USRE46965E1 - Intermediates for the preparation of analogs of Halichondrin B - Google Patents

Intermediates for the preparation of analogs of Halichondrin B Download PDF

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USRE46965E1
USRE46965E1 US13/924,892 US200513924892A USRE46965E US RE46965 E1 USRE46965 E1 US RE46965E1 US 200513924892 A US200513924892 A US 200513924892A US RE46965 E USRE46965 E US RE46965E
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Brian Austad
Charles E. Chase
Francis G. Fang
Trevor Calkins
Bryan M. Lewis
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Eisai R&D Management Co Ltd
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Definitions

  • the present invention relates to compounds useful as intermediates in the synthesis of pharmaceutically active macrolide compounds.
  • Halichondrin B is a potent anticancer agent originally isolated from the marine sponge Halichondria okadai, and subsequently found in Axinella sp., Phakellia carteri, and Lissondendryx sp. A total synthesis of Halichondrin B was published in 1992 (Aicher, T. D. et al., J. Am. Chem. Soc. 114: 3162-3164).
  • Halichondrin B has demonstrated in vitro inhibition of tubulin polymerization, microtubule assembly, beta s -tubulin crosslinking, GTP and vinblastine binding to tubulin, and tubulin-dependent GTP hydrolysis and has shown in vitro and in vivo anti-cancer properties. Accordingly, there is a need to develop synthetic methods for preparing analogs of Halichondrin B useful as anti-cancer agents.
  • the present invention provides methods for preparing analogs of Halichondrin B having pharmaceutical activity, such as anticancer or antimitotic (mitosis-blocking) activity.
  • These compounds include a compound of formula B-1939:
  • These compounds are useful for treating cancer and other proliferative disorders including, but not limited to, melanoma, fibrosarcoma, leukemia, colon carcinoma, ovarian carcinoma, breast carcinoma, osteosarcoma, prostate carcinoma, and lung carcinoma.
  • the present invention also provides synthetic intermediates useful for preparing said analogs of Halichondrin B.
  • Halichondrin B As described in, e.g. U.S. Pat. No. 6,365,759 and U.S. Pat. No. 6,469,182 the entirety of which are incorporated herein by reference.
  • These Halichondrin B analogs are prepared generally by the assembly of three fragments F-1, F-2, and F-3, as shown by Scheme I below:
  • the present invention provides a compound F-1:
  • R 1 is OR. In other embodiments, R 1 is OR wherein R is hydrogen, methyl, or benzyl.
  • PG 1 and PG 2 are hydrogen. In other embodiments, one of PG 1 and PG 2 is hydrogen.
  • each of PG 1 and PG 2 taken with the oxygen atom to which it is bound, is independently selected from esters, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates.
  • Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio) pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate, or carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl.
  • silyl ethers examples include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers.
  • Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives.
  • Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers.
  • arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, 2- and 4-picolyl.
  • one or both of the PG 1 and PG 2 moieties of F-1 are silyl ethers or arylalkyl ethers. In yet other embodiments, one or both of the PG 1 and PG 2 moieties of F-1 are t-butyldimethylsilyl or benzoyl. In still other embodiments, both of the PG 1 and PG 2 moieties of F-1 are t-butyldimethylsilyl.
  • PG 1 and PG 2 are taken together, with the oxygen atoms to which they are bound, to form a diol protecting group, such as a cyclic acetal or ketal.
  • a diol protecting group such as a cyclic acetal or ketal.
  • groups include methylene, ethylidene, benzylidene, isopropylidene, cyclohexylidene, and cyclopentylidene, a silylene derivative such as di-t-butylsilylene and a 1,1,3,3-tetraisopropyldisiloxanylidene derivative, a cyclic carbonate, and a cyclic boronate.
  • PG 1 and PG 2 are taken together to form an acetonide group.
  • R 2 is CHO.
  • R 2 is —CH ⁇ CH 2 .
  • the present invention provides a compound of formula F-1 having the stereochemistry depicted in compound F-1′:
  • TBS refers to t-butyldimethylsilyl
  • the present invention provides a compound F-2:
  • a suitable leaving group is a chemical moiety that is readily displaced by a desired incoming chemical moiety.
  • Suitable leaving groups are well known in the art, e.g., see, “Advanced Organic Chemistry,” Jerry March, 4 th Ed., pp. 351-357, John Wiley and Sons, N.Y. (1992).
  • Such leaving groups include, but are not limited to, halogen, alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, and diazonium moieties.
  • Suitable leaving groups include chloro, iodo, bromo, fluoro, methanesulfonyloxy (mesyloxy), tosyloxy, triflate, nitro-phenylsulfonyloxy (nosyloxy), and bromo-phenylsulfonyloxy (brosyloxy).
  • the LG 1 moiety of F-2 is sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, or optionally substituted arylsulfonyloxy.
  • the LG 1 moiety of F-2 is optionally substituted alkylsulphonyloxy.
  • the LG 1 moiety of F-2 is mesyloxy or tosyloxy.
  • the X moiety of F-2 is halogen. In other embodiments, the X moiety of F-2 is sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, or optionally substituted arylsulfonyloxy. In still other embodiments, the X moiety of F-2 is triflate.
  • the PG 3 moiety of F-2, taken with the oxygen atom to which it is bound is a silyl ether. In other embodiments, the PG 3 moiety of F-2, taken with the oxygen atom to which it is bound, is an ester group. According to one aspect of the present invention, the PG 3 moiety of F-2 is t-butyldimethylsilyl. According to another aspect of the present invention, the PG 3 moiety of F-2 is pivaloyl or benzoyl.
  • the present invention provides a compound of formula F-2 having the stereochemistry depicted in formula F-2′:
  • a compound F-2a or F-2b is provided:
  • MsO mesylate
  • TfO triflate
  • OPv pivaloate
  • OBz benzoate
  • TSO tosylate
  • the present invention provides a compound of formula F-2b wherein said compound is crystalline.
  • a compound of formula F-2b is provided wherein said compound is crystallized from an alkane solvent.
  • crystalline F-2b is provided wherein said compound is crystallized from pentane or heptane.
  • crystalline F-2b is provided wherein said compound is crystallized at about 0° C.
  • Suitable hydroxyl protecting group PG 5 is as described and defined for the PG 3 moiety of compound F-2, supra.
  • PG 5 taken with the oxygen atom to which it is bound, is a silyl ether.
  • PG 5 is t-butyldimethylsilyl.
  • the Alk moiety of compound F-2d is methyl.
  • R′′ moiety of compound F-2e may be transformed from OH to a protected hydroxyl group, OPG 3 , or, alternatively, directly to LG 4 . Such transformations are known to one skilled in the art and include, among others, those described herein.
  • R′′ is OH or LG 4 .
  • the LG 4 leaving group of formula F-2e is as described and defined for the LG 1 moiety of compound F-2, supra.
  • LG 4 is tosyloxy or mesyloxy.
  • PG 3 moiety of compound F-2e is as defined and described for the PG 3 moiety of compound F-2, supra.
  • PG 3 taken with the oxygen atom to which it is bound, is a silyl ether.
  • PG 3 is t-butyldiphenylsilyl.
  • Still another aspect of the present invention provides a compound F-2f:
  • Alk, PG 3 and PG 5 are as defined generally and in classes and subclasses described above and herein.
  • Compounds of formula F-2f are used to prepare compounds of formula F-2 by methods described herein and those known in the art.
  • compounds of formula F-2 are prepared from D-quinic acid as shown by Scheme II below. Details of the preparation of compounds of formula F-2 are set forth in the Examples infra.
  • Scheme III above shows an alternate method for preparing intermediate 17 from intermediate 12 via Eschenmoser-Tanabe Fragmentation, wherein each Rx R x is independently OPG x or CN wherein PG x is a suitable hydroxyl protecting group as described herein.
  • Intermediate 17 is then used to prepare compounds of formula F-2 according to Scheme II above.
  • Still another method for preparing compounds of formula F-2 from D-quinic acid provides an alternative route from intermediate 9 to intermediate 17 as shown in Scheme IV below.
  • PG y is a suitable carboxyl protecting group, as described herein, and each PG x is independently a suitable hydroxyl protecting group as described herein.
  • each PG 5 and PG 6 is independently a suitable hydroxyl protecting group.
  • PG 5 and PG 6 are taken together to form a cyclic diol protecting group.
  • PG 5 and PG 6 are taken together to form a cyclohexylidene protecting group.
  • LG 5 is a suitable leaving group. Such suitable leaving groups are well known in the art and include those described herein.
  • LG 5 is mesyloxy or tosyloxy.
  • the present invention provides a compound of formula A:
  • the present invention provides a compound of formula A having the stereochemistry as depicted in formula A′:
  • the present invention provides a compound of formula A′ wherein W is C(O) and said compound is of formula A′-1:
  • the A group of formulae A and A′ is a C 1-6 aliphatic group, wherein A is optionally substituted with Q 1 .
  • the A group of formulae A and A′ is a C 2-5 aliphatic group, wherein A is substituted with one or more Q 1 groups.
  • each Q 1 group of formulae A and A′ is independently selected from cyano, halo, azido, oxo, OR, SR, SO 2 R, OSO 2 R, N(R) 2 , NR(CO)R, NR(CO) (CO)R, NR(CO)N(R) 2 , NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R) 2 , O(CO)N(R) 2 , or OPG 1 , wherein PG 1 is a suitable hydroxyl protecting group.
  • each Q 1 group of formulae A and A′ is independently selected from cyano, halo, azido, oxo, N(R) 2 , OR, SR, SO 2 R, or OSO 2 R. In other embodiments, each Q 1 group of formulae A and A′ is independently selected from cyano, halo, azido, oxo, OR, SR, SO 2 R, OSO 2 R, N(R) 2 , NR(CO)R, NR(CO)R, and O(CO)N (R) 2 .
  • exemplary Q 1 groups include NH(CO) (CO)-(heterocyclic radical or heteroaryl), OSO 2 -(aryl or substituted aryl), O(CO)NH-(aryl or substituted aryl), aminoalkyl, hydroxyalkyl, NH(CO) (CO)-(aryl or substituted aryl), NH(CO) (alkyl) (heteroaryl or heterocyclic radical), O(substituted or unsubstituted alkyl) (substituted or unsubstituted aryl), and NH(CO) (alkyl) (aryl or substituted aryl).
  • the A group of formulae A and A′ has one of the following characteristics:
  • (S)-hydroxyl means that the configuration of the carbon atom having the hydroxyl group is (S).
  • Embodiments of the invention also include compounds wherein A is substituted at least once on each carbon atom: (1) alpha and gamma, (2) beta and gamma, or (3) alpha and beta to the carbon atom to which A is attached.
  • Each of the alpha, beta, and gamma carbon atoms are independently in the (R) or (S) configuration.
  • the invention provides said compound wherein A is substituted at least once on each carbon atom alpha and beta to the carbon atom to which A is attached.
  • Exemplary A groups of formulae A and A′ include 2,3-dihydroxypropyl, 2-hydroxyethyl, 3-hydroxy-4-perfluorobutyl, 2,4,5-trihydroxypentyl, 3-amino-2-hydroxypropyl, 1,2-dihydroxyethyl, 2,3-dihyroxy-4-perflurobutyl 2,3-dihydroxy-4-perfluorobutyl, 3-cyano-2-hydroxypropyl, 2-amino-1-hydroxy ethyl, 3-azido-2-hydroxypropyl, 3,3-difluoro-2,4-dihydroxybutyl, 2,4-dihydroxybutyl, 2-hydroxy-2-(p-fluorophenyl)-ethyl, —CH 2 (CO) (substituted or unsubstituted aryl), —CH 2 (CO) (alkyl or substituted alkyl, such as haloalkyl or hydroxyalkyl) and 3,3-diflu
  • the A group of either of formulae A and A′ is 3-amino-2-hydroxypropyl.
  • the present invention provides a compound of either of formulae A and A′, wherein Q 1 is OPG 1 , wherein PG 1 is a suitable hydroxyl protecting group.
  • Suitable hydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • the PG 1 moiety of either of formulae A and A′, taken with the oxygen atom to which it is bound is selected from esters, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers.
  • esters include formates, acetates, carbonates, and sulfonates.
  • Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl.
  • silyl ethers examples include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers.
  • Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives.
  • Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers.
  • arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, 2- and 4-picolyl.
  • the PG 1 moiety of either of formulae A and A′, taken with the oxygen atom to which it is bound, is a silyl ether or arylalkyl ether.
  • the PG 1 moiety of either of formulae A and A′ is t-butyldimethylsilyl or benzoyl.
  • the PG 1 moiety of either of formulae A and A′ is t-butyldimethylsilyl (“TBS”).
  • two Q 1 on A are optionally taken together to form a 3-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, two Q 1 on A are taken together to form an epoxide ring.
  • the PG 5 and PG 6 groups of formula A and A′ are independently selected from those suitable protecting groups described above for the PG 1 group of formula A and A′. In other embodiments, the PG 5 and PG 6 groups of formula A and A′ are taken together to form a cyclic diol protecting group.
  • diol protecting groups are well known in the art and include those described by Greene and include cyclohexylidene and benzylidene diol protecting groups.
  • the present invention provides a method for preparing compounds of formula F-2 according to Schemes V-a, V-b, and V-c below:
  • the present invention provides crystalline ER-817664.
  • Scheme VI-a shows a general method for using this compound in the preparation of intermediates useful for preparing compounds of formula F-2.
