WO2019009956A1 - Synthèse de cétone médiée par fe/cu - Google Patents

Synthèse de cétone médiée par fe/cu Download PDF

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WO2019009956A1
WO2019009956A1 PCT/US2018/031765 US2018031765W WO2019009956A1 WO 2019009956 A1 WO2019009956 A1 WO 2019009956A1 US 2018031765 W US2018031765 W US 2018031765W WO 2019009956 A1 WO2019009956 A1 WO 2019009956A1
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Prior art keywords
optionally substituted
alkyl
compound
certain embodiments
formula
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PCT/US2018/031765
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English (en)
Inventor
Yoshito Kishi
Kenzo YAHATA
Vemula Praveen KUMAR
Sudheer Babu VADDELA
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President And Fellows Of Harvard College
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Priority claimed from JP2017217255A external-priority patent/JP7266267B2/ja
Application filed by President And Fellows Of Harvard College filed Critical President And Fellows Of Harvard College
Priority to US16/628,419 priority Critical patent/US11498892B2/en
Publication of WO2019009956A1 publication Critical patent/WO2019009956A1/fr
Priority to US18/053,921 priority patent/US20230135188A1/en

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    • 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
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • RSnX 3 /Pd Wittenberg, R.; Srogl, J.; Egi, M.; Liebeskind, L. S. Org. Lett. 2003, 5, 3033; RB(OH) 2 /Pd: Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260; RSnX 3 /Cu: Li, H.; He, A.; Falck, J. R.; Liebeskind, L. S. Org. Lett. 2011, 13, 3682; R 2 Zn/Ni: Zhang, Y.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 15964.
  • ketones are needed, especially for use in the preparation of complex molecules, such as halichondrins and analogs thereof.
  • Halichondrins are polyether natural products, originally isolated from the marine scavenger Halichondria okadai by Uemura, Hirata, and coworkers. See, e.g., Uemura, D.; Takahashi, K.; Yamamoto, T.; Katayama, C; Tanaka, J.; Okumura, Y.; Hirata, Y. . Am. Chem. Soc. 1985, 107, 4796; Hirata, Y.; Uemura, D. Pure Appl. Chem. 1986, 58, 701.
  • halistatin Several additional members, including halistatin, were isolated from various marine scavengers.
  • This class of natural products displays interesting structural diversity, such as the oxidation state of the carbons of the C8-C14 polycycle, and the length of the carbon backbone.
  • this class of natural products is sub-grouped into the norhalichondrin series (e.g., norhalichondrin A, B, and C), the halichondrin series (e.g., halichondrin A, B, C), and the homohalichondrin series (e.g., homohalichondrin A, B, C).
  • norhalichondrin series e.g., norhalichondrin A, B, and C
  • halichondrin series e.g., halichondrin A, B, C
  • homohalichondrin series e.g., homohalichondrin A, B, C
  • halichondrin A is when
  • R and FT are both -OH; halichondrin B is when R and R are both hydrogen; and
  • halichondrin C is when R is -OH and R is h dro en:
  • Fe/Cu-mediated coupling reaction can be used in the preparation of complex molecules, such as halichondrins and analogs thereof.
  • Fe/Cu-mediated ketolization reactions described herein are useful in the preparation of intermediates en route to halichondrins. Therefore, the present invention also provides methods for the preparation of intermediates useful in the synthesis of halichondrins.
  • the present invention provides methods for preparing ketones using a Fe/Cu-mediated coupling reaction, as outlined in Scheme 1A.
  • the groups R A , X 1 , X 2 , and R B are defined herein.
  • the coupling reactions provided herein can be used in the synthesis of ketone- containing compounds, such as intermediates en route to halichondrins ⁇ e.g., halichondrin A, B, C; homohalichondrin A, B, C; norhalichondrin A, B, C) and analogs thereof.
  • Scheme 2 shows a Fe/Cu-mediated coupling reaction to yield a compound of Formula (1-13), which is an intermediate useful in the synthesis of halichondrins ⁇ e.g., halichondrin A, B, C), and analogs thereof.
  • Groups R pl , R p2 , R p3 , R p5 , R 1 , X 2 , X 1 , R 2 , R p4 , and X 3 are defined herein.
  • Scheme 3 shows a Fe/Cu-mediated coupling reaction to yield a compound of Formula (1-11), which is an intermediate useful in the synthesis of
  • Scheme 4 shows a Fe/Cu-mediated coupling reaction to yield compounds of Formula (II-3), which are intermediates useful in the synthesis of
  • halichondrins and analogs thereof i.e., C20-C26 fragments of halichondrins.
  • X 3 3 , R 5 J , and R 8° are as defined herein.
  • T -C26 carbons of compounds in the halichondrin series are denoted below.
  • an advantage of the Fe/Cu-mediated couplings described herein over existing ketolization methods is that the novel Fe/Cu-mediated reactions allow for selective coupling of alkyl halides (e.g., alkyl iodides) in the presence of vinyl halides (e.g., vinyl iodides).
  • alkyl halides e.g., alkyl iodides
  • vinyl halides e.g., vinyl iodides
  • Other ketone-forming coupling reactions, as well as methods for the synthesis of halichondrins can be found in, for example, international PCT publications, WO
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of 12 C with 13 C or 14 C are within the scope of the disclosure.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • Ci_6 alkyl is intended to encompass, Q, C 2 , C 3 , C 4 , C5, C 6 , Ci-6, Ci-5, Ci_ 4 , Ci- 3 , Ci_ 2 , C 2 _6, C 2 _5, C2-4, C2-3, C 3 -6, C 3 -5, C 3 _ 4 , C 4 -6, C 4 -5, and C5-6 alkyl.
  • aliphatic refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.
  • heteroaliphatic refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“Ci-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“Ci_9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci_ 8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”).
  • an alkyl group has 1 to 4 carbon atoms (“Ci_ 4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“Ci_ 3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“Ci_ 2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2 -6 alkyl”). Examples of Ci_ 6 alkyl groups include methyl (Q), ethyl (C 2 ), propyl (C 3 ) (e.g.
  • n-propyl isopropyl
  • butyl C 4
  • pentyl C5
  • hexyl C 6
  • alkyl groups include n-heptyl (C 7 ), n- octyl (C 8 ), and the like.
  • each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents (e.g. , halogen, such as F).
  • the alkyl group is an unsubstituted Ci-10 alkyl (such as unsubstituted Ci_6 alkyl, e.g. , -CH 3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g.
  • the alkyl group is a substituted Ci-10 alkyl (such as substituted Ci_ 6 alkyl, e.g. , -CF 3 , Bn).
  • haloalkyl is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • the haloalkyl moiety has 1 to 8 carbon atoms ("C 1-8 haloalkyl”).
  • the haloalkyl moiety has 1 to 6 carbon atoms ("C 1-6 haloalkyl”).
  • the haloalkyl moiety has 1 to 4 carbon atoms ("C 1-4 haloalkyl").
  • the haloalkyl moiety has 1 to 3 carbon atoms ("C 1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("CM haloalkyl").
  • CM haloalkyl examples include -CHF 2 , -CH 2 F, -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , -CF 2 CF 2 CF 3 , -CC1 3 , -CFCI2, -CF2CI, and the like.
  • heteroalkyl refers to an alkyl group, which further includes at least one heteroatom (e.g. , 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-10 alkyl").
  • a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain
  • heteroCi_9 alkyl a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi_ 8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-7 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi_6 alkyl").
  • a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain ("heteroCi-5 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain ("heteroCi_ 4 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroCi_ 3 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroCi_ 2 alkyl").
  • a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain ("heteroC 2 _6 alkyl"). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi_io alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi_io alkyl.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds).
  • an alkenyl group has 2 to 9 carbon atoms ("C 2 -9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms ("C 2 -8 alkenyl”).
  • an alkenyl group has 2 to 7 carbon atoms ("C 2 -7 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms (“C 2 -6 alkenyl”).
  • an alkenyl group has 2 to 5 carbon atoms ("C 2 -5 alkenyl”).
  • an alkenyl group has 2 to 4 carbon atoms ("C 2 - 4 alkenyl"). In some
  • an alkenyl group has 2 to 3 carbon atoms ("C 2 -3 alkenyl"). In some
  • an alkenyl group has 2 carbon atoms ("C 2 alkenyl”).
  • the one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C 2-4 alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1- butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • C 2 -6 alkenyl groups include the aforementioned C 2 - 4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted (a
  • heteroalkenyl refers to an alkenyl group, which further includes at least one heteroatom (e.g. , 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e. , inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 -io alkenyl").
  • a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -9 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -8 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 -7 alkenyl").
  • a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -6 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heteroC 2 -5 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2 - 4 alkenyl").
  • a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain ("heteroC 2 -3 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heteroC 2 -6 alkenyl"). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC 2 io alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC 2 io alkenyl.
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g. , 1, 2, 3, or 4 triple bonds) ("C 2 - 10 alkynyl").
  • an alkynyl group has 2 to 9 carbon atoms ("C 2 -9 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms (“C 2 -8 alkynyl”).
  • an alkynyl group has 2 to 7 carbon atoms (“C 2- 7 alkynyl”).
  • an alkynyl group has 2 to 6 carbon atoms ("C 2 -6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2 -5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2 - 4 alkynyl”). In some
  • an alkynyl group has 2 to 3 carbon atoms ("C 2 -3 alkynyl").
  • an alkynyl group has 2 carbon atoms ("C 2 alkynyl").
  • the one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • Examples of C 2 - 4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2- propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • C 2 -6 alkenyl groups include the aforementioned C 2 - 4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C 2-1 o alkynyl. In certain embodiments, the alkynyl group is a substituted C 2 _io alkynyl.
  • heteroalkynyl refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e. , inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 _io alkynyl").
  • a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 _9 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 _ 8 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 _7 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 _6 alkynyl"). In some embodiments, a
  • a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroC 2 _5 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain (“heteroC 2 _ 4 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC 2 _3 alkynyl").
  • a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroC 2 _6 alkynyl"). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl") or substituted (a "substituted
  • heteroalkynyl with one or more substituents.
  • the heteroalkynyl group is an unsubstituted heteroC 2 _io alkynyl.
  • the heteroalkynyl group is a substituted heteroC 2 _io alkynyl.
  • a "hydrocarbon chain” refers to a substituted or unsubstituted divalent alkyl, alkenyl, or alkynyl group.
  • a hydrocarbon chain includes (1) one or more chains of carbon atoms immediately between the two radicals of the hydrocarbon chain; (2) optionally one or more hydrogen atoms on the chain(s) of carbon atoms; and (3) optionally one or more substituents ("non-chain substituents," which are not hydrogen) on the chain(s) of carbon atoms.
