WO2023144733A1 - Compounds and processes for the preparation of eribulin - Google Patents

Compounds and processes for the preparation of eribulin Download PDF

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Publication number
WO2023144733A1
WO2023144733A1 PCT/IB2023/050650 IB2023050650W WO2023144733A1 WO 2023144733 A1 WO2023144733 A1 WO 2023144733A1 IB 2023050650 W IB2023050650 W IB 2023050650W WO 2023144733 A1 WO2023144733 A1 WO 2023144733A1
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protecting group
compound
alcohol
mmol
aldehyde
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PCT/IB2023/050650
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French (fr)
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Robert Britton
Anissa KAGHAD
Dimitrios Panagopoulos
Guillermo CABALLERO
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Simon Fraser University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds and processes for the preparation of halichondrin B analogs. More specifically, the present invention relates to compounds and processes for the preparation of eribulin.
  • Halichondrin B 1 ( Figure 1A), 1 a polyether macrolide from the sponge Halichondria okadai, exhibits significant activity against cancer cells. 1-3
  • the initial synthesis of halichondrin B required more than a hundred (100) synthetic transformations or steps 3 and provided insight into the relationship between structure and anticancer activity of the halichondrins.
  • Eribulin 2 ( Figure 1A), which represents a simplified version of halichondrin B in which the C35-C54 fragment of the natural product is removed and the lactone oxygen is replaced by a methylene group 5 , was developed as a cancer therapeutic for use in pretreated metastatic breast cancer and inoperable liposarcoma.
  • Biological characterization of eribulin has revealed a mechanism of action that involves binding to the growing end of microtubules, disruption of microtubule dynamics and ultimately irreversible mitotic arrest and cell death by apoptosis.
  • a process for the preparation of a C14-C35 sulfone by reacting a C14-C26 ketone with a C27-C35 sulfonium salt under Corey-Chaykovsky reaction conditions, to form the C14-C35 sulfone.
  • the C14-C35 sulfone may be compound 3, 4; 39, 47, 73 or 82.
  • the C14-C35 sulfone may be used in the preparation of eribulin.
  • a process for the preparation of a C14-C26 ketone by performing a Horner-Wadsworth-Emmons reaction with an ⁇ - chloroaldehyde to form an enone; and reducing the alkene function in the enone, to form the C14-C26 ketone.
  • the ⁇ -chloroaldehyde may be compound 12, 30 or 67.
  • the enone may be compound 31 or 68.
  • the C14-C26 ketone may be compound 10, 33; 44 or 69.
  • a process for the preparation of a C27-C35 sulfonium salt by reacting an aldehyde with NCS and thiopyranone by proline catalysis to form an anti-aldol syn-chlorohydrin; performing a carbonyl reduction followed by cyclization to form a tetrahydrofuran;performing an alcohol inversion followed by hydrolysis to form a tetrahydrofuranol; and performing a methylation of the free alcohol and arylation of the thioether function of the tetrahydrofuranol to form the C27-C35 sulfonium salt.
  • the aldehyde may be compound 16, 49, 56, or 61.
  • the anti-aldol syn-chlorohydrin may be compound 19, 50, 58, or 63.
  • the tetrahydrofuran may be compound 20, 51, 59, or 64.
  • the tetrahydrofuranol may be compound 21, 52, 60, or 65.
  • the C27-C35 sulfonium salt may be compound 9, 22, 40, 43, 53, 66 or 74.
  • a process for the preparation of a C27-C35 aldehyde by: performing a C27 regioselective deprotonation of a C27-C35 sulfonium salt to form a sulfur ylide; and trapping the sulfur ylide with bis(pinacolborane) and subsequent oxidation to form the C27-C35 aldehyde.
  • the regioselective deprotonation may be performed using a sterically hindered base.
  • the C27-C35 sulfonium salt may be compound 9; 22; 40; 43, 53, 66; or 74.
  • the C27-C35 aldehyde may be compound 5, 42; 48, 85, or 86.
  • the C27-C35 aldehyde may be used in the preparation of eribulin. [0011]
  • the compound of Formula I may be compound 38, 72, 73, 77, 78, or 81 or a pharmaceutically acceptable salt thereof.
  • a compound of Formula II or a pharmaceutically acceptable salt thereof where R 5 may be H or an alcohol protecting group; R 6 may be a leaving group; R 7 may be a leaving group; R 9 may be H or OR 16 ; R 8 may be H or OR 16 ; or R 8 and R 9 may be O or CH 2 ; R 10 may be CH 2 OR 5 , CHO, CHCH 2 , CCH, CHC(CH 3 )COCH 3 or CH 2 CH(CH 3 )CO(CH 3 ); and R 16 may be H or an alcohol protecting group.
  • the compound of Formula II may be compound 10, 28, 29, 30, 31, 32, or 33 or a pharmaceutically acceptable salt thereof.
  • a compound of Formula III or a pharmaceutically acceptable salt thereof where R 5 may be H or an alcohol protecting group; R 6 may be a leaving group; R 7 may be a leaving group; R 9 may be H or OR 16
  • R 11 may be H, CH 3 or an alcohol protecting group;
  • R 12 and R 13 may be C(CH 3 ) 2 or a 1,2-diol protecting group;
  • R 14 may be H or an amine protecting group;
  • the compound of Formula III may be compound 9,
  • R 17 may be H and R 18 may be OR 9 , R 17 and R 18 may be O, R 18 may be H and R 17 may be OR 9 , or R 17 and R 18 may be CH;
  • R 11 may be H, CH 3 or an alcohol protecting group;
  • R 12 and R 13 may be C(CH 3 ) 2 or a 1,2-diol protecting group;
  • R 14 may be H or an amine protecting group;
  • R 15 may be H or an amine protecting group; or R 15
  • the compound of Formula IV may be compound is 41 or a pharmaceutically acceptable salt thereof.
  • FIGURE 1A shows the structures of Halichondrin B (1) and eribulin (2)
  • FIGURE 1C shows a summary of an exemplary eribulin synthesis process using ⁇ -chloroaldehydes 11 (C31-C35 chloraldehyde), 12 (C14-C24 chloraldehyde), and 13 (C19-C24 chloraldehyde), in which X is O/NBoc, the arrows represent epoxide opening, the solid bars represent chloride displacement and [O] represents oxidation of sulfur to sulfone; [0025] Figure 2 shows a synthesis scheme for the C
  • FIG. 1 shows a proposed synthesis scheme in which the ⁇ - chloroaldehyde-derived sulfone 39 and known vinyl iodide 7 may be used to produce of eribulin (2); and
  • Figure 6 shows a synthesis scheme for the C27-C35 aldehyde 42 from sulfonium salt 40.
  • the present disclosure provides, in part, processes for the preparation of eribulin and intermediates thereof.
  • the present disclosure provides, in part, a process for the preparation of eribulin using ⁇ -chloroaldehydes. This process allows the production of eribulin in 52 steps and reduces the longest linear sequence to 28 steps.
  • the present disclosure utilizes enantiomerically enriched ⁇ - chloroaldehydes for constructing the three densely functionalized oxygen heterocycles found in the C14-C35 region of eribulin.
  • the present disclosure exploits the inherent stereochemistry of ⁇ -chloroaldehydes to control the relative and absolute stereochemistry at 9 of the 10 stereogenic centers in the C14-C35 fragment of eribulin.
  • each chlorine atom is ultimately displaced in the formation of one of the three heterocyclic rings.
  • the present disclosure also utilizes a doubly diastereoselective Corey- Chaykovsky reaction for preparation of the C27 stereocenter and for the two ⁇ - chloroaldehyde-derived intermediates: C27-C35 sulfonium salt and C14-C26 ketone.
  • the present disclosure also utilizes a sequence including deprotonation, borylation and oxidation for the preparation of the C27-C35 aldehyde from the C27-C35 sulfonium salt. [0036] Accordingly, the present disclosure provides in part the following general Scheme I:
  • R 1 may be aryl (e.g., phenyl, 4-toluyl, etc.);
  • X may be a suitable counterion (e.g., BF 4 -, I-, Br-, Cl-, OTf-, PF 6 - etc.);
  • R 2 may be H or OR 11 ;
  • R 3 may be H or OR 11 ; or
  • R 2 and R 3 may be O;
  • R 4 may be CHCH 2 , CCH, C*H(OR 12 )CH 2 (OR 13 ), or C*H(OR 12 )CH 2 (NR 14 R 15 ), where the asterisk (*) indicates that the stereochemistry is (S);
  • R 11 may be H, CH 3 or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn, etc.);
  • R 12 and R 13 may be C
  • R 5 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.);
  • R 9 may be H or OR 16 ;
  • R 8 may be H or OR 16 ; or
  • R 8 and R 9 may be O or CH 2 ;
  • R 6 may be H, Cl, Br, OTs, OMs, OTf or other suitable leaving group;
  • R 7 may be H, Cl, Br, OTs, OMs, OTf or other suitable leaving group;
  • R 10 may be CH 2 OR 5 or CHO or CHCH 2 or CCH or CHC(CH 3 )COCH 3 or CH 2 CH(CH 3 )CO(CH 3 );
  • R 16 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.).
  • R 1 may be aryl (e.g., phenyl, 4-toluyl, etc.);
  • R 2 may be H or OR 11 ;
  • R 3 may be H or OR 11 ; or
  • R 2 and R 3 may be O;
  • R 4 may be CHCH 2 , CCH, C*H(OR 12 )CH 2 (OR 13 ), or C*H(OR 12 )CH 2 (NR 14 R 15 ), where the asterisk (*) indicates that the stereochemistry is (S);
  • R 5 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.);
  • R 7 may be H, Cl, Br, OTs, OMs, OTf or other suitable leaving group;
  • R 9 may be H or OR 16 ;
  • R 8 may be H or OR 16 ; or
  • R 8 and R 9 may be H or OR 16 ;
  • R 1 may be aryl (e.g., phenyl, 4-toluyl, etc.);
  • R 2 may be H or OR 11 ;
  • R 3 may be H or OR 11 ; or
  • R 2 and R 3 may be O;
  • R 4 may be CHCH 2 , CCH, C*H(OR 12 )CH 2 (OR 13 ), or C*H(OR 12 )CH 2 (NR 14 R 15 ), where the asterisk (*) indicates that the stereochemistry is (S);
  • R 9 may be H and R 8 may be OR 16 or R 9 and R 9 may be O, or R 9 and R 8 may be CH 2 , or R 8 may be H and R 9 may be OR 16 or R 9 and R 8 may be CH;
  • R 11 may be H, CH 3 or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.);
  • a Corey- Chaykovsky reaction 34 is utilized to effect the union of C14-C26 ketone 10 and C27- C35 sulfonium salt 9.
  • This coupling reaction includes regioselective deprotonation of the sulfonium 9 at C27 and a subsequent doubly diastereoselective addition to ketone 10, thus establishing the C26 and C27 stereocenters.
  • Several functional group interconversions, including regioselective opening of the resulting C26-C27 epoxide results in the formation of the C23-C27 tetrahydropyran via chloride displacement 19 and ultimately converges with intermediate 4.
  • the two tetrahydrofuran units in 4 are accessible from ⁇ -chloroaldehydes 11 and 13.
  • the C23 chloride function in 8 that is eventually required for tetrahydropyran formation can be derived from an ⁇ -chloroaldehyde (e.g., 12) via a sequence involving a Horner-Wadsworth-Emmons (HWE) reaction 35 and subsequent enone reduction, capable of ultimately leading to 3 or 4.
  • HWE Horner-Wadsworth-Emmons
  • each of the 9 stereocenters found in the C14-C33 fragment of eribulin can be introduced using substrate-based stereocontrol starting from one of the ⁇ -chloroaldehydes 11 – 13.
  • the Corey-Chaykovsky reaction in general, has been used in organic synthesis to prepare three membered rings like epoxides, aziridines or cyclopropanes by reacting sulfur ylides with electrophiles for example carbonyls, thiocarbonyls, imines or olefins. It is to be understood that a person skilled in the art would readily understand the meaning and use of Corey-Chaykovsky reactions, as used in the art and described herein.
  • the HWE reaction in general, has been used in organic synthesis to prepare an alkene by reacting a carbonyl compound with a phosphonate.
  • R 1 may be aryl (e.g., phenyl, 4-toluyl, etc.);
  • X may be a suitable counterion (e.g., BF 4 -, I-, Br-, Cl-, OTf-, PF 6 - etc.);
  • R 2 may be H or OR 11 ;
  • R 3 may be H or OR 11 ; or
  • R 2 and R 3 may be O;
  • R 4 may be CHCH 2 , CCH, C*H(OR 12 )CH 2 (OR 13 ), or C*H(OR 12 )CH 2 (NR 14 R 15 ), where the asterisk (*) indicates that the stereochemistry is (S);
  • R 1 may be aryl (e.g., phenyl, 4-toluyl, etc.); [00103] R 2 may be H or OR 11 ; R 3 may be H or OR 11 ; or R 2 and R 3 may be O; [00104] R 4 may be CHCH 2 , CCH, C*H(OR 12 )CH 2 (OR 13 ), or C*H(OR 12 )CH 2 (NR 14 R 15 ), where the asterisk (*) indicates that the stereochemistry is (S); [00105] R 17 may be H and R 18 may be OR 9 or R 17 and R 18 may be O, R 18 may be H and R 17 may be OR 9 or R 17 and R 18 may be CH; [00106] R 11 may be H, CH 3 , or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, n etc.); [00107] R 12 and R 13 may be
  • a C27-C35 sulfonium salt can be prepared by reacting an aldehyde with NCS and thiopyranone by proline catalysis to form an anti- aldol syn-chlorohydrin; performing a carbonyl reduction followed by cyclization to form a tetrahydrofuran; performing an alcohol inversion followed by hydrolysis to form a tetrahydrofuranol; and performing a methylation of the free alcohol and arylation of the thioether function of the tetrahydrofuranol to form the C27-C35 sulfonium salt as a mixture of diastereomeric sulfonium salts, as set out in for example Scheme III, where: [00115] R 1 may be aryl (e.g., phenyl, 4-toluyl, etc.); [00116] X
  • a C27-C35 sulfonium salt can be prepared by reacting an aldehyde of the structure 49 with NCS and thiopyranone by proline catalysis to form an anti-aldol syn-chlorohydrin of the structure 50; performing a carbonyl reduction followed by cyclization to form a tetrahydrofuran of the structure 51; performing an alcohol inversion followed by hydrolysis to form a tetrahydrofuranol of the structure 52; and performing a methylation of the free alcohol and arylation of the thioether function of the tetrahydrofuranol to form the C27-C35 sulfonium salt 53 as a mixture of diastereomeric sulfonium salts.
  • aldehyde 49 can be produced from commercially available starting materials using standard techniques as described herein or known in the art, and coupled to thiopyranone via proline catalysis, resulting in formation of the anti-aldol syn-chlorohydrin 50 36 .
  • a subsequent carbonyl reduction followed by cyclization results in the tetrahydrofuran 51.
  • alcohol inversion followed by hydrolysis results in correctly configured tetrahydrofuranol 52.
  • methylation of the free alcohol and arylation of the thioether function provides the Corey-Chaykovsky coupling partner 53, as a mixture of diastereomeric sulfonium salts.
  • PG 1 may be an alcohol protecting group including, without limitation, silyl ether (for example, TBS, TIPS, TMS, TES, SEM); acetate, pivalate or other ester or carbonate protecting group; benzyl, allyl, methoxymethyl or p-methoxybenzyl or other ether protecting group; THP or other related protecting groups; or may be a cyclic protecting group that is connected to Y including without limitation an acetonide or benzylidene or related protecting group, a cyclic silyl protecting groups or a carbonyl (cyclic carbamate).
  • Y may be oxygen with a protecting group listed above for PG 1 (i.e.
  • Ar may be an aryl group.
  • X may be a suitable counterion for the sulfonium group including without limitation a halide (F-, Cl-, Br-, I-), trifluoromethylsulfonate, methyl sulfonate, phenyl sulfonate or other sulfonate, tetrafluoroborate or other borates, hexafluoroantimonate or other antimonates, hexafluorophosphate or other phosphates.
  • a halide F-, Cl-, Br-, I-
  • trifluoromethylsulfonate methyl sulfonate
  • phenyl sulfonate or other sulfonate tetrafluoroborate or other borates
  • hexafluoroantimonate or other antimonates hexafluorophosphate or other phosphates.
  • the aldehyde 56 can be produced from commercially available lactone 54, or also commercially available glutamic acidusing standard techniques as described herein or known in the art and coupled to thiopyranone via proline catalysis.
  • An ⁇ -chlorination of the aldehyde 56 produces a mixture of ⁇ -chloroaldehydes (2R)-57 and (2S)-57.
  • the subsequent proline-catalyzed aldol reaction with thiopyranone results in the formation of the anti-aldol syn- chlorohydrin 58 36 .
  • a C27-C35 sulfonium salt may be used in the preparation of eribulin, as described herein or known in the art.
  • sulfonium salt 53 undergoes regioselective C27 deprotonation to form a sulfur ylide.
  • This ylide is trapped with bis(pinacolborate) to form intermediate 83.
  • This intermediate is then oxidized, which also opens the six- membered ring to generate aldehyde 85.
  • alcohol 84 is formed in the oxidation-ring-opening stage. Oxidation of alcohol 84 provides aldehyde 85.
  • sulfonium salt 74 undergoes regioselective C27 deprotonation to form a sulfur ylide which is tapped by bis(pinacolborane) and oxidized to give aldehyde 86. Further dihydroxylation or amino hydroxylation- protection provides aldehyde 85.
  • PG 1 may be an alcohol protecting group including, without limitation, silyl ether (for example, TBS, TIPS, TMS, TES, SEM); acetate, pivalate or other ester or carbonate protecting group; benzyl, allyl, methoxymethyl or p-methoxybenzyl or other ether protecting group; THP or other related protecting groups; or may be a cyclic protecting group that is connected to Y including without limitation an acetonide or benzylidene or related protecting group, a cyclic silyl protecting groups or a carbonyl (cyclic carbamate).
  • Y may be oxygen with a protecting group listed above for PG 1 (i.e.
  • Ar may be an aryl group.
  • X may be a suitable counterion for the sulfonium group including without limitation a halide (F-, Cl-, Br-, I-), trifluoromethylsulfonate, methyl sulfonate, phenyl sulfonate or other sulfonate, tetrafluoroborate or other borates, hexafluoroantimonate or other antimonates, hexafluorophosphate or other phosphates.
  • a halide F-, Cl-, Br-, I-
  • trifluoromethylsulfonate methyl sulfonate
  • phenyl sulfonate or other sulfonate tetrafluoroborate or other borates
  • hexafluoroantimonate or other antimonates hexafluorophosphate or other phosphates.
  • a C27-C35 aldehyde may have the following chemical structure: [00157] where [00158] R 1 may be aryl (e.g., phenyl, 4-toluyl, etc.); [00159] R 4 may be CHCH 2 , CCH, C*H(OR 12 )CH 2 (OR 13 ), or C*H(OR 12 )CH 2 (NR 14 R 15 ), where the asterisk (*) indicates that the stereochemistry is (S); [00160] R 17 may be H and R 18 may be OR 9 or R 17 and R 18 may be O, R 18 may be H and R 17 may be OR 9 or R 17 and R 18 may be CH; [00161] R 12 and R 13 may be H, C(CH 3 ) 2 or a suitable 1,2-diol protecting group; [00162] R 12 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB,
  • R 12 may be H or
  • a C27-C35 aldehyde may be used in the preparation of eribulin, as described herein or known in the art.
  • a C14-C26 ketone can be prepared by performing a HWE reaction with an ⁇ -chloroaldehyde to form an enone and reducing the alkene function in the enone to form the C14-C26 ketone, as set out in for example Scheme V, where: [00170] R 5 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); [00171] R 9 may be H or OR 16 ; R 8 may be H or OR 16 ; or R 8 and R 9 may be O or CH 2 ; [00172] R 6 may be H, Cl, Br, OTs, OMs, OTf or other suitable leaving group; [00173] R 7 may be H, Cl, Br, OTs, OMs, OTf or other suitable leaving group; [00174] R 10 may be CH
  • C14-C26 ketone 69 can be prepared by performing a HWE reaction with ⁇ -chloroaldehyde 67 to form enone 68 and reducing the alkene function in the enone to form C14-C26 ketone 69.
  • the ⁇ -chloroaldehyde 67 is prepared using standard techniques as described herein or known in the art. Subsequently, a HWE reaction involving the ⁇ - chloroaldehyde 67 results in the enone 68.
  • PG 2 and PG 3 may each independently be an alcohol protecting group including, without limitation, silyl ether (for example, TBS, TIPS, TMS, TES, SEM); acetate, pivalate or other ester or carbonate protecting group; benzyl, allyl, methoxymethyl or p-methoxybenzyl or other ether protecting group; THP or other related protecting groups; or may be a cyclic protecting group that is connected to Y including without limitation an acetonide or benzylidene or related protecting group, a cyclic silyl protecting groups or a carbonyl (cyclic carbamate).
  • a C14-C26 ketone may be used in the preparation of eribulin, as described herein or known in the art.
  • a C14-C35 sulfone can be prepared by reacting a C14-C26 ketone with a complementary C27-C35 sulfonium salt under Corey- Chaykovsky reaction conditions, as set out in for example Scheme VI, where: [00182] R 1 may be aryl (e.g., phenyl, 4-toluyl, etc.); [00183] R 2 may be H or OR 11 ; R 3 may be H or OR 11 ; or R 2 and R 3 may be O; [00184] R 4 may be CHCH 2 , CCH, C*H(OR 12 )CH 2 (OR 13 ), or C*H(OR 12 )CH 2 (NR 14 R 15 ), where the asterisk (*) indicates that the stereochemistry is (S); [00185] R 9 may be H and R 8 may be OR 16 or R 9 and R 9 may be O, or R 9
  • a C14-C35 sulfone can be prepared as follows.
  • Corey-Chaykovsky coupling can be performed using sulfonium salt 53 and ketone 69.
  • Regioselective deprotonation at C27 and reaction of the resulting ylide with the ketone function in 69 followed by direct oxidation to the corresponding sulfone affords the epoxide 70.
  • the allylic alcohol 71 is produced after rearrangement of epoxide 70. Cyclization to the tetrahydropyran 72 is accomplished using double displacement conditions.
  • Completion of the synthesis of the C14-C35 sulfone 73 may be performed by removal of the protecting group PG2, oxidation, and olefination.
  • Corey-Chaykovsky coupling can be performed using sulfonium salt 74 and ketone 69.
  • Regioselective deprotonation at C27 and reaction of the resulting ylide with the ketone function in 69 followed by direct oxidation to the corresponding sulfone affords the epoxide 75.
  • the allylic alcohol 76 is produced after rearrangement of epoxide 75. Cyclization to the tetrahydropyran 77 is accomplished using double displacement conditions.
  • Completion of the synthesis of the C14-C35 sulfone 73 is performed by removal of the protecting group PG2, oxidation and olefination, resulting in 78 followed by dihydroxylation or amino hydroxylation then protection.
  • Corey-Chaykovsky coupling can be performed using sulfonium salt 40 and ketone 69. Regioselective deprotonation at C27 and reaction of the resulting ylide with the ketone function in 69 followed by direct oxidation to the corresponding sulfone afforded the epoxide 79.
  • the allylic alcohol 80 is produced after rearrangement of epoxide 79. Cyclization to the tetrahydropyran 81 is accomplished using double displacement conditions as described herein or known in the art.
  • C14-C35 sulfone 82 can be performed by removal of the protecting group, oxidation, and olefination.
  • a C14-C35 sulfone can be prepared using a C27-C35 aldehyde in accordance with standard procedures as known in the art or described herein.