  • intermediate 2 (from Scheme II) is used to prepare ER-812829 in a stereoselective manner.
  • protecting groups are useful for protecting the diol of ER-812829.
  • Such groups are known to one of ordinary skill in the art and include cyclohexylidene and benzylidene diol protecting groups.
  • step (a) the hydroxyl group of ER-811510 is treated with 2-bromo acetylchloride to form ER-812771.
  • the bromo intermediate is treated with triphenylphosphine to form a Wittig reagent in situ in a manner substantially similar to that described by Murphy, et al, Tetrahedron Letters, 40, (1999) 3455-3456.
  • This Wittig reagent then forms the lactone ER-812772.
  • stereoselective hydrogenation of the double bond affords ER-812829.
  • the present invention also provides a method for preparing intermediates useful for preparing compounds of formula F-2 from D-quinic acid, from intermediate ER-812829 depicted in Scheme VII above, as shown in Scheme VII-a below.
  • the present invention provides a compound F-3:
  • R 4 group of F-3 is an optionally substituted C 1-6 aliphatic group or an optionally substituted aryl group.
  • suitable R 4 groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, and phenyl wherein each group is optionally substituted.
  • suitable leaving groups are well known in the art, e.g., see “Advanced Organic Chemistry,” Jerry March, 4 th Ed., pp. 351-357, John Wiley and Sons, N.Y. (1992).
  • Such leaving groups include, but are not limited to, halogen, alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, silyl, and diazonium moieties.
  • Suitable leaving groups include chloro, iodo, bromo, fluoro, methanesulfonyloxy (mesyloxy), tosyloxy, triflate, nitro-phenylsulfonyloxy (nosyloxy), and bromo-phenylsulfonyloxy (brosyloxy).
  • the LG 2 moiety of F-3 is iodo.
  • the suitable leaving group may be generated in situ within the reaction medium.
  • LG 2 in a compound of formula F-3 may be generated in situ from a precursor of that compound of formula F-3 wherein said precursor contains a group readily replaced by LG 2 in situ.
  • said precursor of a compound of formula F-3 contains a group (for example, a trimethylsilyl group) which is replaced in situ by LG 2 , such as an iodo group.
  • the source of the iodo group may be, e.g., N-iodosuccinimide.
  • Such an in situ generation of a suitable leaving group is well known in the art, e.g., see Id.
  • each PG 4 taken with the oxygen atom to which it is bound, is independently selected from esters, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates.
  • Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl.
  • silyl ethers examples include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers.
  • Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives.
  • Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers.
  • arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, 2- and 4-picolyl.
  • one, two, or three of the PG 4 moieties of F-3, taken with the oxygen atom(s) to which they are bound, are silyl ethers or arylalkyl ethers.
  • one, two, or three of the PG 4 moieties of F-3 are t-butyldimethylsilyl or benzyl.
  • all three of the PG 4 moieties of F-3 are t-butyldimethylsilyl.
  • a compound of formula F-3 wherein said compound has the stereochemistry as depicted in formula F-3′:
  • a compound F-3a is provided:
  • TBS refers to t-butyldimethylsilyl
  • Scheme VIII above shows a general method for preparing intermediate F-5a from fragments F-1 and F-2.
  • fragments F-1 and F-2 are coupled using methods substantially similar to that described by Kishi, et al., Org Lett 4:25 p 4431 (2002) to afford intermediate F-4.
  • This coupling is performed in the presence of the chiral oxazole (ER-807363) or, alternatively, in the absence of ER-807363.
  • the coupling reaction of F-1 and F-2 proceeds with higher selectivity when performed in the presence of ER-807363.
  • Intramolecular Williamson ether formation of F-4 by treating F-4 with potassium hexamethyldisilazide, then furnishes tetrahydropyran F-5 as a mixture of stereoisomers. The stereoisomers are then separated to afford F-5a. The details of these steps are set forth in the Examples infra.
  • the present invention provides a compound F-4:
  • PG 1 , PG 2 , PG 3 , LG 1 , and R 1 are as defined in general and in subclasses above and herein.
  • PG 3 is hydrogen or a suitable hydroxyl protecting group.
  • the present invention provides a compound of formula F-4 wherein said compound has the stereochemistry depicted in formula F-4′:
  • PG 1 , PG 2 , PG 3 , LG 1 , and R 1 are as defined in general and in subclasses above and herein.
  • the present invention also provides a compound F-4a:
  • MsO mesylate
  • TSS t-butyldimethylsilyl
  • OPv pivaloate
  • the present invention provides a compound F-5:
  • each PG 1 , PG 2 , PG 3 , and R 1 is as defined in general and in subclasses above and herein.
  • the present invention provides a compound of formula F-5 having the stereochemistry as depicted in formula F-5′ or F-5a:
  • each PG 1 , PG 2 , PG 3 , and R 1 is as defined in general and in subclasses above and herein.
  • Scheme IX above shows a general method for preparing an intermediate-F-9 from F-3′and F-6.
  • the sulfone intermediate F-6 is treated with n-butyl lithium then with the aldehyde F-3′.
  • the resulting diol intermediate F-7 is then oxidized with Dess-Martin reagent to form the ketone-aldehyde intermediate F-8 which is then treated with SmI 2 to afford intermediate F-9.
  • SmI 2 SmI 2
  • Scheme X above sets forth a general method for preparing the Halichondrin B analogs of the present invention from F-9a (LG 2 is iodo).
  • an intramolecular coupling is achieved, by conditions substantially similar to those described at Scheme V above, to form hydroxyl compound F-10.
  • the intramolecular coupling is performed in the presence of the chiral oxazole ligand, described herein.
  • the addition of the chiral oxazole ligand imparts a higher yield and greater efficiency for the reaction.
  • the details of this reaction are set forth in the Examples below.
  • Compound F-10 is then oxidized to form F-11.
  • the hydroxyl protecting groups of F-11 are removed by appropriate means to afford F-12.
  • Halichondrin B analog B-1939 Using the preparation of Halichondrin B analog B-1939 to exemplify, the following Examples describe the synthesis of Halichondrin B analogs using the methods and compounds of the present invention.
  • Halichondrin B is prepared by the methods and from the compounds of the present invention including, but not limited to, those analogs of Halichondrin B described in U.S. Pat. Nos. 6,214,865 and 6,365,759, the entirety of which are herein incorporated by reference. Accordingly, it will be appreciated that the synthetic methods described below, by way of example, do not limit the scope of the invention which is defined by the appended claims.
  • D-glucurono-6,3-lactone (1 wt., 1 eq.) was combined with ACN (3 vol.) and acetone (9 vol.).
  • Catalytic conc. sulfuric acid was added and the system held at reflux for 3 hours.
  • the system was checked for dissolution of D-glucurono-6,3-lactone.
  • the reaction was cooled to 25° C. and stirred for 15 hours.
  • Solid sodium bicarbonate (0.5 wts) was added and the reaction stirred for 3 additional hours. Solids were removed by filtration and the organics were partially concentrated and azeotroped with additional ACN (2 wts).
  • ER-806045 was taken into the next reaction without isolation.
  • ER-806050 was isolated as a tBuOH solution (2.5 vol.) after concentration at reduced pressure (95% yield).
  • the toluene solution (10.1 wt %, 9.9 wts) of ER-806051/52 (1 wt, 1 eq.) was further diluted with additional toluene (3 wts).
  • N-Methylmorpholine (0.94 wts, 3.0 eq.) and DMAP (0.075 wts, 0.2 eq.) were added to the toluene solution and the resulting mixture was cooled below 15° C.
  • Benzoyl chloride was added keeping the internal temperature below 25° C.
  • the reaction was then stirred for 12 hours at 75° C.
  • the reaction was cooled to 15° C. and the temperature kept below 25° C. during the 1N HCl (5 vol.) quench.
  • AllylTMS (1.03 wts, 4.8 eq.) was premixed with ER-806053/54 (1 wt, 1 eq.), available as a 22 wt % solution in toluene from the previous step (4.55 wts, 1 eq.), and added to the freshly generated Ti(OiPr)Cl 3 .
  • the internal temperature during the addition was kept below 30° C.
  • the reaction was stirred between 20-30° C. for 2 hours.
  • the reaction was cooled to ⁇ 5° C. and quenched with 1N HCl (6 vol.), keeping the internal temperature below 30° C.
  • the layers were separated and the organic layer sequentially washed with aqueous NaHCO 3 (5 wt.) and water (3 vol.).
  • the organic layer was partially concentrated at reduced pressure (100% crude yield) and further azeotroped with additional toluene (4 vol.).
  • the resulting ketone (ER-806058) was dissolved in a final 4 vol. of toluene, checked for water content and used as is in the next reaction.
  • ER-806059 was dissolved in 1:1 toluene/CH 3 CN (5 vol.) at room temperature. Filtered TMSI (1.23 wt., 4 eq.) was added, keeping the initial temperature below 40° C. The reaction was heated to 60° C. for 2 hours. The reaction was cooled to ⁇ 15° and quenched with 25% aqueous ammonium hydroxide below 30° C. The reaction contents were stirred overnight and the layers separated. The organic layer was charged with additional toluene (5 vol.) and water (2 vol.). The layers were mixed well and separated.
  • ER-806068 (1 wt., 1 eq.) was dissolved in 1 vol. of MeOH. Water (1.5 vol.) and 2 N HCl (1.25 vol., 1 eq.) were added and the reaction stirred at 25° C. The reaction was quenched by inverse addition to 2M NaOH (1.34 vol.) at 10° C. The reaction was diluted with isopropyl acetate (5 vol.), the layers were mixed well and separated. The aqueous layer was back extracted with 5 vol. of isopropyl acetate and the combined organic layers were dried over MgSO 4 (0.5 wt.), filtered, and concentrated at reduced pressure to afford crude diol ER-806063.
  • ER-806065 (1 wt., 1 eq.) was dissolved in heptane, isooctane, or IPA (10 vol.) The solution was cooled below ⁇ 60° C. ( ⁇ 10° C.). Ozone was bubbled through the solution at low temperature until the solution retained a blue color. Nitrogen was purged through the solution for 15-30 minutes, and the reaction warmed to 5° C. while the nitrogen flush was continued. 7-15 wt. % Lindlar Catalyst (5% Pd on CaCO 3 poisoned with Pb, 0.1 wt.) was added. The reactor head was purged several times with nitrogen, evacuated, and placed under 1 atmosphere H 2 (g).
  • a reactor was charged with pre-rinsed Amberlyst 15 (0.05 wt.) and water (4.63 vol.) and cooled to an internal temperature of 0-5° C.
  • the reactor was charged with 2,3-dihydrofuran (1 wt., 1 eq.) and stirred for 1.5 hours maintaining internal temperature around 5° C.
  • a second reactor was charged with water (4.63 vol.) and heated to an internal temperature of 35° C.
  • the same reactor was charged with tin powder (2.2 wt., 1.3 eq.), distilled 2,3-dibromopropene (3.71 wt., 1.3 eq.), and 48% hydrobromic acid (0.002 vol.), respectively.
  • the second reactor was charged with 2,3-dibromopropene portion-wise (9 ⁇ 0.37 wt.) while maintaining the internal temperature below 45° C. After complete addition, the contents of the second reactor were stirred at an internal temperature of 35° C. for an additional 60 minutes. The filtered contents of the first reactor were charged into the second reactor at a rate such that internal temperature did not exceed 45° C. After complete addition, the heat source was removed and the second reactor was charged with Celite® 545 (2.0 wt.) and the resulting mixture stirred for 30 minutes.
  • the heterogeneous mixture was filtered through a Celite® 545 pad (2.0 wt.) and the cake washed with additional water (5 vol.). All filtrates were combined into a reactor and charged with concentrated hydrochloric acid (1.5 vol.) until the cloudy solution becomes clear. With vigorous stirring, the reactor was charged with sodium chloride (3.6 wt.) and the layers allowed to partition. The organic layer was separated and set aside. The aqueous layer was extracted with n-butanol (20 vol.). The aqueous layer was drained and the reactor charged with the organics from the first separation. The organics were washed with concentrated sodium bicarbonate (24 vol.), followed by a back extraction of the aqueous layer with n-butanol (20 vol.).
  • a reactor was charged with imidazole (0.65 wt., 2 eq.), ER-806909 (1 wt., 1 eq.), and anhydrous DMF (4.04 vol.). With stirring, the reactor was cooled to an internal temperature of 0° C. and then with tert-butylchlorodiphenylsilane (1.25 wt., 0.95 eq.) at a rate such that internal temperature did not exceed 15° C. While maintaining the internal temperature ⁇ 15° C., the reaction was stirred for an additional 1 hour. The reactor was charged with water (3.2 vol.) and n-heptane (6.4 vol.). The mixture was stirred for 5-15 minutes and the layers allowed to separate.
  • the enantiomers of ER-806545 were separated via Simulated Moving Bed (SMB) chromatography to yield ER-808373 (0.55 wt., 0.55 eq.) and ER-806721 (0.45 wt., 0.45 eq.) as yellow oils.
  • SMB chromatography protocol used to separate the enantiomers of ER-806545 is as follows.
  • the enantiomers of ER-806545 were separated using the above protocol in the following manner.
  • 10 L of 36 g/L ER-806545 in mobile phase was pumped (Silog model Chemtech) through a 142 mm diameter 0.45 ⁇ m pore size nylon filter (Cole-Parmer # 2916-48) and into the Feed tank.
  • the Eluant tank was filled with 36L mobile phase that has been filtered through an in-line 45 mm diameter 1 ⁇ m glass fiber filter (Whatman GFC), additional vol. were added throughout the run.
