 H) , 2.21 (d, J = 8.8 Hz, 1 H) ; 13C NMR (75 MHz, CDCl3) δ 173.7, 167.5, 148.9, 147.6, 142.6, 139.7, 137.6, 133.6, 119.0, 117.3, 111.7, 111.1, 98.9, 72.2, 55.8, 55.7, 52.1, 51.5, 48.9, 48.8, 46.5, 41.6, 41.1, 40.3; HRMS (FAB) calcd for C24H30O9 + [M+] 462.1890, found 462.1897. Hydroxyketone 36. To a solution of alcohol 35 (0.026 g, 0.056 itunol, 1.0 equiv) in toluene (2 mL) at 0 0C was sequentially added water (0.050 mL) and HCl (4.0 M in dioxane, 0.100 mL) . The resultant biphasic solution was then stirred vigorously at 0 0C for 20 h. Upon completion, the reaction contents were quenched with saturated aqueous NaHCO3 (10 mL) , poured into water (10 mL) , and extracted with EtOAc (3 x 15 mL) . The combined organic layers were then washed with brine (10 mL) , dried (MgSO4), and concentrated. The resultant crude oil was purified by flash column chromatography (silica gel, hexanes : EtOAc , 1:1) to afford hydroxyketone 36 (0.020 g, 86% yield) as a colorless oil. 36: Rf = 0.22 (silica gel, hexanes : EtOAc , 2:3); IR (film) {max 3727, 3475, 2947, 1730, 1631, 1517, 1435, 1313, 1237, 1172, 1146, 1026, 803 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 15.6 Hz, 1 H), 6.93 (d, J = 7.2 Hz, 1 H), 6.83-6.79 (m, 3 H), 6.03 (d, J" = 16.0 Hz, 1 H), 4.05 (app t, J" = 2.2 Hz, 1 H), 3.88 (s, 3 H), 3.88-3.85 (m, l'H) 3.85 (s, 3 H), 3.77 (s, 3 H), 3.64 (s, 3 H), 3.64-3.61 (m, 1 H), 3.57-3.54 (m, 2 H), 2.08 (d, J = 5.2 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 208.9, 171.8, 167.0, 149.0, 148.1, 140.8, 140.6, 135.1, 131.8, 119.5, 118.9, 111.9, 110.9, 72.2, 55.9, 52.6, 51.8, 49.3, 47.3, 46.3, 42.5; HRMS (FAB) calcd for C22H24O8 [M+] 416.1471, found 416.1489.
Hydroxyketone 37. Water (0.050 mL) and HCl (4.0 M in dioxane, 0.750 mL) were added sequentially to a solution of alcohol 35 (0.102 g, 0.220 mmol, 1.0 equiv) in THF (5 mL) at 25 0C to obtain a final acid concentration of 0.5 M. The resultant solution was stirred at 25 0C for 14 h. Upon completion, the reaction was poured into EtOAc (30 mL) , washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL) , dried (MgSO4), and concentrated. The resultant crude solid was purified by flash column chromatography (silica gel, hexanes : EtOAc , 3:2) and crystallized from Et2O to afford the desired hydroxyketone 37 (0.077 g, 84% yield) as a white crystalline solid. 37: Rf = 0.51 (silica gel, hexanes : EtOAc , 3:7); m.p. = 170.0-170.3 0C; IR (film) imax 3727, 3456, 2947, 1730, 1629, 1518, 1436, 1312, 1194, 1173, 1026, 811 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 15.6 Hz, 1 H), 6.78-6.77 (m, 3 H), 6.65 (dd, J = 6.4, 2.0 Hz, 1 H), 6.13 (d, J = 15.6 Hz, 1 H), 3.87 (dt, J = 3.2, 2.0 Hz, 1 H), 3.83 (s, 6 H), 3.78 (s, 3 H), 3.64 (s, 3 H), 3.61 (dd, J = 7.6, 2.4 Hz, 1 H), 3.57 (dd, J" = 7.2, 2.0 Hz, 1 H), 3.28 (dd, J" = 6.4, 2.4 Hz, 1 H), 3.23 (d, J = 2.0 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 208.2, 173.7, 167.2, 148.8, 148.1, 140.8, 140.2, 134.7, 132.3, 120.1, 118.6, 111.4, 111.1, 69.8, 55.7, 52.3, 51.8, 49.1, 41.8, 41.8; HRMS (FAB) calcd for C22H24O8 + [M+] 416.1471, found 416.1489.
Ketone 39. AcOH (0.3 mL) and tetramethylammonium triacetoxyborohydride (0.146 g, 0.555 mmol, 3.0 equiv) were added sequentially to a solution of hydroxyketone 37 (0.077 g, 0.185 mmol, 1.0 equiv) in MeCN (3 mL) at 0 0C. The resultant solution was then warmed to 25 0C, and the reaction contents were stirred at 25 0C for 3 h. A second portion of tetramethylammonium triacetoxyborohydride (0.097 g, 0.370 mmol, 2.0 equiv) was then added, and stirring was continued at 25 0C for 2 h. Upon completion, the reaction contents were diluted with EtOAc (30 mL) , poured into water (20 mL) , and extracted with EtOAc (3 x 20 mL) . The combined organic layers were then washed with saturated aqueous NaHCO3 (2 x 20 mL) and brine (20 mL) , dried (MgSO4), and concentrated. The resultant crude yellow solid was purified by flash column chromatography (silica gel, hexanes : EtOAc , 3:7) to afford the desired anti-disposed diol (0.066 g, 75% yield) as a white solid. With this step complete, Et3N (0.110 mL, 0.789 mmol, 5.0 equiv) and TBSOTf (0.036 mL, 0.158 mmol, 1.0 equiv) were added sequentially to a solution of this newly formed anti-disposed diol (0.066 g, 0.158 mmol, 1.0 equiv) in CH2Cl2 (2 mL) at -78 0C. The reaction contents were then slowly warmed to 25 0C over 1 h with constant stirring. Upon completion, the reaction contents were diluted with EtOAc (30 mL) , poured into water (20 mL) , and extracted with EtOAc (3 x 20 mL) . The combined organic layers were then washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL) , dried (MgSO4) , and concentrated to afford the desired mono-silylated diol as a white solid which was used directly without any additional purification. With this operation complete, solid NaHCO3 (0.132 g, 1.58 mmol, 10 equiv) and Dess-Martin periodinane (0.134 g, 0.315 mmol, 2.0 equiv) were added sequentially in single portions to a solution of this newly formed intermediate in CH2Cl2 (2 mL) at 25 0C. The resultant suspension was stirred at 25 0C for 1 h. Upon completion, saturated aqueous Na2SO3 (2 mL) was added and the resultant biphasic mixture was stirred vigorously for 1 h to quench any remaining oxidizing agents. The reaction contents were then diluted with EtOAc (30 mL) , poured into water (20 mL) , and extracted with EtOAc (3 x 20 mL) . The combined organic layers were washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL) , dried (MgSO4) , and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes : EtOAc , 7:3) to afford ketone 39 (0.079 g, 94% yield over 2 steps, 71% overall yield from 37) as a light yellow solid. 39: Rf = 0.69 (silica gel, hexanes : EtOAc , 3:7); 1H NMR (500 MHz, CDCl3) δ 7.37 (d, J = 15.5 Hz, 1 H), 6.88 (d, J" = 6.5 Hz, 1 H), 6.85 (d, J = 8.5 Hz, 1 H), 6.77 (d, J = 7.5 Hz, 1 H), 6.02 (d, J = 15.5 Hz, 1 H), 3.95 (s, 1 H), 3.91 (d, J" = 2.0 Hz, 1 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.76 (s, 3 H), 3.65 (s, 3 H), 3.51 (dd, J = 7.0, 2.5 Hz, 1 H), 3.36 (dd, J = 6.8, 1.8 Hz, 1 H), 3.08 (dt, J = 6.0, 2.5 Hz, 1 H), 0.76 (s, 9 H), -0.08 (s, 3 H), -0.10 (s, 3 H) .
Hydroxyketone 40. AcOH (0.012 mL, 0.196 iranol, 2.0 equiv) and TBAF (1.0 M in THF, 0.196 mL, 0.196 mmol, 2.0 equiv) were added sequentially in single portions to a solution of 39 (0.052 g, 0.098 mmol, 1.0 equiv) in THF (2 mL) at 25 0C, and the resultant solution was stirred at 25 0C for 2 h. Upon completion, the reaction contents were poured into EtOAc (20 mL) and washed with saturated aqueous NH4Cl (15 mL) and brine (15 mL) , dried (MgSO4), and concentrated. The resultant crude yellow solid was purified by flash column chromatography (silica gel, hexanes : EtOAc , 3:2) to afford recovered 39 (0.015 g) alongside hydroxyketone 40 (0.022 g, 54% yield, 76% yield based on recovered starting material) as a white amorphous solid. 40: Rf = 0.32 (silica gel, hexanes : EtOAc , 3:7); IR (film) imax 3728, 3460, 1731, 1631, 1518, 1436, 1313, 1238, 1172, 1089, 1026, 808 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 16.0 Hz, 1 H), 6.91 (d, J = 6.8 Hz, 1 H), 6.86-6.79 (m, 3 H), 6.06 (d, J = 15.6 Hz, 1 H), 4.03 (t, J = 1.6 Hz, 1 H), 3.98 (s, 1 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.77 (s, 3 H), 3.64 (s, 3 H), 3.55 (dd, J" = 7.2, 2.8 Hz, 1 H), 3.41 (dd, J = 7.2, 2.0 Hz, 1 H),
3.30 (dt, J = 6.4, 2.4 Hz, 1 H), 2.55 (d, J = 1.6 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 207.4, 172.2, 167.0, 149.3, 148.4, 141.6, 140.4, 133.0, 131.3, 119.1, 118.5, 111.7, 111.3, 66.9, 56.0, 52.7, 51.8, 46.1, 44.2, 41.6; HRMS (FAB) calcd for C22H25O8 + [M+H+] 417.1549, found 417.1548.
Hydroxykβtal 42. HCl (4.0 M in dioxane, 0.3 mL) was added to a solution of ketone 39 (0.027 g, 0.051 mmol, 1.0 equiv) in MeOH: CH (OMe) 3 (4:1, 2.5 mL) at 25 0C, and the resultant solution was stirred at 25 0C for 14 h. Upon completion, the reaction contents were concentrated directly and the resultant crude yellow solid was purified by flash column chromatography (silica gel, hexanes : EtOAc , 3:2) to afford monomer 42 (0.022 g, 93% yield) as a light yellow solid. 42: Rf = 0.45 (silica gel, hexanes : EtOAc , 3:7); IR (film) imax 3525, 2950, 1717, 1628, 1516, 1436, 1240, 1171, 1123, 1083, 1027, 733 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 15.6 Hz, 1 H), 6.90-6.83 (m, 3 H), 6.78 (d, J = 7.2 Hz, 1 H), 6.01 (d, J = 16.0 Hz, 1 H), 3.92 (dd, J = 6.6, 2.2 Hz, 1 H), 3.90 (s, 3 H), 3.77 (s, 3 H), 3.76 (app s, 1 H), 3.60 (s, 3 H), 3.53 (dd, J = 6.8, 2.0 Hz, 1 H), 3.32 (s, 3 H),
3.31 (s, 3 H), 3.26 (dd, J" = 6.8, 2.8 Hz, 1 H), 2.92 (dt, J" = 6.8, 2.6 Hz, 1 H), 2.86 (d, J = 6.4 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 173.8, 167.4, 149.0, 147.9, 142.5, 141.4, 136.8, 132.5, 120.0, 116.4, 111.8, 111.2, 101.9, 68.3, 55.9, 55.8, 52.1, 51.6, 49.8, 49.6, 48.2, 44.3, 41.6, 41.5; HRMS (FAB) calcd for C24H30O9 + [M+] 462.1890, found 462.1889.
Unsymmβtrical Dimer 43. Solid NaH (60% dispersion in mineral oil, 5.8 mg, 0.144 mmol, 10 equiv) was added in a single portion to a solution of hydroxyketone 40 (6.0 mg, 0.014 iranol, 1.0 equiv) in THF (0.5 mL) at 0 0C. The resultant slurry was then warmed to 25 0C and stirred for 20 min. Upon completion, the reaction mixture was carefully quenched with saturated aqueous NH4Cl (10 mL) , poured into water (10 mL) and extracted with EtOAc (3 x 15 mL) . The combined organic layers were then washed with brine (10 mL) , dried (MgSO4) , and concentrated. The resultant crude off-white solid was purified by flash column chromatography (silica gel, hexanes : EtOAc , 1:1) to afford unsymmetrical dimer 43 (6.0 mg, 99% yield) which was recrystallized from CHCl3: Et2O (2:1) as white needles. 43: Rf = 0.17 (silica gel, hexanes : EtOAc , 3:7); m.p. = 189.0-189.3 0C; IR (film) imax 3426, 2904, 1720, 1632, 1518, 1436, 1311, 1238, 1196, 1027, 810 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 16.0 Hz, 1 H), 7.28 (d, J = 16.5 Hz, 1 H), 7.00-6.97 (m, 2 H), 6.89 (d, J = 8.0 Hz, 1 H), 6.85-6.80 (m, 3 H), 6.71 (d, J = 6.5 Hz, 1 H), 6.59 (d, J = 6.0 Hz, 1 H), 5.96 (d, J = 15.5 Hz, 1 H), 5.80 (d, J = 15.5 Hz, 1 H), 5.43 (br s, 1 H) , 4.14 (d, J = 3.0 Hz, 1 H), 3.88 (s, 6 H), 3.84 (s, 3 H), 3.79 (s, 3 H), 3.79 (s, 3 H), 3.79-3.76 (m, 2 H), 3.73 (s, 3 H), 3.58 (s, 3 H), 3.57 (s, 3 H), 3.53 (dd, J = 6.0, 2.0 Hz, 1 H), 3.45 (dd, J = 5.8, 2.7 Hz, 1 H), 3.34 (dd, J = 6.5, 2.0 Hz, 1 H), 3.25 (dd, J = 6.5, 2.5 Hz, 1 H), 3.16 (s, 1 H) , 3.12 (dt, J- = 6.5, 3.0 Hz, 1 H) , 2.91 (dt, J = 6.5, 2.8 Hz, 1 H) , 2.51 (br s, 1 H) ; 13C NMR (125 MHz, CDCl3) δ 173.4, 173.3, 167.2, 149.0, 148.0, 142.0, 141.5, 138.6, 138.2, 137.7, 136.9, 132.4, 132.2, 120.4, 119.6, 118.1, 117.5, 112.3, 111.4, 111.3, 111.2, 106.6, 80.7, 71.5, 55.9, 55.9, 55.8, 52.3, 51.6, 51.5, 47.4, 45.0, 44.4, 44.2, 43.9, 43.1, 42.9, 41.7; HRMS (FAB) calcd for C44H48Oi6 + [M+] 832.2942, found 832.2975.
Ketone 44. Anhydrous HCl gas (1 atm, generated in another flask linked via rubber tubing by slowly adding concentrated H2SO4 to solid NaCl) was ducted into a round- bottom flask containing alcohol 42 (0.7 mg, 0.0015 nnnol) and immersed in a 100 0C oil bath. A positive pressure of HCl was maintained in the reaction flask for 5 min, after which time no further HCl was added. The reaction was then maintained at 100 0C for an additional 40 min. Upon completion, the reaction contents were cooled to 25 0C, affording ketone 44 (0.6 mg, 99% yield) as a light yellow amorphous solid. 44: Rf = 0.38 (silica gel, hexanes : EtOAc , 3:2); IR (film) imax 2953, 1715, 1631, 1518, 1436, 1264, 1170, 1101, 1026, 811 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 16.0 Hz, 1 H), 6.86 (d, J" = 1.6 Hz, 1 H), 6.83-6.77 (m, 2 H), 6.65 (d, J = 6.4 Hz, 1 H), 6.13 (d, J = 15.6 Hz, 1 H), 3.91 (app s, 1 H), 3.85 (s, 3 H), 3.85 (s, 3 H), 3.79 (s, 3 H), 3.71 (s, 3 H), 3.66 (s, 3 H), 3.57 (dd, J = 7.4, 2.2 Hz, 1 H), 3.49 (dd, J = 6.8, 2.0 Hz, 1 H), 3.37 (d, J = 3.6 Hz, 1 H) , 3.24 (dd, J" = 6.6, 2.6 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 205.0, 173.7, 167.1, 165.3, 148.9, 148.1, 140.9, 139.8, 135.4, 133.0, 120.3, 118.5, 111.2, 59.0, 56.4, 55.8, 52.3, 51.8, 48.3, 42.8, 39.9; HRMS (FAB) calcd for C23H26O8 + [M+] 430.1628, found 430.1635.
Enol Triflate 45. KHMDS (0.5 M in toluene, 0.604 mL, 0.302 mmol, 1.3 equiv) was added dropwise to a solution of Tf2NPh (0.216 g, 0.604 mmol, 2.6 equiv) and ketone 44 (0.100 g, 0.232 mmol, 1.0 equiv) in THF (5 mL) at -78 0C, and the reaction was stirred at -78 0C for 10 min. Upon completion, the reaction contents were quenched sequentially at -78 0C with water (10 inL) and saturated aqueous NaHCO3 (10 mL) . After warming to 25 0C, the mixture was extracted with EtOAc (2 x 20 mL) . The combined organic layers were then washed with brine (20 mL) , dried (MgSO4) and concentrated. The resultant crude yellow solid was purified by flash column chromatography (silica gel, hexanes : EtOAc , 7:3) to afford enol triflate 45 (0.097 g, 74% yield) as a white amorphous solid. 45: Rf = 0.37 (silica gel, hexanes : EtOAc , 3:2); IR (film) {max 2953, 1718, 1632, 1516, 1420, 1205, 1138, 1085, 1027, 878 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.34 (d, J" = 16.0 Hz, 1 H), 6.92 (d, J = 5.5 Hz, 1 H), 6.81 (d, J" = 9.0 Hz, 1 H), 6.72-6.71 (m, 2 H), 6.00 (d, J" = 16.0 Hz, 1 H), 4.28 (app s, 1 H), 3.88 (s, 1 H), 3.87 (s, 6 H), 3.77 (s, 3 H), 3.62 (s, 3 H), 3.56 (dd, J = 6.5, 2.0 Hz, 1 H), 3.44 (dd, J = 5.0, 2.0 Hz, 1 H), 3.04 (dd, J = 5.0, 2.5 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 171.9, 167.1, 149.7, 149.2, 148.3, 142.6, 140.5, 140.1, 133.8, 127.8, 119.3, 117.4, 111.4, 110.5, 58.4, 55.9, 55.8, 52.2, 51.7, 48.5, 47.9, 42.2; HRMS (FAB) calcd for C24H26O10F3S+ [M+] 563.1199, found 563.1191.
Ketone 47. Alcohol 42 (3.5 mg, 0.008 mmol, 1.0 equiv) was heated neat under an argon atmosphere at 160 0C for 4 h.
Upon completion, the reaction contents were cooled to 25
0C, concentrated, and purified by flash column chromatography (silica gel, hexanes : EtOAc , 3:2) to afford recovered 42 (1.8 mg) alongside 47 (0.5 mg, 15% yield, 32% yield based on recovered starting material) as a colorless oil. 47: Rf = 0.55 (silica gel, hexanes : EtOAc , 3:7); 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 16.0 Hz, 1 H), 6.79 (d, J = 8.4 Hz, 1 H), 6.70-6.64 (m, 3 H), 6.08 (d, J = 15.6 Hz, 1 H), 3.90 (s, 1 H), 3.85 (s, 6 H), 3.78 (s, 3 H), 3.71 (s, 3 H), 3.61 (dd, J- = 6.2, 2.2 Hz, 1 H), 3.58 (s, 3 H), 3.54 (d, J = 2.8 Hz, 1 H), 3.49 (dd, J = 6.8, 2.4 Hz, 1 H), 3.01 (dd, J = 6.4, 2.0 Hz, 1 H); LRMS (FAB) calcd for C23H26O8 + [M+] 430.2, found 430.1.
Hβlictβrin A Core 48. BF3-OEt2 (0.057 mL, 0.450 itimol, 4.0 equiv) was added in a single portion under strictly anhydrous conditions to a solution of monomer 42 (0.052 g, 0.112 mmol, 1.0 equiv) in CH2Cl2 (1 mL) at 0 0C, and the reaction was stirred at 0 0C for 30 min. Upon completion, the reaction contents were quenched at 0 0C with saturated aqueous NaHCO3 (10 mL) , poured into water (10 mL) , and extracted with EtOAc (2 x 20 mL) . The combined organic layers were then washed with brine (20 mL) , dried (MgSU4) , and concentrated. The resultant crude yellow solid was purified by flash column chromatography (silica gel, hexanes : EtOAc , 3:2) and recrystallized from Et2O:hexanes (3:1) to afford dimer 48 (0.038 g, 79% yield) as a white crystalline solid. 48: Rf = 0.51 (silica gel, hexanes : EtOAc , 3:7); m.p. = 215.0-215.8 0C; IR (film) ^max 2950, 1705, 1632, 1517, 1435, 1362, 1234, 1170, 1145, 1026 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 15.2 Hz, 2 H), 6.95-6.91 (m, 4 H), 6.80 (d, J = 8.4 Hz, 2 H), 5.88 (d, J = 15.6 Hz, 2 H), 3.88 (s, 6 H), 3.86 (s, 6 H), 3.80 (s, 6 H), 3.63 (d, J" = 3.2 Hz, 2 H), 3.57 (s, 6 H), 3.29 (s, 6 H), 3.24 (dd, J = 6.4, 2.8 Hz, 2 H), 3.14 (dd, J" = 6.4, 1.6 Hz, 2 H), 2.79 (dt, J- = 6.4, 1.6 Hz, 2 H) ; 13C NMR (75 MHz, CDCl3) δ 173.6, 167.7, 148.8, 147.7, 142.9, 139.7, 135.7, 133.0, 120.0, 116.1, 112.2, 111.1, 100.1, 69.1, 55.8, 52.1, 51.6, 49.0, 44.4, 43.2, 42.2, 40.1; HRMS (FAB) calcd for C46H52Oi6 + [M+] 860.3255, found 860.3262.