  • a chain of carbon atoms consists of consecutively connected carbon atoms ("chain atoms") and does not include hydrogen atoms or heteroatoms.
  • a non-chain substituent of a hydrocarbon chain may include any atoms, including hydrogen atoms, carbon atoms, and
  • hydrocarbon chain -C H(C H 2 C 3 ⁇ 4)- includes one chain atom
  • C x hydrocarbon chain refers to a hydrocarbon chain that includes x number of chain atom(s) between the two radicals of the hydrocarbon chain. If there is more than one possible value of x, the smallest possible value of x is used for the defi ydrocarbon chain. For example, -CH(C 2 Hs)- is a Ci hydrocarbon chain,
  • a C 3 _io hydrocarbon chain refers to a hydrocarbon chain where the number of chain atoms of the shortest chain of carbon atoms immediately between the two radicals of the hydrocarbon chain is 3, 4, 5, 6, 7, 8, 9, or 10.
  • a hydrocarbon chain may be saturated (e.g., -(CH 2 ) 4 -).
  • the hydrocarbon chain is substituted (e.g. , -CH(C 2 Hs)- and -CF 2 -). Any two substituents on the hydrocarbon chain may be joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring.
  • ⁇ ⁇ ⁇ is a C 3 hydrocarbon chain wherein one chain atom is replaced with an oxygen atom.
  • carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms ("C 3-14 carbocyclyl") and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 10 ring carbon atoms ("C 3 - 10 carbocyclyl”).
  • a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3 _ 8 carbocyclyl”).
  • a carbocyclyl group has 3 to 7 ring carbon atoms (“C 3 _7 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3 -6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4 _6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“Cs_6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("Cs-io carbocyclyl”).
  • Exemplary C 3 _ 6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3 _ 8 carbocyclyl groups include, without limitation, the aforementioned C 3 _ 6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3 _io carbocyclyl groups include, without limitation, the aforementioned C 3 _ 8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (Qo), cyclodecenyl (C 10 ), octahydro-lH-indenyl (C9), decahydronaphthalenyl (C 10 ),
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g. , containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is an unsubstituted C 3-14 carbocyclyl.
  • the carbocyclyl group is a substituted C 3-14 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms ("C 3 _i 4 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C 3 _io cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3 _ 8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3 -6 cycloalkyl").
  • a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("Cs_6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("Cs-io cycloalkyl”). Examples of Cs_6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ).
  • C 3 -6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • Examples of C 3 _ 8 cycloalkyl groups include the aforementioned C 3 _ 6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
  • each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents.
  • the cycloalkyl group is an unsubstituted C 3 _i 4 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C 3 _i 4 cycloalkyl.
  • heterocyclyl refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3- 14 membered heterocyclyl").
  • heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g.
  • a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)
  • bicyclic heterocyclyl bicyclic system
  • tricyclic heterocyclyl tricyclic system
  • Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently
  • a heterocyclyl group is an unsubstituted 3- 14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl. [0031] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl").
  • a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl").
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl").
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl.
  • Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.
  • Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl.
  • Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • heteroatoms include, without limitation, triazinyl.
  • Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,
  • aryl refers to a radical of a monocyclic or polycyclic (e.g. , bicyclic or tricyclic) 4n+2 aromatic ring system (e.g. , having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C 6-14 aryl").
  • an aryl group has 6 ring carbon atoms ("C 6 aryl”; e.g. , phenyl).
  • an aryl group has 10 ring carbon atoms ("Cio aryl"; e.g.
  • an aryl group has 14 ring carbon atoms ("C 14 aryl”; e.g. , anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents.
  • the aryl group is an unsubstituted C 6-14 aryl.
  • the aryl group is a substituted C 6-14 aryl.
  • heteroaryl refers to a radical of a 5- 14 membered monocyclic or polycyclic (e.g. , bicyclic, tricyclic) 4n+2 aromatic ring system (e.g. , having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- 14 membered heteroaryl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g. , indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e. , either the ring bearing a heteroatom (e.g. , 2-indolyl) or the ring that does not contain a heteroatom (e.g. , 5-indolyl).
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl").
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl").
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl").
  • the 5- 6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl”) with one or more substituents.
  • the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • 5- membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • 6- membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,
  • Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.
  • saturated refers to a moiety that does not contain a double or triple bond, i.e. , the moiety only contains single bonds.
  • alkylene is the divalent moiety of alkyl
  • alkenylene is the divalent moiety of alkenyl
  • alkynylene is the divalent moiety of alkynyl
  • heteroalkylene is the divalent moiety of heteroalkyl
  • heteroalkenylene is the divalent moiety of heteroalkenyl
  • heteroalkynylene is the divalent moiety of heteroalkynyl
  • carbocyclylene is the divalent moiety of carbocyclyl
  • heterocyclylene is the divalent moiety of heterocyclyl
  • arylene is the divalent moiety of aryl
  • heteroarylene is the divalent moiety of heteroaryl.
  • a group is optionally substituted unless expressly provided otherwise.
  • the term “optionally substituted” refers to being substituted or unsubstituted.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted.
  • Optionally substituted refers to a group which may be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, "substituted” or “unsubstituted” alkynyl,
  • substituted means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound.
  • the present invention contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • the invention is not intended to be limited in any manner by the exemplary substituents described herein.
  • R aa is, independently, selected from Ci_io alkyl, Ci_io perhaloalkyl, C 2 -io alkenyl, C 2 -io alkynyl, heteroCi_io alkyl, heteroC 2 -io alkenyl, heteroC 2 -io alkynyl, C 3 _io carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R aa groups are joined to form a 3-14 membered heterocyclyl or 5
  • each instance of R bb is, independently, selected from hydrogen, -OH, -OR aa ,
  • each instance of R cc is, independently, selected from hydrogen, Ci_io alkyl, Ci_io perhaloalkyl, C 2 _io alkenyl, C 2 _io alkynyl, heteroCi_io alkyl, heteroC 2 _io alkenyl, heteroC 2 _io alkynyl, C 3 _io carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R ee is, independently, selected from C 1-6 alkyl, C 1-6 perhaloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, heteroCi_6 alkyl, heteroC 2 _6 alkenyl, heteroC 2 _6 alkynyl, C 3-1 o carbocyclyl, C 6-1 o aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • each instance of R ff is, independently, selected from hydrogen, Ci_ 6 alkyl, Ci_ 6 perhaloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, heteroC 1-6 alkyl, heteroC 2 _6 alkenyl, heteroC 2 _6 alkynyl, C 3-1 o carbocyclyl, 3-10 membered heterocyclyl, C 6-1 o aryl and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; and
  • carbon atom substituents include: halogen, -CN, -N0 2 , -N 3 , -S0 2 H, -S0 3 H, -OH, -OCi_6 alkyl, -ON(Ci_ 6 alkyl) 2 , -N(Ci_ 6 alkyl) 2 , -N(Ci_ 6 alkyl) 3 + X-, -NH(Ci_6 alkyl) 2 + X " , -NH 2 (Ci_ 6 alkyl) + X " , -NH 3 + X " , -N(OCi_ 6 alkyl)(Ci_ 6 alkyl),
  • halo refers to fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), or iodine (iodo, -I).
  • hydroxyl refers to the group -OH.
  • amino refers to the group -NH 2 .
  • substituted amino by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the "substituted amino” is a monosubstituted amino or a
  • trisubstituted amino refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from -N(R bb ) 3 and -N(R bb ) 3 + X " , wherein R bb and X " are as defined herein.
  • sulfonyl refers to a group selected from -S0 2 N(R bb ) 2 , -S0 2 R aa , and - S0 2 OR aa , wherein R aa and R bb are as defined herein.
  • R xl is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl,
  • heteroaryloxy aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two R groups taken together form a 5- to 6-membered heterocyclic ring.
  • acyl groups include aldehydes (-CHO), carboxylic acids (-C0 2 H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.
  • Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alky
  • sil refers to the group -Si(R aa ) 3 , wherein R aa is as defined herein.
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
  • Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa , -N(R CC ) 2 , -CN,
  • the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an "amino protecting group").
  • heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and wherein R aa , R bb , R cc and R dd are as defined herein.
  • Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • Nitrogen protecting groups such as carbamate groups include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t- butyl-[9-(10,10-dioxo- 10,10, 10,10-tetrahydrothioxanthyl)] methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l-
  • TLBOC 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)- l- methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, t
  • Nitrogen protecting groups such as sulfonamide groups include, but are not limited to, /?-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6- dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7, 8-pentamethylchroman-6-sulfonamide (Pmc), methan
  • nitrogen protecting groups include, but are not limited to, phenothiazinyl-(lO)- acyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3- oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5- dimethylpyrrole, N-l, l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted l,3-dimethyl- l,3,5-triazacyclohexan-2-one, 5-substituted l,3-dibenzyl- l,3,5- triazacyclohexan-2
  • diphenylthiophosphinamide Ppt
  • dialkyl phosphoramidates dibenzyl phosphoramidate, diphenyl phosphoramidate
  • benzenesulfenamide o-nitrobenzenesulfenamide
  • Nps 2,4- dinitrobenzenesulfenamide
  • pentachlorobenzenesulfenamide 2-nitro-4- methoxybenzenesulfenamide
  • triphenylmethylsulfenamide triphenylmethylsulfenamide
  • 3-nitropyridinesulfenamide Npys
  • a nitrogen protecting group is benzyl (Bn), tert- butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-f urenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).
  • Bn benzyl
  • BOC tert- butyloxycarbonyl
  • Cbz carbobenzyloxy
  • Fmoc 9-f urenyl
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an "hydroxyl protecting group").
  • Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,
  • DEIPS diethylisopropylsilyl
  • TDMS t-butyldimethylsilyl
  • TDPS t- butyldiphenylsilyl
  • tribenzylsilyl tri-p-xylylsilyl, triphenylsilyl
  • DPMS diphenylmethylsilyl
  • TMPS t-butylmethoxyphenylsilyl
  • formate benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate
  • an oxygen protecting group is silyl.
  • an oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t- butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate,
  • methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2- trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p- methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, /?-methoxybenzyl (PMB), i-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).
  • MOM methoxymethyl
  • EE 1-ethoxyethyl
  • MOP 2-methyoxy-2-propyl
  • SEM 2-trimethylsilylethoxymethyl
  • MTM
  • the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group").
  • a sulfur protecting group is acetamidomethyl, i-butyl, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or
  • a "counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality.
  • An anionic counterion may be monovalent (i.e. , including one formal negative charge).
  • An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent.