  • the internal temperature of the SMB apparatus was adjusted to 27° C.
  • the Feed and Eluant inlets were both connected to the Eluant tank.
  • the Feed and Eluant pumps were primed and purged with mobile phase solvent.
  • the SMB apparatus column switching was initiated, the pumps were turned on and the flow rates were gradually increased to full speed while maintaining absolute flow rate differences between each pump. Once fall speed was achieved the Raffinate and Extract flow rates were measured and adjustments to pump flow rates were made to correct for deviations in pump specifications.
  • the Feed pump (Pump 1) was reduced to 0 mL/min, the inlet reconnected to the Feed tank, the pump primed with Feed solution and then the flow rate gradually increased back to full operating speed.
  • the Raffinate and Extract outlets were collected into separate tanks and samples of each of each were acquired every 2 hours. The samples were monitored for chiral purity by analytical HPLC using the HPLC method set forth below. Adjustments to the flow rates of Pumps 2, 3 and 4 as well as to the tact time were made to afford the desired outlet purities.
  • the Feed pump was once again reduced to zero flow rate and connected to the Eluant tank.
  • the Feed pump was brought back to full speed and the system was allowed to wash for 20 minutes.
  • the Raffinate and Extract outlets were maintained for 10 minutes (10 tacts) during the wash period and, for the remainder of the wash, the outlets were collected into a separate tank.
  • the column wash was eventually concentrated and added to the Feed on subsequent runs.
  • the collected Extract (ER-806721) at the end of each run was pooled with material collected from the same starting material lot and the final pooled lot was analyzed again for chiral purity by the analytical HPLC method described in Table 1 below. The same procedure was applied to the collected Raffinate (ER-808373).
  • a reactor was charged with triphenylphosphine (0.7 wt., 1.2 eq.), p-nitrobenzoic acid (0.45 wt., 1.2 eq.), ER-808373 (1 wt., 1 eq.), and anhydrous toluene (8 vol.).
  • the reaction was cooled to internal temperature of 0° C. and DEAD (1.17 wt., 1.2 eq.) was slowly added at a rate such that the internal temperature did not exceed 7° C.
  • n-Heptane 3.3 vol. was added and the mixture cooled to an internal temperature 10° C. then stirred for 30-40 minutes. The resulting precipitate was removed by filtration.
  • the filter-cake was washed with n-heptane (3.3 vol.), TBME (0.55 vol.), n-heptane (1.1 vol.), and MTBE (0.55 vol.), respectively. All filtrates were combined and concentrated in vacuo.
  • the crude concentrate was dissolved in THF (8 vol.) then water (0.8 vol.) and lithium hydroxide dihydrate (0.18 wt., 2 eq.) were added. The mixture was stirred at ambient temperature then n-heptane (3.3 vol.) was added and stirred for 5 minutes. Water (2.2 vol.) and n-heptane (3.3 vol.) were added, the biphasic mixture was stirred for 5 minutes, and the layers were allowed to partition.
  • a reactor was charged with ER-806721 (1 wt., 1 eq.) and anhydrous dichloromethane (4.2 vol.). The reaction was cooled to an internal temperature of 0-5° C., then triethylamine (0.34 wt., 1.5 eq.), p-toluenesulfonyl chloride (0.51 wt., 1.2 eq.), and 4-(dimethylamino)-pyridine (0.001 wt., 0.25 eq.) were added. The resulting mixture was stirred at ambient temperature for 48 hours then water (1.8 vol.) and dichloromethane (1.8 vol.) were added. After sufficient mixing, the organics were separated and concentrated.
  • the concentrate was dissolved in MTBE (1.8 vol.) and washed with brine (1.8 vol.). The organic layer was separated and set aside. The aqueous layer was back extracted with MTBE (1.8 vol.) then all organics were combined and concentrated in vacuo.
  • the crude oil was filtered through a plug of SiO 2 (70-230 mesh, 1 wt.) eluting with MTBE (7 vol.) and the filtrates were concentrated in vacuo.
  • the concentrate was dissolved in IPA (5 vol.) and water (0.25 vol.) was added. The resulting mixture was cooled to an internal temperature of 15° C. and then seeded with ER-807204. After seeding, the mixture was cooled to an internal temperature of 0° C.
  • a reactor was charged with 21% sodium ethoxide in ethanol (2.97 wt., 0.9 eq.). The solution was heated to an internal temperature of 65° C. then diethyl malonate (3.24 wt., 2 eq.) was added at a rate such that the internal temperature did not exceed 70° C. The mixture was stirred for 30 minutes and then ER-806906 (1 wt., 1 eq.) was added over 3-5 hours. Upon complete addition, the reaction was stirred for 60 minutes and then cooled to an internal temperature of 50° C. Concentrated hydrochloric acid (0.84 wt., 1.05 eq.) was added at a rate such that internal temperature did not exceed 65° C.
  • a reactor was charged with LHMDS 1.0 M in toluene (6.61 wt., 1.04 eq.) and cooled to an internal temperature of ⁇ 75° C.
  • ER-805552 (1 wt., 1 eq.) was dissolved in anhydrous THF and added to the reactor at a rate such that internal temperature did not exceed ⁇ 70° C. Upon complete addition, the resulting mixture was stirred for 30 minutes.
  • a second reactor was charged with anhydrous THF (2.5 vol.) and methyl iodide (1.27 wt., 1.25 eq.) and cooled to an internal temperature of ⁇ 75° C.
  • a reactor was charged with N,O-dimethylhydroxylamine HCl (1.05 wt., 1.5 eq.) and anhydrous CH 2 Cl 2 (8.1 vol.) and cooled to an internal temperature of 0° C. 2 M trimethylaluminum in toluene (3.93 wt., 1.5 eq.) was added at a rate such that internal temperature did not exceed 5° C. The reaction was stirred for an additional 10 minutes and ER-806724 was added at a rate such that internal temperature did not exceed 5° C. The reaction was diluted with CH 2 Cl 2 (15 vol.) then inverse quenched into 1.3 M sodium tartrate (20 vol.) at an internal temperature of 0° C.
  • a reactor was charged with ER-806753 (1 wt., 1 eq.), CH 2 Cl 2 (5 vol.) and NMO-50% in water (0.8 wt., 1.1 eq.). The mixture was cooled to an internal temperature of 10° C. and then 0.197 M OsO 4 in toluene (0.06 vol., 0.004 eq.) was added. Sodium sulfite (0.1 wt., 0.25 eq.) and water (0.85 vol.) were added and the reaction stirred for 1 hour. The mixture was diluted with brine (0.85 vol.) and the organics were concentrated in vacuo to approximately 1 ⁇ 3 vol.
  • a second reactor was charged with sodium periodate (1.3 wt., 2 eq.) followed by THF (2.5 vol.).
  • the concentrated diol was added at a rate such that the internal temperature did not exceed 30° C.
  • the resulting mixture was stirred at room temperature.
  • Water (1.25 vol.), MTBE (7 vol.) and brine solution (1.25 vol.) were added and the layers separated. The organics were washed a second time with a mixture of brine solution (1 vol.) and saturated sodium bicarbonate (1 vol.).
  • a reactor was charged with ER-806629 (1.53 wt., 3.1 eq.) and THF (10.5 vol.) and the solution was degassed with nitrogen sparge for 60 minutes.
  • a second inserted reactor was charged with ER-807204 (1 wt., 1.0 eq.), ER-806754 (0.66 wt., 1.2 eq.) and THF (2.7 vol.) and this solution was degassed with argon sparge for 45 minutes.
  • the reactor containing ER-806629 was charged with CrCl 2 (0.63 wt., 3.1 eq.) and followed by Et 3 N (0.52 wt., 3.1 eq.). The dark green suspension was stirred at an internal temperature of 30 to 35° C.
  • a reactor was charged with ER-807524 (1 wt., 1 eq.) and anhydrous THF (1.25 vol.). The mixture was cooled to an internal temperature of ⁇ 20° C. and 3 M methyl magnesium chloride (0.59 vol., 1.2 eq.) was added at a rate such that the internal temperature did not exceed 0° C. Upon complete addition, the mixture was warmed to an internal temperature of 0° C. over 2 hours. The reaction mixture was inverse quenched into semi-saturated ammonium chloride (2.62 vol.) and the resulting mixture diluted with TBME (2 vol.) with vigorous mixing. The aqueous layer was discarded and the organics washed with brine (2 vol.) then concentrated in vacuo. The crude product was purified via SiO 2 column chromatography to yield ER-807525 (0.79-0.82 wt., 0.85-0.88 eq.) as yellow oil.
  • a reactor was charged with ER-807525 (1 wt., 1 eq.), N-phenylbistrifluoromethanesulfonamide (0.59 wt., 1.1 eq.), and anhydrous THF (4.1 vol.) and the mixture cooled to an internal temperature of ⁇ 75° C.
  • 0.5 M KHMDS in toluene (2.75 wt., 1 eq.) was added at a rate such that internal temperature did not exceed ⁇ 60° C. then the reaction was warmed to ⁇ 20° C. over 2 hours.
  • the reaction was quenched with semi-saturated NH 4 Cl (2.4 vol.) at a rate such that internal temperature did not exceed 0° C.
  • ER-807527 was separated by preparative HPLC chromatography and the desired fractions concentrated to yield ER-806730 (0.56 wt., 0.56 eq.) as a clear yellow oil.
  • the preparative HPLC chromatography protocol used to isolate ER-806730 is as follows.
  • ER-807527 was first diluted to 0.1 g/ml in the mobile phase and filtered under vacuum through a 47 mm, 1 ⁇ m pore size, glass fiber filter (Whatman GFC). The filtrate was then concentrated under vacuum on a rotary evaporator. Flow on the SD-1 HPLC pump A (primed and purged with mobile phase) was initiated and the flow rate gradually increased to 140 mL/minute. The system was washed until the UV and RI detectors achieved a stable baseline. The RI detector reference flow cell was flushed with fresh mobile phase.
  • Chromatography of 8 g injections of ER-807527 was accomplished by diluting the current lot of ER-807527 to a concentration of 0.8 g/mL in the mobile phase. Injecting 10 mL aliquots of the dissolved material and collecting the eluant corresponding to the ER-806730 peak approximately beginning at the peak apex approximately 24 minutes and continuing to 35 minutes. Subsequent injections and fraction collection were continued until the starting material is exhausted.
  • a reactor was charged with ER-806730 (1 wt., 1 eq.) and anhydrous dichloromethane (4.8 vol.) and cooled to an internal temperature of 0° C. 2,4,6-Collidine (1.16 wt., 4 eq.) and DMAP (0.03 wt., 0.1 eq.) were added and the resulting mixture stirred for 15 minutes and then trimethylacetyl chloride (0.3 wt., 1.05 eq.) was added at a rate such that internal temperature did not exceed 10° C. Water (3 vol.) was added and the mixture stirred for 15 minutes. TBME (10 vol.) was added and the mixture stirred for an additional 10 minutes.
  • the organic layer was washed with 1N HCl (10 vol.) washing until a negative result for 2,4,6-collidine is obtained then with water (5 vol.), saturated sodium bicarbonate (5 vol.), and saturated brine (5 vol.), respectively.
  • the organic layer was concentrated in vacuo and the concentrate purified via SiO 2 column chromatography to yield ER-806732 (1.02 wt., 0.85 eq.) as a yellow oil.
  • a reactor was charged with ER-806732 (1 wt., 1 eq.) and anhydrous THF (2.35 vol.) and cooled to an internal temperature of 0° C.
  • Triethylamine (0.22 wt., 1.1 eq.) was added followed by methanesulfonyl chloride (0.24 wt., 1.05 eq.) at a rate such that internal temperature did not exceed 10° C.
  • the reaction was stirred at an internal temperature of 0° C. then n-heptane (3.4 vol.) was added with vigorous stirring and the layers were allowed to partition.
  • PPh 3 (5 eq, 2.3 wt), pyridine (10 eq 1 vol), and NIS (3.0 eq, 1.1 wt) were added to the solution of 16 (1 wt) in THF (10 v). 20% wt/wt aqueous citric acid (10 eq, 14 wt) was then added and the resulting mixture allowed to stir for 10 minutes. The reaction was diluted with heptane (10 v) and the aqueous layer separated. The organic layer was washed with water (5 v), 10% wt/v aqueous sodium thiosulfate (5 v), water (5 v) and brine (5 v). The solvent was exchanged with EtOH and concentrated to 5 v. Water (10 v) was added and the resulting precipitate was collected by filtration to obtain 17 (0.65 wt) as a white solid.
  • AlMe 3 (2 M in toluene, 1.5 eq, 1.5 v) was added to a suspension of dimethylhydroxylamine hydrogen chloride (1 wt) in CH 2 Cl 2 (2.5 v) at 0° C.
  • the reaction mixture was then added to aqueous sodium tartrate (1.3 M, 20 v) keeping the temperature below 10° C.
  • the layers were allowed to partition, were separated, and the organic layer was dried with Na 2 SO 4 (5 wt).
  • the resulting suspension was filtered and the filtrate concentrated.
  • Methyl magnesium chloride (3.0 M, 59 wt, 1.2 eq) was is added to a solution of 21 (1 wt) in anhydrous THF (1.11 wt, 1.25 v) at a rate that maintained the reaction temperature below 0° C. After stirring at 0° C., the reaction was reverse quenched into saturated ammonium chloride (2.5 v) and water (2.3 v). The resulting mixture was diluted with MTBE (10 v) and stirred vigorously. The aqueous layer was separated and the organic layer washed with brine (2.5 v) and concentrated to provide 22 (0.84 wt).