Hydroxykβtonβ 49. NaBH4 (0.022 g, 0.586 mmol, 1.5 equiv) was added in a single portion to a solution of Diels-Alder adduct 34 (0.680 g, 0.390 mmol, 1.0 equiv) in MeOH: THF (4:1, 7.5 mL) at -30 0C. The reaction was then stirred at - 30 0C for 1 h. Upon completion, the reaction mixture was carefully quenched at -30 0C with 1 M aqueous HCl (15 mL) , poured into water (10 mL) , and extracted with EtOAc (3 x 30 mL) . The combined organic layers were then washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL) , dried
(MgSO4) , and concentrated. The resultant crude material was then purified by flash column chromatography (silica gel, toluene: acetone, 9:1) to afford the desired intermediate alcohol as a yellow solid. Next, this newly formed alcohol was taken up in MeCN (5 mL) , and water (0.050 mL) and HCl (4.0 M in dioxane, 0.750 mL) were then added sequentially at 25 0C to obtain a final acid concentration of 0.5 M. The resultant solution was stirred at 25 0C for 14 h. Upon completion, the reaction contents were diluted with EtOAc (30 mL) , poured into water (10 mL) , and extracted with EtOAc (3 x 10 mL) . The combined organic layers were then washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL) , dried (MgSO4) , and concentrated. The resultant crude material was purified by flash column chromatography (silica gel, toluene: acetone, 19:1) to afford 49 (0.370 g, 56% yield over 2 steps) as a light yellow solid. 49: Rf = 0.44 (silica gel, toluene: acetone, 9:1); [α]25 D = +49.2° (c = 0.19, CHCl3); IR (film) <!max 3628, 2928, 1734, 1513, 1324, 1161, 1110, 1066, 1017, 824 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.63-7.43 (m, 24 H), 7.32 (d, J = 15.6 Hz, 1 H), 6.86-6.78 (m, 5 H), 6.70-6.65 (m, 3 H), 6.61 (dd, J = 6.4, 1.2 Hz, 1 H), 6.53 (dd, J" = 8.4, 2.0 Hz, 1 H), 6.21 (d, J = 15.6 Hz, 1 H), 5.30 (dd, J = 7.6, 5.2 Hz, 1 H), 5.15-5.01 (m, 13 H), 3.88 (d, J = 2.8 Hz, 1 H), 3.69 (d, J" = 3.6 Hz, 1 H), 3.66 (s, 3 H), 3.53 (s, 3 H), 3.51 (app d, J = 1.6 Hz, 1 H), 3.42 (dd, J = 7.6, 2.4 Hz, 1 H), 3.25 (dd, J" = 6.4, 2.0 Hz, 1 H), 3.14 (dd, J" =14.4, 5.2 Hz, 1 H), 3.07 (dd, J = 14.4, 8.0 Hz, 1 H), 3.00 (dd, J = 14.4, 4.4 Hz, 1 H), 2.89 (dd, J = 14.8, 8.4 Hz, 1 H), 2.71 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 207.6, 172.6, 169.9, 169.3, 165.9, 148.5, 147.9, 147.8, 147.7, 141.4, 141.0, 140.4, 134.9, 133.3, 130.8, 130.3, 129.9, 129.5, 129.2, 127.3, 127.3, 127.2, 127.1, 125.8, 125.5, 122.7, 122.5, 122.2, 121.3, 118.7, 116.2, 116.0, 115.0, 114.8, 77.2, 73.3, 73.0, 70.6, 70.4, 70.4, 70.1, 54.7, 52.3, 49.0, 41.8, 41.5, 36.9, 36.7; HRMS (FAB) calcd for C86H67Fi8Oi6 + [M + H+] 1697.41, found 1697.77.
Hydroxykβtal 50. AcOH (0.2 mL) and tetramethylammonium triacetoxyborohydride (0.239 g, 0.912 inmol, 3.0 equiv) were added sequentially to a solution of hydroxyketone 49 (0.515 g, 0.303 rranol, 1.0 equiv) in MeCN (10 mL) at 0 0C. The resultant solution was then warmed to 25 0C, and the reaction contents were stirred at 25 0C for 10 h. A second portion of tetramethylammonium triacetoxyborohydride (0.159 g, 0.606 mmol, 2.0 equiv) was then added, and stirring was continued at 25 0C for 4 h. Upon completion, the reaction contents were diluted with EtOAc (20 mL) , poured into water (15 mL) , and extracted with EtOAc (2 x 20 mL) . The combined organic layers were then washed with saturated aqueous NaHCO3 (2 x 20 mL) and brine (20 mL) , dried (MgSO4), and concentrated. The resultant crude orange solid was purified by flash column chromatography (silica gel, toluene: acetone, 9:1) to afford recovered 49 (0.162 g) alongside the desired anti-disposed diol product (0.270 g, 52% yield, 76% yield based on recovered starting material) as a colorless, glassy solid. Next, Et3N (0.082 mL, 0.585 mmol, 5.0 equiv) and TBSOTf (0.028 mL, 0.123 mmol, 1.05 equiv) were added sequentially to a solution of a portion of this newly formed anti-disposed diol (0.199 g, 0.117 mmol, 1.0 equiv) in CH2Cl2 (3 mL) at -78 0C. The reaction was then slowly warmed to 25 0C over 1 h with constant stirring. Upon completion, the reaction contents were diluted with EtOAc (20 mL) , poured into water (15 mL) , and extracted with EtOAc (2 x 20 mL) . The combined organic layers were then washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL) , dried (MgSO4) , and concentrated to afford the desired mono-silylated diol as a white solid which was used directly without any additional purification. With this operation complete, NaHCO3 (0.986 g, 1.17 mmol, 10 equiv) and Dess-Martin periodinane (0.074 g, 0.176 mmol, 1.5 equiv) were added sequentially in single portions to a solution of this newly formed intermediate in CH2Cl2 (2 mL) at 25 0C. The resultant suspension was then stirred at 25 0C for 1 h. Upon completion, saturated aqueous Na2SO3 (2 mL) was added and the resultant biphasic mixture was stirred vigorously for 1 h to quench any remaining oxidizing agents. The reaction contents were then diluted with EtOAc (20 mL) , poured into water (15 mL) , and extracted with EtOAc (2 x 20 mL) . The combined organic layers were washed with saturated aqueous NaHCO3 (2 x 20 mL) and brine (20 mL) , dried (MgSO4) , and concentrated to afford the desired crude ketone as a light yellow solid which was carried forward without any additional purification. Finally, HCl (0.3 mL) was added to a solution of the newly formed crude ketone in MeOHiCH(OMe)3 (4:1, 2.5 mL) at 25 0C, and the resultant solution was stirred at 25 0C for 14 h. Upon completion, the reaction contents were diluted with EtOAc (20 mL) , poured into water (15 mL) , and extracted with EtOAc (2 x 20 mL) . The combined organic layers were then washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL) , dried (MgSO4), and concentrated. The resultant crude yellow solid was purified by flash column chromatography (silica gel, toluene: acetone, 19:1) to afford the desired alcohol 50 (0.148 g, 73% yield over the final 3 steps, 43% overall from 49) as a light yellow solid. 50: Rf = 0.28 (silica gel, toluene: acetone, 9:1); [CC]25D = +14.2° (c = 0.38, CHCl3); IR (film) <!max 3727, 2953, 1743, 1715, 1623, 1513, 1420, 1324, 1161, 1118, 1066, 824 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.63-7.35 (m, 25 H), 6.93- 6.73 (m, 8 H), 6.64-6.61 (m, 2 H), 6.41 (dd, J = 8.0, 1.6 Hz, 1 H), 6.14 (d, J = 15.6 Hz, 1 H), 5.28 (dd, J" = 7.2, 5.6 Hz, 1 H), 5.16-4.98 (m, 13 H), 3.82 (app d, J = 6.4 Hz, 1 H), 3.72 (s, 1 H), 3.65 (s, 3 H), 3.57 (s, 3 H), 3.54 (app d, J = 7.2 Hz, 1 H), 3.26 (s, 3 H), 3.17 (s, 3 H), 3.10 (dd, J = 6.8, 4.0 Hz, 1 H) , 3.00-2.87 (m, 5 H) , 2.85 (d, J = 6.4 Hz, 1 H) ; 13C NMR (75 MHz, CDCl3) δ 172.8, 170.0,
169.5, 166.2, 148.7 148.5, 148.3, 147.7, 147.6, 147.5,
143.3, 141.4, 141.1 141.0, 137.3, 133.8, 130.3, 129.9,
129.6, 129.4, 129.1 127.3, 127.2, 127.1, 127.1, 125.8, 112255..44,, 112222..77,. 112222..77, 122.2, 121.0, 116.5, 116.2, 115.9, 115.4, 114.9, 114.7, 101.9, 77.2, 73.0, 70.5, 70.4, 70.3, 68.6, 52.2, 49.9, 49.7, 47.3, 44.5, 41.7, 41.1, 37.0, 36.6; HRMS (FAB) calcd for C88H72Fi8Oi7 + [M+] 1742.45, found 1742.67.
Hβlicterin B (2). BF3-OEt2 (0.033 mL, 0.262 iranol, 8.0 equiv) was added in a single portion under rigorously anhydrous conditions to a solution of monomer 50 (0.057 g, 0.033 mmol, 1.0 equiv) in CH2Cl2 (0.2 mL) at 0 0C, and the resultant solution was stirred at 0 0C for 30 min. Upon completion, the reaction contents were quenched at 0 0C with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (2 x 15 mL) . The combined organic layers were washed with brine (20 mL) , dried (MgSO4) , and concentrated. The resultant crude yellow solid was purified by flash column chromatography (silica gel, toluene: acetone, 19:1) to afford protected helicterin A (0.038 g, 67% yield) as a white amorphous solid. Next, BBr3 (1.0 M in CH2Cl2, 0.126 mL, 0.126 mmol, 18 equiv) was added in a single portion to a solution of protected helicterin A (0.024 g, 0.007 mmol, 1.0 equiv) in CH2Cl2 (0.5 mL) at -78 0C, and the resultant solution was stirred at -78 0C for 45 minutes. Upon completion, the reaction mixture was quenched at -78 0C with saturated aqueous NaHCO3 (1 mL) , re-acidified with 1.0 M HCl (1 mL) , warmed to 25 0C, poured into water (10 mL) , and extracted with EtOAc (2 x 10 mL) . The combined organic layers were then washed with brine (10 mL) , dried (MgSO4), and concentrated. The crude yellow solid was then triturated with CH2Cl2 (3 x 1 mL) to afford helicterin B (2)
(8.0 mg, 76% yield) as a white solid. The natural product was further purified by preparative TLC (silica gel, CH2Cl2:Me0H, 4:1). [Note: some decomposition was observed on silica gel]. 2: Rf = 0.05 (silica gel, CH2Cl2 :MeOH, 4:1); [Cl]25 D = +6.5° (C = 0.15, CH3OH); IR (film) {max 3412, 2924, 1730, 1701, 1627, 1521, 1442, 1363, 1284, 1174, 1117, 816 cm'1; 1H NMR (500 MHz, CD3OD) δ 7.26 (d, J- = 15.5 Hz, 1 H) , 7.25 (d, J = 15.5 Hz, 1 H), 6.88 (d, J = 1.0 Hz, 1 H), 6.82 (d, J- = 2.5 Hz, 1 H), 6.73 (d, J- = 8.5 Hz, 1 H), 6.71 (d, J = 8.5 Hz, 1 H), 6.71 (br s, 2 H), 6.70 (d, J = 7.0 Hz, 1 H), 6.695 (d, J = 8.0 Hz, 1 H), 6.64-6.58 (m, 6 H), 6.53 (d, J- = 1.5 Hz, 1 H), 6.39 (dd, J = 8.0, 1.0 Hz, 1 H), 6.34 (d, J- = 5.0 Hz, 1 H), 6.32 (dd, J- = 7.8, 1.7 Hz, 1 H), 6.29 (d, J = 6.0 Hz, 1 H), 5.93 (d, J = 15.5 Hz, 1 H), 5.92 (d, J- = 15.5 Hz, 1 H), 5.28 (dd, J = 8.3, 4.3 Hz, 1 H), 5.27 (dd, J- = 8.8, 4.3 Hz, 1 H), 4.99 (dd, J- = 7.5, 4.5 Hz, 1 H), 4.97 (dd, J- = 8.0, 4.0 Hz, 1 H), 3.83 (d, J- = 2.0 Hz, 1 H), 3.73 (s, 3 H), 3.71 (s, 3 H), 3.58 (br d, J- = 1.5 Hz, 2 H), 3.54 (s, 3 H), 3.53 (s, 3 H), 3.48 (dd, J = 6.8, 1.8 Hz, 1 H), 3.28 (br s, 1 H), 3.24 (s, 3 H), 3.12-3.08 (m, 3 H), 3.03 (dd, J = 14.5, 8.5 Hz, 2 H), 2.99 (dd, J- = 6.2, 3.7 Hz, 2 H), 2.93 (dd, J- = 14.8, 3.8 Hz, 1 H), 2.89 (dd, J = 14.5, 4.5 Hz, 1 H), 2.80 (dd, J = 13.8, 8.7 Hz, 1 H), 2.80 (dd, J- = 14.0, 8.0 Hz, 1 H), 2.75-2.72 (m, 1 H), 2.66 (dt, J- = 6.5, 2.8 Hz, 1 H); 13C NMR (75 MHz, CD3OD) δ 175.8, 175.3, 170.3, 170.3, 172.3, 172.2, 169.3, 169.3, 147.1, 147. ,1 146.9, 146.9, 146.9, 146.9, 146.8, 146.6, 146.1,
146.1, 146.1, 146.0, 146.0, 145.8, 143.3, 141.7, 139.3, 137.8, 134.4, 134.3, 129.6, 129.6, 129.3, 129.2, 122.7,
122.6, 122.6, 122.6, 121.7, 121.6, 118.2, 118.0, 117.9, 117.9, 117.4, 117.4, 117.4, 117.2, 117.2, 117.2, 117.2,
117.2, 117.2, 117.2, 102.4, 98.8, 75.8, 75.6, 75.5, 75.4, 71.1, 70.9, 53.5, 53.5, 53.5, 53.5, 50.0, 50.0, 48.0, 46.9, 46.9, 45.5, 45.1, 44.8, 43.8, 42.0, 38.6, 38.6, 38.4, 38.4. All spectroscopic data for this synthetic material match those reported by Tezuka and co-workers for natural helicterin B (2) ; see Table S2 at the end of this section for a direct comparison [Ib] .
Helisterculin A (4). A solution of 17 (0.190 g, 0.129 mrnol, 1.0 equiv) and dienophile 27 (0.441 g, 0.864 mmol, 6.7 equiv) in mesitylene (1.0 mL) was carefully degassed 3 times using the freeze-pump-thaw method, and then sealed under argon in a tube equipped with a magnetic stir bar. The reaction mixture was then stirred at 225 0C (oil bath) for 35 min. After cooling the reaction contents to 25 0C, the reaction mixture was purified directly by flash column chromatography (silica gel, hexanes : EtOAc : CH2Cl2 , 8:1:1→5:4:1) to provide recovered 27 (1.22 g) alongside the desired Diels-Alder adduct (0.142 g, 44% yield, 78% based on recovered starting material) as a light yellow solid. Next, a portion of this newly formed ketone (0.128 g, 0.103 mmol, 1.0 equiv) was taken up in MeOH: THF (4:1, 5.0 mL) and NaBH4 (6.0 mg, 0.154 mmol, 1.5 equiv) was added in a single portion at 0 0C. The reaction was then stirred at 0 0C for 30 minutes. Upon completion, the reaction mixture was carefully quenched at 0 0C with 1 M aqueous HCl (10 mL) , poured into water (10 mL) , and extracted with EtOAc (3 x 10 mL) . The combined organic layers were then washed with saturated aqueous NaHCU3 (10 mL) and brine (10 mL) , dried (MgSO4) , and concentrated. The resultant crude material was then purified by flash column chromatography (silica gel, hexanes : EtOAc , 3:2) to afford the desired intermediate alcohol (0.111 g, 79% yield) as a yellow solid. Next, this newly formed alcohol was taken up in MeCN (2 mL) and a solution of HCl (4.0 M in dioxane, 0.133 mL) was then added at 25 0C to obtain a final acid concentration of 0.2 M. The resultant solution was stirred at 25 0C for 2 h. Upon completion, the reaction contents were diluted with EtOAc
(10 itiL), poured into water (10 mL) , and extracted with EtOAc (3 x 10 mL) . The combined organic layers were then washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL) , dried (MgSO4 ) , and concentrated. The resultant crude material was purified by flash column chromatography
(silica gel, hexanes : EtOAc , 3:2) to afford the desired hydroxyketone (0.037 g, 33% yield) as a white amorphous solid. Finally, BBr3 (1.0 M in CH2Cl2, 0.140 mL, 0.140 mmol, 8.0 equiv) was added to a solution this newly formed intermediate (0.021 g, 0.017 mmol, 1.0 equiv) in CH2Cl2 (0.5 mL) at -78 0C, and the reaction was stirred at -78 0C for 30 min. Upon completion, the reaction mixture was quenched at -78 0C with water (1 mL) , warmed to 25 0C, poured into water (10 mL) , and extracted with EtOAc (2 x 10 mL) . The combined organic layers were then washed with brine (10 mL) , dried (MgSO4) , and concentrated. The resultant crude yellow solid was triturated with CH2Cl2 (3 x 1 mL) to afford a 1:1 diastereomeric mixture of helisterculin A (4, 8.8 mg, 92% yield, 12% overall yield from 17) as a white solid. [Note: some decomposition was observed on silica gel]. 4: Rf = 0.50 (silica gel, CH2Cl2 :MeOH, 4:1); IR (film) {max 3412, 2918, 1701, 1627, 1521, 1438, 1284, 1165, 1066, 816 cm-1; 1H NMR (400 MHz, acetone-d6) δ 7.64 (br s, 4 H), 7.34 (d, J" = 15.6 Hz, 1 H), 6.85 (dd, J" = 7.0, 1.8 Hz, 1 H), 6.82 (br s, 1 H), 6.79 (d, J = 2.0 Hz, 1 H), 6.74 (d, J = 8.0 Hz, 1 H), 6.70 (d, J" = 8.0 Hz, 1 H), 6.66 (dd, J = 8.2, 1.8 Hz, 1 H), 6.61 (dd, J" = 8.0, 2.0 Hz, 1 H), 6.12 (d, J" = 15.6 Hz, 1 H), 5.18 (dd, J = 8.6, 4.6 Hz, 1 H), 3.82 (d, J = 2.4 Hz, 1 H), 3.78 (d, J = 3.2 Hz, 1 H), 3.68 (s, 3 H), 3.59 (s, 3 H), 3.56 (dd, J = 7.2, 2.0 Hz, 1 H), 3.46 (dd, J = 7.2, 2.4 Hz, 1 H), 3.17 (dd, J = 6.6, 2.6 Hz, 1 H), 3.07 (dd, J = 14.6, 4.6 Hz, 1 H), 3.00 (dd, J = 14.2, 5.4 Hz, 1 H); 13C NMR (75 MHz, acetone-d6) δ 207.3, 175.1, 171.0, 166.9, 146.2, 146.1, 145.3, 143.5, 141.6, 138.1, 134.1, 129.0, 121.9, 121.1, 118.4, 117.7, 116.7, 116.4, 116.3, 74.5, 70.2, 57.7, 52.7, 52.7, 49.6, 44.2, 43.5, 37.8; HRMS (FAB) calcd for C29H29Oi2 [M+H+] 569.1659, found 569.1656. All spectroscopic data for this synthetic material match those reported by Tezuka and co-workers for natural helisterculin A (4) ; see Table S3 at the end of this section for a direct comparison [Ia] .
51. Thiocarbonyl diimidazole (0.069 g, 0.389 mmol, 6.0 equiv) and 4-DMAP (0.012 g, 0.097 mmol, 1.5 equiv) were added sequentially to a solution of alcohol 35 (0.030 g, 0.065 mmol, 1.0 equiv) in CH2Cl2 (1 mL) at 25 0C, and the reaction mixture was stirred at 40 0C in a sealed tube for 48 h. Upon completion, the reaction contents were poured into saturated aqueous NH4Cl (15 mL) and extracted with EtOAc (2 x 10 mL) . The combined organic layers were then washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL) , dried (MgSO4) , and concentrated. The resultant thick orange oil was purified by flash column chromatography (silica gel, hexanes : EtOAc , 2:3) to afford compound 51 (0.032 g, 91% yield) as a white amorphous solid. 51: Rf = 0.17 (silica gel, hexanes : EtOAc , 3:7); 1H NMR (500 MHz, CDCl3) δ 7.73 (s, 1 H), 7.39 (d, J = 16.0 Hz, 1 H), 7.18 (s, 1 H), 6.82 (m, 2 H), 6.73 (m, 2 H), 6.61 (d, J = 8.5 Hz, 1 H), 6.07 (d, J = 16.0 Hz, 1 H), 5.21 (d, J = 3.0 Hz, 1 H), 3.94 (dt, J- = 15.0, 3.0 Hz, 1 H) , 3.81 (s, 3 H) , 3.79 (s, 3 H) , 3.78 (s, 3 H) , 3.71 (s, 3 H) , 3.71 (m, 1 H) , 3.68 (s, 3 H) , 3.42 (s, 3 H) , 3.35 (d, J = 7.5 Hz, 1 H) , 3.10 (s, 3 H) .