  • a C14-C35 sulfone may have the chemical structure:
  • R 1 may be aryl (e.g., phenyl, 4-toluyl, etc.); R 4 may be CHCH 2 , CCH, C*H(OR 12 )CH 2 (OR 13 ), or C*H(OR 12 )CH 2 (NR 14 R 15 ), where the asterisk (*) indicates that the stereochemistry is (S); R 9 may be H and R 8 may be OR 16 or R 9 and R 8 may be O, or R 9 and R 8 may be CH 2 , or R 8 may be H and R 9 may be OR 16 or R 9 and R 8 may be CH; R 5 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); R 12 and R 13 may be C(CH 3 ) 2 or a suitable 1,2-diol protecting group; R 12 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB
  • a C14-C35 sulfone may be used in the preparation of eribulin, as described herein or known in the art.
  • Preparation of eribulin [00203] Eribulin can be prepared using a C14-C35 sulfone in accordance with standard procedures as known in the art or described herein. [00204] For example, with the protected amino alcohol 39 in hand and vinyl iodide 7, 11 the synthesis of eribulin 2 may be completed as reported by Jin et al. 15 ( Figure 5) or WO 2015/000070 17 .
  • ketone 32 or 33 may be prepared using the solvent iPrOH alone or with DCE or DCM as co- solvent.
  • suitable catalysts may include Mn(dpm) 3 , Mn(acac) 3 or Co(dpm) 2 .
  • LiHMDS, NaHMDS, LDA, tBuOK or NaH may be used in the Corey-Chaykovsky reaction and/or TPAP, NMO, CH 3 CN may be used at room temperature for the oxidation.
  • Mn or Zn powder may be used in the isomerization of compounds 70 or 75.
  • AgBF 4 , AgOTf, AgPF 6 , or Ag 2 O may be used for the cyclization
  • HF-pyridine or TBAF may be used for TBS deprotection
  • DMP, NaHCO 3 , CH 2 Cl 2 may be used at room temperature or (COCl) 2 , DMSO, Et 3 N, or CH 2 Cl 2 may be used at - 78 °C (Swern) for the oxidation.
  • eribulin can be prepared using a C27-C35 aldehyde in accordance with standard procedures as known in the art or described herein.
  • An “aryl” group as used herein, means a mono- or bicyclic aromatic ring containing only carbon atoms, including for example, 6-14 members, such as 6, 7, 8, 9, 10, 11, 12, 13, or 14 members.
  • aryl groups include 4-toluyl, phenyl, biphenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1,4-benzodioxanyl, and the like.
  • aryl is meant to include aryl groups optionally substituted by one or more substituents as described herein. “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • aryl may refer to heteroaryl with, for example, rings of 5 or 6 or more atoms containing one or two heteroatoms such as N, S, or O.
  • substituent groups include benzyloxy; O-alkyl; O-aryl; aryl; aryl-lower alkyl, etc.
  • a substituted group may have 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 substituent groups.
  • these substituent groups may optionally be further substituted with a substituent as listed herein.
  • Substituents may also be optionally substituted by a bridge structure, for example -OC(O)O- or -OC(O)NH-. In some embodiments, substituents are not further substituted.
  • a “protecting group” as used herein, means a reversibly formed derivative of an existing functional group in a molecule that is temporarily attached to decrease reactivity such that the protected functional group does not react under synthetic conditions to which the molecule is subjected in one or more subsequent steps.
  • Protecting groups are as known in the art and described herein. It is to be understood that a person skilled in the art will readily be able to determine a suitable protecting group for a particular synthesis.
  • a “suitable alcohol protecting group” or an “alcohol protecting group” includes, without limitation, a silyl ether for example, tert- butyl(dimethyl)silyl (TBS), triisopropylsilyl (TIPS), trimethylsilyl (TMS), tert- butyldiphenylsilyl (TBDPS), triethylsilyl (TES), 2-(trimethylsilyl)ethoxymethyl ether (SEM), etc.; acetate (Ac), pivalate (Piv) or other ester or carbonate protecting group etc.; benzyl, allyl, methoxymethyl or p-methoxybenzyl (PMB) or other ether protecting group, etc.; tetrahydropyranyl (THP) ether or other related protecting groups, etc.; or may be a cyclic protecting group that is connected to Y including without limitation an acetonide or benzylidene (
  • a “suitable 1,2-diol protecting group” or “a 1,2-diol protecting group,” as used herein, includes, without limitation, (CH3)2C, Me2Si, BnCH, (iPr)2Si, C(O), etc.
  • a “suitable amine protecting group” or “an amine protecting group,” as used herein, includes, without limitation, acetate (Ac), pivalate (Piv), tert-butyloxycarbonyl (Boc), carboxybenzyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), toluenesulfonyl (Ts), etc.
  • a “suitable 1,2-aminoalcohol protecting group” or “a 1,2-aminoalcohol protecting group,” as used herein, includes, without limitation, Me2C, C(O), Me2Si, (iP2)2Si, etc.
  • a “leaving group,” is an atom, or a group of atoms, that is displaced as stable species taking with it the bonding electrons i.e., a group that can stabilize a negative charge and be displaced by a nucleophile, for example an anion (e.g. Cl-) or a neutral molecule (e.g. H 2 O). Leaving groups are as known in the art and described herein.
  • a “suitable leaving group” or “a leaving group,” as used herein, includes, without limitation, Cl, Br, tosylate (OTs), mesylate (Oms), trifluoromethanesulfonate (OTf) etc.
  • a counterion is meant an ion or atom that has the opposite charge to that of another ion or atom within the same solution. Counterions are as known in the art and described herein. It is to be understood that a person skilled in the art will readily be able to determine a suitable counterion for a particular synthesis.
  • a suitable counterion includes, without limitation, halide (F-, Cl-, Br-, I- ), trifluoromethylsulfonate, methyl sulfonate, phenyl sulfonate or other sulfonate, tetrafluoroborate or other borates, hexafluoroantimonate or other antimonates, hexafluorophosphate or other phosphates, BF 4 -, I-, Br-, Cl-, OTf-, PF 6 -, etc.
  • Steric hindrance refers to the prevention or retardation of a chemical reaction, resulting from the arrangement of atoms in a molecule i.e., the physical structure of the molecule.
  • a sterically hindered base can be a “strong” base i.e., if it can remove a proton from a weak acid. It is to be understood that a person skilled in the art will readily be able to determine a suitable sterically hindered and/or strong base, for a particular synthesis.
  • a “suitable sterically hindered and/or strong base,” “sterically hindered base,” or “strong base” or “sterically hindered strong base,” as used herein, includes, without limitation, LiHMDS, LDA, KHMDS, etc.
  • one or more compounds 3, 4, 5, 39, 42, 82, 85, 86 may be specifically excluded.
  • the present invention will be further illustrated in the following examples. [00221] Examples [00222] Materials and methods [00223] All reagents and starting materials were purchased from Sigma Aldrich, TCI, Alfa Aesar, CarboSynth, and AK Sci and were used without further purification.
  • Dichloromethane was distilled from CaH 2 and stored under nitrogen, THF was distilled from sodium wire/benzophenone ketyl radical and stored under nitrogen.
  • Column chromatography was carried out with 230-400 mesh silica gel (E. Merck, Silica Gel 60). Concentration and removal of trace solvents was done via a Buchi rotary evaporator using acetone-dry-ice condenser and a Welch vacuum pump.
  • ketochlorohydrin 27 [00268] To a cold (–78 °C) solution of diisopropylamine (2.16 mL, 15.4 mmol) in THF (91 mL) was added n-butyllithium dropwise (2 M soln. in hexane, 7.42 mL, 14.8 mmol). The resulting solution was stirred at –78 °C for 30 minutes. After this time, ketone 26 (2.62 g, 14.1 mmol) in THF (2 mL) was added in one portion. The reaction mixture was stirred for 30 minutes.
  • the MacMillan catalyst ent-24.TFA (262 mg, 0.92 mmol, freshly prepared according to the litterature) and N- chlorosuccinimide (615 mg, 4.60 mmol) were then added.
  • the ice bath was removed after 30 minutes allowing the solution to slowly warm to room temperature.
  • the reaction mixture was stirred until complete consumption of starting material as determined by 1 H NMR spectroscopy. After this time, NH 4 Cl (10 mL) and diethyl ether (10 mL) were added and the layers were separated. Then, the aqueous layer was extracted with diethyl ether (2 x 10 mL) and the combined organic phases were dried (Na 2 SO 4 ), filtered, and concentrated to provide a crude mixture.
  • reaction mixture was diluted in CH 2 Cl 2 (15 mL), washed with NaHCO 3 (15 mL) and brine (15 mL), dried with MgSO 4 , and concentrated to provide a crude yellow oil. Purification of the crude product by flash chromatography (silica gel, hexanes-ethylacetate 95:5) afforded compound 31 (1.39 g, 54% yield from 28) as a colorless oil.
  • the aqueous phase was extracted with ethyl acetate (0.5 ml x 3), and the combined organic phases were washed with water (1 mL) and brine (1 mL), dried (MgSO 4 ) and concentrated to provide a crude yellow oil that was directly used in the next step without further purification.
  • the crude alcohol was diluted in CH 2 Cl 2 (0.6 mL) and cooled to 0 °C. NaHCO 3 (28 mg, 0.32 mmol) in and DMP (28 mg, 0.071 mmol) were then added, and the mixture was stirred at room temperature for 1 hour.
  • Ph 2 IPF 6 (721 mg, 1.7 mmol) was added as well, the tube was sealed and the reaction mixture was stirred at 100 oC for 3.5h. The mixture was then allowed to cool to rt and it was loaded directly onto a chromatography column. Purification by flash chromatography (silica gel, EtOAc:Hexanes 50:50 to Acetone:CH 2 Cl 2 50:50) afforded the title compound, contaminated with ⁇ 2% Ph 2 IPF 6 , as a white foam (638 mg, 74%).
  • the aqueous phase was extracted with ethyl acetate (0.5 ml x 3), and the combined organic phases were washed with water (1 mL) and brine (1 mL), dried (MgSO 4 ) and concentrated to provide a crude yellow oil that was directly used in the next step without further purification.
  • the crude alcohol was diluted in CH 2 Cl 2 (0.6 mL) and cooled to 0 °C. NaHCO 3 (28 mg, 0.32 mmol) in and DMP (28 mg, 0.071 mmol) were then added and the mixture was stirred at room temperature for 1 hour.
  • the aqueous phase was extracted with ethyl acetate (0.5 ml x 3), and the combined organic phases were washed with water (1 mL) and brine (1 mL), dried (MgSO 4 ) and concentrated to provide a crude yellow oil that was directly used in the next step without further purification.
  • the crude diol was diluted in CH 2 Cl 2 (0.3 mL) and cooled to 0 °C. Et 3 N (12 ⁇ L, 0.088 mmol) and TBSOTf (19 ⁇ L, 0.083 mmol) were then added and the reaction mixture was stirred for 1 hour. After this time, water (0.5 mL) was added and the phases were separated.
  • Each batch was then microwaved in an 80 mL sealed vessel in a CEM Discover Microwave reactor, using the following method: 5 min ramp time to 60 °C, 5 min hold, 5 min ramp to 75 °C, 5 min hold, 5 min ramp to 90 °C, 5 min hold, 5 min ramp to 120 °C, 120 min hold, max power 300 W, max pressure 250 psi.
  • the solutions were recombined and the solvent evaporated to afford 1.25 g of a crude brown oil. Purification of the crude material by flash column chromatography (silica gel, EtOAc:Hexanes 1:2) afforded the title compound as a yellow oil (657 mg, 44% over two steps).
  • an ⁇ -chlorination of the aldehyde produces a mixture of ⁇ - chloroaldehydes (2R)-17 and (2S)-17. While the ⁇ -chlorination is not stereoselective, proline also promotes the epimerization of the diastereomeric ⁇ -chloroaldehydes (2R)-17 and (2S)-17, and the subsequent proline-catalyzed aldol reaction with thiopyranone 36 is sufficiently slow to effect a dynamic kinetic resolution, favoring reaction with (2S)-17 and formation of the anti-aldol syn-chlorohydrin 19 allowing the chlorohydrin 19 to be prepared on multi-gram scale 36 .
  • the ketone function in this material was then reduced in a 1,3-syn- selective manner using DIBAL to afford the corresponding diol.
  • thermal (MeOH, 120 oC, mwave) 29 and silver(I)-promoted (AgOTf, Ag 2 O, THF) 28 cyclization conditions as well as a SrCO 3 -promoted cyclization protocol 18 and used the Ag(I)- promoted cyclization conditions to obtain the desired tetrahydrofuranol that was protected as the corresponding TBS ether 28 in excellent overall yield.
  • a titanocene (III) complex (Cp 2 TiCl 2 ), 44 which promotes formation of an intermediate ⁇ -titanoxy tertiary radical.
  • Reduction of the tertiary radical by a second equivalent of Ti(III) then affords a titanium carbanion that can undergo ⁇ -hydride elimination to afford the observed allylic alcohol. Applying these conditions to the more elaborate epoxide 34, the allylic alcohol 35 was produced as the major product in excellent yield.
  • aldehyde 42 is a key building block towards eribulin. Accordingly, regioselective deprotonation of sulfonium 40, followed by borylation, oxidation, ring-opening, oxidation provided easy access to the C27-C35 aldehyde 42. Therefore, aldehyde 42 can be obtained in 12 steps from commercially available starting materials. References 1 Hirata, Y. & Uemura, D. Halichondrins—antitumor polyether macrolides from a marine sponge. Pure & Appl. Chem.58, 701-710 (1986).
  • Enantioselective linchpin catalysis by SOMO catalysis an approach to the asymmetric alpha-chlorination of aldehydes and terminal epoxide formation.
  • the word “comprising” is used as an open-ended term, substantially equivalent to the phrase “including, but not limited to,” and the word “comprises” has a corresponding meaning. It is to be however understood that, where the words “comprising” or “comprises,” or a variation having the same root, are used herein, variation or modification to “consisting” or “consists,” which excludes any element, step, or ingredient not specified, or to “consisting essentially of” or “consists essentially of,” which limits to the specified materials or recited steps together with those that do not materially affect the basic and novel characteristics of the claimed invention, is also contemplated.

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Abstract

The present invention relates to compounds and a process for the preparation of eribulin. More specifically, the process to prepare the C14- C35 sulfone fragment of eribulin (i.e. compounds of formula I) by reacting a C14-C26 ketone fragment of eribulin (i.e. compounds of formula II) with a C27-C35 sulfonium salt fragment (i.e. compounds of formula III) under Corey-Chaykovsky reaction conditions is explored. The processes to prepare the intermediate C14-C26 ketone (i.e. compounds of formula II), the intermediate C27-C35 sulfonium salt (i.e. compounds of formula III) and the intermediate C27-C35 aldehyde (i.e. compounds of formula IV) arc also disclosed.

Description

COMPOUNDS AND PROCESSES FOR THE PREPARATION OF ERIBULIN FIELD OF INVENTION [0001] The present invention relates to compounds and processes for the preparation of halichondrin B analogs. More specifically, the present invention relates to compounds and processes for the preparation of eribulin. BACKGROUND OF THE INVENTION [0002] Halichondrin B 1 (Figure 1A),1 a polyether macrolide from the sponge Halichondria okadai, exhibits significant activity against cancer cells.1-3 The initial synthesis of halichondrin B required more than a hundred (100) synthetic transformations or steps3 and provided insight into the relationship between structure and anticancer activity of the halichondrins.4 [0003] Eribulin 2 (Figure 1A), which represents a simplified version of halichondrin B in which the C35-C54 fragment of the natural product is removed and the lactone oxygen is replaced by a methylene group5, was developed as a cancer therapeutic for use in pretreated metastatic breast cancer and inoperable liposarcoma. Biological characterization of eribulin has revealed a mechanism of action that involves binding to the growing end of microtubules, disruption of microtubule dynamics and ultimately irreversible mitotic arrest and cell death by apoptosis.6 [0004] The structure of eribulin is complex, with 19 stereocenters, 3 tetrahydrofuran and 3 tetrahydropyran rings and a 22-membered macrocyclic ketone.7 Accordingly, there have been extensive efforts dedicated to eribulin synthesis, using various intermediates (Figure 1B), much of which was predicated by synthesis of halichondrin B.3,8-22 [0005] α-chloroaldehydes23-27 are a class of chemical compounds that have been used in tetrahydrofuran28-30 and natural product synthesis.31-33 SUMMARY OF THE INVENTION [0006] The present invention relates to compounds and processes for the preparation of eribulin. [0007] In some embodiments, there is provided a process for the preparation of a C14-C35 sulfone by reacting a C14-C26 ketone with a C27-C35 sulfonium salt under Corey-Chaykovsky reaction conditions, to form the C14-C35 sulfone. The C14-C35 sulfone may be compound 3, 4; 39, 47, 73 or 82. The C14-C35 sulfone may be used in the preparation of eribulin. [0008] In some embodiments, there is provided a process for the preparation of a C14-C26 ketone by performing a Horner-Wadsworth-Emmons reaction with an α- chloroaldehyde to form an enone; and reducing the alkene function in the enone, to form the C14-C26 ketone. The α-chloroaldehyde may be compound 12, 30 or 67. The enone may be compound 31 or 68. The C14-C26 ketone may be compound 10, 33; 44 or 69. [0009] In some embodiments, there is provided a process for the preparation of a C27-C35 sulfonium salt by reacting an aldehyde with NCS and thiopyranone by proline catalysis to form an anti-aldol syn-chlorohydrin; performing a carbonyl reduction followed by cyclization to form a tetrahydrofuran;performing an alcohol inversion followed by hydrolysis to form a tetrahydrofuranol; and performing a methylation of the free alcohol and arylation of the thioether function of the tetrahydrofuranol to form the C27-C35 sulfonium salt. The aldehyde may be compound 16, 49, 56, or 61. The anti-aldol syn-chlorohydrin may be compound 19, 50, 58, or 63. The tetrahydrofuran may be compound 20, 51, 59, or 64. The tetrahydrofuranol may be compound 21, 52, 60, or 65. The C27-C35 sulfonium salt may be compound 9, 22, 40, 43, 53, 66 or 74. [0010] In some embodiments, there is provided a process for the preparation of a C27-C35 aldehyde by: performing a C27 regioselective deprotonation of a C27-C35 sulfonium salt to form a sulfur ylide; and trapping the sulfur ylide with bis(pinacolborane) and subsequent oxidation to form the C27-C35 aldehyde. The regioselective deprotonation may be performed using a sterically hindered base. The C27-C35 sulfonium salt may be compound 9; 22; 40; 43, 53, 66; or 74. The C27-C35 aldehyde may be compound 5, 42; 48, 85, or 86. The C27-C35 aldehyde may be used in the preparation of eribulin. [0011] In some embodiments, there is provided a compound of Formula I or a pharmaceutically acceptable salt thereof:
Figure imgf000005_0001
where R1 may be aryl; R2 may be H or OR11; R3 may be H or OR11; or R2 and R3 may be O; R4 may be CHCH2, CCH, C*H(OR12)CH2(OR13), or C*H(OR12)CH2(NR14R15), wherein the asterisk (*) indicates that the stereochemistry is (S); R5 may be H or an alcohol protecting group; R9 may be H and R8 may be OR16, or R9 and R9 may be O, or R9 and R8 may be CH2, or R8 is H and R9 may be OR16, or R9 and R8 may be CH; R11 may be H, CH3 or an alcohol protecting group; R12 and R13 may be C(CH3)2 or a 1,2-diol protecting group; R12 may be H or an alcohol protecting group; and R13 may be H or an alcohol protecting group; R14 may be H or an amine protecting group; R15 may be H or an amine protecting group; or R15 and R12 may be C(CH3)2 or a 1,2-aminoalcohol protecting group; and R16 may be H or an alcohol protecting group. [0012] The compound of Formula I may be compound 38, 72, 73, 77, 78, or 81 or a pharmaceutically acceptable salt thereof. [0013] In some embodiments, there is provided a compound of Formula II or a pharmaceutically acceptable salt thereof:
Figure imgf000006_0001
where R5 may be H or an alcohol protecting group; R6 may be a leaving group; R7 may be a leaving group; R9 may be H or OR16; R8 may be H or OR16; or R8 and R9 may be O or CH2; R10 may be CH2OR5, CHO, CHCH2, CCH, CHC(CH3)COCH3 or CH2CH(CH3)CO(CH3); and R16 may be H or an alcohol protecting group. [0014] The compound of Formula II may be compound 10, 28, 29, 30, 31, 32, or 33 or a pharmaceutically acceptable salt thereof. [0015] In some embodiments, there is provided a compound of Formula III or a pharmaceutically acceptable salt thereof:
Figure imgf000007_0001
wherein R1 may be aryl; X may be a counterion; R2 may be H or OR11; R3 may be H or OR11; or R2 and R3 may be O; R4 may be CHCH2, CCH, C*H(OR12)CH2(OR13), or C*H(OR12)CH2(NR14R15), wherein the asterisk (*) indicates that the stereochemistry is (S); R11 may be H, CH3 or an alcohol protecting group; R12 and R13 may be C(CH3)2 or a 1,2-diol protecting group; R12 may be H or an alcohol protecting group; and R13 may be H or an alcohol protecting group; R14 may be H or an amine protecting group; R15 may be H or an amine protecting group; or R15 and R12 may be C(CH3)2 or a 1,2-aminoalcohol protecting group. [0016] The compound of Formula III may be compound 9, 22, 40, 43, 53, 66 or 74 or a pharmaceutically acceptable salt thereof. [0017] In some embodiments, there is provided a compound of Formula IV or a pharmaceutically acceptable salt thereof:
Figure imgf000008_0001
wherein R1 may be aryl; R2 may be H or OR11; R3 may be H or OR11; or R2 and R3 may be O; R4 may be CHCH2, CCH, C*H(OR12)CH2(OR13), or C*H(OR12)CH2(NR14R15), wherein the asterisk (*) indicates that the stereochemistry is (S); R17 may be H and R18 may be OR9, R17 and R18 may be O, R18 may be H and R17 may be OR9, or R17 and R18 may be CH; R11 may be H, CH3 or an alcohol protecting group; R12 and R13 may be C(CH3)2 or a 1,2-diol protecting group; R12 may be H or an alcohol protecting group; and R13 may be H or an alcohol protecting group; R14 may be H or an amine protecting group; R15 may be H or an amine protecting group; or R15 and R12 may be C(CH3)2 or a 1,2-aminoalcohol protecting group. [0018] The compound of Formula IV may be compound is 41 or a pharmaceutically acceptable salt thereof. [0019] In some embodiments, there is provided compound 9, 10, 22, 33, 39, 40, 42, 43, 44, 47, 48, 53, 66, 69, 73, 74, or 82, or a pharmaceutically acceptable salt thereof. [0020] This summary of the invention does not necessarily describe all features of the invention. BRIEF DESCRIPTION OF THE DRAWINGS [0021] These and other features of the invention will become more apparent from the following description in which reference is made to the appended drawings wherein: [0022] FIGURE 1A shows the structures of Halichondrin B (1) and eribulin (2); [0023] FIGURE 1B shows the structures of compounds and intermediates used in standard syntheses of eribulin, in which Ar = Ph in 3 and Ar = Tol; [0024] FIGURE 1C shows a summary of an exemplary eribulin synthesis process using α-chloroaldehydes 11 (C31-C35 chloraldehyde), 12 (C14-C24 chloraldehyde), and 13 (C19-C24 chloraldehyde), in which X is O/NBoc, the arrows represent epoxide opening, the solid bars represent chloride displacement and [O] represents oxidation of sulfur to sulfone; [0025] Figure 2 shows a synthesis scheme for the C27-C35 sulfonium 22 which includes a one-pot proline catalyzed α-chlorination/aldol reaction; [0026] Figure 3 shows a synthesis scheme for the C14-C26 methyl ketone 33 in which two separate asymmetric α-chlorination reactions are employed in the synthesis of the chloroketone 33; [0027] Figure 4 shows a synthesis scheme for the C14-C35 sulfone 39 in which a doubly diastereoselective Corey-Chaykovsky reaction connects the sulfonium salt 22 and chloroketone 33 through proposed transition state 36. A subsequent regioselective epoxide opening sets the stage for the formation of the C23-C27 tetrahydropyran ring. The inset depicts an overlay of 1H NMR spectra (3.0 to 6.0 ppm only) recorded on the sulfone 39 (top trace) and the equivalent material produced via GMP process (bottom trace); [0028] Figure 5 shows a proposed synthesis scheme in which the α- chloroaldehyde-derived sulfone 39 and known vinyl iodide 7 may be used to produce of eribulin (2); and [0029] Figure 6 shows a synthesis scheme for the C27-C35 aldehyde 42 from sulfonium salt 40. DETAILED DESCRIPTION [0030] The present disclosure provides, in part, processes for the preparation of eribulin and intermediates thereof. [0031] Accordingly, the present disclosure provides, in part, a process for the preparation of eribulin using α-chloroaldehydes. This process allows the production of eribulin in 52 steps and reduces the longest linear sequence to 28 steps. [0032] In general, the present disclosure utilizes enantiomerically enriched α- chloroaldehydes for constructing the three densely functionalized oxygen heterocycles found in the C14-C35 region of eribulin. [0033] Accordingly, the present disclosure exploits the inherent stereochemistry of α-chloroaldehydes to control the relative and absolute stereochemistry at 9 of the 10 stereogenic centers in the C14-C35 fragment of eribulin. In addition to orchestrating diastereoselective reactions, each chlorine atom is ultimately displaced in the formation of one of the three heterocyclic rings. [0034] The present disclosure also utilizes a doubly diastereoselective Corey- Chaykovsky reaction for preparation of the C27 stereocenter and for the two α- chloroaldehyde-derived intermediates: C27-C35 sulfonium salt and C14-C26 ketone. [0035] In some embodiments, the present disclosure also utilizes a sequence including deprotonation, borylation and oxidation for the preparation of the C27-C35 aldehyde from the C27-C35 sulfonium salt. [0036] Accordingly, the present disclosure provides in part the following general Scheme I:
Figure imgf000011_0001
[0037] In Scheme I, for structure 43: [0038] R1 may be aryl (e.g., phenyl, 4-toluyl, etc.); [0039] X may be a suitable counterion (e.g., BF4-, I-, Br-, Cl-, OTf-, PF6- etc.); [0040] R2 may be H or OR11; R3 may be H or OR11; or R2 and R3 may be O; [0041] R4 may be CHCH2, CCH, C*H(OR12)CH2(OR13), or C*H(OR12)CH2(NR14R15), where the asterisk (*) indicates that the stereochemistry is (S); [0042] R11 may be H, CH3 or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn, etc.); [0043] R12 and R13 may be C(CH3)2 or a suitable 1,2-diol protecting group; [0044] R12 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); and [0045] R13 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); [0046] R14 may be H or Boc or Cbz or Ac or a suitable amine protecting group; [0047] R15 may be H or Boc or Cbz or Ac or a suitable amine protecting group; or [0048] R15 and R12 may together be C(CH3)2 or a suitable 1,2-aminoalcohol protecting group. [0049] In Scheme I, for structure 44: [0050] R5 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); [0051] R9 may be H or OR16; R8 may be H or OR16; or R8 and R9 may be O or CH2; [0052] R6 may be H, Cl, Br, OTs, OMs, OTf or other suitable leaving group; [0053] R7 may be H, Cl, Br, OTs, OMs, OTf or other suitable leaving group; [0054] R10 may be CH2OR5 or CHO or CHCH2 or CCH or CHC(CH3)COCH3 or CH2CH(CH3)CO(CH3); [0055] R16 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.). [0056] In Scheme I, for structures 45 and 46: [0057] R1 may be aryl (e.g., phenyl, 4-toluyl, etc.); [0058] R2 may be H or OR11; R3 may be H or OR11; or R2 and R3 may be O; [0059] R4 may be CHCH2, CCH, C*H(OR12)CH2(OR13), or C*H(OR12)CH2(NR14R15), where the asterisk (*) indicates that the stereochemistry is (S); [0060] R5 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); [0061] R7 may be H, Cl, Br, OTs, OMs, OTf or other suitable leaving group; [0062] R9 may be H or OR16; R8 may be H or OR16; or R8 and R9 may be O or CH2; [0063] R6 may be H, Cl, Br, OTs, OMs, OTf or other suitable leaving group; [0064] R11 may be H, CH3 or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); [0065] R12 and R13 may be C(CH3)2 or a suitable 1,2-diol protecting group; [0066] R12 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); and [0067] R13 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); [0068] R14 may be H or Boc or Cbz or Ac or a suitable amine protecting group; [0069] R15 may be H or Boc or Cbz or Ac or a suitable amine protecting group; or [0070] R12 and R15 may together be C(CH3)2 or a suitable 1,2-aminoalcohol protecting group; and [0071] R16 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.). [0072] In Scheme I, for structure 47: [0073] R1 may be aryl (e.g., phenyl, 4-toluyl, etc.); [0074] R2 may be H or OR11; R3 may be H or OR11; or R2 and R3 may be O; [0075] R4 may be CHCH2, CCH, C*H(OR12)CH2(OR13), or C*H(OR12)CH2(NR14R15), where the asterisk (*) indicates that the stereochemistry is (S); [0076] R9 may be H and R8 may be OR16 or R9 and R9 may be O, or R9 and R8 may be CH2, or R8 may be H and R9may be OR16 or R9 and R8 may be CH; [0077] R11 may be H, CH3 or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); [0078] R12 and R13 may be C(CH3)2 or a suitable 1,2-diol protecting group; [0079] R12 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); and [0080] R13 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); [0081] R14 may be H or Boc or Cbz or Ac or a suitable amine protecting group; [0082] R15 may be H or Boc or Cbz or Ac or a suitable amine protecting group; or [0083] R15 and R12 may be C(CH3)2 or a suitable 1,2-aminoalcohol protecting group; and [0084] R16 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.). [0085] Accordingly, in one embodiment, and as outlined in Figure 1C, a Corey- Chaykovsky reaction34 is utilized to effect the union of C14-C26 ketone 10 and C27- C35 sulfonium salt 9. This coupling reaction includes regioselective deprotonation of the sulfonium 9 at C27 and a subsequent doubly diastereoselective addition to ketone 10, thus establishing the C26 and C27 stereocenters. Several functional group interconversions, including regioselective opening of the resulting C26-C27 epoxide, results in the formation of the C23-C27 tetrahydropyran via chloride displacement19 and ultimately converges with intermediate 4.17 The two tetrahydrofuran units in 4 are accessible from α-chloroaldehydes 11 and 13. Likewise, the C23 chloride function in 8 that is eventually required for tetrahydropyran formation can be derived from an α-chloroaldehyde (e.g., 12) via a sequence involving a Horner-Wadsworth-Emmons (HWE) reaction35 and subsequent enone reduction, capable of ultimately leading to 3 or 4. Following this strategy, each of the 9 stereocenters found in the C14-C33 fragment of eribulin can be introduced using substrate-based stereocontrol starting from one of the α-chloroaldehydes 11 – 13. [0086] The Corey-Chaykovsky reaction, in general, has been used in organic synthesis to prepare three membered rings like epoxides, aziridines or cyclopropanes by reacting sulfur ylides with electrophiles for example carbonyls, thiocarbonyls, imines or olefins. It is to be understood that a person skilled in the art would readily understand the meaning and use of Corey-Chaykovsky reactions, as used in the art and described herein. [0087] The HWE reaction, in general, has been used in organic synthesis to prepare an alkene by reacting a carbonyl compound with a phosphonate. It is to be understood that a person skilled in the art would readily understand the meaning and use of Corey-Chaykovsky reactions, as used in the art and described herein. [0088] In some embodiments, the present disclosure provides in part the following general Scheme II:
Figure imgf000015_0001
[0089] In Scheme II, for structure 43: [0090] R1 may be aryl (e.g., phenyl, 4-toluyl, etc.); [0091] X may be a suitable counterion (e.g., BF4-, I-, Br-, Cl-, OTf-, PF6- etc.); [0092] R2 may be H or OR11; R3 may be H or OR11; or R2 and R3 may be O; [0093] R4 may be CHCH2, CCH, C*H(OR12)CH2(OR13), or C*H(OR12)CH2(NR14R15), where the asterisk (*) indicates that the stereochemistry is (S); [0094] R11 may be H, CH3 or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn, etc.); [0095] R12 and R13 may be C(CH3)2 or a suitable 1,2-diol protecting group; or [0096] R12 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); and [0097] R13 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); [0098] R14 may be H or Boc or Cbz or Ac or a suitable amine protecting group; [0099] R15 may be H or Boc or Cbz or Ac or a suitable amine protecting group; or [00100] R15 and R12 may be C(CH3)2 or a suitable 1,2-aminoalcohol protecting group. [00101] In Scheme II, for structure 48: [00102] R1 may be aryl (e.g., phenyl, 4-toluyl, etc.); [00103] R2 may be H or OR11; R3 may be H or OR11; or R2 and R3 may be O; [00104] R4 may be CHCH2, CCH, C*H(OR12)CH2(OR13), or C*H(OR12)CH2(NR14R15), where the asterisk (*) indicates that the stereochemistry is (S); [00105] R17 may be H and R18 may be OR9 or R17 and R18 may be O, R18 may be H and R17 may be OR9 or R17 and R18 may be CH; [00106] R11 may be H, CH3, or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, n etc.); [00107] R12 and R13 may be C(CH3)2 or a suitable 1,2-diol protecting group; [00108] R12 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); and [00109] R13 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); [00110] R14 may be H or Boc or Cbz or Ac or a suitable amine protecting group; [00111] R15 may be H or Boc or Cbz or Ac or a suitable amine protecting group; or [00112] R15 and R12 may be C(CH3)2 or a suitable 1,2-aminoalcohol protecting group. [00113] Preparation of the C27-C35 sulfonium salt [00114] In some embodiments, a C27-C35 sulfonium salt can be prepared by reacting an aldehyde with NCS and thiopyranone by proline catalysis to form an anti- aldol syn-chlorohydrin; performing a carbonyl reduction followed by cyclization to form a tetrahydrofuran; performing an alcohol inversion followed by hydrolysis to form a tetrahydrofuranol; and performing a methylation of the free alcohol and arylation of the thioether function of the tetrahydrofuranol to form the C27-C35 sulfonium salt as a mixture of diastereomeric sulfonium salts, as set out in for example Scheme III, where: [00115] R1 may be aryl (e.g., phenyl, 4-toluyl, etc.); [00116] X may be a suitable counterion (e.g., BF4-, I-, Br-, Cl-, OTf-, PF6- etc.); [00117] R2 may be H or OR11; R3 may be H or OR11; or R2 and R3 may be O; [00118] R4 may be CHCH2, CCH, C*H(OR12)CH2(OR13), or C*H(OR12)CH2(NR14R15), where the asterisk (*) indicates that the stereochemistry is (S); [00119] R11 may be H, CH3 or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn, etc.); [00120] R12 and R13 may be C(CH3)2 or a suitable 1,2-diol protecting group; [00121] R12 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); and [00122] R13 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); [00123] R14 may be H or Boc or Cbz or Ac or a suitable amine protecting group; [00124] R15 may be H or Boc or Cbz or Ac or a suitable amine protecting group; or [00125] R15 and R12 may be together C(CH3)2 or a suitable 1,2-aminoalcohol protecting group.
Figure imgf000018_0001
[00126] Accordingly, in one embodiment, a C27-C35 sulfonium salt can be prepared by reacting an aldehyde of the structure 49 with NCS and thiopyranone by proline catalysis to form an anti-aldol syn-chlorohydrin of the structure 50; performing a carbonyl reduction followed by cyclization to form a tetrahydrofuran of the structure 51; performing an alcohol inversion followed by hydrolysis to form a tetrahydrofuranol of the structure 52; and performing a methylation of the free alcohol and arylation of the thioether function of the tetrahydrofuranol to form the C27-C35 sulfonium salt 53 as a mixture of diastereomeric sulfonium salts.
Figure imgf000018_0002
[00127] In this embodiment, aldehyde 49 can be produced from commercially available starting materials using standard techniques as described herein or known in the art, and coupled to thiopyranone via proline catalysis, resulting in formation of the anti-aldol syn-chlorohydrin 5036. [00128] A subsequent carbonyl reduction followed by cyclization results in the tetrahydrofuran 51. Subsequently, alcohol inversion followed by hydrolysis results in correctly configured tetrahydrofuranol 52. Finally, methylation of the free alcohol and arylation of the thioether function provides the Corey-Chaykovsky coupling partner 53, as a mixture of diastereomeric sulfonium salts. [00129] PG1 may be an alcohol protecting group including, without limitation, silyl ether (for example, TBS, TIPS, TMS, TES, SEM); acetate, pivalate or other ester or carbonate protecting group; benzyl, allyl, methoxymethyl or p-methoxybenzyl or other ether protecting group; THP or other related protecting groups; or may be a cyclic protecting group that is connected to Y including without limitation an acetonide or benzylidene or related protecting group, a cyclic silyl protecting groups or a carbonyl (cyclic carbamate). [00130] Y may be oxygen with a protecting group listed above for PG1 (i.e. OPG1) or nitrogen with any protecting group listed for PG1 together with either a proton (i.e., NHPG1) or a second protecting group (i.e., NPG1PG4). Suitable protecting groups are as described herein or known in the art. [00131] Ar may be an aryl group. [00132] X may be a suitable counterion for the sulfonium group including without limitation a halide (F-, Cl-, Br-, I-), trifluoromethylsulfonate, methyl sulfonate, phenyl sulfonate or other sulfonate, tetrafluoroborate or other borates, hexafluoroantimonate or other antimonates, hexafluorophosphate or other phosphates.
Figure imgf000020_0001
[00133] In another embodiment, the aldehyde 56 can be produced from commercially available lactone 54, or also commercially available glutamic acidusing standard techniques as described herein or known in the art and coupled to thiopyranone via proline catalysis. An α-chlorination of the aldehyde 56 produces a mixture of α-chloroaldehydes (2R)-57 and (2S)-57. The subsequent proline-catalyzed aldol reaction with thiopyranone results in the formation of the anti-aldol syn- chlorohydrin 5836. [00134] A subsequent diastereoselective carbonyl reduction using NaBH(OAc)3 followed by a SrCO3 promoted cyclization results in the tetrahydrofuran 59. Subsequently, alcohol inversion followed by hydrolysis results in correctly configured tetrahydrofuranol 60. Finally, methylation of the free alcohol and arylation of the thioether function provides the Corey-Chaykovsky coupling partner 40, as a mixture of diastereomeric sulfonium salts.
Figure imgf000021_0001
[00135] In another embodiment, the aldehyde 61, which is commercially available, can be coupled to thiopyranone via proline catalysis. An α-chlorination of the aldehyde produces a mixture of α-chloroaldehydes (2R)-62 and (2S)-62. The subsequent proline-catalyzed aldol reaction with thiopyranone results in the formation of the anti-aldol syn-chlorohydrin 6336. A subsequent diastereoselective carbonyl reduction followed by cyclization results in the tetrahydrofuran 64. Subsequently, alcohol inversion followed by hydrolysis results in correctly configured tetrahydrofuranol 65. Finally, methylation of the free alcohol and arylation of the thioether function using a diaryliodonium salt provides the Corey-Chaykovsky coupling partner 66, as a mixture of diastereomeric sulfonium salts. [00136] A C27-C35 sulfonium salt may be used in the preparation of eribulin, as described herein or known in the art. A C27-C35 sulfonium salt in accordance with chemical structure 43 or 53, as described herein, includes without limitation compound 9, 22, 40, 66 or 74. [00137] Preparation of the C27-C35 aldehyde [00138] In some embodiments, a C27-C35 aldehyde can be prepared from a C27- C35 sulfonium salt to form a sulfur ylide, using for example, a sterically hindered strong base, such as LiHMDS, LDA, KHMDS; trapping the sulfur ylide with an alkoxy or halo boron reagent, for example, bis(pinacolborane) or BPin, followed by oxidation to form the C27-C35 aldehyde, as set out in for example Scheme IV, where: [00139] R1 may be aryl (e.g., phenyl, 4-toluyl, etc.); [00140] X may be a suitable counterion (e.g., BF4-, I-, Br-, Cl-, OTf-, PF6- etc.); [00141] R2 may be H or OR11; R3 may be H or OR11; or R2 and R3 may be O; [00142] R4 may be CHCH2, CCH, C*H(OR12)CH2(OR13), or C*H(OR12)CH2(NR14R15), where the asterisk (*) indicates that the stereochemistry is (S); [00143] R11 may be H, CH3 or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn, etc.); [00144] R12 and R13 may be C(CH3)2 or a suitable 1,2-diol protecting group; [00145] R12 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); and [00146] R13 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); [00147] R14 may be H or Boc or Cbz or Ac or a suitable amine protecting group; [00148] R15 may be H or Boc or Cbz or Ac or a suitable amine protecting group; or [00149] R15 and R12 may be together C(CH3)2 or a suitable 1,2-aminoalcohol protecting group.
Figure imgf000022_0001
[00150] In one embodiment, sulfonium salt 53 undergoes regioselective C27 deprotonation to form a sulfur ylide. This ylide is trapped with bis(pinacolborate) to form intermediate 83. This intermediate is then oxidized, which also opens the six- membered ring to generate aldehyde 85. In other cases, it happens that alcohol 84 is formed in the oxidation-ring-opening stage. Oxidation of alcohol 84 provides aldehyde 85.
Figure imgf000023_0001
[00151] In another embodiment, sulfonium salt 74 undergoes regioselective C27 deprotonation to form a sulfur ylide which is tapped by bis(pinacolborane) and oxidized to give aldehyde 86. Further dihydroxylation or amino hydroxylation- protection provides aldehyde 85.
Figure imgf000023_0002
[00152] In these processes, PG1 may be an alcohol protecting group including, without limitation, silyl ether (for example, TBS, TIPS, TMS, TES, SEM); acetate, pivalate or other ester or carbonate protecting group; benzyl, allyl, methoxymethyl or p-methoxybenzyl or other ether protecting group; THP or other related protecting groups; or may be a cyclic protecting group that is connected to Y including without limitation an acetonide or benzylidene or related protecting group, a cyclic silyl protecting groups or a carbonyl (cyclic carbamate). [00153] Y may be oxygen with a protecting group listed above for PG1 (i.e. OPG1) or nitrogen with any protecting group listed for PG1 together with either a proton (i.e., NHPG1) or a second protecting group (i.e., NPG1PG4). Suitable protecting groups are as described herein or known in the art. [00154] Ar may be an aryl group. [00155] X may be a suitable counterion for the sulfonium group including without limitation a halide (F-, Cl-, Br-, I-), trifluoromethylsulfonate, methyl sulfonate, phenyl sulfonate or other sulfonate, tetrafluoroborate or other borates, hexafluoroantimonate or other antimonates, hexafluorophosphate or other phosphates. [00156] In some embodiments, a C27-C35 aldehyde, may have the following chemical structure:
Figure imgf000024_0001
[00157] where [00158] R1 may be aryl (e.g., phenyl, 4-toluyl, etc.); [00159] R4 may be CHCH2, CCH, C*H(OR12)CH2(OR13), or C*H(OR12)CH2(NR14R15), where the asterisk (*) indicates that the stereochemistry is (S); [00160] R17 may be H and R18 may be OR9 or R17 and R18 may be O, R18 may be H and R17 may be OR9 or R17 and R18 may be CH; [00161] R12 and R13 may be H, C(CH3)2 or a suitable 1,2-diol protecting group; [00162] R12 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); and [00163] R13 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); [00164] R14 may be H or Boc or Cbz or Ac or a suitable amine protecting group; [00165] R15 may be H or Boc or Cbz or Ac or a suitable amine protecting group; or [00166] R15 and R12 may be C(CH3)2 or a suitable 1,2-aminoalcohol protecting group. [00167] A C27-C35 aldehyde may be used in the preparation of eribulin, as described herein or known in the art. A C27-C35 aldehyde in accordance with chemical structure 48 or 85, as described herein, includes without limitation compound 5, 42, or 86. [00168] Preparation of the C14-C26 ketone [00169] In general, a C14-C26 ketone can be prepared by performing a HWE reaction with an α-chloroaldehyde to form an enone and reducing the alkene function in the enone to form the C14-C26 ketone, as set out in for example Scheme V, where: [00170] R5 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); [00171] R9 may be H or OR16; R8 may be H or OR16; or R8 and R9 may be O or CH2; [00172] R6 may be H, Cl, Br, OTs, OMs, OTf or other suitable leaving group; [00173] R7 may be H, Cl, Br, OTs, OMs, OTf or other suitable leaving group; [00174] R10 may be CH2OR5 or CHO or CHCH2 or CCH or CHC(CH3)COCH3 or CH2CH(CH3)CO(CH3); [00175] R16 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.).
Figure imgf000025_0001
[00176] In one embodiment, C14-C26 ketone 69 can be prepared by performing a HWE reaction with α-chloroaldehyde 67 to form enone 68 and reducing the alkene function in the enone to form C14-C26 ketone 69.
Figure imgf000026_0001
[00177] The α-chloroaldehyde 67 is prepared using standard techniques as described herein or known in the art. Subsequently, a HWE reaction involving the α- chloroaldehyde 67 results in the enone 68. Reduction of the alkene function in 68 using established protocols for the conjugate reduction of enones (e.g., catalytic hydrogenation, Ni-mediated hydride transfer or CuH reduction) results in the ketone 69. [00178] PG2 and PG3 may each independently be an alcohol protecting group including, without limitation, silyl ether (for example, TBS, TIPS, TMS, TES, SEM); acetate, pivalate or other ester or carbonate protecting group; benzyl, allyl, methoxymethyl or p-methoxybenzyl or other ether protecting group; THP or other related protecting groups; or may be a cyclic protecting group that is connected to Y including without limitation an acetonide or benzylidene or related protecting group, a cyclic silyl protecting groups or a carbonyl (cyclic carbamate). [00179] A C14-C26 ketone may be used in the preparation of eribulin, as described herein or known in the art. A C14-C26 ketone in accordance with chemical structure 44 or 69, as described herein, includes without limitation compound 10, 31, 32, or 33. [00180] Preparation of the C14-C35 sulfone [00181] In some embodiments, a C14-C35 sulfone can be prepared by reacting a C14-C26 ketone with a complementary C27-C35 sulfonium salt under Corey- Chaykovsky reaction conditions, as set out in for example Scheme VI, where: [00182] R1 may be aryl (e.g., phenyl, 4-toluyl, etc.); [00183] R2 may be H or OR11; R3 may be H or OR11; or R2 and R3 may be O; [00184] R4 may be CHCH2, CCH, C*H(OR12)CH2(OR13), or C*H(OR12)CH2(NR14R15), where the asterisk (*) indicates that the stereochemistry is (S); [00185] R9 may be H and R8 may be OR16 or R9 and R9 may be O, or R9 and R8 may be CH2, or R8 may be H and R9may be OR16 or R9 and R8 may be CH; [00186] R11 may be H, CH3 or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); [00187] R12 and R13 may be C(CH3)2 or a suitable 1,2-diol protecting group; [00188] R12 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); and [00189] R13 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); [00190] R14 may be H or Boc or Cbz or Ac or a suitable amine protecting group; [00191] R15 may be H or Boc or Cbz or Ac or a suitable amine protecting group; or [00192] R15 and R12 may be C(CH3)2 or a suitable 1,2-aminoalcohol protecting group; [00193] R16 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.). [00194] A C14-C26 ketone and a C27-C35 sulfonium salt may be complementary if they are capable of reacting with each other, as described herein, to form a C14-C35 sulfone.
Figure imgf000028_0001
Scheme VI [00195] Accordingly, a C14-C35 sulfone can be prepared as follows.
Figure imgf000028_0002
[00196] In one embodiment, Corey-Chaykovsky coupling can be performed using sulfonium salt 53 and ketone 69. Regioselective deprotonation at C27 and reaction of the resulting ylide with the ketone function in 69 followed by direct oxidation to the corresponding sulfone affords the epoxide 70. The allylic alcohol 71 is produced after rearrangement of epoxide 70. Cyclization to the tetrahydropyran 72 is accomplished using double displacement conditions.19 Completion of the synthesis of the C14-C35 sulfone 73 may be performed by removal of the protecting group PG2, oxidation, and olefination.