  • Example 4a provides an alternate method of preparing compounds of formula A, an intermediate to F 2, using the general scheme set forth at Scheme V above. This method uses ER-812935 as an intermediate as prepared according to Example 3 (compound 4), above.
  • ER-812935 (1 wt) was dissolved in THF (10 v) and cooled to 0° C. LAH (1.0 M in THF, 0.70 eq, 2.0 v) was added keeping the temperature below 5° C. While stirring vigorously, excess reagent was quenched with water (0.078 v) keeping the temperature below 5° C. While maintaining the vigorous stirring, NaOH (15% wt/wt in water (0.078 v)) was added followed by water (0.18 v). After adding Celite® (2 wt), the suspension was filtered and the cake rinsed with THF (5 v). The solution of ER-817633 (0.92 wt, calcd. based on 100% conversion) was concentrated to 5 v and used directly in the next stage.
  • ER-818950 was dissolved in acetic acid (5 v) and hydrogen chloride (1.0 M, 1 eq, 3 v) was added and the reaction was stirred at ambient temperature. The reaction was cooled to 0° C. and NaOH (50% wt/wt, 30 eq, 7 wt) was added at a rate that maintained the temperature below 10° C. The solution was extracted with heptane (2 ⁇ 10 vol). The aqueous phase was saturated with NaCl and extracted with ACN (2 ⁇ 10 v). The combined ACN extracts were concentrated and solvent exchanged with EtOAc by atmospheric distillation to provide a solution of ER-817664 in EtOAc (3 v). Salts were filtered from the hot solution which was then cooled to 0° C. The suspension was filtered to provide ER-817664 as a white crystalline solid.
  • Example 4b provides an alternate method of preparing compounds of formula F-2 using the general scheme set forth at Schemes Vb and Vc above. This method uses ER-817664 as an intermediate as prepared according to Example 4a, above.
  • ER-817664 (1 wt) was dissolved in ACN (10 v), the suspension was cooled to 0° C. and 2-acetoxy-2-methylpropanyl bromide (4.0 eq, 2.4 v) was added followed by the addition of H 2 O (1.0 eq., 0.07 v). The resulting mixture was stirred at 0° C. for 2 hours. NaHCO 3 (sat. aqueous, 8.0 eq. 40 v) was added slowly at 0° C. The resulting mixture was stirred at room temperature for 30 minutes prior to extraction with MTBE (2 ⁇ 20 v). The organic layer was washed with brine (5 v) and concentrated to give the product as colorless oil.
  • ER-818638 (1 wt) and LiCl (2.0 eq, 0.35 wt) was stirred in ACN (8.7 v). Hunig's base (1.5 eq) was added at 25° C. 1 N HCl (5 v) was added and the mixture was extracted with MTBE (10 v). The organics were concentrated to provide ER-818640 which was used as is in the next step.
  • the starting lactone as depicted immediately above, was dissolved in DCM (50 v), Et 3 N (5.0 eq.), DMAP (0.3 eq.) and TBDPSCl (1.5 eq.) were added separately at ambient temperature under N 2 , and the resulting solution was stirred at ambient temperature for 2-3 hours. Upon the completion of the reaction, the mixture was diluted with TBME (100 v), washed with sat. aq. NaHCO 3 solution (10 v), H 2 O (10 v) and brine (10 v). The organic layer was concentrated and purified by flash chromatography to give the product as colorless oil.
  • Example 4c provides another alternate method of preparing compounds of formula F-2 using the general scheme set forth at Scheme VII above. This method uses ER-811510 as an intermediate as prepared according to Example 3, above where acetone is used instead of cyclohexanone.
  • ER-811510 (1 wt, 1 eq) was dissolved in methylene chloride (6.3 v) and cooled to ⁇ 5° C. Pyridine (0.41 vol, 1.1 eq) was added followed by bromoacetyl bromide (0.44 vol, 1.1 eq) while keeping the temperature below 0° C. The reaction was stirred at I 1 hour and warmed to room temperature. Water (8 vol) was added and the layers separated. The organic layer was washed sequentially with aqueous copper sulfate pentahydrate (1.0 M, 10 vol), water (8 vol), and brine (10 vol) then dried over magnesium sulfate, filtered and concentrated in vacuo to afford ER-812771 as a tan solid.
  • ER-812771 (1 wt, 1 eq) was dissolved in acetonitrile (6 v) and triphenylphosphine was added and the reaction heated at 50° C. for 45 minutes. The reaction was cooled to ⁇ 10° C. then 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.35 vol, 0.8 eq) was added. The reaction was stirred for 15 minutes, heated to 80° C. for 45 minutes then cooled to ambient temperature. Ammonium chloride (saturated aqueous, 10 vol) was added and the aqueous layer extracted with ethyl acetate (3 ⁇ 10 v). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by chromatography to afford ER-812772 as a white solid.
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • ER-812772 (1 wt, 1 eq) was dissolved in ethyl acetate (8 v). 10% Palladium on carbon (0.05 wt, 0.01 eq) was added, the reaction purged with nitrogen then stirred under hydrogen atmosphere for 2 hours. The catalyst was removed by filtration through Celite with ethyl acetate washed. The combined filtrates were concentrated in vacuo to afford ER-812829 as a white solid.
  • the mixture was heated to reflux for at least 1 hour before it was cooled to and aged at 85° C. for 3 hours, at 80° C. for 3 hrs and then cooled to 40° C. in 12 hrs.
  • the product was collected by filtration and the cake washed with heptane (2 vol).
  • the filter cake was dried by airflow to afford ER-805715 (1.48 wt) in 78% of yield.
  • ER-805715 (1 wt., 1 eq.) was charged to reaction vessel and dissolved in anhydrous THF (3.34 vol.) and anhydrous toluene (2.5 vol.). The mixture was cooled to ⁇ 15 to ⁇ 10° C. DIBALH (1.5M in toluene, 2.4 vol., 1.2 eq.) was added over 1 hour and the mixture stirred for 15-30 minutes at ⁇ 15 to ⁇ 10° C. The reaction was inverse quenched into KNa-Tartrate solution (1 wt. KNa Tartrate in 2.9 wt. water) at 10° C. and the resulting mixture allowed to warm to room temperature and stir for 4 hours. The mixture was filtered then the layers separated and extracted with MTBE (2 vol.). The organic layers were combined and the solvents removed in vacuo to afford ER-805814. Yield 100%, (1.02 wt.).
  • ER 805814 (1 wt.) was dissolved in anhydrous THF (3.3 vol.) and treated with (methoxymethyl)triphenylphosphonium chloride (2.11 wt., 2.1 eq.). The reaction mixture was heated to 28-32° C. then a solution of KOtBu (0.66 wt., 2 eq.) in anhydrous THF (2.64 vol.) was added over 100-140 minutes, maintaining reaction temperature 30-35° C. After 5 hours, the reaction was cooled to 20-25° C., MTBE (5.11 vol.) was added and the mixture stirred. Brine (3 wt.) and water (3 wt.) were added (exothermic at start of addition, controlled by bath @20-25° C.).
  • a solution of t-BuOK (0.989 wt, 3 eq) in THF (4 wt) was added to a suspension of (methoxymethyl)triphenylphosphonium chloride (3.12 wt, 3.1 eq) in THF (1.78 wt), maintaining the reaction temperature between 0-10° C.
  • the addition vessel was rinsed with THF (2 ⁇ 0.7 wt).
  • a solution of ER-805814 (1 wt, 1 eq) in THF (1.42 wt) was added to the reaction, maintaining 0-10° C.
  • the addition vessel was rinsed with THF (2 ⁇ 0.7 wt). The mixture was stirred at 20-30° C. overnight and 30-35° C.
  • ER-805815 In an alternative method for workup of ER-805815, the crude organic layer that is produced following brine wash and concentration is treated with MTBE (2.86 wt) and celite (0.5 wt). After stirring for 2.5 h, heptane (1.46 wt) was added over 2 hrs and the mixture stirred overnight. The precipitate was filtered. The filter cake was washed with MTBE/Heptane (1:1) (5 wt). The filtrate was concentrated in vacuo until the volume was decreased to about 3 volume. The residue was dissolved in MeOH (2 wts) and H 2 O (6 wts). The mixture was extracted with heptane/MTBE (5:1) (3*6 wts). The organic layer was separated and concentrated to provide ER-805815 which was used as is for the following step.
  • ER-805815 (1 wt) was dissolved in acetone (2.4 vol) and water (0.4 vol). N-Methylmorpholine N-oxide (0.62 wt, 2 eq) was added and the mixture cooled to 0-5° C. OSO 4 (0.15M in water, 0.065 vol) was added and the reaction was maintained at 0-5° C. The reaction mixture was stirred at 0-5° C. for 12 hours. Water (0.2 vol) was added over 1 hour at 0-2° C. The mixture was stirred for one hour at 0-5° C. The product was filtered and the solids washed twice with pre-cooled (0-5° C.) acetone/water (1/1, v/v, 2 ⁇ 0.7 vol). The product was dried to afford ER-805816 (0.526 wt, 52% yield, residual Os ⁇ 17 ppm).
  • ER-805816 In an alternate method for preparing ER-805816, a solution of ER-805815 (1 wt, 1 eq) in acetone (4 wt) was charged into a four-necked flask, then water (0.5 wt) was added at ambient temperature. To the mixture was added anhydrous N-methylmorpholine-N-oxide (0.38 wt, 1.2 eq). Potassium osmate dihydrate (0.003 wt, 0.003 eq) was added portion-wise at 25 to 35° C. while cooling with water. The mixture was kept at this temperature for 4 hours.
  • the precipitate was filtered and washed with water (1.53 wt) to afford the crude wet cake (1.05 wt).
  • the crude ER-805816 (1.05 wt) was added to water (2.81 wt) and stirred for 2 hours at about 25° C.
  • the precipitate was filtered and washed with water (1.4 wt) and methanol (0.45 wt) to afford the crude ER-805816 (0.736 wt).
  • ER-805816 (0.56 wt) was dissolved in acetone (1.76 wt) at 45 to 55° C. To the solution was added active carbon (0.027 wt) and stirred at same temperature for 0.5 hour. The mixture was filtered and the cake was washed with hot acetone (0.214 wt). The filtrate was kept at 45 to 50° C. and water (0.83 wt) was added over 10 minutes and temperature was kept at 40 to 50° C. during water addition. The mixture was cooled to 0 to 5° C. and stirred for 1.5 hours.
  • ER-805816 (1 wt) was slurried in acetic acid (0.89 vol, 5.8 eq) and acetic anhydride (3.57 wt, 13 eq). Anhydrous ZnCl 2 (0.2 wt, 0.54 eq) was added. Reaction mixture was stirred for 24 hours 18-22° C. Reaction was quenched into ice (5 wt) and water (5 vol). EtOAc (10 vol) was added with stirring and the aqueous layer is separated. The aqueous layer was back extracted with EtOAc (10 vol). The combined organic layers were washed sequentially with brine (10 vol), 5% aqueous NaOAc (6 vol), and brine (6 vol). The organic layer was concentrated.
  • ER-805819 In an alternate method for preparing ER-805819, zinc chloride (0.2 wt, 0.54 eq), acetic anhydride (2.75 wt, 10 eq), and acetic acid (1 wt, 6 eq) were combined. The mixture was cooled to 15-20° C. ER-805816 (1 wt, 1 eq) was added, maintaining the internal temperature at 15 to 30° C. The mixture was then stirred at 35-40° C. for 6 hours. The reaction mixture was cooled below 25° C. Methanol (3.2 wt, 4 vol) was added drop-wise maintaining reaction temperature below 25° C. Heptane (2.7 wt, 4 vol) was added. Water was added (4 wt, 4 vol) maintaining reaction temperature below 25° C.
  • the mixture was stirred for 15 minutes, and then the phases were separated.
  • the lower layer was washed twice with heptane (2.7 wt, 4 vol) and the heptane layers were discarded.
  • the lower layer was extracted twice with toluene (6.1 wt, 8 vol).
  • the combined toluene layers were washed twice with 17 wt % potassium bicarbonate aqueous solution (0.82 wt KHCO3 in 3.98 wt water, 4.36 vol), twice with water (4 wt), and concentrated.
  • Methanol (3.95 wt, 5 vol) was added at 25-30° C. and the mixture stirred for 10 minutes. Water (0.3 wt) was added at 25-30° C. The mixture was cooled to 0° C.
  • ER-805819 (1 wt) was dissolved in anhydrous acetonitrile (15 vol) and treated with methyl 3-trimethylsilylpent-4-eneoate (0.93 vol, 2 eq). The reaction mixture was cooled to 0-5° C. and BF 3 ⁇ OEt 2 (0.54 vol, 1.95 eq) was added over 5 minutes, maintaining reaction temperature between 0-5° C. Reaction mixture was stirred 0-5° C. for 12 hours. Reaction was quenched into saturated sodium bicarbonate (20 vol) with vigorous stirring. Extracted twice with EtOAc (2 ⁇ 8 vol). The combined organics were washed with brine (12 vol) and concentrated to give ER-805821 (1 wt, 88% yield, use as is).
  • ER 805819 (1 wt, 1 eq) and ER methyl 3-trimethysilylpent-4-eneoate (0.93 vol, 2 eq) were dissolved in anhydrous acetonitrile (5.46 wt, 7 vol).