52. Oxygen gas passed through a drying tube was bubbled into a solution of 51 (5.0 mg, 0.009 rtimol, 1.0 equiv) , Et3B (1.0 M in hexanes, 0.046 mL, 0.046 mmol, 5.0 equiv) and n- Bu3SnH (0.012 mL, 0.046 mmol, 5.0 equiv) in CH2Cl2 (1 mL) at 0 0C for 30 min. The resultant solution was then stirred at 0 0C for an additional 30 min. Upon completion, the reaction was quenched with 1 M aqueous HCl (10 mL) and extracted with EtOAc (2 x 10 mL) . The combined organic layers were then washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL) , dried (MgSO4) , and concentrated. The crude was purified by flash column chromatography (silica gel, hexanes : EtOAc , 2:3) to afford compound 52 (3.5 mg, 72% yield) as a white amorphous solid. 52: Rf = 0.14 (silica gel, hexanes : EtOAc , 3:7); 1H NMR (500 MHz, CDCl3) δ 7.51 (s, 1 H), 7.37 (d, J = 15.5 Hz, 1 H), 6.87 (m, 2 H), 6.83 (s, 1 H), 6.80 (s, 1 H), 6.73 (d, J = 7.0 Hz, 1 H), 6.69 (d, J = 8.0 Hz, 1 H), 6.05 (d, J = 15.5 Hz, 1 H), 4.77 (d, J = 3.0 Hz, 1 H), 3.82 (s, 3 H), 3.78 (s, 3 H), 3.77 (m, 2 H), 3.76 (s, 3 H), 3.71 (m, 2 H), 3.67 (s, 3 H), 3.42 (s, 3 H), 3.34 (d, J- = 6.0 Hz, 1 H), 3.17 (s, 3 H).
Xanthatθ Ester 53. NaH (60% dispersion in mineral oil, 0.086 g, 2.16 mmol, 5.0 equiv) and carbon disulfide (1 mL) were added in single portions to a solution of alcohol 35 (0.200 g, 0.432 mmol, 1.0 equiv) in THF (4 mL) at 0 0C, and the resultant mixture was stirred at 0 0C for 30 min. MeI (1 mL, gross excess) was then added and the reaction contents were stirred at 40 0C for an additional 15 h. Upon completion, the reaction mixture was diluted with ether (20 mL) , extracted with saturated aqueous NH4Cl (20 mL) , dried (MgSC>4) , and concentrated. The crude was purified by flash column chromatography (silica gel, hexanes : EtOAc , 7:3) to afford xanthate ester 53 (0.225 g, 94% yield) as a yellow amorphous solid. 53: Rf = 0.59 (silica gel, hexanes : EtOAc , 3:7); 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 16.0 Hz, 1 H), 7.03 (d, J = 2.0 Hz, 1 H), 6.85 (d, J = 9.2 Hz, 1 H), 6.78 (d, J = 8.4 Hz, 1 H), 6.77 (d, J" = 6.8 Hz, 1 H), 6.03 (d, J = 16.0 Hz, 1 H), 5.48 (d, J = 3.2 Hz, 1 H), 3.93 (s, 3 H), 3.84 (s, 3 H), 3.77 (s, 3 H), 3.66 (m, 1 H), 3.64 (s, 3 H), 3.53 (dt, J = 5.6, 3.2 Hz, 1 H), 3.43 (s, 3 H), 3.30 (d, J = 6.4 Hz, 1 H), 3.13 (s, 3 H), 2.23 (s, 3 H).
Thiol 54. A solution of 53 (0.027 g, 0.049 mmol, 1.0 equiv) , AIBN (0.032 g, 0.195 mmol, 4.0 equiv) , H-Bu3SnH (0.078 mL, 0.293 mmol, 6.0 equiv) and PhSeSePh (0.061 g, 0.195 mmol, 4.0 equiv) in freshly degassed wet toluene (2 mL) was stirred in a sealed tube at 80 0C for 15 min. Upon completion, the reaction contents were concentrated directly and purified by flash column chromatography (silica gel, hexanes : EtOAc , 4:1) to afford thiol 54 (0.021 g, 84% yield) which was recrystallized from hexanes : Et2O (1:1). 54: Rf = 0.59 (silica gel, hexanes : EtOAc , 3:7); 1H NMR (500 MHz, CDCl3) δ 7.35 (d, J = 15.5 Hz, 1 H), 6.98 (d, J = 7.0 Hz, 1 H), 6.97 (s, 1 H), 6.77 (d, J = 8.0 Hz, 1 H), 6.68 (d, J" = 7.0 Hz, 1 H), 6.02 (d, J" = 15.5 Hz, 1 H), 4.32 (dd, J = 11.5, 8.5 Hz, 1 H), 4.03 (dd, J" = 8.0, 7.0 Hz, 1 H), 3.90 (s, 3 H), 3.83 (s, 3 H), 3.81 (m, 1 H), 3.76 (s, 3 H) , 3.71 (app s, 1 H) , 3.60 (s, 3 H) , 3.57 (dd, J = 7.0, 1.5 Hz, 1 H) , 3.51 (s, 3 H) , 3.22 (m, 1 H) , 3.20 (s, 3 H) , 3.19 (m, 1 H) , 1.69 (dd, J = 10.5, 9.0 Hz, 1 H) .
Hβterocyclβ 55. HCl (4.0 M in dioxane, 0.1 mL) was added to a solution of thiol 54 (4.0 mg, 0.008 inmol, 1.0 equiv) in THF (0.5 mL) at 25 0C to obtain a final acid concentration of 0.7 M. The resultant solution was stirred at 25 0C for 3 h. The reaction contents were concentrated directly and purified by preparative TLC (silica gel, hexanes : EtOAc , 2:3) to afford heterocycle 55 (2.5 mg, 66% yield) as a thick colorless oil. 55: Rf = 0.69 (silica gel, hexanes : EtOAc , 3:7); 1H NMR (500 MHz, CDCl3) δ 7.41 (d, J = 15.5 Hz, 1 H), 6.96 (s, 1 H), 6.93 (d, J = 8.5 Hz, 1 H), 6.79 (d, J = 8.0 Hz, 1 H), 6.78 (d, J = 7.5 Hz, 1 H), 6.01 (d, J = 15.5 Hz, 1 H), 4.87 (AB, J = 29.5, 6.5 Hz, 2 H), 4.04 (d, J = 7.5 Hz, 1 H), 4.02 (app s, 1 H), 3.89 (s, 3 H), 3.84 (s, 3 H), 3.83 (m, 1 H), 3.77 (s, 3 H), 3.75 (d, J = 3.5 Hz, 1 H), 3.62 (s, 3 H), 3.41 (m, 1 H), 3.38 (s, 3 H) , 3.25 (d, J = 7.5 Hz, 1 H) .
Thiocarbonyl 56. A solution of 53 (0.030 g, 0.054 mmol, 1.0 equiv), AIBN (0.011 g, 0.065 mmol, 1.2 equiv), Ti-Bu3SnH (0.019 mL, 0.109 mmol, 3.0 equiv) and PhSeSePh (0.022 g, 0.072 mmol, 2.0 equiv) in freshly degassed toluene (1 mL) was stirred in a sealed tube at 80 0C for 3 h. Upon completion, the reaction contents were concentrated directly and purified by. flash column chromatography (silica gel, hexanes : EtOAc , 4:1) to afford recovered 53 (0.027 g) alongside 56 (2.0 mg, 7% yield, 72% yield based on recovered starting material) as a colorless solid. 56: Rf = 0.49 (silica gel, hexanes : EtOAc , 3:7); 1H NMR (500 MHz, CDCl3) δ 7.48 (s, 1 H), 7.35 (d, J = 16.0 Hz, 1 H), 6.98 (d, J" = 2.0 Hz, 1 H), 6.93 (d, J" = 8.5 Hz, 1 H), 6.78 (d, J" = 8.0 Hz, 1 H), 6.70 (d, J = 6.5 Hz, 1 H), 6.03 (d, J = 16.0 Hz, 1 H), 4.77 (app s, 1 H), 3.89 (s, 3 H), 3.85 (s, 3 H), 3.84 (m, 1 H), 3.78 (s, 3 H), 3.76 (m, 1 H), 3.62 (s, 3 H), 3.60 (d, J = 6.5 Hz, 1 H), 3.48 (s, 3 H), 3.30 (d, J = 6.5 Hz, 1 H) , 3.12 (s, 3 H) .
Boronate 57. Oxygen gas passed through a drying tube was bubbled into a solution of 53 (8.0 mg, 0.014 mmol, 1.0 equiv) and Et3B (1.0 M in hexanes, 0.087 mL, 0.087 mmol, 6.0 equiv) in CH2Cl2 (1 mL) at 0 0C for 30 min. The resultant solution was then stirred at 25 0C for an additional 48 h under an O2 atmosphere. Upon completion, the reaction contents were concentrated directly and purified by preparative TLC (silica gel, hexanes : EtOAc , 2:3) to afford recovered 53 (5.0 mg) alongside boronate 57 (2.0 mg, 29% yield, 75% yield based on recovered starting material) as a colorless solid. 57: Rf = 0.58 (silica gel, hexanes : EtOAc ,
3:7); 1H NMR (500 MHz, CDCl3) δ 7.35 (d, J = 15.5 Hz, 1 H), 7.00 (d, J = 2.0 Hz, 1 H), 6.91 (d, J = 8.0 Hz, 1 H), 6.78 (d, J" = 8.5 Hz, 1 H), 6.69 (d, J" = 7.0 Hz, 1 H), 6.01 (d, J = 15.5 Hz, 1 H), 4.45 (d, J = 3.0 Hz, 1 H), 3.91 (app s, 1 H) , 3.86 (m, 2 H) , 3.85 (s, 3 H) , 3.77 (s, 3 H) , 3.72 (app s, 1 H) , 3.62 (s, 3 H) , 3.60 (dd, J = 7.5, 2.0 Hz, 1 H) , 3.46 (s, 3 H) , 3.41 (m, 1 H) , 3.25 (d, J = 7.0 Hz, 1 H) , 3.14 (S, 3 H) , 1.05 (app t, J = 7.0 Hz, 3 H) ; LRMS (FAB) calcd for C26H36BO9 [M+H+] 503.2, found 503.7.
-Λ, Phosphinatθ 58. Diphenylphosphinic chloride (0.020 mL, 0.108 mmol, 5.0 equiv) , Et3N (0.030 mL, 0.216 mmol, 10 equiv) and 4-DMAP (catalytic) were sequentially added to a solution of alcohol 35 (0.010 g, 0.022 mmol, 1.0 equiv) in 1,2-dichloroethane:THF (1:1, 1 mL) at 25 0C, and the resultant reaction mixture was stirred at 60 0C in a sealed tube for 48 h. Upon completion, the reaction contents were quenched with 1 M aqueous HCl (10 mL) and extracted with EtOAc (2 x 10 mL) . The combined organic layers were then washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL) , dried (MgSO4) , and concentrated. The crude was purified by flash column chromatography (silica gel, hexanes : EtOAc , 3:7) to afford phosphinate 58 (0.013 g, 89% yield) as a white amorphous solid. 58: Rf = 0.22 (silica gel, hexanes : EtOAc , 3:7); 1H NMR (300 MHz, CDCl3) δ 7.63 (m, 2 H), 7.49-7.32 (m, 5 H), 7.29 (d, J = 15.6 Hz, 1 H), 7.28- 7.18 (m, 2 H), 7.03-6.97 (m, 4 H), 6.60 (d, J = 7.5 Hz, 1 H), 6.57 (d, J = 6.9 Hz, 1 H), 5.96 (d, J = 15.6 Hz, 1 H), 4.57 (dd, J- = 12.0, 3.0 Hz, 1 H), 3.78 (m, 1 H), 3.77 (s, 3 H), 3.75 (s, 3 H), 3.74 (s, 3 H), 3.69 (app s, 1 H), 3.59 (s, 3 H), 3.56 (dd, J = 7.2, 2.1 Hz, 1 H), 3.43 (s, 3 H), 3.26 (d, J" = 6.9 Hz, 1 H), 3.11 (s, 3 H), 2.96 (dt, J = 6.9, 2.4 Hz, 1 H); LRMS (FAB) calcd for C36H40O10P [M+H+] 663.2, found 663.0.
Mesylate 59. Et3N (0.023 mL, 0.162 mmol, 15 equiv) and MsCl (0.008 mL, 0.108 mmol, 10 equiv) were added sequentially to a solution of alcohol 35 (5.0 mg, 0.011 mmol, 1.0 equiv) in THF (0.5 mL) at 0 0C, and the mixture was stirred at 25 0C for 6 h. The reaction contents were then concentrated directly and purified by preparative TLC (silica gel, hexanes : EtOAc , 2:3) to afford mesylate 59 (1.2 mg, 20% yield) as a white amorphous solid. 59: Rf = 0.41 (silica gel, hexanes : EtOAc , 2:3); 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J" = 16.0 Hz, 1 H), 7.08 (d, J" = 2.0 Hz, 1 H), 6.96 (d, J = 8.0 Hz, 1 H), 6.81 (d, J = 8.4 Hz, 1 H), 6.64 (d, J" = 7.6 Hz, 1 H), 6.02 (d, J" = 16.0 Hz, 1 H), 4.56 (d, J" = 3.2 Hz, 1 H), 3.92 (s, 3 H), 3.86 (s, 3 H), 3.78 (s, 3 H), 3.76 (app s, 1 H), 3.62 (s, 3 H), 3.58 (dd, J = 7.4, 2.0 Hz, 1 H), 3.51 (s, 3 H), 3.48-3.30 (m, 4 H), 3.21 (s, 3 H), 2.28 (s, 3 H) .
Triflatβs 61 and 62. A solution of alcohol 35 (0.050 g, 0.108 mmol, 1.0 equiv) in pyridine (0.3 mL) was added dropwise over 10 min to a solution of Tf2O (0.073 mL, 0.432 mmol, 4.0 equiv) in pyridine (0.7 mL) at 0 0C. The resultant reaction mixture was stirred at 25 0C for 1 h and then at 35 0C for another 1 h. Upon completion, the reaction contents were diluted with EtOAc (20 mL) and washed repeatedly with 0.3 M aqueous HCl (10 mL) until the aqueous layer remained acidic. The organic layer was then washed with brine (10 mL) , dried (MgSO4), and concentrated. The resultant crude material was purified by flash column chromatography (silica gel, hexanes : EtOAc , 3:2) to afford recovered 35 (0.036 g) alongside 61 (8.0 mg, 13% yield, 22% yield based on recovered starting material) as a colorless solid and 62 (4.0 mg, 7% yield, 46% yield based on recovered starting material) as a colorless solid. 61: Rf = 0.58 (silica gel, hexanes : EtOAc , 2:3); 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J" = 16.0 Hz, 1 H), 7.12 (d, J = 8.4 Hz, 1 H), 7.10 (d, J = 2.0 Hz, 1 H), 6.98 (dd, J = 8.4, 1.6 Hz, 1 H), 6.68 (d, J = 7.2 Hz, 1 H), 6.00 (d, J" = 16.0 Hz, 1 H), 3.92 (s, 3 H) , 3.76 (s, 3 H) , 3.72 (d, J = 1.6 Hz, 1 H) , 3.64 (s, 3 H) , 3.61 (dd, J = 6.8, 2.8 Hz, 1 H) , 3.56 (s, 3 H) , 3.43 (d, J = 5.6 Hz, 1 H) , 3.34 (dd, J = 6.4, 2.0 Hz, 1 H) , 3.29 (dt, J = 6.8, 2.8 Hz, 1 H) , 3.12 (s,t 3 H) , 2.38 (d, J = 7.2 Hz, 1 H) ; LRMS (FAB) calcd for C24H27F3OnS [M+] 580.1, found 580.4.
62: Rf = 0.64 (silica gel, hexanes : EtOAc , 2 :3) ; 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J- = 16.0 Hz, 1 H) , 6.74 (d, J = 8.4 Hz, 1 H) , 6.73 (s, 1 H) , 6.63 (m, 2 H) , 6.18 (d, J = 16.0 Hz, 1 H) , 5.02 (d, J = 3.6 Hz, 1 H) , 3.94 (app s, 1 H) , 3.85 (s, 3 H) , 3.83 (s, 3 H) , 3.82 (s, 3 H) , 3.70 (s, 3 H) , 3.61 (d, J = 8.0 Hz, 1 H) , 3.32 (s, 3 H) , 3.30 (s, 3 H) , 3.18 (m, 1 H) , 2.36 (dd, J = 8.4, 1.6 Hz, 1 H) .
63. A solution of 1-Bu2AlOi-Pr (0.93 M in toluene) was prepared by adding i-PrOH (0.38 inL, 5.0 mmol, 1.0 equiv) dropwise to a commercial solution of 1-Bu2AlH (1.0 M in toluene, 5.0 mL, 5.0 mmol, 1.0 equiv) at 25 0C, and the resultant solution was stirred at 25 0C for 30 min until the evolution of H2 gas was no longer observed. Next, freshly prepared 1-Bu2AlOi-Pr (0.93 M in toluene, 0.028 mL, 0.026 mmol, 1.1 equiv) was added to a solution of ketone 21 (0.011 g, 0.024 mmol, 1.0 equiv) in toluene (0.5 mL) at 25 0C, and the reaction contents were stirred at 60 0C in a sealed tube for 48 h. Upon completion, the reaction mixture was concentrated directly and purified by preparative TLC (silica gel, hexanes : EtOAc , 3:2) to afford recovered 21 (7.0 mg) alongside 63 (2.0 mg, 17% yield, 46% yield based on recovered starting material) as a thick colorless oil. 63: Rf = 0.40 (silica gel, hexanes : EtOAc, 3:2); 1H NMR (500 MHz, CDCl3) δ 7.36 (d, J = 15.5 Hz, 1 H) , 6.83 (s, 1 H) , 6.80 (d, J = 8.0 Hz, 1 H) , 6.63 (d, J = 5.0 Hz, 1 H) , 6.10
(d, J = 15.5 Hz, 1 H) , 3.97 (dd, J- = 7.0, 3.5 Hz, 1 H) ,
3.94 (app s, 1 H) , 3.86 (s, 3 H) , 3.85 (s, 3 H) , 3.84 (m, 1 H) , 3.68 (s, 3 H) , 3.59 (dd, J = 6.5, 2.0 Hz, 1 H) , 3.49
(s, 3 H) , 3.45 (dd, J- = 7.0, 2.0 Hz, 1 H) , 3.35 (s, 3 H) , 3.30 (dd, J = 7.0, 2.0 Hz, 1 H) , 2.00 (app t, J = 6.5 Hz, 1 H) , 0.98 (s, 3 H) , 0.97 (s, 3 H) .
Analogues 64-80 were prepared according to the methods described hereinabove.
64. 1H NMR (CDCl3, 400 MHz): 8.06 (s, 1 H), 7.89 (s, 1 H),
7.38 (d, J = 15.6 Hz, 1 H), 6.82 (m, 1 H), 6.73 (m, 2 H), 6.62 (m, 1 H), 6.07 (d, J = 15.6 Hz, 1 H), 5.29 (d, J = 3.2
Hz, 1 H), 3.93 (m, 1 H), 3.81 (m, 1 H), 3.79 (s, 3 H), 3.78
(s, 3 H), 3.72 (s, 3 H), 3.69 (m, 1 H), 3.68 (s, 3 H), 3.47
(s, 3 H), 3.39 (m, 1 H), 3.12 (s, 3 H).
65. 1H NMR (CDCl3, 300 MHz): 8.38 (s, 1 H), 7.68 (s, 1 H), 7.03 (m, 3 H), 5.74 (d, J" = 6.6 Hz, 1 H), 5.23 (d, J = 3.3 Hz, 1 H), 3.67 (s, 3 H), 3.63 (s, 3 H), 3.29 (m, 1 H), 3.05 (s, 3 H), 2.98 (m, 1 H), 2.81 (s, 1 H), 2.49 (m, 4 H), 2.13 (m, 1 H) , 1.62 (m, 1 H) .
66. 1H NMR (CDCl3, 300 MHz): 8.30 (s, 1 H), 7.62 (s, 1 H), 7.03 (S, 1 H), 5.68 (d, J = 5.7 Hz, 1 H), 5.46 (d, J = 2.7 Hz, 1 H), 3.68 (s, 3 H), 3.63 (s, 3 H), 3.30 (m, 1 H), 3.25 (s, 3 H), 3.16 (s, 3 H), 2.82 (m, 2 H), 2.53 (m, 4 H), 2.09 (m, 1 H) , 1.51 (m, 1 H) . 67. 1H NMR (CDCl3, 400 MHz): 8.36 (s, 1 H), 7.65 (s, 1 H), 7.06 (s, 1 H), 5.91 (d, J = 6.4 Hz, 1 H), 5.23 (d, J- = 3.2 Hz, 1 H), 3.70 (s, 3 H), 3.29 (m, 1 H), 3.28 (s, 3 H), 3.05 (s, 3 H), 3.04 (s, 1 H), 2.90 (app s, 1 H), 2.54 (s, 1 H), 2.31 (m, 1 H) , 1.52 (m, 1 H) .
68. 1H NMR (CDCl3, 400 MHz): 8.29 (s, 1 H), 7.60 (s, 1 H), 7.03 (s, 1 H), 5.84 (d, J = 6.0 Hz, 1 H), 5.39 (d, J- = 3.2 Hz, 1 H), 3.71 (s, 3 H), 3.26 (m, 1 H), 3.25 (s, 3 H), 3.19 (s, 3 H), 2.92 (m, 2 H), 2.61 (s, 4 H), 2.31 (m, 1 H), 1.42 (m, 1 H) .
69. 1H NMR (CDCl3, 400 MHz): 7.39 (d, J = 15.6 Hz, 1 H), 7.15 (m, 2 H), 6.90 (s, 1 H), 6.72-6.67 (m, 5 H), 6.08 (d, J- = 15.6 Hz, 1 H), 5.39 (br s, 1 H), 5.31 (d, J = 3.6 Hz, 1 H), 3.91 (s, 3 H), 3.89 (m, 1 H), 3.71 (app s, 6 H), 3.70 (m, 1H), 3.68 (m, 1 H), 3.67 (s, 3 H), 3.52 (s, 3 H), 3.38 (s, 3 H), 3.20 (app s, 3 H), 3.18 (app s, 1 H) .