  • Exemplary counterions include halide ions (e.g.
  • sulfonate ions e.g., methansulfonate, trifluoromethanesulfonate, p- toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-1 -sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g.
  • Exemplary counterions which may be multivalent include C0 3 , HP0 4 , P0 4 , ⁇ 4 0 7 ,
  • carboxylate anions e.g. , tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
  • carboxylate anions e.g. , tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
  • carboranes e.g. , tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate
  • leaving group is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502).
  • Suitable leaving groups include, but are not limited to, halogen (such as F, CI, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, ⁇ , ⁇ - dimethylhydroxylamino, pixyl, and haloformates.
  • halogen such as F, CI, Br, or I (iodine)
  • alkoxycarbonyloxy such as F, CI, Br, or I (iodine)
  • alkanesulfonyloxy alkanesulfonyloxy
  • arenesulfonyloxy alkyl-carbonyloxy (e.g., acetoxy)
  • alkyl-carbonyloxy e.g., acetoxy
  • the leaving group is a brosylate, such as /?-bromobenzenesulfonyloxy.
  • the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy.
  • the leaving group may also be a phosphineoxide (e.g. , formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate.
  • phosphineoxide e.g. , formed during a Mitsunobu reaction
  • an internal leaving group such as an epoxide or cyclic sulfate.
  • Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.
  • At least one instance refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.
  • non-hydrogen group refers to any group that is defined for a particular variable that is not hydrogen.
  • salt refers to any and all salts, and encompasses
  • pharmaceutically acceptable salts refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe
  • Pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (Ci_ 4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimpo sable mirror images of each other are termed “enantiomers”.
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. , as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • small molecule refers to molecules, whether naturally-occurring or artificially created (e.g. , via chemical synthesis) that have a relatively low molecular weight.
  • a small molecule is an organic compound (i.e. , it contains carbon).
  • the small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g. , amines, hydroxyl, carbonyls, and heterocyclic rings, etc.).
  • functional groups e.g. , amines, hydroxyl, carbonyls, and heterocyclic rings, etc.
  • the molecular weight of a small molecule is not more than about 1,000 g/mol, not more than about 900 g/mol, not more than about 800 g/mol, not more than about 700 g/mol, not more than about 600 g/mol, not more than about 500 g/mol, not more than about 400 g/mol, not more than about 300 g/mol, not more than about 200 g/mol, or not more than about 100 g/mol.
  • the molecular weight of a small molecule is at least about 100 g/mol, at least about 200 g/mol, at least about 300 g/mol, at least about 400 g/mol, at least about 500 g/mol, at least about 600 g/mol, at least about 700 g/mol, at least about 800 g/mol, or at least about 900 g/mol, or at least about 1,000 g/mol. Combinations of the above ranges (e.g., at least about 200 g/mol and not more than about 500 g/mol) are also possible.
  • the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (C.F.R.)).
  • catalysis refers to the increase in rate of a chemical reaction due to the participation of a substance called a "catalyst.”
  • the amount and nature of a catalyst remains essentially unchanged during a reaction.
  • a catalyst is regenerated, or the nature of a catalyst is essentially restored after a reaction.
  • a catalyst may participate in multiple chemical transformations. The effect of a catalyst may vary due to the presence of other substances known as inhibitors or poisons (which reduce the catalytic activity) or promoters (which increase the activity).
  • Catalyzed reactions have lower activation energy (rate-limiting free energy of activation) than the corresponding uncatalyzed reaction, resulting in a higher reaction rate at the same temperature.
  • Catalysts may affect the reaction environment favorably, bind to the reagents to polarize bonds, form specific intermediates that are not typically produced by a uncatalyzed reaction, or cause dissociation of reagents to reactive forms.
  • solvent refers to a substance that dissolves one or more solutes, resulting in a solution.
  • a solvent may serve as a medium for any reaction or transformation described herein.
  • the solvent may dissolve one or more reactants or reagents in a reaction mixture.
  • the solvent may facilitate the mixing of one or more reagents or reactants in a reaction mixture.
  • the solvent may also serve to increase or decrease the rate of a reaction relative to the reaction in a different solvent.
  • Solvents can be polar or non-polar, protic or aprotic.
  • Common organic solvents useful in the methods described herein include, but are not limited to, acetone, acetonitrile, benzene, benzonitrile, 1-butanol, 2-butanone, butyl acetate, ie/ -butyl methyl ether, carbon disulfide carbon tetrachloride, chlorobenzene, 1-chlorobutane, chloroform, cyclohexane, cyclopentane, 1,2-dichlorobenzene, 1,2-dichloroethane, dichloromethane (DCM), N,N-dimethylacetamide N,N-dimethylformamide (DMF), 1,3- dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU), 1,4-dioxane, 1,3-dioxane, diethylether, 2-ethoxyethyl ether, ethyl acetate, ethyl alcohol, ethylene glyco
  • Figure 1A outlines exemplary coupling reactions to form ketones.
  • Figure IB shows exemplary iron catalysts useful in the Fe/Cu-mediated coupling reactions described herein.
  • Figure 1C shows exemplary Fe-mediated coupling reactions.
  • Figure 2 shows exemplary Fe/Cu-mediated coupling reactions to form ketones using a wide array of substrates.
  • Figure 3 shows exemplary Fe/Cu-mediated coupling reactions forming intermediates useful in the synthesis of halichondrins and analogs thereof (compounds 11 and 13).
  • Figure 4 outlines the Fe/Cu-mediated coupling reactions with common radical probes.
  • FIG. 5 outlines the results of lithium halide screening. LiCl, LiBr, and Lil were found to be useful in the coupling reactions described herein.
  • Figure 6 shows an exemplary synthesis of a C20-C26 building block of halichondrins.
  • an advantage of the Fe/Cu-mediated couplings described herein over existing ketolization methods is that the Fe/Cu-mediated methods allow for selective coupling of alkyl halides in the presence of vinyl halides.
  • the Fe/Cu-mediated coupling reactions can be used in the preparation of halichondrins and analogs thereof-specifically, in the preparation of intermediates en route to halichondrins and analogs thereof.
  • the present invention also provides methods for the preparation of intermediates useful in the synthesis of halichondrins.
  • the present invention provides compounds, reagents, ligands, catalysts, and kits useful in the coupling methods provided herein, as well as compounds ⁇ i.e., intermediates) useful in the preparation of halichondrins and analogs thereof.
  • ketolization reactions are carried out in the presence of iron and copper, e.g., in the presence of an iron complex and a copper salt.
  • the ketolization reactions may be intermolecular or intramolecular ⁇ i.e., in Scheme 1A,
  • X 1 is halogen or a leaving group
  • X is halogen, a leaving group, or -SR ;
  • R is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;
  • R A is optionally substituted alkyl
  • R is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • linker is selected from the group consisting of optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted
  • carbocyclylene optionally substituted heterocyclylene, optionally substituted acylene, and combinations thereof.
  • R A is part of a complex molecule, such as a natural product, pharmaceutical agent, fragment thereof, or intermediate thereto. In certain embodiments, R is part of a complex molecule, such as a natural product, pharmaceutical agent, fragment thereof, or intermediate thereto.
  • a “linker” is a group comprising optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted acylene, or any combination thereof.
  • "linker” is an optionally substituted hydrocarbon chain.
  • the compound of Formula (A) is of Formula (A-l):
  • X is halogen or a leaving group
  • X 2 is halogen, a leaving group, or -SR S ;
  • R is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; and each instance of R A1 , R ⁇ , R B1 , and R B2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; optionally wherein R A1 and R B1 are joined together via a linker.
  • R A1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
  • R A1 is hydrogen.
  • R A1 is optionally substituted alkyl.
  • R A1 is optionally substituted alkenyl.
  • R A1 is optionally substituted alkynyl.
  • R A1 is optionally substituted aryl.
  • R A1 is optionally substituted carbocyclyl.
  • R A1 is optionally substituted heteroaryl. In certain embodiments, R A1 is optionally substituted heterocyclyl.
  • R ⁇ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
  • R A2 is hydrogen.
  • R ⁇ is optionally substituted alkyl.
  • R A2 is optionally substituted alkenyl.
  • R ⁇ is optionally substituted alkynyl.
  • R ⁇ is optionally substituted aryl.
  • R A2 is optionally substituted carbocyclyl.
  • R ⁇ is optionally substituted heteroaryl.
  • R A2 is optionally substituted heterocyclyl.
  • R B 1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. In certain embodiments, R B 1 is hydrogen. In certain embodiments, R B 1 is optionally substituted alkyl. In certain embodiments, R B 1 is optionally substituted alkenyl. In certain embodiments,
  • R B 1 is optionally substituted alkynyl. In certain embodiments, R B 1 is optionally substituted aryl. In certain embodiments, R B 1 is optionally substituted carbocyclyl. In certain
  • R B 1 is optionally substituted heteroaryl. In certain embodiments, R B 1 is optionally substituted heterocyclyl. [0094] As defined herein, R is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. In certain embodiments, R B2 is hydrogen. In certain embodiments, R B2 is optionally substituted alkyl. In certain embodiments, R B2 is optionally substituted alkenyl. In certain embodiments,
  • R B2 is optionally substituted alkynyl. In certain embodiments, R B2 is optionally substituted aryl. In certain embodiments, R B2 is optionally substituted carbocyclyl. In certain
  • R B2 is optionally substituted heteroaryl. In certain embodiments, R B2 is optionally substituted heterocyclyl.
  • R A1 and/or R ⁇ is part of a complex molecule, such as a natural product, pharmaceutical agent, fragment thereof, or intermediate thereto.
  • R Bl , R B2 , and/or R B3 is part of a complex molecule, such as a natural product, pharmaceutical agent, fragment thereof, or intermediate thereto.
  • X 1 is halogen or a leaving group
  • X is halogen, a leaving group, or -SR ;
  • R is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;
  • R ⁇ and R are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; and represents a linker.
  • X 1 is a halogen (e.g. , -I, -Br, -CI, -F).
  • halogen e.g. , -I, -Br, -CI, -F.
  • X 1 is a halogen bonded to an alkyl group (i.e. , an "alkyl halide").
  • the Fe/Cu-mediated ketolization reaction is selective for an alkyl halide over a vinyl halide.
  • the alkyl halide reacts at a faster rate than the vinyl halide.
  • the Fe/Cu-mediated reactions described herein are selective for alkyl iodides over vinyl halides (e.g. , vinyl iodides).
  • the selectivity is greater than 2: 1, 3: 1, 4: 1, 5: 1, 10: 1, 15: 1, 20: 1, 25: 1, 30: 1, 40: 1, 50: 1, 60: 1, 70: 1, 80: 1, 90: 1, 100: 1, or 100: 1.