Figure imgf000029_0001
[00197] In another embodiment, Corey-Chaykovsky coupling can be performed using sulfonium salt 74 and ketone 69. Regioselective deprotonation at C27 and reaction of the resulting ylide with the ketone function in 69 followed by direct oxidation to the corresponding sulfone affords the epoxide 75. The allylic alcohol 76 is produced after rearrangement of epoxide 75. Cyclization to the tetrahydropyran 77 is accomplished using double displacement conditions. Completion of the synthesis of the C14-C35 sulfone 73 is performed by removal of the protecting group PG2, oxidation and olefination, resulting in 78 followed by dihydroxylation or amino hydroxylation then protection.
Figure imgf000030_0001
[00198] In another embodiment, Corey-Chaykovsky coupling can be performed using sulfonium salt 40 and ketone 69. Regioselective deprotonation at C27 and reaction of the resulting ylide with the ketone function in 69 followed by direct oxidation to the corresponding sulfone afforded the epoxide 79. The allylic alcohol 80 is produced after rearrangement of epoxide 79. Cyclization to the tetrahydropyran 81 is accomplished using double displacement conditions as described herein or known in the art.19 Completion of the synthesis of the C14-C35 sulfone 82 can be performed by removal of the protecting group, oxidation, and olefination. [00199] In alternative embodiments, a C14-C35 sulfone can be prepared using a C27-C35 aldehyde in accordance with standard procedures as known in the art or described herein. [00200] In some embodiments, a C14-C35 sulfone, may have the chemical structure:
where
Figure imgf000031_0001
R1 may be aryl (e.g., phenyl, 4-toluyl, etc.); R4 may be CHCH2, CCH, C*H(OR12)CH2(OR13), or C*H(OR12)CH2(NR14R15), where the asterisk (*) indicates that the stereochemistry is (S); R9 may be H and R8 may be OR16 or R9 and R8 may be O, or R9 and R8 may be CH2, or R8 may be H and R9 may be OR16 or R9 and R8 may be CH; R5 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); R12 and R13 may be C(CH3)2 or a suitable 1,2-diol protecting group; R12 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); R13 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.); R14 may be H or Boc or Cbz or Ac or a suitable amine protecting group; R15 may be H or Boc or Cbz or Ac or a suitable amine protecting group; or R15 and R12 may be C(CH3)2 or a suitable 1,2-aminoalcohol protecting group; R16 may be H or a suitable alcohol protecting group (e.g., TBS, TES, TMS, Piv, Ac, THP, PMB, Bn etc.). [00201] A C14-C35 sulfone may be used in the preparation of eribulin, as described herein or known in the art. A C14-C35 sulfone, in accordance with chemical structure 47 or 73 as described herein, includes without limitation compound 3, 4, 39, or 82. [00202] Preparation of eribulin [00203] Eribulin can be prepared using a C14-C35 sulfone in accordance with standard procedures as known in the art or described herein. [00204] For example, with the protected amino alcohol 39 in hand and vinyl iodide 7,11 the synthesis of eribulin 2 may be completed as reported by Jin et al.15 (Figure 5) or WO 2015/00007017. [00205] It is to be understood that suitable reagents may be used in the processes described herein or known in the art. Accordingly, in some embodiments, ketone 32 or 33 may be prepared using the solvent iPrOH alone or with DCE or DCM as co- solvent. In some embodiments, suitable catalysts may include Mn(dpm)3, Mn(acac)3 or Co(dpm)2. [00206] In some embodiments, for compounds 53 and 74, LiHMDS, NaHMDS, LDA, tBuOK or NaH may be used in the Corey-Chaykovsky reaction and/or TPAP, NMO, CH3CN may be used at room temperature for the oxidation. [00207] In some embodiments, Mn or Zn powder may be used in the isomerization of compounds 70 or 75. [00208] In some embodiments, for compounds 71 or 76, AgBF4, AgOTf, AgPF6, or Ag2O may be used for the cyclization, HF-pyridine or TBAF may be used for TBS deprotection, and/or DMP, NaHCO3, CH2Cl2, may be used at room temperature or (COCl)2, DMSO, Et3N, or CH2Cl2 may be used at - 78 °C (Swern) for the oxidation. [00209] In some embodiments, eribulin can be prepared using a C27-C35 aldehyde in accordance with standard procedures as known in the art or described herein. [00210] An “aryl” group, as used herein, means a mono- or bicyclic aromatic ring containing only carbon atoms, including for example, 6-14 members, such as 6, 7, 8, 9, 10, 11, 12, 13, or 14 members. Examples of aryl groups include 4-toluyl, phenyl, biphenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1,4-benzodioxanyl, and the like. Unless stated otherwise specifically herein, the term “aryl” is meant to include aryl groups optionally substituted by one or more substituents as described herein. “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Accordingly, in some embodiments, the term “aryl” may refer to heteroaryl with, for example, rings of 5 or 6 or more atoms containing one or two heteroatoms such as N, S, or O. When substituted, a group may be substituted with any desired substituent or substituents such as one or more of the following group: H, alkyl (C1-10), alkenyl (C2-10), alkynyl (C2-10), aryl (5-12 members), arylalkyl, arylalkenyl, or arylalkynyl, each of which may optionally contain one or more heteroatoms selected from O, S, P, N, F, Cl, Br, I, or B, and each of which may be further substituted, for example, by =O; or optionally substituted forms of acyl, arylacyl, alkyl- alkenyl-, alkynyl- or arylsulfonyl and forms thereof which contain heteroatoms in the alkyl, alkenyl, alkynyl or aryl moieties; halogen (e.g., chloro, iodo, bromo, or fluoro); hydroxyl; C1-10alkoxyl; amino (primary, secondary, or tertiary); nitro; thiol; thioether; imine; cyano; amido; carbamoyl; phosphonato; bisphosphonate; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxo; haloalkyl (e.g., trifluoromethyl); cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or non-aromatic heterocyclic, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); and aromatic carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl). Specific substituent groups include benzyloxy; O-alkyl; O-aryl; aryl; aryl-lower alkyl, etc. A substituted group may have 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 substituent groups. In some embodiments, these substituent groups may optionally be further substituted with a substituent as listed herein. Substituents may also be optionally substituted by a bridge structure, for example -OC(O)O- or -OC(O)NH-. In some embodiments, substituents are not further substituted. [00211] A “protecting group” as used herein, means a reversibly formed derivative of an existing functional group in a molecule that is temporarily attached to decrease reactivity such that the protected functional group does not react under synthetic conditions to which the molecule is subjected in one or more subsequent steps. Protecting groups are as known in the art and described herein. It is to be understood that a person skilled in the art will readily be able to determine a suitable protecting group for a particular synthesis. [00212] In some embodiments, a “suitable alcohol protecting group” or an “alcohol protecting group” includes, without limitation, a silyl ether for example, tert- butyl(dimethyl)silyl (TBS), triisopropylsilyl (TIPS), trimethylsilyl (TMS), tert- butyldiphenylsilyl (TBDPS), triethylsilyl (TES), 2-(trimethylsilyl)ethoxymethyl ether (SEM), etc.; acetate (Ac), pivalate (Piv) or other ester or carbonate protecting group etc.; benzyl, allyl, methoxymethyl or p-methoxybenzyl (PMB) or other ether protecting group, etc.; tetrahydropyranyl (THP) ether or other related protecting groups, etc.; or may be a cyclic protecting group that is connected to Y including without limitation an acetonide or benzylidene (Bn) or related protecting group, a cyclic silyl protecting groups or a carbonyl (cyclic carbamate) etc. [00213] In some embodiments, a “suitable 1,2-diol protecting group” or “a 1,2-diol protecting group,” as used herein, includes, without limitation, (CH3)2C, Me2Si, BnCH, (iPr)2Si, C(O), etc. [00214] In some embodiments, a “suitable amine protecting group” or “an amine protecting group,” as used herein, includes, without limitation, acetate (Ac), pivalate (Piv), tert-butyloxycarbonyl (Boc), carboxybenzyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), toluenesulfonyl (Ts), etc. [00215] In some embodiments, a “suitable 1,2-aminoalcohol protecting group” or “a 1,2-aminoalcohol protecting group,” as used herein, includes, without limitation, Me2C, C(O), Me2Si, (iP2)2Si, etc. [00216] A “leaving group,” is an atom, or a group of atoms, that is displaced as stable species taking with it the bonding electrons i.e., a group that can stabilize a negative charge and be displaced by a nucleophile, for example an anion (e.g. Cl-) or a neutral molecule (e.g. H2O). Leaving groups are as known in the art and described herein. It is to be understood that a person skilled in the art will readily be able to determine a suitable leaving group for a particular synthesis. In some embodiments, a “suitable leaving group” or “a leaving group,” as used herein, includes, without limitation, Cl, Br, tosylate (OTs), mesylate (Oms), trifluoromethanesulfonate (OTf) etc. [00217] By a counterion is meant an ion or atom that has the opposite charge to that of another ion or atom within the same solution. Counterions are as known in the art and described herein. It is to be understood that a person skilled in the art will readily be able to determine a suitable counterion for a particular synthesis. In some embodiments, a suitable counterion includes, without limitation, halide (F-, Cl-, Br-, I- ), trifluoromethylsulfonate, methyl sulfonate, phenyl sulfonate or other sulfonate, tetrafluoroborate or other borates, hexafluoroantimonate or other antimonates, hexafluorophosphate or other phosphates, BF4-, I-, Br-, Cl-, OTf-, PF6-, etc. [00218] Steric hindrance refers to the prevention or retardation of a chemical reaction, resulting from the arrangement of atoms in a molecule i.e., the physical structure of the molecule. A sterically hindered base can be a “strong” base i.e., if it can remove a proton from a weak acid. It is to be understood that a person skilled in the art will readily be able to determine a suitable sterically hindered and/or strong base, for a particular synthesis. In some embodiments, a “suitable sterically hindered and/or strong base,” “sterically hindered base,” or “strong base” or “sterically hindered strong base,” as used herein, includes, without limitation, LiHMDS, LDA, KHMDS, etc. [00219] In some embodiments, one or more compounds 3, 4, 5, 39, 42, 82, 85, 86 may be specifically excluded. [00220] The present invention will be further illustrated in the following examples. [00221] Examples [00222] Materials and methods [00223] All reagents and starting materials were purchased from Sigma Aldrich, TCI, Alfa Aesar, CarboSynth, and AK Sci and were used without further purification. Dichloromethane was distilled from CaH2 and stored under nitrogen, THF was distilled from sodium wire/benzophenone ketyl radical and stored under nitrogen. Column chromatography was carried out with 230-400 mesh silica gel (E. Merck, Silica Gel 60). Concentration and removal of trace solvents was done via a Buchi rotary evaporator using acetone-dry-ice condenser and a Welch vacuum pump. [00224] Analytical Data [00225] Nuclear magnetic resonance (NMR) spectra were recorded using deuterochloroform (CDCl3), deuteromethanol (CD3OD), deuteroacetonitrile (CD3CN) or deuterodimethyl sulfoxide (DMSO-d6) as the solvent. Signal positions (δ) are given in parts per million from tetramethylsilane (δ 0) and were measured relative to the signal of the solvent (1H NMR: CDCl3: δ 7.26; CD3OD: δ3.31; CD3CN: δ1.96; DMSO- d6: δ 2.50; 13C NMR: CDCl3: δ 77.16; CD3OD: δ 49.00; CD3CN: δ1.32; DMSO-d6: 39.5). Coupling constants (J values) are given in Hertz (Hz) and are reported to the nearest 0.1 Hz.1H NMR spectral data are tabulated in the order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; sept, septet; m, multiplet; br, broad), coupling constants, number of protons. NMR spectra were recorded on a Bruker Avance 600 equipped with a QNP or TCI cryoprobe (600 MHz), Bruker 400 (400 MHz) or Bruker 500 (500 MHz). [00226] Synthesis of carbamate 14a
Figure imgf000036_0001
[00227] Tartrate salt 14 (11.14 g, 44.2 mmol) was suspended in THF (110 mL). Then, K2CO3 was added portion-wise (110 mL, std. sln.). The mixture was vigorously stirred for 20 min to allow the free amine to be formed. Then, at room temperature, di-tert-butyl dicarbonate (12.2 mL, 53.0 mmol) was added dropwise. The reaction was vigorously stirred until full consumption of the starting material was observed (45-60 min). After that, the solvent is removed under reduced pressure and the residue redissolved in 2,2,2-trifluoroethanol (30 mL). A catalytic amount of pyridine was added and the reaction was stirred at room temperature for 1 h. After this time, the solvent was removed under reduced pressure and the product dried in high vacuum. This procedure afforded the clean product as a white thick oil (8.59 g, 97%). [00228] 1H NMR (400 MHz, CDCl3) δ 4.86 (br s, 1H), 4.00 – 3.89 (m, 1H), 3.89 – 3.81 (m, 1H), 3.79 – 3.69 (m, 1H), 3.41 – 3.28 (m, 1H), 3.06 (dt, J = 13.1, 6.1 Hz, 1H), 2.03 – 1.82 (m, 3H), 1.58 – 1.51 (m, 1H), 1.44 (s, 9H) [00229] 13C NMR (101 MHz, CDCl3) δ 156.17, 79.09, 78.11, 68.04, 44.45, 28.48, 28.42, 25.85 [00230] Synthesis of lactone 15
Figure imgf000037_0001
[00231] N-Boc protected amine 14a (3.33 g, 16.54 mmol) was dissolved in EtOAc (80 mL). Then, water (80 mL) was added, followed by NaBrO3 (10 g, 66.16 mmol) and Ru(acac)3 (330 mg, 0.83 mmol). The mixture was stirred vigorously overnight at room temperature. The reaction was quenched with Na2S2O3 (30 mL, std. sln.) and diluted with water (30 mL). The organic layer was separated and the aqueous phase extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine (80 mL), dried over MgSO4 and the solvent removed under reduced pressure. Flash chromatography (silica gel, 1:1 EtOAc – hexanes) provided the product as a white wax (1.70 g, 48%). [00232] 1H NMR (400 MHz, CDCl3) δ 4.88 (br s, 1H), 4.70 – 4.50 (m, 1H), 3.63 – 3.42 (m, 1H), 3.27 (dt, J = 14.6, 6.2 Hz, 1H), 2.64 – 2.45 (m, 2H), 2.42 – 2.16 (m, 1H), 2.11 – 1.86 (m, 1H), 1.44 (s, 9H) [00233] 13C NMR (101 MHz, CDCl3) δ 176.83, 156.17, 80.09, 79.78, 44.21, 28.72, 28.46, 24.69 [00234] Synthesis of aldehyde 16
Figure imgf000037_0002
[00235] To a solution of 15 (7.46 g, 34.6 mmol) in THF (350 mL) was added NaBH4 (5.2 g, 138.6 mmol). The mixture was stirred at rt for 5min and then it was heated to 60 ºC. At that temperature, MeOH (70 mL) was added dropwise over 60 min. After the addition was completed, full consumption of the starting material was observed by TLC. It was then allowed to cool to rt and then the reaction mixture was quenched with saturated NH4Cl (150 mL). The aqueous phase was then extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with brine (200 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford the crude product (7.18 g). This material was used immediately, without purification, for the next step. [00236] The product from the previous step was dissolved in acetone (350 mL), and then 2,2-dimethoxypropane (85 mL, 693 mmol) was added, followed by TsOH•H2O (657 mg, 3.46 mmol). The reaction mixture was then stirred at rt for 1 h. The reaction was quenched with triethyl amine (0.6 mL, 4.15 mmol) and stirred at room temperature for 5 min. The solvent was then removed under reduced pressure and the resulting mixture was used in the next step without further purification. [00237] The crude mixture was dissolved in DCM (350 mL). Then, celite was added (11.2 g) followed by PCC (11.2 g, 52.0 mmol). The reaction was stirred overnight at room temperature. The reaction was then filtered through celite and thoroughly washed with DCM. The solvent was removed under reduced pressure and the residue was loaded into a silica column. Flash chromatography (silica gel, 30% EtOAc in hexanes) provided the product as a clear, colorless liquid (6.14 g, 69% yield over three steps). [00238] 1H NMR (500 MHz, CDCl3) δ 9.80 (t, J = 1.4 Hz, 1H), 4.17 – 3.99 (m, 1H), 3.66 (m, 1H), 3.06 (br s, 1H), 2.59 (br s, 2H), 2.03 – 1.93 (m, 1H), 1.92 – 1.78 (m, 1H), 1.69 – 1.35 (m, 15H). [00239] 13C NMR (101 MHz, CDCl3) δ 201.47, 152.34, 151.95, 93.73, 93.28, 80.24, 79.62, 72.76, 72.54, 71.23, 62.05, 50.63, 39.89, 28.54, 27.36, 26.34, 25.51, 25.35, 24.43 (mixture of rotamers) [00240] Synthesis of chlorohydrin 19
Figure imgf000038_0001
[00241] To a solution of 16 (3.62 g, 14.0 mmol) in CH2Cl2 (47 mL) at 0 °C was added NCS (1.88 g, 14.0 mmol) and D-proline (1.89 g, 17.0 mmol). After 1 h, tetrahydrothiopyran-4-one (4.9 g, 42.0 mmol) was added, followed by DMSO (9 mL). The mixture was then allowed to warm to rt and stirred for 3 days. After that, the reaction was quenched with brine (80 mL) and the layers were separated. The aqueous was extracted with CH2Cl2 (3 x 30 mL) and the combined organic were washed with brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification of this material by flash chromatography (silica gel, EtOAc:Hexanes 15:85 to 50:50) afforded the title compound as a slightly yellow foam (2.22 g, 38%). [00242] 1H NMR (600 MHz, CDCl3) δ 4.32 (tdd, J = 9.4, 5.8, 2.6 Hz, 1H), 4.24 (br s, 1H), 4.12 (ddd, J = 8.7, 5.3, 1.9 Hz, 1H), 3.72 (d, J = 46.5 Hz, 1H), 3.22 br (s, 1H), 3.17 – 3.01 (m, 3H), 3.01 – 2.94 (m, 2H), 2.88 – 2.67 (m, 3H), 2.35 (d, J = 12.9 Hz, 1H), 1.88 (br s, 1H), 1.65 – 1.40 (m, 15H). [00243] 13C NMR (151 MHz, CDCl3) δ 211.69, 211.60, 152.37, 151.97, 93.87, 93.37, 80.35, 79.74, 72.72, 70.93, 70.64, 63.30, 60.02, 56.56, 50.84, 44.62, 39.31, 39.18, 33.80, 31.85, 30.78, 28.59, 27.56, 26.57, 25.36, 24.46. (mixture of rotamers) [00244] Synthesis of cyclized alcohol 20
Figure imgf000039_0001
[00245] To a solution of 19 (626 mg, 1.53 mmol) in THF (10.2 mL) at -78 ºC was added a 1 M sln. of DIBAL in hexanes (3.1 mL, 3.06 mmol) dropwise and slowly over 45 min. After 1h, the reaction mixture was quenched with methanol (0.1 mL) and Rochelle’s salt (3 mL, std. sln.). After allowing to reach room temperature, Rochelle’s salt (30 mL, std. sln.) was added and diluted with EtOAc (10 mL). The emulsion was vigorously stirred until the two layers separated. The organic layer was separated and the aqueous was extracted with EtOAc (3 x 20 mL). The combined organic layers were then washed with brine (60 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound as a ~18:1 mixture of inseparable diastereomers. This material was used immediately for the next step without further purification. [00246] To the previous crude in MeOH (80 mL), H2O was added (4 mL). Then, SrCO3 (4.52 g, 30.6 mmol) was added and the reaction was stirred at 75 ºC overnight. After 12 h, the reaction mixture was allowed to cool to rt and then it was filtered through a Celite pad. The filtrate was dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the crude material by flash chromatography (silica gel, EtOAc:Hexanes 50:50) afforded the title compound as a white foam (560 mg, 82% over two steps). [00247] 1H NMR (500 MHz, CDCl3) δ 4.21 (dq, J = 11.9, 6.0 Hz, 1H), 4.15 (m, 1H), 3.84 – 3.63 (m, 2H), 3.41 (t, J = 10.0 Hz, 1H), 3.22 – 3.07 (m, 1H), 2.90 – 2.83 (m, 1H), 2.77 – 2.61 (m, 3H), 2.52 – 2.39 (m, 1H), 2.04 – 1.90 (m, 1H), 1.89 – 1.77 (m, 2H), 1.75 – 1.61 (m, 2H), 1.59 – 1.40 (m, 15H). [00248] 13C NMR (151 MHz, CDCl3) δ 152.39, 151.98, 93.57, 93.08, 83.68, 80.32, 79.67, 79.35, 70.80, 70.62, 50.87, 49.49, 36.89, 33.91, 28.59, 27.50, 27.45, 26.39, 25.33, 24.39. (mixture of rotamers) [00249] Synthesis of inverted alcohol 21