70. 1H NMR (CDCl3, 400 MHz): 7.37 (d, J- = 15.6 Hz, 1 H),
6.98 (m, 1 H), 6.86 (d, J- = 7.6 Hz, 1 H), 6.83 (d, J = 2.0
Hz, 1 H), 6.73 (d, J = 6.8 Hz, 1 H), 6.61 (d, J = 8.4 Hz, 1
H), 6.60 (m, 1 H), 6.03 (d, J- = 15.6 Hz, 1 H), 6.02 (m, 1
H), 4.78 (d, J- = 3.2 Hz, 1 H), 3.81 (s, 3 H), 3.79 (m, 1 H), 3.78 (s, 3 H), 3.74 (s, 3 H), 3.71 (m, 1 H), 3.69 (s, 3
H), 3.62 (m, 1 H), 3.41 (s, 3 H), 3.32 (d, J = 6.4 Hz, 1
H) , 3.17 (s, 3 H) .
71. 1H NMR (CDCl3, 400 MHz): 7.38 (d, J = 15.6 Hz, 1 H), 6.92 (m, 2 H), 6.80 (d, J = 8.4 Hz, 1 H), 6.73 (m, 2 H),
6.60 (d, J = 8.0 Hz, 1 H), 6.04 (d, J- = 15.6 Hz, 1 H), 6.01
(app s, 1 H), 5.31 (d, J = 2.8 Hz, 1 H), 3.91 (m, 1 H), 3.78 (s, 3 H), 3.77 (s, 3 H), 3.72 (m, 1 H), 3.69 (s, 3 H),
3.68 (m, 1 H), 3.67 (s, 3 H), 3.39 (s, 3 H), 3.34 (m, 1 H), 3.13 (m, 1 H) , 3.11 (s, 3 H) .
72. 1H NMR (CDCl3, 400 MHz) : 7.36 (d, J- = 15.6 Hz, 1 H), 6.89 (d, J = 1.6 Hz, 1 H), 6.73 (m, 3 H), 5.98 (d, J = 15.6 Hz, 1 H), 5.32 (d, J- = 2.8 Hz, 1 H), 4.11 (m, 1 H), 3.88 (s, 3 H), 3.87 (m, 1 H), 3.84 (s, 3 H), 3.76 (s, 3 H), 3.70 (s, 1 H), 3.67 (s, 3 H), 3.58 (dd, J = 7.2, 1.6 Hz, 1 H), 3.47 (m, 1 H), 3.33 (s, 3 H), 3.31 (m, 2 H), 3.09 (s, 3 H), 2.57 (m, 1 H), 1.40-1.52 (m, 3H), 1.19-1.10 (m, 2 H).
73. 1H NMR (CDCl3, 400 MHz): 8.33 (s, 1 H), 7.64 (s, 1 H), 7.05 (s, 1 H), 5.71 (d, J = 6.4 Hz, 1 H), 5.51 (d, J = 2.8 Hz, 1 H), 5.21 (d, J = 3.2 Hz, 1 H), 4.99 (sept, J = 6.4 Hz, 1 H), 3.72 (s, 3 H), 3.31 (m, 1 H), 3.30 (s, 3 H), 2.89 (s, 1 H), 2.79 (dd, J = 7.6, 1.6 Hz, 1 H), 2.56 (s, 4 H), 2.11 (m, 1 H), 1.52 (m, 1 H), 1.28 (m, 6 H).
74. 1H NMR (CDCl3, 400 MHz): 7.76 (s, 2 H), 7.41 (d, J- = 16.0 Hz, 2 H), 7.20 (s, 2 H), 6.87-6.76 (m, 12 H), 6.65 (d, J = 8.4 Hz, 2 H), 6.11 (d, J- = 16.0 Hz, 1 H), 6.10 (d, J = 16.0 Hz, 1 H), 5.35 (dd, J- = 7.6, 5.2 Hz, 2 H), 5.24 (d, J = 3.6 Hz, 2 H), 3.97-3.94 (m, 2 H), 3.91 (s, 3 H), 3.91 (s, 3 H), 3.90 (s, 3 H), 3.89 (s, 3 H), 3.86-3.81 (m, 2 H), 3.82 (s, 6 H), 3.78 (s, 3 H), 3.76 (s, 3 H), 3.74 (s, 6 H),
3.69 (s, 3 H), 3.64 (s, 3 H), 3.59 (t, J- = 2.8 Hz, 2 H), 3.46 (s, 6 H), 3.40-3.35 (m, 2 H), 3.25-3.15 (m, 4 H), 3.12 (s, 6 H) .
75. 1H NMR (CDCl3, 400 MHz) : 7.76 (s, 1 H), 7.41 (d, J = 15.6 Hz, 1 H), 7.20 (s, 1 H), 6.86 (br s, 2 H), 6.76 (br s, 2 H), 6.64 (d, J = 8.4 Hz, 1 H), 6.09 (d, J = 16.0 Hz, 1 H), 5.93-5.85 (m, 1 H), 5.32 (d, J = 1.6 Hz, 1 H), 5.29- 5.23 (m, 2 H), 4.59 (dd, J = 6.0, 4.8 Hz, 2 H), 3.98-3.66 (m, 1 H), 3.85 (s, 1 H), 3.81 (s, 6 H), 3.74 (s, 3 H), 3.74-3.70 (m, 1 H), 3.45 (s, 3 H), 3.39 (d, J = 6.4 Hz, 1 H) , 3.13 (s, 3 H) .
76. 1H NMR (CDCl3, 400 MHz): 8.32 (s, 1 H), 7.62 (s, 1 H),
7.05 (s, 1 H), 5.89 (m, 1 H), 5.71 (m, 1 H), 5.50 (m, 1 H), 5.31 (m, 1 H), 5.28 (m, 2 H), 4.59 (m, 2 H), 3.71 (m, 4 H),
3.38 (m, 1 H), 3.30 (m, 4 H), 3.21 (s, 3 H), 3.29 (m, 2 H),
2.56 (m, 4 H), 2.50 (app s, 1 H) , 2.15 (m, 1 H), 1.52 (m, 1 H) .
77. 1H NMR (CDCl3, 400 MHz): 8.41 (s, 1 H), 7.71 (s, 1 H), 7.07 (s, 1 H), 5.77 (d, J = 2.8 Hz, 1 H), 5.27 (d, J = 2.6 Hz, 1 H), 4.08 (m, 2 H), 3.70 (s, 3 H), 3.32 (m, 1 H), 3.30 (s, 1 H), 3.08 (s,. 3 H), 2.91 (m, 1 H), 2.82 (s, 1 H), 2.52 (m, 1 H), 2.51 (s, 4 H), 2.13 (m, 1 H), 1.71-1.52 (m, 5 H), 1.32 (m, 3 H) .
78. 1H NMR (CDCl3, 400 MHz): 7.72 (s, 1 H), 7.69 (s, 1 H), 7.38 (d, J = 15.6 Hz, 1 H), 7.37 (d, J- = 15.6 Hz, 1 H), 7.15 (S, 2 H), 6.92-6.55 (m, 20 H), 6.23 (d, J = 16.0 Hz, 1 H), 5.92 (d, J = 15.6 Hz, 1 H), 5.36-5.32 (m, 2 H), 5.24- 5.20 (m, 3 H), 5.15 (dd, J = 8.4, 4.4 Hz, 1 H), 4.01-3.95 (m, 2 H), 3.95-3.55 (m, 4 H, buried signals), 3.89 (s, 9 H), 3.88 (s, 3 H), 3.86 (s, 6 H), 3.85 (s, 3 H), 3.82 (s, 3 H), 3.81 (s, 3 H), 3.77 (s, 3 H), 3.75 (s, 6 H), 3.70 (s, 3 H), 3.67 (s, 3 H), 3.43 (s, 3 H), 3.33 (s, 3 H), 3.20-3.13 (m, 4 ,H), 3.12 (s, 3 H), 3.08 (s, 3 H), 3.03-2.93 (m, 4 H). 79. 1H NMR (CDCl3, 400 MHz, 1:1 mix of diastereomers) : CDCl3 (400 MHz): 8.34 (s, 1 H), 7.62 (s, 1 H), 7.08 (s, 1 H), 5.76 (d, J = 8.4 Hz, 1 H), 5.42 (d, J = 3.6 Hz, 1 H), 3.71 (s, 9 H), 3.52 (m, 4 H), 3.31 (s, 3 H), 3.22 (s, 3 H), 3.20 (m, 1 H), 2.91 (m, 2 H), 2.61 (s, 4 H), 2.07 (m, 1 H), 1.50 (m, 1 H) .
80. 1H NMR (CDCl3, 400 MHz, 1:1 mix of diastereomers): CDCl3 (400 MHz): 8.41 (s, 1 H), 8.32 (s, 1 H), 7.72 (s, 1 H), 7.63 (s, 1 H), 7.09 (s, 1 H), 7.03 (s, 1 H), 6.48 (app t, J = 8.0 Hz, 1 H), 6.41 (app t, J = 7.6 Hz, 1 H), 6.18 (app t, J = 7.6 Hz, 1 H), 6.12 (app t, J = 8.0 Hz, 1 H), 5.51 (d, J = 3.6 Hz, 1 H), 5.31 (d, J" = 3.6 Hz, 1 H), 3.69 (s, 3 H), 3.68 (s, 3 H), 3.46 (m, 2 H), 3.31 (s, 3 H), 3.28 (s, 3 H), 3.26 (s, 3 H), 3.13 (s, 3 H), 3.05 (m, 2 H), 2.98 (m, 1 H), 2.91 (m, 1 H), 2.20 (m, 2 H), 1.72 (m, 1 H), 1.63 (m, 1 H).
TableSl.NMRSpectralDataComparison ofNatural and SyntheticHelisorin(3); CouplingConstants (J) inHz.
Figure imgf000256_0001
TableS2.NMRSpectralDataComparisonofNaturaland SyntheticHelicterinB (2);Coupling Constants (J) inHz.
Figure imgf000257_0001
Figure imgf000258_0001
Table S3 NMR Spectral Data Comparison ofNatural and Synthetic Helisterculin A (4), Coupling Constants (J) in Hz
Figure imgf000259_0001
Results and Discussion
In efforts to temper the latter of the reactivity issues desribed in the background of the invention by using an orfcήo-quinone monoketal as a surrogate for the needed diene as provided upon oxidation of model compound 14 by PhI(OAc)2 in MeOH, the resultant molecule underwent a Diels-Alder- based homodimerization that afforded 15 in 87% yield no matter how many equivalents of dienophile 13 were present in solution [7] (see Figure 3). Only through major structural alteration, such as removal of the conjugated olefin and the use of a smaller dienophile, were it possible to achieve direct [4+2] reactions, though, as illustrated with a reaction between acrylonitrile and the oxidized form of 16, the resultant products (such as 17) possessed regiochemistry opposite that found in the helicterin family. The regiochemistry of this product matches that reported by several other investigators [8] . In the same vein, attempts to achieve controlled radical- based dimerizations of 14 using single-electron transfer (SET) reagents, such as AgOAc, consistently led to a combinatorial array of products from which only dihydrofuran 18, which is a known oxidation product of methyl ferulate [10] , has been isolated and characterized. Despite the absence of control in endeavors to dimerize this substrate, others have reported a number of instances where high levels of selectivity can be achieved using SET agents [9] .
Overarching Synthetic Approach and Initial Model Studies Given the inability to temper the reactive pathways of model compounds related to rosmarinic acid (5, Figure 4) , it was wondered whether the varied architectural complexity of the helicterin family could be controllably accessed from a different starting material. Such an idea was inspired by previous studies with the resveratrol-based collection of natural products where exposure of a common precursor, one distinct from Nature's building block, to a variety of simple reagents enabled creation of a variety of structurally unique natural products and analogs with complete selectivity [11] . Specifically, it was postulated that 19, a fully functionalized form of the Diels-Alder homodimer (15) discussed above, could constitute that starting material based on the notion that it could be funneled into a protected version of the desired core structure (8, cf. Figure 2) by heating it at a high enough temperature in the presence of the requisite dienophile (9). In other words, it was hypothesized that the Diels- Alder reaction modeled earlier with phenol 14 provided a kinetic outcome (i.e. 15), while the desired product (21, Figure 5) might represent a thermodynamic sink reachable by breaking apart that material (15) through a retro Diels- Alder reaction and inducing its participation in a [4+2]- cycloaddition reaction with dienophile 13. Examples of the reaction concept using masked ortλo-benzoquinones have been described. It is important to note that in all these examples, only mono-substituted dienophiles were employed; none has explored a substrate as complex as that reported here. Also, the regiochemistry observed in these cases is in line with that observed for compound 17 [12] .
Given this idea, this model system was re-explored, and pleasingly, compound 21 was produced in 83% yield based on recovered starting material (43% isolated yield) following
30 min of heating a mixture of 15 and 13 at 220 0C in mesitylene in a sealed tube; its structure was verified by- X-ray crystallographic analysis. As shown in Table 1, this unique retro Diels-Alder/Diels-Alder sequence was not effectively promoted by microwave radiation irrespective of reaction solvent (entries 1-3), did not appear to benefit from any "on-water" effect under thermal activation (entry 4 and entry 6 versus entry 7) [13], and required slightly more than 5 equivalents of dienophile to obtain a maximal yield (entries 7-11) . It also required significant activation as no product was observed under thermal conditions if the reaction temperature was below 160 0C. As such, the general harshness of this protocol appears to implicate the role of an enzyme if Nature employs a direct Diels-Alder reaction in her synthetic approach to these neolignans, as a retro-based pathway would be highly unlikely. At a strategic level, however, the outcome validated the general concept of using 19 (Figure 4) as a starting material to fashion 1-4.
Table 1. Screening of conditions to form Diels-Alder product 21.
Figure imgf000263_0001
Entry Heating Conditions source μwave EtOH, 200 °C, 5 min, 5.0 equiv 13 0 μwave ethylene glycol, 210 °C, 10 min, 5.0 equiv 13 16 μwave toluene/APrOH, 190 °C, 35 min, 5.0 equiv 13 11 oil batha H2O/LiCI, 160 °C, 60 min, 5.0 equiv 13 23 oil batha DMA, 220 °C, 30 min, 5.0 equiv 13 26 oil batha mesitylene/H2O, 220 °C, 30 min, 5.0 equiv 13 34 oil batha mesitylene, 220 °C, 30 min, 5.0 equiv 13 40 oil batha mesitylene, 220 °C, 30 min, 3.3 equiv 13 33 oil bath" mesitylene, 220 °C, 30 min, 6.7 equiv 13 43
10 oil batha mesitylene, 220 °C, 30 min, 10 equiv 13 42
11 oil batha mesitylene, 220 °C, 30 min, 20 equiv 13 44 a Reaction performed in a sealed tube. DMA = N.N-dimethylacetamide
From this new compound (21, Figure 5), performance of an additional model study was sought, namely a search for conditions that could achieve a Friedel-Crafts-like union between C-6 and the C-4' carbonyl as required to create the core of helisorin (3) . Compound 21 was exposed to a variety of protic acids in an array of reaction solvents (such as HCl or TFA in wet THF and p-TsOH in acetone) in hopes of effecting both acetal cleavage as well as the desired C-C bond construction. However, the starting material was consistently recovered in near quantitative yield from all these experiments. Fortunately, select Lewis acids provided the needed activation. For instance, controlled exposure of 21 to 6 equivalents of BF3-OEt2 in CH2Cl2 at 0 0C, followed by slow warming to ambient temperature and 16 h of additional stirring, accomplished the desired event in 82% yield. Others, such as FeCl3-SiO2 [14], also provided 23, but in significantly reduced yield (13%). Mechanistically, it was postulate that this step leading to 23 proceeded via initial Friedel-Crafts cyclization (generating intermediate 22) , followed by acetal cleavage. This statement is not based on the direct observation or isolation of any 22. Rather, it reflects the fact that when the putative diketone intermediate (24) that would arise from the alternate order of events was exposed separately to the same reaction conditions involving BF3-OEt2, only the unique rearranged adduct 25 was obtained. The structure of 25 was confirmed by X-ray crystallographic analysis. As indicated below, it is believed that the formation of this product follows a Pinacol-like mechanism, with slightly different pathways depending upon whether the sequence commences with 23 or 24 .
Figure imgf000264_0001
Moreover, 23 could be converted into the same material only- through far more forcing conditions (20 equivalents of BF3«OEt2) . As a final and more general note, if more powerful Lewis acids were employed in attempts to convert 21 into 23, unexpected reaction products were typically obtained; for instance, the use of 6 equivalents of BBr3 at -78 0C in CH2Cl2 smoothly provided halogenated intermediate 26 in 82% yield. The existence of such bromoacetals has been documented previously [15] . Several other Lewis acids, such as In(OTf)3, TiCl4 and Me2AlCl in CH2Cl2 at 25 0C, did not induce any reactions with 21 despite several hours of stirring and their use in superstoichiometric amounts (10- 15 equivalents).
Protecting Group Selection, Synthesis of Fully Functionalized Starting Materials, and Total Synthesis of Helisorin (3)
Although the above studies were promising in revealing that the core motifs of at least one of the target molecules could be accessed (i.e. 3), the main issue for their translation to fully functional materials was the identification of an appropriate protecting group for the phenols. Though such an issue is a standard concern for any synthetic plan [16], these natural products, and the developed conditions up to this point for the critical C-C bond constructions, presented a unique array of combined challenges. First, under no circumstance could the chosen protecting group require aqueous acid to cleave as such conditions could rupture the acetal linkage in the two helicterins (1 and 2) ; aqueous base would presumably be just as deleterious as it could hydrolyze the ester linkages within all the target molecules and/or racemize their chiral centers. Moreover, given the oxidation potential of the 3 , 4-diphenoxy ring systems within all of the targets (each was isolated from the plant extracts in less than 30 min in a cold room; ambient temperatures, light, and oxygen caused their decomposition) , every member of the phenol protecting group array would have to be cleaved quickly and cleanly so as to avoid over- manipulation of the final product, especially during purification. Finally, based on a series of additional model studies (not shown) , it became evident that both the Diels-Alder reaction leading to 21, as well as the Friedel- Crafts reaction that afforded 24 (cf. Figure 5), required an electron-donating protecting group to proceed.
Given these collated criteria, it was anticipated that the ideal protective group would likely need to be an ether, one with just the right balance of stability versus reactivity so as to be able to survive exposure to stoichiometric amounts of mild Lewis acids (such as BF3»OEt2) at 25 0C over several hours, but which could be ruptured quickly in the presence of more powerful Lewis acids (such as BBr3) at much lower temperatures. Based on literature precedent, benzyl ethers appeared ideal in this regard [17] ; however, simple model studies (not shown) quickly demonstrated that this group was sensitive to prolonged exposure to BF3^OEt2. Thus, substituted benzyl ethers were explored, in hopes that the addition of a mildly electron withdrawing group, such as a p-CF3 group, which has a σ value of 0.54 as determined by a known method [18] and the reactivity of which has previously been explored [19] , could deactivate the protecting group enough to survive exposure to BF3»OEt2 while still permitting the Diels-Alder and Friedel-Crafts reactions to succeed. While p-CF3-benzyl ethers have been used to protect aliphatic alcohols on a select number of occasions, they have never been employed to protect phenols .
This conjecture was tested by preparing the differentially protected rosmarinic acid derivatives 27 and 32 as shown in Figure 6. Starting from commercially-available 5, initial chemoselective methylation of its free carboxylic acid was achieved through treatment with 0.95 equivalents of TMSCH2N2 and was followed by a subsequent alkylation of the four phenol residues using p-CF3-benzyl bromide under Finkelstein. conditions. Elements of the sequence leading to this piece were inspired by the work of O'Malley et al [20] . These operations completed the synthesis of 27 in 84% overall yield. Methanolysis of the internal ester linkage within this new product then provided both 28 and 29, the latter of which was coupled with carboxylic acid 31 under standard conditions (EDC, 4-DMAP, CH2Cl2, 25 0C) to afford, following silyl ether cleavage, the differentially-protected intermediate 32. These operations set the stage to explore the key sequence of steps that would hopefully lead to a total synthesis of helisorin (3) .
As indicated in Figure 7, the first of these operations, oxidative homodimerization of 32 via a Diels-Alder reaction, proceeded quickly and cleanly in near quantitative yield (99%) with PhI(OAc)2 in MeOH at 25 0C. Next, in a test of the robustness of the retro Diels- Alder/Diels-Alder sequence that worked so effectively in model systems, this intermediate (33) was then heated in mesitylene in a sealed tube at 220 0C in the presence of 6.7 equivalents of dienophile 27, and the desired Diels- Alder product (34) was obtained in 71% yield based on recovered 27. Interestingly, though both fragments contained a single chiral center, this new product (34) was generated as a 1:1 mixture of diastereomers, indicating that such stereochemical information was too remote to control the facial presentation of the two partners in this key event. Again, such an outcome supports the intervention of an enzyme in Nature's synthesis of such a framework if a Diels-Alder reaction [21] is involved, since only a single natural product enantiomer has been isolated thus far. Recently, some very unique approaches have been developed to create chiral masked ortho-benzoquinones that could conceivably afford a diastereoselective solution to this key step [22] .
Given the uncertainty regarding some of the stereochemistry of the final natural products as mentioned in the Background, the two Diels-Alder diastereomers (34) were- separated at this stage via standard column chromatography, and then subjected separately to BF3»OEt2 in hopes of creating the remaining C-C bond of the helisorin core. Fortunately, this step proceeded smoothly in 82% yield based on recovered 34 if the original model conditions (BF3»OEt2 in CH2Cl2) were slightly adjusted in terms of solvent and water content (benzene and 5 equivalents of added water) . Finally, controlled exposure to BBr3 in CH2Cl2 at -78 0C quickly and cleanly cleaved all six p-CF3- benzyl ethers in 30 min, providing a synthetic sample of 3 in 77% yield that was identical to naturally-derived helisorin (3) in all respects (1H and 13C NMR, IR, HRMS, αD) . As such, the first laboratory synthesis of this neolignan was complete and a definitive assignment of this molecule's relative stereochemistry and the connection of the family to 5 and/or 6 could finally be made. As a concluding note for this synthesis, if the final deprotection was stirred for prolonged periods (greater than 1 h) , executed at reaction temperatures above -50 0C, and/or left unprotected from atmospheric oxygen and light (especially upon purification) , significant decomposition was observed.