  • X is a halogen (e.g. , -I, -Br, -CI, -F).
  • halogen e.g. , -I, -Br, -CI, -F.
  • X is -CI. In other embodiments, X is -SR , wherein R is as defined herein.
  • X is -S-heteroar embodiments, X is -S-pyridyl. In certain embodiments, X is -S-2-pyridyl:
  • Fe/Cu-mediated ketolization reactions are carried out in the presence of iron.
  • the iron source may be an iron complex, iron salt, iron catalyst, or pre-catalyst.
  • the iron source is iron (II).
  • the iron source is iron (III).
  • an iron complex is of the formula Fe(ligand) 3 .
  • "ligand” is TMHD, DBM, or acac.
  • the iron complex is of the formula Fe(ligand) 3 .
  • the iron complex is of the formula: 3 .
  • the iron complex is of the formula: 3 .
  • iron complex is Fe(DBM) 3i which is of the formula:
  • the iron complex is Fe(acac) 3i which is of the formula:
  • the iron complex comprises two phosphine ligands.
  • the iron complex comprises a bisphosphine ligand.
  • the iron complex is of the formula Fe(X) 2 (ligand), wherein each instance of X is independently halogen (e.g. , CI, Br, I, or F), and "ligand" is a bisphosphine ligand.
  • the bisphosphine ligand is dppb or SciOPP. In certain embodiments,
  • the iron complex is of the formula: n each instance of Ar is independently optionally substituted aryl, and each instance of X is independently halogen (e.g. , CI, Br, I, or F).
  • the iron complex is Fe(X) 2 (dppb) (each instance of Ar is phenyl (Ph)).
  • the iron complex is Fe(Br) 2 (dppb),
  • the iron complex is Fe(Cl) 2 (dppb), which is of the formula: i n certain iron
  • the iron complex is Fe(X) 2 (SciOPP) (each instan ce of Ar is of the formula: In certain embodiments, the iron complex is Fe(Br) 2 (SciOPP), which is of the formula:
  • the iron complex is
  • Fe(Cl) 2 (SciOPP), which is of the formula: .
  • the iron complex is of the fo rmula: , wherein each instance of Ar is independently optionally substituted aryl; and each instance of X is independently halogen (e.g. , CI, Br, I, or F).
  • the iron complex is of the formula FeX 2 (dppe), wherein each instance of X is independently halogen (e.g. , CI, Br, I, or F).
  • the iron complex is FeBr 2 (dppe), which is of the formula: i n certain embodiments, the iron complex is FeCl 2 (dppe).
  • the iron complex is of the formula: , wherein each instance of Ar is independently optionally substituted aryl, and each instance of X is independently halogen (e.g. , CI, Br, I, or F).
  • the iron complex is of the formula: FeX 2 (PPh 3 ) 2 , wherein each instance of X is independently halogen (e.g. , CI, Br, I, or F).
  • the iron complex is of the formula: FeBr 2 (PPh 3 ) 2 or
  • the iron is present in a catalytic amount. In certain embodiments, the iron is present at approximately 1-5 mol%, 5- 10 mol%, 1-10 mol%, 5-20 mol%, 10-20 mol%, 20-30 mol%, 20-40 mol%, 30-40 mol%, 40-50 mol%, 50-60 mol%, 60- 70 mol%, 70-80 mol%, or 80-90 mol% relative to a compound of Formula (A) or (B) in the reaction mixture. In certain embodiments, the iron is present in from 1-50 mol%. In certain embodiments, the iron is present in from 1- 10 mol%. In certain embodiments, the iron is present in from 1-20 mol%.
  • the iron is present in approximately 5 mol%. In certain embodiments, the iron is present in approximately 10 mol%. In certain embodiments, the iron is present in approximately 15 mol%. In certain embodiments, the iron is present in a stoichiometric or excess amount relative to a compound of Formula (A) or (B) in the reaction mixture.
  • the copper source may be a copper complex, copper salt, copper catalyst, or pre- catalyst.
  • the copper source is copper(I).
  • the copper source is copper(II).
  • the copper source is a copper salt.
  • the copper salt is selected from CuCl, CuBr, Cul, CuCN, CuTc, CuBr 2 , and CuCl 2 .
  • the copper salt is CuCl 2.
  • the copper salt is Cul.
  • the copper is present in a stoichiometric or excess amount relative to a compound of Formula (A) or (B) in the reaction mixture.
  • approximately 1 equivalent of copper is present (i.e. , stoichiometric). In other embodiments, greater than 1 equivalent of copper is present (i.e. , excess). In certain embodiments, approximately 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0, 9.0, or 10.0 equivalents of copper are present. In certain embodiments, the copper is present in a catalytic amount.
  • the copper is present at approximately 1-5 mol%, 5-10 mol%, 1- 10 mol%, 5-20 mol%, 10-20 mol%, 20-30 mol%, 20-40 mol%, 30-40 mol%, 40-50 mol%, 50-60 mol%, 60-70 mol%, 70-80 mol%, or 80-90 mol% relative to a compound of Formula (A) or (B) in the reaction mixture.
  • the Fe/Cu-mediated ketolization reactions may be carried out in the presence of one or more additional reagents or catalysts.
  • the reaction is carried out in the presence of zirconium.
  • the reaction is carried out in the presence of a zirconium complex.
  • the zirconium complex is of the formula: (ligand) n ZrX 2 ; wherein n is the number of ligands (e.g. , 0, 1, 2, 3, 4), and X is halogen (e.g., CI, Br, I, or F).
  • n is 2, and the ligand is cyclopentadienyl.
  • the zirconium source is Cp 2 ZrX 2 .
  • the zirconium source is Cp 2 ZrCl 2 .
  • the zirconium is present in a catalytic amount. In certain embodiments, the zirconium is present in between 1-5 mol%, 5-10 mol%, 1- 10 mol%, 5-20 mol%, 10-20 mol%, 20-30 mol%, 30-40 mol%, 40-50 mol%, 50-60 mol%, 60-70 mol%, 70- 80 mol%, or 80-90 mol% relative to a compound of Formula (A) or (B) in the reaction mixture. In certain embodiments, the zirconium is present in a stoichiometric or excess amount relative to a compound of Formula (A) or (B) in the reaction mixture.
  • greater than 1 equivalent of zirconium is present (i.e., excess). In certain embodiments, approximately 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 equivalents of zirconium are present. In certain embodiments, approximately 1 equivalent of zirconium is present (i.e. , stoichiometric). In certain embodiments, a zirconium complex is employed in the reaction when a thioester is used as a coupling partner (e.g., when X 2 is -SR S ).
  • the reaction is carried out in the presence of a lithium salt.
  • the lithium salt is LiCl, LiBr, or Lil.
  • the lithium salt is LiCl.
  • the lithium salt is present in catalytic amount.
  • the lithium salt is present in a stoichiometric or excess amount relative to a compound of Formula (A) or (B) in the reaction mixture. In certain embodiments, approximately 1 equivalent of lithium salt is present (i.e. , stoichiometric). In other embodiments, greater than 1 equivalent of lithium salt is present (i.e. , excess).
  • the reaction is carried out in the presence of a reducing metal.
  • the reducing metal is zinc or manganese (e.g., zinc (0) or manganese (0)).
  • the zinc source is zinc powder, zinc foil, zinc beads, or any other form of zinc metal.
  • the zinc may be present in a catalytic, stoichiometric, or excess amount.
  • the zinc is present in excess (i.e., greater than 1 equivalent) relative to a compound of Formula (A) or Formula (B).
  • between 1 and 10 equivalents of zinc are used.
  • approximately 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, or 10 equivalents of zinc are present.
  • approximately 2 equivalents of zinc are used.
  • the manganese source is manganese powder, manganese foil, manganese beads, or any other form of manganese metal.
  • the manganese may be present in a catalytic, stoichiometric, or excess amount. In certain embodiments, the manganese is present in excess (i.e., greater than 1 equivalent) relative to a compound of Formula (A) or Formula (B). In certain embodiments, between 1 and 10 equivalents of manganese are used. In certain embodiments, approximately 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, or 10 equivalents of manganese are present. In certain embodiments, approximately 2 equivalents of manganese are used.
  • the Fe/Cu-mediated ketolization described herein is carried out in a solvent.
  • Any solvent may be used, and the scope of the method is not limited to any particular solvent or mixture of solvents.
  • the solvent may be polar or non-polar, protic or aprotic, or a combination of solvents (e.g. , co-solvents). Examples of useful organic solvents are provided herein.
  • the ketolization is carried out in a polar solvent, such as an ethereal solvent.
  • the ketolization reaction is carried out in dimethoxyethane (DME).
  • the Fe/Cu-mediated ketolization reactions described herein may be carried out at any concentration in solvent. Concentration refers to the molar concentration (mol/L) of a coupling partners (e.g., compounds of Formula (A) or (B)) in a solvent. In certain
  • the concentration is approximately 0.5 M. In certain embodiments, the concentration is approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 M. In certain embodiments, the concentration is greater than 1 M. In certain embodiments, the
  • the Fe/Cu-mediated ketolization reactions described herein can be carried out at any temperature.
  • the reaction is carried out at around room temperature (i.e., between 18 and 24 °C).
  • the reaction is carried out below room temperature (e.g., between 0 °C and room temperature).
  • the reaction is carried out at above room temperature (e.g., between room temperature and 100 °C).
  • the reaction is carried out at approximately 0 °C.
  • a reaction described herein may be carried out over any amount of time. In certain embodiments, a reaction is allowed to run for seconds, minutes, hours, or days.
  • the Fe/Cu-mediated ketolization is carried out in the presence of an iron complex, a copper salt, a lithium salt, and a reducing metal.
  • the ketolization is carried out in the presence of Fe(TMHD) 3 , CuCl 2 , LiCl, and Mn.
  • the ketolization is carried out in the presence of FeBr 2 (dppb), CuCl 2 , LiCl, and Mn metal.
  • the reaction is carried out in a polar solvent.
  • the polar solvent is an ethereal solvent, such as DME.
  • the reaction is carried out at or below room temperature. In certain embodiments, the reaction is carried out at a temperature around 0 °C.
  • the coupling may be carried out under the following conditions: Fe(TMHD) 3 (10 mol%), CuCl 2 (1.0 equiv.), Mn (2 equiv.), LiCl (3 equiv.), DME, 0 °C, for 10-20 hours.
  • FeBr 2 (dppb) 5 mol%), CuCl 2 (1.0 equiv.), LiCl (3 equiv.), Mn (2 equiv.), DME, 0 °C, for 10-20 hours.