  • the reaction mixture was cooled to 0-5° C. and BF 3 ⁇ -OEt 2 (0.54 vol, 1.95 eq) was added over 5 minutes, while maintaining reaction temperature between 0-5° C.
  • the reaction mixture was stirred at 0-5° C. for 20 hours then heptane (5.47 wt, 8 vol) was added at 0-5° C.
  • ER-805821 (1 wt) was dissolved in anhydrous THF (8.4 vol) and anhydrous MeOAc (2 vol). Triton B(OH) (3.6 vol) was added over 2 minutes, reaction maintained 17-23° C. Reaction was stirred for 1.5 hour. Reaction mixture was filtered. The filtrate was concentrated and passed through a pad of SiO 2 (5 wt, EtOAc, 20 vol). The filtrate was washed with brine (2.2 vol) and evaporated to give ER-805822 (0.54 wt, 72% yield).
  • ER-805821 (1 wt, 1 eq, 11.18 g, 21.81 mmol) was dissolved in anhydrous MTBE (4.4 wt, 6 vol.) and cooled to 0-5° C.
  • NaOMe 28 wt % in MeOH, 0.564 wt, 1.5 eq
  • the reaction was quenched by addition of acetic acid (0.188 wt, 1.6 eq.), maintaining 0-5° C. during addition.
  • ER 805822 (1 wt) was dissolved in ethyl acetate or another appropriate solvent (5 vol) and water (5 vol).
  • NaIO 4 (0.58 wt, 1.05 eq) is added portionwise over 30 min to 1 hour, maintaining reaction temperature 0-10° C. Reaction is stirred for up to 2 hours.
  • the reaction mixture was treated with NaCl (1 wt) and stirred for 30 min at 0 to 10° C.
  • the reaction mixture was filtered and the cake is rinsed with ethyl acetate (2 vol).
  • the phases were separated and the lower layer extracted with EtOAc (5 vol) three times.
  • the combined organic layer was washed with 20% aqueous NaCl (5 wt).
  • the organic layer was concentrated to give ER 804697 (1 wt).
  • the residue was dissolved in toluene (2 vol) and the solution concentrated.
  • the residue was dissolved in acetonitrile (7 vol) and used for the next step.
  • NiCl 2 (0.025 wt) and CrCl 2 (2.5 wt) were charged to reaction vessel under inert atmosphere.
  • Anhydrous dichloromethane (5 vol) was charged. Stirring was initiated and the mixture was cooled to 0-3° C.
  • Anhydrous DMSO (6.7 vol) was added with vigorous stirring over 45 minutes, maintaining temperature below 20° C.
  • ER-804697 (1 wt) was dissolved in anhydrous dichloromethane (1 vol) and charged to the reaction vessel.
  • the resulting mixture was warmed to 25° C. and 1-bromo-2-trimethylsilylethylene (2.58 wt) was added neat over 20 minutes. The reaction temperature was maintained below 45° C.
  • this reaction was performed in the presence of the chiral ligand ER-807363 in a manner substantially similar to that described for the preparation of ER-118047, infra.
  • DMSO (7 vol.) and MeCN (7 vol) were degassed and cooled to 0-10° C.
  • the solution was treated portionwise with CrCl 2 (10 eq, 3.47 wt) and NiCl 2 (0.1 eq, 0.037 wt) such that the internal temperature did not exceed 20° C.
  • a solution of ER-804697 (1 wt, 1 eq) in MeCN (7 vol) and 1-bromo-2-trimethylsilylethylene (5 eq, 2.5 wt) were added dropwise at 0-10° C., not allowing the internal temperature to exceed 15° C.
  • the reaction mixture was stirred at 5-15° C. overnight.
  • the reactor was charged with layer 1, methanol (2.8 wts), and MTBE (2.8 wts). The mixture was stirred overnight. The lower layer was separated and discarded. The upper layer was treated with layer 2. The mixture was stirred for 1 hour and the lower layer was separated and discarded. The upper layer was treated with layer 3 and heptane (4.8 wts). The mixture was stirred for 1 hour and the lower layer was separated and discarded. The upper layer was drained and saved (organic 2). The reactor was charged with layer 3, MTBE (0.8 wts), and heptane (2.7 wts). The mixture was stirred for 1 hour and the lower layers was separated and discarded. The upper layer was combined with organic 1 and organic 2.
  • ER 804698 (1 wt, 1 eq) was treated with AcOH (4.2 wts) and water (4.2 wts). The mixture was heated to 90-97° C. for 100 min. The mixture was cooled to below 15° C. then washed with heptane (2 ⁇ 2.7 wts) twice below 15° C. After phase separation, a mixture of 20 wt % aqueous KHCO 3 solution (7.7 wts, 35 eq) and MTBE (5.95 wts) was added dropwise to the lower layer such that temperature does not exceed 15° C.
  • ER-807023 (1 wt, 1 eq) and MTBE (7.43 wts) were charged to a reactor under a nitrogen atmosphere.
  • 2,6-lutidine (2.15 wts, 7.5 eq).
  • TBSOTf (2.47 wts, 3.5 eq) at 0° C.
  • MeOH (0.21 wts, 2.5 eq.) and water (14.8 wts) were added dropwise sequentially to the reaction mixture, maintaining temperature below 30° C.
  • a pre-dried glass lined reactor was charged with triphosgene (1 wt., 1 eq.) and anhydrous THF (2 vol.) and was cooled to an internal temperature of ⁇ 10° C.
  • a second pre-dried glass lined reactor was charged with ER-807244 (1.27 wt., 2.5 eq.) and anhydrous THF (3 vol.) then cooled to an internal temperature of ⁇ 10° C.
  • the contents of the first reactor were transferred into the second reactor at a rate such that internal temperature did not exceed 15° C.
  • the reaction was stirred at an internal temperature of 0° C. for 1 hour and then gradually warmed to 25° C.
  • MTBE (2.6 vol.), was added followed by process water (2 vol.) at a rate such that the internal temperature did not exceed 35° C.
  • the phases were allowed to partition and the aqueous phase separated. All organics were combined with water (0.7 vol.) and the aqueous phase discarded.
  • the MTBE was distilled to a level of ⁇ 2 vol. at atmosphere pressure to constant bp 55° C. and KF ⁇ 500 ppm.
  • ER-806629 or ER-807363 (1.7 wt., 0.57 eq.) as a crystalline solid.
  • Reactor 2 was charged with triethylamine (0.62 wt, 3.55 eq) at a rate such that internal temperature did not exceed 45° C. After complete addition, an internal temperature of 30° C. was maintained for 1 hour. After 1 hour, reactor 2 was cooled to 0° C. and charged in an inert fashion with NiCl 2 (0.02 wt, 0.1 eq), followed by the contents of reactor 1 and the reaction was warmed to rt. Reactor 2 was cooled to an internal temperature of 0° C. and then ethylenediamine (1.2 vol, 10 eq) was added at a rate such that the internal temperature did not exceed 10° C. Note: An exotherm was observed.
  • the ER-808227/THF solution from the previous step was analyzed via KF analysis. If KF ⁇ 1000 ppm, then proceeded. If KF 1000 ppm KF>1000 ppm, azeotroped in vacuo with anhydrous THF (4.1 vol.). Repeated azeotrope until specification was met. The final solution meeting specifications contained the dissolved crude ER-808227 in anhydrous THF (4.1 vol.). Once the specification was met, an appropriately sized inerted reactor was charged with anhydrous THF (106 vol.) and the ER-808227/THF solution from the previous step.
  • the reactor was cooled to an internal temperature of ⁇ 15 to ⁇ 20° C., then 0.5 M KHMDS in toluene (9.1 wt., 3.0 eq.) was added at a rate such that internal temperature did not exceed ⁇ 12° C. Approximately 4.5 eq. KHMDS was necessary to drive the reaction to completion.
  • the reaction was reverse quenched into semi-saturated ammonium chloride (40 vol.) at an internal temperature of 0° C. n-Heptane (80 vol.) was added, stirred for 2-5 minutes, and then allowed to partition.
  • the crude ER-806746 was purified via SiO 2 column chromatography to yield ER-804027 (1.16 wt., 0.55 eq.) as a clear yellowish oil.
  • the chromatography was performed as follows: the column was first flushed with sufficient MTBE to remove water then flushed with heptane to remove the MTBE.
  • the ER-806746 was loaded onto the column as a solution in heptane then eluted from the column with heptane/MTBE (5:1) then heptane/MTBE (4:1) with the fractions monitored at 230 nm by UV detector.
  • a reactor was charged with ER-804027 (1 wt, 1 eq) and anhydrous dichloromethane (7.6 vol). The reactor was cooled to an internal temperature of ⁇ 78° C. and then 1 M DIBALH in dichloromethane (3.0 wt, 2.25 eq) was added at a rate such that internal temperature did not exceed ⁇ 60° C. Methanol (0.1 vol) was added at a rate such that internal temperature did not exceed ⁇ 60° C. Note: hydrogen gas evolved and was diluted with a stream of nitrogen. Upon complete addition, the mixture was warmed to ambient temperature and then 1 N hydrochloric acid (10.6 vol) and MTBE (25 vol) were added. The mixture was stirred for 20 minutes and the layers allowed to partition.
  • the organic layer was separated and the aqueous layer was back extracted layer with MTBE (15.3 vol).
  • the organic layers were combined and washed with water (3 vol), saturated sodium bicarbonate (3 vol), and saturated sodium chloride (3 vol), respectively, then concentrated in vacuo.
  • the crude concentrate was purified via SiO 2 column chromatography to yield ER-804028 (0.84 wt, 0.93 eq) as a white foam.
  • ER-803895 (F-3a) was dissolved in anhydrous toluene (14 wt.) and cooled to ⁇ 75° C. ⁇ 75° C. under an argon atmosphere. DIBALH (1.5M in toluene, 0.95 wt., 1.3 eq.) was added at a rate to maintain the internal reaction temperature ⁇ 70° C. ⁇ 70° C. The resulting mixture was stirred for 30 minutes then quenched with anhydrous methanol (0.13 wt., 3.2 eq.), maintaining the internal reaction temperature ⁇ 65° C. ⁇ 65° C. The reaction mixture was allowed to warm to ⁇ 10° C.
  • DIBALH 1.5M in toluene, 0.95 wt., 1.3 eq.
  • a solution of azeotropically dried sulfone ER-804028 (1.0 wt., 1 eq.) in anhydrous tetrahydrofuran (5 vol., 4.45 wt.) was treated with n-butyl lithium (1.6M in hexanes, 1.02 wt., 1.5 vol., 2.05 eq.) such that the internal temperature did not exceed 5° C.
  • the mixture was stirred at internal temperature 0 to 5° C. for 10 minutes then cooled to ⁇ 75° C. ⁇ 75° C.
  • Azeotropically dried aldehyde ER-803896 (1.07 wt., 1.23 eq.) was dissolved in anhydrous hexanes (3.53 wt., 5.35 vol.) then cooled to ⁇ 75° C. ⁇ 75° C.
  • the aldehyde solution was added to the ER-804028 anion by cannula such that internal temperature ⁇ 65° C.
  • the mixture was stirred for 45 minutes at internal temperature ⁇ 78° C. then quenched by the addition of saturated ammonium chloride (5 vol.), methyl tert-butyl ether (10 vol.), and water (5 vol.).
  • the aqueous layer was discarded and the organic layer concentrated under reduced pressure.
  • the crude material was purified via C-18 reverse phase chromatography to afford ER-804029 (84%, 1.57 wt.).
  • samarium diiodide solution (2.5 eq.) and the solution cooled to internal temperature ⁇ 70° C. ⁇ 70° C.
  • ER-804030 (1 wt.) was dissolved in anhydrous methanol (4.1 wt.) and anhydrous THF (2.3 wt.) and then cooled to ⁇ 70° C. ⁇ 70° C.
  • ER-804030 was added to the cold samarium solution at a rate such that the internal temperature did not exceed ⁇ 70° C.
  • the reaction was quenched with potassium carbonate/Rochelle's Salts/water (1/10/100; w/w/v, 15 vol.) and MTBE (5 vol.) such that internal temperature did not exceed ⁇ 65° C.
  • the reaction was warmed to room temperature and the mixture transferred to a separatory vessel using the workup solution (20 vol. rinse) and MTBE (20 vol. rinse).
  • the aqueous layer was discarded, the organic layer evaporated, and the residue purified via silica gel chromatography to afford ER-118049 (0.77 wt., 85%).
  • the product was stored at ⁇ 20° C. under inert atmosphere.
  • the crude material was purified by flash chromatography (prepped with 3 CV (1:1 (V/V) DCM/heptane, the material was loaded with 1:1 DCM/heptane then eluted with 10/10/1 heptane/DCM/MTBE).
  • the product-containing fractions were concentrated and stored under inert atmosphere at ⁇ 20° C.
  • ER-118047/48 the oxidation of ER-118047/48 to form the di-ketone ER-118046 was accomplished as follows. A flask was charged with ER-118047/48 (1 wt, 1.0 eq) and toluene (10 vol) and DMSO (0.15 wts, 2.5 eq) were added at room temperature. Et 3 N (0.31 wts, 4.0 eq) was added and the solution was cooled to ⁇ 15° C. TCAA (0.33 wts, 1.4 eq) was added neat and the reaction warmed to 0° C. then stirred for 10 minutes at 0° C. The reaction was stirred for additional 10 minutes then was quenched with IPA (0.15 vol).
  • reaction solution was loaded onto a column and purified by silica gel chromatography.
