Chromium-mediated coupling and application to the synthesis of halichondrins

The present invention provides unified synthesis of the CI-CI 9 building blocks of halichondrins and analogs thereof using selective coupling of poly-halogenated nucleophiles in chromium-mediated coupling reactions. The present invention also provides a practical and efficient synthesis of C20-C38 building blocks of halichondrins and analogs thereof. Also provided herein are general methods of selective activation and coupling of poly-halogenated analogs with an aldehyde. The provided coupling reactions are selective for halo-enone and halo-acetylenic ketal over vinyl halide and halide attached to a sp hydridized carbon. The provided efficient selective coupling reactions can allow easy access to the CI-CI 9 building blocks and C20-C38 building blocks of halichondrins and analogs thereof with limited or no purification or separation of the intermediates.

BACKGROUND OF THE INVENTION

The halichondrins are polyether macrolides, originally isolated from the marine spongeHalichondria okadaiby Uemura, Hirata, and coworkers. Due to their intriguing structural architecture and extraordinary in vitro and in vivo anti-proliferative activity, the halichondrins have received much attention from the scientific community. Synthetic methods that streamline the preparation of these natural products or related derivatives are important given the structural complexity of the halichondrin backbone. A highly convergent approach has been adopted to synthesize halichondrins and analogs thereof. Because of its high degree of convergence, one can expect a high overall efficiency for the longest linear synthetic sequence. Interestingly, the key two couplings have been achieved efficiently with Ni/Cr-mediated reactions: one between the building blocks C20-C38 and C1-C19 to synthesize the macrolide; and another between a vinyl iodide and an aldehyde to synthesize the building block C1-C19. The structure of Halichondrin B is shown below, with carbon atoms numbered.

Ni/Cr-mediated couplings of alkenyl halides/triflates with aldehydes were originally reported by Takai, Hiyama, Nozaki, and coworkers in 1983. Since then, it has been shown that the coupling is initiated by a catalytic amount of NiCl2as a contaminant in the with CrCl2. It is now generally accepted that this coupling involves: (1) oxidative addition of Ni(0), formed from NiCl2via reduction with CrCl2in situ, to an alkenyl halide/triflate to form an alkenyl Ni(II)-species, (2) transmetallation of the resultant Ni(II)-species to Cr(II)Cl2to form alkenyl Cr(III)-species, and (3) carbonyl addition of the resultant Cr(III)-species to an aldehyde to form the product Cr(III)-alkoxide (FIG. 5). Chemistry has been developed to achieve this coupling in a catalytic and asymmetric manner.

Due to the important biological activities of halichondrins, it is valuable to develop a unified and practical synthesis of the C1-C19 building block, as well as C20-C38 building blocks, to allow easy access to halichondrins (e.g., halichondrin A, B, C; norhalichondrin A, B, C; homohalichondrin A, B, C; eribulin), and analogs thereof.

SUMMARY OF THE INVENTION

As part of the ongoing research effort aimed at a unified total synthesis of members of the halichondrin class of marine natural products, an efficient synthesis of the C1-C19 building block has been developed (FIG. 4), and is provided herein. Furthermore, a practical and efficient synthesis of C20-C38 building blocks has also been developed and is provided herein. In the recently reported total synthesis of halichondrin A (Ueda et al.,J. Am. Chem. Soc.,2014, 136, 5171), the C1-C19 building block is joined with the C20-C38 building block to synthesize halichondrin A, B, and C, as well as their analogs (e.g., norhalichondrin A, B, C; homohalichondrin A, B, C; eribulin).

In one aspect, the present invention provides chromium-mediated coupling reactions which can be applied to the synthesis of halichondrins as well as other molecules. In one aspect, the present invention provides a method of preparing a compound of Formula (I):

or a salt thereof, the method comprises coupling a compound of Formula (i):

or a salt thereof, with an aldehyde of Formula (ii):

in the presence of a chromium catalyst and optionally one or more catalysts (e.g., a nickel catalyst and a zirconium catalyst), wherein R1, R2, R3, R4, and R7are as defined herein. The provided coupling method effectively furnishes the coupling a wide range of halo-enone, halo-enone ketal, halo-acetylenic ketone, or halo-acetylenic ketal substrates and an aldehyde. Since a hydroxyl group is generated in the coupling product, an R- or S-isomer can be introduced in the chiral center. In some embodiments, the provided coupling method is a catalytic asymmetric coupling between the compound of Formula (i) and the aldehyde of Formula (ii). The chromium catalyst and one or more catalysts in the coupling can provide efficient asymmetric induction, geometrical isomerization, and coupling rate. In certain embodiments, the coupling reaction is catalyzed by a chromoium complex. In certain embodiments, the coupling reaction is catalyzed by a chromoium complex and one or more catalysts. In certain embodiments, the coupling reaction is catalyzed by a chromoium complex and a zirconium complex. In certain embodiments, the coupling reaction is catalyzed by a chromium complex and a nickel complex. In certain embodiments, the coupling reaction is catalyzed by a combination of a chromoium complex, a nickel complex, and a zirconium complex. In certain embodiments, the coupling reaction is catalyzed by a chromoium complex, wherein the chromoium complex comprises a chiral ligand. In certain embodiments, the coupling reaction is catalyzed by a chromoium complex and one or more catalysts, wherein the chromoium complex comprises a chiral ligand. In certain embodiments, the coupling reaction is catalyzed by a chromoium complex and a zirconium complex, wherein the chromoium complex comprises a chiral ligand. In certain embodiments, the coupling reaction is catalyzed by a chromium complex and a nickel complex, wherein the chromoium complex comprises a chiral ligand. In certain embodiments, the coupling reaction is catalyzed by a combination of a chromoium complex, a nickel complex, and a zirconium complex, wherein the chromoium complex comprises a chiral ligand.

In certain embodiments, the provided coupling method is stereoselective in installing a chiral center having a hydroxyl group. In certain embodiments, the compound of Formula (i) is a halo-enone or halo-enone ketal of Formula (i-a):

or a salt thereof, and the asymmetric coupling product is of Formula (I-a):

or salt thereof. In certain embodiments, the compound of Formula (i) is a halo-acetylenic ketone or halo-acetylenic ketal of Formula (i-b):

or a salt thereof, and the asymmetric coupling product is of Formula (I-b):

or a salt thereof.

In certain embodiments, the provided coupling method is selective for halo-enone, halo-enone ketal, halo-acetylenic enone, and halo-acetylenic ketal, over vinyl halide and a halide attached to a sp3hybridized carbon. A vinyl halide or a halide attached to a sp3hybridized carbon can remain intact during the coupling reaction between a halo-enone, halo-enone ketal, halo-acetylenic enone, or halo-acetylenic ketal, with an aldehyde of Formula (ii). The vinyl halide moiety can be a part of the compound of Formula (i), the aldehyde of Formula (ii), or another compound in the coupling reaction mixture. In certain embodiments, the provided coupling method is selective for halo-enone, halo-enone ketal, halo-acetylenic enone, and halo-acetylenic ketal, over vinyl iodide and chloride or iodide attached to a sp3hybridized carbon. In certain embodiments, the provided coupling method is selective for halo-acetylenic ketone or halo-acetylenic ketal over vinyl iodide or a iodide and chloride attached to a sp3hybridized carbon. The provided coupling methods are applicable to synthesizing the C1-C19 building block of halichondrins and analogs thereof as well as other compounds. The provided coupling methods are also applicable to the preparation of C20-C38 building blocks of halichondrins and analogs thereof. Furthermore, the provided coupling methods are useful in joining C1-C19 building blocks with C20-C38 building blocks, as well as joining the right half and left half of halichondrins and analogs thereof. For examples, see Schemes T1-T4.

or a salt thereof;
and the aldehyde of Formula (ii) is of Formula (ii-a):

or a salt thereof;
and the compound of Formula (I) is of Formula (I-a-3):

In certain embodiments, the compound of Formula (i) is of Formula (i-b-5):

or a salt thereof, and
and the aldehyde of Formula (ii) is of Formula (ii-a):

or a salt thereof, and
the compound of Formula (I) is of Formula (I-b-5):

In another aspect, the present invention provides the synthesis of the C1-C19 building block of halichondrin A:

or a salt thereof, wherein R4a, R1a, and R1dare as defined herein.

In another aspect, the present invention provides the synthesis of the C1-C19 building block of halichondrin B:

or a salt thereof, wherein R4a, R1a, and R1dare as defined herein.

In another aspect, the present invention provides the synthesis of the C1-C19 building block of halichondrin C:

or a salt thereof, wherein R4a, R1a, R1d, and R10are as defined herein.

In certain embodiments, a C20-C38 building block is a compound of Formula (III-11). Provided herein are methods of preparing a compound of Formula (III-11):

In another aspect, the prevent invention provides compounds which are useful intermediates in the preparation of halichondrins and building blocks described herein.

The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments of the Invention, as described below. Other features, objects, and advantages of the invention will be apparent from the Claims.

DEFINITIONS

Chemical Definitions

The term “heteroatom” refers to an atom that is not hydrogen or carbon. In certain embodiments, the heteroatom is nitrogen. In certain embodiments, the heteroatom is oxygen.

In certain embodiments, the heteroatom is sulfur.

The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C1-10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6alkyl”). Examples of C1-6alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents. In certain embodiments, the alkyl group is an unsubstituted C1-10alkyl (e.g., —CH3). In certain embodiments, the alkyl group is a substituted C1-10alkyl.

The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1-8haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1-4haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are replaced with fluoro to provide a perfluoroalkyl group. In some embodiments, all of the haloalkyl hydrogen atoms are replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include —CHF2, —CH2F, —CF3, —CH2CF3, —CF2CF3, —CF2CF2CF3, —CCl3, —CFCl2, —CF2Cl, and the like.

The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-10alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-9alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-8alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-7alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-6alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1-5alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1-4alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-3alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-2alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1-4alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC2-6alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-10alkyl.

may be an (E)- or (Z)-double bond.

The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.

“Aralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.

The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

“Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.

The term “unsaturated bond” refers to a double or triple bond.

The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

The term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.

Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

or two geminal hydrogens on a carbon atom are replaced with the group ═O, ═S, ═NN(Rbb)2, ═NNRbbC(═O)Raa, ═NNRbbC(═O)ORaa, ═NNRbbS(═O)2Raa, ═NRbb, or ═NORcc;

The term “hydroxyl” or “hydroxy” refers to the group —OH. The term “substituted hydroxyl” or “substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from —ORaa, —ON(Rbb)2, —OC(═O)SRaa, —OC(═O)Raa, —OCO2Raa, —OC(═O)N(Rbb)2, —OC(═NRbb)Raa, —OC(═NRbb)ORaa, —OC(═NRbb)N(Rbb)2, —OS(═O)Raa, —OSO2Raa, —OSi(Raa)3, —OP(Rcc)2, —OP(Rcc)3, —OP(═O)2Raa, —OP(═O)(Raa)2, —OP(═O)(ORcc)2, —OP(═O)2N(Rbb)2, and —OP(═O)(NRbb)2, wherein Raa, Rbb, and Rccare as defined herein.

The term “thiol” or “thio” refers to the group —SH. The term “substituted thiol” or “substituted thio,” by extension, refers to a thiol group wherein the sulfur atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from —SRaa, —S═SRcc, —SC(═S)SRaa, —SC(═O)SRaa, —SC(═O)ORaa, and —SC(═O)Raa, wherein Raaand Rccare as defined herein.

The term “amino” refers to the group —NH2. The term “substituted amino,” by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.

The term “monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from —NH(Rbb), —NHC(═O)Raa, —NHCO2Raa, —NHC(═O)N(Rbb)2, —NHC(═NRbb)N(Rbb)2, —NHSO2Raa, —NHP(═O)(ORcc)2, and —NHP(═O)(N(Rbb)2)2, wherein Raa, Rbband Rccare as defined herein, and wherein Rbbof the group —NH(Rbb) is not hydrogen.

The term “disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from —N(Rbb)2, —NRbbC(═O)Raa, —NRbbCO2Raa, —NRbbC(═O)N(Rbb)2, —NRbbC(═NRbb)N(Rbb)2, —NRbbSO2Raa, —NRbbP(═O)(ORcc)2, and —NRbbP(═O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

The term “trisubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from —N(Rbb)3and —N(Rbb)3+X−, wherein Rbband X−are as defined herein.

The term “sulfonyl” refers to a group selected from —SO2N(Rbb)2, —SO2Raa, and —SO2ORaa, wherein Raaand Rbbare as defined herein.

The term “sulfinyl” refers to the group —S(═O)Raa, wherein Raais as defined herein.

The term “carbonyl” refers a group wherein the carbon directly attached to the parent molecule is sp2hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (—C(═O)Raa), carboxylic acids (—CO2H), aldehydes (—CHO), esters (—CO2Raa, —C(═O)SRaa, —C(═S)SRaa), amides (—C(═O)N(Rbb)2, —C(═O)NRbbSO2Raa, —C(═S)N(Rbb)2), and imines (—C(═NRbb)Raa, —C(═NRbb)ORaa), —C(═NRbb)N(Rbb)2), wherein Raaand Rbbare as defined herein.

The term “silyl” refers to the group —Si(Raa)3, wherein Raais as defined herein.

The term “oxo” refers to the group ═O, and the term “thiooxo” refers to the group ═S.

A “hydrocarbon chain” refers to a substituted or unsubstituted divalent alkyl, alkenyl, or alkynyl group. A hydrocarbon chain includes (1) one or more chains of carbon atoms immediately between the two radicals of the hydrocarbon chain; (2) optionally one or more hydrogen atoms on the chain(s) of carbon atoms; and (3) optionally one or more substituents (“non-chain substituents,” which are not hydrogen) on the chain(s) of carbon atoms. A chain of carbon atoms consists of consecutively connected carbon atoms (“chain atoms”) and does not include hydrogen atoms or heteroatoms. However, a non-chain substituent of a hydrocarbon chain may include any atoms, including hydrogen atoms, carbon atoms, and heteroatoms. For example, hydrocarbon chain —CAH(CBH2CCH3)— includes one chain atom CA, one hydrogen atom on CA, and non-chain substituent —(CBH2CCH3). The term “Cxhydrocarbon chain,” wherein x is a positive integer, refers to a hydrocarbon chain that includes x number of chain atom(s) between the two radicals of the hydrocarbon chain. If there is more than one possible value of x, the smallest possible value of x is used for the definition of the hydrocarbon chain. For example, —CH(C2H5)— is a C1hydrocarbon chain, and

is a C3hydrocarbon chain. When a range of values is used, the meaning of the range is as described herein. For example, a C3-10hydrocarbon chain refers to a hydrocarbon chain where the number of chain atoms of the shortest chain of carbon atoms immediately between the two radicals of the hydrocarbon chain is 3, 4, 5, 6, 7, 8, 9, or 10. A hydrocarbon chain may be saturated (e.g., —(CH2)4—). A hydrocarbon chain may also be unsaturated and include one or more C═C and/or C≡C bonds anywhere in the hydrocarbon chain. For instance, —CH═CH—(CH2)2—, —CH2—C≡C—CH2—, and —C≡C—CH═CH— are all examples of a unsubstituted and unsaturated hydrocarbon chain. In certain embodiments, the hydrocarbon chain is unsubstituted (e.g., —C≡C— or —(CH2)4—). In certain embodiments, the hydrocarbon chain is substituted (e.g., —CH(C2H5)— and —CF2—). Any two substituents on the hydrocarbon chain may be joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring. For instance

are all examples of a hydrocarbon chain. In contrast, in certain embodiments,

are not within the scope of the hydrocarbon chains described herein. When a chain atom of a Cxhydrocarbon chain is replaced with a heteroatom, the resulting group is referred to as a Cxhydrocarbon chain wherein a chain atom is replaced with a heteroatom, as opposed to a Cx-1hydrocarbon chain. For example,

is a C3hydrocarbon chain wherein one chain atom is replaced with an oxygen atom.

The term “acyl” refers a group wherein the carbon directly attached to the parent molecule is sp2hybridized, and is substituted with an oxygen, nitrogen, or sulfur atom, e.g., a group selected from ketones (—C(═O)Raa), carboxylic acids (—CO2H), aldehydes (—CHO), esters (—CO2Raa, —C(═O)SRaa, —C(═S)SRaa), amides (—C(═O)N(Rbb)2, —C(═O)NRbbSO2Raa, —C(═S)N(Rbb)2), and imines (—C(═NRbb)Raa, —C(═NRbb)ORaa), —C(═NRbb)N(Rbb)2), wherein Raaand Rbbare as defined herein.

The term “Lewis acid” refers to a species as defined by IUPAC, that is “a molecular entity (and the corresponding chemical species) that is an electron-pair acceptor and therefore able to react with a Lewis base to form a Lewis adduct, by sharing the electron pair furnished by the Lewis base.” Exemplary Lewis acids include, without limitation, boron trifluoride, aluminum trichloride, tin tetrachloride, titanium tetrachloride, and iron tribromide.

The term “tautomers” or “tautomeric” refers to two or more interconvertable compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

As used herein, a “leaving group” (LG) is an art-understood term referring to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. As used herein, a leaving group can be an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., —OC(═O)SRaa, —OC(═O)Raa, —OCO2Raa, —OC(═O)N(Rbb)2, —OC(═NRbb)Raa, —OC(═NRbb)ORaa, —OC(═NRbb)N(Rbb)2, —OS(═O)Raa, —OSO2Raa, —OP(Rcc)2, —OP(Rcc)3, —OP(═O)2Raa, —OP(═O)(Raa)2, —OP(═O)(ORcc)2, —OP(═O)2N(Rbb)2, and —OP(═O)(NRbb)2, wherein Raa, Rbb, and Rccare as defined herein).

As used herein, use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

This Cr-mediated coupling process is a Grignard-type carbonyl addition reaction. It displays selectivity towards aldehydes over other carbonyl compounds. Activation of halides or triflates in the presence of aldehydes provides not only an experimental convenience, but also an opportunity to achieve chemical transformations in an unconventional manner, e.g., cyclization. The most valuable feature of this coupling is its compatibility with a wide range of functional groups. This unique potential is especially important when applied to polyfunctional molecules, especially in the late-stages of a multi-step synthesis. Provided herein are chromium-mediated coupling reactions which are applicable to the preparation of halichondrins (e.g., halichondrin A, B, C; norhalichondrin A, B, C; homohalichondrin A, B, C; eribulin) and intermediates in the synthesis thereof.

In one aspect, the present invention provides a method of preparing a compound of Formula (I):

or a salt thereof,
the method comprising coupling a compound of Formula (i):

or a salt thereof,
with an aldehyde of Formula (ii):

in the presence of a chromium catalyst and optionally one or more catalysts;
wherein

R5is optionally substituted alkyl, or an oxygen protecting group;

R6is optionally substituted alkyl, or an oxygen protecting group;

or R2and R3are taken together to form ═O;

or R5and R6are taken together with the intervening atoms to form an optionally substituted heterocyclic ring;

L is optionally substituted ethenylene or ethynylene.

Since a hydroxyl group is generated in the coupling product of Formula (I), a chiral center can be introduced in the process. In some embodiments, the provided coupling method is a catalytic asymmetric coupling between a compound of Formula (i) and an aldehyde of Formula (ii) to provide a compound of Formula (Ia):

or a salt thereof. In some embodiments, the provided coupling method is a catalytic asymmetric coupling between a compound of Formula (i) and an aldehyde of Formula (ii) to provide a compound of Formula (Ia):

or a salt thereof.

In certain embodiments, the provided coupling reaction between the compound of Formula (i) and the aldehyde of Formula (ii) is selective for halo-enone, halo-enone ketal, halo-acetylenic ketone, or halo-acetylenic ketal, over a halide attached to a sp3hybridized carbon. A vinyl halide or a halide attached to a sp3hybridized carbon can remain intact during the coupling reaction between a halo-enone, halo-enone ketal, halo-acetylenic enone, or halo-acetylenic ketal, with an aldehyde of Formula (ii). The vinyl halide moiety can be a portion of the compound of Formula (i), the aldehyde of Formula (ii), or another compound in the coupling reaction mixture. In certain embodiments, the provided coupling reaction between the compound of Formula (i) and the aldehyde of Formula (ii) is selective for the halo-enone or halo-acetylenic ketal over a halide attached to a sp3hybridized carbon. In certain embodiments, the halide attached to a sp3hybridized carbon is chloride. In certain embodiments, the halide attached to a sp3hybridized carbon is bromide. In certain embodiments, the halide attached to a sp3hybridized carbon is iodide. In certain embodiments, the compound of Formula (i) comprises a halide attached to a sp3hybridized carbon, for example, in R1. In certain embodiments, the step of coupling is performed in the presence of another compound other than the compounds of Formulae (i) and (ii), wherein the another compound comprises a halide attached to a sp3 hybridized carbon.

In certain embodiments, the provided coupling reaction between the compound of Formula (i) and the aldehyde of Formula (ii) is selective for halo-enone, halo-enone ketal, halo-acetylenic ketone, or halo-acetylenic ketal over a vinyl halide. In certain embodiments, the provided coupling reaction between the compound of Formula (i) and the aldehyde of Formula (ii) is selective for the halo-enone or halo-acetylenic ketal over a vinyl halide. In certain embodiments, the compound of Formula (i) comprises a vinyl halide moiety, for example, as part of R1. In certain embodiments, the step of coupling is performed in the presence of another compound other than the compounds of Formulae (i) and (ii), wherein the other compound includes a vinyl halide moiety. In certain embodiments, the vinyl halide moiety is a vinyl iodide moiety. In certain embodiments, the vinyl halide is a vinyl bromide moiety. In certain embodiments, the vinyl halide is a vinyl chloride moiety. In certain embodiments, the vinyl halide moiety is a vinyl iodide moiety in the compound of Formula (i). In certain embodiments, the vinyl halide is a vinyl bromide moiety in the compound of Formula (i). In certain embodiments, the vinyl halide is a vinyl chloride moiety in the compound of Formula (i). In certain embodiments, the vinyl halide moiety is a vinyl iodide moiety in R1of the compound of Formula (i). In certain embodiments, the vinyl halide is a vinyl bromide moiety in R1of the compound of Formula (i). In certain embodiments, the vinyl halide is a vinyl chloride moiety in R1of the compound of Formula (i). In certain embodiments, the vinyl halide moiety is a vinyl iodide moiety in the aldehyde of Formula (ii). In certain embodiments, the vinyl halide is a vinyl bromide moiety in the aldehyde of Formula (ii). In certain embodiments, the vinyl halide is a vinyl chloride moiety in the aldehyde of Formula (ii). In certain embodiments, the vinyl halide moiety is a vinyl iodide moiety in another compound other than the compounds of Formulae (i) and (ii) in the coupling reaction mixture. In certain embodiments, the vinyl halide is a vinyl bromide moiety in another compound other than the compounds of Formulae (i) and (ii) in the coupling reaction mixture. In certain embodiments, the vinyl halide is a vinyl chloride moiety in another compound other than the compounds of Formulae (i) and (ii) in the coupling reaction mixture.

In certain embodiments, R1comprises a halide attached to a sp3hybridized carbon. In certain embodiments, R1comprises a chloride attached to a sp3hybridized carbon. In certain embodiments, R1comprises a bromide attached to a sp3hybridized carbon. In certain embodiments, R1comprises an iodide attached to a sp3hybridized carbon.

In certain embodiments, R1comprises a vinyl halide moiety. In certain embodiments, R1comprises a vinyl iodide moiety. In certain embodiments, R1comprises a vinyl bromide moiety. In certain embodiments, R1comprises a vinyl chloride moiety.

As generally used herein, a vinyl halide is a compound of Formula (VY):

or a salt thereof,
wherein

As generally used herein, a vinyl halide is a vinyl iodide of Formula (VY-1):

or a salt thereof, wherein RVY1, RVY2, and RVY3are as defined herein.

In certain embodiments, R1comprises a vinyl halide moiety and is of Formula (F-1):

wherein

n is an integer between 1 to 10, inclusive.

As generally defined herein, each instance of R1dis independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, at least one instance of R1dis hydrogen. In certain embodiments, each instance of R1dis hydrogen. In certain embodiments, at least one instance of R1dis halogen. In certain embodiments, at least one instance of R1dis iodide. In certain embodiments, at least one instance of R1dis bromide. In certain embodiments, at least one instance of R1dis chloride. In certain embodiments, at least one instance of R1dis optionally substituted alkyl. In certain embodiments, at least one instance of R1dis unsubstituted alkyl. In certain embodiments, at least one instance of R1dis methyl or ethyl. In certain embodiments, at least one instance of R1dis substituted alkyl.

In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6.

In certain embodiments, n is 4, and at least one instance of R1dis halogen. In certain embodiments, n is 4, and one instance of R1dis halogen. In certain embodiments, n is 4, and one instance of R1dis chloride.