  • the Fe/Cu-mediated ketolization is carried out in the presence of an iron complex, a copper salt, a zirconium complex, a lithium salt, and a reducing metal.
  • the ketolization is carried out in the presence of FeBr 2 (dppb), Cul, ZrCp 2 Cl 2 , LiCl, and Mn metal.
  • the reaction is carried out in a polar solvent.
  • the polar solvent is an ethereal solvent, such as DME.
  • the reaction is carried out at or below room
  • the reaction is carried out at a temperature around 0 °C.
  • the coupling may be carried out under the following conditions: FeBr 2 (dppb) (5 mol%), Cul (1.0 equiv.), ZrCp 2 Cl 2 (1.0 equiv), LiCl (3 equiv.), Mn (2 equiv.), DME, 0 °C, for 10-20 hours.
  • the Fe/Cu-mediated ketolization reactions provided herein can be applied to the synthesis of complex molecules, such intermediates en route to halichondrins and analogs thereof.
  • Scheme 2 shows that a compound of Formula (1-13) can be prepared via Fe/Cu-mediated coupling of a compound of Formula (1-12) with a compound of Formula (1-10).
  • compounds of Formula (1-13) are useful intermediates in the synthesis of halichondrins (e.g., halichondrin A, B, C), and analogs thereof.
  • X 1 and X 3 are each independently a halogen or a leaving group
  • X is halogen, a leaving group, or -SR ;
  • R and R" are each independently hydrogen, halogen, or optionally substituted alkyl
  • R P1 , R P2 , R P3 , R p4 , and R p5 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group.
  • the compound of Formula (1-12) is a compound of Formula (I-12-S):
  • R is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
  • the step of coupling a compound of Formula (1-12), or a salt thereof, with a compound of Formula (1-10), or a salt thereof involves a Fe/Cu-mediated ketolization reaction as described herein (e.g. , carried out in the presence of iron and copper). Any reagents or conditions described for the Fe/Cu-mediated ketolizations described herein can be used in the coupling step.
  • the selectivity is greater than 2: 1, 3: 1, 4: 1, 5: 1, 10: 1, 15: 1, 20: 1, 25: 1, 30: 1, 40: 1, 50: 1, 60: 1, 70: 1, 80: 1, 90: 1, 100: 1, or 100: 1.
  • R pl , R p2 , R p3 , R p4 , and R p5 are each optionally substituted silyl protecting groups.
  • R pl , R p2 , R p3 , R p4 , and R p5 are each trialkylsilyl protecting groups.
  • R pl and R p4 are TBS protecting groups, and R p2 , R p3 , and R p5 are TES protecting groups.
  • the coupling to form a compound of Formula (1-13), or a salt thereof is carried out in the presence of an iron complex, a copper salt, a lithium salt, a zirconium complex, and a reducing metal.
  • the coupling is carried out in the presence of FeBr2(SciOPP), Cul, ZrCp 2 Cl2, LiCl, and Mn metal.
  • the reaction is carried out in a polar solvent.
  • the polar solvent is an ethereal solvent, such as DME.
  • the reaction is carried out at or below room temperature. In certain embodiments, the reaction is carried out at a temperature around 0 °C.
  • the coupling may be carried out under the following conditions: FeBr 2 (SciOPP) (5 mol%), Cul (1.0 equiv.), ZrCp 2 Cl 2 (1.0 equiv.), LiCl (3 equiv.), and Mn (2.0 equiv), DME, 0 °C, 10-20 hours.
  • Ketolization reactions provided herein can be applied to the preparation of other intermediates useful in the synthesis of halichondrins and analogs thereof.
  • a compound of Formula (1-11) can be prepared via Fe/Cu-mediated coupling of a compound of Formula (1-9) with a compound of Formula (I- 10).
  • Compounds of Formula (1-11) are useful intermediates in the synthesis of halichondrins and analogs thereof.
  • X 1 1 and X 3 3 are each independently a halogen or a leaving group
  • X 2 is halogen, a leaving group, or -SR S ;
  • R 1 and R 2" are each independently hydrogen, halogen, or optionally substituted alkyl
  • R , R , and R are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally wherein two R p6 are joined with the intervening atoms to form optionally substituted heterocyclyl.
  • a compound of Formula (1-9) is of Formula (I-9-S):
  • R is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
  • the step of coupling a compound of Formula (1-9), or a salt thereof, with a compound of Formula (1-10), or a salt thereof is a Fe/Cu-mediated ketolization described herein (e.g., carried out in the presence of iron and copper). Any reagents or conditions described for the Fe/Cu-mediated ketolizations described herein can be used in the coupling step.
  • the selectivity is greater than 2: 1, 3: 1, 4: 1, 5: 1, 10: 1, 15: 1, 20: 1, 25: 1, 30: 1, 40: 1, 50: 1, 60: 1, 70: 1, 80: 1, 90: 1, 100: 1, or 100: 1.
  • R p4 , R p5 , and R p6 are each silyl protecting groups.
  • R p4 and R p5 are trialkylsilyl protecting groups, and the two R p6 groups are
  • R is a TBS protecting group
  • R p5 is a TES protecting group
  • the two R p6 groups are joined together to form:
  • the coupling to yield a compound of Formula (1-11) is carried out in the presence of an iron complex, a copper salt, a lithium salt, a zirconium complex, and a reducing metal.
  • the coupling is carried out in the presence of FeBr 2 (SciOPP), Cul, ZrCp 2 Cl 2 , LiCl, and Mn metal.
  • the reaction is carried out in a polar solvent.
  • the polar solvent is an ethereal solvent such as DME.
  • the reaction is carried out at or below room temperature. In certain embodiments, the reaction is carried out at a temperature around 0 °C.
  • the coupling may be carried out under the following conditions: FeBr 2 (SciOPP) (5 mol%), Cul (1.0 equiv.), ZrCp 2 Cl 2 (1.0 equiv.), LiCl (3 equiv.), and Mn (2.0 equiv), DME, 0 °C, 10-20 hours.
  • Methods described herein can be used to prepare compounds in any chemical yield.
  • a compound is produced in from 1-10%, 10-20% 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% yield.
  • the desired product is obtained in greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% yield. In certain embodiments, it is greater than 50% yield. In certain embodiments, it is greater than 70% yield.
  • the yield is the percent yield after one synthetic step. In certain embodiments, the yield is the percent yield after more than one synthetic step (e.g., 2, 3, 4, or 5 synthetic steps).
  • the Fe/Cu-mediated ketolizations are selective for alkyl halides over vinyl halides. Therefore, in certain embodiments, when X 1 and X 3 are both halogen, the reaction occurs selectively at X 1 rather than X 3.
  • the selectivity is approximately 2: 1, 3: 1, 4: 1, 5: 1, 10: 1, 15: 1, 20: 1, 25: 1, 30: 1, 40: 1, 50: 1, 60: 1, 70: 1, 80: 1, 90: 1, 100: 1, or greater than 100: 1.
  • the selectivity is greater than 2: 1, 3: 1, 4: 1, 5: 1, 10: 1, 15: 1, 20: 1, 25: 1, 30: 1, 40: 1, 50: 1, 60: 1, 70: 1, 80: 1, 90: 1, 100: 1, or 100: 1.
  • Methods described herein may further comprise one or more purification steps.
  • a compound produced by a method described herein may be purified by chromatography, extraction, filtration, precipitation, crystallization, or any other method known in the art.
  • a compound or mixture is carried forward to the next synthetic step without purification (i.e., crude).
  • Scheme 4 shows that a compound of Formula (II-3) can be prepared via Fe/Cu- mediated coupling of a compound of Formula (II-l) with a compound of Formula (II-2).
  • compounds of Formula (II-3) are useful intermediates in the synthesis of compounds in the halichondrin series (e.g., halichondrin A, B, C), and analogs thereof.
  • compounds of Formula (II-3) are useful as the C20-C26 fragments (i.e., building blocks) of halichondrins.
  • X 3 are each independently a halogen or a leaving group
  • X 2 is halogen, a leaving group, or -SR S ;
  • R 5 is hydrogen, halogen, or optionally substituted alkyl
  • R is alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.
  • the compound of Formula (II-l) is a compound of Formula (II-1-C1):
  • the compound of Formula (II-l) is the following:
  • the compound of Formula (II-l) is the following:
  • the compound of Formula (II-2) is a compound of Formula (II-l-I):
  • the compound of Formula (II-2) is the following:
  • t compound of Formula (II-3) is the following:
  • the com ound of Formula (II-3) is the following:
  • the step of coupling a compound of Formula (II-l), or a salt thereof, with a compound of Formula (II-2), or a salt thereof involves a Fe/Cu-mediated ketolization reaction as described herein (e.g. , carried out in the presence of iron and copper). Any reagents or conditions described for the Fe/Cu-mediated ketolizations described herein can be used in the coupling step.
  • the selectivity is greater than 2: 1, 3 : 1, 4: 1, 5: 1, 10: 1, 15: 1, 20: 1, 25: 1, 30: 1, 40: 1, 50: 1, 60: 1, 70: 1, 80: 1, 90: 1, 100: 1, or 100: 1.
  • the selectivity is greater than 2: 1, 3 : 1, 4: 1, 5: 1, 10: 1, 15: 1, 20: 1, 25: 1, 30: 1, 40: 1, 50: 1, 60: 1, 70: 1, 80: 1, 90: 1, 100: 1, or 100: 1.
  • X is -I; X is -I; and X is -CI.
  • R is ethyl; and R is methyl. In certain embodiments, R is methyl; and R 5 is methyl.
  • the Fe/Cu-mediated ketolization is carried out in the presence of an iron complex, a copper salt, a lithium salt, and a reducing metal.
  • the ketolization is carried out in the presence of Fe(TMHD) 3 , CuCl 2 , LiCl, and Mn.
  • the ketolization is carried out in the presence of FeBr 2 (dppb), CuCl 2 , LiCl, and Mn metal.
  • the reaction is carried out in a polar solvent.
  • the polar solvent is an ethereal solvent, such as DME.
  • the reaction is carried out at or below room temperature. In certain embodiments, the reaction is carried out at a temperature around 0 °C.
  • the coupling may be carried out under the following conditions: FeBr 2 (dppb) (5 mol%), CuCl 2 (20 mol%), LiCl (3 equiv.), Mn (2 equiv.), DME, approximately 0 °C (e.g. , about 0-5 °C), for 10- 30 hours.
  • the method further comprises a step of reacting the compound of Formula (II-3):
  • X is halogen
  • R is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group;
  • each R P9 is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally wherein two R P9 groups are joined together with the intervening atoms.
  • the reaction is carried out in the presence of an acid.