Final isolations of each synthetic natural product were handled with extreme care so as to minimize exposure to heat and air. Typically, upon completion of the BBr3- induced deprotection, the reaction would be quenched while still cold, quickly engaged in an extractive work-up, and concentrated via rotary evaporation using an ice-cold water bath (all performed in less than 5 min) . The crude product was then loaded onto a preparative TLC plate, with the separation performed in the dark using an argon-purged chamber and degassed solvents (typically in less than 30" min) .
Total Synthesis of Helicterin B (2)
With these successes in hand, the most complex members of the family, helicterins A and B (1 and 2) , beginning with model studies seeking to create the acetal core of these rosmarinic acid tetramers, were targeted next. The initial goal was to convert compound 21 into either hydroxyketone
40 or hydroxyketal 42 (Figure 8) given literature precedent indicating that such systems in [2.2.1] -bicyclic frameworks could be induced to dimerize simply upon standing or upon exposure to anhydrous acids [23] . As such, efforts began with attempts to achieve a stereoselective reduction of the ketone within 21 to generate 42 directly. Unfortunately, no condition screened, including several that can accomplish such a reaction in [2.2.1] -systems (such as Meerwein-Pondorff-Verley reduction, samarium-based reducing agents, or NaBH4ZCeCl3) [24] , rose to the occasion. Instead, 35 was formed consistently, and proved resistant to all efforts at inversion (either under standard Mitsunobu conditions or attempted displacement of a triflate with KO2 or NaNO2) [25] . The same inversion challenge was also observed with hydroxyketone 36, formed from 35 in 86% yield via its controlled exposure to aqueous HCl in toluene at 0 0C.
As such, an indirect approach to 40 and 42 was developed wherein 35 was first exposed to 0.5 M HCl in a more polar solvent (THF) to effect both acetal cleavage as well as an equilibrative rearrangement which ultimately provided hydroxyketone 37, the core of the natural product helisterculin A (4) . This compound, formed in 84% yield, was the most likely of the four possible hydroxyketone isomers to be produced based on the mechanism drawn in Figure 8, since it would result from proton capture by enol 38 from the least hindered face [26] at the most accessible position; it also happens to be the most thermodynamically stable (1.7 kcal/mol) based on DFT calculations. These calculations were performed at the DFT-B3LYP(1) /6-31+G* level in acetonitrile and THF continuum solvents. All four possible isomers were subjected to conformational searching within MacroModel 6.0 using the OPLS 2001 force field. The lowest energy structures for each possible isomer were then optimized in the gas phase at the B3LYP/6-31+G* level within Jaguar 7.0. Single-point solvation calculations, including first-shell correction terms and activation energy, were then performed in acetonitrile and THF continuum solvents [27] .
From here, compound 39 was accessed via 1) directed reduction of the remaining ketone as mediated by Me4NBH(OAc)3, [28] 2) selective silyl protection of the resultant C-4 ' hydroxyl, and 3) oxidation of the remaining alcohol. Desilylation under basic conditions (TBAF, THF) then completed the synthesis of 40 in 76% yield, while controlled treatment of 39 with a solution of 0.5 M HCl in a 4:1 mixture of MeOH/CH (OMe) 3 led to 42 in 93% yield. It is important to note that in the latter of these two operations the added CH(OMe)3 ensured initial acetal formation followed by silyl ether cleavage, thereby preventing any equilibration back to 37 by way of an intermediate hydroxyketone .
At this juncture, it was expected that both compounds 40 and 42 would dimerize readily to generate the core of helicterin A (1) based upon the precedent mentioned above [23] . However, as quickly revealed by pilot experiments (Figure 9), no such facility was observed. Despite the facility of forming such dimers from [2.2.1] -bicyclic monomers, no examples of successfully employing [2.2.2]- systems exist. In fact, there are several examples that reveal failed attempts to forge such dimeric cores [29] . For instance, exposure of 42 to anhydrous HCl afforded only 44 (likely though a mechanism similar to the one leading to 37, vide supra), while treatment with acids such as CSA in toluene led to 44 alongside an unsymmetrical dimer (43, verified by X-ray crystallography) whose connectivity reflects the core structure of yunnaneic acid C [30] , a member of a related group of natural products. Similarly, heating 42 neat at 160 0C for several hours primarily generated 47, while efforts to dimerize hydroxyketone 40 under both acidic and basic protocols (NaH/THF or HCl/MeOH) delivered 43 exclusively in near quantitative yield (99%). Even efforts to utilize a more circuitous route, such as attempts to convert 44 into enol triflate 45 as part of an effort to generate a different dimerization precursor (i.e. epoxide 46) , were thwarted, in this case by the relative ease with which 45 underwent a retro Diels-Alder reaction upon its exposure to various Pd(II) sources in attempts to replace the triflate group with a hydrogen atom. Once again, as with the Friedel-Crafts reaction leading to helisorin (3, cf. Figure 7)., only a Lewis acid would prove capable of forging the requisite bond constructions . That reagent was BF3^OEt2, which delivered a model helicterin A core (48) in 79% yield when used in CH2Cl2 at 0 0C for 30 min. The structure of 48 was verified by X-ray- crystallography. Interestingly, exposure of hydroxyketone 40 to a number of different Lewis acids did not afford a helicterin A-like core.
Pleasingly, these explorations were readily transferred to fully functionalized intermediates, as compound 32 was smoothly advanced to intermediate 50 via the same reaction sequence as shown in Figure 10. The only major surprise came two steps later, as following the formation of the desired acetal core of helicterin A (1) with BF3^OEt2, subsequent exposure of the resultant product to BBr3 in CH2Cl2 not only cleaved all 12 p-CF3-benzyl ethers, but also led to the replacement of one of the methyl ethers in the acetal core with a hydroxyl group. As such, the first total synthesis of helicterin B (2) had been achieved. Thus far, all efforts to convert helicterin B (2) into helicterin A (1), such as exposure to anhydrous MeOH under acidic catalysis, have led solely to the recovery of 2. It was hypothesized that the difficulty in executing this conversion, as well as the general ease of forming 2 in the absence of obtaining even trace amounts of 1 in the final deprotection, emanates from the additional intramolecular hydrogen bond that is obtained from the exchange.
Total Synthesis of Helisterculin A (4)
As a final demonstration of the robustness and utility of the developed sequences, the remaining dimeric member of the family, helisterculin A (4) , was prepared using a number of the critical steps discussed earlier. As shown in Figure 11, the common dimeric starting material (33) was subjected to the same retro Diels-Alder/Diels-Alder cascade, this time using a different dienophile (28) to yield the bicyclic core of the target molecule. This intermediate was then subjected to reduction followed by an acid-catalyzed acetal cleavage and equilibrative rearrangement, as discussed above in the context of Figure 8, to afford the thermodynamic hydroxyketone product. Global phenol deprotection with BBr3 then smoothly converted this compound into the natural product (4) , completing the sequence in a final, overall yield of 42%.
An efficient approach capable of controllably accessing the major architectures within this neolignan family, culminating here in total syntheses of three natural products as well as providing the first route to the core of several others (the yunnaneic acids) , have been developed. In the process, the stereochemical ambiguities of the side-chains have been resolved and their connection to rosmarinic acid established. Each route proceeds in good overall yield, requiring 14 or fewer steps from commercially available materials. Key features of these sequences include some of the most complex retro Diels- Alder/Diels-Alder reactions to date, an unconventional protecting group to achieve the proper balance of chemical reactivity on sensitive scaffolds, several carefully developed reaction conditions that effectively balanced competing reaction pathways, and the illustration that Lewis acids were typically needed to accomplish the biomimetic steps of the sequence. This synthesis also reaffirms a synthetic principle previously expressed: diverse, oligomeric natural products can be easily accessed by way of common precursors that differ from Nature's presumed building block (i.e. 33) [10] . The intermediates described herein are useful for the synthesis of the structurally unique natural products helicterin B (2) , helisorin (3) , and helisterculin A (4) , which all have established inhibitory activity against avian myeloblastosis virus reverse transcriptase [1] .
Synthesis of Analogs
Beyond the importance of synthesizing the natural products themselves given their established biological activity, pathways to a number of analogs with which far broader biological screening through collaborative effort could be attempted are desirable. Additional monomeric and oligomeric neolignan analogs can be synthesized using the synthetic sequences described above. The requisite precursor used in the formation of the Diels-Alder homodimer may comprise carbogenic chains of various lengths and saturation between the phenyl ring and the carboxyl group, which may be in the form of a carboxylic acid or an ester. The precursor for the Diels- Alder homodimer may be obtained commercially with carbogenic chains of various lengths and saturation, as well as various substituents on the ester group already in place. However, when the desired precursors are not readily available, substituents can be installed on the phenyl ring of the molecule using standard aryl substitution reactions well known in organic synthesis and the ester may be formed using esterification or transesterfication reactions well known to the skilled artisan.
Furthermore, modifications can be made to the dienophile that is used in the retro-Diels-Alder step. For example, the desired 3-phenylacrylic acid or its ester may have various substituents on the phenyl ring as well as the ester. When the desired 3-phenylacrylic acid dienophile or ester thereof is not readily available, substituents are installed on the phenyl ring using standard aryl substitution reactions and the ester group can be formed using esterification or transesterfication reactions well known in organic synthesis.
It is also understood that the skilled artisan may choose a starting material having a specific chirality in order to arrive at a product having the desired chirality. For example, while the choice of naturally-occurring (R)- rosmarinic acid as a starting material results in the synthesis of natural helisorin, helicterin B, and helisterculin A as described above, the choice of (S)- rosmarinic acid as a starting material would result in the synthesis of non-natural stereoisomers of helisorin, helicterin B, and helisterculin A.
Nucleophilic substituents, such as hydroxyl, mercapto, and amino groups, may also be modified through nucleophilic substitution reactions by exposure to electrophilic compounds. For example, free hydroxyl groups may be alkylated by exposure to an alkyl halide or silylated by exposure to a trialkylsilyl halide or triflate.
Figures 12 and 13 provide examples of representative sequences that have been used thus far to create analogs 51-63. The majority of these sequences are based on standard functionalization chemistry, as well as some unique radical-based rearrangement to create a diversity of architectures [31] .
Similarly, compounds 64-80 (see Figures 15-20) are synthesized according to the respresentative sequences shown on Figures 12 and 13.
Preliminary Biological Screening
Screening structural analogs in PC12 cell-based alamar blue assay:
A mother plate of the hit compound and the structural analogs was prepared in a Greiner 384-well plate. In this mother plate, 50 μL of DMSO were added to the wells in the outer two rows while ten different concentrations of each compound in DMSO were added to the inner wells. To make the ten different dilutions of each compound, a 20 mg/mL stock solution of each compound was first prepared by dissolving 2.0 mg of the compound in 100 μL of DMSO. Each stock solution was then diluted down by a factor of 2 nine times using 50 μL of DMSO for each dilution to result in a 2-fold, 10 point dilution. Once the various concentrations of each compound were added to their respective wells, the mother plate was tightly sealed and thawed in a desiccator overnight .
For the PC12 screen, cell stock solutions for uninduced and induced PC12 cells were prepared with 3 rnL of trypsin to remove the cells from the surface of the container and 7 mL of PC12 cell media. These solutions were then further diluted so that the volume of cell stock solution delivered to each well in the assay plates would contain 7500 cells.
Using the Biomek (Figure 21), 2 μL of each compound solution from the mother plate were added to individual wells containing 98 μL of PC12 cell media in a Greiner deep well daughter plate for a 1:50 compound to cell media dilution. Immediately before preparation of the assay plates, 20 μL of tebufenozide was added to the induced cell stock solution. A protocol on the Biomek was then designed to add in triplicate 3 μL of compound from the daughter plate to assay plates with wells containing 57 μL of PC12 cell media, resulting in an overall 1:1000 dilution of compound to cell media. The assay plates were placed in the incubator (39°C, 9.5% CO2) for 48 hours. Using the Biomek, 20 μL of a solution of 40% alamar blue and 60% PC12 cell media were added to each well in every assay plate. The assay plates were then incubated (39°C, 9.5% CO2) for 16 hours. Each assay plate was read using the wsyAB setting on the plate reader.
As evidence for the value of this initial compound collection, preliminary screens of it, along with many of the molecules presented above, have revealed that compound 51 possesses the capability to rescue cells infected with the human huntingtin gene containing mutant polyglutamine repeats with no real cytotoxic effect on uninduced cells (see Figure 14) . Therefore, compound 51 is shown to be useful for reducing cell death in conditions where cells express mutant huntingtin genes, the expression of which result in mutant huntingtin proteins having abnormal numbers of N-terminal polyglutamine repeats, such as Huntington's disease.
Analogs of compound 51 may be made according to the synthetic sequences and principles described above. Diversity around active compound 51 is generated by varying the substituents on the phenyl ring of the Diels-Alder homodimer precursor as well as the substituents on the dienophile utilized in the retro-Diels-Alder step. Further diversity may be accessed by derivatization of nucleophilic groups, such as free hydroxyl groups, using well-known nucleophilic substitution chemistry. The substituents are chosen and resulting analogs are evaluated according to principles well known in the art of medicinal and pharmaceutical chemistry, such as quantification of structure-activity relationships, optimization of biological activity and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties.
Compounds 64-80 (see Figures 15-20) were synthesized according to the synthetic sequences and principles described above. Diversity around the bicyclo [2.2.2] octane core is generated by varying the substituents on the phenyl ring of the Diels-Alder homodimer precursor as well as the substituents on the dienophile utilized in the retro-Diels- Alder step. For example, acrylonitrile, alkyl acrylates, or acrylamides, among others, may be used as the dienophile. Further diversity may be accessed by derivatization of nucleophilic groups, such as free hydroxyl groups, using well-known nucleophilic substitution chemistry.
References
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[3] Huang, H.; Sun, H. -D.; Wang, M. -S.; Zhou, S. -X. J. Nat. Prod. 1996, 59, 1079-1080.
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[9] For one recent example leading to a dihydrofuran product, see: Sako, M.; Hosokawa, H.; Ito, T.; Iinuma, M. J". Org. Chem. 2004, 69, 2598-2600. For efforts to dimerize an oxazolidine derivative of rosmarinic acid, work that led to products very similar to 18, see: Bruschi, M.; Orlandi, M.; Rindone, B.; Rummakko, P.; Zoia, L. J". Phys. Org. Chem. 2006, 19, 592-596.
[10] Masuda, T.; Kazuki , Y.; Maekawa, T.; Takeda, Y.; Yamaguchi, H. Food Sci . Technol. Res. 2006, 12(3), 173-177.
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Claims

Claims
What is claimed is :
1. A compound having the structure
Figure imgf000286_0001
wherein α, Y, δ and σ are each, independently, present or absent;
wherein when δ is absent,
Figure imgf000286_0002
is absent;
Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
R1 is H, C1-10 alkyl, C2-10 alkenyl , C2-10 alkynyl, or
Figure imgf000286_0003
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R1O, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl;
R9 is H, C1-10 alkyl , C2-10 alkenyl , or C2-10 alkynyl ; and when R7 and R8 are H and R9 is CH3 , then R1 is
Figure imgf000286_0004
; and when Y is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORn, wherein Ru is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000287_0001
Pn* , -SO2R12, , or -Si (R15) 3; wherein R12 and each occurrence of R15 is C1-10 alkyl; or unsubstituted or substituted aryl; and
R13 is S or 0; and R14 is -SCH3,
Figure imgf000287_0002
t or
Figure imgf000287_0003
when Y is absent; R5 is present and A is a direct bond or
Figure imgf000287_0004
wherein R3 and R4 are each, independently, H, halogen, or OR16; wherein R16 is H, Cx-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000287_0005
, -SO2R17, ( or -Si (R20) 3; wherein R17 and each occurrence of R20 is C1_10 alkyl, or unsubstituted or substituted aryl; and
R18 is S or 0; and R19 is -SCH3,
Figure imgf000287_0006
t or
Figure imgf000287_0007
R3 and R4 taken together form =0 ; and wherein R5 is H, halogen, or OR21 , wherein R21 is H, C1-10 alkyl , -CH2SH, -BHCH2CH3 , -CH=SH,
Figure imgf000288_0001
, -SO2R22 , , or -Si (R25 ) 3 , wherein R22 and each occurrence of R25 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R23 is S or 0; and R24 is -SCH3,
Figure imgf000288_0002
t Or ,OH
O ; and when σ is absent ;
Figure imgf000288_0003
wherein R25, R26, R27, R28, and R29 are each, independently,
H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -0R3i, -SR3I,
-OSO2R31, or -NR3iR32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; and
R30 is H, C1-iQ alkyl , C2-10 alkenyl , C2-10 alkynyl , or
Figure imgf000288_0004
wherein R33 and R34 are each, independently, H, C1- 10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1_10) alkyl; or -SO2R36, wherein R36 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C1-10 alkyl , C2-10 alkenyl , or C2-10 alkynyl ; and when R33 and R34 are H and R35 is CH3 , then R30 is
Figure imgf000289_0001
R6 is H, halogen, or OR37 ; wherein R37 is H, C1-10 alkyl , -CH2SH, -BHCH2CH3 , -CH=SH,
Figure imgf000289_0002
, or -Si (R4I ) 3 ; wherein R38 and each occurrence of R41 is C1-10 alkyl; or unsubstituted or substituted aryl; R3g is S or 0; and R40 is -SCH3; -NH-aryl, heteroaryl,
heterocyclyl; or
Figure imgf000289_0003
; Or R5 when present and R6 taken together form =0; or R4 joined to R6 form a 5-membered heterocyclic ring; and
when σ is present;
; and
Figure imgf000289_0004
wherein X is a direct bond, Mc s^, or C(OMe)2; O
Y is H or OR42 ; or when α is present , Y is Ms. wherein R42 is H, C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl ,
Figure imgf000290_0001
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H , C1-10 alkyl , C2-10 alkenyl , or C2-10 alkynyl ; and when R43 and R44 are H and R45 is CH3 , then R42 is
Figure imgf000290_0002
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Figure imgf000290_0003
wherein Ra is S or 0; Rb is -0- (C1-C10) alkyl, -O- (C2- C10) alkenyl, heterocyclyl , or heteroaryl; or
when α is present, Z is -CH=CH-;
and when α is present, R1 is other than methyl;
or a salt thereof.
2. The compound of claim 1 having the structure
Figure imgf000291_0001
wherein α, Y, and σ are each, independently, present or absent;
Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl , or
Figure imgf000291_0002
wherein R7 and Ra are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R1O, wherein R10 is C1_10 alkyl, or unsubstituted or substituted aryl;
R9 is H, C1-10 alkyl , C2-10 alkenyl , or C2-10 alkynyl ; and when R7 and R8 are H and R9 is CH3 , then R1 is
Figure imgf000291_0003
when Y is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORn, wherein Rn is H, C1-10 alkyl, -CH2SH, -BHCH2CH3,
CH=SH,
Figure imgf000291_0004
, -SO2R12, , or -Si (R15) 3; wherein R12 and each occurrence of R15 is C1-10 alkyl; or unsubstituted or substituted aryl; and
R13 is S or O; and R14 is -SCH3,
Figure imgf000292_0001
, or
Figure imgf000292_0002
when Y is absent; R5 is present and A is a direct bond or
Figure imgf000292_0003
wherein R3 and R4 are each, independently, H, halogen, or OR16; wherein R16 is H, C1_10 alkyl, -CH2SH, -BHCH2CH3, -
, -SO2
Figure imgf000292_0004
Figure imgf000292_0005
R17, , or -Si(R20)3; wherein R17 and each occurrence of R2o is C1-10 alkyl, or unsubstituted or substituted aryl; and
R18 is S or 0; and R19 is -SCH3,
Figure imgf000292_0006
, or
Figure imgf000292_0007
R3 and R4 taken together form =0; and wherein R5 is H, halogen, or 0R2i, wherein R21 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000292_0008
, or -Si(R25)3, wherein R22 and each occurrence of R25 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R23 is S or O; and R24 is -SCH3,
Figure imgf000293_0001
or
Figure imgf000293_0002
wherein R25, R26# R27, R28, and R29 are each, independently,
H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR31, -SR31,
-OSO2R3I, or -NR3xR32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1_10 alkylene, C2-10 alkenylene, or C2-10 alkyny1ene; and
R30 is H , C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl , or
Figure imgf000293_0003
wherein R33 and R34 are each, independently, H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R36, wherein R36 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C1-10 alkyl, C2-10 alkenyl, or C2 -10 alkynyl ; and when R33 and R34 are H and R35 is CH3 , then R30 is
Figure imgf000294_0001
R6 is H, halogen, or OR37 ; wherein R37 is H , C1-10 alkyl , -CH2SH , -BHCH2CH3 , -CH=SH ,
Figure imgf000294_0002
, or -Si(R4I)3; wherein R3s and each occurrence of R41 is C1-10 alkyl; or unsubstituted or substituted aryl;
R3g is S or 0; and R40 is -SCH3;
Figure imgf000294_0003
; Or
Figure imgf000294_0004
R5 when present and R6 taken together form =0; or
R4 joined to R6 form a 5-membered heterocyclic ring; and
when σ is present;
R2 is
Figure imgf000294_0005
; and
wherein X is a direct bond,
Figure imgf000294_0006
or C(OMe)2; O
Y is H or OR42; or when α is present, Y is wherein R42 is H, C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl ,
Figure imgf000295_0001
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl , C2-10 alkenyl , or C2-10 alkynyl ; and when R43 and R44 are H and R45 is CH3 , then R42 is
Figure imgf000295_0002
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Z is H or CN; or when α is present, Z is -CH=CH-; and
when α is present, R1 is other than methyl;
or a salt thereof."
3. The compound of claim 1 having the structure
Figure imgf000296_0001
wherein δ is present or absent;
wherein when δ is absent,
Figure imgf000296_0002
is absent;
R6 is OR37;
wherein R37 is
Figure imgf000296_0003
; wherein R39 is S or 0; and R4o is -NH-aryl, heteroaryl , heterocyclyl ; or
O
X is a direct bond or M4.
Figure imgf000296_0004
wherein R3 is S or 0; Rb is -0- (C1-C10) alkyl , -0-(C2- C10)alkenyl, heterocyclyl, or heteroaryl; or
or a salt thereof.