As generally defined herein, R2is —OR5, wherein R5is optionally substituted alkyl or an oxygen protecting group. In certain embodiments, R5is optionally substituted alkyl. In certain embodiments, R5is unsubstituted alkyl (e.g. methyl or ethyl). In certain embodiments, R is substituted alkyl. In certain embodiments, R is an oxygen protecting group.

As generally defined herein, R3is —OR6, wherein R6is optionally substituted alkyl or an oxygen protecting group. In certain embodiments, R6is optionally substituted alkyl. In certain embodiments, R6is unsubstituted alkyl (e.g. methyl or ethyl). In certain embodiments, R6is substituted alkyl. In certain embodiments, R6is an oxygen protecting group.

In certain embodiments, R2and R3are taken together to form ═O. In certain embodiments, the compound of Formula (I) is of one of the formulae:

or a salt thereof; and the compound of Formula (i) is of the formula:

or a salt thereof.

In certain embodiments, R2is —OR5; R3is —OR6; and R5and R6are each independently oxygen protecting groups. In certain embodiments, the compound of Formula (I) is of the formula:

or a salt thereof; and the compound of Formula (i) is of the formula:

or a salt thereof.

As generally defined herein, L is optionally substituted ethenylene or ethynylene. In certain embodiments, L is optionally substituted ethenylene. In certain embodiments, L is unsubstituted ethenylene. In certain embodiments, L is substituted ethenylene. In certain embodiments, L is optionally substituted trans-ethenylene. In certain embodiments, L is unsubstituted trans-ethenylene. In certain embodiments, L is substituted trans-ethenylene. In certain embodiments, L is optionally substituted cis-ethenylene. In certain embodiments, L is unsubstituted cis-ethenylene. In certain embodiments, L is substituted cis-ethenylene. In certain embodiments, L is ethynylene.

L being Optionally Substituted Ethenylene

In certain embodiments of the provided coupling method between a compound of Formula (i) and the aldehyde of Formula (ii), the compound of Formula (i) is of Formula (i-a):

or a salt thereof, wherein R1, R2, R3, and R7are as defined herein, and each of R8and R9is independently hydrogen or optionally substituted alkyl.

In certain embodiments of the provided coupling method between a compound of Formula (i) and the aldehyde of Formula (ii), the compound of Formula (i) is of Formula (i-a):

or a salt thereof, wherein R1, R2, R3, and R7are as defined herein, and each of R8and R9is independently hydrogen or optionally substituted alkyl.

In certain embodiments, the coupling step is between a compound of Formula (i-a) and an aldehyde of Formula (ii) to yield a compound of one of the following formulae:

and salts thereof. In certain embodiments, the compound of Formula (I) is of Formula (I-a):

In certain embodiments, the compound of Formula (I) is of Formula (I-a-2):

In certain embodiments, the coupling step is between a compound of Formula (i-a′) and an aldehyde of Formula (ii) to yield a compound of one of the following formulae:

and salts thereof. In certain embodiments, the coupling step is between a compound of Formula (i-a′) and an aldehyde of Formula (ii) to yield a compound of one of the following formulae:

or a salt thereof; and the compound of Formula (I) is of Formula (I-a-1):

or a salt thereof; wherein R1, R7, and R4are as defined herein.

In some embodiments, the coupling product of Formulae (I)-(I-a-1) are stable enough to isolate and characterize. In some embodiments, the coupling product of Formula (I)-(I-a-1) cyclizes to form an optionally substituted furan of Formula (FU-1):

or a salt thereof,
wherein R1and R4are as defined herein; and

In certain embodiments, the step of cyclizing occurs in situ (i.e. in the reaction mixture without isolation). In certain embodiments, the step of cyclizing occurs upon addition of an acid. In certain embodiments, the acid is a Lewis acid. In certain embodiments, the acid is a Brønsted acid. In certain embodiments, the acid is one or more selected from the group consisting of p-toluenesulfonic acid (PTSA), p-toluenesulfonic acid (p-TSA), or camphorsulfonic acid (CSA), pyridinium p-toluenesulfonate (PPTS), or sulfonic acid exchange resin (Amberlyst, Dowex). In certain embodiments, the acid is p-toluenesulfonic acid (p-TSA) or camphorsulfonic acid (CSA).

In certain embodiments, the provided coupling method is applied to synthesis of the C1-C19 building block of hhalichondrins and analogs thereof. In certain embodiments, the provided coupling method is applied to the synthesis of the C1-C19 building block of halichondrin B.

In certain embodiments, the compound of Formula (i-a-1) is of Formula (i-a-3):

or a salt thereof; the aldehyde of Formula (ii) is of Formula (ii-a):

or a salt thereof; and the compound of Formula (I) is of Formula (I-a-3):

or a salt thereof,
wherein

R4band R4care each independently substituted or unsubstituted alkyl, or an oxygen protecting group; or R4band R4care taken with the intervening oxygen atoms to form an optionally substituted heterocyclic ring.

In certain embodiments, R4bis optionally substituted alkyl. In certain embodiments, R4bis unsubstituted alkyl. In certain embodiments, R4bis methyl or ethyl. In certain embodiments, R4bis an oxygen protecting group. In certain embodiments, R4bis a silyl protecting group. In certain embodiments, R4bis a trialkyl silyl protecting group. In certain embodiments, R4bis a t-butyldimethylsilyl protecting group. In certain embodiments, R4bis a trimethylsilyl protecting group. In certain embodiments, R4bis a triethylsilyl protecting group. In certain embodiments, R4bis a t-butyldiphenylsilyl protecting group. In certain embodiments, R4bis a triisopropylsilyl protecting group. In certain embodiments, R4bis a benzylic protecting group. In certain embodiments, R4bis a p-methoxybenzyl protecting group. In certain embodiments, R4bis an acyl protecting group. In certain embodiments, R4bis an acetyl protecting group. In certain embodiments, R4bis a benzoyl protecting group. In certain embodiments, R4bis a p-nitro benzoyl protecting group. In certain embodiments, R4bis a pivaloyl protecting group. In certain embodiments, R4bis a t-butyl carbonate (BOC) protecting group. In certain embodiments, R4bis an acetal protecting group. In certain embodiments, R4bis a tetrahydropyranyl protecting group. In certain embodiments, R4bis an alkoxyalkyl protecting group. In certain embodiments, R4bis an ethoxyethyl protecting group.

In certain embodiments, R4band R4care taken with the intervening oxygen atoms to form an optionally substituted heterocyclic ring. In certain embodiments, R4band R4care taken with the intervening oxygen atoms to form an optionally substituted monocyclic heterocyclic ring. In certain embodiments, R4band R4care taken with the intervening oxygen atoms to form an optionally substituted bicyclic heterocyclic ring. In certain embodiments, R4band R4care taken with the intervening oxygen atoms to form an optionally substituted bicyclic heterocyclic ring of formula:

In certain embodiments, the compound of Formula (ii-a) is of Formula (ii-a-1):

or a salt thereof. In certain embodiments, the compound of Formula (I-a-3) is of the Formula (I-a-3-i):

or a salt thereof.

In certain embodiments, the coupling reaction between the compounds of Formula (i-a-3) and Formula (ii-a) is achieved with high regioselectivity of the bromo-enone over R1aand high stereoselectivity with one or more chiral catalyst ligands (see the Catalystic Condition Section). The compounds of Formulae (I-a-3) and (I-a-3-i) provide an efficient synthesis of the C1-C19 building block of halichodrin B.

In one aspect, provided herein is a method of preparing a compound of Formula (I-a-4):

or a salt thereof, comprising cyclizing a compound of Formula (I-a-5):

or a salt thereof, wherein R1a, R1d, R4a, R4b, and R4care as defined herein; and RPAis optionally substituted alkyl or an oxygen protecting group.

In certain embodiments, the step of cyclizing comprises deprotecting the compound of Formula (I-a-5), i.e., converting R4band R4cto hydrogen.

In certain embodiments, the steps of cyclizing further comprising equilibrating the deprotected compound of Formula (I-a-5) with one or more bases. The equilibrating step isomerizes the C12 chiral center (seeFIG. 15). It is to be understood that any organic and inorgance base is applicable as long as the base does not interfere with any functional groups of the deprotected compound of Formula (I-a-5). In certain embodiments, the base is one or more organic or inorganic bases. In certain embodiments, the base is one organic or inorganic base. In certain embodiments, the base is sodium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or tetramethylguanidine In certain embodiments, the base is a combination of two or more organic or inorganic bases. In certain embodiments, the bases are 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and tetramethylguanidine.

In certain embodiments, the step of cyclizing further comprising contacting the equilibrating reaction mixture with an acid. In certain embodiments, the acid is a Lewis acid. In certain embodiments, the acid is a Brønsted acid. In certain embodiments, the acid is one or more selected from the group consisting of p-toluenesulfonic acid (PTSA), p-toluenesulfonic acid (p-TSA), camphorsulfonic acid (CSA), pyridinium p-toluenesulfonate (PPTS), and sulfonic acid exchange resin (Amberlyst, Dowex). In certain embodiments, the acid is pyridinium p-toluenesulfonate (PPTS).

In certain embodiments, the steps of cyclizing further comprises contacting the equilibration reaction mixture with one or more ion-exchange resins. In certain embodiments, the ion-exchange resins are polymer-bound guanidine and polymer-bound pyridinium p-toluenesulfonate (PPTS).

In certain embodiments, the step of cyclizing further comprising contacting the equilibrating reaction mixture with an acid in an ion-exchange resin device. In certain embodiments, the ion-exchange resin device comprises a first column with basic ion exchange resins and a second column with acidic ion exchange resins. In certain embodiments, the ion-exchange resin device comprises a first column with basic ion exchange resins and a dehydrating reagent (e.g., 4 Å molecular sieves); and a second column with acidic ion exchange resins and a dehydrating reagent (e.g., 4 Å molecular sieves). In certain embodiments, the ion-exchange resin device is as shown inFIG. 2.

In certain embodiments, the provided method of synthesizing the C1-C19 building block of halichodrin B further comprises the step of protecting a compound of Formula (I-a-3):

or a salt thereof, to yield a compound of Formula (I-a-5):

In certain embodiments, R4band R4care taken with the intervening oxygen atoms to form an optionally substituted heterocyclic ring and RPAis an acyl protecting group an acyl protecting group. In certain embodiments, R4band R4care taken with the intervening oxygen atoms to form an optionally substituted monocyclic heterocyclic ring and RPAis an acyl protecting group an acyl protecting group. In certain embodiments, R4band R4care taken with the intervening oxygen atoms to form an optionally substituted bicyclic heterocyclic ring of the formula:

and RPAis an optionally substituted benzoylic protecting group. In certain embodiments, R4band R4care taken with the intervening oxygen atoms to form an optionally substituted bicyclic heterocyclic ring of the formula:

and RPAis an optionally substituted p-NO2-benzoylic protecting group.
L being Ethynylene

In certain embodiments of the provided coupling method between the compound of Formula (i) and the aldehyde of Formula (ii), the compound of Formula (i) is of Formula (i-b):

or a salt thereof, and the compound of Formula (I) is of Formula (I-b):

In certain embodiments, the compound of Formula (i) is of Formula (i-b-1):

or a salt thereof, and the compound of Formula (I) is of Formula (I-b-1)

or a salt thereof, wherein R1, R4, and R7are as defined herein.

In certain embodiments, the compound of Formula (i) is of Formula (i-b-2):

or a salt thereof, and the compound of Formula (I) is of Formula (I-b-2):

or a salt thereof, wherein R1, R4, and R7are as defined herein.

In certain embodiments, the compound of Formula (i) is of Formula (i-b-3):

or a salt thereof, and the compound of Formula (I) is of Formula (I-b-3)

or a salt thereof, wherein R1, R4, and R7are as defined herein.

In certain embodiments, the compound of Formula (i) is of Formula (i-b-4):

or a salt thereof, and the compound of Formula (I) is of Formula (I-b-4):

or a salt thereof, wherein R1, R4, and R7are as defined herein.
Methods for Preparing C1-C19 Building Block of Halichondrins

In certain embodiments, the provided coupling method can be applied to synthesizing the C1-C19 building blocks of halichodrin A, B, and C, and analogs thereof (e.g., norhalichondrin A, B, C; homohalichondrin A, B, C). The synthesis involves formation of an intermediate of Formula (I-b-5). In certain embodiments, the compound of Formula (i) is of Formula (i-b-5):

or a salt thereof, and the aldehyde of Formula (ii) is of Formula (ii-a):

or a salt thereof, and the compound of Formula (I) is of Formula (I-b-5):

In another aspect of the present invention, provided herein is a method of synthesizing the C1-C19 building block of halichodrin C and analogs (e.g., norhalichondrin C, homohalichondrin C). In certain embodiments, provided herein is a method of preparing a compound of Formula (I-b-6):

or a salt thereof, comprising contacting a compound of Formula (I-b-7):

or a salt thereof,
with a Lewis acid and an alcohol, wherein R1a, R1d, R4a, R4b, and R4care as defined herein, and R10is hydrogen, optionally substituted alkyl, or an oxygen protecting group.

As generally defined herein, the Lewis acid is a chemical species that reacts with a Lewis base to form a Lewis adduct. In certain embodiments, the Lewis acid is a metal salt that can accept a pair of electrons. In certain embodiments, the Lewis acid is a metal halide.

In certain embodiments, the Lewis acid is a metal acetate. In certain embodiments, the Lewis acid is a metal triflate. In certain embodiments, the Lewis acid is a transition metal halide. In certain embodiments, the Lewis acid is a transition metal acetate. In certain embodiments, the Lewis acid is a transition metal triflate. In certain embodiments, the Lewis acid is Sc(OTf)3, Ln(OTf)3, Yb(OTf)3, Lu(OTf)3, Hf(OTf)4, CuOTf. In certain embodiments, the Lewis acid is a hafnium(IV) salt. In certain embodiments, the Lewis acid is Hf(OTf)4.

In certain embodiments, the alcohol is an optionally substituted alkyl alcohol. In certain embodiments, the alcohol is an optionally substituted alkenylalkyl alcohol. In certain embodiments, the alcohol is an unsubstituted alkenylalkyl alcohol. In certain embodiments, the alcohol is CH2═CHCH2OH.

In certain embodiments of synthesizing the C1-C19 building block of halichodrin C and analogs, the step of contacting the compound of Formula (I-b-7) with a Lewis acid and an alcohol further comprising the step of deprotecting a compound of Formula (I-b-8):

or a salt thereof, to yield a compound of Formula (I-b-7):

or a salt thereof, wherein R1a, R1d, R4a, R4band R4care as defined herein. In certain embodiments, this step of deprotecting comprises converting the protecting groups at R4band R4cto hydrogen. In certain embodiments, the protecting groups at R4band R4care silyl protecting groups. In certain embodiments, this step of deprotecting is performed in the presence of a source of fluoride. In certain embodiments, the step of deprotecting is performed in the presence of HF.pyridine. In certain embodiments, the step of deprotecting is performed in the presence of HF.pyridine followed by treatment with a base. In certain embodiments, the step of deprotecting is performed in the presence of HF.pyridine followed by treatment with an organic base. In certain embodiments, the step of deprotecting is performed in the presence of HF.pyridine followed by treatment with Et3N.

In certain embodiments of synthesizing the C1-C19 building block of halichodrin C and analogs, the method further comprises the step of deprotecting a compound of Formula (I-b-5):

or a salt thereof, to yield a compound of Formula (I-b-8):

or a salt thereof, wherein R1a, R1d, R4a, R4b, and R4care as defined herein. In certain embodiments, this step of deprotecting comprises converting the ketal of the compound of Formula (I-b-5) to a ketone of the compound of Formula (I-b-8). In certain embodiments, the step of deprotecting is performed in the presence of an acid. In certain embodiments, this step of deprotecting is performed in the presence of a Brønsted acid (i.e., a source of H+).

In another aspect of the present invention, provided herein is a method of synthesizing the C1-C19 building block of halichodrin B and analogs (e.g., norhalichondrin B, homohalichondrin B). In certain embodiments, provided herein is a method of preparing a compound of Formula (I-a-4):

or a salt thereof, comprising the steps of deprotecting a compound of Formula (I-b-10):

or a salt thereof, followed by cyclizing the deprotected compound, wherein R1a, R1d, R4a, and R4bare as defined herein. In certain embodiments, the step of cyclizing comprises contacting the compound of Formula (I-b-10) with an acid. In certain embodiments, the acid in the step of cyclizing is a Lewis acid. In certain embodiments, the acid in the step of cyclizing is a Brønsted acid. In certain embodiments, the acid in the step of cyclizing is an organic acid. In certain embodiments, the acid is one or more selected from the group consisting of p-toluenesulfonic acid (PTSA), p-toluenesulfonic acid (p-TSA), or camphorsulfonic acid (CSA), pyridinium p-toluenesulfonate (PPTS), or sulfonic acid exchange resin (Amberlyst, Dowex). In certain embodiments, the acid is p-toluenesulfonic acid (p-TSA) or camphorsulfonic acid (CSA). In certain embodiments, the acid in the step of cyclizing is pyridinium p-toluenesulfonate (PPTS) or p-toluenesulfonic acid (p-TSA). In certain embodiments, the step of cyclizing comprises contacting the compound of Formula (I-b-10) with an ion-exchange resin. In certain embodiments, the ion-exchange resin is an acidic polymer-bound resin. In certain embodiments, the ion-exchange resin is a polymer-bound PPTS.

In certain embodiments, the step of cyclizing further comprising contacting the equilibrating reaction mixture with an acid in an ion-exchange resin device. In certain embodiments, the ion-exchange resin device comprises a first column with basic ion exchange resins and a second column with acidic ion exchange resins. In certain embodiments, the ion-exchange resin device comprises a first column with basic ion exchange resins and a dehydrating reagent (e.g., 4 Å molecular sieves); and a second column with acidic ion exchange resins and a dehydrating reagent (e.g., 4 Å molecular sieves). In certain embodiments, the ion-exchange resin device is as shown inFIG. 2.

In certain embodiments of synthesizing the C1-C19 building block of halichodrin B and analogs, the method further comprises the step of reducing a compound of Formula (I-b-11):

or a salt thereof, to yield a compound of Formula (I-b-10):

or a salt thereof, wherein R1a, R1d, R4a, and R4bare as defined herein. In certain embodiments, the step of reducing is performed in the presence of a source of hydride. In certain embodiments, the source of hydride is one or more reagents selected from the group of consisting of lithium hydrides, copper hydrides, and boron hydrides. In certain embodiments, the source of hydride is a boron hydride. In certain embodiments, the source of hydride is (Me)4NBH(OAc).

In certain embodiments of synthesizing the C1-C19 building block of halichodrin B and analogs, the method further comprises the step of deprotecting a compound of Formula (I-b-8):

or a salt thereof, to yield a compound of Formula (I-b-11):

or a salt thereof, wherein R1a, R1d, R4a, R4b, and R4care as defined herein. In certain embodiments, the step of deprotecting is to convert the protecting group at R4cto hydrogen. In certain embodiments, the step of deprotecting is to convert the protecting group at R4cto hydrogen, wherein both R4band R4care independently silyl protecting groups. In certain embodiments, this step of deprotecting is performed in the presence of a source of fluoride. In certain embodiments, the step of deprotecting is performed in the presence of HF.pyridine.

In another aspect of the present invention, provided herein is a method of synthesizing the C1-C19 building block of halichodrin B and analogs. In certain embodiments, provided herein is a method of preparing a compound of Formula (I-a-4):

or a salt thereof, comprising the step of deprotecting a compound of Formula (I-b-12):

or a salt thereof; and cyclizing the deprotected compound, wherein R1a, R1d, R4a, R4b, and R4care as defined herein. In certain embodiments, the step of deprotecting is to convert the protecting group at R4cto hydrogen. In certain embodiments, the step of deprotecting is to convert the protecting group at R4cto hydrogen, wherein both R4band R4care independently silyl protecting groups. In certain embodiments, this step of deprotecting is performed in the presence of a source of fluoride. In certain embodiments, the step of deprotecting is performed in the presence of TBAF. In certain embodiments, the step of cyclizing comprises contacting the reduced compound of Formula (I-b-12) with an organic acid. In certain embodiments, the step of cyclizing comprises contacting the compound of Formula (I-b-12) with an acid. In certain embodiments, the acid in the step of cyclizing is a Lewis acid. In certain embodiments, the acid in the step of cyclizing is a Brønsted acid. In certain embodiments, the acid in the step of cyclizing is pyridinium p-toluenesulfonate (PPTS) or p-toluenesulfonic acid (p-TSA). In certain embodiments, the step of cyclizing comprises contacting the compound of Formula (I-b-12) with an ion-exchange resin. In certain embodiments, the ion-exchange resin is an acidic polymer-bound resin. In certain embodiments, the ion-exchange resin is a polymer-bound PPTS.

In certain embodiments, the step of cyclizing further comprising contacting the equilibrating reaction mixture with an acid in an ion-exchange resin device. In certain embodiments, the ion-exchange resin device comprises a first column with basic ion exchange resins and a second column with acidic ion exchange resins. In certain embodiments, the ion-exchange resin device comprises a first column with basic ion exchange resins and a dehydrating reagent (e.g., 4 Å molecular sieves); and a second column with acidic ion exchange resins and a dehydrating reagent (e.g., 4 Å molecular sieves). In certain embodiments, the ion-exchange resin device is as shown inFIG. 2.

In certain embodiments of synthesizing the C1-C19 building block of halichodrin B and analogs, the method further comprises the step of reducing a compound of Formula (I-b-8):

or a salt thereof, to yield a compound of Formula (I-b-12):

or a salt thereof, wherein R1a, R1d, R4a, R4b, and R4care as defined herein. In certain embodiments, the step of reducing is performed in the presence of a source of hydride. In certain embodiments, the source of hydride is one or more selected from the group of consisting of lithium hydrides, copper hydrides, and boron hydrides. In certain embodiments, the soured of hydride is a copper hydride. In certain embodiments, the soured of hydride is 1,2-bis(diphenylphosphino)benzenecopper hydride ((BDP)CuH).

In anther aspect of the present invention, provided herein is a method of synthesizing the C1-C19 building block of halichodrin A and analogs (e.g., norhalichondrin A, homohalichondrin A). In certain embodiments, provided herein is a method of preparing a compound of Formula (I-b-13):

or a salt thereof, comprising cyclizing a compound of Formula (I-b-14):

or a salt thereof, wherein R1a, R1d, R4a, R4b, and 10 are as defined herein, and R11is hydrogen, optionally substituted alkyl, or an oxygen protecting group. In certain embodiments, the step of cyclizing comprises oxidizing the compound of Formula (I-b-14). In certain embodiment, the step of oxidizing is to introduce the C13 hydroxyl group. In certain embodiments, the step of oxidizing is performed in the presence of an organic peroxide (e.g. a compound comprising an O—O bond). In certain embodiments, the step of oxidizing is performed in the presence of dimethyldioxirane (DMDO). In certain embodiments, the step of oxidizing further comprises contacting the oxidized compound of Formula (I-b-14) with an acid. In certain embodiments, the acid is a Lewis acid. In certain embodiments, the acid is a Brønsted acid. In certain embodiments, the acid in the step of cyclizing is an organic acid. In certain embodiments, the acid is one or more selected from the group consisting of p-toluenesulfonic acid (PTSA), p-toluenesulfonic acid (p-TSA), or camphorsulfonic acid (CSA), pyridinium p-toluenesulfonate (PPTS), or sulfonic acid exchange resin (Amberlyst, Dowex). In certain embodiments, the acid is p-toluenesulfonic acid (p-TSA) or camphorsulfonic acid (CSA). In certain embodiments, the acid in the step of cyclizing is pyridinium p-toluenesulfonate (PPTS) or p-toluenesulfonic acid (p-TSA).

In certain embodiments, the step of cyclizing comprises contacting the oxidized compound of Formula (I-b-14) with PPTS. In certain embodiments, the step of cyclizing comprises contacting the oxidized compound of Formula (I-b-14) with an ion-exchange resin. In certain embodiments, the ion-exchange resin is an acidic polymer-bound resin. In certain embodiments, the ion-exchange resin is a polymer-bound PPTS.

In certain embodiments, the step of cyclizing further comprising contacting the equilibrating reaction mixture with an acid in an ion-exchange resin device. In certain embodiments, the ion-exchange resin device comprises a first column with basic ion exchange resins and a second column with acidic ion exchange resins. In certain embodiments, the ion-exchange resin device comprises a first column with basic ion exchange resins and a dehydrating reagent (e.g., 4 A molecular sieves); and a second column with acidic ion exchange resins and a dehydrating reagent (e.g., 4 A molecular sieves). In certain embodiments, the ion-exchange resin device is as shown inFIG. 2.