Figure imgf000040_0001
[00250] To a solution of Ph3P (399 mg, 1.5 mmol) in THF (6 mL) at 0 ºC was added DIAD (300 μL, 1.5 mmol). The yellow solution was stirred at 0 ºC for 30 min, by which time it had turned into a white suspension. A solution of 20 (379 mg, 1.0 mmol) and p-nitrobenzoic acid (254 mg, 1.5 mmol) in THF (4 mL) was then added dropwise over 5 min. The resulting yellow solution was stirred at 0 ºC for 50min, then it was allowed to warm to rt over 2.5 h. The solvents were then removed under reduced pressure and the residue was redissolved in MeOH (14.5 mL). Freshly ground NaOH (122 mg, 3.0 mmol) was then added and the mixture was stirred at rt overnight. After 15 h, the reaction was quenched by the addition of saturated NH4Cl (20 mL) and the aqueous layer was then extracted with Et2O (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, EtOAc:Hexanes 30:70 to 40:60) afforded the title compound as a white foam (254 mg, 67% over two steps). [00251] 1H NMR (500 MHz, CDCl3) δ 4.49 – 4.29 (m, 1H), 4.16 – 4.06 (m, 1H), 3.99 (q, J = 8.9, 8.4 Hz, 1H), 3.69 (m, 1H), 3.54 (s, 1H), 3.15 (s, 1H), 3.08 – 2.88 (m, 2H), 2.81 – 2.64 (m, 2H), 2.65 – 2.54 (m, 1H), 2.49 – 2.27 (m, 1H), 2.11 (s, 1H), 1.96 – 1.75 (m, 2H), 1.69 (dtd, J = 20.0, 11.6, 9.8, 4.6 Hz, 1H), 1.64 – 1.38 (m, 15H). [00252] 13C NMR (151 MHz, CDCl3) δ 152.18, 151.84, 94.38, 93.83, 80.55, 79.89, 78.33, 75.06, 69.02, 68.84, 52.63, 52.51, 50.44, 33.51, 31.74, 31.18, 28.57, 27.60, 27.32, 26.27, 25.37, 24.45. (mixture of rotamers) [00253] Synthesis of methyl ether 21a
Figure imgf000041_0001
[00254] To a suspension of NaOt-Bu (136 mg, 1.42 mmol) in THF (0.8 mL) at 0 ºC was added a solution of 21 (265 mg, 0.71 mmol) in THF (2 mL). Then, the reaction was stirred at room temperature for 1 h. After that time, MeI (133 μL, 1.42 mmol) was added dropwise at room temperature and the resulting suspension stirred for 1 h. The reaction was quenched at 0 ºC with NH4Cl (5 mL) and the aqueous was extracted with EtOAc (3 x 5 mL). The combined organic were washed with brine (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the crude material by flash chromatography (silica gel, EtOAc:Hexanes 40:60) afforded the title compound as a white foam (246 mg, 90%). [00255] 1H NMR (600 MHz, CDCl3) δ 4.25 (m, 1H), 4.06 – 3.87 (m, 1H), 3.84 – 3.75 (m, 0.5H), 3.71 (dd, J = 9.7, 5.4 Hz, 0.5H), 3.66 – 3.58 (m, 1H), 3.38 (s, 3H), 3.15 – 3.03 (m, 1H), 3.03 – 2.88 (m, 2H), 2.81 – 2.57 (m, 3H), 2.36 (s, 1H), 1.97 (ddd, J = 13.8, 8.6, 5.1 Hz, 1H), 1.90 – 1.79 (m, 2H), 1.74 (q, J = 11.7, 11.1 Hz, 1H), 1.63 – 1.39 (m, 15H). [00256] 13C NMR (151 MHz, CDCl3) δ 152.46, 152.02, 93.26, 92.78, 85.47, 80.10, 79.47, 79.16, 75.16, 75.11, 71.57, 71.45, 58.95, 51.70, 51.60, 51.13, 51.06, 33.85, 33.54, 31.86, 28.66, 28.59, 27.69, 27.44, 26.38, 25.39, 24.44. (mixture of rotamers) [00257] Synthesis of sulfonium salt 22
Figure imgf000041_0002
[00258] A pressure tube was charged with 21-a (41 mg, 0.106 mmol) in ClCH2CH2Cl (0.7 mL), (Tol)2IOTf (51 mg, 0.111 mmol) and Cu(OBz)2 (0.8 mg, 2.65 ^mol). The tube was then sealed and the reaction mixture was stirred at 110 ºC for 40 min. It was then allowed to cool to rt and the reaction filtered through a short pad of silica and washed with acetonitrile to remove the copper salt. Purification of the crude material by flash chromatography (silica gel – prewashed with 5% triethyl amine in hexane, CH3CN:CH2Cl21:1) afforded the title compound as a light brown foam (45 mg, 69%). [00259] 1H NMR (500 MHz, CDCl3) δ 8.0 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 4.85 – 4.67 (m, 1H), 4.40 – 4.31 (m, 1H), 4.29 – 4.04 (m, 4H), 3.90 – 3.69 (m, 2H), 3.54 (dd, J = 12.1, 3.2 Hz, 1H), 3.38 (s, 3H), 3.24 – 3.01 (m, 1H), 2.76 (d, J = 13.9 Hz, 1H), 2.48 (s, 3H), 2.11 – 1.91 (m, 3H), 1.89 – 1.65 (m, 1H), 1.65 – 1.42 (m, 15H) [00260] 13C NMR (101 MHz, CDCl3) δ 152.37, 147.21, 132.24, 131.49, 122.08, 119.53, 117.82, 93.30, 92.85, 84.18, 80.13, 79.62, 76.56, 73.72, 71.34, 71.06, 59.52, 50.94, 48.33, 48.26, 43.78, 41.86, 33.61, 29.32, 28.62, 27.36, 26.32, 25.35, 24.42, 21.85 [00261] Synthesis of (R)-2-chlorohept-6-enal 25
Figure imgf000042_0001
[00262] To a cold (0 °C), stirred solution of heptenal 23 (4.43 g, 39.56 mmol) in CH3CN (79 mL), was added the MacMillan catalyst 24 (2.25 g, 7.91 mmol, freshly prepared according to the literature) and N-chlorosuccinimide (5.28 g, 39.56 mmol). The ice bath was removed after 30 minutes allowing the solution to slowly warm to room temperature. The reaction mixture was stirred until complete consumption of starting material as determined by 1H NMR spectroscopy. After this time, NH4Cl (30 mL) and diethyl ether (70 mL) were added and the layers were separated. Then, the aqueous layer was extracted with diethyl ether (2 x 30 mL) and the combined organic phases were dried (Na2SO4), filtered, and concentrated to provide a crude mixture. The mixture was then diluted with pentane (5 mL), filtered and concentrated to provide a crude α-chloroaldehyde 25 (5.80.g, 94% purity, 95% ee) as a colourless oil. [00263] Synthesis of 4-oxopentyl pivalate 26
Figure imgf000042_0002
[00264] 5-hydroxy-2-pentanone (3.42 g, 33 mmol) and DMAP (82 mg, 0.7 mmol) were dissolved in dry CH2Cl2 (63 mL) and pyridine (21 mL). The solution was cooled to 0 °C and then PivCl (5.36 mL, 44 mmol) was slowly added. The reaction mixture was then allowed to warm to room temperature over 16 h. The entire reaction mixture was then transferred to a separatory funnel and was washed three times with 1M HCl. The aqueous layers were extracted once with CH2Cl2 and the combined organic layers were washed with H2O and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to afford 6.09 g of a clear liquid. Purification by flash chromatography (silica gel, hexanes-EtOAc 9:1 to 8:2) afforded 26 as a clear liquid (4.22 g, 68%). [00265] 1H NMR (400 MHz, CDCl3) δ 4.05 (t, J = 6.4 Hz, 2 H), 2.54–2.46 (m, 2 H), 2.15 (s, 3 H), 1.98–1.85 (m, 2 H), 1.19 (s, 9 H) [00266] 13C NMR (125 MHz, CDCl3) δ 207.8, 178.6, 63.6, 40.0, 38.9, 30.1, 27.3, 23.0. [00267] Synthesis of ketochlorohydrin 27
Figure imgf000043_0001
[00268] To a cold (–78 °C) solution of diisopropylamine (2.16 mL, 15.4 mmol) in THF (91 mL) was added n-butyllithium dropwise (2 M soln. in hexane, 7.42 mL, 14.8 mmol). The resulting solution was stirred at –78 °C for 30 minutes. After this time, ketone 26 (2.62 g, 14.1 mmol) in THF (2 mL) was added in one portion. The reaction mixture was stirred for 30 minutes. A solution of 25 – prepared according to literature1 in 90%, 95% ee (2.09 g, 13.4 mmol) in THF (10 mL) was then added dropwise over 10 minutes at –78 °C and the resulting mixture was stirred for an additional 75 minutes. Saturated aqueous NH4Cl (50 ml) was then added, the mixture was diluted with EtOAc (50 ml) and the phases were separated. The aqueous phase was extracted with EtOAc (3 × 50 ml) and the combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to provide a crude oil which showed a 4:1 diastereoisomeric ratio as determined by 1H NMR. Purification of the crude product by flash chromatography (silica gel, hexanes- acetone 9:1) provided the title compound 27 as a colourless oil (2.89 g, 65%). [00269] 1H NMR (400 MHz, CDCl3) δ 5.79 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.06 – 4.95 (m, 2H), 4.15 – 4.09 (m, 1H), 4.07 (t, J = 6.4 Hz, 2H), 3.91 (ddd, J = 9.3, 6.1, 3.1 Hz, 1H), 3.21 (d, J = 5.2 Hz, 1H), 2.82 (dd, J = 17.4, 3.5 Hz, 1H), 2.76 (dd, J = 17.5, 8.0 Hz, 1H), 2.56 (t, J = 7.2 Hz, 2H), 2.17 – 2.01 (m, 2H), 1.98 – 1.86 (m, 3H), 1.78 – 1.44 (m, 3H), 1.19 (s, 9H) [00270] 13C NMR (101 MHz, CDCl3) δ 210.31, 178.65, 138.24, 115.21, 71.09, 65.93, 63.39, 45.31, 40.11, 38.91, 33.34, 33.23, 27.34, 25.64, 22.72 [00271] Synthesis of chlorodiol 27a
Figure imgf000044_0001
[00272] To a cold (–78 °C) solution of ketone 25 (3.37 g, 10.14 mmol) in THF (149 mL) was added diisobutylaluminum hydride (1.00 M solution in THF, 20.3 mL, 20.3 mmol) and the reaction mixture was stirred for 3.5 hours at the same temperature. After this time, an aqueous solution of HCl (1.0 M, 100 mL) was added, the mixture was diluted with ether (100 mL) and the phases were separated. The aqueous phase was extracted with ether (2 × 75 mL), and the combined organic phases were washed with water (100 mL) and brine (100 mL), dried (Na2SO4), filtered, and concentrated to provide a crude oil. Purification of the crude product by flash chromatography (silica gel, hexanes-ethylacetate 8:1) afforded 1,3-diol 27a (2.72 g, 80%) as a colorless oil. [00273] 1H NMR (400 MHz, CDCl3) δ 5.80 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.06 – 5.00 (m, 1H), 4.98 (ddt, J = 10.1, 2.1, 1.2 Hz, 1H), 4.09 (t, J = 6.5 Hz, 2H), 3.97 (d, J = 10.4 Hz, 0H), 3.94 – 3.87 (m, 2H), 3.27 (s, 1H), 2.99 (s, 1H), 2.16 – 2.04 (m, 2H), 1.88 – 1.46 (m, 10H), 1.20 (s, 9H). [00274] 13C NMR (101 MHz, CDCl3) δ 178.79, 138.22, 115.23, 115.19, 75.87, 72.10, 67.79, 64.43, 64.31, 38.88, 38.82, 34.44, 33.21, 32.28, 27.32, 25.89, 24.73. [00275] Synthesis of tetrahydrofuran 27b
Figure imgf000044_0002
[00276] To a cold (0 °C), stirred solution of 1,3-diol f (2.71 g, 8.11 mmol) in THF (16 mL) was added AgOTf (1.88 g, 8.11 mmol) and Ag2O (2.08 g, 8.11 mmol) and the reaction mixture was sonicated at rt for 1 h. The reaction mixture was then stirred for another 15 hours. The resulting suspension was then filtered through Celite and washed with Et2O and concentrated to provide a crude oil. The crude oil was dissolved in Et2O (30 mL) and washed with saturated aq NaHCO3 (15 mL) and the layers were separated. The aqueous layer was extracted with Et2O (2 × 30 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated to provide a crude oil. Purification of the crude product by flash chromatography (silica gel, hexanes-acetone 9:1) afforded the desired alcohol 27b (1.94 g, 82%) as a colorless oil. [00277] 1H NMR (400 MHz, CDCl3) δ 5.81 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.01 (ddt, J = 17.1, 2.0, 1.6 Hz, 1H), 4.95 (ddt, J = 10.2, 2.2, 1.2 Hz, 1H), 4.26 – 4.16 (m, 2H), 4.08 (t, J = 6.1 Hz, 2H), 3.77 (ddd, J = 7.3, 6.2, 2.9 Hz, 1H), 2.15 – 2.06 (m, 3H), 1.82 – 1.41 (m, 9H), 1.19 (s, 9H). [00278] 13C NMR (101 MHz, CDCl3) δ 178.71, 138.71, 114.87, 81.84, 73.48, 64.38, 41.92, 38.89, 33.99, 32.77, 28.65, 27.36, 25.80, 25.62. [00279] Synthesis of TBS-protected tetrahydrofuran 28
Figure imgf000045_0001
[00280] To a cold (0 °C) solution of alcohol 27b (1.93 g, 6.49 mmol) and Et3N (2.17 mL, 15.6 mmol) in CH2Cl2 (32.5 mL) was added TBSOTf (1.79 mL, 7.79 mmol) and the reaction mixture was stirred for 1 hour. After this time, water (15 mL) was added and the phases were separated. The aqueous phase was extracted with CH2Cl2 (2 × 25 mL), and the combined organic phases were washed with water (10 mL) and brine (10 mL), dried (Na2SO4), filtered, and concentrated to provide a crude oil. Purification of the crude product by flash chromatography (silica gel, hexanes- ethylacetate 97:3) afforded compound 28 (2.41, 90%) as a colorless oil. [00281] 1H NMR (400 MHz, CDCl3) δ 5.81 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 4.99 (ddt, J = 17.1, 2.2, 1.5 Hz, 1H), 4.93 (ddt, J = 10.2, 2.2, 1.2 Hz, 1H), 4.22 (td, J = 3.8, 3.3, 1.4 Hz, 1H), 4.21 – 4.13 (m, 1H), 4.07 (t, J = 6.1 Hz, 2H), 3.78 (ddd, J = 7.1, 5.9, 3.3 Hz, 1H), 2.12 – 2.05 (m, 2H), 1.95 (ddd, J = 12.8, 5.8, 1.4 Hz, 1H), 1.82 – 1.33 (m, 9H), 1.19 (s, 9H), 0.89 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H). [00282] 13C NMR (101 MHz, CDCl3) δ 178.73, 138.97, 114.57, 82.76, 76.67, 73.67, 64.57, 42.31, 38.89, 34.20, 32.75, 29.33, 27.37, 25.93, 25.89, 25.63, 18.22, -4.31, - 4.88. [00283] Synthesis of α,β-conjugated ketone 31
Figure imgf000046_0001
[00284] To a solution of alkene 28 (2.11 g, 5.12 mmol) in a 1:1 mixture of THF:H2O (50.2 mL) was added OsO4 (5% in H2O, 0.54 mL, cat) and the reaction mixture was stirred for 10 min. After this time, NaIO4 (2.74 g, 12.8 mmol) was added and the resulting mixture was stirred for another 4 hours. The reaction was then quenched with NaHCO3:Na2S2O3 (1:1, 30 mL) and ethyl acetate (50 mL) was added. The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 × 50 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried (Na2SO4), filtered, and concentrated. The resulting oil was filtered through a plug of silica (hexanes-ethylacetate 4:1) and directly used in the next step without further purification. Subsequently, the crude aldehyde 29 (1.91 g, 4.60 mmol) was diluted in CH3CN (9.2 mL) and cooled to (0 °C). The MacMillan catalyst ent-24.TFA (262 mg, 0.92 mmol, freshly prepared according to the litterature) and N- chlorosuccinimide (615 mg, 4.60 mmol) were then added. The ice bath was removed after 30 minutes allowing the solution to slowly warm to room temperature. The reaction mixture was stirred until complete consumption of starting material as determined by 1H NMR spectroscopy. After this time, NH4Cl (10 mL) and diethyl ether (10 mL) were added and the layers were separated. Then, the aqueous layer was extracted with diethyl ether (2 x 10 mL) and the combined organic phases were dried (Na2SO4), filtered, and concentrated to provide a crude mixture. The mixture was diluted with pentane (2 mL), filtered and concentrated to provide a crude α- chloroaldehyde 30 as a colourless oil. After that, a mixture of ketophosphonate (959 mg, 4.60 mmol) and Ba(OH)2.8H2O (1.16 g, 3.68 mmol) in THF (6.8 mL) was stirred at room temperature for 30 minutes. A solution of crude α-chloroaldehyde 30 in THF (6.8 mL) was then added and the resulting mixture was stirred for 24 hours. After this time, the reaction mixture was diluted in CH2Cl2 (15 mL), washed with NaHCO3 (15 mL) and brine (15 mL), dried with MgSO4, and concentrated to provide a crude yellow oil. Purification of the crude product by flash chromatography (silica gel, hexanes-ethylacetate 95:5) afforded compound 31 (1.39 g, 54% yield from 28) as a colorless oil. [00285] 1H NMR (400 MHz, CDCl3) δ 6.51 (dq, J = 9.9, 1.5 Hz, 1H), 4.80 (dt, J = 9.8, 6.9 Hz, 1H), 4.25 – 4.22 (m, 1H), 4.19 – 4.11 (m, 1H), 4.07 (td, J = 6.4, 1.1 Hz, 2H), 3.83 (ddd, J = 8.3, 4.7, 3.5 Hz, 1H), 2.33 (s, 3H), 2.12 – 2.04 (m, 1H), 1.98 – 1.85 (m, 2H), 1.83 (d, J = 1.4 Hz, 3H), 1.82 – 1.45 (m, 7H), 1.19 (s, 9H), 0.88 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H). [00286] 13C NMR (101 MHz, CDCl3) δ 199.57, 178.70, 140.87, 138.14, 81.79, 76.91, 73.91, 64.46, 57.39, 42.21, 38.90, 35.37, 32.65, 27.37, 26.70, 25.89, 25.76, 25.61, 18.21, 11.55, -4.34, -4.86. [00287] Synthesis of ketone 33
Figure imgf000047_0001
[00288] Phenylsilane (0.55 mL, 4.46 mmol) was added to a strictly deoxygenated solution of enone 31 (1.87 g, 3.72 mmol) and Mn(dpm)3 (450 mg, 0.74 mmol) in isopropyl alcohol (12.4 mL). After completion of the reaction (TLC monitoring), the reaction mixture was filtered through a pad of silica gel and concentrated to provide a crude yellow oil (32:33 = 1.5:1). Purification by flash chromatography (silica gel, hexanes-ethylacetate 95:5) afforded a mixture of compounds 32+33 (1.31 g) and clean 33 (440 mg) as clear oils. Subsequently, to a cold (0 °C) solution of mixed fraction 32+33 (1.31 g, 2.57 mmol) in acetonitrile (26 mL), was added DBU (0.78 mL, 5.14 mmol) and the resulting mixture was stirred at 4 °C for 48 hours. After this time, water (10 mL) and ethyl acetate (10 mL) were added and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 × 25 mL). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried (Na2SO4), filtered, and concentrated to provide a crude oil. Purification of the crude product by flash chromatography (silica gel, hexanes-ethylacetate 95:5) afforded 869 mg of 32+33 and 250 mg of 33. The above procedure was repeated with 869 mg of 32+33 to furnish another 340 mg of 33. The different fractions of 33 were combined to provide the desired ketone 33 (1.03 g, 55%) as a colorless oil. [00289] 1H NMR (400 MHz, CDCl3) δ 4.25 – 4.21 (m, 1H), 4.16 (dt, J = 9.1, 5.9 Hz, 1H), 4.11 – 4.02 (m, 2H), 3.97 (ddt, J = 11.2, 8.0, 3.9 Hz, 1H), 3.80 (tq, J = 9.0, 4.9 Hz, 1H), 2.91 – 2.80 (m, 1H), 2.18 (s, 3H), 2.07 (ddd, J = 14.8, 10.6, 4.5 Hz, 1H), 1.95 (ddd, J = 12.8, 5.8, 1.5 Hz, 1H), 1.89 – 1.45 (m, 10H), 1.19 (s, 9H), 1.10 (d, J = 7.0 Hz, 3H), 0.89 (d, J = 0.9 Hz, 9H), 0.07 (d, J = 1.1 Hz, 3H), 0.06 (s, 3H). [00290] 13C NMR (101 MHz, CDCl3) δ 211.70, 178.71, 81.74, 76.77, 73.81, 64.50, 61.54, 44.46, 42.20, 40.73, 38.88, 35.75, 32.64, 28.40, 27.36, 26.74, 25.91, 25.59, 18.22, 15.46, -4.34, -4.84. [00291] Synthesis of sulfone 34
Figure imgf000048_0001
[00292] To a cold (-78 °C) solution of sulfonium salt 22 (20 mg, 0.03 mmol) in dry THF (0.3 mL) was added LiHMDS (1 M in hexanes, 64 μL, 0.08 mmol). The resulting solution was stirred at -78 °C for 1 hour. Ketone 33 (16 mg, 0.03 mmol), diluted in a minimum amount of THF (0.1 mL), was then slowly added. Stirring was continued for an additional hour at -78 °C and then 15 hours at room temperature. After this time, an aqueous solution of NH4Cl (1 mL) was added, the mixture was diluted with CH2Cl2 (1 mL) and the phases were separated. The aqueous phase was extracted with CH2Cl2 (1 ml x 3), and the combined organic phases were washed with water (1 mL) and brine (1 mL), dried (MgSO4) and concentrated to provide a crude yellow solid. The crude product was then dilute in CH2Cl2 (0.3 mL) and cooled to -78 °C. MCPBA was added (21 mg, 0.09 mmol) and the resulting mixture was allowed to warm up to ambient temperature for 1 hour. After this time, the mixture was cooled to -78 °C and quenched with NaHCO3 (1 mL). After slowly warming up to room temperature, the layers were separated, and the aqueous phase was extracted with CH2Cl2 (2 x 1 mL). The combined organic phases were washed with brine (1 mL), dried (Na2SO4), filtered, and concentrated to provide a crude oil. Purification of the crude product by flash chromatography (silica gel, hexanes-ethylacetate 3:1) provided sulfone 34 (19.5 mg, 60%) as a foamy solid. [00293] 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 4.24 (br s, 1H), 4.20 – 4.10 (m, 2H), 4.06 (dt, J = 6.4, 2.9 Hz, 2H), 4.04 – 3.90 (m, 2H), 3.88 – 3.75 (m, 3H), 3.74 – 3.54 (m, 3H), 3.39 (s, 3H), 3.18 – 3.04 (m, 2H), 2.66 – 2.55(br s, 1H), 2.45 (s, 3H), 2.11 – 1.51 (m, 20H), 1.47 (s, 15H), 1.19 (s, 9H), 1.13 (s, 3H), 0.89 (s, 9H), 0.07 (d, J = 1.8 Hz, 6H). [00294] 13C NMR (101 MHz, CDCl3) δ 178.70, 145.22, 136.58, 130.32, 130.27, 130.19, 128.18, 128.13, 86.27, 81.97, 81.73, 78.34, 77.36, 76.75, 73.80, 64.51, 64.48, 63.48, 61.46, 59.78, 58.24, 57.51, 51.02, 43.64, 42.20, 40.98, 38.93, 38.88, 35.80, 33.68, 32.68, 32.13, 32.07, 29.84, 28.62, 27.36, 26.72, 25.93, 25.59, 21.79, 18.23, 15.47, 12.86, -4.33, -4.80. [00295] Synthesis of alcohol 35
Figure imgf000049_0001