  • the acid is a sulfonic acid.
  • the acid is p- toluenesulfonic acid.
  • the reaction is carried out in the presence of an orthoformate.
  • the reaction is carried out in the presence of trimethyl orthoformate.
  • the reagent of formula R P9 OH is a diol; and two R P9 are joined together with the intervening atoms. In these embodiments, in the compound of Formula (III-l), two R P9 are taken together with the intervening atoms to form optional substituted heterocyclyl. In certain embodiments, the reagent is an 1,3-diol. In certain R R embodiments, the reagent R P9 OH is of the formula: OH OH . in certain embodiments, the
  • reagent is 2,2-dimethyl- 1 ,3 -propanediol, having the structure: H .
  • the com ound of Formula (II-3) is of the formula:
  • the compound of Formula (III-l) is of the formula:
  • the reaction to yield a compound of Formula (III-l) is carried out in the presence of a diol and an acid. In certain embodiments, the reaction is carried out in the presence of 2,2-dimethyl- 1,3-propanediol and an acid. In certain embodiments, the reaction is carried out in the presence of 2,2-dimethyl- 1,3-propanediol and / ⁇ -toluenesulfonic acid. In certain embodiments, the reaction to yield a compound of Formula (III-l) is carried out in the presence of a diol, an acid, and an orthoformate.
  • the reaction is carried out in the presence of 2,2-dimethyl- 1,3-propanediol, p- toluenesulfonic acid, and trimethyl orthoformate.
  • the reaction is carried out in a polar solvent such as acetonitrile.
  • the reaction is carried out in the presence of 2,2-dimethyl- 1,3-propanediol (5 equiv.), p- toluenesulfonic acid hydrate (2 mol%), and trimethyl orthoformate (1.5 equiv), in MeCN, at room temperature ⁇ e.g. , for approximately 20 hours).
  • halichondrins e.g., halichondrins A, B, C
  • compounds of Formula 1-13 are compounds which are useful intermediates in the synthesis of halichondrins (e.g., halichondrins A, B, C), and analogs thereof.
  • halichondrins A, B, C e.g., halichondrins A, B, C
  • compounds of Formula 1-13 are compounds which are useful intermediates in the synthesis of halichondrins (e.g., halichondrins A, B, C), and analogs thereof.
  • X is halogen or a leaving group
  • R 1 and FT 2 are each independently hydrogen, halogen, or optionally substituted alkyl
  • R P1 , R P2 , R P3 , R p4 , and R p5 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group.
  • X 2 is halogen, a leaving group, or -SR S ;
  • R 1 and R 2" are each independently hydrogen, halogen, or optionally substituted alkyl
  • R P1 , R P2 , R P3 , R p4 , and R p5 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group.
  • the compound of Formula (1-12) is a compound of Formula (I-12-S):
  • R is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
  • X 3 are each independently a halogen or a leaving group
  • R is hydrogen, halogen, or optionally substituted alkyl
  • R p4 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group.
  • X is halogen or a leaving group
  • R 1 and R 2" are each independently hydrogen, halogen, or optionally substituted alkyl; and R , R , and R are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally wherein two R p6 are joined with the intervening atoms to form optionally substituted heterocyclyl.
  • XX 2 iiss hhaallooggeenn,, aa lleeaaving group, or -SR S ;
  • R 1 and R 2" are each independently hydrogen, halogen, or optionally substituted alkyl
  • R and R are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally wherein two R are joined with the intervening atoms to form optionally substituted heterocyclyl.
  • a compound of Formula (1-9) is of Formula (I-9-S):
  • R is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
  • X 1 is halogen or a leaving group.
  • X 1 is a halogen.
  • X 1 is -CI (i.e. , chloride).
  • X 1 is -Br (i.e. , bromide).
  • X 1 is -I (i.e. , iodide).
  • X 1 is - F (i.e. , fluoride).
  • X 1 is a leaving group.
  • X is halogen, a leaving group, or -SR .
  • X is halogen, a leaving group, or -SR .
  • X is a halogen. In certain embodiments, X is -CI. In certain embodiments, X is -Br. In
  • X is -I. In certain embodiments, X is -F. In certain embodiments, X
  • X is -SR .
  • R is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In certain embodiments, R is optionally substituted alkyl. In certain s s
  • R is optionally substituted Ci_ 6 alkyl. In certain embodiments, R is unsubstituted C 1-6 alkyl. In certain embodiments, R is selected from the group consisting of methyl, ethyl, n-propyl, z ' so-propyl, n-butyl, wo-butyl, sec-butyl, and tert-butyl. In certain s s embodiments, R is optionally substituted carbocyclyl. In certain embodiments, R is optionally substituted aryl. In certain embodiments, R is optionally substituted heterocyclyl.
  • R is optionally substituted heteroaryl. In certain embodiments, R is optionally substituted 6-membered heteroaryl. In certain embodiments, R is optionally substituted 6-membered heteroaryl comprising 1, 2, or 3 nitrogen atoms. In certain
  • R is optionally substituted pyridyl. In certain embodiments, R is
  • R unsubstituted pyridyl (Py).
  • R is optionally substituted 2-pyridyl.
  • R is unsubstituted 2-pyridyl (2-Py).
  • R is selected from the group consisting of: .
  • X 3 is halogen or a leaving group. In certain embodiments, X 3 is a halogen. In certain embodiments, X 3 is -CI. In certain embodiments, X 3 is -Br. In certain embodiments, X 3 is -I. In certain embodiments, X 3 is -F. In certain embodiments, X 3 is a leaving group.
  • R is optionally substituted alkyl, optionally substituted
  • R is optionally substituted alkyl. In certain embodiments, R is optionally substituted Ci_ 6 alkyl. In certain embodiments, R is
  • R is optionally substituted C 1-3 alkyl. In certain embodiments, R is unsubstituted C 1-3 alkyl. In certain embodiments, R is selected from the group consisting of methyl, ethyl, n-propyl, z ' so-propyl, n-butyl, z ' so-butyl, sec-butyl, and tert-butyl. In certain embodiments, R is methyl. In certain embodiments, R is optionally substituted aryl. In certain embodiments, R is optionally substituted phenyl. In certain embodiments, R is phenyl (-Ph).
  • Ar is optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments, Ar is optionally substituted aryl. In certain embodiments, Ar is optionally substituted phenyl. In certain embodiments, Ar is unsubstituted phenyl (-Ph).
  • R 1 is hydrogen, halogen, or optionally substituted alky. In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 is halogen. In certain
  • R 1 is optionally substituted alkyl. In certain embodiments, R 1 is optionally substituted C 1-6 alkyl. In certain embodiments, R 1 is unsubstituted C 1-6 alkyl. In certain embodiments, R 1 is optionally substituted C 1-3 alkyl. In certain embodiments, R 1 is unsubstituted Ci_ 3 alkyl. In certain embodiments, R 1 is selected from the group consisting of methyl, ethyl, n-propyl, z ' so-propyl, n-butyl, z ' so-butyl, sec-butyl, and tert-butyl. In certain embodiments, R 1 is methyl.
  • R is hydrogen, halogen, or optionally substituted alky.
  • R 2 is hydrogen. In certain embodiments, R 2 is halogen. In certain embodiments, R 2 is optionally substituted alkyl. In certain embodiments, R 2 is optionally substituted Ci_ 6 alkyl. In certain embodiments, R is unsubstituted Ci_ 6 alkyl. In certain embodiments, R 2 is optionally substituted C 1-3 alkyl. In certain embodiments, R 2 is unsubstituted C 1-3 alkyl.
  • R is selected from the group consisting of methyl, ethyl, n-propyl, z ' so-propyl, n-butyl, z ' so-butyl, sec-butyl, and tert-butyl. In certain embodiments, R is methyl.
  • R is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.
  • R 8 is hydrogen.
  • R 8 is optionally substituted alkyl.
  • R is optionally substituted C 1-6 alkyl.
  • R 8 is unsubstituted C 1-6 alkyl.
  • R 8 is optionally substituted Ci_ 3 alkyl.
  • R is unsubstituted Ci_ 3 alkyl.
  • R is selected from the group consisting of methyl, ethyl, n-propyl, z ' so-propyl, ft-butyl, z ' so-butyl, sec-butyl, and tert-butyl. In certain embodiments, R is methyl. In certain embodiments, R 8 is ethyl. In certain embodiments, R 8 is benzyl (-CH 2 Ph; "Bn").
  • R 5 is hydrogen, halogen, or optionally substituted alky. In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 is halogen. In certain
  • R 3 is optionally substituted alkyl.
  • R 5 is optionally substituted C 1-6 alkyl.
  • R 5 is unsubstituted C 1-6 alkyl.
  • R 5 is optionally substituted Ci_ 3 alkyl.
  • R 5 is unsubstituted Ci_ 3 alkyl.
  • R 5 is selected from the group consisting of methyl, ethyl, n-propyl, z ' so-propyl, n-butyl, z ' so-butyl, sec-butyl, and tert-butyl. In certain embodiments, R 5 is methyl.
  • R pl is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group.
  • R pl is hydrogen.
  • R pl is optionally substituted alkyl.
  • R pl is optionally substituted C 1-6 alkyl.
  • R pl is unsubstituted C 1-6 alkyl.
  • R pl is optionally substituted C 1-3 alkyl.
  • R pl is unsubstituted Ci_ 3 alkyl.
  • R pl is selected from the group consisting of methyl, ethyl, n-propyl, z ' so-propyl, n-butyl, z ' so-butyl, sec-butyl, and tert-butyl.
  • R is optionally substituted acyl.
  • R pl is an oxygen protecting group.
  • R pl is optionally substituted allyl.
  • R pl is allyl.
  • R pl is optionally substituted silyl.
  • R pl is trialkylsilyl.
  • R pl is triethylsilyl (-SiEt 3 ; "TES"). In certain embodiments, R pl is
  • R pl is tert-butyl dimethylsilyl (— Sii- BuMe 2 ; “TBS”). In certain embodiments, R pl is tert-butyl diphenylsilyl (-Sit-BuPh 2 ;
  • R pl is an optionally substituted benzyl protecting group.
  • R pl is benzyl (-CH 2 Ph; "Bn”).
  • R pl is a methox benzyl protecting group.
  • R pl is /?ara-methoxybenzyl:
  • R and R are joined with the intervening atoms to form optionally substituted heterocyclyl.
  • R P2 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R P2 is hydrogen. In certain embodiments, R P2 is optionally substituted alkyl. In certain embodiments, R P2 is optionally substituted C 1-6 alkyl. In certain embodiments, R P2 is unsubstituted C 1-6 alkyl. In certain embodiments, R P2 is optionally substituted C 1-3 alkyl. In certain embodiments, R P2 is unsubstituted Ci_ 3 alkyl.