In certain embodiments of synthesizing the C1-C19 building block of halichodrin A and analogs, the method further comprises the step of deprotecting a compound of Formula (I-b-8):

or a salt thereof,
to give a compound of Formula (I-b-14):

or a salt thereof,
wherein R1a, R1d, R4a, R4b, and 10 are as defined herein. In certain embodiments, the step of deprotecting is to convert the protecting group at R4cto hydrogen. In certain embodiments, the step of deprotecting is to convert the protecting group at R4cto hydrogen, wherein both R4band R4care independently silyl protecting groups. In certain embodiments, this step of deprotecting is performed in the presence of a source of fluoride. In certain embodiments, the step of deprotecting is performed in the presence of HF.pyridine.
Methods for Preparing C20-C38 Building Block of Halicondrins

In certain embodiments, a compound of Formula (TJ-1) is a compound of Formula (III-1). Compounds of Formula (III-1) can be prepared as shown in Scheme A.

Provided herein is a method of preparing a compound of Formula (III-1):

or a salt thereof, the method comprising a step of reducing a compound of Formula (III-2):

or a salt thereof. The step of reducing converts the —CO2RZ5amoiety to an aldehyde moiety. In certain embodiments, the step of reducing is carried out in the presence of a hydride (i.e., H−) source. Any hydride source known in the art may be used in this transformation. Examples of hydride sources include, but are not limited to, lithium aluminum hydride, sodium borohydride, and diisobutylaluminum hydride. In certain embodiments, the hydride source is diisobutylaluminum hydride (DIBAL). The step of reducing may optionally comprise reducing the —CO2RZ5amoiety to an alcohol, followed by oxidation of the resulting alcohol to an aldehyde to yield a compound of Formula (III-1).

As shown in Scheme A, the method of preparing a compound of Formula (III-1) optionally comprises steps of deprotecting and reprotecting the moiety corresponding to —ORP5. The steps of deprotection and reprotection serve to change the group RP5from one protecting group to another. For example, in certain embodiments, the group RP5can be changed from a para-methoxyphenyl (MPM) group to an acyl group via deprotection and reprotection.

In certain embodiments, the method of preparing a C20-C38 building block comprises a step of deprotecting a compound of Formula (III-1), or a salt thereof, to yield a compound of Formula (III-1-a):

or a salt thereof, wherein R of Formula (III-1) is an oxygen protecting group. In certain embodiments, the step of deprotecting comprises reacting a compound of Formula (III-1) in the presence of a reagent for deprotection. For example, in certain embodiments, RP5is a para-methoxyphenyl protecting group (MPM), and the reagent for deprotection is an oxidant. In certain embodiments, RP5is a para-methoxyphenyl protecting group (MPM), and the reagent for deprotection is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). In certain embodiments, RP5is a para-methoxyphenyl protecting group (MPM), and the reagent for deprotection is an oxidant. In certain embodiments, the reagent for deprotection is dimethylboron bromide, magnesium bromide-dimethyl sulfide, ceric ammonium nitrate (CAN), or an acid. The MPM protecting group may also be removed via hydrogenolysis using hydrogen gas.

As described herein, a compound of Formula (III-a) may be reprotected to yield a compound of Formula (III-1). Therefore, in certain embodiments, the method of preparing a C20-C38 building block comprises a step of protecting a compound of Formula (III-1-a), or a salt thereof, to yield a compound of Formula (III-1), or a salt thereof. In certain embodiments, the step of protecting involves acylating the free alcohol (e.g., installing RP5as an acyl protecting group). In certain embodiments, the step of protecting is carried out in the presence of an acylating agent (e.g., an acyl halide or acyl anhydride). In certain embodiments, the step of protecting is carried out in the presence of acetyl chloride or acetyl anhydride (e.g., to install RP5as —C(═O)CH3). In certain embodiments, the step of protecting is carried out in the presence of acetyl anhydride. In certain embodiments, the step of protecting is carried out in the presence of a coupling reagent and/or a base. In certain embodiments, the step of protecting is carried out in the presence of an amine base (e.g., a trialkylamine such as triethylamine or N,N-diisoproylethylamine). In certain embodiments, the step of protecting is carried out in the presence of a pyridine base or coupling reagent. In certain embodiments, the step of coupling is carried out in the presence of pyridine. In certain embodiments, the step of coupling is carried out in the presence of 4-dimethylaminopyridine (DMAP).

In certain embodiments, the method of preparing a C20-C38 buliding block comprises a step of protecting a compound of Formula (III-3):

or a salt thereof, to yield a compound of Formula (III-2):

or a salt thereof. The step of protecting involves protecting the primary and secondary free alcohols of a compound of Formula (III-3) to introduce the groups RZ4aand RP4. The two alcohols may be protected in separate steps or the same step, and may be protected with the same or different protecting groups (e.g., RZ4aand RP4are the same or different). In certain embodiments, the step of protecting is carried out in the presence of a protecting reagent. For example, in certain embodiments, RZ4aand RP4are trialkylsilyl groups, and the step of protecting is carried out in the presence of a trialkylsilyl halide or a trialkylsilyl sulfonate. For example, in certain embodiments, RZ4aand RP4are tert-butyldimethylsilyl (TBS), and the step of protecting is carried out in the presence of tert-butyldimethylsilyl trifluoromethanesulfonate (“TBS-triflate” or “TBSOTf”). The step of protecting may optionally be carried out in the presence of a base.

In certain embodiments, the method of preparing a C20-C38 buliding block comprises a step of deprotecting and cyclizing a compound of Formula (III-4):

or a salt thereof, to yield a compound of Formula (III-3):

or a salt thereof. The step of deprotecting and cyclizing involves deprotecting the two ketals of a compound of Formula (III-4), followed by a cyclization reaction to provide the new six-membered ring of the compound of Formula (III-3). The deprotecting and cyclizing may be done in the same step, or in separate steps, and in either order. In certain embodiments, the step of deprotecting and cyclizing is carried out in the presence of an acid (e.g., Lewis acid, Bronsted acid). In certain embodiments, the step of deprotecting and cyclizing is carried out in the presence of a hydride source. In certain embodiments, the step of deprotecting and cyclizing is carried out in the presence of a trialkylsilyl sulfonate or trialkylsilyl halide. In certain embodiments, the step of deprotecting and cyclizing is carried out in the presence of a trialkylsilane. In certain embodiments, the step of deprotecting and cyclizing is carried out in the presence of triethylsilyl trifluoromethylsulfonate (“TES-triflate” or “TESOTf”). In certain embodiments, the step of deprotecting and cyclizing is carried out in the presence of triethylsilane. In certain embodiments, the step of deprotecting and cyclizing is carried out in the presence of TESOTf and triethylsilane.

In certain embodiments, the method of preparing a C20-C38 building block comprises a step of coupling a compound of Formula (III-5):

or a salt thereof, with a compound of Formula (III-6):

or a salt thereof, in the presence of a chromium catalyst and optionally one or more catalysts, to yield a compound of Formula (III-4):

or a salt thereof. The coupling may be any chromium-mediated coupling reaction known in the art or described herein, and involve any catalysts or reagents known in the art or described herein. In certain embodiments, the chromium catalyst is a chromium complex (i.e., comprising a ligand). In certain embodiments, the chromium catalyst is chromium sulfonamide (see, e.g., Namba K et al.,Org. Lett.,2004, 6(26), 5031-5033; Ueda et al.J. Am. Chem. Soc.2014, 136, 5171-5176). In certain embodiments, the chromium sulfonamide is of Formula (S-1), described herein. In certain embodiments, the chromium sulfonamide is of the following formula:

In certain embodiments, the chromium sulfonamde is formed by contacting a chromium salt (e.g., CrCl2) with a sulfonamide. In certain embodiments, the sulfonamide is of Formula (S-2), as described herein. In certain embodiments, the sulfonamide is of the formula:

In certain embodiments, the step of coupling is carried out in the presence of a nickel catalyst. Any nickel catalyst known in art or described herein may be used. In certain embodiments, the nickel catalyst is a catalyst of Formula (N-1), described herein. In certain embodiments, the nickel catalyst is of the following formula:

In certain embodiments, the nickel catalyst is (Me)6Phen-NiCl2, of the formula:

In certain embodiments, the step of coupling may be carried out in the presence of one or more additional reagents (e.g., salts, bases, metals). In certain embodiments, the step of coupling may be carried out in the presence of one or more additional agents selected from the group consisting of lithium salts (e.g., LiCl), transition metals (e.g., Mn), and zirconium complexes (e.g., Cp2ZrCl2). In certain embodiments, the step of coupling is be carried out in the presence of LiCl, Mn, and Cp2ZrCl2. In certain embodiments, the step of coupling is carried out in the presence of a proton sponge.

In certain embodiments, the method of preparing C20-C38 buliding block comprises a step of reducing a compound of Formula (III-7):

or a salt thereof, to yield a compound of Formula (III-5):

or a salt thereof. The step of reducing is to convert the —CO2RZ5amoiety to an aldehyde moiety. In certain embodiments, the step of reducing is carried out in the presence of a hydride (i.e., H−) source. Any hydride source known in the art may be used in this transformation. Examples of hydride sources include, but are not limited to, lithium aluminum hydride, sodium borohydride, and diisobutylaluminum hydride. In certain embodiments, the hydride source is diisobutylaluminum hydride (DIBAL). The step of reducing may optionally comprise reducing the —CO2RZ5amoiety to an alcohol, followed by oxidation of the alcohol to an aldehyde to yield a compound of Formula (III-5).

The present invention provides methods of preparing C20-C38 building blocks of halichondrins, including compounds of Formula (III-11). Compounds of Formula (III-11) can be coupled with C1-C19 building blocks described herein (e.g., compounds of Formula (TC-1) in order to prepare the macrocyclic right halves of the halichondrins. Compounds of Formula (III-11) may be prepared as shown in Scheme B.

In certain embodiments, the method of preparing a compound of Formula (III-11) comprises a step of protecting a compound of Formula (III-10):

or a salt thereof, to yield a compound of Formula (III-11). The step of protecting serves to protect the free secondary alcohol of a compound of Formula (III-10) and install the group RP5. In certain embodiments, the step of protecting involves acylating the free alcohol (e.g., installing RP5as an acyl protecting group). In certain embodiments, the step of protecting is carried out in the presence of an acylating agent (e.g., an acyl halide or acyl anhydride). In certain embodiments, the step of protecting is carried out in the presence of acetyl chloride or acetyl anhydride (e.g., to install RP5as —C(═O)CH3). In certain embodiments, the step of protecting is carried out in the presence of acetyl anhydride. In certain embodiments, the step of protecting is carried out in the presence of an amine base (e.g., a trialkylamine such as triethylamine or N,N-diisoproylethylamine). In certain embodiments, the step of protecting is carried out in the presence of a pyridine base or coupling reagent. In certain embodiments, the step of coupling is carried out in the presence of pyridine. In certain embodiments, the step of protecting is carried out in the presence of a coupling reagent and/or a base. In certain embodiments, the step of coupling is carried out in the presence of 4-dimethylaminopyridine (DMAP).

In certain embodiments, the method of preparing a C20-C38 building block comprises a step of reducing a compound of Formula (III-9):

or a salt thereof, to yield a compound of Formula (III-10):

or a salt thereof. The step of reducing is to convert the —CO2RZ5amoiety to an aldehyde. In certain embodiments, the step of reducing is carried out in the presence of a hydride (i.e., H−) source. Any hydride source known in the art may be used in this transformation. Examples of hydride sources include, but are not limited to, lithium aluminum hydride, sodium borohydride, and diisobutylaluminum hydride. In certain embodiments, the hydride source is diisobutylaluminum hydride (DIBAL). The step of reducing may optionally comprise reducing the —CO2RZ5amoiety to an alcohol, followed by oxidation of the resulting alcohol to an aldehyde to yield a compound of Formula (III-10).

In certain embodiments, the method of preparing a C20-C38 buliding block comprises a step of ketalizing a compound of Formula (III-8), or a salt thereof, to yield a compound of Formula (III-9), or a salt thereof. For example, in certain embodiments, the method of preparing a C20-C38 building block comprises a step of contacting a compound of Formula (III-8):

or a salt thereof, with a compound of the formula:

or a salt thereof, in the presence of an acid to yield a compound of Formula (III-9):

or a salt thereof. The acid used in this transformation may be a Lewis acid or a Bronsted acid. The acid may be used in a catalytic, stoichiometric, or excess amount. In certain embodiments, the acid is a Bronsted acid. In certain embodiments, the acid is a sulfonic acid. In certain embodiments, the acid is a pyridinium salt. In certain embodiments, the acid is a pyridinium salt of a sulfonic acid. In certain embodiments, the acid is pyridinium p-toluenesulfonate (PPTS). In certain embodiments, the step of ketalizing is carried out in the presence of one or more additional reagents (e.g., ketals). In certain embodiments, the reaction is carried out in the presence of an additional ketal (e.g., 2,2-dimethoxypropane). In certain embodiments, the reaction is carried out in the presence of 2,2-dimethoxypropane.

In certain embodiments, the method of preparing a C20-C38 building block comprises steps of deprotecting and cyclizing a compound of Formula (III-4):

or a salt thereof, to yield a compound of Formula (III-8):

or a salt thereof. The steps of deprotecting and cyclizing may be carried out in separate steps and in either order; or optionally in the same step. In certain embodiments, the deprotecting and cyclizing are carried out in the same step. In certain embodiments, the step of deprotecting and cyclizing is carried out in the presence of an acid (e.g., Lewis acid, Bronsted acid). In certain embodiments, the step of deprotecting and cyclizing is carried out in the presence of a hydride source. In certain embodiments, the step of deprotecting and cyclizing is carried out in the presence of a trialkylsilyl sulfonate or trialkylsilyl halide. In certain embodiments, the step of deprotecting and cyclizing is carried out in the presence of a trialkylsilane. In certain embodiments, the step of deprotecting and cyclizing is carried out in the presence of triethylsilyl trifluoromethylsulfonate (“TES-triflate” or “TESOTf”). In certain embodiments, the step of deprotecting and cyclizing is carried out in the presence of triethylsilane. In certain embodiments, the step of deprotecting and cyclizing is carried out in the presence of TESOTf and triethylsilane.
Catalytic Coupling Reaction Condition

The provided coupling method between the compound of Formula (i) and the aldehyde of Formula (ii) is a catalytic chromium-mediated coupling reaction.

In certain embodiments, the provided coupling method is a catalytic asymmetric Cr-mediated coupling reaction. In certain embodiments, the chromium catalyst is a chromium complex (i.e., comprising a ligand). In certain embodiments, the chromium catalyst is chromium sulfonamide (see, e.g., Namba K et al.,Org. Lett.,2004, 6(26), 5031-5033).

In certain embodiments, the chromium sulfonamide is of Formula (S-1):

wherein

each instance of X2is independently halogen or a solvent;

u is 0 or an integer between 1 and 4, inclusive; and

In certain embodiments, the chromium sulfonamide is of Formula (S-1-a) or (S-1-a′):

In certain embodiments, the chromium sulfonamide is of Formula (S-1-a):

In certain embodiments, the chromium sulfonamide is of Formula (S-1-b):

In certain embodiments, the chromium sulfonamide is of Formula (S-1-c):

In certain embodiments, the chromium sulfonamide is prepared by contacting a chromium salt with a ligand of Formula (S-2):

wherein Rs1, Rs2, Rs3, Rs4, and u are as defined herein.

In certain embodiments, the ligand of Formula (S-2) is of Formula (S-2-a)

In certain embodiments, the ligand of Formula (S-2) is of Formula (S-2-b):

In certain embodiments, the ligand of Formula (S-2) is of Formula (S-2-b-i):

In certain embodiments, the ligand of Formula (S-2) is of Formula (S-2-c):

wherein Rs1, Rs2, Rs3, Rs4, and v are as defined herein.

In certain embodiments, the ligand of Formula (S-2) is of Formula (S-2-c-i):

In certain embodiments, the ligand of Formula (S-2) is of Formula (S-2-c-iii):

In certain embodiments, X2is a halogen. In certain embodiments, X2is Cl. In certain embodiments, X2is Br. In certain embodiments, X2is I. In certain embodiments, X2is a solvent. In certain embodiments, the solvent comprises N, O, and/or S. In certain embodiments, the solvent for generating the chromium sulfonamide is THF. In certain embodiments, the solvent for generating the chromium sulfonamide is pyridine.

In certain embodiments, g is 1. In certain embodiments, g is 2. In certain embodiments, g is 3.

In certain embodiments, u is 0. In certain embodiments, u is 1. In certain embodiments, u is 2. In certain embodiments, u is 3.

In certain embodiments, X1is chloride; X2is pyridine; g is 1 or 2; and u is 1, 2, or 3. In certain embodiments, X1is chloride; X2is pyridine; g is 1; and u is 1, 2, or 3. In certain embodiments, X1is chloride; X2is pyridine; g is 2; and u is 1, 2, or 3.

In certain embodiments, each instance of Rs4is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted alkoxy. In certain embodiments, at least one instance of Rs4is hydrogen. In certain embodiments, at least one instance of Rs4is optionally substituted alkyl. In certain embodiments, one instance of Rs4is optionally substituted alkyl. In certain embodiments, one instance of Rs4is unsubstituted alkyl (e.g., methyl or ethyl). In certain embodiments, two instances of Rs4are optionally substituted alkyl. In certain embodiments, two instances of Rs4are unsubstituted alkyl (e.g., methyl or ethyl). In certain embodiments, at least once instance of of Rs4is optionally substituted alkoxy. In certain embodiments, two instances of Rs4are optionally substituted alkoxy. In certain embodiments, two instances of Rs4are unsubstituted alkoxy (e.g. —OCH3).

In certain embodiments, each instance of Rs5is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, at least one instance of Rs5is hydrogen. In certain embodiments, at least one instance of Rs5is halogen. In certain embodiments, two instances of Rs5are halogen.

In certain embodiments, v is 1. In certain embodiments, v is 2.

In certain embodiments, the ligand of Formula (S-2) is of the following formula:

In certain embodiments, the chromium salt used to prepare the chromimum complex is chromium halide. In certain embodiments, the chromium salt is a chromium (II) salt. In certain embodiments, the chromium salt is CrCl2. In certain embodiments, the chromium salt is CrBr2. In certain embodiments, the chromium salt is a chromium (III) salt. In certain embodiments, the chromium salt is CrCl3. In certain embodiments, the chromium salt is CrBr3.

In certain embodiments, the amount of chromium or chromium complex is catalytic. In certain embodiments, the chromium catalyst is at a concentration of about 1 mol % to about 30 mol % of the compound of Formula (i) or Formula (ii). In certain embodiments, the chromium catalyst is at a concentration of about 1 mol % to about 25 mol % of the compound of Formula (i) or Formula (ii). In certain embodiments, the chromium catalyst is at a concentration of about 1 mol % to about 20 mol % of the compound of Formula (i) or Formula (ii). In certain embodiments, the chromium catalyst is at a concentration of about 1 mol % to about 15 mol % of the compound of Formula (i) or Formula (ii). In certain embodiments, the chromium catalyst is at a concentration of about 5 mol % to about 15 mol % of the compound of Formula (i) or Formula (ii). In certain embodiments, the chromium catalyst is at a concentration of about 10 mol % of the compound of Formula (i) or Formula (ii).

In certain embodiments, the provided coupling method comprises a second catalyst. In certain embodiments, the second catalyst is a transition metal or transition metal complex. In certain embodiments, the second catalyst is a nickel complex.

In certain embodiments, the nickel complex is of Formula (N-1):

wherein

s is an integer between 1 and 3, inclusive; and

t is an integer between 1 and 3, inclusive.

In certain embodiments, the nickel complex of Formula (N-1) is of Formula (N-1-a):

In certain embodiments, the nickel complex of Formula (N-1) is of Formula (N-1-a):

In certain embodiments, the nickel complex of Formula (N-1) is of Formula (N-1-b):

In certain embodiments, the nickel complex of Formula (N-1) is of Formula (N-1-c):

wherein

In certain embodiments, the nickel complex of Formula (N-1) is of one of the following formulae:

In certain embodiments, each instance of Rn1is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted alkoxy. In certain embodiments, at least one instance of Rn1is hydrogen. In certain embodiments, at least one instance of Rn1is optionally substituted alkyl. In certain embodiments, one instance of Rn1is optionally substituted alkyl. In certain embodiments, one instance of Rn1is unsubstituted alkyl (e.g. methyl or ethyl). In certain embodiments, two instances of Rn1are optionally substituted alkyl. In certain embodiments, two instances of Rn1are unsubstituted alkyl (e.g. methyl or ethyl). In certain embodiments, at least one instance of Rn1is optionally substituted. In certain embodiments, two instances of Rn1are optionally substituted alkoxy. In certain embodiments, two instances of Rn1are unsubstituted alkoxy (e.g. —OCH3). In certain embodiments, two instances of Rn1are substituted alkoxy.

In certain embodiments, each instance of Rn2is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted alkoxy. In certain embodiments, at least one instance of Rn2is hydrogen. In certain embodiments, at least one instance of Rn2is optionally substituted alkyl. In certain embodiments, one instance of Rn2is optionally substituted alkyl. In certain embodiments, one instance of Rn2is unsubstituted alkyl (e.g. methyl or ethyl). In certain embodiments, two instances of Rn2are optionally substituted alkyl. In certain embodiments, two instances of Rn2are unsubstituted alkyl (e.g. methyl or ethyl). In certain embodiments, at least one instance of Rn2is optionally substituted. In certain embodiments, two instances of Rn2are optionally substituted alkoxy. In certain embodiments, two instances of Rn2are unsubstituted alkoxy (e.g. —OCH3). In certain embodiments, two instances of Rn2are substituted alkoxy.

In certain embodiments, at least one instance of Rn1and Rn2are the same. In certain embodiments, two instances of Rn1and Rn2are the same.

In certain embodiments, the amount of nickel or nickel complex is catalytic. In certain embodiments, the nickel catalyst is at a concentration of about 0.001 mol % to about 30 mol % of the compound of Formula (i) or Formula (ii). In certain embodiments, the nickel catalyst is at a concentration of about 0.001 mol % to about 20 mol % of the compound of Formula (i) or Formula (ii). In certain embodiments, the nickel catalyst is at a concentration of about 0.001 mol % to about 10 mol % of the compound of Formula (i) or Formula (ii). In certain embodiments, the nickel catalyst is at a concentration of about 0.001 mol % to about 5 mol % of the compound of Formula (i) or Formula (ii). In certain embodiments, the nickel catalyst is at a concentration of about 0.001 mol % to about 1 mol % of the compound of Formula (i) or Formula (ii). In certain embodiments, the nickel catalyst is at a concentration of about 0.01 mol % to about 0.5 mol % of the compound of Formula (i) or Formula (ii). In certain embodiments, the nickel catalyst is at a concentration of about 0.05 mol % to about 0.1 mol % of the compound of Formula (i) or Formula (ii). In certain embodiments, the nickel catalyst is at a concentration of about 0.1 mol % of the compound of Formula (i) or Formula (ii). In certain embodiments, the nickel catalyst is at a concentration of about 0.01 mol % to about 0.05 mol % of the compound of Formula (i) or Formula (ii). In certain embodiments, the nickel catalyst is at a concentration of about 0.05 mol % of the compound of Formula (i) or Formula (ii).

In certain embodiments, the chromium catalyst is at a concentration of about 1 mol % to about 20 mol % of the compound of Formula (i) or Formula (ii) and the nickel catalyst is at a concentration of about 0.01 mol % to about 0.5 mol % of the compound of Formula (i) or Formula (ii). In certain embodiments, the chromium catalyst is at a concentration of about 1 mol % to about 20 mol % of the compound of Formula (i) or Formula (ii) and the nickel catalyst is at a concentration of about 0.01 mol % to about 0.1 mol % of the compound of Formula (i) or Formula (ii). In certain embodiments, the chromium catalyst is at a concentration of about 10 mol % of the compound of Formula (i) or Formula (ii) and the nickel catalyst is at a concentration of about 0.1 mol % of the compound of Formula (i) or Formula (ii). In certain embodiments, the chromium catalyst is at a concentration of about 10 mol % of the compound of Formula (i) or Formula (ii) and the nickel catalyst is at a concentration of about 0.05 mol % of the compound of Formula (i) or Formula (ii).

In certain embodiments, an additional catalyst is present in the step of coupling. In certain embodiments, the additional catalyst is a transition metal or transitional metal complex. In certain embodiments, the additional catalyst is a silyl complex. In certain embodiments, the additional catalyst is TES-Cl. In certain embodiments, the additional catalyst is a zirconium catalyst. In certain embodiments, the zirconium catalyst is a zirconium complex. In certain embodiments, the zirconium catalyst is Zr(Cp)2Cl2.