4. The compound of claim 2 having the structure
Figure imgf000297_0001
wherein α, Y, and σ are each, independently, present or absent; Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000297_0002
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R1O, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl; R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and at least one of R7 and R8 is other than H; and when Y is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORn, wherein R11 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000297_0003
, or -Si(R15J3; wherein R12 and each occurrence of R15 is C1-10 alkyl; or unsubstituted or substituted aryl; and R13 is S or 0; and R14 is -SCH3,
Figure imgf000298_0001
t or
Figure imgf000298_0002
when Y is absent; R5 is present and A is a direct bond or
Figure imgf000298_0003
wherein R3 and R4 are each, independently, H, halogen, or OR16 ; wherein R16 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000298_0004
, or -Si(R20)3; wherein R17 and each occurrence of R20 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R18 is S or 0; and R19 is -SCH3,
Figure imgf000298_0005
# or
Figure imgf000298_0006
R3 and R4 taken together form =0; and wherein R5 is H, halogen, or 0R2i, wherein R21 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000298_0007
, or -Si(R25)3, wherein R22 and each occurrence of R25 is C1-10 alkyl, or unsubstituted or substituted aryl; and R23 is S or O ; and R24 is -SCH3 ,
Figure imgf000299_0001
, or
Figure imgf000299_0002
when σ is absent;
Figure imgf000299_0003
wherein R25, R2β, R27, R28, and R29 are each, independently,
H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR31, -SR31,
-OSO2R3I, or -NR31R32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; and
R30 is H , C1-10 alkyl , C2 -10 alkenyl , C2-10 alkynyl , or
Figure imgf000299_0004
wherein R33 and R34 are each, independently, H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R3S, wherein R36 is C1-10 alkyl, or unsubstituted or substituted aryl; and at least one of R33 and R34 is other than H; and wherein R35 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and
R6 is H, halogen, or OR37; wherein R37 is H , C1-10 alkyl , -CH2SH , -BHCH2CH3 , -CH=SH,
Figure imgf000300_0001
wherein R38 and each occurrence of R4χ is C1-10 alkyl; or unsubstituted or substituted aryl;
R39 is S or O; and R40 is -SCH3;
Figure imgf000300_0002
; Or
OH ; or
R5 when present and R6 taken together form =0; or
R4 joined to Re form a 5-membered heterocyclic ring; and
when σ is present;
R2 is ;. and
wherei
Figure imgf000300_0003
X is a direct bond, or C(OMe)2;
Y is H or OR42; or when α is present, Y is
Figure imgf000300_0004
wherein R42 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl,
Figure imgf000300_0005
wherein R43 and R44 are independently H, C1-io alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R4S, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and at least one of R43 and R44 is other than H; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Z is H or CN; or when α is present, Z is -CH=CH-; and
when α is present, R1 is other than methyl;
or a salt thereof.
5. The compound of claim 2 having the structure
Figure imgf000301_0001
wherein α, Y, and σ are each, independently, present or absent;
Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000301_0002
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R1O, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl; R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when Y is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORn, wherein Ru is H, C1_10 alkyl, -CH2SH, -BHCH2CH3, -
, -SO2R12,
Figure imgf000302_0001
Figure imgf000302_0002
, or -Si (R15) 3; wherein R12 and each occurrence of R15 is C1-10 alkyl; or unsubstituted or substituted aryl; and
R13 is S or O; and R14 is -SCH3,
Figure imgf000302_0003
t or
OH ; and when Y is absent; R5 is present and A is a direct bond or
Figure imgf000302_0004
wherein R3 and R4 are each, independently, H, halogen, or OR16 ; wherein R16 is H , C1-10 alkyl , -CH2SH, -BHCH2CH3 , -
Il |?18
CH=SH, vpς Phpn , -SO2R17 , vV9 , or -Si (R20) 3 ; wherein R17 and each occurrence of R20 is C1-10 alkyl , or unsubstituted or substituted aryl ; and R18 is S or 0; and R1g is -SCH3,
Figure imgf000303_0001
r or
Figure imgf000303_0002
R3 and R4 taken together form =0; and wherein R5 is H, halogen-, or OR21, wherein R2i is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000303_0003
, or -Si(R25)S, wherein R22 and each occurrence of R25 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R23 is S or 0; and R24 is -SCH3,
Figure imgf000303_0004
# or
Figure imgf000303_0005
when σ is absent;
Figure imgf000303_0006
wherein R25, R2e, R27, R28, and R29 are each, independently,
H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR31, -SR31,
-OSO2R3I, or -NR3χR32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1-10 alkylene, C2-10 alkenylene, or C2-10 a1kyny1ene ; and R30 is H, C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl , or
Figure imgf000304_0001
wherein R33 and R34 are each, independently, H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R36, wherein R36 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and R6 is H, halogen, or OR37; wherein R37 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000304_0002
wherein R38 and each occurrence of R41 is C1-10 alkyl ; or unsubstituted or substituted aryl ;
R3g is S or O ; and R40 is -SCH3 ;
Figure imgf000304_0003
; Or
Figure imgf000304_0004
R5 when present and R6 taken together form =0; or R4 joined to R6 form a 5-membered heterocyclic ring; and
when σ is present;
Figure imgf000304_0005
Figure imgf000305_0001
or C(OMe)2;
Y is H or OR42 ; or when α is present , Y is
Figure imgf000305_0002
; wherein R42 is H, C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl ,
Figure imgf000305_0003
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Z is H or CN; or when α is present, Z is -CH=CH-; and
when α is present, R1 is other than methyl;
or a salt thereof.
6. The compound of claim 1, 2, 4, or 5 having the structure
Figure imgf000306_0001
wherein
Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl , or
Figure imgf000306_0002
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R1O, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl;
R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when R7 and R8 are H and R9 is CH3, then Rx is
Figure imgf000306_0003
wherein R3 and R4 are each, independently, H, halogen, or OR1β; wherein R16 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH, v
Figure imgf000306_0004
Prnph, -SO2R17, , or -Si (R20) 3; wherein R17 and each occurrence of R2o is C1-Io alkyl, or unsubstituted or substituted aryl; and R18 is S or 0 ; and R19 is -SCH3 ,
Figure imgf000307_0001
t or
Figure imgf000307_0002
R3 and R4 taken together form =0 ; and wherein R5 is H, halogen, or OR21 , wherein R21 is H, C1-10 alkyl , -CH2SH, -BHCH2CH3 , -CH=SH,
Figure imgf000307_0003
, or -Si (R25 ) 3 , wherein R22 and each occurrence of R25 is C1-10 alkyl , or unsubstituted or substituted aryl; and
R23 is S or 0; and R24 is -SCH3,
Figure imgf000307_0004
t Or
Figure imgf000307_0005
wherein R25, R26, R27, R28, and R2g are each, independently,
H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 a.lkynyl; unsubstituted or substituted aryl (C1-io) alkyl; -OR3I, -SR3I,
-OSO2R3I, or -NR3xR32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene ; and R30 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000308_0001
wherein R33 and R34 are each, independently, H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1_10) alkyl; or -SO2R36, wherein R36 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and when R33 and R34 are H and R35 is CH3, then R30 is
Figure imgf000308_0002
R6 is H, halogen, or OR37; wherein R37 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000308_0003
, or -Si(R4I)3; wherein R3β and each occurrence of R41 is C1-10 alkyl; or unsubstituted or substituted aryl;
R39 is S or 0; and R40 is -SCH3;
Figure imgf000308_0004
; Or
Figure imgf000308_0005
R5 when present and R6 taken together form =0; or R4 joined to R6 form a 5-membered heterocyclic ring; and
O wherein X is a direct bond or Mc s? ; and Y is H or OR42, wherein R42 is H , C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl ,
Figure imgf000309_0001
wherein R43 and R44 are independently H, Cχ-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R4S, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H , C1-10 alkyl , C2-10 alkenyl , or C2-10 alkynyl ; and when R43 and R44 are H and R45 is CH3 , then R42 is
Figure imgf000309_0002
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Z is H or CN; or a salt thereof.
7. The compound of claim 6 having the structure
Figure imgf000309_0003
wherein
Figure imgf000310_0001
wherein R7 and Re are p-trif luoromethylbenzyl ; and R9 is CH3 ; and wherein R3 is H, OCH3, Br, -OSO2CF3, or -OiPr; R4 is H, OH, or OCH3;
R5 is H, OH, -OSO2CF3, or -OSi (CH3) 2 (t-butyl ); and R6 is H or ORn,
O
11
V1TPh wherein Ru is H, -CH2SH, -BHCH2CH3 , -CH=SH, Ph
Figure imgf000310_0002
wherein R12 is CH3 or CF3 ;
R13 is S or 0 ; and R14 is -SCH3 ;
Figure imgf000310_0003
,OH
O ; or R5 and R6 together form =0; or R3 and R4 together form =0; or R4 joined to R6 form a 5-membered heterocyclic ring; and
wherein R2 is H,
Figure imgf000310_0004
, or wherein R26 and R27 are each, independently, -OCH3 ,
Figure imgf000310_0005
, or -OSO2R24, wherein R24 is
wherein R30 is C
Figure imgf000311_0001
H3 or
wherein R25 and R26 are each
Figure imgf000311_0002
wherein R27 is CH3; and
O wherein X is a direct bond, Ms , or C (OMe) 2 ; Y is H or OR34,
wherein R34 is CH3 or
wherein R35 and R
Figure imgf000311_0003
36 are each ; and R37 is CH3; and
Z is H or CN;
or a salt thereof.
8. The compound of claim 7 selected from the group consisting of Compound 17, 21, 24, 26, 33, 34, 36, 36, 37, 39, 40, 42, 44, 45, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63.
9. The compound of claim 8 selected from the group consisting of Compound 51.
10. The compound of claim 1, 2, 4, or 5 having the structure
Figure imgf000312_0001
wherein
Gi is C1-10 alkylene , C2-10 alkenylene , or C2-10 alkynyl ene ; R1 is H , C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl , or
Figure imgf000312_0002
wherein R7 and R8 are independently H; C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl( C1-10) alkyl, or -SO2R1O, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl; and R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when R7 and R8 are H and R9 is CH3, then Rx is
A is a
Figure imgf000312_0003
direct bond or wherein R3 and R4 are each, independently, H, halogen, or OR16; wherein R16 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000313_0001
, -SO2R17, , or -Si (R20) 3; wherein R17 and each occurrence of R20 is C1-10 alkyl, or unsubstituted or substituted aryl; and
RI8 is S or 0; and R19 is -SCH3,
Figure imgf000313_0002
f or
Figure imgf000313_0003
R3 and R4 taken together form =0; and wherein R5 is H, halogen, or OR21, wherein R21 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000313_0004
, or -Si(R25J3, wherein R22 and each occurrence of R25 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R23 is S or 0; and R24 is -SCH3, 155Ss/ t or
,OH
O ; and
wherein R6 is a direct bond or
Figure imgf000313_0005
wherein R26, R27 , R28, and R2g are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1_10) alkyl; -0R3i, -SR31, OSO2R3I, or -NR3xR32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2- I0 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl ; wherein R42 is H, C1-10 alkyl, C2 -10 alkenyl, C2-10 alkynyl, or
Figure imgf000314_0001
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R4S, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H , C1-10 alkyl , C2-10 alkenyl , or C2-10 alkynyl ; and when R43 and R44 are H and R45 is CH3 , then R42 is
Figure imgf000314_0002
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof.
11. The compound of claim 10 having the structure
Figure imgf000315_0001
wherein
Figure imgf000315_0002
wherein R7 and R8 are ; and R9 is CH3 ;
A is a direct bond or
Figure imgf000315_0003
wherein R3 and R4 taken together form =0 ; R5 is H or OH;
O
R6 is a direct bond or c ? ; R27 and R28 are each -OCH3; and wherein R42 is CH3; or a salt thereof.
12. The compound of claim 11 selected from the group consisting of: Compound 23 and 25.
13. The compound of claim 3 having the structure
Figure imgf000316_0001
wherein δ is present or absent;
wherein when δ is absent,
Figure imgf000316_0002
is absent;
R6 is OR37;
wherein R37 is
Figure imgf000316_0003
Figure imgf000316_0004
O
X is a direct bond or Ms.
Figure imgf000316_0005
wherein Ra is S or 0; Rb is -O- (C1-C10) alkyl, -0-(C2- C1o)alkenyl, heterocyclyl, or heteroaryl; or
or a salt thereof.
14. The compound of claim 13 having the structure
Figure imgf000317_0001
wherein δ is present or absent;
O
R1O wherein when δ is absent, ^1 is absent;
R1 is H, methyl or
Figure imgf000317_0002
Figure imgf000317_0003
R3 and R4 are each -OCH3;
R5 is H or OR2I,
wherein R2i is
wherein R2
Figure imgf000317_0004
3 is S; and R24 is ; and
R6 is OR37; wherein R37 is
wherein R3g
Figure imgf000318_0001
is S; and R40 is or
X is a direct bond or
Figure imgf000318_0002
Y is H or OR42 ; wherein R42 is methyl , -CH2CH=CH2 or
Figure imgf000318_0003
Figure imgf000318_0004
wherein Ra is S or 0 ; Rb is -OCH3 , -OCH ( CH3 ) 2 , -OCH2CH=CH2 ,
Figure imgf000318_0005
or a salt thereof.
15. The compound of claim 14 selected from the group consisting of Compound 64, 65, 66, 67, 68, 73, 74, 75, 76, 77, 78, 79, 80, and a pharmaceutically acceptable salt thereof.
16. A compound having the structure
Figure imgf000319_0001
wherein ε and δ are present or absent; wherein R54 and R55 are present or absent; and when ε is present; δ and R54 are absent, and R55 is present; and when δ is present; ε and R55 are absent, and R54 is present;
wherein G3 and G4 are each, independently, is C1-10 alkylene, C2-
10 alkenylene, or C2-10 alkynylene;
R48, R49, R50, and R51 are each, independently, H, C1-10 alkyl, C2-
10 alkenyl, C2-10 alkynyl; or
Figure imgf000319_0002
wherein R57 and R5s are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R60, wherein R6o is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when R57 and R5s are H and R59 is CH3, then
R48, R49, R5Q, or R5i is
Figure imgf000319_0003
; and wherein R53 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6i, wherein R6i is C1-10 alkyl, or unsubstituted or substituted aryl ; .-
Figure imgf000320_0001
whe.rei-n R6-2, R63.,.R.β4, R.β5, and R66 are each, independently,
H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67,
-OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; and wherein R54 when present, R55 when present, and R56 are each, independently, H or 0R6g, wherein R69 is H or C1-10 alkyl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof.
17. The compound of claim 16 having the structure
Figure imgf000320_0002
wherein ε and δ are present or absent; wherein R54 and R55 are present or absent; and when ε is present; δ and R54 are absent, and R55 is present; and when δ is present ; ε and R55 are absent , and R54 is present ; wherein G3 and G4 are each, independently, is C1-10 alkylene , C2- 10 alkenylene , or C2-10 alkynylene ;
R48, R49, R50, and R51 are each, independently, H , C1-10 alkyl , C2-
10 alkenyl, C2-10 alkynyl; or
Figure imgf000321_0001
wherein R57 and R58 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R60, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and at least one of R57 and R58 is other than H; and wherein R53 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6i, wherein R61 is C1_10 alkyl, or unsubstituted or substituted aryl ;
R47 and R52 are each H, CN, or
Figure imgf000321_0002
wherein R62, R63, Rβ4, R6s, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; and wherein R54 when present, R55 when present, and R56 are each, independently, H or OR6g, wherein R6g is H or C1-10 alkyl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof.
18. The compound of claim 16 having the structure
Figure imgf000322_0001
wherein ε and δ are present or absent; wherein R54 and R55 are present or absent; and when ε is present; δ and R54 are absent, and R55 is present; and when δ is present; ε and R55 are absent, and R54 is present; wherein G3 and G4 are each, independently, is C1-10 alkylene, C2- 10 alkenylene, or C2-10 alkynylene;
R48, R49, R50, and R5i are each, independently, H, C1-10 alkyl, C2-
10 alkenyl, C2-10 alkynyl; or
Figure imgf000322_0002
wherein R57 and R5s are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -S02R6o, wherein R6o is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H , C1-10 alkyl , C2-10 alkenyl , or C2-10 alkynyl ; and wherein R53 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6I, wherein R6i is C1-10 alkyl, or unsubstituted or substituted aryl ;
R47 and R52 are each H, CN, or
Figure imgf000323_0001
wherein R62, R63, R64,
Figure imgf000323_0002
and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67,
Figure imgf000323_0003
wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; and wherein R54 when present, R55 when present, and R56 are each, independently, H or OR69, wherein R69 is H or C1-10 alkyl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof.
19. The compound of claim 16, 17, or 18 having the structure
Figure imgf000324_0001
wherein ε and δ are present or absent; wherein R54 and R55 are present or absent; and when ε is present; δ and R54 are absent, and R55 is present; and when δ is present; ε and R55 are absent, and R54 is present;
R48, R49, R50, and R51 are each CH3;
R53 is H or CH3;
Figure imgf000324_0002
R47 and R52 are each wherein R63 and R64 are each -OCH3; and wherein R54 when present, R55 when present, and R56 are each, independently, H or OR69, wherein R69 is H or CH3;
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof.
20. The compound of claim 19 selected from the group consisting of: Compound 43 and 48.
21. A compound having the structure
Figure imgf000325_0001
wherein v is present or absent; wherein R70 and R7i are each, independently, H, OH, -CO2R74, wherein R74 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl,
Figure imgf000325_0002
wherein R75 and R76 are independently H; C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R7S, wherein R78 is C1-10 alkyl; or unsubstituted or substituted aryl; and wherein R77 is H; C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and at least one of R75 and R76 is other than H; wherein R72 and R73 are each, independently, H, C1_10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1- 10) alkyl; -SO2R79, or -Si(R8Q)3, wherein R79 is C1-10 alkyl, or unsubstituted or substituted aryl ; and wherein each occurrence of R80 is, independently, C1-10 alkyl, or unsubstituted or substituted aryl; and when R74 is H or CH3, R73 is other than H or Me; and
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted; or a salt thereof.
22. The compound of claim 21 having the structure
Figure imgf000326_0001
wherein v is present or absent; wherein R70 and R71 are each, independently, H, OH, -CO2R74, wherein R74 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl,
Figure imgf000326_0002
wherein R75 and R76 are independently H; C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R7S, wherein R78 is C1-10 alkyl; or unsubstituted or substituted aryl; and wherein R77 is H; C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and at least one of R75 and R76 is other than H; wherein R72 and R73 are each, independently, H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1- I0) alkyl; -SO2R79, or -Si (R80) 3, wherein R79 is C1-10 alkyl, or unsubstituted or substituted aryl ; and wherein each occurrence of R8o is, independently, C1-10 alkyl, or unsubstituted or substituted aryl; and when R74 is H or CH3, R73 is other than H or Me; and wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof.
23. The compound of claim 22 having the structure
Figure imgf000327_0001
wherein v is present or absent; wherein R70 and R71 are each, independently, H, OH, -CO2R74, wherein R74 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl,
Figure imgf000327_0002
wherein R75 and R76 are independently H; C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R7S, wherein R78 is C1-10 alkyl; or unsubstituted or substituted aryl; and wherein R77 is H; C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and at least one of R75 and R76 is other than H; wherein R72 and R73 are each, independently, H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl ( C1- 10) alkyl; -SO2R79, or -Si(R8O)3, wherein R79 is C1-10 alkyl, or unsubstituted or substituted aryl ; and wherein each occurrence of R80 is, independently, C1-10 alkyl, or unsubstituted or substituted aryl; and when R74 is H or CH3, R73 is other than H or Me; and
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof.
24. The compound of claim 21, 22, or 23 having the structure
Figure imgf000328_0001
wherein v is present or absent; wherein R70 and R7i are each, independently, H, OH, -CO2R74,
wherein R74 is H, CH3 , or
Figure imgf000328_0002
wherein R75 and R76 are each
Figure imgf000328_0003
wherein R77 is CH3 ; wherein R72 and R73 are each, independently, H, CH3 ,
Figure imgf000328_0004
, - SO2R79 , or -Si ( R8Q ) 3 , wherein R79 is
Figure imgf000329_0001
and wherein each occurrence of R8o is, independently, CH3 or t-butyl; and
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof.