[00296] Thoroughly deoxygenated THF (0.4 mL) was added to a mixture of commercial Cp2TiCl2 (30 mg, 0.12 mmol) and Zn dust (52 mg, 0.80 mmol) under an Ar atmosphere and the suspension was stirred at room temperature until it turned lime green (after about 5 min). A solution of epoxide 34 (41 mg, 0.04 mmol) in THF (0.4 mL) was then added and the mixture was stirred for 2 h, after which the reaction was quenched with a saturated solution of NaH2PO4 (1 mL). The resulting mixture was filtered through celite, and the layers were separated. The organic phase was washed with brine (1 mL), dried (Na2SO4), filtered, and concentrated to provide a crude oil. Purification of the crude product by flash chromatography (silica gel, hexanes-ethylacetate 3:1) provided the alcohol 35 (29 mg, 70%) as a foamy solid. [00297] 1H NMR (500 MHz, CDCl3) δ 7.84 – 7.77 (m, 2H), 7.38 (d, J = 7.9 Hz, 2H), 5.15 (s, 1H), 4.87 (s, 1H), 4.27 – 4.21 (m, 1H), 4.20 – 4.08 (m, 3H), 4.06 (td, J = 6.4, 2.3 Hz, 2H), 3.90 – 3.77 (m, 3H), 3.76 – 3.59 (m, 3H), 3.38 (s, 3H), 3.26 – 3.17 (m, 1H), 3.14 – 3.06 (m, 2H), 2.60 – 2.53 (br s, 1H), 2.46 (s, 3H), 2.41 – 2.33 (br s, 1H), 2.10 – 2.01 (m, 1H), 2.00 – 1.90 (m, 2H), 1.89 – 1.70 (m, 6H), 1.69 – 1.40 (m, 21H), 1.25 (s, 1H), 1.18 (s, 9H), 1.05 (d, J = 6.7 Hz, 2H), 0.89 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H). [00298] 13C NMR (101 MHz, CDCl3) δ 178.70, 152.25, 156.77, 145.28, 136.70, 130.27, 128.10, 108.50, 93.18, 85.80, 83.68, 81.80, 79.12, 77.36, 76.74, 73.79, 73.49, 71.51, 64.51, 62.29, 58.25, 57.56, 51.12, 46.34, 44.54, 42.19, 41.61, 38.88, 35.82, 32.72, 32.65, 32.43, 31.05, 29.84, 28.63, 27.36, 26.82, 25.93, 25.58, 21.81, 19.38, 18.23, -4.33, -4.82. [00299] Synthesis of ketone 38
Figure imgf000050_0001
[00300] To a solution of alcohol 35 (60 mg, 0.067 mmol) in t-BuOAc (5.7 ml) at 0 °C were added 2,6-di-tert-butyl-4-methylpyridine (69 mg, 0.33 mmol) and AgBF4 (39 mg, 0.20 mmol). The resulting reaction flask was wrapped with aluminum foil and warmed to rt. After stirring 2 h at rt, the reaction mixture was treated with a NH4Cl (5 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 5 mL). The combined organic phases were washed with brine (5 mL), dried (Na2SO4), filtered, and concentrated to provide a clear oil. The crude product was dissolved in THF (0.2 mL) and pyridine (0.36 mL), cooled to 0 °C, and HF- pyridine (70% in pyridine, 0.18 mL, 5 mmol) was subsequently added. The resulting solution was stirred at room temperature for 15 hours. After this time, an aqueous solution of NaHCO3 (0.5 mL) was added, the mixture was diluted with ethyl acetate (0.5 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (0.5 ml x 3), and the combined organic phases were washed with water (1 mL) and brine (1 mL), dried (MgSO4) and concentrated to provide a crude yellow oil that was directly used in the next step without further purification. The crude alcohol was diluted in CH2Cl2 (0.6 mL) and cooled to 0 °C. NaHCO3 (28 mg, 0.32 mmol) in and DMP (28 mg, 0.071 mmol) were then added, and the mixture was stirred at room temperature for 1 hour. After this time, the reaction was quenched with H2O/Na2S2O3(aq)/NaHCO3(aq) = 1/1/1 (1 mL) and the resulting mixture was stirred for another 30 minutes. The mixture was extracted with CH2Cl2 (0.5 ml x 3), washed with brine, dried over anhydrous MgSO4, and concentrated to provide a crude oil. Purification by flash chromatography (silica gel, hexanes-ethylacetate 5:1) provided ketone 38 (34 mg, 58%) as a clear oil. [00301] 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 4.87 (s, 1H), 4.81 (s, 1H), 4.34 – 4.26 (m, 1H), 4.21 – 4.06 (m, 3H), 3.85 – 3.79 (m, 2H), 3.78 – 3.64 (m, 3H), 3.60 (br d, J = 9.8 Hz, 1H), 3.43 (s, 3H), 3.43 – 3.37 (m, 1H), 3.20 – 3.08 (m, 2H), 3.01 (dd, J = 14.5, 2.6 Hz, 1H), 2.61 – 2.51 (m, 2H), 2.48 (s, 3H), 2.25 – 2.08 (m, 3H), 2.00 (dt, J = 13.8, 6.3 Hz, 1H), 1.91 (ddd, J = 12.9, 9.3, 2.7 Hz, 1H), 1.85 – 1.54 (m, 10H), 1.53 – 1.46 (m, 15H), 1.22 (s, 9H), 1.09 (d, J = 6.3 Hz, 3H). [00302] 13C NMR (101 MHz, CDCl3) δ 215.98, 178.47, 150.44, 144.97, 136.87, 130.09, 127.99, 104.97, 86.04, 81.02, 78.57, 77.99, 77.26, 76.11, 75.26, 74.65, 63.86, 60.35, 58.19, 57.51, 53.42, 50.85, 43.46, 42.65, 42.35, 38.73, 37.45, 36.64, 35.49, 31.99, 31.86, 31.43, 28.47, 27.20, 26.65, 24.90, 24.68, 21.62, 21.01, 17.88, 14.18. [The 13C resonances corresponding to the hemiaminal carbon of the acetonide and the carbamate carbonyl were too broad to detect] [00303] Synthesis of alkene 4
Figure imgf000051_0001
[00304] To a suspension of methyltriphenylphosphonium bromide (17 mg, 0.048 mmol) in dry THF (0.3 mL) was added tBuOK (48 μL of 1.0 M solution in THF, 0.048 mmol) at 0 °C. After the mixture was stirred for 30 minutes at the same temperature, a solution of ketone 38 (12 mg, 0.016 mmol) in dry THF (0.3 mL) was slowly added. After stirring for an additional 3 hours at room temperature, the resulting mixture was quenched with water (0.5 mL). The mixture was extracted with EtOAc (0.5 mL), washed with brine (0.5 mL), dried over anhydrous MgSO4, and concentrated to provide the crude product as a yellow oil. Purification by flash chromatography (silica gel, hexanes-EtOAc 9:1) afforded the desired alkene 4 (8 mg, 70%). [00305] 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 7.9 Hz, 2H), 4.90 (q, J = 2.1 Hz, 1H), 4.84 (s, 1H), 4.77 (s, 1H), 4.64 (q, J = 1.7 Hz, 1H), 4.24 (br s, 1H), 4.17 – 4.11 (m, 1H), 4.06 (td, J = 6.3, 4.8 Hz, 2H), 3.95 (p, J = 6.5 Hz, 1H), 3.87 (br s, 1H), 3.78 – 3.63 (m, 3H), 3.57 – 3.50 (m, 1H), 3.44 (s, 3H), 3.38 – 3.32 (m, 1H), 3.17 – 3.05 (m, 3H), 3.01 (br d, J = 14.2 Hz, 1H), 2.61 (dd, J = 15.5, 6.3 Hz, 1H), 2.58 – 2.50 (m, 1H), 2.48 (s, 3H), 2.46 (s, 3H), 2.25 – 2.06 (m, 3H), 2.03 – 1.95 (m, 1H), 1.89 – 1.82 (m, 1H), 1.76 – 1.70 (m, 2H), 1.66 – 1.49 (m, 9H), 1.48 – 1.43 (m, 15H), 1.18 (s, 9H), 1.06 (d, J = 6.2 Hz, 3H). [00306] 13C NMR (101 MHz, CDCl3) δ 178.69, 151.39, 150.75, 145.19, 137.01, 130.26, 128.20, 115.47, 105.09, 105.02, 86.08, 81.16, 79.59, 79.57, 77.36, 76.91, 75.43, 64.38, 58.26, 57.68, 51.02, 43.60, 42.91, 38.91, 38.88, 37.64, 35.70, 31.99, 31.88, 31.76, 31.64, 29.84, 28.63, 27.36, 25.43, 21.77, 18.06. [00307] Synthesis of chlorohydrin 58
Figure imgf000052_0001
[00308] To a slurry of NCS (3.19 g, 24 mmol) and D-proline (3.22 g, 29 mmol) in CH2Cl2 (70 mL) at 0 ºC was added a solution of 42 (3.78 g, 24 mmol) in CH2Cl2 (10 mL). After 1h 10min, tetrahydriothiopyran-4-one (8.33 g, 72 mmol) was added, followed by DMSO (16 mL). The reaction mixture was then allowed to warm to rt over 4 days. It was then quenched with the addition of brine (100 mL) and the layers were separated. The aqueous was extracted with CH2Cl2 (3 x 80 mL) and the combined organic layers were washed with brine (150 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford 13.18 g of a brown solid. Purification of the crude material by flash chromatography (silica gel, EtOAc:Hexanes 20:80 to 60:40) afforded the title compound as a slightly yellow, semi-crystalline solid (2.40 g, 33%). [00309] 1H NMR (500 MHz, CDCl3) δ 4.47 – 4.31 (m, 1H), 4.24 (dt, J = 10.7, 2.4 Hz, 1H), 4.12 (td, J = 7.2, 6.1, 3.7 Hz, 2H), 3.59 (dd, J = 8.1, 6.6 Hz, 1H), 3.19 (d, J = 4.6 Hz, 1H), 3.14 (ddd, J = 9.6, 8.4, 4.8 Hz, 1H), 3.07 – 3.02 (m, 1H), 3.02 – 2.94 (m, 2H), 2.86 – 2.68 (m, 3H), 2.24 (ddd, J = 14.7, 10.7, 2.7 Hz, 1H), 1.90 (ddd, J = 14.7, 9.7, 2.8 Hz, 1H), 1.40 (s, 3H), 1.36 (s, 3H). [00310] 13C NMR (126 MHz, CDCl3) δ 211.54, 109.38, 73.18, 72.92, 69.41, 60.52, 56.56, 44.58, 39.99, 31.89, 30.77, 27.27, 25.77. [00311] Synthesis of cyclic alcohol 59
Figure imgf000053_0001
[00312] To a solution of 58 (3.12 g, 10 mmol) in MeCN (101 mL) at -15 ºC was added glacial acetic acid (5.78 mL, 101 mmol). Then, NaBH(OAc)3 (10 g, 47 mmol) was added and the resulting slurry was stirred at -15 ºC overnight.6,7 After 16 h, the reaction mixture was warmed to 0 ºC and quenched with saturated Rochelle’s salt solution (100 mL). The mixture was further diluted with EtOAc (100 mL) and stirred vigorously for 1 h. The layers were then separated and the aqueous was extracted with EtOAc (2 x 100 mL). The combined organic layers were then washed with brine (200 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford a yellow oil, which was an inseparable mixture of diastereomers (3.65 g, 100%, dr ~ 4:1). This material was advanced to the next step without further purification. [00313] To a solution of the freshly prepared diol (1.64 g, 5.3 mmol) in tBuOH (168 mL) and H2O (8.5 mL) was added SrCO3 (38.9 g, 264 mmol). The resulting white slurry was then stirred at 100 ºC for 25h. It was then allowed to cool to rt and was diluted with EtOAc (~100 mL). The slurry was then filtered through a plug of silica and the filtrate was concentrated under reduced pressure to afford 1.56 g of a brown oil. Purification of the crude material by flash chromatography (silica gel, EtOAc:Hexanes 50:50 to 70:30) afforded the title compound as a yellow oil (753 mg, 52% over two steps). [00314] 1H NMR (400 MHz, CDCl3) δ 4.21 (p, J = 6.3 Hz, 1H), 4.13 (t, J = 4.0 Hz, 1H), 4.06 (dd, J = 8.0, 6.0 Hz, 1H), 3.85 – 3.73 (m, 1H), 3.59 (t, J = 7.7 Hz, 1H), 3.39 (td, J = 11.0, 3.6 Hz, 1H), 2.90 – 2.78 (m, 1H), 2.76 – 2.57 (m, 3H), 2.51 – 2.39 (m, 1H), 2.09 (d, J = 3.9 Hz, 1H), 1.92 (dt, J = 12.7, 6.3 Hz, 1H), 1.84 – 1.57 (m, 3H), 1.39 (s, 3H), 1.33 (s, 3H). [00315] 13C NMR (101 MHz, CDCl3) δ 108.95, 83.77, 79.24, 76.71, 72.85, 69.33, 49.43, 37.39, 33.87, 27.42, 27.41, 27.00, 25.78. [00316] Synthesis of cyclic inverted alcohol 60
Figure imgf000054_0001
[00317] To a solution of 59 (1.12 g, 4 mmol) in THF (27 mL) were added p- nitrobenzoic acid (1.02 g, 6 mmol) and Ph3P (1.61 g, 6 mmol). The yellow solution was cooled to 0 ºC and then DIAD (1.2 mL, 6 mmol) was added dropwise. After stirring at 0 ºC for 1h, the reaction mixture was allowed to warm to rt over 3h. The solvent was then removed under reduced pressure and the thick yellow residue was redissolved in MeOH (58 mL). Then, freshly ground NaOH (490 mg, 12 mmol) was added and the reaction mixture was stirred at rt for 1h. It was then quenched by the addition of H2O (~40 mL). The mixture was further diluted with brine (~20 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with saturated NH4Cl (40 mL) and brine (40 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford 4.44 g of a thick yellow oil. This material was dissolved in a minimum amount of CH2Cl2 and then diluted with Et2O, then placed in the freezer overnight. The following day the mixture was filtered, the white solid was discarded and the filtrate was concentrated under reduced pressure to afford 2.2 g of a yellow oil. Purification of this material by flash chromatography (silica gel, EtOAc:Hexanes 50:50 to 80:20) afforded the title compound as low melting white solid (653 mg, 58% over two steps). [00318] 1H NMR (400 MHz, CDCl3) δ 4.48 – 4.31 (m, 1H), 4.24 – 4.05 (m, 2H), 4.04 – 3.91 (m, 1H), 3.73 (d, J = 9.4 Hz, 1H), 3.62 (td, J = 8.0, 2.0 Hz, 1H), 3.14 – 2.89 (m, 2H), 2.76 – 2.64 (m, 2H), 2.64 – 2.54 (m, 1H), 2.42 – 2.31 (m, 1H), 2.08 (ddd, J = 12.4, 7.1, 3.6 Hz, 1H), 1.93 – 1.64 (m, 3H), 1.44 (s, 3H), 1.38 (s, 3H). [00319] 13C NMR (101 MHz, CDCl3) δ 109.78, 78.35, 76.93, 75.31, 70.97, 69.33, 52.49, 33.40, 32.63, 31.23, 27.60, 26.72, 25.65. [00320] Synthesis of methyl ether 60a
Figure imgf000055_0001
[00321] To a slurry of 60% NaH (206 mg, 124 mg active reagent, 5.2 mmol) in THF (5 mL) at 0 ºC was added dropwise a solution of 60 (354 mg, 1.3 mmol) in THF (4 mL). Then, Me2SO4 (140 μL, 1,5 mmol) was added as well and then the reaction mixture was stirred at 0 ºC for 2h. It was then quenched (while still at 0 ºC) with H2O (10 mL) and the aqueous was extracted with Et2O (3 x 10 mL). The combined organic layers were washed with H2O (10 mL) and brine (10 mL), dried over MgSO4, filtered and evaporated to afford 471 mg of a white solid. Purification of the crude material by flash chromatography (silica gel, EtOAc:Hexanes 40:60) afforded the title compound as a white solid (330 mg, 89%). [00322] 1H NMR (500 MHz, CDCl3) δ 4.29 (ddd, J = 13.0, 7.2, 5.9 Hz, 1H), 4.09 (dd, J = 8.0, 5.9 Hz, 1H), 3.95 (td, J = 7.4, 5.5 Hz, 1H), 3.63 (dt, J = 13.3, 7.8 Hz, 2H), 3.39 (s, 3H), 2.95 (ddd, J = 21.2, 10.9, 2.8 Hz, 2H), 2.81 – 2.58 (m, 3H), 2.37 (dq, J = 12.0, 3.3 Hz, 1H), 1.93 (ddd, J = 13.3, 7.4, 5.7 Hz, 1H), 1.90 – 1.80 (m, 2H), 1.74 (qd, J = 11.6, 4.6 Hz, 1H), 1.42 (s, 3H), 1.36 (s, 3H). [00323] 13C NMR (101 MHz, CDCl3) δ 108.60, 85.51, 79.22, 75.38, 73.76, 69.66, 58.89, 51.94, 34.12, 33.59, 31.98, 27.71, 27.11, 25.92. [00324] Synthesis of sulfonium salt 40
Figure imgf000055_0002
[00325] A sealed tube was charged with Cu(OBz)2 (13 mg, 0.04 mmol) and j (485 mg, 1.7 mmol) in ClCH2CH2Cl (11 mL). Then, Ph2IPF6 (721 mg, 1.7 mmol) was added as well, the tube was sealed and the reaction mixture was stirred at 100 ºC for 3.5h. The mixture was then allowed to cool to rt and it was loaded directly onto a chromatography column. Purification by flash chromatography (silica gel, EtOAc:Hexanes 50:50 to Acetone:CH2Cl250:50) afforded the title compound, contaminated with ~2% Ph2IPF6, as a white foam (638 mg, 74%). [00326] 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.6 Hz, 2H), 7.81 (t, J = 7.5 Hz, 1H), 7.73 (t, J = 7.7 Hz, 2H), 4.28 (td, J = 12.5, 5.8 Hz, 2H), 4.22 – 4.13 (m, 1H), 4.13 – 4.04 (m, 2H), 4.00 – 3.80 (m, 3H), 3.75 – 3.67 (m, 1H), 3.67 – 3.54 (m, 1H), 3.39 (s, 3H), 2.81 – 2.70 (m, 1H), 2.14 – 1.91 (m, 2H), 1.86 – 1.74 (m, 1H), 1.43 (s, 3H), 1.36 (s, 3H). [00327] Synthesis of sulfone 79
Figure imgf000056_0001
[00328] To a cold (-78 °C) solution of sulfonium salt 40 (103 mg, 0.20 mmol) in dry THF (1.5 mL) was added LiHMDS (1 M in hexanes, 0.56 mL, 0.56 mmol). The resulting solution was stirred at -78 °C for 1 hour. Ketone 33 (110 mg, 0.20 mmol), diluted in a minimum amount of THF (0.3 mL), was then slowly added. Stirring was continued for an additional hour at -78 °C and then 15 hours at room temperature. After this time, an aqueous solution of NH4Cl (1 mL) was added, the mixture was diluted with CH2Cl2 (1 mL) and the phases were separated. The aqueous phase was extracted with CH2Cl2 (1 ml x 3), and the combined organic phases were washed with water (1 mL) and brine (1 mL), dried (MgSO4) and concentrated to provide a crude yellow solid. The crude product was then dilute in CH2Cl2 (2 mL) and cooled to -78 °C. MCPBA was added (150 mg, 0.60 mmol) and the resulting mixture was allowed to warm up to ambient temperature for 1 hour. After this time, the mixture was cooled to -78 °C and quenched with NaHCO3 (2 mL). After slowly warming up to room temperature, the layers were separated, and the aqueous phase was extracted with CH2Cl2 (2 x 2 mL). The combined organic phases were washed with brine (1 mL), dried (Na2SO4), filtered, and concentrated to provide a crude oil. Purification of the crude product by flash chromatography (silica gel, hexanes-ethylacetate 3:1) provided sulfone 79 (135 mg, 75%) as a clear oil. [00329] 1H NMR (400 MHz, CDCl3) δ 7.97 – 7.91 (m, 2H), 7.71 – 7.64 (m, 1H), 7.63 – 7.56 (m, 2H), 4.25 (t, J = 3.2 Hz, 1H), 4.16 (p, J = 6.1 Hz, 2H), 4.10 – 3.96 (m, 3H), 3.86 – 3.79 (m, 2H), 3.67 (q, J = 5.8 Hz, 1H), 3.62 (t, J = 7.5 Hz, 1H), 3.42 – 3.39 (m, 1H), 3.40 (s, 3H), 3.20 – 3.11 (m, 2H), 2.67 – 2.60 (m, 1H), 2.03 – 1.60 (m, 15H), 1.57 (s, 3H), 1.55 – 1.45 (m, 2H), 1.40 (s, 3H), 1.35 (s, 3H), 1.19 (s, 9H), 0.90 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H). [00330] 13C NMR (151 MHz, CDCl3) δ 178.76, 139.39, 134.19, 134.03, 129.70, 129.64, 129.53, 129.48, 128.12, 128.10, 109.03, 86.05, 81.97, 81.73, 78.59, 76.79, 73.74, 73.47, 69.52, 64.52, 63.54, 61.47, 59.82, 58.11, 57.39, 43.31, 42.19, 40.91, 38.87, 35.76, 33.66, 32.67, 32.44, 29.85, 27.36, 27.09, 26.69, 25.92, 25.91, 25.57, 18.23, 15.47, 12.87, -4.31, -4.82. [00331] Synthesis of alcohol 80
Figure imgf000057_0001
[00332] Thoroughly deoxygenated THF (1.5 mL) was added to a mixture of commercial Cp2TiCl2 (0.33 mmol) and Mn dust (143 mg, 2.6 mmol) under an Ar atmosphere and the suspension was stirred at room temperature until it turned lime green (after about 15 min). A solution of epoxide 79 (90 mg, 0.1 mmol) in THF (1 mL) was then added and the mixture was stirred for 15 h, after which the reaction was quenched with a saturated solution of NaH2PO4 (1 mL). The resulting mixture was filtered through celite and the layers were separated. The organic phase was washed with brine (1 mL), dried (Na2SO4), filtered, and concentrated to provide a crude oil. Purification of the crude product by flash chromatography (silica gel, hexanes- ethylacetate 70:30) provided alcohol 80 (54 mg, 60%) as a clear oil. [00333] 1H NMR (400 MHz, CDCl3) δ 7.97 – 7.90 (m, 2H), 7.73 – 7.65 (m, 1H), 7.63 – 7.57 (m, 2H), 5.15 (s, 1H), 4.87 (s, 1H), 4.27 – 4.21 (m, 1H), 4.20 – 4.10 (m, 3H), 4.05 (ddt, J = 8.5, 4.3, 2.3 Hz, 3H), 3.97 (td, J = 8.5, 7.7, 3.4 Hz, 1H), 3.90 (td, J = 6.7, 3.6 Hz, 4H), 3.86 – 3.78 (m, 1H), 3.74 (dt, J = 9.0, 4.6 Hz, 1H), 3.59 (dd, J = 7.9, 7.1 Hz, 1H), 3.39 (s, 3H), 3.14 (d, J = 6.8 Hz, 2H), 2.64 – 2.57 (m, 1H), 2.42 – 2.32 (m, 1H), 2.01 – 1.91 (m, 2H), 1.91 – 1.70 (m, 3H), 1.54 – 1.44 (m, 0H), 1.40 (s, 3H), 1.35 (s, 4H), 1.18 (s, 9H), 1.06 (d, J = 6.7 Hz, 2H), 0.89 (s, 9H), 0.07 (s, 3H), 0.06 (s, 2H). [00334] 13C NMR (101 MHz, CDCl3) δ 178.71, 156.75, 139.62, 134.22, 129.68, 128.07, 109.19, 85.77, 83.77, 81.80, 79.33, 77.36, 76.75, 73.78, 73.68, 73.53, 69.56, 64.51, 62.30, 58.21, 57.47, 46.33, 44.33, 42.18, 41.64, 38.88, 36.79, 35.81, 32.77, 32.71, 32.64, 29.83, 29.79, 27.36, 27.07, 27.06, 26.81, 25.95, 25.93, 25.91, 25.85, 25.57, 24.83, 19.36, 18.22, -4.33, -4.78, -4.82. [00335] Synthesis of tetrahydropyran 80a
Figure imgf000058_0001
[00336] To a solution of alcohol 80 (60 mg, 0.067 mmol) in t-BuOAc (5.7 ml) at 0 °C were added 2,6-di-tert-butyl-4-methylpyridine (69 mg, 0.33 mmol) and AgBF4 (39 mg, 0.20 mmol). The resulting reaction flask was wrapped with aluminum foil and warmed to rt. After stirring 12 h at rt, the reaction mixture was treated with a NH4Cl (5 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 5 mL). The combined organic phases were washed with brine (5 mL), dried (Na2SO4), filtered, and concentrated to provide a crude oil. Purification of the crude product by flash chromatography (silica gel, hexanes-ethylacetate 5:1) provided tetrahydropyran c (43 mg, 75%) as a clear oil. [00337] 1H NMR (400 MHz, CDCl3) δ 7.99 – 7.92 (m, 2H), 7.71 – 7.64 (m, 1H), 7.64 – 7.58 (m, 2H), 4.84 (s, 1H), 4.77 (d, J = 1.8 Hz, 1H), 4.23 – 4.10 (m, 3H), 4.09 – 4.00 (m, 3H), 3.89 (d, J = 3.2 Hz, 1H), 3.79 – 3.66 (m, 3H), 3.63 (t, J = 7.6 Hz, 1H), 3.57 (dd, J = 10.1, 3.4 Hz, 1H), 3.44 (s, 3H), 3.40 – 3.33 (m, 1H), 3.18 – 3.03 (m, 2H), 2.57 (dt, J = 10.1, 4.5 Hz, 1H), 2.26 – 2.12 (m, 2H), 2.09 – 1.91 (m, 3H), 1.91 – 1.83 (m, 1H), 1.78 – 1.43 (m, 10H), 1.41 (s, 3H), 1.36 (s, 3H), 1.28 – 1.22 (m, 1H), 1.19 (s, 9H), 1.06 (d, J = 6.5 Hz, 3H), 0.90 (s, 8H), 0.07 (s, 3H), 0.04 (s, 2H). [00338] 13C NMR (101 MHz, CDCl3) δ 178.70, 150.83, 139.89, 134.01, 129.69, 128.12, 108.96, 104.96, 86.10, 82.69, 81.14, 78.32, 77.35, 76.68, 75.40, 73.58, 73.44, 69.52, 64.51, 58.22, 57.60, 43.36, 42.78, 42.30, 38.89, 37.71, 35.61, 32.67, 32.33, 27.38, 27.12, 25.98, 25.95, 25.71, 25.64, 18.21, 18.10, -4.19, -4.70. [00339] Synthesis of ketone 81
Figure imgf000059_0001