In certain embodiments, the catalysts in the step of coupling are a chromium catalyst, a nickel complex, and a zirconium catalyst. In certain embodiments, the catalysts in the step of coupling are a chromium catalyst and a zirconium catalyst. In certain embodiments, the zirconium catalyst is a zirconium complex. In certain embodiments, the zirconium catalyst is Zr(Cp)2Cl2.

In certain embodiments, the amount of the additional catalyst is stoichiometric. In certain embodiments, the amount of zirconium complex is stoichiometric. In certain embodiments, the zirconium complex is at a concentration of about 0.1 eq to about 5.0 eq of the compound of Formula (i) or Formula (ii). In certain embodiments, the zirconium complex is at a concentration of about 1.0 eq to about 4.0 eq of the compound of Formula (i) or Formula (ii). In certain embodiments, the zirconium complex is at a concentration of about 1.0 eq to about 3.0 eq of the compound of Formula (i) or Formula (ii). In certain embodiments, the zirconium complex is at a concentration of about 1.0 eq to about 2.0 eq of the compound of Formula (i) or Formula (ii). In certain embodiments, the zirconium complex is at a concentration of about 1.5 eq of the compound of Formula (i) or Formula (ii).

In certain embodiments, the step of coupling is performed in the presence of a reducing agent. The reducing agent can reduce chromium in the catalytic cycle. In certain embodiments, the reducing agent is a transition metal. In certain embodiments, the reducing agent is manganese (Mn).

In certain embodiments, the reducing agent is at a concentration of about 1.0 eq to about 10.0 eq of the compound of Formula (i) or Formula (ii). In certain embodiments, the reducing agent is at a concentration of about 1.0 eq to about 8.0 eq of the compound of Formula (i) or Formula (ii). In certain embodiments, the reducing agent is at a concentration of about 1.0 eq to about 6.0 eq of the compound of Formula (i) or Formula (ii). In certain embodiments, the reducing agent is at a concentration of about 1.0 eq to about 4.0 eq of the compound of Formula (i) or Formula (ii). In certain embodiments, the reducing agent is at a concentration of about 4.0 eq of the compound of Formula (i) or Formula (ii).

In certain embodiments, the step of coupling is performed in the presence of an inorganic salt. In certain embodiments, the inorganic salt is an IA group salt. In certain embodiments, the inorganic salt is LiCl.

In certain embodiments, the inorganic salt is at a concentration of about 1.0 eq to about 10.0 eq of the compound of Formula (i) or Formula (ii). In certain embodiments, the inorganic salt is at a concentration of about 1.0 eq to about 8.0 eq of the compound of Formula (i) or Formula (ii). In certain embodiments, the inorganic salt is at a concentration of about 1.0 eq to about 6.0 eq of the compound of Formula (i) or Formula (ii). In certain embodiments, the inorganic salt is at a concentration of about 1.0 eq to about 4.0 eq of the compound of Formula (i) or Formula (ii). In certain embodiments, the inorganic salt is at a concentration of about 4.0 eq of the compound of Formula (i) or Formula (ii).

In certain embodiments, the provided coupling reaction can be carried out in one or more aprotic solvents. The term “aprotic solvent” means a non-nucleophilic solvent having a boiling point range above ambient temperature, preferably from about 25° C. to about 190° C. at atmospheric pressure. In certain embodiments, the aprotic solvent has a boiling point from about 80° C. to about 160° C. at atmospheric pressure. In certain embodiments, the aprotic solvent has a boiling point from about 80° C. to about 150° C. at atmospheric pressure. Examples of such solvents are CH2Cl2, MeCN, EtCN, toluene, DMF, diglyme, THF, and DMSO. In certain embodiments, the solvent is EtCN.

In certain embodiments, the compound of Formula (i) or Formula (ii) is at the concentration of about 0.05 to about 5.0 M. In certain embodiments, the compound of Formula (i) or Formula (ii) is at the concentration of about 0.05 to about 3.0 M. In certain embodiments, the compound of Formula (i) or Formula (ii) is at the concentration of about 0.05 to about 1.0 M. In certain embodiments, the compound of Formula (i) or Formula (ii) is at the concentration of about 0.1 to about 1.0 M. In certain embodiments, the compound of Formula (i) or Formula (ii) is at the concentration of about 0.1 to about 0.5 M. In certain embodiments, the compound of Formula (i) or Formula (ii) is at the concentration of about 0.4 M.

Synthesis of Halichondrins

In another aspect, provided herein are methods of synthesizing halichondrin A, B, and C, and analogs thereof (e.g., homohalichondrin A, B, C; norhalichondrin A, B, C), from the C1-C19 building blocks and the C20-C38 building blocks of halichondrins provided herein. The synthetic routes presented herein include: (1) synthesis of the macrocyclic core via an asymmetric nickel/chromium-mediated coupling, followed by base-induced furan formation, and macrolactonization (Scheme T1); (2) synthesis of an unsaturated ketone intermediate via nickel/chromium-mediated coupling, followed by Dess-Martin oxidation (Schemes T2-T4); and (3) a selective acid-mediated equilibration of C38-epi-halichondrins (Schemes T2-T4).

In Scheme T1, compounds of Formula (TJ-1) are C20-C38 building blocks, and compounds of Formula (TC-1) are C1-C19 building blocks of halichondrins. These building blocks can be joined via the process shown in Scheme T1 to form right halves of halichondrins (e.g., compounds of Formula (TE-1)). Once the right half of a halichondrin is assembled, the right half can be coupled to a left halves (e.g., compounds of Formulae (TI-1), (TK-1), and (TK-1)) via the processes shown in Schemes T2-T4.

As shown in Schemes T1-T4, the C1-C19 building block of halichondrins and analogs thereof are of Formula (TC-1). In certain embodiments, the compound of Formula (TC-1) is of Formula (I-a-4) or a salt thereof. In certain embodiments, the compound of Formula (TC-1) is of Formula (I-b-6) or a salt thereof. In certain embodiments, the compound of Formula (TC-1) is of Formula (I-b-9) or a salt thereof. In certain embodiments, the compound of Formula (TC-1) is of Formula (I-b-13) or a salt thereof.

In certain embodiments, as shown in Scheme T2, the halichondrins and analogs synthesized from the C1-C19 building blocks and C20-C38 building blocks are of Formula (TI). In certain embodiments, the compound of Formula (TI) is of the formula:

In certain embodiments, the compound of Formula (TI) is of the formula:

In certain embodiments, the compound of Formula (TI) is of the formula:

In certain embodiments, preparation of compounds of Formula (TI) and salts thereof comprises cyclizing an intermediate compound of Formula (TF-1) or a salt thereof (see Scheme T2). In certain embodiments, when a compound of Formula (TF-1) is protected (e.g., with silyl or benzylic protecting groups), the synthetic route comprises a deprotection step prior to cyclization. In certain embodiments, deprotection of a compound of Formula (TF-1) comprises a source of fluoride (e.g., TBAF, HF.pyridine). In certain embodiments, deprotection of a compound of Formula (TF-1) comprises a hydrogenolysis (e.g., a palladium or nickel catalyst and H2) or oxidation (e.g., DDQ) step. In certain embodiments, the cyclization conditions comprise an acid. In certain embodiments, the cyclization conditions comprise a Brønsted acid (i.e., a source of H+). In certain embodiments, the cyclization conditions comprise an organic acid (e.g., PPTS). In certain embodiments, the cyclization conditions provide a compound of Formula (TI) as a single diastereomer. In certain embodiments, the cyclization conditions provide a diastereomeric mixture that is enriched in one of two epimeric C38 ketals. In certain embodiments, the synthetic route comprises an equilibration step to enrich a compound of Formula (TI) in one of two epimeric C38 ketals. In certain embodiments, the equilibration step enriches a compound of Formula (TI) in the (R)-epimer. In certain embodiments, the equilibration step enriches a compound of Formula (TI) in the (R)-epimer in a range of 2:1, 3:1, 4:1, 5:1, or >5:1. In certain embodiments, the equilibration step enriches a compound of Formula (TI) in the (S)-epimer. In certain embodiments, the equilibration step enriches a compound of Formula (TI) in the (S)-epimer in a range of 2:1, 3:1, 4:1, 5:1, 10:1, or >10:1. In certain embodiments, the equilibration step comprises a Lewis acid. In certain embodiments, the equilibration step comprises a silyl Lewis acid (e.g., a silicon tetrahalide or and organosilicon halide or triflate). In certain embodiments, the equilibration step comprises trimethylsilyl triflate. In certain embodiments, the equilibration step comprises a solvent. In certain embodiments, the equilibration step comprises a halogenated (e.g., dichloromethane) or ethereal (e.g., diethylether) solvent.

As described herein, the deprotection, cyclization, and equilibration of a compound of Formula (TF-1) to yield a compound of Formula (TI) can be performed in two steps when particular protecting groups are utilized on the intermediate (TF-1). For example, when RP1, RP2, and RP8are TBS, and RP3, RP7, and RP4are TES, the deprotection, cyclization, and equilibration can be performed in two steps by treating a compound of Formula (TF-1) with a fluoride source, followed by an acid. Any fluoride source known in the art may be used. Examples of fluoride sources include, but are not limited to, HF.pyridine, KF, CsF, AgF, ammonium fluoride, and tetraalkylammonium fluorides. In certain embodiments, the fluoride source is a tetraalkylammonium fluoride (e.g., tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride, benzyltrimethylammonium fluoride). In certain embodiments, the acid is a Bronsted acid. In certain embodiments, the acid is an inorganic acid (e.g., HCl, HF, HBr). In certain embodiments, the acid is an organic acid (e.g., carboxylic acid, sulfinic acid, sulfonic acid, phosphoric acid). In certain embodiments, the acid is a carboxylic acid (e.g., acetic acid, trfluoroacetic acid (TFA), pivalic acid). For example, in certain embodiments wherein RP1, RP2, and RP8are TBS, and RP3, RP7, and RP4are TES, a compound of Formula (TF-1) can be convered to a compound of Formula (TI) by treatment with TBAF and pivalic acid, followed by treatment with PPTS (see, e.g.,FIG. 29).

In certain embodiments, preparation of C38 epi-halichondrin A comprises an acid-mediated equilibration of the C38 ketal stereocenter of halichondrin A. In certain embodiments, preparation of halichondrin A comprises an acid-mediated equilibration of the C38 ketal stereocenter of C38 epi-halichondrin A.

In certain embodiments, preparation of C38 epi-halichondrin B comprises an acid-mediated equilibration of the C38 ketal stereocenter of halichondrin B. In certain embodiments, preparation of halichondrin B comprises an acid-mediated equilibration of the C38 ketal stereocenter of C38 epi-halichondrin B.

In certain embodiments, preparation of C38 epi-halichondrin C comprises an acid-mediated equilibration of the C38 ketal stereocenter of halichondrin C. In certain embodiments, preparation of halichondrin C comprises an acid-mediated equilibration of the C38 ketal stereocenter of C38 epi-halichondrin C.

In certain embodiments, as shown in Scheme T3, the halichondrins and analogs synthesized from the C1-C19 building blocks and C20-C38 building blocks are of Formula (TII). In certain embodiments, the compound of Formula (TII) is of one of the following formulae:

In certain embodiments, preparation of compounds of Formula (TII) and salts thereof comprises cyclizing an intermediate compound of Formula (TG-1) or a salt thereof (see Scheme T3). In certain embodiments, when a compound of Formula (TG-1) is protected (e.g., with silyl or benzylic protecting groups), the synthetic route comprises a deprotection step prior to cyclization. In certain embodiments, deprotection of a compound of Formula (TG-1) comprises a source of fluoride (e.g., TBAF, HF.pyridine). In certain embodiments, deprotection of a compound of Formula (TG-1) comprises a hydrogenolysis (e.g., a palladium or nickel catalyst and H2) or oxidation (e.g., DDQ) step. In certain embodiments, the cyclization conditions comprise an acid. In certain embodiments, the cyclization conditions comprise a Brønsted acid (i.e., a source of H+). In certain embodiments, the cyclization conditions comprise an organic acid (e.g., PPTS). In certain embodiments, the cyclization conditions provide a compound of Formula (TII) as a single diastereomer. In certain embodiments, the cyclization conditions provide a diastereomeric mixture that is enriched in one of two epimeric C38 ketals. In certain embodiments, the synthetic route comprises an equilibration step to enrich a compound of Formula (TII) in one of two epimeric C38 ketals. In certain embodiments, the equilibration step enriches a compound of Formula (TII) in the (R)-epimer. In certain embodiments, the equilibration step enriches a aldehyde of Formula (ii) in the (R)-epimer in a range of 2:1, 3:1, 4:1, 5:1, or >5:1. In certain embodiments, the equilibration step enriches a aldehyde of Formula (ii) in the (S)-epimer. In certain embodiments, the equilibration step enriches a aldehyde of Formula (ii) in the (S)-epimer in a range of 2:1, 3:1, 4:1, 5:1, 10:1, or >10:1. In certain embodiments, the equilibration step comprises a Lewis acid. In certain embodiments, the equilibration step comprises a silyl Lewis acid (e.g., a silicon tetrahalide or and organosilicon halide or triflate). In certain embodiments, the equilibration step comprises trimethylsilyl triflate. In certain embodiments, the equilibration step comprises a solvent. In certain embodiments, the equilibration step comprises a halogenated (e.g., dichloromethane) or ethereal (e.g., diethylether) solvent. In certain embodiments, when RT7is not hydrogen, the synthetic route comprises a hydrolysis step comprising a base (e.g., lithium, sodium, or potassium hydroxide).

As described herein, the deprotection, cyclization, and equilibration of a compound of Formula (TG-1) to yield a compound of Formula (TII) can be performed in two synthetic steps when particular protecting groups are utilized for the intermediate (TG-1). For example, when RP10is TBS, and RP8and RP9are TES, the deprotection, cyclization, and equilibration can be performed in two steps by treating a compound of Formula (TG-1) with a fluoride source, followed by an acid. Any fluoride source known in the art may be used. Examples of fluoride sources include, but are not limited to, HF.pyridine, KF, CsF, AgF, ammonium fluoride, and tetraalkylammonium fluorides. In certain embodiments, the fluoride source is a tetraalkylammonium fluoride (e.g., tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride, benzyltrimethylammonium fluoride). In certain embodiments, the acid is a Bronsted acid. In certain embodiments, the acid is an inorganic acid (e.g., HCl, HF, HBr). In certain embodiments, the acid is an organic acid (e.g., carboxylic acid, sulfinic acid, sulfonic acid, phosphoric acid). In certain embodiments, the acid is a carboxylic acid (e.g., acetic acid, trfluoroacetic acid (TFA), pivalic acid). For example, in certain embodiments wherein RP10is TBS, and RP8and RP9are TES, a compound of Formula (TG-1) can be convered to a compound of Formula (TII) by treatment with TBAF and pivalic acid, followed by treatment with PPTS (see, e.g.,FIG. 29).

In certain embodiments, preparation of a compound of Formula (TG-1) or salt thereof comprises joining an intermediate compound of Formula (TE-1) or salt thereof and an intermediate of Formula (TK-1) or salt thereof (see Scheme T3). In certain embodiments, when RTZ4is —CH2ORTZ4aand RTZ4ais a protecting group, the synthetic route comprises a deprotection step. In certain embodiments, when RTZ4ais a silyl protecting group (e.g., t-butyldimethylsilyl), selective deprotection of RTZ4acomprises a mild source of fluoride (e.g., TBAF, HF.pyridine). In certain embodiments, when RTZ4is —CH2OH, the synthetic route comprises an oxidation step. In certain embodiments, RTZ4is oxidized into an aldehyde (—CHO) under mild and selective conditions (e.g., Dess-Martin periodinane, SO3.pyridine, or Swern oxidation). Compounds of Formula (TE-1) are joined with a compound of Formula (TK-1) under reductive coupling conditions. In certain embodiments, the conditions used to join a compound of Formula (TE-1) with a compound of Formula (TK-1) comprise a transition metal (e.g., nickel or chromium). In certain embodiments, the coupling reaction is catalytic in transition metal (e.g., 2-40 mol %). In certain embodiments, the coupling reaction is stoichiometric in transition metal (e.g., 1-3 equivalents). In certain embodiments, the coupling comprises a ligand or ligated transition metal complex. The reaction used to join a compound of Formula (TE-1) and Formula (TK-1) provides an intermediate hydroxy group that must be oxidized to provide a compound of Formula (TG-1). In certain embodiments, the oxidation is carried out under mild and selective conditions (e.g., Dess-Martin periodinane, SO3.pyridine, or Swern oxidation).

In certain embodiments, as shown in Scheme T4, the halichondrins and analogs synthesized from the C1-C19 building blocks and C20-C38 building blocks are of Formula (TIII). In certain embodiments, the compound of Formula (TIII) is of one of the following formulae:

In certain embodiments, preparation of compounds of Formula (TIII) and salts thereof comprises cyclizing an intermediate compound of Formula (TH-1) or a salt thereof (see Scheme T4). In certain embodiments, when a compound of Formula (TH-1) is protected (e.g., with silyl or benzylic protecting groups), the synthetic route comprises a deprotection step prior to cyclization. In certain embodiments, deprotection of a compound of Formula (TG-1) comprises a source of fluoride (e.g., TBAF, HF.pyridine). In certain embodiments, deprotection of a compound of Formula (TH-1) comprises a hydrogenolysis (e.g., a palladium or nickel catalyst and H2) or oxidation (e.g., DDQ) step. In certain embodiments, the cyclization conditions comprise an acid. In certain embodiments, the cyclization conditions comprise a Brønsted acid (i.e., a source of H+). In certain embodiments, the cyclization conditions comprise an organic acid (e.g., PPTS). In certain embodiments, the cyclization conditions provide a compound of Formula (TIII) as a single diastereomer. In certain embodiments, the cyclization conditions provide a diastereomeric mixture that is enriched in one of two epimeric C38 ketals. In certain embodiments, the synthetic route comprises an equilibration step to enrich a compound of Formula (TIII) in one of two epimeric C38 ketals. In certain embodiments, the equilibration step enriches a compound of Formula (TIII) in the (R)-epimer. In certain embodiments, the equilibration step enriches a compound of Formula (TIII) in the (R)-epimer in a range of 2:1, 3:1, 4:1, 5:1, or >5:1. In certain embodiments, the equilibration step enriches a compound of Formula (TIII) in the (S)-epimer. In certain embodiments, the equilibration step enriches a compound of Formula (TIII) in the (S)-epimer in a range of 2:1, 3:1, 4:1, 5:1, 10:1, or >10:1. In certain embodiments, the equilibration step comprises a Lewis acid. In certain embodiments, the equilibration step comprises a silyl Lewis acid (e.g., a silicon tetrahalide or and organosilicon halide or triflate). In certain embodiments, the equilibration step comprises trimethylsilyl triflate. In certain embodiments, the equilibration step comprises a solvent. In certain embodiments, the equilibration step comprises a halogenated (e.g., dichloromethane) or ethereal (e.g., diethylether) solvent.

In certain embodiments, preparation of a compound of Formula (TH-1) or a salt thereof comprises joining an intermediate compound of Formula (TE-1) or a salt thereof and an intermediate of Formula (TL-1) or a salt thereof. In certain embodiments, when RTZ4is —CH2ORTZ4aand RTZ4ais a protecting group, the synthetic route comprises a deprotection step. In certain embodiments, when RTZ4ais a silyl protecting group (e.g., t-butyldimethylsilyl), selective deprotection of RTZ4acomprises a mild source of fluoride (e.g., TBAF, HF.pyridine). In certain embodiments, when RTZ4is —CH2OH, the synthetic route comprises an oxidation step. In certain embodiments, RTZ4is oxidized into an aldehyde (—CHO) under mild and selective conditions (e.g., Dess-Martin periodinane, SO3.pyridine, or Swern oxidation). Compounds of Formula (TE-1) are joined with a compound of Formula (TL-1) under reductive coupling conditions. In certain embodiments, the conditions used to join a compound of Formula (TE-1) with a compound of Formula (TL-1) comprise a transition metal (e.g., nickel or chromium). In certain embodiments, the coupling reaction is catalytic in transition metal (e.g., 2-40 mol %). In certain embodiments, the coupling reaction is stoichiometric in transition metal (e.g., 1-3 equivalents). In certain embodiments, the coupling comprises a ligand or ligated transition metal complex. The reaction used to join a compound of Formula (TE-1) and Formula (TL-1) provides an intermediate hydroxy group that must be oxidized to provide a compound of Formula (TH-1). In certain embodiments, the oxidation is carried out under mild and selective conditions (e.g., Dess-Martin periodinane, SO3.pyridine, or Swern oxidation).

In certain embodiments, R is hydrogen. In certain embodiments, R is substituted or unsubstituted alkyl. In certain embodiments, R is substituted or unsubstituted C1-6alkyl. In certain embodiments, RP8is substituted or unsubstituted, branched C1-6alkyl. In certain embodiments, RP8is unsubstituted C1-6alkyl. In certain embodiments, RP8is methyl. In certain embodiments, RP8is ethyl. In certain embodiments, RP8is propyl. In certain embodiments, RP8is iso-propyl. In certain embodiments, RP8is t-butyl. In certain embodiments, R is an oxygen protecting group. In certain embodiments, R is a silyl protecting group. In certain embodiments, R is a trialkyl silyl protecting group. In certain embodiments, R is a t-butyldimethylsilyl protecting group. In certain embodiments, R is a trimethylsilyl protecting group. In certain embodiments, R is a triethylsilyl protecting group. In certain embodiments, RP8is a t-butyldiphenylsilyl protecting group. In certain embodiments, RP8is a triisopropylsilyl protecting group. In certain embodiments, RP8is a benzylic protecting group. In certain embodiments, RP8is a p-methoxybenzyl protecting group. In certain embodiments, RP8is an acyl protecting group. In certain embodiments, RP8is an acetyl protecting group. In certain embodiments, R is a benzoyl protecting group. In certain embodiments, R is a p-nitro benzoyl protecting group. In certain embodiments, RP8is a pivaloyl protecting group. In certain embodiments, R is a t-butyl carbonate (BOC) protecting group. In certain embodiments, R is an acetal protecting group. In certain embodiments, RP8is a tetrahydropyranyl protecting group. In certain embodiments, RP8is an alkoxyalkyl protecting group. In certain embodiments, RP8is an ethoxyethyl protecting group.

In certain embodiments, RT1is hydrogen. In certain embodiments, RT1is halogen (e.g., —F, —Cl, —Br, or —I). In certain embodiments, RT1is fluorine. In certain embodiments, RT1is chlorine. In certain embodiments, RT1is substituted or unsubstituted alkyl. In certain embodiments, RT1is substituted or unsubstituted C1-6alkyl. In certain embodiments, RT1is substituted or unsubstituted, branched C1-6alkyl. In certain embodiments, RT1is unsubstituted C1-6alkyl. In certain embodiments, RT1is methyl. In certain embodiments, RT1is methyl; and the carbon to which the methyl group is attached is in the (S)-configuration. In certain embodiments, R1is methyl; and the carbon to which the methyl group is attached is in the (R)-configuration. In certain embodiments, RT1is ethyl. In certain embodiments, RT1is propyl. In certain embodiments, RT1is iso-propyl. In certain embodiments, RT1is butyl. In certain embodiments, RT1is t-butyl.

In certain embodiments, the stereochemical configuration of the carbon atom to which RT1is attached is (S). In certain embodiments, the stereochemical configuration of the carbon atom to which RT1is attached is (R).

In certain embodiments, RT2is hydrogen. In certain embodiments, RT2is halogen (e.g., —F, —Cl, —Br, or —I). In certain embodiments, RT2is fluorine. In certain embodiments, RT2is chlorine. In certain embodiments, RT2is substituted or unsubstituted alkyl. In certain embodiments, RT2is substituted or unsubstituted C1-6alkyl. In certain embodiments, RT2is substituted or unsubstituted, branched C1-6alkyl. In certain embodiments, RT2is unsubstituted C1-6alkyl. In certain embodiments, RT2is methyl. In certain embodiments, RT2is methyl; and the carbon to which the methyl group is attached is in the (S)-configuration. In certain embodiments, RT2is methyl; and the carbon to which the methyl group is attached is in the (R)-configuration. In certain embodiments, RT2is ethyl. In certain embodiments, RT2is propyl. In certain embodiments, RT2is iso-propyl. In certain embodiments, RT2is butyl. In certain embodiments, RT2is t-butyl.

In certain embodiments, the stereochemical configuration of the carbon atom to which RT2is attached is (S). In certain embodiments, the stereochemical configuration of the carbon atom to which RT2is attached is (R).