25. The compound of claim 24 selected from the group consisting of: Compound 14, 27, 28, 29, 31, and 32.
26. A process for preparing a compound having the structure
Figure imgf000329_0002
wherein α, Y, δ and σ are each, independently, present or absent;
O
R1O^n wherein when δ is absent , 1 is absent ;
Gi is C1-10 alkylene , C2-10 alkenylene , or C2-10 alkynylene ; C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000330_0001
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R1O, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl;
R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when R7 and R8 are H and R9 is CH3, then R1 is
Figure imgf000330_0002
when γ is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORn, wherein Rn is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000330_0003
, or -Si(R15J3; wherein R12 and each occurrence of R15 is C1-10 alkyl; or unsubstituted or substituted aryl; and
RI3 is S or 0; and R14 is -SCH3,
Figure imgf000330_0004
f or
Figure imgf000330_0005
when Y is absent; R5 is present and A is a direct bond or
Figure imgf000330_0006
. wherein R3 and R4 are each, independently, H, halogen, or OR16; wherein R16 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
Figure imgf000331_0001
wherein R17 and each occurrence of R20 is C1-10 alkyl, or unsubstituted or substituted aryl; and
RI8 is S or 0; and R19 is -SCH3, ****/ t or
Figure imgf000331_0002
R3 and R4 taken together form =0; and wherein R5 is H, halogen, or OR21, wherein R21 is H, Cx-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000331_0003
, or -Si(R25)3, wherein R22 and each occurrence of R25 is CX-Xo alkyl, or unsubstituted or substituted aryl; and
R23 is S or 0; and R24 is -SCH3,
Figure imgf000331_0004
t or
Figure imgf000331_0005
when σ is absent;
R2 is H,
Figure imgf000331_0006
R30 wherein R25, R26, R27, R28, and R29 are each, independently,
H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR31, -SR31,
Figure imgf000332_0001
wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; and
R30 is H , C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl , or
Figure imgf000332_0002
wherein R33 and R34 are each, independently, H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1_10) alkyl; or -SO2R36, wherein R36 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C1_10 alkyl , C2-10 alkenyl , or C2-10 alkynyl ; and when R33 and R34 are H and R35 is CH3 , then R30 is
Figure imgf000332_0003
H, halogen, or OR37 ; wherein R37 is H, C1-10 alkyl , -CH2SH, -BHCH2CH3 , -CH=SH,
Figure imgf000332_0004
, or -Si (R4I ) 3 ; wherein R38 and each occurrence of R41 is C1-10 alkyl; or unsubstituted or substituted aryl; R39 is S or 0; and R40 is -SCH3; -NH-aryl, heteroaryl
heterocyclyl; or
Figure imgf000333_0001
; Or R5 when present and R6 taken together form =0; or R4 joined to R6 form a 5-membered heterocyclic ring; and
when σ is present;
R2 is ;. and
wherei
Figure imgf000333_0002
X is a direct bond, , or C(OMe)2;
O
Y is H or OR42 ; or when α is present , Y is Ms ? ; wherein R42 is H , C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl ,
Figure imgf000333_0003
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl , C2-10 alkenyl , or C2-10 alkynyl ; and when R43 and R44 are H and R45 is CH3 , then R42 is
Figure imgf000333_0004
; or wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Figure imgf000334_0001
wherein Ra is S or 0; Rb is -O- (C1-C10) alkyl, -0-(C2- C10) alkenyl, heterocyclyl, or heteroaryl; or
when α is present, Z is -CH=CH-;
and when α is present, R1 is other than methyl;
comprising: a) contacting a compound having the structure
Figure imgf000334_0002
wherein
R1O^V5 when δ is absent, ^ is absent;
Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000334_0003
wherein R7 and R8 are independently H, C1-10 alkyl, C2- io alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1_10) alkyl; or -SO2R1O, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl; R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; with a first suitable oxidizing agent in the presence of methanol so as to form the compound having the structure
Figure imgf000335_0001
b) contacting the product of step a) with a compound having the structure
Figure imgf000335_0002
wherein R42 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl,
Figure imgf000335_0003
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; R25, R26, R27, R28, and R29 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR31, -SR31, -OSO2R3I, or -NR31R32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; and
wherein Ra is S or 0; Rb is -0- (C1-C10) alkyl, -0-(C2- C10) alkenyl, heterocyclyl , or heteroaryl;
in the presence of a first suitable energy source so as to form the compound having the structure
or
Figure imgf000336_0001
27 . The process of claim 26 for preparing a compound having the structure
Figure imgf000337_0001
wherein α , Y, and σ are each, independently, present or absent ;
Gi is C1-10 alkylene , C2 -10 alkenylene , or C2-10 alkynylene ; R1 is H , C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl , or
Figure imgf000337_0002
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl( C1-10) alkyl; or -SO2R10, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl;
R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when Y is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORn, wherein R11 is H, d-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000337_0003
, -SO2R12, , or -Si (R15) 3; wherein R12 and each occurrence of R15 is C1-10 alkyl; or unsubstituted or substituted aryl; and R13 is S or 0; and R14 is -SCH3,
Figure imgf000338_0001
, or
Figure imgf000338_0002
when Y is absent; R5 is present and A is a direct bond or
Figure imgf000338_0003
wherein R3 and R4 are each, independently, H, halogen, or
OR16; wherein R16 is H, d-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000338_0004
, or -Si (R20) 3; wherein R17 and each occurrence of R2o is C1-10 alkyl, or unsubstituted or substituted aryl; and
R18 is S or 0; and R19 is -SCH3,
Figure imgf000338_0005
t or
Figure imgf000338_0006
R3 and R4 taken together form =0; and wherein R5 is H, halogen, or 0R2i, wherein R2x is H, C1_10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000338_0007
, or -Si(R25)3, wherein R22 and each occurrence of R25 is C1-10 alkyl, or unsubstituted or substituted aryl; and R23 is S or 0 ; and R24 is -SCH3 ,
Figure imgf000339_0001
t Or
Figure imgf000339_0002
when σ is absent;
Figure imgf000339_0003
wherein R25, R26, R27, R28, and R29 are each, independently,
H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR3I, -SR3i,
-OSO2R31, or -NR31R32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2 -10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1-10 alkylene, C2-10 alkenylene, or C2 -10 a1kyny1ene ; and
R30 is H , C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl , or
Figure imgf000339_0004
wherein R33 and R34 are each, independently, H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -Sθ2R36# wherein R36 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C1-10 alkyl , C2-10 alkenyl , or C2-10 alkynyl ; and R6 is H , halogen, or OR37 ; wherein R37 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000340_0001
, or -Si(R4I)3; wherein R38 and each occurrence of R41 is C1-10 alkyl; or unsubstituted or substituted aryl;
R39 is S or O; and R40 is -SCH3;
Figure imgf000340_0002
Or
Figure imgf000340_0003
R5 when present and R6 taken together form =0; or
R4 joined to R6 form a 5-membered heterocyclic ring; and
when σ is present;
Figure imgf000340_0004
; and
wherein X is a direct bond,
Figure imgf000340_0005
or C(OMe)2;
Y is H or OR42; or when α is present, Y is
Figure imgf000340_0006
; wherein R42 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl ,
Figure imgf000340_0007
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl ( C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H , C1-10 alkyl , C2-10 alkenyl , or C2-10 alkynyl ; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Z is H or CN; or when α is present, Z is -CH=CH-; and
when α is present, R1 is other than methyl;
or a salt thereof;
comprising: a) contacting a compound having the structure
Figure imgf000341_0001
wherein
Gi is C1-10 alkylene , C2-10 alkenylene , or C2-10 alkynylene ; R1 is H , C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl , or
Figure imgf000341_0002
wherein R7 and R8 are independently H, C1-10 alkyl, C2- 10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R10, wherein R1o is C1-10 alkyl, or unsubstituted or substituted aryl; R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; with a first suitable oxidizing agent in the presence of methanol so as to form the compound having the structure
Figure imgf000342_0001
b) contacting the product of step a) with a compound having the structure
Figure imgf000342_0002
wherein R42 is H , C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl ,
Figure imgf000342_0003
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; R25, R26, R27, . R28, and R2g are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR31, -SR31,
-OSO2R31, or -NR31R32- wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; in the presence of a first suitable energy source so as to form the compound having the structure
Figure imgf000343_0001
28. The process of claim 27, wherein R1 is H , C1-10 alkyl , C2_10 alkenyl , C2-10 alkynyl , or
Figure imgf000343_0002
wherein R7 and R8 are independently H, C1-10 alkyl, C2- 10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R1O, wherein R1o is C1-10 alkyl, or unsubstituted or substituted aryl; and R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl.
29. The process of claim 27, wherein R1 is H, C1-10 alkyl, C2-1Q alkenyl, C2-10 alkynyl, or
Figure imgf000344_0001
wherein R7 and R8 are independently H, C1-10 alkyl, C2- 10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R1O, wherein R10 is C1_10 alkyl, or unsubstituted or substituted aryl; and R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl.
30. The process of claim 27, 28, or 29, further comprising: c) contacting the product of step b) with BBr3 so to form a compound having the structure
Figure imgf000344_0002
31. The process of claim 27, 28, or 29, further comprising: c) contacting the product of step b) with a first suitable hydride reducing agent so as to form a compound having the structure
Figure imgf000345_0001
32. The process of claim 31 further comprising: d) exposing the product of step c) to a first suitable Bronsted acid so as to form a compound having the structure
Figure imgf000345_0002
33. The process of claim 32 further comprising: e) contacting the product of step d) having the structure
Figure imgf000346_0001
with a second suitable hydride reducing agent; f) contacting the product of step e) with a suitable silylating agent; g) contacting the product of step f) with a second suitable oxidizing agent so as to form a compound having the structure
Figure imgf000346_0002
, wherein each occurrence of R25 is C1-10 alkyl; or unsubstituted or substituted aryl .
34. The process of claim 33 further comprising h) exposing the product of step g) to tetra-n- butylammonium fluoride so as to form a compound having the structure
Figure imgf000347_0001
35. The process of claim 33 further comprising h) exposing the product of step g) to a second suitable Bronsted acid in the presence of methanol so as to form a compound having the structure
Figure imgf000347_0002
36. The process of claim 35 further comprising: i) exposing the product of step h) to a second suitable energy source so as to form a compound having the structure
Figure imgf000348_0001
37. The process of claim 35 further comprising: i) exposing the product of step h) to a third suitable
Bronsted acid; j) contacting the product of step i) with Tf2NPh in the presence of a base so as to form a compound having the structure
Figure imgf000348_0002
38. The process of claim 32 further comprising: e) exposing the product of step d) to a first suitable Lewis acid so as to from a compound having the structure
Figure imgf000349_0001
39. The process of claim 31 further comprising: d) exposing the product of step c) to a compound having
the structure R21-L, wherein R16 is
Figure imgf000349_0002
Figure imgf000349_0003
Figure imgf000349_0004
in the presence of a base so as to form a compound having the structure
Figure imgf000350_0001
40. The process of 39 further comprising: e) contacting the product of step d) having the structure
Figure imgf000350_0002
with Et3B and nBu3SnH in the presence of O2 so as to form a compound having the structure
Figure imgf000351_0001
41. The process of claim 31 further comprising: d) exposing the product of step c) to a base and carbon disulfide followed by methyl iodide so as to form a compound having the structure
Figure imgf000351_0002
42. The process of claim 41 further comprising: e) exposing the product of step d) to PhSeSePh in the presence of AIBN and nBu3SnH so as to form a compound having the structure
Figure imgf000352_0001
he process of 42 further comprising: f) exposing the product of step e) having the structure
Figure imgf000352_0002
to HCl so as to form a compound having the structure
Figure imgf000353_0001
44. The process of claim 41 further comprising: e) contacting the product of step d) with Et3B in the presence of O2 so as to form a compound having the structure
Figure imgf000353_0002
45. The process of claim 27, 28, or 29, further comprising: c) contacting the product of step b) with i-Bu2Al (OiPr) so as to form a compound having the structure
Figure imgf000354_0001
46. The process of claim 27, 28, or 29, further comprising: c) exposing the product of step b) to a first suitable Lewis acid so as to form a compound having the structure
Figure imgf000354_0002
47. The process of claim 46 further comprising: d) contacting the product of step c) with a second suitable Lewis acid so as to form a compound having the structure
Figure imgf000355_0001
48. The process of claim 46 further comprising: d) contacting the product of step c) with a second suitable
Figure imgf000355_0002
acid so as to form a compound having the structure
Figure imgf000355_0003
49. The process of any one of claims 27, 28, or 30-48 wherein the compound prepared is selected from a group consisting of: Compound 3, 4, 21, 23, 24, 25, 26, 33, 34, 35, 36, 37, 39, 40, 42, 44, 45, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, and 63.
50. The process of claim 26 further comprising: c) contacting the product of step b) having the structure
Figure imgf000356_0001
wherein δ is present or absent;
wherein when δ is present,
Figure imgf000356_0002
is present;
Ra is S or 0; Rb is -0- (C1-C10) alkyl , -0- (C2-C10) alkenyl, heterocyclyl, or heteroaryl;
with a first suitable hydride reducing agent so as to form a compound having the structure
Figure imgf000356_0003
51. The process of claim 50 further comprising: d) exposing the product of step c) to a first suitable Bronsted acid so as to form a compound having the structure
Figure imgf000357_0001
52. The process of claim 51 further comprising: e) contacting the product of step d) with a second suitable hydride reducing agent; f) contacting the product of step e) with a suitable silylating agent; g) contacting the product of step f) with a second suitable oxidizing agent so as to form a compound having the structure
Figure imgf000357_0002
wherein each occurrence of R25 is C1-10 alkyl; or unsubstituted or substituted aryl .
53. The process of claim 52 further comprising h) exposing the product of step g) to a second suitable Bronsted acid in the presence of methanol so as to form a compound having the structure
Figure imgf000358_0001
54. The process of claim 50 or 53 further comprising: exposing the final product to a compound having the
structure R21-L, wherein R16 is
Figure imgf000358_0002
Figure imgf000358_0003
Figure imgf000358_0004
in the presence of a base so as to form a compound having the structure
Figure imgf000359_0001
55. A process for preparing a compound having the structure
Figure imgf000359_0002
wherein ε and δ are present or absent; wherein R54 and R55 are present or absent; and when ε is present; δ and R54 are absent, and R55 is present; and when δ is present; ε and R55 are absent, and R54 is present; wherein G3 and G4 are each, independently, is C1-10 alkylene, C2-
10 alkenylene, or C2-10 alkynylene; R48, R49, R50, and R51 are each, independently, H, C1-10 alkyl, C2-
10 alkenyl, C2-10 alkynyl; or
Figure imgf000360_0001
wherein R57 and R58 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6O, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and wherein R53 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6i, wherein R6i is C1-10 alkyl, or unsubstituted or substituted aryl ;
R47 and R52 are each H, CN, or
Figure imgf000360_0002
wherein R62, R63, R64, R65, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; and wherein R54 when present, R55 when present, and R56 are each, independently, H or OR69, wherein R69 is H or C1-10 alkyl; or wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof;
comprising: a) contacting a compound having the structure
Figure imgf000361_0001
wherein G3 is C1-10 alkylene , C2-10 alkenylene , or C2-10 alkynylene ;
Figure imgf000361_0002
wherein R62, R63, R64, R6s, and R66 are each, independently,
H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67,
-OSO2R6?, or -NR67R68, wherein R67 and R6a are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl;
R48 and R49 are each, independently, H, C1-10 alkyl, C2-10
alkenyl, C2-10 alkynyl; or
Figure imgf000361_0003
wherein R57 and R5s are independently H, C1-10 alkyl,
C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6O, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2 -10 alkynyl; and wherein each occurrence of Rβi is, independently, C1-10 alkyl, or unsubstituted or substituted aryl; with tetra-n-butylammonium fluoride so as to form a compound having the structure
Figure imgf000362_0001
b) contacting the product of step a) with sodium hydride so as to form a compound having the structure
Figure imgf000362_0002
or
a' ) contacting a compound having the structure
Figure imgf000363_0001
wherein G3 is C1-Io alkylene, C2-10 alkenylene, or C2-10 alkynylene;
Figure imgf000363_0002
wherein R62, R63, R64, Rβ5, and R66 are each, independently,
H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67,
-OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl;
R48 and R49 are each, independently, H, C1-10 alkyl, C2 -10
alkenyl, C2-10 alkynyl; or
Figure imgf000363_0003
wherein R57 and R58 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6O, wherein R6o is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2 -10 alkynyl ; and wherein each occurrence of R8i is, independently, C1-10 alkyl, or unsubstituted or substituted aryl; with a first suitable Bronsted acid in the presence of methanol so as to form a compound having the structure
Figure imgf000364_0001
b' ) contacting the product of a') with a first suitable Lewis acid so as to form a compound having the structure
Figure imgf000364_0002
C) contacting the product of step b' ) with a second suitable Lewis acid so as to form a compound having the structure
Figure imgf000364_0003
56. The process of claim 55, wherein R48 and R49 are each, independently, H, C1-10 alkyl,
C2-Io alkenyl, C2-10 alkynyl; or
Figure imgf000365_0001
wherein R57 and R58 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R60, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl .
57. The process of claim 55, wherein R48 and R49 are each, independently, H, C1-10 alkyl,
C2-10 alkenyl, C2-10 alkynyl; or
Figure imgf000365_0002
wherein R57 and R58 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -S02R6o, wherein Rβo is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl .
58. The process of claim 55, 56, or 57, comprising: a) contacting a compound having the structure
Figure imgf000366_0001
wherein G3 is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
Figure imgf000366_0002
wherein R62 , R63 , R64, R65, and R66 are each , independently,
H, halogen , -NO2 , C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl ; unsubstituted or substituted aryl ( C1-10) alkyl ; -OR67 , -SR67 ,
-OSO2R67 , or -NR67R68 , wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl;
R48 and R49 are each, independently, H, C1-10 alkyl, C2-10
alkenyl, C2-10 alkynyl; or
Figure imgf000366_0003
wherein R57 and R5s are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6O, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2 -10 alkynyl ; and wherein each occurrence of Rβi is, independently, C1-10 alkyl, or unsubstituted or substituted aryl; with tetra-n-butylammonium fluoride so as to form a compound having the structure
Figure imgf000367_0001
b) contacting the product of step a) with sodium hydride so as to form a compound having the structure
Figure imgf000367_0002
59. The process of claim 55, 56, or 57, comprising: a') contacting a compound having the structure
Figure imgf000367_0003
wherein G3 is C1-Io alkylene, C2-10 alkenylene, or C2-10 alkynylene;
Figure imgf000368_0001
wherein R62, Rβ3, Rβ4, Rβ5, and R66 are each, independently,
H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67,
-OSO2R6V, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl;
R48 and R49 are each, independently, H, C1-10 alkyl, C2 -10
alkenyl, C2-10 alkynyl; or
Figure imgf000368_0002
wherein R57 and R58 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6O, wherein Rβo is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and wherein each occurrence of R8i is, independently, C1-10 alkyl, or unsubstituted or substituted aryl; with a first suitable Bronsted acid in the presence of methanol so as to form a compound having the structure
Figure imgf000369_0001
b' ) contacting the product of a') with a first suitable Lewis acid so as to form a compound having the structure
Figure imgf000369_0002
C) contacting the product of step b') with a second suitable Lewis acid so as to form a compound having the structure
Figure imgf000369_0003
60. The process of claims 55, 56, 58, or 59 wherein the compound prepared is selected from the group consisting of: Compound 2, 43, and 48.
61. A process for preparing a compound having the structure
Figure imgf000370_0001
wherein v is present or absent; wherein R70 and R7i are each, independently, H, OH, -CO2R74, wherein R74 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl,
Figure imgf000370_0002
wherein R75 and R76 are independently H; C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -Sθ2R78, wherein R78 is C1-10 alkyl; or unsubstituted or substituted aryl; and wherein R77 is H; C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; wherein R72 and R73 are each, independently, H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1- 10) alkyl; -SO2R79, or -Si(R8Oh, wherein R79 is C1-10 alkyl, or unsubstituted or substituted aryl ; and wherein each occurrence of R80 is, independently, C1-10 alkyl, or unsubstituted or substituted aryl; and
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl; or alkynylene is branched or unbranched, unsubstituted or substituted; or a salt thereof;
comprising: a) contacting rosmarinic acid with TMSCHN2; b) contacting the product of step a) with a compound
having the structure
Figure imgf000371_0001
In the presence of a first suitable base so as to form a compound having the structure
Figure imgf000371_0002
62. The process of claim 61 further comprising: c) contacting the product of step b) with a second suitable base so as to form a compound having the structure
Figure imgf000371_0003
d) contacting the product of step c) with a compound having the structure
Figure imgf000372_0001
in the presence of JV-ethyl-iV' - (3- dimethylaminopropyl) carbodiimide and a third suitable base; e) contacting the product of step d) with tetra-n- butylaπunonium fluoride so as to form a compound having the structure
Figure imgf000372_0002
63. A process for preparing a compound having the structure
Figure imgf000372_0003
wherein Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000372_0004
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R1O, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl;
R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; R26, R27, R28, and R29 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1_10) alkyl; -OR3x, -SR31, -OSO2R3I, or -NR3xR32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2- 10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl ; and R42 is H, C1-10 alkyl, C2 -10 alkenyl, C2-10 alkynyl, or
Figure imgf000373_0001
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl;
comprising: a) exposing a compound having the structure
Figure imgf000374_0001
to a suitable Lewis acid so as to form the compound.
64. A process for preparing a compound having the structure
Figure imgf000374_0002
wherein G3 and G4 are each, independently, is C1-10 alkylene, C2-
10 alkenylene, or C2-10 alkynylene;
R48, R49, R50, and R51 are each, independently, H, C1-10 alkyl, C2-
10 alkenyl, C2-10 alkynyl ; or
Figure imgf000374_0003
wherein R57 and R5s are independently H, C1-10 alkyl, C2 -10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R60, wherein Rβo is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H , C1-10 alkyl , C2-10 alkenyl , or C2-10 alkynyl ; and wherein R53 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl , or -SO2R6I, wherein R61 is C1-10 alkyl, or unsubstituted or substituted aryl ;
R47 and R52 are each H, CN, or
Figure imgf000375_0001
wherein R62, R63, Rβ4, R65, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2- 10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl ; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof;
comprising: a) contacting a compound having the structure
Figure imgf000376_0001
wherein G3 is C1-10 alkylene , C2-10 alkenylene , or C2-10 alkynylene ;
Figure imgf000376_0002
wherein R62, Rβ3, R64, RΘS, and R66 are each, independently,
H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67,
-OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl;
R48 and R49 are each, independently, H, C1-10 alkyl, C2-10
alkenyl, C2-10 alkynyl; or
Figure imgf000376_0003
wherein R57 and R58 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R60, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R5g is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; with a suitable Lewis acid so as to form the compound.
65. A process for preparing a compound having the structure
Figure imgf000377_0001
wherein G3 and G4 are each, independently, is C1-10 alkylene, C2- io alkenylene, or C2-10 alkynylene;
R48, R49, R50, and R51 are each, independently, H, C1-10 alkyl, C2-
10 alkenyl, C2-10 alkynyl; or
Figure imgf000377_0002
wherein R57 and R58 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R60, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and
R47 and R52 are each H, CN, or
Figure imgf000377_0003
wherein R62, Rβ3, Rβ4, Rβ5, and Rβ6 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl ,• unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67, -OSO2R6?, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2- io alkenyl, C2 -10 alkynyl, or unsubstituted or substituted aryl ; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof;
comprising: a) contacting a compound having the- structure
Figure imgf000378_0001
wherein G3 is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene;
Figure imgf000378_0002
wherein R62 , R63, R64, Rβ5, and R66 are each , independently,
H , halogen, -NO2 , C1_10 alkyl , C2-10 alkenyl , C2-10 alkynyl ; unsubstituted or substituted aryl (C1-10) alkyl ; -OR67 , -SR67 ,
-OSO2R67 , or -NR67R68 , wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; R48 and R49 are each, independently, H, C1-10 alkyl, C2-10
alkenyl, C2-10 alkynyl; or
Figure imgf000379_0001
wherein R57 and R58 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1_10) alkyl, or -SO2R6O, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1_10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; with a suitable base so as to form the compound.