  • the dried ER-118064 (F-12 wherein R 1 is MeO) residue was dissolved in anhydrous dichloromethane (28 vol) under a nitrogen atmosphere and treated with PPTS (1.0 wt, 5.2 eq) in one portion. After 30-90 minutes, the reaction mixture was directly loaded atop an appropriate column and purified by silica gel chromatography. The desired fractions of ER-076349 were concentrated in vacuo. The material resulting from the concentration of all pure fractions was azeotroped twice from toluene (20 vol), affording ER-076349 as a crunchy colorless solid/foam (0.44 wt, 0.79 eq after correction for residual toluene).
  • ER-076349 (1 wt, 1 eq) was dissolved in anhydrous toluene (20 vol) and concentrated to dryness under reduced pressure.
  • the substrate was re-dissolved in anhydrous toluene (20 vol) and concentrated to dryness.
  • the substrate was dissolved in DCM (5 vol), and the solution placed under an argon atmosphere.
  • Collidine (0.66 wts, 4.0 eq) was added as a single portion.
  • Pyridine, as a solution in DCM (Flask B) was added as a single portion (5 mole %).
  • the resulting mixture in flask C was cooled to an internal temperature of ⁇ 20 to ⁇ 25° C.
  • a DCM solution of Ts 2 O was added drop-wise keeping the internal temperature below ⁇ 16° C. (1.02 eq).
  • the reaction was stirred at ⁇ 20 to ⁇ 25° C. for 80 minutes then warmed to 0° C. over 20 minutes and stirred for an additional 20 minutes.
  • the reaction was quenched with water (2 vol). The bath was removed, and the reaction allowed to warm to room temperature (15-20° C.) and stirred (20 minutes).
  • the reaction was rinsed to a larger vessel using the IPA (100 vol) and aqueous ammonium hydroxide (100 vol) was added to the reaction.
  • the reaction was stirred at room temperature for 15-36 hours, monitoring for the disappearance of the tosylate (ER-082892) and epoxide (ER-809681) which formed in situ.
  • the reaction was concentrated to dryness or near dryness at reduced pressure.
  • the resulting material was diluted with DCM (25-40 vol) and washed pH 10 buffer (NaHCO 3 /Na 2 CO 3 (aq), 10 vol).
  • the aqueous phase was back extracted with 25 vol of DCM and the combined organic layers were concentrated to dryness.
  • the resulting free amine was purified by silica gel chromatography using a buffered ACN/water mobile phase. The pooled fractions were concentrated at reduced pressure to remove ACN.
  • the resulting aqueous layer was diluted with DCM (40 vol) and with 30 vol of a pH 10 buffered stock solution (NaHCO 3 /Na 2 CO 3 ). The layers were mixed well and separated. The aqueous phase was back extracted with 25 vol of DCM and the combined organic layers were concentrated to dryness. The resulting free amine was polish filtered as a solution in 3:1 DCM/pentane and concentrated to dryness (0.80 wts) to afford B-1939.

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10308661B2 (en) 2015-05-07 2019-06-04 Eisai R&D Management Co., Ltd. Macrocyclization reactions and intermediates and other fragments useful in the synthesis of halichondrin macrolides
US10450324B2 (en) 2013-12-06 2019-10-22 Eisai R&D Management Co., Ltd. Methods useful in the synthesis of halichondrin B analogs
US10494388B2 (en) 2010-01-26 2019-12-03 Eisai R&D Management Co., Ltd. Compounds useful in the synthesis of halichondrin B analogs
USRE47797E1 (en) 2004-06-03 2020-01-07 Eisai R&D Management Co., Ltd. Intermediates for the preparation of analogs of halichondrin B
US10611773B2 (en) 2013-11-04 2020-04-07 Eisai R&D Management Co., Ltd. Macrocyclization reactions and intermediates and other fragments useful in the synthesis of analogs of halichondrin B
US10676481B2 (en) 2016-02-12 2020-06-09 Eisai R&D Management Co., Ltd. Intermediates in the synthesis of eribulin and related methods of synthesis
US10717743B2 (en) 2007-10-03 2020-07-21 Eisai R&D Management Co., Ltd. Intermediates and methods for the synthesis of halichondrin B analogs
US11136335B2 (en) 2016-06-30 2021-10-05 Eisai R&D Management Co., Ltd. Prins reaction and intermediates useful in the synthesis of halichondrin macrolides and analogs thereof
US11542269B2 (en) 2018-01-03 2023-01-03 Eisai R&D Management Co., Ltd. Prins reaction and compounds useful in the synthesis of halichondrin macrolides and analogs thereof

Families Citing this family (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT1087960E (pt) * 1998-06-17 2011-06-17 Eisai R&D Man Co Ltd Análogos macrocíclicos e métodos de sua utilização e preparação
WO2009064029A1 (en) * 2007-11-16 2009-05-22 Eisai R & D Management Co., Ltd. Novel intermediate for halichondrin b analog synthesis and novel desulfonylation reaction used for the intermediate
CA2720632C (en) 2008-04-04 2016-12-20 Eisai R&D Management Co., Ltd. Halichondrin b analogs
DK2415470T3 (en) 2009-03-30 2016-09-19 Eisai R&D Man Co Ltd liposome
EP2420504B1 (de) * 2009-04-14 2014-01-15 Nissan Chemical Industries, Ltd. Verfahren zur herstellung einer makrolidverbindung und zwischenprodukt daraus
WO2012147900A1 (en) 2011-04-28 2012-11-01 Eisai R&D Management Co., Ltd. Microreactor process for halichondrin b analog synthesis
WO2013053102A1 (en) 2011-10-11 2013-04-18 Givaudan Sa Improvements in or relating to organic compounds
EP2785687B1 (de) 2011-11-30 2019-02-20 Sandoz AG Verfahren zur herstellung von (3r-)2,4-di-abganbgsgruppen-3-methylbut-1-en
CN104024237B (zh) 2011-12-16 2016-02-24 阿方拉研究股份有限公司 用于制备3-((2s,5s)-4-亚甲基-5-(3-氧代丙基)四氢呋喃-2-基)丙醇衍生物的方法及其有用的中间体
US9062020B2 (en) 2011-12-29 2015-06-23 Alphora Research Inc. 2-((2S,3S,4R,5R)-5-((S)-3-amino-2-hydroxyprop-1-yl)-4-methoxy-3-(phenylsulfonylmethyl)tetrahydrofuran-2-yl)acetaldehyde derivatives and process for their preparation
IN2014MN02106A (de) 2012-03-30 2015-09-11 Alphora Res Inc
KR20150090921A (ko) 2012-12-04 2015-08-06 에자이 알앤드디 매니지먼트 가부시키가이샤 유방암 치료에서 에리불린의 용도
BR112015029386B1 (pt) * 2013-06-26 2023-11-14 Eisai R&D Management Co., Ltd. Uso de eribulina e lenvatinibe como terapia de combinação e kit
AU2014286880B2 (en) 2013-07-03 2017-12-14 Sandoz Ag Synthetic process for preparation of macrocyclic C1-keto analogs of Halichondrin B and intermediates useful therein including intermediates containing -SO2-(p-TOLYL) groups
TW201617326A (zh) 2014-03-06 2016-05-16 Ａｌｐｈｏｒａ研發股份有限公司 （ｓ）－１－（（２ｒ，３ｒ，４ｓ，５ｓ）－５－烯丙－３－甲氧－４－（對甲苯磺醯甲基）四氫呋喃－２－基）－３－氨基丙－２－醇之結晶衍生物
WO2015183961A1 (en) 2014-05-28 2015-12-03 Eisai R&D Management Co., Ltd Use of eribulin in the treatment of cancer
EP3160970A4 (de) 2014-06-30 2017-12-27 President and Fellows of Harvard College Synthese von halichondrinanaloga und verwendungen davon
WO2016038624A1 (en) * 2014-09-09 2016-03-17 Cipla Limited "process for the preparation of macrocyclic ketone analogs of halichondrin b or pharmaceutically acceptable salts and intermediates thereof"
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WO2016176560A1 (en) 2015-04-30 2016-11-03 President And Fellows Of Harvard College Chromium-mediated coupling and application to the synthesis of halichondrins
KR101777634B1 (ko) 2016-01-18 2017-09-12 연성정밀화학(주) 3-((2s,5s)-4-메틸렌-5-(3-옥소프로필)테트라히드로퓨란-2-일)프로판올 유도체의 제조방법 및 이를 위한 중간체
SG10202007520WA (en) 2016-03-02 2020-09-29 Eisai R&D Man Co Ltd Eribulin-based antibody-drug conjugates and methods of use
EP3449921B1 (de) 2016-04-28 2023-05-31 Eisai R&D Management Co., Ltd. Eribulin zur hemmung des tumorwachstums
CN109415383A (zh) * 2016-05-26 2019-03-01 雷迪博士实验室有限公司 制备艾日布林的方法及其中间体
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JP6978758B2 (ja) 2016-11-11 2021-12-08 プレジデント アンド フェローズ オブ ハーバード カレッジ パラジウム媒介ケトール化
KR20190084065A (ko) 2016-11-23 2019-07-15 닥터 레디스 레보러터리즈 리미티드 에리불린 및 그 중간체의 제조방법
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US10865212B2 (en) 2017-01-02 2020-12-15 Yonsung Fine Chemical Co.. Ltd. Intermediate for preparing eribulin mesylate and process for preparing the same
US9938288B1 (en) 2017-04-05 2018-04-10 President And Fellows Of Harvard College Macrocyclic compound and uses thereof
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CN108948064B (zh) 2017-05-17 2021-02-02 上海时莱生物技术有限公司 一种艾日布林中间体及其制备方法
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US20190046513A1 (en) 2017-08-10 2019-02-14 Huya Bioscience International, Llc Combination therapies of hdac inhibitors and tubulin inhibitors
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US11419856B2 (en) 2017-11-20 2022-08-23 Basilea Pharmaceutica International AG Pharmaceutical combinations for use in the treatment of neoplastic diseases
US11008296B2 (en) 2017-11-21 2021-05-18 Natco Pharma Limited Intermediates for the preparation of eribulin thereof
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WO2019211877A1 (en) 2018-05-03 2019-11-07 Cipla Limited Process for the preparation of macrocyclic ketone analogs of halichondrin b
WO2020008382A1 (en) * 2018-07-04 2020-01-09 Dr. Reddy’S Laboratories Limited Process for preparation of eribulin and intermediates thereof
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US11447499B2 (en) 2019-06-14 2022-09-20 Rk Pharma Inc. Process for the preparation of eribulin mesylate intermediate
JP2022537785A (ja) 2019-06-21 2022-08-29 カウンスィル オブ サイエンティフィック アンド インダストリアル リサーチ ホモプロパルギルアルコールを調製するための化学酵素的プロセス
US11083705B2 (en) 2019-07-26 2021-08-10 Eisai R&D Management Co., Ltd. Pharmaceutical composition for treating tumor
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IL279168B (en) * 2020-12-02 2022-04-01 Finetech Pharmaceutical Ltd A process for the preparation of eribulin
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WO2023157015A1 (en) * 2022-02-17 2023-08-24 Natco Pharma Limited An improved process for the preparation of eribulin intermediates

Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993017690A1 (en) 1992-03-12 1993-09-16 President And Fellows Of Harvard College Halichondrins and related compounds
EP0572109A1 (de) 1992-03-23 1993-12-01 Pharma Mar, S.A. Halichondrine: zytotoxische Polyäther-Makrolide
US5436238A (en) 1992-03-12 1995-07-25 President And Fellows Of Harvard College Halichondrins and related compounds
WO1999065894A1 (en) 1998-06-17 1999-12-23 Eisai Co., Ltd. Macrocyclic analogs and methods of their use and preparation
US6653341B1 (en) 1998-06-17 2003-11-25 Eisai Co., Ltd. Methods and compositions for use in treating cancer
WO2005118565A1 (en) 2004-06-03 2005-12-15 Eisai Co., Ltd. Intermediates for the preparation of halichondrin b
US20060154312A1 (en) 2004-12-09 2006-07-13 Sergei Agoulnik Tubulin isotype screening in cancer therapy using halichondrin B analogs
WO2007061874A2 (en) 2005-11-18 2007-05-31 Eisai Co., Ltd Methods and compositions for use in treating cancer
WO2009046308A1 (en) 2007-10-03 2009-04-09 Eisai R & D Management Co., Ltd. Intermediates and methods for the synthesis of halichondrin b analogs
WO2009064029A1 (en) 2007-11-16 2009-05-22 Eisai R & D Management Co., Ltd. Novel intermediate for halichondrin b analog synthesis and novel desulfonylation reaction used for the intermediate
WO2009124237A1 (en) 2008-04-04 2009-10-08 Eisai R&D Management Co., Ltd. Halichondrin b analogs
US20110184190A1 (en) 2010-01-26 2011-07-28 Eisai R&D Management Co., Ltd. Compounds useful in the synthesis of halichondrin b analogs
WO2012147900A1 (en) 2011-04-28 2012-11-01 Eisai R&D Management Co., Ltd. Microreactor process for halichondrin b analog synthesis
US20140163095A1 (en) 2012-12-04 2014-06-12 Eisai R&D Management Co., Ltd. Use of eribulin in the treatment of breast cancer
WO2015066729A1 (en) 2013-11-04 2015-05-07 Eisai R&D Management Co., Ltd. Macrocyclization reactions and intermediates useful in the synthesis of analogs of halichondrin b
WO2015085193A1 (en) 2013-12-06 2015-06-11 Eisai R&D Management Co., Ltd. Methods useful in the synthesis of halichondrin b analogs