In certain embodiments, RT3is hydrogen. In certain embodiments, RT3is halogen (e.g., —F, —Cl, —Br, or —I). In certain embodiments, RT3is fluorine. In certain embodiments, RT3is chlorine. In certain embodiments, RT3is substituted or unsubstituted alkyl. In certain embodiments, RT3is substituted or unsubstituted C1-6alkyl. In certain embodiments, RT3is substituted or unsubstituted, branched C1-6alkyl. In certain embodiments, RT3is unsubstituted C1-6alkyl. In certain embodiments, RT3is methyl. In certain embodiments, RT3is methyl; and the carbon to which the methyl group is attached is in the (S)-configuration. In certain embodiments, RT3is methyl; and the carbon to which the methyl group is attached is in the (R)-configuration. In certain embodiments, RT3is ethyl. In certain embodiments, R3is propyl. In certain embodiments, RT3is iso-propyl. In certain embodiments, RT3is butyl. In certain embodiments, RT3is t-butyl.

In certain embodiments, the stereochemical configuration of the carbon atom to which RT3is attached is (S). In certain embodiments, the stereochemical configuration of the carbon atom to which RT3is attached is (R).

In certain embodiments, RT5is hydrogen. In certain embodiments, RT5is halogen (e.g., —F, —Cl, —Br, or —I). In certain embodiments, RT5is fluorine. In certain embodiments, RT5is chlorine. In certain embodiments, RT5is substituted or unsubstituted alkyl. In certain embodiments, RT5is substituted or unsubstituted C1-6alkyl. In certain embodiments, RT5is substituted or unsubstituted, branched C1-6alkyl. In certain embodiments, RT5is unsubstituted C1-6alkyl. In certain embodiments, RT5is methyl. In certain embodiments, RT5is methyl; and the carbon to which the methyl group is attached is in the (S)-configuration. In certain embodiments, RT5is methyl; and the carbon to which the methyl group is attached is in the (R)-configuration. In certain embodiments, RT5is ethyl. In certain embodiments, RT5is propyl. In certain embodiments, RT5is iso-propyl. In certain embodiments, RT5is butyl. In certain embodiments, RT5is t-butyl.

In certain embodiments, the stereochemical configuration of the carbon atom to which RT5is attached is (S). In certain embodiments, the stereochemical configuration of the carbon atom to which RT5is attached is (R).

In certain embodiments, all of RT1, RT2, RT3, and RT5are independently substituted or unsubstituted alkyl. In certain embodiments, all of RT1, RT2, RT3, and RT5are independently substituted or unsubstituted C1-6alkyl. In certain embodiments, all of RT1, RT2, RT3, and RT5are independently substituted or unsubstituted, branched C1-6alkyl. In certain embodiments, all of RT1, RT2, RT3, and RT5are independently unsubstituted C1-6alkyl. In certain embodiments, all of RT1, RT2, RT3, and RT5are methyl. In certain embodiments, the stereochemical configuration of the carbon atom to which each of RT1, RT2, and RT3is attached is (S); and the stereochemical configuration of the carbon atom to which RT5is attached is (R). In certain embodiments, the stereochemical configuration of the carbon atom to which each of RT1, RT2, and RT3is attached is (S); the stereochemical configuration of the carbon atom to which RT5is attached is (R); and all of RT1, RT2, RT3, and RT5are methyl.

As generally described herein, RT4and RT6are each independently hydrogen, halogen, or substituted or unsubstituted alkyl, or two RT4groups can be taken together to form a

group. In certain embodiments, at least one RT4is hydrogen. In certain embodiments, both of RT4are hydrogen. In certain embodiments, at least one RT4is halogen (e.g., —F, —Cl, —Br, or —I). In certain embodiments, at least one RT4is fluorine. In certain embodiments, at least one RT4is chlorine. In certain embodiments, at least one RT4is substituted or unsubstituted alkyl. In certain embodiments, at least one RT4is substituted or unsubstituted C1-6alkyl. In certain embodiments, at least one RT4is substituted or unsubstituted, branched C1-6alkyl. In certain embodiments, at least one RT4is unsubstituted C1-6alkyl. In certain embodiments, at least one RT4is methyl. In certain embodiments, at least one RT4is methyl; and the carbon to which the methyl group is attached is in the (S)-configuration. In certain embodiments, at least one RT4is methyl; and the carbon to which the methyl group is attached is in the (R)-configuration. In certain embodiments, both of RT4are methyl. In certain embodiments, at least one RT4is ethyl. In certain embodiments, at least one RT4is propyl. In certain embodiments, at least one RT4is butyl. In certain embodiments, at least one RT4is t-butyl. In certain embodiments, the stereochemical configuration of the carbon atom to which RT4is attached is (S). In certain embodiments, the stereochemical configuration of the carbon atom to which RT4is attached is (R). In certain embodiments, two RT4groups are taken together to form a

In certain embodiments, at least one RT6is hydrogen. In certain embodiments, both of RT6are hydrogen. In certain embodiments, at least one RT6is halogen (e.g., —F, —Cl, —Br, or —I). In certain embodiments, at least one RT6is fluorine. In certain embodiments, at least one RT6is chlorine. In certain embodiments, at least one RT6is substituted or unsubstituted alkyl. In certain embodiments, at least one RT6is substituted or unsubstituted C1-6alkyl. In certain embodiments, at least one RT6is substituted or unsubstituted, branched C1-6alkyl. In certain embodiments, at least one RT6is unsubstituted C1-6alkyl. In certain embodiments, at least one RT6is methyl. In certain embodiments, at least one RT6is methyl; and the carbon to which the methyl group is attached is in the (S)-configuration. In certain embodiments, at least one RT6is methyl; and the carbon to which the methyl group is attached is in the (R)-configuration. In certain embodiments, both of RT6are methyl. In certain embodiments, at least one RT6is ethyl. In certain embodiments, at least one RT6is propyl. In certain embodiments, at least one RT6is butyl. In certain embodiments, at least one RT6is t-butyl. In certain embodiments, the stereochemical configuration of the carbon atom to which RT6is attached is (S). In certain embodiments, the stereochemical configuration of the carbon atom to which RT6is attached is (R). In certain embodiments, two RT6groups are taken together to form a

In certain embodiments, two RT4groups are taken together to form a

group; and two RT6groups are taken together to form a

As generally described herein, RTXis hydrogen or —ORTX1, wherein RTX1is hydrogen, substituted or unsubstituted alkyl, or an oxygen protecting group; RTYis hydrogen or —ORTY1, wherein RTY1is hydrogen, substituted or unsubstituted alkyl, or an oxygen protecting group; and RTXand RTYcan be taken with their intervening atoms to form a substituted or unsubstituted heterocyclic ring.

In certain embodiments, the stereochemical configuration of the carbon atom to which RTXis attached is (S). In certain embodiments, the stereochemical configuration of the carbon atom to which RTXis attached is (R).

In certain embodiments, the stereochemical configuration of RTYis (S). In certain embodiments, the stereochemical configuration of RTYis (R).

In certain embodiments, RTXis hydrogen. In certain embodiments, RTXis —ORTX1. In certain embodiments, RTYis hydrogen. In certain embodiments, RTYis —ORTY1. In certain embodiments, RTXand RTYare hydrogen. In certain embodiments, one of RTXand RTYis hydrogen. In certain embodiments, RTXis hydrogen, and RTYis —ORTY1. In certain embodiments, RTYis hydrogen, and RTXis —ORTX1. In certain embodiments, each of RTXis —ORTX1; and RTYis —ORTY1. In certain embodiments, RTXis —ORTX1; RTYis —ORTY1; and RTX1and RTX1are taken together with the intervening atoms to form an optionally substituted heterocyclic ring. In certain embodiments, RTXis —ORTX1; RTYis —ORTY; and RTX1and RTX1are taken together with the intervening atoms to form an optionally substituted dioxane.

In certain embodiments, the stereochemical configuration of the carbon atom to which RTXis attached is (S). In certain embodiments, the stereochemical configuration of the carbon atom to which RTXis attached is (R). In certain embodiments, the stereochemical configuration of the carbon atom to which RTYis attached is (S). In certain embodiments, the stereochemical configuration of the carbon atom to which RTYis attached is (R).

In certain embodiments, the stereochemical configuration of the carbon atom to which RTXis attached is (S); and the stereochemical configuration of the carbon atom to which RTYis attached is (S). In certain embodiments, the stereochemical configuration of the carbon atom to which RTXis attached is (R); and the stereochemical configuration of the carbon atom to which RTYis attached is (R). In certain embodiments, the stereochemical configuration of the carbon atom to which RTXis attached is (S); and the stereochemical configuration of the carbon atom to which RTYis attached is (R). In certain embodiments, the stereochemical configuration of the carbon atom to which RTXis attached is (R); and the stereochemical configuration of the carbon atom to which RTYis attached is (S).

In certain embodiments, RTXand RTYare taken with their intervening atoms to form a substituted or unsubstituted heterocyclic ring. In certain embodiments, RTXand RTYform a substituted or unsubstituted, 5-membered heterocyclic ring. In certain embodiments, RXand RTYform a substituted or unsubstituted, 6-membered heterocyclic ring. In certain embodiments, RTXand RTYform a substituted or unsubstituted dioxolane. In certain embodiments, RTXand RTYform a mono-substituted dioxolane. In certain embodiments, RTXand RTYform a dioxolane substituted with one instance of a substituted or unsubstituted phenyl ring. In certain embodiments, RTXand RTYform a dioxolane substituted with one instance of a mono-substituted phenyl ring. In certain embodiments, RTXand RTYform a substituted or unsubstituted dioxane.

Group RA

As generally defined herein, each instance of RAis independently hydrogen, optionally substituted alkyl, or an oxygen protecting group; or optionally two RAare joined to thether with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, at least one of RAis optionally substituted alkyl. In certain embodiments, at least one of RAis an oxygen protecting group. In certain embodiments, two RAare joined together to form optionally substituted heterocyclyl. In certain embodiments, two RAare joined together to form optionally substituted 5-to-6 membered heterocyclyl. In certain embodiments, two RAare joined together to form optionally substituted 6-membered heterocyclyl. In certain embodiments, two RAare joined together to form substituted 6-membered heterocyclyl. In certain embodiments, two RAare joined together to form the following structure:

Group RB

As generally defined herein, each instance of RBis independently hydrogen or optionally substituted alkyl. In certain embodiments, at least one instance of RBis optionally substituted alkyl. In certain embodiments, at least one instance of RBis optionally substituted alkyl. In certain embodiments, at least one instance of RBis optionally substituted C1-6alkyl. In certain embodiments, at least one instance of RBis optionally substituted C1-3alkyl. In certain embodiments, at least one instance of RBis unsubstituted C1-3alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl). In certain embodiments, at least one instance of RBis methyl. In certain embodiments, both RBare methyl.

Group RB

As generally defined herein, each instance of RBis independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, at least one instance of RBis optionally substituted alkyl. In certain embodiments, at least one instance of RBis optionally substituted alkyl. In certain embodiments, at least one instance of RBis optionally substituted C1-6alkyl. In certain embodiments, at least one instance of RBis optionally substituted C1-3alkyl. In certain embodiments, at least one instance of RBis unsubstituted C1-3alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl). In certain embodiments, at least one instance of RBis methyl. In certain embodiments, both RBare methyl.

Group RPC

Group RPC

Group RPC

As generally defined herein, X3is a halogen (e.g., —F, —Cl, —Br, or —I) or a leaving group. In certain embodiments, X3is a fluorine. In certain embodiments, X3is a chlorine. In certain embodiments, X3is a bromine. In certain embodiments, X3is an iodine. I certain embodiments, X3is a leaving group.

Compounds

In another aspect, provided herein are intermediates in the synthesis of halichondrins A, B, and C, and analogs thereof. In another aspect, provided herein are compounds of Formula (I-b-6):

In another aspect, provided herein are compounds of Formula (I-b-7):

In another aspect, provided herein are compounds of Formula (I-b-12):

In another aspect, provided herein are compounds of Formula (III-2):

In another aspect, provided herein are compounds of Formula (III-3):

In another aspect, provided herein are compounds of Formula (III-4):

In another aspect, provided herein are compounds of Formula (III-5):

In another aspect, provided herein are compounds of Formula (III-8):

In another aspect, provided herein are compounds of Formula (III-9):

In another aspect, provided herein are compounds of Formula (III-10):

In another aspect, provided herein are compounds of Formula (III-11):

In another aspect, provided herein are compounds of Formula (TD-1):

In another aspect, provided herein are compounds of Formula (TE-1):

In another aspect, provided herein are compounds of Formula (TF-1):

In another aspect, provided herein are compounds of Formula (TG-1):

In another aspect, provided herein are compounds of Formula (TH-1):

EXAMPLES

General Procedures and Methods

NMR spectra were recorded on a Varian Inova 600 MHz, 500 MHz spectrometer. Chemical shifts are reported in parts per million (ppm). For1H NMR spectra (CDCl3and C6D6), the residual solvent peak was used as the internal reference (7.26 ppm in CDCl3; 7.16 ppm in C6D6), while the central solvent peak as the reference (77.0 ppm in CDCl3, 128.0 ppm in C6D6) for13C NMR spectra. Optical rotations were measured at 20° C. using a Perkin-Elmer 241 polarimeter. Analytical and semi-preparative thin layer chromatography (TLC) was performed with E. Merck pre-coated TLC plates, silica gel 60 F254, layer thickness 0.50 and 1.00 mm, respectively. TLC plates were visualized by staining with p-anisaldehyde stain. Flash chromatography separations were performed on E. Merck Kieselgel 60 (230-400) mesh silica gel. High performance liquid chromatography (HPLC) was carried out with Waters 1525 on a UV spectrophotometric detector (254 nm, Waters 2489) to which a 21.2×250 mm size column (Zobrax SIL) packed with silica gel (7.0 μm) was attached. All moisture sensitive reactions were conducted under an inert atmosphere. Reaction vessels were oven-dried and allowed to cool under vacuum (1 mmHg). Reagents and solvents were commercial grade and were used as supplied, unless otherwise noted.

Example 1. Selective Activation/Coupling of Poly-Halogenated Nucleophiles in Ni/Cr-Mediated Reactions: Synthesis of C1-C19 Building Block of Halichondrin Bs

The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures.

Synthesis Outlined in FIG.7

Synthesis of Model Trans-Haloenone

To a solution of trimethylsilyl acetylene (5.4 g, 55 mmol) in THF (140 mL) was added slowly n-butyllithium (2.5 M in hexanes, 21 mL, 52.5 mmol) at −78° C. for about 30 min. After 1 h, a solution of octanal (6.4 g, 50 mmol) in THF (60 mL) was added over another 30 min. The resulting mixture was stirred at −78° C. for 2 h and then quenched by saturated NH4Cl solution (100 mL) and extracted with EtOAc (150 mL×3). The extracts were washed with brine (300 mL), dried over MgSO4, and then passed through a pad of silica gel (40 g; hexanes/EtOAc=10:1→4:1) and the eluent was concentrated under reduced pressure, to give the product as light yellow liquid. This material was immediately used for the next step without further purification.

To a solution of crude propargyl alcohol product from previous step in methanol (200 mL) was added K2CO3(13.8 g, 100 mmol) at 0° C. After 6 h, to the reaction mixture was added 100 mL water to quench the reaction. The reaction mixture was extracted with EtOAc (100 mL×3) and the combined organic layer was washed with 200 mL brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel with eluent of hexanes/EtOAc (10:1 to 3:1) to give pure alcohol product XS-1 as light yellow oil in 6.6 g.

Jones Oxidation

To a solution of terminal propargyl alcohol XS-1 (6.6 g, 21.8 mmol) in acetone (106 mL) was added dropwise 30 mL of freshly prepared Jones' reagent ((a) Bowden, K.; Heilbron, I. M.; Jones, E. R. H.; Weedon, B. C. L.J. Chem. Soc.1946, 39, (b) Eisenbraun, E.J. Org. Synth.1965, 45, 28). The isopropyl alcohol was added dropwise until the excess Jones' reagent was destroyed (the color of reaction mixture became deep green). Saturated NaHCO3solution was added in small portions, and the suspension was stirred vigorously until the pH of the reaction mixture became neutral (pH=7). The suspension was filtered and the filter cake was washed with 50 mL of acetone. The filtrate was extracted with hexane (100 mL×3) and combined organic layer was washed with 200 mL brine. The organic layer was dried over anhydrous MgSO4and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel with eluent of hexanes/EtOAc (10:1 to 2:1), to give 1-decyn-3-one XS-2 product as light yellow oil (6.2 g, 82% yield in 3 steps).

HX Addition of Ynone

To a solution of 1-decyn-3-one XS-2 (0.76 g, 5 mmol) in trifluoroacetic acid (TFA, 10 mL) was added LiI, LiBr, or LiCl salt (5 mmol). The reaction mixture was stirred for 1 h, and then poured in 20 mL saturated NaHCO3solution. NaHCO3(solid) was added in small portions, and the solution was stirred vigorously until the pH of reaction became neutral. The reaction mixture was extracted with Et2O (50 mL×3) and combined organic extracts were washed with 50 mL of saturated NaHCO3solution and 50 mL of brine. The organic layer was dried over anhydrous MgSO4an concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel with eluent of hexanes/Et2O (100:1), to give trans-haloenone product X-9a-c as light yellow oil.

General Procedure (A) of Asymmetric Catalytic Ni/Cr-Mediated Coupling with Trans-Haloenone X-9a-c

Synthesis of Chiral Sulfonamide X-12

To a solution of vanillin (20.0 g, 0.13 mol) in THF (400 mL) was added acetic anhydride Ac2O (15 mL, 0.16 mol), Et3N (28 mL, 0.20 mol), and DMAP (50 mg). The solution was stirred at rt for 2 h, then concentrated under reduced pressure. 200 mL of CH2Cl2and 200 mL of aq. 1N HCl were added. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2(100 mL×2). The combined organic solution was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure, to give acetate product as a white solid (25.4 g), which was used directly for the next step without further purification (Rege, P. D.; Tian, Y.; Corey, E.J. Org. Lett.2006, 8, 3117).

Fuming nitric acid (100 mL) was cooled to −15° C., and the acetate from the last step was carefully added in small portions. After addition, the resulting deep red solution was stirred for 3 h at −10-0° C., then poured into 400 mL of cold ice water and stirred for 20 min. The yellow solid formed was filtered, thoroughly washed with cold water, and dried under house vacuum overnight. The crude product (21.3 g) was directly used for the next step without further purification.

The yellow solid from the previous step was added to 200 mL of aq. 2N KOH solution. The reaction mixture was heated to reflux for 10 min, and then cooled to rt. A 50 mL of cold concentrated HCl was carefully added to quench the reaction. The light yellow solid formed was filtered, thoroughly washed with cold water, and dried at rt. The crude product phenol (15.7 g) was obtained.

The light yellow solid from the last step was dissolved in 200 mL of THF. To this solution was added aq. NH4OH (28-30%) (200 mL) and iodine (38 g). The dark mixture was stirred at rt for 24 h, then acidified with aq. 2N HCl until pH=7, and extracted with Et2O (200 mL×3). The combined organic layer was washed with 10% Na2S2O3solution and brine, dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The crude product obtained was further recrystallized in CH2Cl2to give 4-hydroxy-3-methoxy-2-nitrobenzonitrile as light yellow crystal (11.8 g) (Talukdar, S.; Hsu, J. L.; Chou, T. C.; Fang, J. M.Tetrahedron Lett.2001, 42, 1103).

To a mixture of NaH (3.0 g, 73.0 mmol) in 15 mL of DMF at 0° C., was added the solution of 4-hydroxy-3-methoxy-2-nitrobenzonitrile (11.8 g, 60.8 mmol) in 15 mL of DMF. After 30 min, MeI (17.3 g, 121.6 mmol) was added dropwise. The mixture was stirred at rt for 2 h, and heated up to 60° C. for 30 min. After cooled to rt, it was quenched with aq. 1N HCl. The reaction mixture was extracted with EtOAc (100 mL×3). The combined organic solution was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluted with hexanes/EtOAc/CH2Cl2; 5:1:2, then 2:1:1), to give compound XS-3 as white solid (10.2 g, 37% yield over 5 steps).

To a solution of XS-3 (2.47 g, 11.8 mmol) in anhydrous chlorobenzene (25 mL) was added anhydrous ZnCl2(3.38 g, 24.8 mmol) and (R)-valinol (1.82 g, 17.7 mmol) at rt. The solution was heated to reflux for 20 h before quenched with water. The slurry was treated with ammonium hydroxide (20 mL) with stirring for 30 min and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous Mg2SO4and filtered. The solvent was removed under vacuum and the residual was purified on silica gel by flash chromatography (eluted with hexanes/EtOAc (5:1 to 1:1)) to give product XS-4 (3.30 g, 95% yield) as a white solid.

To a solution of XS-4 (3.30 g, 11.2 mmol) in EtOAc (22 mL) was added Pd/C (1.19 g, 10 mmol %). A hydrogen balloon was attached and the reaction was stirred for 3 h at rt. The slurry was filtered through Celite pad and concentrated under vacuum. The residue was purified on silica gel by flash chromatography (eluted with hexanes/EtOAc (10:1)) to give product XS-5 (2.43 g, 82%) as white solid.

To a solution of XS-5 (0.90 g, 3.4 mmol) in anhydrous pyridine (8 mL) was added 3,5-dichlorobenzenesulfonyl chloride (1.68 g, 6.8 mmol). The solution was stirred overnight at rt, then quenched with water (10 mL). The mixture was extracted with EtOAc (20 mL×3) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residual was purified on silica gel by flash chromatography (eluted with hexanes/EtOAc (5:1)) to give pure product X-12 as a white solid (1.29 g, 80% yield). Recrystallization from hexanes gave white crystals.

To a solution of trimethylsilyl acetylene (196.5 mg, 2.0 mmol) in THF (8.0 mL) was added dropwise n-butyllithium (2.5 M in hexanes, 0.72 mL, 1.8 mmol) at −78° C. After 1 h, a solution of aldehyde XS-6 (1.0 mmol) in THF (2.0 mL) was added over 10 min. The resulting mixture was stirred at −78° C. for 2 h and then quenched with saturated NH4Cl solution (10 mL). The aqueous layer was extracted with EtOAc (10 mL×3) and hexanes (20 mL). The combined organic extracts were washed with brine (500 mL), dried over Na2SO4, and then passed through a pad of silica gel (10 g). Elution with hexanes/EtOAc (1:4, 50 mL) and concentration gave the crude product XS-7, which was used for the next step without further purification.

To a solution of propargyl alcohol XS-7 (1.0 mmol) in acetone (10 mL) was added NBS (267 mg, 1.5 mmol) and silver nitrate AgNO3(17.2 mg, 0.1 mmol) at rt. After 1 h, the reaction mixture was diluted with 10 mL Et2O and quenched by 10 mL 10% Na2S2O3solution. The aqueous layer was extracted with Et2O (10 mL×3) and the combined organic layer was washed with 10% Na2S2O3solution (10 mL×2) and 20 mL brine. The organic layer was dried over anhydrous MgSO4and concentrated under reduced pressure. The residue was passed through a silica gel pad (4:1 hexanes/EtOAc, 50 mL) and the eluents was concentrated. The crude product XS-8 (a yellow liquid) was used for the next step without further purification.

The white solid was precipitated out from the reaction solution with addition of DIBAL solution. On the continuous addition of DIBAL solution, the white solid dissolved, and the solution became clear yellow or white precipitated yellow color. After the completion of DIBAL addition, the reaction mixture was stirred for 10-15 min. The solution of propargyl alcohol XS-8 (˜1.0 mmol) in ethyl ether Et2O (4.0+1.0 mL) was slowly added to the reaction mixture for ˜10 mins at 0° C. The reaction mixture was warmed to room temperature and stirred for 1 h. With the completion of reaction (check TLC to make sure no SM left), the reaction mixture was cooled down to 0° C. and quenched slowly by MeOH (1.0 mL) (hydrogen gas release rapidly). To the reaction mixture was added the 20 mL saturated sodium potassium tartrate solution, and the mixture was stirred vigorously overnight. The white aqueous layer was extracted with EtOAc (3×10 mL) and the combined organic layer was washed with 20 mL brine. The organic layer was dried over anhydrous MgSO4and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel gave trans-allylic alcohol XS-9 as yellow oil.

trans-Allylic alcohol XS-9 was dissolved in wet CH2Cl2(10 mL) at rt and then DMP (636 mg, 1.5 mmol) and NaHCO3(840 mg, 10 mmol) were added to the reaction solution. The reaction mixture was stirred for 1 h (monitored by TLC) and quenched by a mixture of 10% Na2S2O3solution (caution: cannot be saturated) (15 mL) and saturated NaHCO3solution (10 mL). The solution was diluted with CH2Cl2(10 mL) and stirred vigorously for 15-30 min. The aqueous layer was extracted with CH2Cl2(10 mL×4) and combined organic layer was washed with 10% Na2S2O3solution twice (10 mL), saturated aq. NaHCO3solution (10 mL) and brine (10 mL). The organic layer was dried over anhydrous MgSO4and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the desired trans-bromoenone X-15-X-18.