  • R P2 is selected from the group consisting of methyl, ethyl, n-propyl, z ' so-propyl, n-butyl, wo-butyl, sec-butyl, and tert-butyl.
  • R P2 is optionally substituted acyl.
  • R P2 is an oxygen protecting group.
  • R P2 is optionally substituted allyl.
  • R P2 is allyl.
  • R P2 is optionally substituted silyl.
  • R P2 is trialkylsilyl.
  • R P2 is triethylsilyl (-SiEt 3 ; "TES”). In certain embodiments, R p2 is trimethylsilyl (-SiMe 3 ; “TMS”). In certain embodiments, R P2 is tert-butyl dimethylsilyl (-Sit-BuMe 2 ; “TBS”). In certain embodiments,
  • R P2 is tert-butyl diphenylsilyl (-Sit-BuPh 2 ; "TBDPS"). In certain embodiments, R P2 is an optionally substituted benzyl protecting group. In certain embodiments, R P2 is benzyl (-
  • R P2 is a methox benzyl protecting group.
  • R p2 is para-methoxybenzyl: or "PMB”).
  • R and R are joined with the intervening atoms to form optionally substituted heterocyclyl.
  • R P3 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R P3 is hydrogen. In certain embodiments, R P3 is optionally substituted alkyl. In certain embodiments, R P3 is optionally substituted Ci_ 6 alkyl. In certain embodiments, R P3 is unsubstituted Ci_ 6 alkyl. In certain embodiments, R P3 is optionally substituted C 1-3 alkyl. In certain embodiments, R P3 is unsubstituted C 1-3 alkyl.
  • R P3 is selected from the group consisting of methyl, ethyl, n-propyl, z ' so-propyl, n-butyl, z ' so-butyl, sec-butyl, and tert-butyl.
  • R P3 is optionally substituted acyl.
  • R P3 is an oxygen protecting group.
  • R P3 is optionally substituted allyl.
  • R P3 is allyl.
  • R P3 is optionally substituted silyl.
  • R P3 is trialkylsilyl.
  • R P3 is triethylsilyl (-SiEt 3 ; "TES”). In certain embodiments, R p3 is trimethyl silyl (-SiMe 3 ; “TMS”). In certain embodiments, R P3 is tert-butyl dimethylsilyl (-Sit-BuMe 2 ; “TBS”). In certain embodiments,
  • R P3 is tert-butyl diphenylsilyl (-Sit-BuPh 2 ; "TBDPS"). In certain embodiments, R P3 is an optionally substituted benzyl protecting group. In certain embodiments, R P3 is benzyl (-
  • R P3 is a methoxybenzyl protecting group.
  • R is /?ara-methoxybenzyl: or "PMB").
  • R p4 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R p4 is hydrogen. In certain embodiments, R p4 is optionally substituted alkyl. In certain embodiments, R p4 is optionally substituted Ci_ 6 alkyl. In certain embodiments, R p4 is unsubstituted Ci_ 6 alkyl. In certain embodiments, R p4 is optionally substituted Ci_ 3 alkyl. In certain embodiments, R p4 is unsubstituted C 1-3 alkyl.
  • R p4 is selected from the group consisting of methyl, ethyl, n-propyl, wo-propyl, n-butyl, wo-butyl, sec-butyl, and tert-butyl. In certain embodiments, R p4 is optionally substituted acyl. In certain embodiments, R p4 is an oxygen protecting group. In certain embodiments, R p4 is optionally substituted allyl. In certain embodiments, R p4 is allyl. In certain embodiments, R p4 is optionally substituted silyl. In certain embodiments, R p4 is trialkylsilyl.
  • R p4 is triethylsilyl (-SiEt 3 ; "TES"). In certain embodiments, R p4 is trimethyl silyl (-SiMe 3 ; “TMS”). In certain embodiments, R p4 is tert-butyl dimethylsilyl (-Sit-BuMe 2 ; “TBS”). In certain embodiments, R is tert-butyl diphenylsilyl (-Sii-BuPh 2 ; "TBDPS”). In certain embodiments, R is an optionally substituted benzyl protecting group. In certain embodiments, R p4 is benzyl (- CH 2 PI1; "Bn”). In certain embodiments, R p4 is a methoxybenzyl protecting group. In certain embodiments, R is /?ara-methoxybenzyl: (“MPM” or "PMB”).
  • R is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group.
  • R p5 is hydrogen.
  • R p5 is optionally substituted alkyl.
  • R p5 is optionally substituted C 1-6 alkyl.
  • R p5 is unsubstituted C 1-6 alkyl.
  • R p5 is optionally substituted C 1-3 alkyl.
  • R p5 is unsubstituted Ci_ 3 alkyl.
  • R p5 is selected from the group consisting of methyl, ethyl, n-propyl, z ' so-propyl, n-butyl, z ' so-butyl, sec-butyl, and tert-butyl.
  • R p5 is optionally substituted acyl.
  • R p5 is an oxygen protecting group.
  • R p5 is optionally substituted allyl.
  • R p5 is allyl.
  • R p5 is optionally substituted silyl.
  • R p5 is trialkylsilyl.
  • R p5 is triethylsilyl (-SiEt 3 ; "TES"). In certain embodiments, R p5 is trimethyl silyl (-SiMe 3 ; “TMS”). In certain embodiments, R p5 is tert-butyl dimethylsilyl (-Sii-BuMe 2 ; “TBS”). In certain embodiments, R p5 is tert-butyl diphenylsilyl (-Sii-BuPh 2 ; "TBDPS”). In certain embodiments, R p5 is an optionally substituted benzyl protecting group. In certain embodiments, R p5 is benzyl (- CH 2 Ph; “Bn”). In certain embodiments, R p5 is a methoxybenzyl protecting group. In certain embodiments,
  • R is /?ara-methoxybenzyl: or "PMB").
  • R p6 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally wherein two R p6 are joined with the intervening atoms to form optionally substituted heterocyclyl.
  • R p6 is hydrogen.
  • R p6 is optionally substituted alkyl.
  • R p6 is optionally substituted Ci_ 6 alkyl.
  • R p6 is unsubstituted C 1-6 alkyl.
  • R p6 is optionally substituted C 1-3 alkyl.
  • R p6 is unsubstituted C 1-3 alkyl.
  • R p6 is selected from the group consisting of methyl, ethyl, n-propyl, z ' so-propyl, n-butyl, z ' so-butyl, sec-butyl, and tert-butyl.
  • R p6 is optionally substituted acyl.
  • R p6 is an oxygen protecting group.
  • R p6 is optionally substituted allyl.
  • R is allyl.
  • R is optionally substituted silyl.
  • R p6 is trialkylsilyl.
  • R p6 is triethylsilyl (-SiEt 3 ; "TES"). In certain embodiments, R p6 is
  • R p6 is tert-butyl dimethylsilyl (— Sii- BuMe 2 ; “TBS”). In certain embodiments, R p6 is tert-butyl diphenylsilyl (-Sii-BuPh 2 ;
  • R p6 is an optionally substituted benzyl protecting group.
  • R p6 is benzyl (-CH 2 Ph; "Bn”).
  • R p6 is a methoxybenzyl protecting group.
  • R p6 is /?ara-methoxybenzyl: ("MPM” or "PMB”).
  • MPM or "PMB”
  • two R are joined with the intervening atoms to form optionally substituted heterocyclyl.
  • two R p6 are joined with the intervening atoms to form optionally substituted six-membered heterocyclyl.
  • two R p6 are joined with the intervening atoms to form a
  • R P9 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R P9 is hydrogen. In certain embodiments, R P9 is optionally substituted alkyl. In certain embodiments, R P9 is optionally substituted Ci_ 6 alkyl. In certain embodiments, R P9 is unsubstituted Ci_ 6 alkyl. In certain embodiments, R P9 is optionally substituted Ci_ 3 alkyl. In certain embodiments, R P9 is unsubstituted Ci_ 3 alkyl.
  • R P9 is selected from the group consisting of methyl, ethyl, n-propyl, z ' so-propyl, n-butyl, z ' so-butyl, sec-butyl, and tert-butyl. In certain embodiments, R P9 is optionally substituted acyl. In certain embodiments, R P9 is an oxygen protecting group. In certain embodiments, R P9 is optionally substituted allyl. In certain embodiments, R P9 is allyl. In certain embodiments, R P9 is optionally substituted silyl. In certain embodiments, R P9 is trialkylsilyl.
  • R P9 is triethylsilyl (-SiEt 3 ; "TES”). In certain embodiments, R P9 is trimethylsilyl (-SiMe 3 ; “TMS”). In certain embodiments, R P9 is tert-butyl dimethylsilyl (-Sii-BuMe 2 ; “TBS”). In certain embodiments, R P9 is tert-butyl diphenylsilyl (-Sii-BuPh 2 ; "TBDPS”). In certain embodiments, R P9 is an optionally substituted benzyl protecting group. In certain embodiments, R is benzyl (- CH2PI1; “Bn”). In certain embodiments, R P9 is a methoxybenzyl protecting group. In certain embodiments,
  • R r " is /?ara-methoxybenzyl: or "PMB"). In certain embodiments, two R P9 are joined together with the intervening atoms. In certain
  • two R ry are joined together with the intervening atoms to
  • two R P9 are joined together with the intervening atoms to form: certain embodiments, two R are joined together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, two R P9 are joined together
  • Group R is as defined herein.
  • C 0.4M was chosen for the study), and (7) additives.
  • the condition of [la (1.0 equiv.), 2a (3.0 equiv.), Fe(TMHD) 3 (10 mol%; 4 in Figure IB), CuCl 2 (1.0 equiv.), Mn (2 equiv.), LiCl (3 equiv.), DME (C 0.4 M), 0 °C, 15 h] was found effective for the (la+2a)-coupling (76% isolated yield). See Method A in Figure 2.
  • This Fe/Cu-mediated method exhibited one appealing reactivity-profile; that was, unlike other state of the art methods, this Fe/Cu-mediated method allowed selectively to activate an alkyl iodide over a vinyl or aryl iodide, e.g., compounds lj-m. This selectivity is of great importance to the synthesis of complex molecules.
  • this coupling was done in multiple steps, i.e., Co/Cr-mediated coupling, followed by oxidation: Kim, D.-S.; Dong, C.-G.; Kim, J.