WO2015134399A1 (en) 2014-03-03 2015-09-11 Eisai R&D Management Co., Ltd. Use of eribulin and mtor inhibitors as combination therapy for the treatment of cancer
WO2015183961A1 (en) 2014-05-28 2015-12-03 Eisai R&D Management Co., Ltd Use of eribulin in the treatment of cancer
WO2015184145A1 (en) 2014-05-28 2015-12-03 Eisai R&D Management Co., Ltd. Use of eribulin and poly (adp ribose) polymerase (parp) inhibitors as combination therapy for the treatment of cancer
WO2016141209A1 (en) 2015-03-04 2016-09-09 Merck Sharp & Dohme Corp. Combination of a pd-1 antagonist and eribulin for treating cancer
WO2016179607A1 (en) 2015-05-07 2016-11-10 Eisai R&D Management Co., Ltd. Macrocyclization reactions and intermediates and other fragments useful in the synthesis of halichondrin macrolides

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW255880B (de) 1992-09-09 1995-09-01 Hoechst Ag
CA2264298A1 (en) 1996-09-06 1998-03-12 Eli Lilly And Company Catalytic selective sulfonylation process
US6870058B2 (en) * 1996-12-03 2005-03-22 The Trustees Of The University Of Pennsylvania Compounds which mimic the chemical and biological properties of discodermolide
DE10106647A1 (de) * 2001-02-12 2002-08-22 Univ Hannover Ratjadon-Derivate zum Hemmen des Zellwachstums
US20060045846A1 (en) 2004-08-30 2006-03-02 Horstmann Thomas E Reagents and methods for labeling terminal olefins
WO2008010776A1 (en) 2006-07-21 2008-01-24 Agency For Science, Technology And Research Aigialomycin d and derivatives thereof and their use in treating cancer or malaria or a microbial infection
EP2785687B1 (de) 2011-11-30 2019-02-20 Sandoz AG Verfahren zur herstellung von (3r-)2,4-di-abganbgsgruppen-3-methylbut-1-en
IN2014MN02106A (de) 2012-03-30 2015-09-11 Alphora Res Inc
AU2014286880B2 (en) 2013-07-03 2017-12-14 Sandoz Ag Synthetic process for preparation of macrocyclic C1-keto analogs of Halichondrin B and intermediates useful therein including intermediates containing -SO2-(p-TOLYL) groups
WO2017139664A1 (en) 2016-02-12 2017-08-17 Eisai & R&D Management Co., Ltd. Intermediates in the synthesis of eribulin and related methods of synthesis
US11136335B2 (en) 2016-06-30 2021-10-05 Eisai R&D Management Co., Ltd. Prins reaction and intermediates useful in the synthesis of halichondrin macrolides and analogs thereof

Patent Citations (70)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993017690A1 (en) 1992-03-12 1993-09-16 President And Fellows Of Harvard College Halichondrins and related compounds
US5338865A (en) 1992-03-12 1994-08-16 President And Fellows Of Harvard College Synthesis of halichondrin B and norhalichondrin B
US5436238A (en) 1992-03-12 1995-07-25 President And Fellows Of Harvard College Halichondrins and related compounds
EP0572109A1 (de) 1992-03-23 1993-12-01 Pharma Mar, S.A. Halichondrine: zytotoxische Polyäther-Makrolide
US6469182B1 (en) 1998-06-17 2002-10-22 Eisai Co., Ltd. Intermediates in the preparation of macrocyclic analogs
US6214865B1 (en) 1998-06-17 2001-04-10 Eisai Co., Ltd. Macrocyclic analogs and methods of their use and preparation
US6365759B1 (en) 1998-06-17 2002-04-02 Eisai Co., Ltd. Intermediate compounds for preparing macrocylcic analogs
JP2002518384A (ja) 1998-06-17 2002-06-25 エーザイ株式会社 大環状類似体及びそれらの使用並びに調製方法
US7470720B2 (en) 1998-06-17 2008-12-30 Eisai R&D Management Co., Ltd. Methods and compositions for use in treating cancer
US6653341B1 (en) 1998-06-17 2003-11-25 Eisai Co., Ltd. Methods and compositions for use in treating cancer
US20040198806A1 (en) * 1998-06-17 2004-10-07 Littlefield Bruce A. Methods and compositions for use in treating cancer
US8097648B2 (en) 1998-06-17 2012-01-17 Eisai R&D Management Co., Ltd. Methods and compositions for use in treating cancer
US8148554B2 (en) 1998-06-17 2012-04-03 Eisai R&D Management Co., Ltd. Methods and compositions for use in treating cancer
WO1999065894A1 (en) 1998-06-17 1999-12-23 Eisai Co., Ltd. Macrocyclic analogs and methods of their use and preparation
US20110172446A1 (en) 1998-06-17 2011-07-14 Littlefield Bruce A Methods and compositions for use in treating cancer
US20090104285A1 (en) 1998-06-17 2009-04-23 Littlefield Bruce A Methods and Compositions for Use in Treating Cancer
WO2004034990A2 (en) 2002-10-16 2004-04-29 Eisai Co., Ltd. Methods and compositions for use in treating cancer
US20070244187A1 (en) 2004-06-03 2007-10-18 Eisai Co., Ltd Intermediates for the Preparation of Halichondrin B
US7982060B2 (en) 2004-06-03 2011-07-19 Eisai R&D Management Co., Ltd. Intermediates for the preparation of analogs of Halichondrin B
US20120029213A1 (en) 2004-06-03 2012-02-02 Eisai R&D Management Co., Ltd. Intermediates for the preparation of analogs of halichondrin b
US8975422B2 (en) 2004-06-03 2015-03-10 Eisai R&D Management Co., Ltd. Intermediates for the preparation of analogs of halichondrin B
USRE45324E1 (en) 2004-06-03 2015-01-06 Eisai R&D Management Co., Ltd. Intermediates for the preparation of analogs of halichondrin B
US8884031B2 (en) 2004-06-03 2014-11-11 Eisai R&D Management Co., Ltd. Intermediates for the preparation of analogs of halichondrin B
US8618313B2 (en) 2004-06-03 2013-12-31 Eisai R&D Management Co., Ltd. Intermediates for the preparation of analogs of Halichondrin B
WO2005118565A1 (en) 2004-06-03 2005-12-15 Eisai Co., Ltd. Intermediates for the preparation of halichondrin b
US8445701B2 (en) 2004-06-03 2013-05-21 Eisai R&D Management Co., Ltd. Intermediates for the preparation of analogs of halichondrin B
US20120309988A1 (en) 2004-06-03 2012-12-06 Eisai R&D Management Co., Ltd. Intermediates for the preparation of analogs of halichondrin b
US9303050B2 (en) 2004-06-03 2016-04-05 Eisai R&D Management Co., Ltd. Intermediates for the preparation of analogs of Halichondrin B
WO2006076100A2 (en) 2004-12-09 2006-07-20 Eisai Co. Ltd. Tubulin isotype screening in cancer therapy using halichondrin b analogs
US20060154312A1 (en) 2004-12-09 2006-07-13 Sergei Agoulnik Tubulin isotype screening in cancer therapy using halichondrin B analogs
US20100190843A1 (en) 2004-12-09 2010-07-29 Eisai R&D Management Co., Ltd. Tubulin Isotype Screening in Cancer Therapy Using Halichondrin B Analogs
WO2007061874A2 (en) 2005-11-18 2007-05-31 Eisai Co., Ltd Methods and compositions for use in treating cancer
US20120095242A1 (en) 2007-10-03 2012-04-19 Eisai R&D Management Co., Ltd. Intermediates and methods for the synthesis of halichondrin b analogs
US9604993B2 (en) 2007-10-03 2017-03-28 Eisai R&D Management Co., Ltd. Intermediates and methods for the synthesis of halichondrin B analogs
US8987479B2 (en) 2007-10-03 2015-03-24 Eisai R&D Management Co., Ltd. Intermediates and methods for the synthesis of halichondrin B analogs
US20160214992A1 (en) 2007-10-03 2016-07-28 Eisai R&D Management Co., Ltd. Intermediates and methods for the synthesis of halichondrin b analogs
US8093410B2 (en) 2007-10-03 2012-01-10 Eisai R&D Management Co., Ltd. Intermediates and methods for the synthesis of halichondrin B analogs
US20090198074A1 (en) 2007-10-03 2009-08-06 Eisai Co., Ltd. Intermediates and methods for the synthesis of halichondrin b analogs
WO2009046308A1 (en) 2007-10-03 2009-04-09 Eisai R & D Management Co., Ltd. Intermediates and methods for the synthesis of halichondrin b analogs
US20090203771A1 (en) 2007-11-16 2009-08-13 Eisai R&D Management Co., Ltd. Novel intermediate for halichondrin b analog synthesis and novel desulfonylation reaction used for the intermediate
WO2009064029A1 (en) 2007-11-16 2009-05-22 Eisai R & D Management Co., Ltd. Novel intermediate for halichondrin b analog synthesis and novel desulfonylation reaction used for the intermediate
US20110054194A1 (en) 2008-04-04 2011-03-03 Eisai R&D Management Co., Ltd. Halichondrin B Analogs
US8598373B2 (en) * 2008-04-04 2013-12-03 Eisai R&D Management Co., Ltd. Halichondrin B analogs
WO2009124237A1 (en) 2008-04-04 2009-10-08 Eisai R&D Management Co., Ltd. Halichondrin b analogs
US9469651B2 (en) 2008-04-04 2016-10-18 Eisai R&D Management Co., Ltd. Halichondrin B analogs
US9206194B2 (en) * 2008-04-04 2015-12-08 Eisai R&D Management Co., Ltd. Halichondrin B analogs
US8350067B2 (en) 2010-01-26 2013-01-08 Eisai R&D Management Co., Ltd. Compounds useful in the synthesis of halichondrin B analogs
US8927597B2 (en) 2010-01-26 2015-01-06 Eisai R&D Management Co., Ltd. Compounds useful in the synthesis of halichondrin B analogs
US20160376294A1 (en) 2010-01-26 2016-12-29 Eisai R&D Management Co., Ltd. Compounds useful in the synthesis of halichondrin b analogs
US20110184190A1 (en) 2010-01-26 2011-07-28 Eisai R&D Management Co., Ltd. Compounds useful in the synthesis of halichondrin b analogs
US8203010B2 (en) 2010-01-26 2012-06-19 Eisai R&D Management Co., Ltd. Compounds useful in the synthesis of halichondrin B analogs
WO2011094339A1 (en) 2010-01-26 2011-08-04 Eisai R&D Management Co., Ltd. Furo [3, 2 -b] pyrane derivatives useful in the synthesis of halichondrin b analogs
US9382262B2 (en) 2010-01-26 2016-07-05 Eisai R&D Management Co., Ltd. Compounds useful in the synthesis of halichondrin B analogs
WO2012147900A1 (en) 2011-04-28 2012-11-01 Eisai R&D Management Co., Ltd. Microreactor process for halichondrin b analog synthesis
WO2014087230A1 (en) 2012-12-04 2014-06-12 Eisai R&D Management Co., Ltd. Use of eribulin in the treatment of breast cancer
US20140163095A1 (en) 2012-12-04 2014-06-12 Eisai R&D Management Co., Ltd. Use of eribulin in the treatment of breast cancer
US20160264594A1 (en) 2013-11-04 2016-09-15 Eisai R&D Management Co., Ltd. Macrocyclization reactions and intermediates useful in the synthesis of analogs of halichondrin b
WO2015066729A1 (en) 2013-11-04 2015-05-07 Eisai R&D Management Co., Ltd. Macrocyclization reactions and intermediates useful in the synthesis of analogs of halichondrin b
US20170298078A1 (en) 2013-12-06 2017-10-19 Eisai R&D Management Co., Ltd. Methods useful in the synthesis of halichondrin b analogs
US9695188B2 (en) 2013-12-06 2017-07-04 Eisai R&D Management Co., Ltd. Methods useful in the synthesis of halichondrin B analogs
US9303039B2 (en) * 2013-12-06 2016-04-05 Eisai R&D Management Co., Ltd. Methods useful in the synthesis of halichondrin B analogs
WO2015085193A1 (en) 2013-12-06 2015-06-11 Eisai R&D Management Co., Ltd. Methods useful in the synthesis of halichondrin b analogs
US20170071903A1 (en) 2014-03-03 2017-03-16 Eisai R&D Management Co., Ltd. Use of eribulin and mtor inhibitors as combination therapy for the treatment of cancer
WO2015134399A1 (en) 2014-03-03 2015-09-11 Eisai R&D Management Co., Ltd. Use of eribulin and mtor inhibitors as combination therapy for the treatment of cancer
WO2015183961A1 (en) 2014-05-28 2015-12-03 Eisai R&D Management Co., Ltd Use of eribulin in the treatment of cancer
US20170100367A1 (en) 2014-05-28 2017-04-13 Eisai R&D Management Co., Ltd. Use of eribulin in the treatment of cancer
US20170100368A1 (en) 2014-05-28 2017-04-13 Eisai R&D Management Co., Ltd. Use of eribulin and poly (adp ribose) polymerase (parp) inhibitors as combination therapy for the treatment of cancer
WO2015184145A1 (en) 2014-05-28 2015-12-03 Eisai R&D Management Co., Ltd. Use of eribulin and poly (adp ribose) polymerase (parp) inhibitors as combination therapy for the treatment of cancer
WO2016141209A1 (en) 2015-03-04 2016-09-09 Merck Sharp & Dohme Corp. Combination of a pd-1 antagonist and eribulin for treating cancer
WO2016179607A1 (en) 2015-05-07 2016-11-10 Eisai R&D Management Co., Ltd. Macrocyclization reactions and intermediates and other fragments useful in the synthesis of halichondrin macrolides

Non-Patent Citations (121)

* Cited by examiner, † Cited by third party
Title
Aicher et al., "Total Synthesis of Halichondrin Band Norhalichondrin B," J. Am. Chem. Soc. 114(8): 3162-3164 (1992).