General Procedure (B) of Asymmetric Catalytic Ni/Cr-Mediated Coupling with Trans Bromoenone X-14-X-18

To a mixture of natural sulfonamide X-12 (5.20 mg, 11.0 μmol), proton sponge (Aldrich, purified by sublimation; 2.36 mg, 11.0 μmol) and CrCl2(Aldrich, 99.99% mg, 1.23 mg, 10.0 μmol) was added MeCN (Baker, ultra low water; 100 μL) in a glovebox. The mixture was stirred for 60 min at rt under nitrogen. To the second new vial were added Zr(cp)2Cl2(Aldrich, 98%; 43.8 mg, 0.15 mmol), Mn powder (Aldrich, 99.99%, powder; 11.0 mg, 0.20 mmol), LiCl (Aldrich, anhydrous, grinded; 8.5 mg, 0.20 mmol), NiCl2catalyst X-13b (0.033 mg, 0.05 μmol), aldehyde (32.7 mg, 0.10 mmol), trans-bromoenone X-14-X-18 (0.15 mmol) and MeCN (Baker, ultra low water; 150 μL). The mixture in the first vial was transferred to the second vial with syringe under nitrogen. The reaction mixture was stirred under nitrogen until the reaction was completed in about 3 h (by TLC), and diluted with EtOAc (2.0 mL). Florisil (ca. 50 mg) was added, and the mixture was stirred for 30 min, filtered through a short silica gel pad using EtOAc/hexanes (1:1). The eluent was concentrated in vacuo to furnish the crude coupling product. The crude product was purified by preparative TLC (EtOAc/hexanes=1:4) to give X-11 to XS-21 as a yellow liquid.

Synthesis Outlined in FIG.9

The procedure was the same as procedure B. The products were obtained as a mixture of furan X-20 and X-11 (80% yield, 1:9) (Sammond, D. M.; Sammakia, T.Tetrahedron Lett.1996, 37, 6065).

Acid Catalyzed Formation of Furan from Corresponding Trans-Coupling Product

The trans-coupling product (20 μmol) was dissolved in MeCN (0.5 mL) containing p-toluenesulfonic acid (p-TSA, 0.69 mg, 4 μmol) and the reaction mixture was stirred at rt for 2 h. The reaction was quenched with solid NaHCO3(3.36 mg, 40 μmol) and passed through a short silica gel pad with Hex/EtOAc (10:1). On removal of solvent, the furan product was obtained as yellow oil.

To a solution of undec-2-yn-4-one (0.33 g, 2 mmol) in trifluoroacetic acid (TFA, 4.0 mL) was added LiBr (208 mg, 2.4 mmol). The reaction mixture was stirred for 1 h, and then poured in 20 mL saturated aq. NaHCO3solution. NaHCO3(solid) was added in small portions, and the solution was vigorously stirred until the pH of the reaction mixture became neutral. The reaction mixture was extracted with Et2O (30 mL×3) and combined organic extracts were washed with 50 mL of saturated NaHCO3solution and 30 mL of brine. The organic layer was dried over anhydrous MgSO4and concentrated under reduced pressure to give a residue, which was separated by preparative TLC (hexanes/EtOAc=4:1), to give E-isomer X-21 and Z-isomer X-22 as light yellow oils in 30% and 24% yields, respectively.

The procedure was similar to procedure A. The NiCl2catalyst was X-13b with 1.0 mol % loading. By preparative TLC (20% EtOAc in hexanes), alcohol X-23 and furan X-24 were isolated.

Synthesis Outlined in FIG.11

Competition Studies of Ni/Cr-Mediated Coupling Reactions with Trans-Bromoenone and Alkenyl Iodides X-31a-c

Preparation of Chromium Sulfonamide Solution

In a glove box, to a 5.0 mL black cap vial, was added chiral sulfonamide X-12 (52.0 mg, 0.11 mmol), proton sponge (Aldrich, purified by sublimation; 23.6 mg, 0.11 mmol) and CrCl2(Aldrich, 99.99% mg, 12.3 mg, 0.1 mmol), and MeCN (Baker, ultra low water; 1.0 mL). The mixture was stirred for 60 min at rt under nitrogen and changed to deep green homogeneous solution which is ready to use for coupling reaction.

Synthesis Outlined in FIG.12

Synthesis of C14-C19 Building Block XS-27

A 1000 mL round-bottom flask was charged with penten-1-ol (TCI, 51.8 g, 0.6 mol, 1.0 equiv) and dissolved in CH2Cl2(500 mL, 1.2 M). The reaction was then added sequentially with tert-butyldimethylsilyl chloride (99.5 g, 0.66 mol, 1.1 equiv) and imidazole (49.0 g, 0.72 mol, 1.2 equiv), and allowed to stir at rt for 2 h. The reaction slurry was then washed with saturated NaCl solution (200 mL twice). The aqueous phase was extracted with CH2Cl2(100 mL twice) and the combined organic layer was dried over anhydrous MgSO4. The solvent was removed under reduced pressure to afford a crude product, which was purified by house vacuum distillation at 105° C. to afford the product tert-butyldimethyl(pent-4-en-1-yloxy)silane as a clear oil (119.3 g, 99% yield).

A solution of oxone (246.0 g, 0.40 mol) in water (1000 mL) was added dropwise at 0° C. to a vigorously stirred biphasic mixture of tert-butyldimethyl(pent-4-en-1-yloxy)silane (40.0 g, 0.4 mol), tetrabutylammonium hydrogen sulfate (22.6 g, 66.6 mmol), acetone (84 mL), CH2Cl2(840 mL) and a saturated NaHCO3solution (1400 mL) (Lafont, D.; D'Attoma, J.; Gomez, R.; Goekjian, P. G.Tetrahedron: Asymmetry2011, 22, 1197). With stirring, the mixture was maintained for 30 min at 0° C., and 40 h at room temperature. The aqueous phase was extracted with CH2Cl2(400 mL twice) and the combined organic phases were washed with saturated Na2S2O3solution (400 mL twice), saturated NaHCO3solution (600 mL) and brine (400 mL twice) and dried over anhydrous MgSO4. After filtration, the solution was concentrated under reduced pressure and the residue was purified by column chromatography to remove unreacted starting materials (about 10%), and the racemic epoxide XS-23 was obtained as a light yellow oil (38.0 g, 88% yield).

Catalyst Activation for Jacobsen Kinetic Resolution

(Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N.Science1997, 277, 936): a mixture of (S,S)-Jacobsen catalyst (604 mg, 1 mmol), toluene (11 mL), and acetic acid (120 mg, 2 mmol, 2 equivalents to catalyst) was stirred while open to the air for 2 h at room temperature. The solvent was removed by rotary evaporation, and the deep brown residue was dried under vacuum overnight.

The solution of racimic epoxide XS-23 (48 g, 0.22 mol) in tert-BuOMe (50 mL) and water (2.0 g, 0.11 mol) were added to the activated catalyst flask, and then the reaction mixture was stirred at room temperature for 6 h (1H NMR indicated about 67% conversion). The reaction solvent was removed by reduced pressure and the residue was purified by column chromatography to yield (S)-epoxide product XS-24 (yellow oil, 20.8 g, 43% yield) and crude (R)-diol (23.4 g, 48% yield).

To a solution of trimethylsilyl acetylene (12.0 g, 122.2 mmol) in THF (150 mL) was added slowly n-butyllithium (1.6 M in hexanes, 76.4 mL, 122.2 mmol) at −78° C. After 1.5 h, a solution of boron trifluoride etherate BF3.Et2O (16.8 mL, 135.8 mmol) in THF (30 mL) was added over 30 min and the mixture was stirred for another 1 h. A solution of chiral epoxide XS-24 (14.7 g, 67.9 mmol) in THF (30 mL) was added over 30 min. The resulting mixture was stirred at −78° C. for 2 h and then directly poured into a saturated aq. NaHCO3solution (500 mL) and extracted with EtOAc (500 mL×3) and hexanes (500 mL). The extracts were washed with brine (500 mL), dried over Na2SO4, passed through a pad of silica gel (60 g), and eluted with hexanes/EtOAc (1:4, 500 mL). The eluent was concentration under reduced pressure, to give the crude product (19.6 g), which was used for the next step without further purification.

The crude product (19.6 g, 62.3 mmol) was dissolved in anhydrous methanol (200 mL). To the solution, anhydrous K2CO3(17.2 g, 124.6 mmol) was added in one portion and the reaction mixture was stirred at rt for 4 h. The mixture was filtrated to remove excess amount of K2CO3solids and quenched by saturated NaHCO3solution (300 mL) and extracted with EtOAc (300 mL×3) and hexanes (300 mL). The combined extracts were washed with brine (400 mL) and dried over Na2SO4. Concentration of the extracts under reduced pressure gave a residue, which was purified by column chromatography (100 g of silica gel). The homopropargylic alcohol XS-25 was obtained as a yellow liquid (14.2 g, 86.5% in two steps). The optical purity of alcohol XS-25 was determined as >99% ee by1H NMR (500 MHz) analysis of its (S)-(+)-Mosher ester.

To a solution of homopropargylic alcohol XS-25 (7.3 g, 30.0 mmol) in CH2Cl2(150 mL) was added pyridine (7.1 g, 90 mmol), triphenylphosphine (PPh3, 11.8 g, 45 mmol) and trichloroacetamide (7.3 g, 45 mmol) at rt. The reaction was stirred at rt for 20 h under N2, and then washed with brine (60 mL×3). The organic layer was dried over Na2SO4and concentrated under reduced pressure. The residue was passed through a silica gel pad (50 g) with hexanes/EtOAc (30:1, 600 mL), to give homopropargylic chloride XS-26 (7.2 g, 92.0%) as a light yellow oil.

To a solution of alkyne XS-26 (20.8 g, 80 mmol) in CH2Cl2(400 mL) was dropped B-iodo-9-BBN (Liu, S.; Kim, J. T.; Dong, C. G.; Kishi, Y.Org. Lett.2009, 11, 4520) solution (1 M in CH2Cl2, 96 mL, 96 mmol) at 0° C. and stirred for 4 h at the same temperature prior to the addition of AcOH (18.2 mL, 320 mmol). After stirring at 0° C. for 60 min, the reaction mixture was titrated with 30% aqueous H2O2solution (red color) and then with slow addition of aqueous Na2S2O3(colorless) (caution: this process released tremendous heat). The aqueous phase was extracted with CH2Cl2three times and the combined organic extracts were washed with 10 wt. % Na2S2O3and saturated NaHCO3solution, dried over anhydrous MgSO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluted with hexanes/EtOAc (10:1 to 2:1) to give alcohol XS-27 (18.8 g, 86%) as a light yellow liquid.

The optical purity of alcohol XS-27 was determined as >99% ee by HPLC analysis (OJ-H chiral column) of its 4-acetylphenylurethane derivative XS-28 prepared from XS-27.

To a solution of alcohol XS-27 (51 mg, 0.2 mmol) in CH2Cl2(1.0 mL) were added 4-acetylphenyl isocyanate (52 mg, 0.24 mmol) and DMAP (4 mg, 40 μmol) at room temperature. The reaction mixture was stirred for 1 h at the same temperature prior to quenching with saturated NaHCO3solution. The aqueous phase was extracted with EtOAc twice and the combined organic phases were dried over anhydrous MgSO4and concentrated in vacuo. The residue was purified by preparative TLC (hexanes/EtOAc=2:1) to give urethane XS-27′ (74 mg, 85%) as a white solid. The optical purity of urethane XS-27′ was determined as >99% ee by HPLC analysis (FIG. 1).

Synthesis of C12-C19 Building Block X-34

Aldehyde X-33 was obtained from Dess-Martin oxidation of alcohol XS-27 with the procedure same as shown in section 3.1.

To a solution of trimethylsilyl acetylene (3.63 g, 37 mmol) in THF (30 mL) was added slowly n-butyllithium (2.5 M in hexanes, 14.8 mL, 37 mmol) at −78° C. about 30 min. After 1 h, a solution of boron trifluoride etherate (5.6 g, 39.6 mmol) in THF (20 mL) was added over 30 min and the mixture was stirred for another 1 h (Yamauchi, M.; Hirao, I.Tetrahedron Lett.1983, 24, 391). A solution of aldehyde X-33 (3.6 g, 13.2 mmol) in THF (20 mL) was added over another 30 min. The resulting mixture was stirred at −78° C. for 3 h, then directly poured into a saturated NaHCO3solution (300 mL), and extracted with EtOAc (200 mL×3) and hexanes (200 mL×2). The extracts were washed with brine (300 mL), dried over anhydrous MgSO4, and then passed through a pad of silica gel (40 g). Elution with hexanes/EtOAc (1:4, 500 mL) and concentration gave the crude product, which was purified by silica gel column chromatography (hexanes/CH2Cl2=50:1→25:1→10:1→5:1→2:1), to give XS-28 (4.4 g) as a yellow oil.

To a solution of propargyl alcohol XS-28 (4.4 g, 11.8 mmol) in acetone (60 mL) was added NBS (3.15 g, 17.7 mmol) and silver nitrate AgNO3(0.4 g, 2.36 mmol) at rt. After 1.0 h, the reaction mixture was diluted with 200 mL EtOAc and quenched by 100 mL saturated aq. Na2S2O3solution. The aqueous layer was extracted with EtOAc (2×100 mL) and the combined organic layer was washed with saturated Na2S2O3solution (2×100 mL) and 200 mL brine. The organic solution was dried over anhydrous MgSO4and concentrated under reduced pressure. The residue was passed through a silica gel pad with eluent (2:1 hexanes/EtOAc, 300 mL), to give crude XS-29 (4.1 g, silica gel TLC Rf˜0.5 in 6:1 hexanes/EtOAc) as a yellow oil. The crude XS-29 was used for the next step without further purification.

To a solution of AlCl3(2.9 g, 21.8 mmol) in Et2O (40 mL) was added slowly DIBAL solution (1.0M in THF, 43.6 mL, 43.6 mmol) at 0° C. (The white solid was precipitated out from the reaction mixture on adding DIBAL. The white solid dissolved with a continuous addition of DIBAL solution, and eventually the solution became clear yellow or white precipitated yellow color). The reaction mixture was stirred for 10□ (40 mL) was added slowly DIBAL solution (1.0M in THF, 43.6 mL, 43.6 mmol) at XS-29 from the previous step in ethyl ether Et2O (40+20+10 mL) was added slowly in the reaction mixture about 10 mins. After 1 h (TLC monitor for no SM left), the reaction mixture was cooled down to 0° C. and quenched slowly by MeOH (20 mL). To the reaction mixture was added the 200 mL saturated sodium potassium tartrate solution and then stirred vigorously for overnight. The white aqueous layer was extracted with EtOAc (3×100 mL) and combined organic layer was washed with 200 mL brine. The organic layer was dried over anhydrous MgSO4and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (hexanes/Et2O=50:1→25:1→10:1→5:1→2:1→1:1), to give XS-30 (3.5 g) as a yellow oil.

Alcohol XS-30 was subjected to Dess-Martin oxidation reaction. The crude product was purified by silica gel column chromatography (hexanes/CH2Cl2=100:1→50:1→25:1→10:1→5:1→2:1), to yield trans-bromoenone X-34 (3.0 g) as a light yellow oil.

Synthesis Outlined in FIG.13

Synthesis of Polyether Phenanthroline Ligands

To a mixture of NaH (60% dispersion in mineral oil, 0.40 g, 1.0 mmol, 5.5 equiv.) in 18 mL of DMF at 0° C., was added 15-C-5 (1.25 mL, 3.5 equiv.) and alcohol (1.0 mL, 3.5 equiv.). After 30 min, a solution of 4,7-dichloro-2,9-dimethyl-1,10-phenanthroline ((a) Larsen, A. F.; Ulven, T.Org. Lett.2011, 13, 3546, (b) Schmittel, M.; Ammon, H.Eur. J. Org. Chem.1998, 5, 785) (0.50 g, 1.8 mmol) in a 1:1 mixture of DMF and THF (total: 16 mL) was slowly added. After addition, the purple solution was warmed to room temperature and stirred for 3 h. The reaction was quenched with addition of 10 mL of water at 0° C., and concentrated under vacuum. The residue was purified on Wakogel (50NH2; eluted with first 1:1 hexanes/EtOAc, then pure EtOAc, finally 10:1 EtOAc/MeOH), to give the desired product as a yellow solid.

Preparation of NiCl2Complexes X-37a-c

To a stirred suspension of NiCl2.DME (7.9 mg, 0.036 mmol) in 0.5 mL of MeCN was slowly added the phenanthroline ligand XS-31 (13.4 mg, 0.038 mmol) in 0.5 mL of MeCN. During the reaction, the Ni-complex precipitate out, which was filtered and dried under vacuum. The complex X-37a was obtained as a purple powder in 12.2 mg, which can be used directly for the Ni/Cr-mediated coupling reaction.

To a stirred suspension of NiCl2.DME (7.9 mg, 0.036 mmol) in 0.5 mL of MeCN was slowly added the phenanthroline ligand XS-32 (16.7 mg, 0.038 mmol) in 0.5 mL of MeCN. The resulting clear purple solution was stirred for 24 h at rt, then filtered, concentrated, and dried under high vacuum. The complex X-37b was obtained as a purple paste in 21.6 mg, which can be used directly for the Ni/Cr-mediated coupling reaction.

To a stirred suspension of NiCl2-DME (7.9 mg, 0.036 mmol) in 0.5 mL of MeCN was slowly added the phenanthroline ligand XS-33 (20.0 mg, 0.038 mmol) in 0.5 mL of MeCN. The resulting clear purple solution was stirred for 24 h at rt, then filtered, concentrated, and dried under high vacuum. The complex X-37c was obtained as a purple paste in 25.3 mg, which can be used directly for the Ni/Cr-mediated coupling reaction.

Synthesis of X-36 from Ni/Cr-Mediated Coupling Reaction Between X-34 and X-35

Preparation of Chromium Sulfonamide Solution

In a glove box, to a 50 mL round-bottom flask, was added chiral sulfonamide X-12 (1.20 g, 2.2 mmol), proton sponge (Aldrich, purified by sublimation; 542.2 mg, 2.2 mmol) and CrCl2(Aldrich, 99.99% mg, 246 mg, 2.0 mmol), and MeCN (Baker, ultra low water; 30.0 mL). The mixture was stirred for 60 min at rt under nitrogen and changed to a deep green homogeneous solution which is ready to use for coupling reaction.

To a 250 mL round-bottom flask with C1-C11 aldehyde X-35 (7.09 g, 20 mmol), was added LiCl (Aldrich, anhydrous, grinded; 1.70 mg, 40 mmol), Mn powder (Aldrich, 99.99%, powder; 2.20 g, 40 mmol), Zr(cp)2Cl2(Aldrich, 98%; 8.77 g, 30 mmol) and a solution of bromoenone X-34 (11.3 g, 30 mmol) in MeCN (Baker, ultra low water; 25.0 mL). Then, a red MeCN-solution of NiCl2-catalyst X-37c (6.70 mg, 0.01 mmol, 0.05 mol %; 2.0 mL MeCN (Baker, ultra low water) was added and, lastly, the deep green solution of Cr-catalyst was transferred from the first flask to the reaction flask with syringe. The reaction mixture was stirred under nitrogen for 3 h, and diluted with EtOAc (60 mL). Florisil (ca. 1.0 g) was added, and the mixture was stirred for 30 min, filtered through a silica gel pad (ca. 60 g) using EtOAc/hexanes (1:1). The eluent was concentrated in vacuo to furnish the crude coupling product, which can be used for the next step without further purification.

Coupling Product X-36

Synthesis Outlined in FIG.14

To a mixture of sulfonamide X-12 (2.60 mg, 5.5 μmol), proton sponge (Aldrich, purified by sublimation; 1.18 mg, 5.5 μmol) and CrCl2(Aldrich, 99.99% mg, 0.62 mg, 5.0 mol) was added MeCN (Baker, ultra low water; 50 μL) in a glovebox. The mixture was stirred for 60 min at rt under nitrogen. To the second new vial were added Zr(cp)2Cl2(Aldrich, 98%; 21.9 mg, 75 μmol), Mn powder (Aldrich, 99.99%, powder; 5.5 mg, 100 mol), LiCl (Aldrich, anhydrous, grinded; 4.3 mg, 100 μmol), aldehyde (16.4 mg, 50 μmol), trans-bromoenone X-34 (75 μmol) and MeCN (Baker, ultra low water; 75 μL). Ni-catalyst X-37c (0.033 mg, 0.05 μmol) was added as a solution of MeCN (2.0 mg/mL, 16 μL). The mixture in the first vial was transferred to the second vial with syringe under nitrogen. The reaction mixture was stirred under nitrogen until the reaction was completed (TLC minitor) about 3 h, and diluted with EtOAc (1.0 mL). Florisil (ca. 30 mg) was added, and the mixture was stirred for 30 min, filtered through a short silica gel pad with 1:1 EtOAc/hexanes. The eluent was concentrated in vacuo to furnish the crude coupling product, which was purified by preparative TLC (EtOAc/hexanes=1:4) to give the desired product as a yellow liquid.

Synthesis Outlined in FIG.15

To a solution of X-36 (11.4 g, 17.5 mmol) in CH2Cl2(175 mL) were added pyridine (4.5 mL, 52.5 mmol), PNBCl (6.5 g, 35.0 mmol), and DMAP (214 mg, 1.75 mmol) at 0° C., and the reaction mixture was warmed to room temperature. After stirring for 12 h, the solvent of reaction mixture was removed under reduced pressure and then passed through the silica gel pad with eluent of hexanes/EtOAc (1:1, 1500 mL). The eluent was removed to give the crude product XS-36, which can be used for the next step without further purification.

To the crude product XS-36 from the previous step was added a solvent mixture of 4:1:5 TFA/H2O/CH2Cl2(950 mL). The reaction mixture was stirred for 2 h (TLC monitor), and then poured in small portions into saturated aq. NaHCO3solution (1000 mL). The aqueous mixture solution was neutralized with excess amount of solid NaHCO3, and extracted with EtOAc (500 mL×5). The combined organic layer was washed with saturated NaHCO3solution, saturated NH4Cl solution, brine, and dried over MgSO4. The solvent was removed to give crude product XS-37, which can be used for the next step without further purification.

To a solution of crude product XS-37 from the previous step in 50 mL CH2Cl2was added a mixture of 18:1 MeOH/H2O (950 mL) and Na2CO3solid (10.6 g, 100 mmol). The reaction mixture was stirred until the reaction was completed (TLC monitor) about 6 h. The reaction mixture was diluted with 500 mL Et2O and passed through a pad of Celite to remove white solid. The eluent was concentrated under reduced pressure, to give the crude product, which was purified by flash silica gel column chromatography (hexanes/EtOAc=20:1→1:2), to give a mixture of diastereomers (X-45: X-44=2:1; 8.2 g) as a yellow liquid.

Preparation of Ion-Exchange Resin Device

The mixture of X-44 and X-45 (8.2 g) was dissolved in 500 mL EtOH in a 2000 mL round flask. A pump, reaction flask and ion-exchange column were connected as shown inFIG. 2. The mixture (10 mg/mL solution in EtOH) was circulated for 10 h (flow rate: 2 mL/min). The column was washed with ethanol (300 mL). The combined EtOH solutions were concentrated under reduced pressure. The residue was passed through a short silica gel plug (elution with hexanes/EtOAc=10:1 to 1:1) to give product X-46 as a yellow oil.

Synthesis of C1-C19 Thioester for X-Ray Structure Determination

The C1-C19 carboxylic ester X-46 (200 mg, 0.37 mmol) was dissolved in 3.7 mL of freshly distilled 1,2-dichloroethane and after addition of Me3SnOH (532 mg, 2.94 mmol), the mixture was heated to 80° C. until TLC analysis indicated a complete reaction (about 48 h). After completion of the reaction, the mixture was concentrated in vacuo, and the residue was taken up in 100 mL EtOAc. The organic layer was washed with aqueous 1N HCl solution (20 mL×3) and then washed with brine (15 mL) and dried over anhydrous MgSO4. Removal of the solvent in vacuo afforded the crude product C1-C19 carboxylic acid, which was used directly for the next step without further purification (Nicolaou, K. C.; Estrada, A. A.; Zak, M.; Lee, S. H.; Safina, B. S.Angew. Chem. Int. Ed.2005, 44, 1378).