  • Fe(TMHD) 3 in order for Fe(TMHD) 3 to function as a radical initiator, Fe(III) should be reduced to Fe(II) by Mn metal. The reduction released one molecule of ⁇ -diketone, which consumed some of 6 in a non-productive manner. This side-reaction could be avoided with use of a Fe(II)-initiator. For this reason, various radical initiators were screened for the Cu-mediated ketone coupling. Among them,
  • FeBr 2 (dppb), FeCl 2 (dppb), FeBr 2 (dppe), FeCl 2 (dppe), and FeBr 2 (PPh 3 ) 2 gave product 3a in 90%, 79%, 54%, 46% and 48%, respectively, under the coupling condition Method B-l ( Figure 2).
  • Method B-l Figure 2
  • Nakamura and coworkers See, e.g. , Hatakeyama, T.; Fujiwara, Y.; Okada, Y.; Itoh, T.;
  • NMR spectra were recorded on a Varian Inova 600 MHz, 500 MHz, or 400 MHz spectrometer. Chemical shifts are reported in parts per million (ppm).
  • 1H NMR spectra (CDCI 3 and C 6 D6), the residual solvent peak was used as the internal reference (7.26 ppm in CDCI 3 ; 7.16 ppm in C 6 D6), while the central solvent peak as the reference (77.0 ppm in
  • TLC thin layer chromatography
  • the reaction mixture was cooled to room temperature, 100 mL of water was introduced to the reaction mixture. Filtered the orange solid and was washed with 200 mL of ethanol. The resulting orange solid (19.3 g) was dried under high vacuum for 12 hours. Recrystallization: The above obtained orange solid (19.3 g) was dissolved in 300 mL of ethyl acetate upon heating to 60 °C. Filtered the ethyl acetate solution through a filter paper and the resulting filtrate (ethyl acetate) was concentrated under reduced pressure afforded pure crystalline orange solid 4 (18.3 g) in 82% yield.
  • la was prepared from 3-iodo-2-methylpropan-l-ol (See, e.g., Fleming, F. F.;
  • le was prepared from 3-iodo-3-methylbutan-l-ol (See, e.g., Turhanen, P. A.;
  • lj was prepared from 5-iodohex-5-en- l-ol (See, e.g., Johannes, J. W.; Wenglowsky, S.; Kishi, Y. Org. Lett.2005, 7, 3997 - 4000), using general procedure B.
  • lk was prepared from 5-bromohex-5-en- l-ol (See, e.g. , Ruscoe, R. E.; Fazakerley, N. J.; Huang, H.; Flitsch, S.; Procter, D. J. Chem. Eur. 7.2016, 22, 116-119), using general procedure B.
  • [00217] 11 was prepared from 3-(4-iodophenyl)propan-l-ol (See, e.g., Miyajima, D.; Araoka, F.; Takezoe, H.; Kim, J.; Kato, K.; Takata, M.; Aida, T. Angew. Chem., Int. Ed. 2011, 50, 7865 - 7869), using general procedure B.
  • Compound 7 was synthesized, according to the literature procedure (See, e.g., Kim, D.-S.; Dong, C.-G.; Kim, J. T.; Guo, H.; Huang, J.; Tiseni, P. S.; Kishi, Y. . Am. Chem. Soc. 2009, 131, 15636 - 15641.).
  • Fe(TMHD) 3 as a catalyst: An oven dried 500 mL single-necked flask equipped with a Teflon-coated egg shaped magnetic stirring bar was charged with Iron(III) tris(2,2,6,6- tetramethyl-3,5-heptanedionate) 4 (4.23 g, 6.99 mmol), manganese (5.11 g, 93.2 mmol), copper(II) chloride (6.26 g, 46.6 mmol), lithium chloride (5.91 g, 139.8 mmol) and 1,2- dimethoxyethane (50 mL) at room temperature.
  • FeBr 2 (dppb) as a catalyst In a glove box, an oven dried 250 mL single-necked flask equipped with a magnetic stirring bar was charged with FeBr 2 (dppb) (1.03 g, 1.55 mmol), manganese (3.41 g, 62.2 mmol), copper (II) chloride (4.18 g, 31.1 mmol), lithium chloride (3.95 g, 93.3 mmol) and 1,2-dimethoxyethane (50 mL) at room temperature.
  • FeBr 2 (SciOPP) as a catalyst In a glove box, an oven dried 100 mL single-necked flask equipped with a Teflon-coated magnetic stirring bar was charged with FeBr 2 (SciOPP) (860 mg, 0.78 mmol), manganese (1.7 g, 31.06 mmol), copper (II) chloride (2.08 g, 15.8 mmol), lithium chloride (1.97 g, 46.5 mmol) and 1 ,2-dimethoxyethane (25 mL) at room temperature.
  • the organic layer was concentrated under reduced pressure to give a crude material.
  • This crude material was dissolved in 1-propanol (209mL) at 26°C and cooled to 15°C followed by addition of seed crystals (52mg, 0.12mmol).
  • the collected solid was dried at room temperature under reduced pressure to give desired compound (51.3g, 0.119mol, 98%).
  • the filtrated solution was concentrated under reduced pressure at 10-15°C to give the crude iodide, which was purified by distillation under reduced pressure (bath temperature: 86 ⁇ 94°C, boiling point: 63 ⁇ 64°C at 0.75mmHg) to give pure iodide (22.9g, 0.07 lmol, 61%) as an orange oil.
  • DIBAL-H (1.0 M in hexanes, 3.8 mL, 3.79 mmol) was added dropwise to a solution of lactone S-7 in CH 2 CI 2 (14 mL) at -78 °C under an argon atmosphere.
  • the reaction mixture was stirred for 1 hour at -78 °C, and quenched with methanol (0.2 mL) followed by addition of sodium potassium tartrate solution (10 mL) and stirred the resulting solution at room temperature for 1 hour.
  • the organic layer was separated and the aqueous layer was extracted with CH 2 CI 2 (2 x 50 mL).
  • 9-BBN (0.5 M in THF, 8.27 mL, 4.14 mmol) was added in dropwise to a solution of above prepared crude residue in THF (14 mL) at 0 °C. The clear and colorless solution was stirred for 2 h at room temperature. At this point, TLC analysis indicated complete consumption of starting material. The solution was cooled to 0 °C, and water (8.3 mL) was added (gas evolution!), followed by sodium perborate tetrahydrate (2.47 g, 24.84 mmol). The white suspension was allowed to warm to room temperature and stirred for 2 h. The white suspension was filtered and washed with EtOAc (20 mL). The organic layer was diluted with water (20 mL).
  • thioester 9b An oven dried 100 mL single-necked flask was charged with FeBr 2 (SciOPP) (71 mg, 0.064 mmol), manganese (140 mg, 2.56 mmol), copper (I) iodide (243 mg, 1.28 mmol), lithium chloride (162 mg, 3.84 mmol) and 1,2-dimethoxyethane (4.0 mL) at room temperature.
  • reaction mixture was taken out from glove box, cooled to 0 °C and stirred the reaction mixture under nitrogen atmosphere for 15 hours. After completing the reaction florisil (3 g) was added to the reaction mixture and stirred for 30 min at 0 °C. Filtered the reaction mixture through Celite, washed the filter cake with ethyl acetate (20 mL) and concentrated under reduced pressure to afford the crude product which was then purified by flash column chromatography on silica gel to afford 593 mg (71%) of ketone 11 as a viscous colorless liquid.
  • DIBAL-H (1.0 M in hexanes, 1.55 mL, 1.55 mmol) was added dropwise to a solution of lactone S-14 in CH 2 CI 2 (4 mL) at -78 °C under an argon atmosphere.
  • the reaction mixture was stirred for 1 hour at -78 °C, and quenched with methanol (0.2 mL) followed by addition of sodium potassium tartrate solution (10 mL) and stirred the resulting solution at room temperature for 1 hour.
  • the organic layer was separated and the aqueous layer was extracted with CH 2 CI 2 (2 x 20 mL).
  • reaction mixture was taken out from glove box, cooled to 0 °C and stirred the reaction mixture under nitrogen atmosphere for 15 hours. After completing the reaction florisil (100 mg) was added to the reaction mixture and stirred for 30 min at 0 °C. Filtered the reaction mixture through Celite, washed the filter cake with ethyl acetate (10 mL) and concentrated under reduced pressure to afford the crude product which was then purified by flash column chromatography on silica gel to afford 82 mg (64%) of ketone 13 as a viscous colorless liquid.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des procédés de préparation de molécules organiques contenant de la cétone. Les procédés se basent sur de nouvelles réactions de couplage médiées par fer/cuivre ("médiées par Fe/Cu"). La réaction de couplage médiée par Fe/Cu peut être utilisée dans la préparation de molécules complexes, telles que des halichondrines et analogues de celles-ci. En particulier, les réactions de cétolisation médiées par Fe/Cu ci-décrites sont utiles dans la préparation d'intermédiaires en route vers les halichondrines.
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US10954249B2 (en) 2017-04-05 2021-03-23 President And Fellows Of Harvard College Macrocyclic compound and uses thereof
US11155562B2 (en) 2014-06-30 2021-10-26 President And Fellows Of Harvard College Synthesis of halichondrin analogs and uses thereof
US11220513B2 (en) 2015-04-30 2022-01-11 President And Fellows Of Harvard College Chromium-mediated coupling and application to the synthesis of halichondrins
US11407762B2 (en) 2017-11-15 2022-08-09 President And Fellows Of Harvard College Macrocyclic compounds and uses thereof
US11498892B2 (en) 2017-07-06 2022-11-15 President And Fellows Of Harvard College Fe/Cu-mediated ketone synthesis
US11548898B2 (en) 2017-07-06 2023-01-10 President And Fellows Of Harvard College Synthesis of halichondrins
US11725015B2 (en) 2017-04-05 2023-08-15 President And Fellows Of Harvard College Macrocyclic compound and uses thereof

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US11155562B2 (en) 2014-06-30 2021-10-26 President And Fellows Of Harvard College Synthesis of halichondrin analogs and uses thereof
US11220513B2 (en) 2015-04-30 2022-01-11 President And Fellows Of Harvard College Chromium-mediated coupling and application to the synthesis of halichondrins
US10954249B2 (en) 2017-04-05 2021-03-23 President And Fellows Of Harvard College Macrocyclic compound and uses thereof
US11725015B2 (en) 2017-04-05 2023-08-15 President And Fellows Of Harvard College Macrocyclic compound and uses thereof
US11498892B2 (en) 2017-07-06 2022-11-15 President And Fellows Of Harvard College Fe/Cu-mediated ketone synthesis
US11548898B2 (en) 2017-07-06 2023-01-10 President And Fellows Of Harvard College Synthesis of halichondrins
US11407762B2 (en) 2017-11-15 2022-08-09 President And Fellows Of Harvard College Macrocyclic compounds and uses thereof
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