[00340] To a cold (0 °C) solution of compound 80a (56 mg, 0.065 mmol) in THF (0.2 mL) and pyridine (0.36 mL) was added HF-pyridine (70% in pyridine, 0.18 mL, 5 mmol). The resulting solution was stirred at room temperature for 15 hours. After this time, an aqueous solution of NaHCO3 (0.5 mL) was added, the mixture was diluted with ethyl acetate (0.5 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (0.5 ml x 3), and the combined organic phases were washed with water (1 mL) and brine (1 mL), dried (MgSO4) and concentrated to provide a crude yellow oil that was directly used in the next step without further purification. The crude alcohol was diluted in CH2Cl2 (0.6 mL) and cooled to 0 °C. NaHCO3 (28 mg, 0.32 mmol) in and DMP (28 mg, 0.071 mmol) were then added and the mixture was stirred at room temperature for 1 hour. After this time, the reaction was quenched with H2O/Na2S2O3(aq)/NaHCO3(aq) = 1/1/1 (1 mL) and the resulting mixture was stirred for another 30 minutes. The mixture was extracted with CH2Cl2 (0.5 ml x 3), washed with brine, dried over anhydrous MgSO4, and concentrated to provide a crude oil. Purification by flash chromatography (silica gel, hexanes- ethylacetate 5:1) provided ketone 81 (34 mg, 70%) as a clear oil. [00341] 1H NMR (400 MHz, CDCl3) δ 7.98 – 7.93 (m, 2H), 7.71 – 7.66 (m, 1H), 7.64 – 7.58 (m, 2H), 4.86 (s, 1H), 4.79 (d, J = 1.8 Hz, 1H), 4.32 – 4.22 (m, 1H), 4.16 (h, J = 6.1 Hz, 1H), 4.08 (tdd, J = 7.9, 5.9, 3.8 Hz, 3H), 3.85 (d, J = 3.3 Hz, 1H), 3.76 (ddd, J = 15.8, 8.2, 4.4 Hz, 3H), 3.67 – 3.59 (m, 2H), 3.41 (s, 4H), 3.16 (dd, J = 14.4, 10.8 Hz, 1H), 3.02 (dd, J = 14.4, 2.7 Hz, 1H), 2.61 (ddd, J = 10.8, 5.4, 2.7 Hz, 1H), 2.53 (dd, J = 18.0, 6.7 Hz, 1H), 2.26 – 2.11 (m, 3H), 2.09 – 1.95 (m, 2H), 1.91 (ddd, J = 13.2, 9.4, 3.4 Hz, 1H), 1.83 – 1.44 (m, 10H), 1.41 (s, 3H), 1.36 (s, 3H), 1.20 (s, 9H), 1.07 (d, J = 6.4 Hz, 3H). [00342] 13C NMR (101 MHz, CDCl3) δ 216.16, 178.65, 150.62, 140.04, 134.05, 129.67, 128.11, 109.00, 105.18, 86.04, 81.20, 78.72, 78.42, 77.36, 76.32, 75.47, 74.81, 73.58, 69.57, 64.02, 58.29, 57.59, 43.34, 42.80, 42.52, 38.91, 37.65, 35.66, 32.43, 32.15, 31.60, 27.37, 27.12, 26.84, 25.94, 25.08, 18.06. [00343] Synthesis of alkene 82
Figure imgf000060_0001
[00344] To a suspension of methyltriphenylphosphonium bromide (17 mg, 0.048 mmol) in dry THF (0.3 mL) was added tBuOK (48 μL of 1.0 M solution in THF, 0.048 mmol) at 0 °C. After the mixture was stirred for 30 minutes at the same temperature, a solution of ketone 81 (12 mg, 0.016 mmol) in dry THF (0.3 mL) was slowly added. After stirring for an additional 3 hours at room temperature, the resulting mixture was quenched with water (0.5 mL). The mixture was extracted with EtOAc (0.5 mL), washed with brine (0.5 mL), dried over anhydrous MgSO4, and concentrated to provide the crude product as a yellow oil. Purification by flash chromatography (silica gel, hexanes-EtOAc 9:1) afforded the desired alkene 82 (11 mg, 90%). [00345] 1H NMR (500 MHz, CDCl3) δ 8.00 – 7.92 (m, 2H), 7.72 – 7.66 (m, 1H), 7.61 (t, J = 7.7 Hz, 2H), 4.90 (q, J = 2.1 Hz, 1H), 4.85 (s, 1H), 4.78 (d, J = 1.9 Hz, 1H), 4.64 (q, J = 2.2 Hz, 1H), 4.23 (br s, 1H), 4.17 (p, J = 6.2 Hz, 1H), 4.11 – 4.01 (m, 3H), 3.94 (p, J = 6.2 Hz, 1H), 3.91 (d, J = 3.3 Hz, 1H), 3.77 (td, J = 6.8, 3.2 Hz, 1H), 3.72 (dt, J = 9.8, 5.0 Hz, 1H), 3.65 – 3.57 (m, 2H), 3.44 (s, 3H), 3.41 – 3.33 (m, 1H), 3.12 (dd, J = 14.3, 10.9 Hz, 1H), 3.04 (dd, J = 14.3, 2.7 Hz, 1H), 2.65 – 2.57 (m, 2H), 2.27 – 2.15 (m, 3H), 2.05 – 2.00 (m, 2H), 1.88 (ddd, J = 13.2, 9.5, 3.4 Hz, 1H), 1.77 – 1.70 (m, 2H), 1.67 – 1.39 (m, 8H), 1.41 (s, 3H), 1.37 (s, 3H), 1.35 – 1.25 (m, 2H), 1.19 (s, 9H), 1.07 (d, J = 6.4 Hz, 3H). [00346] 13C NMR (126 MHz, CDCl3) δ 178.70, 151.38, 150.72, 139.94, 134.12, 129.67, 128.13, 109.02, 105.11, 85.84, 81.12, 79.54, 78.42, 77.25, 76.89, 75.43, 73.55, 69.57, 64.37, 58.14, 57.58, 43.28, 42.86, 38.92, 37.64, 35.67, 32.35, 31.89, 31.72, 31.64, 27.36, 27.10, 25.93, 25.43, 18.07. [00347] Synthesis of alkene 3
Figure imgf000061_0001
[00348] To a cold (0 °C) solution of compound 82 (13 mg, 0.017 mmol) in THF (0.25 mL) was added HCl (1 M in H2O, 0.25 mL, 0.25 mmol). The resulting solution was stirred at room temperature for 5 hours. After this time, an aqueous solution of NaHCO3 (0.5 mL) was added, the mixture was diluted with ethyl acetate (0.5 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (0.5 ml x 3), and the combined organic phases were washed with water (1 mL) and brine (1 mL), dried (MgSO4) and concentrated to provide a crude yellow oil that was directly used in the next step without further purification. The crude diol was diluted in CH2Cl2 (0.3 mL) and cooled to 0 °C. Et3N (12 μL, 0.088 mmol) and TBSOTf (19 μL, 0.083 mmol) were then added and the reaction mixture was stirred for 1 hour. After this time, water (0.5 mL) was added and the phases were separated. The aqueous phase was extracted with CH2Cl2 (2 × 0.5 mL), and the combined organic phases were dried (Na2SO4), filtered, and concentrated to provide a crude oil. Purification of the crude product by flash chromatography (silica gel, hexanes-ethylacetate 95:5) afforded compound 3 (11 mg, 69%) as a colorless oil. [00349] 1H NMR (400 MHz, CDCl3) δ 7.98 – 7.91 (m, 2H), 7.73 – 7.65 (m, 1H), 7.64 – 7.57 (m, 2H), 4.90 (q, J = 2.2 Hz, 1H), 4.85 (s, 1H), 4.78 (d, J = 1.9 Hz, 1H), 4.67 (q, J = 2.2 Hz, 1H), 4.25 (s, 1H), 4.06 (td, J = 6.3, 2.5 Hz, 2H), 3.96 (p, J = 6.4 Hz, 1H), 3.89 – 3.75 (m, 3H), 3.68 (dt, J = 9.7, 4.9 Hz, 1H), 3.62 – 3.54 (m, 2H), 3.51 – 3.45 (m, 2H), 3.43 (s, 3H), 3.42 - 3.34 (m, 1H), 3.10 – 2.96 (m, 2H), 2.67 – 2.51 (m, 2H), 2.26 – 2.14 (m, 3H), 2.06 – 1.96 (m, 1H), 1.92 – 1.79 (m, 2H ), 1.79 – 1.69 (m, 2H ), 1.68 - 1.51 (m, 4H), 1.51 - 1.33 (m, 3H), 1.19 (s, 9H),1.07 (d, J = 6.4 Hz, 3H), 1.05 – 0.99 (m, 1H), 0.90 (s, 18H), 0.10 (s, 3H), 0.09 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H). [00350] 13C NMR (151 MHz, CDCl3) δ 178.73, 151.41, 150.71, 139.87, 134.09, 129.66, 128.12, 105.07, 85.91, 80.85, 79.48, 78.46, 76.9, 75.49, 71.54, 68.00, 64.39, 58.22, 57.71, 43.45, 42.84, 38.92, 37.64, 35.65, 33.25, 31.84, 31.72, 31.59, 29.85, 27.35, 26.15, 26.11, 25.41, 18.09, -3.90, -4.56, -5.17. [00351] Synthesis of chlorohydrin 63
Figure imgf000062_0001
[00352] To a slurry of NCS (1.01 g, 7.5 mmol) and D-proline (1.01 g, 9 mmol) in CH2Cl2 (38 mL) at 0 °C, pentenal was added (634 mg, 7.5 mmol). After 1h, tetrahydrothiopyran-4-one (3.06 g, 26 mmol) was added, followed by DMSO (12 mL). The mixture was then allowed to warm to rt over 3 days. After 67h, the reaction mixture was quenched by the addition of brine (20 mL). The layers were then separated and the aqueous was extracted with CH2Cl2 (2 x 30 mL) and the combined organic layers were washed with brine (35 mL), dried over Na2SO4, filtered and evaporated to afford 3.80 g of a crude brown oily solid. Purification of the crude material by flash column chromatography (silica gel, EtOAc:Hexanes 20:80) afforded the title compound as a yellow oil (485 mg, 27%). [00353] 1H NMR (500 MHz, CDCl3) δ 5.84 (ddt, J = 17.1, 10.2, 7.0 Hz, 1H), 5.25 – 5.05 (m, 2H), 4.23 – 4.14 (m, 1H), 4.00 (td, J = 7.1, 2.2 Hz, 1H), 3.19 – 3.07 (m, 1H), 3.06 – 2.90 (m, 4H), 2.85 – 2.61 (m, 5H). [00354] Synthesis of cyclized alcohol 64
Figure imgf000062_0002
[00355] To a cold (0 °C) solution of 63 (1.77 g, 7.5 mmol) in MeOH (54 mL) was added NaBH4 (428 mg, 11 mmol) portionwise. After 1h, the reaction mixture was quenched by the addition of saturated NH4Cl (20 mL) and H2O (20 mL). The aqueous were then extracted with EtOAc (3 x 50 mL) and the combined organic were washed with saturated NaHCO3 (30 mL), H2O (30 mL) and brine (30 mL), dried over Na2SO4, filtered and evaporated to afford 1.53 g of a viscous, colourless oil. This material was dissolved in MeOH (66 mL) and the resulting solution was split in three equal batches. Each batch was then microwaved in an 80 mL sealed vessel in a CEM Discover Microwave reactor, using the following method: 5 min ramp time to 60 °C, 5 min hold, 5 min ramp to 75 °C, 5 min hold, 5 min ramp to 90 °C, 5 min hold, 5 min ramp to 120 °C, 120 min hold, max power 300 W, max pressure 250 psi. After all microwave runs were completed, the solutions were recombined and the solvent evaporated to afford 1.25 g of a crude brown oil. Purification of the crude material by flash column chromatography (silica gel, EtOAc:Hexanes 1:2) afforded the title compound as a yellow oil (657 mg, 44% over two steps). [00356] 1H NMR (400 MHz, CDCl3) δ 5.83 (ddt, J = 17.2, 10.2, 6.9 Hz, 1H), 5.23 – 4.94 (m, 2H), 4.08 – 4.00 (m, 1H), 3.80 (ddd, J = 7.2, 5.8, 1.4 Hz, 1H), 3.44 (td, J = 10.9, 3.7 Hz, 1H), 2.86 (dd, J = 13.1, 11.5 Hz, 1H), 2.78 – 2.59 (m, 3H), 2.54 – 2.42 (m, 1H), 2.43 – 2.32 (m, 1H), 2.32 – 2.19 (m, 1H), 1.78 – 1.62 (m, 2H), 1.52 (d, J = 4.2 Hz, 1H). [00357] Synthesis of cyclized alcohol 65
Figure imgf000063_0001
[00358] To a cold (0 °C) solution of 64 (1.40 g, 7 mmol), p-nitrobenzoic acid (2.34 g, 14 mmol) and Ph3P (3.67 g, 14 mmol) in THF (47 mL), DIAD was added (2.75 mL, 14 mmol). After 10min the ice bath was removed and the reaction mixture was allowed to warm to rt over 2h. The solvent was then evaporated and the thick yellow residue was redissolved in MeOH (89 mL) and THF (7.5 mL). To the resulting yellow solution, freshly ground NaOH (1.12 g, 13 mmol) was added. After 1h, the reaction was quenched by the addition of H2O (50 mL) and brine (50 mL). The aqueous were extracted with EtOAc (3 x 100 mL) and the combined organic were washed with saturated NH4Cl (100 mL), H2O (100 mL) and brine (100 mL), dried over MgSO4, filtered and evaporated to afford 7.21 g of a yellow solid. This material was dissolved in a minimum amount of hot benzene and then cyclohexane was added. The solution was placed in an ice bath and then after 30 min the resulting white solid was filtered off and discarded. Evaporation of the filtrate afforded 2.59 g of a yellow oil. Purification of this material by flash column chromatography (silica gel, EtOAc:Hexanes 1:2) afforded a white solid, which was a 60:40 mixture of the title compound and dihydroDIAD (932 mg, 40% yield over two steps). [00359] 1H NMR (400 MHz, CDCl3) δ 5.96 (ddt, J = 17.1, 10.3, 6.7 Hz, 1H), 5.27 – 5.08 (m, 2H), 4.11 (q, J = 7.6 Hz, 1H), 3.94 (q, J = 6.6 Hz, 1H), 3.04 – 2.88 (m, 2H), 2.80 – 2.57 (m, 3H), 2.55 – 2.29 (m, 3H), 1.90 – 1.72 (m, 2H), 1.69 (d, J = 6.7 Hz, 1H). [00360] Synthesis of methyl ether 65a
Figure imgf000064_0001
[00361] To a cold (0 °C) solution of the 65 mixture (791 mg, 1.96 mmol of 65) in THF (39 mL) was added 65% NaH (868 mg, 564 mg of active reagent, 23.5 mmol). Then, Me2SO4 was added as well (556 μL, 5.9 mmol) and the mixture was allowed to warm to rt overnight. After 20h, the reaction mixture was cooled to 0 °C and was quenched with H2O (20 mL). The aqueous layer was extracted with Et2O (3 x 30 mL) and the combined organic layers were washed with H2O (30 mL) and brine (30 mL), dried over MgSO4, filtered and evaporated to afford 1.19 g of a colourless oil. Purification of this crude material by flash column chromatography (silica gel, EtOAc:Hexanes 1:4) afforded the title compound as a colourless oil, contaminated with ~20% of the bis-methylated DIAD by-product (541 mg, 84% yield of desired product). [00362] 1H NMR (500 MHz, CDCl3) δ 5.90 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 5.19 – 4.99 (m, 2H), 3.95 (ddd, J = 8.4, 7.4, 4.5 Hz, 1H), 3.63 (dd, J = 8.5, 7.4 Hz, 1H), 3.40 (s, 3H), 2.99 (td, J = 10.9, 3.6 Hz, 1H), 2.92 (ddd, J = 12.6, 3.3, 1.5 Hz, 1H), 2.79 – 2.61 (m, 3H), 2.45 – 2.32 (m, 2H), 2.32 – 2.21 (m, 1H), 1.94 – 1.83 (m, 1H), 1.75 (qd, J = 11.7, 4.5 Hz, 1H). [00363] Synthesis of sulfonium salt 55
Figure imgf000065_0001
[00364] A sealed tube was charged with the methyl ether 65a mixture (117 mg, 0.43 mmol of 65a), Cu(OBz)2 (4 mg, 0.01 mmol), Ph2IPF6 (233 mg, 0.55 mmol) and ClCH2CH2Cl (6 mL). It was then sealed and placed in a 110 °C oil bath overnight. After 27 h, the reaction mixture was allowed to cool to rt and the solvent was evaporated to afford 318 mg of a brown oily solid. Purification of the crude material by flash column chromatography (silica gel, Acetone:CH2Cl22:30 afforded the title compound as a white solid (102 mg, 54%). [00365] 1H NMR (400 MHz, CDCl3) δ 8.06 – 7.96 (m, 2H), 7.80 (t, J = 7.4 Hz, 1H), 7.72 (t, J = 7.8 Hz, 2H), 5.87 (ddt, J = 17.1, 10.3, 6.8 Hz, 1H), 5.31 – 5.00 (m, 2H), 4.39 – 4.16 (m, 2H), 4.07 (t, J = 7.8 Hz, 1H), 4.01 – 3.78 (m, 3H), 3.72 (dd, J = 12.5, 3.2 Hz, 1H), 3.40 (s, 3H), 2.75 (dd, J = 14.0, 3.7 Hz, 1H), 2.46 – 2.23 (m, 2H), 2.17 – 1.97 (m, 2H). [00366] Synthesis of alcohol 41
Figure imgf000065_0002
[00367] Sulfonium salt 40 (12.7 mg, 24.8 mmol) was dissolved in dry THF (100 mL). Then, at -78 °C, potassium bis(trimethylsilyl)amide (KHMDS) (31 mL, 31mmol; 1.0 M solution in THF) was added dropwise. The reaction was stirred at -78 °C for 1 h. After that, B2Pin2 (8.8 mg, 34.7 mmol) was dropwise added as a solution in dry THF (200 mL) and further stirred for 1 h. After that time, the solvent was evaporated under reduced pressure and the residue redissolved in dry CH2Cl2 (300 mL). To this solution, mCPBA (23 mg, 93 mmol; 70% wt) was added in one portion at rt and stirred for 1 h. The reaction was was quenched with a Na2S2O3(aq):NaHCO3(aq):water (1:1:1) solution (1.5 mL), the organic layer was separated and the aqueous phase extracted with CH2Cl2 (500 mL x3). The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure. Column chromatography (EtOAc) afforded the pure product as a colorless oil (3.06 mg, 30%). [00368] 1H NMR (500 MHz) d: 7.94 (d, J = 7.6 Hz, 2H), 7.72-7.66 (m, 1H), 7.61 (t, J = 7.7 Hz, 2H), 4.17-4.10 (m, 1H), 4.06 (dd, J = 8.0, 6.0 Hz, 1H), 3.86 (td, J = 6.8, 3.6 Hz, 1H), 3.82-3.77 (m, 2H), 3.76-3.71 (m, 2H), 3.60 (t, J = 7.6 Hz, 1H), 3.39 (s, 3H), 3.16 (dd, J = 14.0, 8.1 Hz, 1H), 3.11 (dd, J = 14.1, 5.8 Hz, 1H), 2.66-2.60 (m, 1H), 2.43 (t, J = 5.7 Hz, 1H), 2.02-1.93 (m, 2H), 1.92-1.85 (m, 2H), 1.40 (s, 3H), 1.35 (s,3H). [00369] Synthesis of aldehyde 42
Figure imgf000066_0001
[00370] Alcohol 41 (4.8 mg, 11.6 mmol) was dissolved in dry CH2Cl2 (350 mL) and NaHCO3 (4 mg, 40.6 mmol) was added. Then, DMP (6.5 mg, 15.1 mmol) was added in one portion and the reaction stirred for 1.5 h at room temperature. After that, the reaction was quenched with a Na2S2O3(aq):NaHCO3(aq):water (1:1:1) solution (1.5 mL), the organic layer was separated and the aqueous phase extracted with CH2Cl2 (500 mL x3). The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure. Column chromatography (50% EtOAc in hexanes) afforded the pure product as a colorless oil (3.3 mg, 70%). [00371] 1H NMR (500 MHz) d: 9.71 (s, 1H), 7.97-7.92 (m, 2H), 7.72-7.66 (m, 1H), 7.63-7.58 (m, 2H), 4.17-4.10 (m, 1H), 4.07-4.02 (m, 2H), 3.90-3.85 (m, 2H), 3.60 (dd, J = 8.0, 7.1 Hz, 1H), 3.38 (s, 3H), 3.35 (dd, J = 14.2, 5.0 Hz, 1H), 3.17 (dd, J = 14.1, 8.7 Hz, 1H), 2.91 (ddd, J = 17.6, 6.5, 1.7 Hz, 1H), 2.80 (ddd, 17.6, 6.1, 1.1 Hz, 1H), 2.55 (dt, 9.1, 5.0 Hz, 1H), 1.99-1.94 (m, 2H), 1.40 (s, 3H), 1.35 (s, 3H) [00372] 13C NMR (125 MHz) d: 200.61, 139.48, 134.23, 129.66, 128.05, 109.08, 85.77, 78.62, 78.54, 73.41, 69.48, 57.95, 57.37, 49.84, 44.07, 32.58, 27.08, 25.87 [00373] Results [00374] The proline-catalyzed coupling of thiopyranone with the aldehyde 16 was performed in 6 steps from (S)-tetrahydrofufurylamine tartrate salt (14) (Figure 2).30 [00375] First, an α-chlorination of the aldehyde produces a mixture of α- chloroaldehydes (2R)-17 and (2S)-17. While the α-chlorination is not stereoselective, proline also promotes the epimerization of the diastereomeric α-chloroaldehydes (2R)-17 and (2S)-17, and the subsequent proline-catalyzed aldol reaction with thiopyranone36 is sufficiently slow to effect a dynamic kinetic resolution, favoring reaction with (2S)-17 and formation of the anti-aldol syn-chlorohydrin 19 allowing the chlorohydrin 19 to be prepared on multi-gram scale36. A subsequent diastereoselective reduction using DIBAL followed by a SrCO3 promoted cyclization18 gave the tetrahydrofuran 20. From here, Mitsunobu inversion37 followed by hydrolysis and methylation gave the correctly configured tetrahydrofuranol 21. Finally, methylation of the free alcohol and arylation of the thioether function using a diaryliodonium salt provided the Corey-Chaykovsky coupling partner 22 as a mixture of diastereomeric sulfonium salts. [00376] Synthesis of the ketone 33 started with an asymmetric α-chlorination of the readily available aldehyde 23 using Christmann’s modification26 of the MacMillan α- chlorination reaction (Figure 3).24 The addition of pentane to the crude reaction mixture (in acetonitrile) allowed for direct extraction of pure (>95%) α-chloroaldehyde 25, which was produced in 95% ee. With the α-chloroaldehyde 25 in hand, a lithium aldol reaction28 with the enolate derived from methyl ketone 26 (made from commercially available 5-hydroxy-2-pentanone) gave the β-hydroxy ketochlorohydrin 27 (dr = 4:1). The ketone function in this material was then reduced in a 1,3-syn- selective manner using DIBAL to afford the corresponding diol. We examined thermal (MeOH, 120 ºC, mwave)29 and silver(I)-promoted (AgOTf, Ag2O, THF)28 cyclization conditions as well as a SrCO3-promoted cyclization protocol18 and used the Ag(I)- promoted cyclization conditions to obtain the desired tetrahydrofuranol that was protected as the corresponding TBS ether 28 in excellent overall yield. Oxidative cleavage of the alkene function followed by a second a-chlorination24 using the MacMillan catalyst ent-24 gave the α-chloroaldehyde 30. This reaction also upgraded the enantiomeric purity to >99% ee. [00377] To complete the sequence outlined in Figure 3, a HWE reaction involving the α-chloroaldehyde 30 gave the enone 31. Reduction of the alkene function in 31 largely delivered dechlorinated products using established protocols for the conjugate reduction of enones (e.g., catalytic hydrogenation,38 Ni-mediated hydride transfer39 or CuH reduction40). We used Mn(III)-catalyzed conjugate reduction using phenylsilane and reported by Magnus41 for preparation of the ^-chloroketones. Reduction of enone 31 using these same conditions gave the C25 epimeric ketones 32 and 33 as a 1:1.5 mixture. The undesired diastereomer could be readily separated by flash column chromatography and treated with DBU in MeCN, which gave a clean 1:1 mixture of diastereomers 32 and 33. Thus, we could routinely produce significant quantities of the ketone 33. [00378] Corey-Chaykovsky34 coupling was performed using 22 and 33 (Figure 4). Discrimination between the two methylenes adjacent to the sulfonium function at C27 and C30 was performed using LiHMDS, which effected a regioselective deprotonation at C27. Reaction of the resulting ylide with the ketone function in 33 followed by direct oxidation to the corresponding sulfone afforded the epoxide 34 as the major product in good yield. Based on the observed diastereoselectivity in the coupling reaction, it appeared that anti-addition42 of the sulfonium ylide from the bottom face (as shown for 36, Figure 4) ultimately controls the stereochemistry at C27. The addition to the ketone function is then governed by Felkin control,43 with the C25 methyl-bearing stereocenter dictating the stereochemical outcome at C26. Accordingly, we used a titanocene (III) complex (Cp2TiCl2),44 which promotes formation of an intermediate β-titanoxy tertiary radical.45 Reduction of the tertiary radical by a second equivalent of Ti(III) then affords a titanium carbanion that can undergo β-hydride elimination to afford the observed allylic alcohol. Applying these conditions to the more elaborate epoxide 34, the allylic alcohol 35 was produced as the major product in excellent yield. From here, cyclization to the tetrahydropyran 38 was accomplished using double displacement conditions.19 Here, displacement of the chloride occurs through initial attack by the C17-C20 tetrahydrofuran ring oxygen to form a bicyclic oxonium ion 37 that is subsequently attacked by the C27 alcohol function to form the correctly configured tetrahydropyran 38. Completion of the synthesis of the C14-C35 sulfone 39 then involved removal of the silyl protecting group, oxidation, olefination and finally removal of the Piv protecting group from the C14 alcohol. The spectroscopic data recorded on sulfone 39 was identical to that reported previously.17 These results confirmed that α-chloroaldehyde-based synthesis of eribulin can successfully merge with established manufacturing routes and deliver active pharmaceutical ingredient (API) suitable for human use. [00379] Furthermore, intermediate aldehydes 5 (Figure 1B), may be prepared as shown in Figure 6. [00380] Herein, sulfonium salt 40 was treated with KHMDS to discriminate between the two methylenes adjacent to the sulfonium function at C27 and C30. This effected a regioselective deprotonation at C27. Reaction of the resulting ylide with bis(pinacolborane) followed by oxidation of the resulting mixture with mCPBA afforded alcohol 41. [00381] Further oxidation of alcohol 41 using DMP provided intermediate aldehyde 42 which is a key building block towards eribulin. Accordingly, regioselective deprotonation of sulfonium 40, followed by borylation, oxidation, ring-opening, oxidation provided easy access to the C27-C35 aldehyde 42. Therefore, aldehyde 42 can be obtained in 12 steps from commercially available starting materials. References 1 Hirata, Y. & Uemura, D. Halichondrins—antitumor polyether macrolides from a marine sponge. Pure & Appl. Chem.58, 701-710 (1986). 