To the solution of crude C1-C19 carboxylic acid product from the previous step in anhydrous CH2Cl2(37 mL) was added DCC (169.3 mg, 0.74 mmol), methyl 2-mercaptoacetate (58.9 mg, 0.56 mmol) and DMAP (5.0 mg, 0.0387 mmol). The reaction mixture was stirred at rt for 4 h (TLC monitor), filtered through a short Celite pad and the eluent was concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc/hexane=1:1) to give the product XS-38 as a white solid (90% yield) (Xiao, J. P.; Tolbert, T.J. Org. Lett.2009, 11, 4144). Compound XS-38 was obtained from the mixture solvent (hexanes and EtOAc) and subjected to X-ray analysis (FIG. 3).

Coupling Efficiency of β-Haloenones with Aldehydes

The first phase of the study was to assess the coupling efficiency of β-iodoenones with aldehydes, with use of model substrates (FIG. 7). The coupling efficiency between β-iodoenone X-9a and aldehyde X-10 with 10 mol % Cr-catalyst, prepared from (S)-sulfonamide X-12, and 1 mol % (Me)2Phen(H)2.NiCl2X-13a in MeCN (FIG. 7) was tested.

β-Iodoenone X-9a was compared with β-bromo- and β-chloroenones X-9b,c. X-9b,c might be less reactive than X-9a because of electronic effects and, therefore, might have a better reactivity-balance between the Ni- and Cr-catalytic cycles. This experiment showed that: (1) X-9b,c gave a better coupling efficiency than X-9a and (2) X-9b gave a slightly better coupling efficiency than X-9c.

β-bromoenone X-9b was used to conduct a second experiment. The overall coupling efficiency with less reactive Ni-catalyst and, then, with a lesser amount of the Ni-catalyst was tested. (Me)2Phen(OMe)2.NiCl2X-13b is a slower activator, based on previous studies, of vinyl iodides than (Me)2Phen(H)2.NiCl2X-13a (Liu, X.; Li, X.; Yu Chen, Hu, Y; Kishi, Y J.Am. Chem. Soc.2012, 134, 6136). On replacing X-13a with X-13b, the coupling efficiency was noticeably improved. The ratio of Ni- over Cr-catalysts was optimized; with 10 mol % Cr-catalyst fixed, 1, 0.5. 0.1, 0.05, and 0.01 mol % Ni-catalyst loadings were tested, thereby revealing that: (1) the coupling efficiency improved with lowering the Ni-catalyst loading and (2) the coupling efficiency reached the plateau at the 0.05-0.01 mol % Ni-catalyst loading. It is worthwhile noting that the coupling reaction did not proceed without Ni-catalysts.

The coupling condition of “10 mol % Cr-catalyst, prepared from sulfonamide X-12, 0.05 mol % Ni-complex X-13b, Zr(cp)2Cl2(1.5 eq), LiCl (2 eq), and Mn (2 eq) in MeCN ([C]0.4 M) at room temperature” is used for a study of coupling efficiency.FIG. 8summarizes the coupling efficiency for di-substituted trans-β-bromoenones with aldehydes. The products thus obtained were stable enough to isolate and characterize. However, on standing in benzene, methylene chloride, and other solvents, at room temperature, they gradually decomposed, to yield the corresponding furans. With acid treatment (p-TSA or CSA/MeCN/RT), they gave the furans almost instantaneously. On acylation, however, the coupling products became stable even in the presence of acids (aq. TFA, CH2Cl2, RT).

FIG. 9summarizes applying this coupling reaction to other types of β-bromoenones. The first case studied was cis-β-bromoenone X-19; a ˜9:1 mixture of coupling product X-11 was abtained, similar to the coupling product obtained from trans-β-bromoenone X-9b, and furan X-20. Trans tri-substituted β-bromoenone X-21 gave a 1:1 mixture of coupling product X-23 and furan X-24, whereas cis tri-substituted β-bromoenone 22 gave only furan X-24.

Overall, the disclosed coupling reaction between an aldehyde and a “naked” vinylogous acyl anion is synthetically useful at least for di-substituted trans-β-bromoenones. Interestingly, the method meets the need to achieve the proposed coupling reaction X-A+X-B→X-C (FIG. 4).

Selective Activation of β-Bromoenone Over Vinyl Iodide and Saturated Chloride

FIG. 10shows exemplary reported selective activation/coupling of a poly-halogenated nucleophile in the Ni/Cr-mediated coupling reactions is shown inFIG. 10. The first example shows that a selective activation/coupling is possible with the use of selective activator in the Cr-mediated couplings; namely, cobalt- and iron-salts are known to activate saturated halides, but not vinyl halides (Takai, K.; Nitta, K.; Fujimura, O.; Utimoto, K.J. Org. Chem. 1989, 4732). The second example shows that a selective activation of iodoacetylene in the Ni/Cr-mediated reaction is possible without disturbing the vinyl iodide present in the electrophile.

Competition experiments were conducted to study the selective activation/coupling. Aldehyde X-10 was coupled with a 1:1 mixture of β-bromoenone X-9b and vinyl iodide X-31a, b, or c in the presence of a different amount of Ni-catalysts X-13a,b, followed by ratio-analysis of the two expected products X-11 and X-32 (1H NMR) (FIG. 11). The competition experiments demonstrated that: (1) 0.05 and 0.1 mol % Ni-catalyst loadings, against 10 mol % Cr-catalyst loading, allow selectively to activate/couple β-bromoenone X-9b over all the three types of vinyl iodides X-31a-c and (2) Ni-catalyst X-13b gives a better discrimination of β-bromoenone X-9b over vinyl iodides X-31a˜c than Ni-catalyst X-13a. Interestingly, 0.05 and 0.1 mol % Ni-catalyst loadings coincided with the Ni-catalyst amount ideal for β-bromoenone couplings (see the previous section).

The coupling study of X-34 and X-35 can be found inFIG. 13. Requisite nucleophile 34 was readily prepared from the previously reported, optically pure aldehyde 33 (FIG. 12) (Liu, S.; Kim, J. T.; Dong, C.-G.; Kishi, Y.Org. Lett.2009, 11, 4520). With respect to the electrophile, several possible protecting groups at C8 and C9 were tested, thereby showing that the cyclohexylidene is the best option.

Aldehyde X-35 was subjected to the Ni/Cr-coupling reaction (10 mol % Cr-catalyst, prepared from sulfonamide X-12, and 0.05 mol % Ni-catalyst X-13b), to furnish a single coupling product in 46% yield. The spectroscopic analysis (HR-MS,1H NMR, and13C NMR) demonstrated that the isolated product was the desired coupling product X-36. In particular, the C10-C11 vicinal proton spin-coupling constant (1.0 Hz) allowed for the assignment of the desired β-configuration to the newly introduced alcohol. Based on the previous examples similar to the present case, the desired diastereomer was anticipated to be formed in a high stereoselectivity with the Cr-catalyst prepared from (S)-sulfonamide X-12 (Aicher, T. D.; Kishi, Y. Tetrahedron Lett. 1987, 28, 3463).

Three polyether-type phenanthrene.NiCl2complexes X-37a-c were prepared. The solubility of these complexes, particularly X-37b and X-37c, was improved. With the use of X-37c, the coupling yield was improved (The coupling yields with X-37a and X-37b were 59% and 75%, respectively. A Ni-catalyst with n-dodecyloxy substituents is also prepared, i.e., X=n-C12H25O in X-13, but found that its solubility was roughly same as that of X-13b and the coupling yield with this Ni-catalyst was 60%).

FIG. 14summarizes the coupling of β-bromoenone X-34 with various aldehydes. Among them, the result with aldehyde X-33 shows a selective activation of a β-bromoenone over a vinyl iodide. Activation of vinyl iodide in X-33 can induce cyclization with the aldehyde.

Synthesis of C1-C19 Building Block of Halichondrin Bs and Analogs Thereof

The coupling product X-36 was prone to furan-formation, but this instability could be overcome by acylation of the resultant allylic alcohol. Among several acyl groups tested, p-nitrobenzoate was chosen, because it was found to be stable under the aq. TFA condition required for hydrolysis of the C8,C9-cyclohexylidene group, cf., step 2 inFIG. 15.

On treatment with aqueous Na2CO3, the p-nitrobenzoate group of aq. TFA-hydrolysis product was smoothly hydrolyzed, followed by an oxy-Michael reaction of the C9 hydroxyl group to the α,β-unsaturated ketone, to furnish a ˜1:2 mixture of X-44 and X-45 (FIG. 15). In the previous studies, the chemical behaviors of these oxy-Michael products, including: (1) PPTS treatment allows to convert the C12-β oxy-Michael product X-45 to the desired polycycle, cf., X-46; (2) undesired C12-α oxy-Michael product X-44 can be recycled via retro oxy-Michael/oxy-Michael equilibration under basic condition; (3) an ion-exchange resin based device allows to convert the mixture of oxy-Michael products to the desired polycycle without isolation and recycling of the undesired oxy-Michael product (Namba, K.; Jun, H.-S.; Kishi, YJ. Am. Chem. Soc.2004, 126, 7770. (b) Kaburagi, Y; Kishi, YOrg. Lett.2007, 9, 723).

An experiment was set up to convert oxy-Michael products X-44 and X-45 into polycycle X-46, thereby revealing that: (1) transformation of X-45 into X-46 under the PPTS condition was cleaned facile, but (2) isomerization of X-44 to X-45 under the previously established basic conditions or ion-exchange-resin protocol was problematic; one problem identified was the elimination of HCl to form iodo-diene (see the lower half ofFIG. 15). With this information, a reaction condition to establish the equilibrium between two oxy-Michael products without elimination of HCl was searched for, and eventually found that the equilibration can be established with DBU or tetramethylguanidine in isopropanol or ethanol at room temperature, without the undesired elimination. DBU, Triton B(OMe), and tetramethylguanidine were tested. DBU and tetramethylguanidine established an equilibrium in isopropanol or ethanol at RT without an elimination of HCl, whereas caused an elimination of HCl in DMF and MeCN. Triton B(OMe) caused unknown decomposition of the oxy-Michael products.

Some of these conditions were translated to an ion-exchange resin based device and found that polymer-bound guanidine base, coupled with polymer-bound PPTS, was effective directly to convert a mixture of oxy-Michael products X-44 and X-45 to polycycle X-46 in a high yield without isolation/separation/equilibration (FIG. 16). Basic ion-exchange resins tested included: Amberlite IRA-400, Amberlite IRA-402, Amberlite IRA-900, Amberlite A-21, Amberlite A-26, ans Amberlite A-27. Acidic ion-exchange resins tested included: Rexyn 101, Amberlite IR-120, Amberlite 15, and Amberlite IRC-86. Both purchased from Aldrich: polymer-bound guanidine: #358754; polymer-bound PPTS: #82817. As ethanol was used as the solvent, an ester exchange was noticed if the reaction was run over 1 day. However, it did not present an issue for preparative purpose, as the conversion was usually complete within 12 hours. The structure of C1-C19 building block X-46 thus synthesized was fully supported by spectroscopic data (HR-MS,1H and13C NMR), which was further confirmed by X-ray analysis of its derivative.

The synthesis reported is easy to scale; the overall yield of X-46 from X-36 was 69% in a 11.4 g scale.

The C1-C19 building block X-46 of halichondrin Bs was synthesized via a selective activation/coupling of β-bromoenone X-34 with aldehyde X-35 in a Ni/Cr-mediated reaction. The first phase of study was a method development to effect a coupling of a “naked” vinylogous anion with an aldehyde. The study with the coupling of X-9+X-10→X-11 revealed: (1) β-bromoenone X-9b is a better nucleophile than the corresponding β-iodo- and β-chloroenones X-9a,c; (2) (Me)2Phen(OMe)2.NiCl2X-13b is a better Ni-catalyst than (Me)2Phen(H)2.NiCl2X-13a; (3) a low Ni-catalyst loading, for example 0.05˜0.01 mol % Ni-catalyst against 10 mol % Cr-catalyst, is crucial for an effective coupling. The second phase of study was a method development to realize a selective activation/coupling of poly-halogenated nucleophiles such as X-34. The competition experiment of X-10+X-9b over X-10+X-31a˜c revealed: (1) (Me)2Phen(OMe)2.NiCl2X-13b is more effective than (Me)2Phen(H)2.NiCl2X-13a for the required selective activation/coupling; (2) a low Ni-catalyst loading, for example 0.05-0.01 mol % Ni-catalyst against 10 mol % Cr-catalyst, can be important for discriminating β-bromoenone X-9b from the three types of vinyl iodides X-31a-c. The third phase of study was an application of the developed method to execute the proposed coupling of X-34+X-35→X-36. For this application, a polyether-type Ni-catalyst X-37c, readily soluble in the reaction medium, was introduced to achieve the selective activation/coupling with higher efficiency. With use of ion-exchange-resin based device, the coupling product X-36 was transformed to the C1-C19 building block X-46 of halichondrin Bs without purification/separation of the intermediates.

Nucleophile X-34 are designed selectively to achieve specific bond-formation in a controlled manner, as illustrated in the synthesis of right-half of halichondrin A (FIG. 17).3cNamely, C19 vinyl iodide was used for the Ni/Cr-mediated coupling stereoselectively to form the C19-C20 bond, whereas C17 chloride allowed stereospecifically to form the tetrahydrofuran ring in an SN2fashion.

Example 2. Unified Synthesis of C1-C19 Building Blocks of Halichondrins Via Selective Activation/Coupling of Poly-Halogenated Nucleophiles in (Ni)/Cr-Mediated Reactions

Synthesis Outlined in FIG.21

Synthesis of Model Halo-Acetylenic Ketones Y-18a-c

To a solution of trimethylsilyl acetylene (432 mg, 4.4 mmol) in THF (14 mL) was added slowly n-BuLi (2.5 M in hexanes, 1.7 mL, 4.2 mmol) at −78° C. about 30 minutes. After 1 h, a solution of hexanal (400 mg, 4.0 mmol) in THF (6 mL) was added over another 30 min. The resulting mixture was stirred at −78° C. for 2 h and then quenched by saturated NH4Cl solution (10 mL) and extracted with EtOAc (15 mL×3). The extracts were washed with brine (30 mL), dried over anhydrous MgSO4, and then passed through a pad of silica gel (10 g). Elution with hexanes/EtOAc (10:1 to 4:1) and concentration gave the crude product YS-1 as light yellow liquid. This material was immediately used for the next step without further purification.

To a solution of propargyl alcohol YS-1 (800 mg, 4.0 mmol) in dry acetone (20 mL) was added silver nitrate AgNO3(135.9 mg, 0.80 mmol) and N-halosuccinimide (NIS: 1.50 g; NBS: 1.07 g; NCS: 801 mg; 6.0 mmol) at room temperature. After being stirred at room temperature for 0.5 h (overnight for NCS case), the reaction mixture was diluted with Et2O (40 mL) and then quenched by 30 mL of 10% aqueous Na2S2O3. The aqueous layer was extracted with Et2O (20 mL×3) and combined organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated under vacuum. Purification of the residue by flash column chromatography on silica gel afforded halogenated propargyl alcohol YS-2 as colorless oil. The material was immediately used for the next step without further purification.

A solution of halogenated propargyl alcohol YS-2 (4.0 mmol) in CH2Cl2(40 mL) were added NaHCO3(3.36 g, 40 mmol) and Dess-Martin periodinane (2.54 g, 6.0 mmol) at room temperature and stirred for 1 h at room temperature. The reaction mixture was diluted with Et2O (60 mL) and then quenched with 10% Na2S2O3solution (60 mL), 40 mL of saturated NaHCO3solution and vigorously stirred for 30 min. The aqueous phase was extracted with Et2O three times and the combined organic phases were washed with 10% Na2S2O3(40 mL×2), saturated NaHCO3solution (40 mL), brine (40 mL) and dried over anhydrous MgSO4. After removal of the solvent, the crude material was purified by flash chromatography on short silica gel column to give the halo-acetylenic ketones Y-18a-c as yellow oils.

To a solution of the above halo-acetylenic ketones Y-18a-c (1.5 mmol) in benzene (30 mL) were added 1,3-propanediol (1.14 g, 15 mmol) and p-TsOH.H2O (14.3 mg, 0.075 mmol) at room temperature and then refluxed for 12 h with azeotropic removal of water using a Dean-Stark trap. The reaction mixture was poured into saturated NaHCO3aq. solution, extracted with Et2O and the extract was washed with brine, dried over by anhydrous MgSO4. After removal of the solvent, the crude material was purified by flash chromatography on short silica gel column to give ketals Y-19a-c as yellow oils.

To a stirred solution of 1,10-phenanthroline anhydrous (5.0 g, 27.7 mmol) in toluene (200 mL) and THF (25 mL) was added 0.7M i-PrLi in pentane solution (24 mL, 84 mmol) dropwise at room temperature. After stirring for 16 h at room temperature, the mixture was added H2O (100 mL). The separated aqueous layer was extracted with CH2Cl2(50 mL×3) and the combined organic layer was treated with MnO2(20 g, 230 mmol) at room temperature. After stirring for 2 h, the mixture was added MgSO4(20 g) and stirred for 15 min. The mixture was filtered through Celite and the filtrate was concentrated. The crude mixture was purified by SiO2flash column chromatography (hexanes/EtOAc=9:1) to provide (i-Pr)2Phen(H)2Y-22′ (6.3 g, 23.8 mmol, 86%) (Metallinos, C.; Barrett, F. B.; Wang, Y.; Xu, S. F.; Taylor, N.J. Tetrahedron2006, 62, 11145).

To a stirred solution of (i-Pr)2Phen(H)2Y-22′ (6.3 g, 23.8 mmol) in EtOH (100 mL) and triethyl room temperaturehoformate (3 mL) was added a solution of NiCl2.6H2O (17 g, 71.5 mmol) in EtOH (100 mL) dropwise at room temperature. After stirring for overnight at room temperature, the precipitate was filtered and the resulting solid was washed Et2O. This purple solid was dissolved into CH3CN and the mixture was refluxed under N2atmosphere. Then this solution was cooled to room temperature, to give purple crystals. The crystals were filtered and washed with Et2O and dried under reduced pressure for overnight to provide Y-22 (4.5 g, 11.4 mmol, 48%) as purple shiny crystal.

General Procedure of Asymmetric Catalytic Ni/Cr-Mediated Coupling

To a separate vial were added ZrCp2Cl2(Aldrich, 98%; 43.8 mg, 0.15 mmol), Mn powder (Aldrich, 99.99%, powder; 11.0 mg, 0.20 mmol), LiCl (Aldrich, anhydrous, grinded; 8.5 mg, 0.20 mmol), NiCl2′ complex Y-22 or i or ii (0.05 mol %) or no NiCl2.catalyst, aldehyde Y-20 (32.7 mg, 0.10 mmol) and halo-acetylenic ketones Y-18a-c or halo-acetylenic ketals Y-19a-c (0.17 mmol). The deep green Cr-catalyst in the first vial was transferred to the second reaction vial with syringe under nitrogen. The reaction mixture was stirred under nitrogen until the reaction was completed (˜3 hr, TLC monitor), and diluted with EtOAc (2.0 mL). Florisil (ca. 50 mg) was added, and the mixture was stirred for 30 min, filtered through a short silica gel pad with 1:1 hexanes/EtOAc. The eluent was concentrated in vacuo to furnish the crude coupling product, which was purified by preparative TLC (hexanes/EtOAc=4:1) to give YS-3 as yellow liquid or YS-4 as colorless oil.

The isolated yield for coupling reactions with Ni-catalysts Y-22 or i or ii and no added Ni-catalyst are summarized below (Table 2).

Coupling Product YS-3

Coupling Product YS-4

Synthesis Outlined in FIG.22

Synthesis of C12-C19 Vinyl Bromide Y-24a

To a solution of trimethylsilyl acetylene (4.93 g, 50 mmol) in THF (50 mL) was added slowly n-BuLi (2.5 M in hexanes, 14.56 mL, 53 mmol) at −78° C. After 1 h, a solution of BF3.Et2O (4.66 mL, 54 mmol) in THF (10 mL) was added over 30 min using syringe pump and the mixture was stirred at −78° C. for 1 h. Then a solution of aldehyde Y-23a (18 mmol) in THF (15 mL) was added over 10 min. After stirring at −78° C. for 3 h, the resulting mixture was poured into a saturated NaHCO3solution at 0° C. The aqueous layer was extracted with EtOAc three times and the combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. Purification of the residue by flash column chromatography on silica gel afforded propargylic alcohol YS-5 (3.21 g, 90%) as a colorless oil.

To a solution of propargyl alcohol YS-5 (998 mg, 3.1 mmol) in dry acetone (12 mL) was added silver nitrate (105 mg, 0.62 mmol) and N-bromosuccinimide (822 mg, 4.6 mmol) at room temperature. The reaction vessel was wrapped by aluminum foil to avoid light. After being stirred at room temperature for 0.5 h, the reaction mixture was cooled to 0° C. and then quenched by water. Then the solution was extracted with ether and the combined organic layer was washed with 10% aqueous Na2S2O3and brine, dried over anhydrous Na2SO4, and concentrated under vacuum. Purification of the residue by flash column chromatography on silica gel afforded bromo-propargyl alcohol YS-6 as a colorless oil. This material was immediately used for the next step without further purification.

To a solution of the above proparglic alcohol YS-6 in CH2Cl2(15 mL) were added NaHCO3(2.6 g, 31 mmol) and Dess-Martin periodinane (2.0 g, 4.6 mmol) at room temperature and stirred for 0.5 h at room temperature. The reaction mixture was quenched with 10% Na2S2O3and saturated NaHCO3solution and vigorously stirred for 30 min. The aqueous phase was extracted with CH2Cl2three times and the combined organic phases were washed with 10% Na2S2O3and saturated NaHCO3solution and then dried over anhydrous Na2SO4. After removal of solvent, the crude material was purified by flash chromatography on short silica gel column to give ynone YS-7 as colorless oil. This material was immediately used for the next step without further purification.

To a solution of the above ynone YS-7 (3.1 mmol) in benzene (62 mL) were added 1,3-propanediol (2.4 g, 31.0 mmol) and p-TsOH.H2O (29.3 mg, 0.16 mmol) at room temperature and then refluxed for 12 h with azetropic removal of water using a Dean-Stark trap. The reaction mixture was poured into saturated NaHCO3aq. solution, extracted with EtOAc and the extract was washed with brine, dried over sodium sulfate. After removal of the solvent, the crude material was purified by flash chromatography on short silica gel column to give the ketal derivative Y-24a (976 mg, 82% in three steps) as colorless oil.

Synthesis of C12-C19 Vinyl Iodide Y-24b

To a solution of trimethylsilyl acetylene (1.0 g, 10.2 mmol) in THF (10 mL) was added slowly n-BuLi (2.5 M in hexanes, 4.1 mL, 10.2 mmol) at −78° C. After 1 h, a solution of BF3.Et2O (1.4 mL, 11.0 mmol) in THF (2.5 mL) was added over 30 min using syringe pump and the mixture was stirred at −78° C. for 1 h (Yamauchi, M.; Hirao, I.Tetrahedron Lett.1983, 24, 391). Then a solution of aldehyde Y-23b (1.0 g, 3.6 mmol) in THF (2.5 mL) was added over 30 min. After stirring at −78° C. for 3 h, the resulting mixture was poured into a saturated NaHCO3solution at 0° C. The aqueous layer was extracted with EtOAc three times and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. Purification of the residue by flash column chromatography on silica gel afforded proparglic alcohol YS-8 (1.15 g, 80%) as a colorless oil.

To a solution of the above trimethylsilyl acetylene YS-8 (1.10 g, 3.0 mmol) in dry acetone (15 mL) was added silver nitrate AgNO3(103 mg, 0.60 mmol) and NBS (806 mg, 4.5 mmol) at room temperature. The reaction vessel was wrapped by aluminum foil to avoid light. After being stirred at room temperature for 0.5 h, the reaction mixture was cooled to 0° C. and then quenched by water. Then the solution was extracted with ether and the combined organic layer was washed with 10% aqueous Na2S2O3and brine, dried over Na2SO4, and concentrated under vacuum. Purification of the residue by flash column chromatography on silica gel afforded bromoacetylene YS-9 as a colorless oil. This material was immediately used for the next step without further purification.

A solution of the above propargylic alcohol YS-9 (3.0 mmol) in CH2Cl2(15 mL) were added NaHCO3(2.5 g, 30.0 mmol) and Dess-Martin periodinane (1.9 g, 4.5 mmol) at room temperature and stirred for 0.5 h at room temperature. The reaction mixture was quenched with 10% Na2S2O3solution and saturated NaHCO3solution and vigorously stirred for 30 min. The aqueous phase was extracted with CH2Cl2three times and the combined organic phase was washed with 10% Na2S2O3solution and saturated NaHCO3solution and then dried over anhydrous Na2SO4. After removal of solvent, the crude material was purified by flash chromatography on short silica gel column to give the ynone YS-10 as colorless oil. This material was immediately used for the next step without further purification.