66. A process for preparing a compound having the structure
Figure imgf000379_0002
wherein G3 is C1_10 alkyl ene, C2-10 alkenyl ene, or C2-10 alkynylene;
Figure imgf000379_0003
wherein R62, R63, R64, R6s, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67, -OSO2R6?, or -NR67R68, wherein R.67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; R48 and R49 are each, independently, H, C1-10 alkyl, C2-10
alkenyl, C2-10 alkynyl; or
Figure imgf000380_0001
wherein R57 and R58 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6O, wherein R6o is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and wherein each occurrence of R8i is, independently, C1-10 alkyl, or unsubstituted or substituted aryl;
comprising: a) contacting a compound having the structure
Figure imgf000380_0002
with a suitable Bronsted acid so as to form a compound having the structure
Figure imgf000381_0001
b) contacting the product of step a) with a suitable hydride reducing agent; c) contacting the product of step b) with a suitable silylating agent; d) contacting the product of step c) with a suitable oxidizing agent so as to form the compound.
67. A process for preparing a compound having the structure
Figure imgf000381_0002
wherein R82 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl;
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof; comprising: a) contacting a compound having the structure
Figure imgf000382_0001
with a compound having the structure
w
Figure imgf000382_0002
herein R83 is halogen, -OH, o-h
Figure imgf000382_0003
in the presence of a suitable base so as to form the compound.
68. A composition, free of plant extract, comprising a compound having the structure
Figure imgf000382_0004
wherein a, Y, δ and σ are each, independently, present or absent; wherein when δ is absent,
Figure imgf000383_0001
is absent;
Gi is C1-iQ alkylene, C2-10 alkenylene, or C2-10 alkynylene;
R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000383_0002
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl ( C1-10) alkyl; or -SO2R10, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl;
R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when R7 and R8 are H and R9 is CH3, then R1 is
Figure imgf000383_0003
when Y is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORn, wherein Rn is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
Figure imgf000383_0004
, or -Si (R15)3; wherein R12 and each occurrence of R15 is C1-10 alkyl; or unsubstituted or substituted aryl; and R13 is S or 0; and R14 is -SCH3,
Figure imgf000384_0001
t or
Figure imgf000384_0002
when Y is absent; R5 is present and A is a direct bond or
Figure imgf000384_0003
wherein R3 and R4 are each, independently, H, halogen, or
OR16 ; wherein R16 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000384_0004
, or -Si (R20) 3; wherein R17 and each occurrence of R20 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R18 is S or 0; and R19 is -SCH3,
Figure imgf000384_0005
f or
Figure imgf000384_0006
R3 and R4 taken together form =0; and wherein R5 is H, halogen, or OR21, wherein R21 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000384_0007
, -SO2R22, , or -Si(R25)3, wherein R22 and each occurrence of R2s is C1-10 alkyl, or unsubstituted or substituted aryl; and R23 is S or O; and R24 is -SCH3,
Figure imgf000385_0001
Figure imgf000385_0002
wherein R25, R26, R27, R2S, and R2g are each, independently,
H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -0R3i, -SR3x,
-OSO2R3I, or -NR3iR32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; and
R30 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000385_0003
wherein R33 and R34 are each, independently, H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1_10) alkyl; or -SO2R36, wherein R36 is C1_10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and when R33 and R34 are H and R35 is CH3, then R30 is
Figure imgf000386_0001
R6 is H, halogen, or OR37; wherein R37 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000386_0002
, or -Si (R41) 3; wherein R38 and each occurrence of R41 is C1-J-O alkyl; or unsubstituted or substituted aryl; R3g is S or 0; and R40 is -SCH3; -NH-aryl , heteroaryl ,
heterocyclyl ; or
Figure imgf000386_0003
; Or R5 when present and R6 taken together form =0; or R4 joined to R6 form a 5-membered heterocyclic ring; and
when σ is present;
R2 is
Figure imgf000386_0004
; and
O wherein X is a direct bond, Ms or C(OMe)2; O
Y is H or OR42; or when α is present, Y is Ms. wherein R42 is H, C1-I-O alkyl, C2-1.0 alkenyl, C2-1.0 alkynyl,
or
Figure imgf000386_0005
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when R43 and R44 are H and R45 is CH3, then R42 is
Figure imgf000387_0001
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Figure imgf000387_0002
w erein Ra is S or O; Rb is -0- (C1-C10) alkyl , -O- (C2- C10) alkenyl, heterocyclyl, or heteroaryl; or
when α is present, Z is -CH=CH-;
and when α is present, R1 is other than methyl;
or a salt thereof.
69. The composition of claim 68 comprising a compound having the structure
Figure imgf000388_0001
wherein α, Y, and σ are each, independently, present or absent;
Gi is C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; R1 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or
Figure imgf000388_0002
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R1O, wherein R10 is C1-10 alkyl, or unsubstituted or substituted aryl; R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when Y is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORn, wherein Ru is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000388_0003
, or -Si (R15) 3; wherein R12 and each occurrence of R15 is C1-10 alkyl; or unsubstituted or substituted aryl; and R13 is S or 0; and R14 is -SCH3,
Figure imgf000389_0001
, or
Figure imgf000389_0002
when Y is absent; R5 is present and A is a direct bond or
Figure imgf000389_0003
wherein R3 and R4 are each, independently, H, halogen, or OR16 ; wherein R16 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000389_0004
, or -Si (R20) 3; wherein R17 and each occurrence of R2o is C1-10 alkyl, or unsubstituted or substituted aryl; and
R18 is S or 0; and R19 is -SCH3,
Figure imgf000389_0005
# or
Figure imgf000389_0006
R3 and R4 taken together form =0; and wherein R5 is H, halogen, or 0R2i, wherein R21 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000389_0007
, or -Si(R25)3, wherein R22 and each occurrence of R25 is C1-10 alkyl, or unsubstituted or substituted aryl; and R23 is S or 0 ; and R24 is -SCH3 ,
Figure imgf000390_0001
, or
Figure imgf000390_0002
when σ is absent;
Figure imgf000390_0003
wherein R25, R26, R27, R28, and R29 are each, independently,
H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR31, -SR31,
-OSO2R3I, or -NR31R32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1-10 alkylene, C2-10 alkenylene, or C2 -10 alkynylene; and
R30 is H , C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl , or
Figure imgf000390_0004
wherein R33 and R34 are each, independently, H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R36, wherein R36 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H , C1-10 alkyl , C2-10 alkenyl , or C2-10 alkynyl ; and
R6 is H, halogen , or OR37 ; wherein R37 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000391_0001
, or -Si(R4I)3; wherein R38 and each occurrence of R41 is C1-10 alkyl; or unsubstituted or substituted aryl;
R39 is S or O; and R40 is -SCH3; ; or
Figure imgf000391_0003
R5 when present and R6 taken together form =0; or
R4 joined to R6 form a 5-membered heterocyclic ring; and
when σ is present;
Figure imgf000391_0004
; and
O wherein X is a direct bond, c ^, or C(OMe)2;
O
Y is H or OR42; or when α is present, Y is ^ c ; wherein R42 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl,
Figure imgf000391_0005
wherein R43 and R44 are independently H, C1-10 alkyl, C2-Io alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1_10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl , C2-10 alkenyl , or C2-10 alkynyl ; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Z is H or CN; or when α is present, Z is -CH=CH-; and
when a is present, R1 is other than methyl;
or a salt thereof.
70. The composition of claim 69, wherein the compound has the structure
Figure imgf000392_0001
wherein α, Y, and σ are each, independently, present or absent;
Gi is C1-10 alkyl ene , C2-10 alkenylene , or C2-10 alkynylene ; R1 is H , C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl , or
Figure imgf000392_0002
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R10, wherein R1o is C1-10 alkyl, or unsubstituted or substituted aryl; R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when Y is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORn, wherein R11 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000393_0001
, or -Si(R1S)3; wherein R12 and each occurrence of R15 is C1-10 alkyl; or unsubstituted or substituted aryl; and
R13 is S or O; and R14 is -SCH3,
Figure imgf000393_0002
or
Figure imgf000393_0003
when Y is absent; R5 is present and A is a direct bond or
Figure imgf000393_0004
wherein R3 and R4 are each, independently, H, halogen, or OR16 ; wherein R16 is H , C1-10 alkyl , -CH2SH , -BHCH2CH3 , -
CH=SH,
Figure imgf000393_0005
, -SO2R17 , , or -Si (R20) 3 ; wherein R17 and each occurrence of R20 is C1-10 alkyl, or unsubstituted or substituted aryl; and R1 a is S or 0; and R19 is -SCH3,
Figure imgf000394_0001
t or
Figure imgf000394_0002
R3 and R4 taken together form =0; and wherein R5 is H, halogen, or OR21, wherein R2i is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000394_0003
, -SO2R22, , or -Si(R25)3, wherein R22 and each occurrence of R25 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R23 is S or 0; and R24 is -SCH3,
Figure imgf000394_0004
; or
Figure imgf000394_0005
when σ is absent;
Figure imgf000394_0006
wherein R25, R26, R27, R28, and R29 are each, independently,
H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -0R3i, -SR31,
-OSO2R31, or -NR31R32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1-10 alkylene, C2-10 alkenylene, or C2-10 a1kyny1ene; and C2-10 alkenyl , C2-10 alkynyl , or
Figure imgf000395_0001
wherein R33 and R34 are each, independently, H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1_10) alkyl; or -SO2R36, wherein R36 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and R6 is H, halogen, or OR37; wherein R37 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000395_0002
wherein R38 and each occurrence of R41 is C1-10 alkyl; or unsubstituted or substituted aryl;
R39 is S or 0; and R40 is -SCH3;
Figure imgf000395_0003
; or
Figure imgf000395_0004
R5 when present and R6 taken together form =0; or R4 joined to R6 form a 5-membered heterocyclic ring; and
when σ is present;
R2 is
Figure imgf000395_0005
. and O wherein X is a direct bond, c ^, or C(OMe)2;
O
Y is H or OR42 ; or when α is present , Y is c c ; wherein R42 is H, C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl ,
Figure imgf000396_0001
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Z is H or CN; or when a. is present, Z is -CH=CH-; and
when α is present, R1 is other than methyl;
or a salt thereof.
71. The composition of claim 69, wherein the compound has the structure
Figure imgf000397_0001
wherein α, Y, and σ are each, independently, present or absent;
Gi is C1-10 alkylene , C2-10 alkenylene , or C2-10 alkynylene ; R1 is H , C1-10 alkyl , C2-10 alkenyl , C2-10 alkynyl , or
Figure imgf000397_0002
wherein R7 and R8 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl ( C1-10) alkyl; or -SO2R1O, wherein R10 is C1_10 alkyl, or unsubstituted or substituted aryl; R9 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; and when Y is present; R5 is absent and A is C-R4, wherein R4 is H, halogen, or ORn, wherein R11 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000397_0003
, or -Si(R15)3; wherein R12 and each occurrence of R15 is C1-10 alkyl; or unsubstituted or substituted aryl; and R13 is S or 0; and R14 is -SCH3,
Figure imgf000398_0001
, or
Figure imgf000398_0002
when Y is absent; R5 is present and A is a direct bond or
Figure imgf000398_0003
wherein R3 and R4 are each, independently, H, halogen, or OR16; wherein R16 is H, C1_10 alkyl, -CH2SH, -BHCH2CH3, -
CH=SH,
Figure imgf000398_0004
, or -Si (R20) 3; wherein R17 and each occurrence of R2o is C1_10 alkyl, or unsubstituted or substituted aryl; and
R18 is S or 0; and R19 is -SCH3,
Figure imgf000398_0005
, Or
Figure imgf000398_0006
R3 and R4 taken together form =0; and wherein R5 is H, halogen, or OR2I, wherein R2x is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000398_0007
, -SO2R22, , or -Si(R25)3, wherein R22 and each occurrence of R2s is C1-10 alkyl, or unsubstituted or substituted aryl; and R23 is S or O; and R24 is -SC
Figure imgf000399_0001
Figure imgf000399_0002
when σ is absent;
R2 is H, R30
Figure imgf000399_0003
; wherein R25, R26, R27, R28, and R2g are each, independently,
H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl , C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR31, -SR31,
-OSO2R3I, or -NR31R32, wherein R31 and R32 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; wherein G2 is C1_10 alkylene, C2-10 alkenylene, or C2-10 alkynylene; and
R30 is H , C1-10 alkyl , C2-10 alkenyl , C2 -10 alkynyl , or
Figure imgf000399_0004
wherein R33 and R34 are each, independently, H, C1_10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1_10) alkyl; or -SO2R36, wherein R36 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R35 is H, C1-10 alkyl , C2-10 alkenyl , or C2-10 alkynyl ; and R6 is H , halogen , or OR37 ; wherein R37 is H, C1-10 alkyl, -CH2SH, -BHCH2CH3, -CH=SH,
Figure imgf000400_0001
, -SO2R38, , or -Si(R4I)3; wherein R38 and each occurrence of R41 is C1-10 alkyl; or unsubstituted or substituted aryl;
R39 is S or 0; and R40 is -SCH3;
Figure imgf000400_0002
; or
Figure imgf000400_0003
R5 when present and R6 taken together form =0; or
R4 joined to R6 form a 5-membered heterocyclic ring; and
when σ is present;
Figure imgf000400_0004
;. and.
wherein X is a direct bond,
Figure imgf000400_0005
or C(OMe)2;
Y is H or OR42; or when a. is present, Y is
Figure imgf000400_0006
; wherein R42 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl,
Figure imgf000400_0007
wherein R43 and R44 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; or -SO2R46, wherein R46 is C1-10 alkyl, or unsubstituted or substituted aryl; and
R45 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is branched or unbranched, unsubstituted or substituted;
Z is H or CN; or when α is present, Z is -CH=CH-; and
when α is present, R1 is other than methyl;
or a salt thereof.
72. The composition of claim 69 or 70 wherein the compound is selected from the group consisting of: Compound 3, 4, 21, 23, 24, 25, 26, 33, 34, 35, 36, 37, 39, 40, 42, 44, 45, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, and 63.
73. The composition of claim 69 or 70 wherein the compound is compound 51.
74. The composition of claim 68 comprising a compound having the structure
Figure imgf000401_0001
wherein δ is present or absent ;
wherein when δ is absent,
Figure imgf000402_0001
is absent;
R6 is OR37 ;
wherein R37 is
Figure imgf000402_0002
; wherein R39 is S or 0 ; and R40 is -NH-aryl , heteroaryl , heterocyclyl ; or
O
X is a direct bond or
Figure imgf000402_0003
wherein Ra is S or O; Rb is -0- (C1-C10) alkyl , -O- (C2- C10)alkenyl, heterocyclyl, or heteroaryl; or
or a salt thereof.
75. The composition of claim 74 comprising a compound having the structure
Figure imgf000402_0004
wherein δ is present or absent ;
O
wherein when δ is absent , R1°^G ^1 is absent ;
R6 is OR37 ;
wherein R37 is
Figure imgf000403_0001
wherein R39 is S; and R40 is
Figure imgf000403_0002
O
X is a direct bond or
Figure imgf000403_0003
wherein Ra is S or O; Rb is -0- (C1-C10) alkyl, -0-(C2- C1O)alkenγl, heterocyclyl, or heteroaryl; or
or a salt thereof.
76. The composition of claim 75 comprising a compound having the structure
Figure imgf000403_0004
wherein δ is present or absent;
wherein when δ is absent,
Figure imgf000404_0001
is absent;
R1 is H, methyl or
Figure imgf000404_0002
R2 is H or
Figure imgf000404_0003
R3 and R4 are each -OCH3;
R5 is H or OR21,
wherein R21 is
Figure imgf000404_0004
wherein R23 is S; and R24 is
Figure imgf000404_0005
; and
R6 is OR37;
wherein R37 is
Figure imgf000404_0006
N wherein R39 is S; and R40 is or
Figure imgf000404_0008
Figure imgf000404_0007
O
X is a direct bond or M4.
Y is H or OR42 ; wherein R42 is methyl , -CH2CH=CH2 or
Figure imgf000405_0001
Figure imgf000405_0002
wherein Ra is S or 0 ; Rb is -OCH3 , -OCH (CH3 ) 2 , -OCH2CH=CH2 ,
Figure imgf000405_0003
or a salt thereof.
77. The composition of claim 76 comprising a compound selected from the group consisting of Compound 64, 65, 66, 67, 68, 73, 74, 75, 76, 77, 78, 79, 80, and a pharmaceutically acceptable salt thereof.
78. A composition, free of plant extract, comprising a compound having the structure
Figure imgf000406_0001
wherein ε and δ are present or absent; wherein R54 and R55 are present or absent; and when ε is present; δ and R54 are absent, and R55 is present; and when δ is present; ε and R55 are absent, and R54 is present;
wherein G3 and G4 are each, independently, is C1-10 alkylene, C2- io alkenylene, or C2-10 alkynylene;
R48, R49, 1*50, and R5i are each, independently, H, C1-10 alkyl, C2-
10 alkenyl, C2-10 alkynyl; or
Figure imgf000406_0002
wherein R57 and R58 are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6O, wherein R6o is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and wherein R53 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6i, wherein R6i is C1-10 alkyl, or unsubstituted or substituted aryl ; R47 and R52 are each H, CN, or
Figure imgf000407_0001
wherein R62, R63, R64» Rβ5, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67,
Figure imgf000407_0002
wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; and wherein R54 when present, R55 when present, and R56 are each, independently, H or OR69, wherein R69 is H or C1-10 alkyl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof.
79. The composition of claim 78, wherein the compound has the structure
Figure imgf000407_0003
wherein ε and δ are present or absent; wherein R54 and R55 are present or absent; and when ε is present; δ and R54 are absent, and R55 is present; and when δ is present; ε and R55 are absent, and R54 is present; wherein G3 and G4 are each, independently, is C1-10 alkylene, C2- 10 alkenylene, or C2-10 alkynylene; R48, R49, R5O, and R51 are each, independently, H, C1-10 alkyl, C2-
10 alkenyl, C2-10 alkynyl; or
Figure imgf000408_0001
wherein R57 and R5s are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -S02R6o, wherein R60 is C1-10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl ; and wherein R53 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6I, wherein R6i is C1-10 alkyl, or unsubstituted or substituted aryl ;
R47 and R52 are each H, CN, or
Figure imgf000408_0002
wherein R62, Rβ3, R64, R6s, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67, -OSO2R67, or -NR67R68, wherein R67 and R68 are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; and wherein R54 when present, R55 when present, and R56 are each, independently, H or OR69, wherein R6g is H or C1-10 alkyl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof.
80. The composition of claim 79, wherein the compound has the structure
Figure imgf000409_0001
wherein ε and δ are present or absent; wherein R54 and R55 are present or absent; and when ε is present; δ and R54 are absent, and R55 is present; and when δ is present; ε and R55 are absent, and R54 is present; wherein G3 and G4 are each, independently, is C1-10 alkylene, C2-
10 alkenylene, or C2-10 alkynylene;
R48, R49, R50, and R51 are each, independently, H, C1-10 alkyl, C2-
10 alkenyl, C2-10 alkynyl; or
Figure imgf000409_0002
wherein R57 and R5s are independently H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6O, wherein R60 is C1_10 alkyl, or unsubstituted or substituted aryl; and wherein R59 is H , C1-10 alkyl , C2-10 alkenyl , or C2-10 alkynyl ; and wherein R53 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, unsubstituted or substituted aryl (C1-10) alkyl, or -SO2R6I, wherein R6χ is C1-10 alkyl, or unsubstituted or substituted aryl ;
Figure imgf000410_0001
wherein R62, R63, R64, R65, and R66 are each, independently, H, halogen, -NO2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl; unsubstituted or substituted aryl (C1-10) alkyl; -OR67, -SR67, -OSO2R6?, or -NR67R68, wherein R67 and R6g are each, independently, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or unsubstituted or substituted aryl; and wherein R54 when present, R55 when present, and R56 are each, independently, H or OR69, wherein R69 is H or C1-10 alkyl; or
wherein each occurrence of alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene is branched or unbranched, unsubstituted or substituted;
or a salt thereof.
81. The composition of claim 79 or 80 wherein the compound is selected from the group consisting of: Compound 2, 43, and 48.
82. The composition of any one of claims 68-81 further comprising a pharmaceutically acceptable carrier.
83. A method of treating a cell expressing a mutant human huntingtin gene, wherein the expression of the mutant huntingtin gene results in a huntingtin protein having a polyglutamine N-terminal, comprising contacting the cell with the composition of any one of claims 68-82 so as to treat the cell.
84. A method of treating a cell expressing a mutant human huntingtin gene, wherein the expression of the mutant huntingtin gene results in a huntingtin protein having a polyglutamine N-terminal, comprising contacting the cell with the compound of any one of claims 1 to 20 so as to treat the cell.
85. A method of reducing cell death in a population of cells expressing a mutant human huntingtin gene, wherein the expression of the mutant huntingtin gene results in a huntingtin protein having a polyglutamine N-terminal, comprising contacting the population of cells with the composition of any one of claims 68-82 so as to reduce cell death in the population of cells.
86. A method of reducing cell death in a population of cells expressing a mutant human huntingtin gene, wherein the expression of the mutant huntingtin gene results in a huntingtin protein having a polyglutamine N-terminal, comprising contacting the population of cells with the compound of any one of claims 1 to 20 so as to reduce cell death in the population of cells.
87. The method of claim 83 or 84, wherein the cell is a mammalian nerve cell.
88. The method of claim 83 or 85, wherein the composition comprises a compound having the structure
Figure imgf000412_0001
89. The method of claim 85 or 86, wherein the population of cells is a population of mammalian nerve cells.
90. The method of claim 84 or 86, wherein the compound has the structure
Figure imgf000412_0002
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TEZUKA ET AL.: "Helicterins A-F, Six New Dimeric (7.5', 8.2')-Neolignans From the Indonesian Medicinal Plant Helicteres Isora.", HELVITICA CHIMICA ACTA, vol. 83, 2000, pages 2908 - 2919 *
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