2 Uemura, D., Takahashi, K., Yamamoto, T., Katayama, C., Tanaka, J., Okumura, Y. & Hirata, Y. Norhalichondrin A: an antitumor polyether macrolide from a marine sponge. J. Am. Chem. Soc.107, 4796-4798 (1985). 3 Aicher, T. D. et al. Total synthesis of halichondrin B and norhalichondrin B. J. Am. Chem. Soc.114, 3162-3164 (1992). 4 Towle, M. J. et al. In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B. Cancer Res.61, 1013-1021 (2001). 5 Zheng, W. et al. Macrocyclic ketone analogues of halichondrin B. Bioorg. Med. Chem. Lett.14, 5551-5554 (2004). 6 Yu, M. J., Zheng, W. J. & Seletsky, B. M. From micrograms to grams: scale- up synthesis of eribulin mesylate. Nat. Prod. Rep.30, 1158-1164 (2013). 7 Yu, M. J., Zheng, W. & Seletsky, B. M. From micrograms to grams: scale-up synthesis of eribulin mesylate. Nat. Prod. Rep.30, 1158-1164 (2013). 8 Ueda, A., Yamamoto, A., Kato, D. & Kishi, Y. Total Synthesis of Halichondrin A, the Missing Member in the Halichondrin Class of Natural Products. J. Am. Chem. Soc.136, 5171-5176 (2014). 9 Yan, W., Li, Z. & Kishi, Y. Selective Activation/Coupling of Poly-halogenated Nucleophiles in Ni/Cr-Mediated Reactions: Synthesis of C1-C19 Building Block of Halichondrin Bs. J. Am. Chem. Soc.137, 6219-6225 (2015). 10 Lee, J., Li, Z., Osawa, A. & Kishi, Y. Extension of Pd-Mediated One-Pot Ketone Synthesis to Macro-cyclization: Application to a New Convergent Synthesis of Eribulin. J. Am. Chem. Soc.138, 16248-16251 (2016). 11 Austad, B. C. et al. Commercial Manufacture of Halaven (R): Chemoselective Transformations En Route to Structurally Complex Macrocyclic Ketones. Synlett 24, 333-337 (2013). 12 Austad, B. C. et al. Process Development of Halaven (R): Synthesis of the C14-C35 Fragment via Iterative Nozaki-Hiyama-Kishi Reaction-Williamson Ether Cyclization. Synlett 24, 327-332 (2013). 13 Chase, C. E., Fang, F. G., Lewis, B. M., Wilkie, G. D., Schnaderbeck, M. J. & Zhu, X. J. Process Development of Halaven (R): Synthesis of the C1-C13 Fragment from D-(-)-Gulono-1,4-lactone. Synlett 24, 323-326 (2013). 14 Okude, Y., Hirano, S., Hiyama, T. & Nozaki, H. Grignard-type carbonyl addition of allyl halides by means of chromous salt. A chemospecific synthesis of homoallyl alcohols. J. Am. Chem. Soc.99, 3179-3181 (1977). 15 Jin, H., Uenishi, J., Christ, W. J. & Kishi, Y. Catalytic effect of nickel(II) chloride and palladium(II) acetate on chromium(II)-mediated coupling reaction of iodo olefins with aldehydes. J. Am. Chem. Soc.108, 5644-5646 (1986). 16 Rudolph, A., Alberico, D., Jordan, R., Pan, M., Souza, F. & Gorin, B. Early introduction of the amino group to the C27–C35 building block of Eribulin. Tetrahedron Lett.54, 7059-7061 (2013). 17 Souza, F., Rudolph, A., Alberico, D., Jordan, R., Pan, M. & Gorin, B. Synthetic process for preparation of macrocyclic C1-keto analogs of halichondrin B and intermediates useful therein including intermediates containing -SO2-(P-tolyl) groups. WO 2015/000070 A1 (2015). 18 Lee, J. H., Li, Z., Osawa, A. & Kishi, Y. Extension of Pd-Mediated One-Pot Ketone Synthesis to Macrocyclization: Application to a New Convergent Synthesis of Eribulin. J. Am. Chem. Soc.138, 16248-16251 (2016). 19 Kim, D.-S., Dong, C.-G., Kim, J. T., Guo, H., Huang, J., Tiseni, P. S. & Kishi, Y. New Syntheses of E7389 C14−C35 and Halichondrin C14−C38 Building Blocks: Double-Inversion Approach. J. Am. Chem. Soc.131, 15636-15641 (2009). 20 Dong, C.-G., Henderson, J. A., Kaburagi, Y., Sasaki, T., Kim, D.-S., Kim, J. T., Urabe, D., Guo, H. & Kishi, Y. New Syntheses of E7389 C14−C35 and Halichondrin C14−C38 Building Blocks: Reductive Cyclization and Oxy- Michael Cyclization Approaches. J. Am. Chem. Soc.131, 15642-15646 (2009). 21 Li, J., Yan, W. & Kishi, Y. Unified Synthesis of C1-C19 Building Blocks of Halichondrins via Selective Activation/Coupling of Poly-halogenated Nucleophiles in (Ni)/Cr-Mediated Reactions. J. Am. Chem. Soc.137, 6226- 6231 (2015). 22 Yamamoto, A., Ueda, A., Brémond, P., Tiseni, P. S. & Kishi, Y. Total Synthesis of Halichondrin C. J. Am. Chem. Soc.134, 893-896 (2012). 23 Brochu, M. P., Brown, S. P. & MacMillan, D. W. C. Direct and Enantioselective Organocatalytic α-Chlorination of Aldehydes. J. Am. Chem. Soc.126, 4108-4109 (2004). 24 Amatore, M., Beeson, T. D., Brown, S. P. & MacMillan, D. W. Enantioselective linchpin catalysis by SOMO catalysis: an approach to the asymmetric alpha-chlorination of aldehydes and terminal epoxide formation. Angew. Chem. Int. Ed.48, 5121-5124 (2009). 25 Halland, N., Braunton, A., Bachmann, S., Marigo, M. & Jorgensen, K. A. Direct organocatalytic asymmetric alpha-chlorination of aldehydes. J. Am. Chem. Soc.126, 4790-4791 (2004). 26 Winter, P., Swatschek, J., Willot, M., Radtke, L., Olbrisch, T., Schäfer, A. & Christmann, M. Transforming terpene-derived aldehydes into 1,2-epoxides via asymmetric α-chlorination: subsequent epoxide opening with carbon nucleophiles. Chem. Commun.47, 12200-12202 (2011). 27 Britton, R. & Kang, B. alpha-Haloaldehydes: Versatile Building Blocks for Natural Product Synthesis. Nat. Prod. Rep.30, 227-236 (2013). 28 Kang, B., Mowat, J., Pinter, T. & Britton, R. Development of a concise and general enantioselective approach to 2,5-disubstituted-3- hydroxytetrahydrofurans. Org. Lett.11, 1717-1720 (2009). 29 Kang, B., Chang, S., Decker, S. & Britton, R. Regioselective and stereoselective cyclizations of chloropolyols in water: rapid synthesis of hydroxytetrahydrofurans. Org. Lett.12, 1716-1719 (2010). 30 Bergeron-Brlek, M., Teoh, T. & Britton, R. A Tandem Organocatalytic alpha- Chlorination-Aldol Reaction that Proceeds with Dynamic Kinetic Resolution: a Powerful Tool for Carbohydrate Synthesis. Org. Lett.15, 3554-3557 (2013). 31 Chang, S., Hur, S. & Britton, R. Total synthesis of ascospiroketal a through a Ag(I) -promoted cyclization cascade. Angew. Chem. Int. Ed.54, 211-214 (2015). 32 Challa, V. R. et al. Total synthesis of biselide A. Chem. Sci.12, 5534-5543 (2021). 33 Holmes, M. T. & Britton, R. Total synthesis and structural revision of laurefurenynes A and B. Chem.: Eur. J.19, 12649-12652 (2013). 34 Corey, E. J. & Chaykovsky, M. Dimethyloxosulfonium Methylide ((CH3)2SOCH2) and Dimethylsulfonium Methylide ((CH3)2SCH2). Formation and Application to Organic Synthesis. J. Am. Chem. Soc.87, 1353-1364 (1965). 35 Vogel, C. V., Pietraszkiewicz, H., Sabry, O. M., Gerwick, W. H., Valeriote, F. A. & Vanderwal, C. D. Enantioselective Divergent Syntheses of Several Polyhalogenated Plocamium Monoterpenes and Evaluation of Their Selectivity for Solid Tumors. Angew. Chem. Int. Ed.53, 12205-12209 (2014). 36 Meanwell, M. et al. Diversity-Oriented Synthesis of Glycomimetics. Comm. Chem. , accepted (2021). 37 Fletcher, S. The Mitsunobu reaction in the 21st century. Org. Chem. Front.2, 739-752 (2015). 38 Haskel, A. & Keinan, E. in Handbook of Organopalladium Chemistry for Organic Synthesis (eds E.-i. Negishi & A. de Meijere) 2767 (Wiley, 2002). 39 Zeng, C., Zhao, J. & Zhao, G. Enantioselective divergent total syntheses of fawcettimine-type Lycopodium alkaloids. Tetrahedron 71, 64-69 (2015). 40 Deutsch, C. & Krause, N. CuH-Catalyzed Reactions. Chem. Rev.108, 2916- 2927 (2008). 41 Magnus, P., Waring, M. J. & Scott, D. A. Conjugate reduction of α,β- unsaturated ketones using an MnIII catalyst, phenylsilane and isopropyl alcohol. Tetrahedron Lett.41, 9731-9733 (2000). 42 Lindvall, M. K. & Koskinen, A. M. P. Origins of Stereoselectivity in the Corey−Chaykovsky Reaction. Insights from Quantum Chemistry. J. Org. Chem.64, 4596-4606 (1999). 43 Chérest, M., Felkin, H. & Prudent, N. Torsional strain involving partial bonds. The stereochemistry of the lithium aluminium hydride reduction of some simple open-chain ketones. Tetrahedron Lett.9, 2199-2204 (1968). 44 Morcillo, S. P., Miguel, D., Campaña, A. G., Álvarez de Cienfuegos, L., Justicia, J. & Cuerva, J. M. Recent applications of Cp2TiCl in natural product synthesis. Org. Chem. Front.1, 15-33 (2014). 45 Bermejo, F. & Sandoval, C. Cp2TiCl-Promoted Isomerization of Trisubstituted Epoxides to exo-Methylene Allylic Alcohols on Carvone Derivatives. J. Org. Chem.69, 5275-5280 (2004). [00382] All citations are hereby incorporated by reference. [00383] The present invention has been described with regard to one or more embodiments. However, it will be apparent to persons skilled in the art that a number of variations and modifications can be made without departing from the scope of the invention as defined in the claims. Therefore, although various embodiments of the invention are disclosed herein, many adaptations and modifications may be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art. Such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way. Numeric ranges are inclusive of the numbers defining the range. Elements listed with specific embodiments, are understood to be subject to combination in any manner and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be construed to limit the present invention to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed and/or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise. [00384] In the specification, the word “comprising” is used as an open-ended term, substantially equivalent to the phrase “including, but not limited to,” and the word “comprises” has a corresponding meaning. It is to be however understood that, where the words “comprising” or “comprises,” or a variation having the same root, are used herein, variation or modification to “consisting” or “consists,” which excludes any element, step, or ingredient not specified, or to “consisting essentially of” or “consists essentially of,” which limits to the specified materials or recited steps together with those that do not materially affect the basic and novel characteristics of the claimed invention, is also contemplated. Citation of references herein shall not be construed as an admission that such references are prior art to the present invention. All publications are incorporated herein by reference as if each individual publication was specifically and individually indicated to be incorporated by reference herein and as though fully set forth herein. The invention includes all embodiments and variations substantially as hereinbefore described and with reference to the examples and drawings.

Claims

WHAT IS CLAIMED IS: 1. A process for the preparation of a C14-C35 sulfone comprising reacting a C14-C26 ketone with a C27-C35 sulfonium salt under Corey-Chaykovsky reaction conditions, to form the C14-C35 sulfone.
2. The process of claim 1, comprising: i) performing a Horner-Wadsworth-Emmons reaction with an α- chloroaldehyde to form an enone; and ii) reducing the alkene function in the enone, to form the C14-C26 ketone.
3. The process of claim 2 wherein the α-chloroaldehyde is compound 12, 30 or 67.
4. The process of claim 2 or 3 wherein the enone is compound 31 or 68.
5. The process of any one of claims 1 to 4 wherein the C14-C26 ketone is compound 10, 33; 44 or 69.
6. The process of any one of claims 1 to 5, comprising: i) reacting an aldehyde with NCS and thiopyranone by proline catalysis to form an anti-aldol syn-chlorohydrin; ii) performing a carbonyl reduction followed by cyclization to form a tetrahydrofuran; iii) performing an alcohol inversion followed by hydrolysis to form a tetrahydrofuranol; and iv) performing a methylation of the free alcohol and arylation of the thioether function of the tetrahydrofuranol to form the C27-C35 sulfonium salt.
7. The process of claim 6 wherein the aldehyde is compound 16, 49, 56, or 61.
8. The process of claim 6 or 7 wherein the anti-aldol syn-chlorohydrin is compound 19, 50, 58, or 63.
9. The process of any one of claims 6 to 8 wherein the tetrahydrofuran is compound 20, 51, 59, or 64.
10. The process of any one of claims 6 to 9 wherein the tetrahydrofuranol is compound 21, 52, 60, or 65.
11. The process of any one of claims 1 to 10 wherein the C27-C35 sulfonium salt is compound 9, 22, 40, 43, 53, 66 or 74.
12. The process of any one of claims 1 to 11 wherein the C14-C35 sulfone is compound 3, 4; 39, 47, 73 or 82.
13. The process of any one of claims 1 to 12 wherein the C14-C35 sulfone is used in the preparation of eribulin.
14. A process for the preparation of a C14-C26 ketone, comprising i) performing a HWE reaction with an α-chloroaldehyde to form an enone; and ii) reducing the alkene function in the enone, to form the C14-C26 ketone.
15. The process of claim 14 wherein the α-chloroaldehyde is compound 12, 30 or 67.
16. The process of claim 14 or 15 wherein the enone is compound 31 or 68.
17. The process of any one of claims 14 to 16 wherein the C14-C26 ketone is compound 10, 33; 44 or 69.
18. A process for the preparation of a C27-C35 sulfonium salt, comprising: i) reacting an aldehyde with NCS and thiopyranone by proline catalysis to form an anti-aldol syn-chlorohydrin; ii) performing a carbonyl reduction followed by cyclization to form a tetrahydrofuran; iii) performing an alcohol inversion followed by hydrolysis to form a tetrahydrofuranol; and iv) performing a methylation of the free alcohol and arylation of the thioether function of the tetrahydrofuranol to form the C27-C35 sulfonium salt.
19. The process of claim 18 wherein the aldehyde is compound 16, 49, 56, or 61.
20. The process of claim 18 or 19 wherein the anti-aldol syn-chlorohydrin is compound 19, 50, 58, or 63.
21. The process of any one of claims 18 to 20 wherein the tetrahydrofuran is compound 20, 51, 59, or 64.
22. The process of any one of claims 18 to 21 wherein the tetrahydrofuranol is compound 21, 52, 60, or 65.
23. The process of any one of claims 18 to 22 wherein the C27-C35 sulfonium salt is compound 9, 22, 40, 43, 53, 66 or 74.
24. A process for the preparation of a C27-C35 aldehyde comprising: i) performing a C27 regioselective deprotonation of a C27-C35 sulfonium salt to form a sulfur ylide; ii) trapping the sulfur ylide with bis(pinacolborane) and subsequent oxidation to form the C27-C35 aldehyde.
25. The process of claim 24 wherein the regioselective deprotonation is performed using a sterically hindered base.
26. The process of claim 24 or 25 wherein the C27-C35 sulfonium salt is compound 9; 22; 40; 43, 53, 66; or 74.
27. The process of any one of claims 24 to 26 wherein the C27-C35 aldehyde is compound 5, 42; 48, 85, or 86. 28. The process of any one of claims 24 to 37 wherein the C27-C35 aldehyde is used in the preparation of eribulin. 29. A compound of Formula I or a pharmaceutically acceptable salt thereof:
wherein
Figure imgf000077_0001
R1 is aryl; R2 is H or OR11; R3 is H or OR11; or R2 and R3 are O; R4 is CHCH2, CCH, C*H(OR12)CH2(OR13), or C*H(OR12)CH2(NR14R15), wherein the asterisk (*) indicates that the stereochemistry is (S); R5 is H or an alcohol protecting group; R9 is H and R8 is OR16, or R9 and R9 are O, or R9 and R8 are CH2, or R8 is H and R9 is OR16, or R9 and R8 are CH; R11 is H, CH3 or an alcohol protecting group; R12 and R13 are C(CH3)2 or a 1,2-diol protecting group; R12 is H or an alcohol protecting group; and R13 is H or an alcohol protecting group; R14 is H or an amine protecting group; R15 is H or an amine protecting group; or R15 and R12 are C(CH3)2 or a 1,2-aminoalcohol protecting group; and R16 is H or an alcohol protecting group. 30. The compound of claim 29 wherein the compound is selected from the group consisting of: compounds 38, 72, 73, 77, 78, and 81 or a pharmaceutically acceptable salt thereof. 31. A compound of Formula II or a pharmaceutically acceptable salt thereof:
Figure imgf000078_0001
wherein R5 is H or an alcohol protecting group; R6 is a leaving group; R7 is a leaving group; R9 is H or OR16; R8 is H or OR16; or R8 and R9 are O or CH2; R10 is CH2OR5, CHO, CHCH2, CCH, CHC(CH3)COCH3 or CH2CH(CH3)CO(CH3); and R16 is H or an alcohol protecting group. 32. The compound of claim 31 wherein the compound is selected from the group consisting of: compounds 10,
28,
29,
30,
31,
32, and 33 or a pharmaceutically acceptable salt thereof.
33. A compound of Formula III or a pharmaceutically acceptable salt thereof:
Figure imgf000079_0001
wherein R1 is aryl; X is a counterion; R2 is H or OR11; R3 is H or OR11; or R2 and R3 are O; R4 is CHCH2, CCH, C*H(OR12)CH2(OR13), or C*H(OR12)CH2(NR14R15), wherein the asterisk (*) indicates that the stereochemistry is (S); R11 is H, CH3 or an alcohol protecting group; R12 and R13 are C(CH3)2 or a 1,2-diol protecting group; R12 is H or an alcohol protecting group; and R13 is H or an alcohol protecting group; R14 is H or an amine protecting group; R15 is H or an amine protecting group; or R15 and R12 are C(CH3)2 or a 1,2-aminoalcohol protecting group.
34. The compound of claim 33 wherein the compound is selected from the group consisting of: 9, 22, 40, 43, 53, 66 and 74 or a pharmaceutically acceptable salt thereof.
35. A compound of Formula IV or a pharmaceutically acceptable salt thereof:
wherein
Figure imgf000080_0001
R1 is aryl; R2 is H or OR11; R3 is H or OR11; or R2 and R3 are O; R4 is CHCH2, CCH, C*H(OR12)CH2(OR13), or C*H(OR12)CH2(NR14R15), wherein the asterisk (*) indicates that the stereochemistry is (S); R17 is H and R18 is OR9, R17 and R18 are O, R18 is H and R17 is OR9, or R17 and R18 are CH; R11 is H, CH3 or an alcohol protecting group; R12 and R13 are C(CH3)2 or a 1,2-diol protecting group; R12 is H or an alcohol protecting group; and R13 is H or an alcohol protecting group; R14 is H or an amine protecting group; R15 is H or an amine protecting group; or R15 and R12 are C(CH3)2 or a 1,2-aminoalcohol protecting group.
36. The compound of claim 35 wherein the compound is 41 or a pharmaceutically acceptable salt thereof.
37. A compound selected from the group consisting of: 9, 10, 22, 33, 39, 40, 42, 43, 44, 47, 48, 53, 66, 69, 73, 74, and 82, or a pharmaceutically acceptable salt thereof.
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