To a solution of the above acetylenic ketone YS-10 (3.0 mmol) in benzene (60 mL) were added 1,3-propanediol (2.3 g, 30.0 mmol) and p-TsOH.H2O (28.5 mg, 0.15 mmol) at room temperature and then refluxed for 12 h with azetropic removal of water using a Dean-Stark trap. The reaction mixture was poured into saturated NaHCO3aq. solution, extracted with EtOAc and the extract was washed with brine, dried over sodium sulfate. After removal of the solvent, the crude material was purified by flash chromatography on short silica gel column to give the ketal Y24b (956 mg, 73% in three steps) as colorless oil.

Synthesis Outlined in FIG.24

Synthesis of Y-27a Via (Ni)/Cr-Mediated Coupling of Y-11 and Y-24a

The fractions eluded with 1:10 EtOAc/hexanes were combined and purified with silica gel column chromatography (1:10 EtOAc/hexanes) to give reduced bromoacetylene YS-12 (˜400 mg, ˜38%) and a fraction containing homo-dimer YS-13. This faction was further purified with preparative TLC (1:10 EtOAc/hexanes), to give homo-dimer YS-13 (5.9 mg, 0.3%).

Coupling Product YS-11

To a solution of TES-protected alcohol YS-11 (25.5 mg, 27.6 μmol) in CH2Cl2(89 μL) was added co-solvent mixture TFA/H2O/CH2Cl2(4:1:10) (42.3 μL) at 0° C. The reaction mixture was stirred vigorously at room temperature until TLC showed a complete disappearance of the starting material (around 0.5 h). The reaction was diluted with EtOAc, quenched carefully with sat. NaHCO3aq., and the organic phases were separated and the aqueous phase was extracted with EtOAc three times, washed with brine. The combined organic phases were dried over Na2SO4and concentrated. The crude material was flushed through a short silica gel column to afford acetylenic ketone Y-27a (16.1 mg, 78%) as colorless oil.

Coupling Product Y-27a

Synthesis of Y-27b Via (Ni)/Cr-Mediated Coupling of Y-11 and Y-24b

(41.6 mg, 0.15 mmol), and proton sponge (32.1 mg, 0.15 mmol) in a glove box was added EtCN (1.5 mL) and stirred for 1 h at room temperature. In a separate flask, bromo-acetylene Y-27b (441 mg, 1.0 mmol), aldehyde Y-11 (305 mg, 0.61 mmol), LiCl (103 mg, 2.5 mmol), Mn (133 mg, 2.5 mmol) were mixed together and the Cr-complex solution was transferred to the flask. Then TES-Cl (254 μL, 1.5 mmol) was added into the reaction mixture. After stirring for 6 h at room temperature, the reaction was removed from the glove box and diluted with anhydrous Et2O. Sat. aq. NaHCO3, followed by potassium serinate solution, was added carefully to quench the reaction and the corresponding mixture was stirred vigorously for 30 min. The resultant mixture was filtered through short pad of silica gel and concentrated. The crude material was purified by flash chromatography on silica gel to give TES-protected alcohol YS-14 (529 mg, 89%).

The fractions eluded with 1:10 EtOAc/hexanes were combined and purified with silica gel column chromatography (1:10 EtOAc/hexanes) to give reduced bromoacetylene YS-15 (˜100 mg, ˜28%) and a fraction containing homo-dimer YS-16. This faction was further purified with preparative TLC (1:10 EtOAc/hexanes), to give homo-dimer YS-16 (2.6 mg, 0.4%).

Coupling Product YS-14

To a solution of TES-protected alcohol YS-14 (16.2 g, 16.7 mmol) in CH2Cl2(167 mL) was added co-solvent mixture TFA/H2O/CH2Cl2(4:1:10) (25.6 mL) at 0° C. The reaction mixture was stirred vigorously at room temperature until TLC showed a complete disappearance of the starting material (around 0.5 h). The reaction was diluted with EtOAc, quenched carefully with sat. NaHCO3aq., and the organic phases were separated and the aqueous phase was extracted with EtOAc three times, washed with brine. The combined organic phases were dried over Na2SO4and concentrated. The crude material was flushed through a short silica gel column to afford the ynone Y-27b (10.9 g, 79%) as colorless oil.

Coupling Product Y-27b

Synthesis Outlined in FIG.25

To a 0° C. solution of acetylenic ketone Y-27b (74.5 mg, 93 μmol) in MeCN (1.9 mL, 0.05 M) and imidazole (443 mg, 6.5 mmol) in a plastic vial was added HF.pyridine complex (70% HF content, 0.17 mL, 6.5 mmol) and stirred at room temperature for 70 h. Then triethylamine (856 mg, 8.5 mmol) was added into the reaction mixture at 0° C. After stirring at room temperature for 1 h, the reaction was carefully neutralized with saturated NaHCO3solution and NaHCO3solid. The mixture was extracted with EtOAc four times, the combined organic phase was washed by 1 N HCl solution and brine before drying over anhydrous Na2SO4, and then concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel to afford double oxy-Michael product Y-29 (46.3 g, 81%).

To a solution of double oxy-Michael product Y-29 (473 mg, 0.83 mmol) in a mixture of anhydrous THF (69 mL, 0.012M) and allyl alcohol (6.9 mL) was added Hf(OTf)4(161 mg, 0.21 mmol). The reaction was stirred for 3 h at room temperature in a glovebox. Then the reaction was quenched by triethylamine, diluted with EtOAc, and quenched with saturated NaHCO3solution. The aqueous layer was extracted with EtOAc, and the combined organic phase was washed with brine, dried over Na2SO4then concentrated under vacuum. Purification of the residual material by flash chromatograph on silica gel afforded halichondrin-C C1-C19 building block Y-10 (374 mg, 74%) as white foam.

Synthesis Outlined in FIG.26

To a 0° C. solution of acetylenic ketone Y-27b (331 mg, 0.36 mmol) in pyridine (3.0 mL, 36.0 mmol) and MeCN (8.1 mL) in a plastic vial was added HF.pyridine complex (70% HF content, 0.95 mL, 36.2 mmol) and stirred at room temperature. Once the reaction was completed, the reaction was cooled to 0° C. and carefully neutralized with saturated NaHCO3solution and NaHCO3solid. The mixture was extracted with EtOAc four times, and the combined EtOAc extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel to afford (E)-Y-31 (161 mg, 65%) and (Z)-Y-31 (18.4 mg, 7%).

To a slurry of tetramethylammonium triacetoxyborohydride (71 mg, 0.27 mmol) in CH3CN (90 μL) at −30° C. was added acetic acid (90 μL) and the mixture was stirred at this temperature for 30 min. The mixture was then added to a solution of (E)-Y-31 (23.1 mg, 33.7 mol) in CH3CN (20 μL). The resulting solution was stirred at −30° C. and slowly warmed up to 0° C. The reaction was quenched by addition of an aqueous solution of sodium, potassium tartrate followed by solid Na2CO3. The aqueous phase was extracted with CH2Cl2, and the combined organic phase was dried over Na2SO4and concentrated under vacuum. Purification of residual material by flash column chromatograph on silica gel afforded a ketone Y-32 (colorless oil, 19.6 mg, 85% yield) as a ˜5:1 mixture of Y-12α and Y-12β diastereomers.

To ketone Y-32 (17.5 mg, 25.4 μmol) was added TBAF solution in THF (2 equiv, buffered with 0.25 equiv. of imidazole hydrochloride) at room temperature. After stirring for 0.5 h at the same temperature, the reaction solution was diluted with DCM followed by EtOAc. The mixture was filtered through silica gel pad (5% MeOH in EtOAc) to remove TBAF residue. After removal of the solvent, the crude diol Y-33 (13.2 mg, 91% yield, ˜1:1 mixture of Y-12α and Y-12β diastereomers) was directly used for the next step.

The crude Y-33 was dissolved in CH2Cl2(0.5 mL) and treated with PPTS (2 equiv) at room temperature. After stirring for 2 h at room temperature, the solvent was removed, to give the residue that was purified by PTLC, to furnish halichondrin-B C1-C19 building block Y-9 (6.1 mg, 46%) and undesired Y-12a Y-33 (6.0 mg, 45%).

On comparison of spectroscopic and chromatographic properties, halichondrin-B C1-C19 building block Y-9 and diol Y-33 thus obtained were found to be identical with the authentic samples synthesized via a different route (Yan, W.; Li, Z.; Kishi, Y.J. Am. Chem. Soc.2015, 137, 0000). Also, that previous work has demonstrated that diol Y-33 with the undesired C12α-stereochemistry can be transformed to Y-9 via ion-exchange resin based device or base-induced equilibration, followed by PPTS treatment.

Reduction of (Z)-Y-31 to Y-32

Following the procedure given above for reduction of (E)-Y-31, (Z)-Y-31 (2.7 mg) was transformed into ketone product that was identical to Y-32, based on comparison of spectroscopic and chromatographic properties.

Synthesis of Halichondrin-B C1-C19 Building Block Y-9 from a (E)- and (Z)-Mixture of Y-31

In this experiment, the crude Y-33 (13.2 mg, a 1:1 Y-12α- and Y-12β-diastereomeric mixture) was dissolved in 2 mL EtOH in a black-cap vial and then connected to ion-exchange resin based device ((a) Namba, K.; Jun, H. S.; Kishi, Y.J. Am. Chem. Soc.2004, 126, 7770. (b) Kaburagi, Y.; Kishi, Y.Org. Lett.2007, 9, 723). The reaction completed in 10 h, and both basic and acidic resins were washed with ethanol (3 mL). The combined EtOH solutions were concentrated under reduced pressure. The residue was passed through a short silica gel plug (elution with hexanes/EtOAc=10:1 to 1:1) to give product Y-9 (12.3 mg, 34% overall yield from Y-27b).

Synthetic Plan

Model Study on Coupling Efficiency

Coupling in the Halichodrin Series

Compounds Y-11 and Y-24a were subjected to the coupling reaction under the condition used in the model study, to furnish the desired product Y-27a in 55% yield, with a 10:1 stereoselectivity. The structure of Y-27a was established via correlation with the authentic sample obtained in the previous route.5cAs anticipated, a product derived through activation of the vinyl iodide or saturated chloride present in Y-24a was not detected.

In order to improve the observed stereoselectivity, the toolbox approach was used and a representative set of sulfonamides was screened (FIG. 23) (Guo, H.; Dong, C.-G.; Kim, D.-S.; Urabe, D.; Wang, J.; Kim, J. T.; Xiang Liu, Sasaki, T.; Kishi, Y.J. Am. Chem. Soc.2009, 131, 15387). This screening showed that: (1) as previously observed, the stereochemistry outcome was dictated by the substrate structure rather than the chirality present in the Cr-catalyst and (2) for this coupling, sulfonamides in the (R)-series gave a better stereoselectivity than the corresponding sulfonamides in the (S)-series. Among the tested ligands, sulfonamide (R)-21 and Ni-catalyst 22 were chosen for the following study.

It was found that the coupling rate with TES-Cl was slower than that with Zr(cp)2Cl2, yet the coupling yield with TES-Cl was noticeably better than that with Zr(cp)2Cl2, i.e., 85% with TES-Cl vs. 70% with Zr(cp)2Cl2. Although its mechanistic reason was not clear, the TES-Cl condition made it possible to achieve the proposed coupling with the synthetically useful efficiency.

As noted before, Cr-mediated coupling of a halo-acetylene with an aldehyde is known to proceed with only a trace amount of Ni-catalyst or even no added Ni-catalyst (Aicher, T. D.; Kishi, Y.Tetrahedron Lett.1987, 28, 3463. (b) Usanov, D.; Yamamoto, H.J. Am. Chem. Soc.2011, 133, 1286). The coupling of Y-11+Y-24a→Y-27a was studied “with” and “without” added Ni-catalyst, thereby showing the coupling efficiency to be comparable. There is no definite experimental evidence to conclude whether this coupling involves activation of bromoacetylene with Ni-catalyst, followed by Cr-mediated coupling, or activation/coupling with only a Cr-catalyst. The homo-dimer of bromoacetylene was isolated in ca. 0.3% yield (based on Y-24a) in the coupling without added Ni-catalyst. Therefore, the coupling is referred to as (Ni)/Cr-mediated reaction.

The coupling studies were carried out with both Y-24a,b simultaneously and obtained the virtually identical results in the both series, although a small reduction in yield was noticed in the Y-24b-series.

Synthesis of C1-C19 Building Blocks of Halichondrins A-C from the Common Synthetic Intermediate Y-27

Synthesis of C1-C19 Building Block of Halichondrin A

In the halichondrin A synthesis, the transformation of Y-27a into C1-C19 building block Y-8 was established (FIG. 25). The key reactions in this transformation included: (1) a selective TBS-deprotection to form E-enone Y-28 and (2) a highly stereoselective DMDO-oxidation to introduce the C13 hydroxyl group. The C1-C19 building block Y-8 bears the C19 vinyl bromide, because the corresponding vinyl iodide was not compatible with the DMDO oxidation (Halichondrin As: Ueda, A.; Yamamoto, A.; Kato, D.; Kishi, Y.J. Am. Chem. Soc.2014, 136, 5171).

Synthesis of C1-C19 Building Block of Halichondrin C

In the halichondrin Y-C synthesis, a synthetic route to construct the polyclic ring system from an acetylenic ketone was reported (Halichondrin Cs: Yamamoto, A.; Ueda, A.; Brémond, P.; Tiseni, P. S.; Kishi, Y.J. Am. Chem. Soc.2012, 134, 893). There was no unexpected difficulty in the transformation of Y-27b to Y-10 in 60% overall yield (FIG. 25). The key reactions in this transformation included: (1) double oxy-Michael addition of C8,C9-hydroxyl groups to the acetylenic ketone to form ketal Y-29 and (2) Hf(OTf)4-induced conversion of the double oxy-Michael product Y-29 to polycycle Y-10 in ally alcohol. The structure Y-10 was fully supported by the spectroscopic data (HR-MS,1H and13C NMR).

Synthesis of C1-C19 Building Block of Halichondrin B

In order to synthesize C1-C19 building block Y-9 in the halichondrin B series from the common synthetic intermediate, an acetylene-to-olefin reduction was needed and tested first the reactivity of Y-27b and its C11-OTBS derivative against CuH, HN═NH, and CrCl2(FIG. 26), thereby indicating that the C11-OTBS substrate exhibited a very poor reactivity. Based on this observation, Y-27b was used for a search of a satisfactory reducing reagent/condition. Among reagents tested, (BDP)CuH, a Stryker CuH modified by Lipshutz, gave a mixture of E- and Z-enones (FIG. 26). As discussed in the preceding paper, Z-enone was found to form readily the furan (Yan, W.; Li, Z.; Kishi, Y.J. Am. Chem. Soc.2015, 137, 0000). Thus, although it was a minor product, Z-enone was wasted. This reduction gave the desired E-enone Y-31 as the major product, but the isolated yield varied from 55% up to 80%.

Under this circumstance, (Me)4NBH(OAc)3reduced the vinylogous ester E-Y-31 to give Y-32 in 80% yield as a 5:1 mixture of Y-12a:Y-123 diastereomers. (Me)4NBH(OAc)3is so-called hydroxyl-directing setting. It was also found that the substrate with the C11—OH masked with a TBS was inert to the reduction.

It was observed that (Me)4NBH(OAc)3reduction of the corresponding Z-enone Z-Y-31 gave Y-32 as a mixture of 1 Y-2a: Y-123 stereoisomers. Thus, for the preparative purpose, it was not necessary to separate E- and Z-enones Y-31.

On TBAF treatment, Y-32 furnished Y-33 as a ˜1:1 mixture of Y-12α:Y-12β diastereomers. With ion-exchange resin based device, this mixture was transformed cleanly to C1-C19 building block Y-9 of halichondrin B without isolation/separation/equilibration of intermediates. On comparison of spectroscopic data (1H and13C NMR, MS, TLC), Y-9 thus obtained was found to be superimposable on the authentic sample (Yan, W.; Li, Z.; Kishi, Y.J. Am. Chem. Soc.2015, 137, 0000).

A unified synthesis of the C1-C19 building blocks Y-8-Y-10 of halichondrins A-C was developed from the common synthetic intermediates Y-27a,b. Acetylenic ketones Y-27a,b were in turn synthesized via selective activation/coupling of poly-halogenated nucleophiles Y-24a,b with aldehyde Y-11 in a (Ni)/Cr-mediated coupling reaction. Compared with Ni/Cr-mediated couplings of vinyl iodides and aldehydes, this (Ni)/Cr-mediated coupling exhibited two unique features. First, the coupling was found to proceed with a trace amount or no added Ni-catalyst. Second, TES-Cl, a dissociating agent to regenerate the Cr-catalyst, was found to give a better yield than Zr(cp)2Cl2.

An adjustment of the oxidation state was required to transform acetylenic ketones Y-27a,b into C1-C19 building blocks Y-8 and Y-9 of halichondrins A and B, respectively. In the halichondrin B series, a hydroxyl-directed (Me)4NBH(OAc)3reduction of E- and Z-vinylogous esters Y-31 was found cleanly to achieve the required transformation, whereas a DMDO oxidation of E-vinylogous ester Y-28 allowed to introduce the C13 hydroxyl group with a high stereoselectivity in the halichondrin A series. In the halichondrin C series, Hf(OTf)4was used to convert double oxy-Michael product Y-29 into C1-C19 building block Y-10.

Synthesis of C20-C38 Building Blocks

One of the key intermediates in the halichondrin syntheses described herein is the C20-C38 aldehyde B, which can be synthesized from methyl ester A. As described herein, this transformation can be achieved in 6 or 7 synthetic steps as depicted in Scheme 4.

Experimental Procedures for the Synthesis of C20-C38 Building Blocks

To a solution of b (4.6 mg) in CH2Cl2(0.2 mL) at −78° C. was added DIBAL (1.0 M solution in hexane, 26 μL). After being stirred for 50 min, the reaction was quenched with EtOAc (5 mL) and 10% aqueous Rochelle's salt (5 mL). The mixture was warmed to room temperature then stirred for 1 h, then extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated to give aldehyde-alcohol, which was used for the next step without further purification.

To a solution of the above aldehyde in CH2Cl2(0.6 mL) and phosphate buffer (1.0 M, pH=7.0, 0.2 mL) was added DDQ (7 mg). The reaction was stirred for 30 min then added another DDQ (7 mg). After being stirred for additional 30 min, the reaction was quenched with 10% aqueous Na2S2O3(3 mL). The mixture was extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated, to give alcohol C30-alcohol, which was used for next step without further purifications.

Exemplary Synthesis of Halichondrins from Right Half/Left Half Fragments

Using the previously developed methods (See, e.g.,J. Am. Chem. Soc.2012, 134, 893; 2014, 136, 5171) requisite enones can be prepared from right and left haves bearing proper protecting groups. An exemplary procedure for halichondrin C is shown below. Using the same experimental procedures, halichondrins A and B can also be prepared. Likewise, the enones of norhalichondrins A-C can be prepared from the C39-C53 iodoolefin of norhalichondrin.

To a solution of bis-TBS ether 1 (280 mg) in THF (5.5 mL) was added TBAF solution (1 M in THF, buffered with 0.5 eq of imidazole-hydrochloride, 1.1 mL) at room temperature. After stirring for 20 h at room temperature, solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (DCM/hexanes 1:1 to EtOAc/hexanes 1/1 to 2/1 to EtOAc) to give diol.

To a stirred solution of the above diol (azeotropically dried with benzene prior to use) in DCM (5.5 mL) and triethylamine (0.55 mL) at 0° C. was added p-nitrobenzoyl chloride (150 mg). The reaction was quenched with MeOH (0.2 mL) at 0° C. and the resultant mixture was further stirred for 15 min at room temperature. The reaction was diluted with Et2O (8 mL) to precipitate white solid and the reaction flask was sonicated for five seconds. After filtration through a Celite pad (1 cm) and evaporation of the solvent, the crude material was purified by silica gel flash column chromatography (DCM to EtOAc/hexanes 1/3 to 1/2) to give p-nitrobenzoate.

To a mixture of p-nitrobenzoate (azeotropically dried with benzene prior to use) and imidazole (110 mg) in DCM (3.0 mL) was added TES-Cl (0.14 mL) at room temperature and the reaction mixture was stirred for 5 h at the same temperature prior to the addition of H2O. The aqueous phase was extracted with EtOAc twice and combined organic phases were dried over Na2SO4, concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (EtOAc/hexanes 1/5 to 1/3) to give TES ether (253 mg, 87% for 3 steps).

Enone intermediates can be prepared by coupling left half and right half fragments using Ni/Cr coupling reaction as demonstrated:

To a solution of 2 (57.3 mg) in DCM (1.0 mL) were added NaHCO3(55.0 mg) and Dess-Martin periodinane (55 mg) at room temperature and the reaction mixture was stirred for 1 h at the same temperature. The reaction was quenched by adding 10 wt % Na2S2O3aq. and sat. NaHCO3aq. and then vigorously stirred for 30 min at room temperature. The aqueous phase was extracted with DCM three times and combined organic phases were dried over Na2SO4. After evaporation of the solvent, the crude material was purified by silica gel flash chromatography (EtOAc/hexanes 1:5 to 1:3 to 1:2) to give aldehyde.

To a mixture of CrCl2(40.0 mg), (S)-i-Pr/Me/OMe sulfonamide (111 mg), and proton sponge (76.1 mg) in a glove box was added MeCN (3.2 mL) and stirred for 1 h at room temperature. In a separate flask, above aldehyde, iodoolefin 3 (88.8 mg), NiCl2.DMP (0.10 mg, doped in LiCl), LiCl (5.0 mg), were mixed together and the Cr-complex solution was transferred to the flask. After stirring for 1 h at room temperature, the reaction was removed from the glove box and diluted with EtOAc (1.5 mL) and added florisil and the mixture was stirred vigorously for 30 min. The resultant mixture was filtered through silica gel plug, and concentrated. The crude material was purified by silica gel flash column chromatography (EtOAc/hexanes 1:10 to 1:5 to 1:3) to give allyl alcohol.

To a solution of the above allyl alcohol in DCM (2.0 mL) were added NaHCO3(60 mg) and Dess-Martin periodinane (60 mg) at room temperature and the reaction mixture was stirred for 1 h at room temperature. The reaction was quenched with 10 wt % Na2S2O3aq. and sat. NaHCO3aq. and vigorously stirred for 30 min. The aqueous phase was extracted with DCM three times and the combined organic phases were dried over Na2SO4and concentrated under vacuum. The residue was purified by silica gel preparative TLC (EtOAc/hexanes 1:2) to provide 4 (51.2 mg, 45% in 3 steps).

An exemplary two-step deprotection/cyclization toward halichondrin C is shown below:

Buffered TBAF solution (0.5 M) was prepared by mixing TBAF (0.5 mL of 1 M solution in THF: TCI (#T1125)), pivalic acid (Pv-OH, 0.3 mL of 1M solution in DMF), and DMF (0.2 mL).

To a solution of enone (21.8 mg) in DMF (2.1 mL) was added the above TBAF solution (0.23 mL) via a syringe pomp at 0° C. over 1 h. After stirring for 1 h at the same temperature, the cooling bath was removed and the reaction mixture was stirred for 12 h (24 h for Nor-series) at room temperature. The reaction was quenched by adding CaCO3(500 mg) and DOWEX 50WX8 (1.3 g: 200-400 mesh H+-form). After stirring for 1 h at room temperature, the resulting suspension was diluted with EtOAc (ca. 2 mL) and filtered through a pad of Celite, and the filter cake was washed with EtOAc. The obtained solution was concentrated under reduced pressure, and the residue was dissolved in CH2Cl2(2.3 mL).

To the solution was added PPTS (29 mg) at room temperature. After stirring for 2.5 h at the same temperature, Wakogel 50NH2(ca. 200 mg) and DCM (2.0 mL) was added. The resulting slurry was loaded onto a column of Wakogel 50NH2(neutral silica gel from Kanto Chemicals was used for Nor-series), and purified (EtOAc/hexanes: 1/5 to 1/2 to 1/1 then MeOH/EtOAc: 1/20 (100% EtOAc for Nor-series)), to furnish a 4:1 mixture of allyl-protected halichondrin-C and its C38-epimer. The obtained mixture was purified with HPLC (YMS-Pack C-18 column; MeCN/H2O, gradient) to give allyl-protected halichondrin C (5.2 mg, 38% for 2 steps) and C38-epi halichondrin C (1.3 mg, 9% for 2 steps).

Other Embodiments