Aicher, T.D., et al.; "Synthetic Studies Towards Halichondrins: Synthesis of the C.27-C.38 Segment," Tetrahedron Lett. 33(12): 1549-1552 (1992).
Alley et al. "Comparison of the Relative Efficacies and Toxicities of Halichondrin B Analogues" Proceedings of the AACR-NCI-EORTC Conference on Molecular Targets and Cancer Therapeutics, Nov. 14-18, 2005, C230, p. 257.
Anderson, "Developing Processes for Crystallization-Induced Asymmetric Transformation," Org. Process. Res. Dev. 9: 800-813 (2005).
Austad et al,, "Process development of Halaven®: Synthesis of the C14-C35 fragment via iterative Nozaki-Hiyama-Kishi reaction—Williamson ether cyclization," Synlett. 24:327-332 (2013).
Austad et al., "Commercial manufacture of Halaven®: Chemoselective transformations en route to structurally complex macrocyclic ketones," Synlett. 24 (2013). Supporting Information, 13 pages.
Austad et al., "Commercial manufacture of Halaven®: Chemoselective transformations en route to structurally complex macrocyclic ketones," Synlett. 24;333-337 (2013).
Bai et al., "Halichondrin B and Homohalichondrin B, Marine Natural Products Binding in the Vinca Domain to Tubulin. Discovery of Tubulin-based Mechanism of Action by Analysis of Differential Cytotoxicity Data," J. Biol. Chem. 266(24): 15882-15889 (1991).
Bernet et al., "Carbocyclische Verbindungen aus Monosacchariden. Umsetzungen in der Glucosereihe," Helv. Chim. Acta. 62: 1990-2016 (1979).
Blanchette et al., "Horner-Wadsworth-Emmons Reaction: Use of Lithium Chloride and an Amine for Base-Sensitive Compounds," Tetrahedron Lett. 25(21): 2183-2186 (1984).
Burke, S.D., et al., "Enantioselective Synthesis of a Halichondrin B C(20) 'C(36) Precursor," Tetrahedron Lett., 36(39): 7023-7026 (1995).
Burke, S.D., et al., "Synthesis of a C(22) ' C(34) Halichondrin Precursor via a Double Dioxanone-to-Dihydropyran Rearrangement," Tetrahedron Lett., 32(32): 3961-3964 (1991 ).
Burke, S.D., et al., "Synthetic Studies Toward Complex Polyether Macrolides of Marine Origin," Spec. Publ. R. Soc. Chem., 198: (Anti-Infectives), 73-85 (1997).
Burke; S.D., et al., "Synthesis of a C(22)-C(34) Halichondrin B Precursor via Ring Opening—Double Ring Closing Metathesis." J. Org. Chem., 63: 8626-8627 (1998).
Carruthers et al., "Modern Methods of Organic Synthesis," Cambridge University Press, Cambridge, Fourth Edition, p. 65 (2004).
Chase et al., "Process development of Halaven®: Synthesis of the Cl1-C13 fragment from D-(−)-Gulono-1, 4-lactone," Synlett. 24:323-326 (2013).
Chen C., et al., "Ni(II)/Cr(II)-Mediated Coupling Reaction: An Asymmetric Process," J. Org. Chem., 60:5386-5387 (1995).
Choi et al., "Assymrnetric Ni(II)/Cr(II)-Mediated Coupling Reaction: Catalytic Process," Org Lett. 4(25): 4435-4438 (2002).
Choi et al., "Synthetic Studies on the Marine Natural Product Halichondrins," Pure Appl. Chem. 75(1): 1-17 (2003).
Choi et al., "Synthetic Studies on the Marine Natural Product Halichondrins," Pure Appl. Chem. 75:1-17, 2003.
Communication enclosing the Extended European Search Report for European Patent Application No. 12178696,6, dated Oct. 16. 2012.
Communication enclosing the extended European search report for European Patent Application No. 15159875.2, dated Oct. 12, 2015 (7 pages).
Communication pursuant to Article 94(3)PEC from the European Patent Office for the counterpart EP Application No. 12178696.6 dated Aug. 8, 2013.
Communication pursuant to Rule 114(2) EPC from counterpart European Application EP 05760356.5, dated Apr. 3, 2012.
Communication pursuant to Rule 114(2) EPC from counterpart European Application EP 05760356.5, dated Jul. 4, 2012.
Cooper, A.J., et al., "Total Synthesis of Halichondrin B from Common Sugars: An F-Ring Intermediate from D-Glucose and Efficient Construction of the C1 to C21 Segment," Tetrahedron Lett., 34(51): 8193-8196 (1993).
Dabybeen et al. "Comparison of the Activities of the Truncated Halichondrin B Analog NSC 707389 (E7389) with Those of the Parent Compound and a Proposed Binding Site on Tubulin" Molecular Pharmacology 2006, 70:1866.
Dong, C. et al. "New Syntheses of E7389 C14 ?C35 and Halichondrin C14 ?C38 Building Blocks: Reductive Cyclization and Oxy-Michael Cyclization Approaches" J. Am. Chem. Soc. 131: 15642-15646 (2009).
Duan and Kishi, "Synthetic Studies on Halichondrins: A New Practical Synthesis of the C.1-C.12 Segment," Tetrahedron Lett. 34(47), pp. 7541-7544 (1993).
Duan and Kishi, "Synthetic studies on halichondrins: A new practical synthesis of the C.1-C.12 segment," Tetrahedron Lett. 34(47):7541-7544 (1993).
English translation of the Office Action from the Chinese Patent Office for the counterpart Chinese Application No. 201010236637.2, dated Jul. 4. 2012.
English translation of the Office Action from the Chinese Patent Office for the counterpart Chinese Application No. 201010236637.2, dated Sep. 16, 2011.
English translation of the Office Action from the Japanese Patent Office for the counterpart Japanese Application No. 2007-515,643, dated Apr. 24, 2012.
English translation of the Office Action from the Japanese Patent Office for the counterpart Japanese Application No. 2007-515,643, dated Aug. 16, 2012.
English translation of the Office Action from the Japanese Patent Office for the counterpart Japanese Application No. 2007-515,643, dated Sep. 13, 2011.
File History of U.S. Appl. No. 13/868,641, "Intermediates for the Preparation of Analogs of Halichondrin B," in the name of Farid Benayoud et al., filed Apr. 23, 2013.
First Examination Report from the India Patent Office for the counterpart India Application No. 4812/CHENP/2006 dated Oct. 12, 2012.
Flemming et al., "Nitrile Anion Cyclizations," Tetrahedron 58:1-23 (2002).
Greene et al., "Protective Groups in Organic Synthesis," John Wiley & Sons, Inc., New York, Third Edition, pp. 24, 127, 128, 134, 142, 170,207,209,215, and 216 (1999).
Hirata et al., "Halchondrins—Antitumor Polyether Macrolides from a Marine Sponge," Pure Appl. Chem. 58(5): 701-710 (1986).
Hirata et al., "Halichondrins—Antitumor Polyether Macrolides from a Marine Sponge," Pure Appl. Chem. 58(5): 701-710 (1986).
Hori et al., "Efficient Synthesis of 2,3-trans-Tetrahydropyrans and Oxepanes: Rearrangement-Ring Expansion of Cyclic Ethers Having a Chloromethanesulfonate," Tetrahedron Lett. 40: 2145-2148 (1999).
Horita et al., "Synthetic Studies of Halichondrin B, an Antitumor Polyether Macrolide Isolated from a Marine Sponge. 8. Synthesis of the Lactone Part (C1-C36) via Horner-Emmons Coupling Between C1-C15 and C16-C36 Fragments and Yamaguchi Lactonization," Tetrahedron Lett, 38(52): 8965-8968 ( 1997).
Horita et al., "Synthetic Studies of Halichondrin B, an Antitumor Polymer Macrolide Isolated from a Marine Sponge. 8. Synthesis of the Lactone Part (C1-C36) via Horner-Emmons Coupling Between C1-C15 and C16-C36 Fragments and Yamaguchi Lactonization," Tetrahedron Lett. 38(52): 8965-8968 (1997).
Horita, K., et al., "Research on Anti-Tumor Active Site of Marine Source Natural Product, Halichondrin B.," International Congress Series, 1157 (Towards Natural Medicine Research in the 21st Century), 327-336 (1998).
Horita, K., et al., "Synthetic Studies of Halichondrin B, an Antitumor Polyether Macrolide Isolated From a Marine Sponge, 2. Efficient Synthesis of C 16-C26 Fragments via Construction of the D Ring by a Highly Stereocontrolled Iodoetherification," Synlett, 40-43 ( 1994 ).
Horita, K., et al., "Synthetic Studies of Halichondrin B, an Antitumor Polyether Macrolide Isolated from a Marine Sponge, 3. Synthesis of C27-C36 Subunit via Completely Stereoselective C-Glycosylation to the F ring," Synlett, 43-45 (1994).
Horita, K., et al., "Synthetic Studies of Halichondrin B. an Antitumor Polyether Macrolide Isolated from a Marine Sponge. 7. Synthesis of Two C27-C36 Units via Construction of the F ring and Completely Stereoselective C-Glycosylation Using Mixed Lewis Acids," Chem. Pharm. Bull., 45(10): 1558-1572 (1997).
Horita, K., et al., "Synthetic Studies on Halichondrin B, an Antitumor Polyether Macrolide Isolated from a Marine Sponge. 9. Synthesis of the C16-C36 unit via Stereoselective Construction of the D and E Rings," Chem. Pharm. Bull., 46(8): 1199-1216 (1998).
Horita, K., et al., "Synthetic Study of a Highly Antitumorigenic Marine Phytochemical, Halichondrin B," Phytochemicals and Phytopharmaceuticals, Shahihi, F. and Ho, C.-T., Eds., AOCS Press, Champaign, IL, 2000. 386-397.
International Preliminary Report on Patentability from International Application No. PCT/US2005/019669, issued Dec. 4, 2006.
International Search Report from International Application No. PCT/US2005/019669 dated Aug. 29, 2005 (date of completion of search) and Sep. 7, 2005 (date of mailing of report).
Jackson et al., "The Halichondrins and E7389," Chem. Rev. 109: 3044-3079 (2009).
Jackson et al.. "A Total Synthesis of Norhalichondrin B" Angew. Chem. Int. Ed. 48: 2346-2350 (2009).
Jerry March, "Advanced Organic Chemistry," 4th Ed., pp. 348-357, John Wiley and Sons, N.Y. (1992).
Jiang, L., et al., "A Novel Route to the F-Ring of Halichondrin B. Diastereoselection in Pd(O)-Mediated meso and C2 Diol Desymmetrization," Org. Lett., 4(20): 3411-3414 (2002).
Jiang, L., et al., "A Practical Synthesis of the F-Ring of Halichondrin B via Ozonolytic Desymmetrization of a C2-Symmetric Dihydroxycyclohexene," J. Org. Chem., 68: 1150-1153 (2003).
Kim, D. et al. "New Syntheses of E7389 C14?C35 and Halichondrin C14?C38 Building Blocks: Double-Inversion Approach" J. Am. Chem. Soc. 131: 15636-15641 (2009).
Kurosu et al., "Fe/Cr- and Co/Cr-Mediated Catalytic Asymmetric 2-Haloallylations of Aldehydes," J. Am. Chem. Soc. 126: 12248-12249 (2004).
March, "Advanced Organic Chemistry," John Wiley & Sons, New York, Fourth Edition, pp. 386-388 (1992).
Mattocks, "Novel Reactions of Some ?-Acyloxy Acid Chlorides," J. Chem. Soc. 371: 1918-1930 (1964).
Mattocks, "Novel Reactions of Some ?-Acyloxy-acid Halides," J. Chem. Soc. 932: 4840-4845 (1964).
Mitsunobu, "The Use of Diethyl Azodicarboxylate and Triphenylphosphine in Synthesis and Transformation of Natural Products," Synthesis. 1-28 (1981).
Namba, K., et al., "New Catalytic Cycle for Couplings of Aldehydes with Organochromium Reagents", Organic Letters., vol. 6, No. 26, pp. 5031-5033 (2004).
Newman, "Drug Evaluation: Eribulin, a Simplified Ketone Analog of the Tubulin Inhibitor Halichondrin B, for the Potential Treatment of Cancer," Curr. Opin. Invest. Drugs, 8:1057-1066 (2007).
Nicolaou et al., "Total Synthesis of Brevetoxin A: Part 3: Construction of GHIJ and BCDE Ring Systems," Chem. Eur. J. 5:628-645, 1999.
Nicolaou et al., "Total Synthesis of the CP Moiecules CP-263, 114 and CP-225,917—Part 1. Synthesis of Key Intermediates and Intelligence Gathering," Angew. Chem. Int. Ed. 38:1669-1675, 1999.
Notice of Oral Proceedings from the European Patent Office scheduling Oral Proceedings on Nov. 21, 2013, for the counterpart EP Application No. 05760356.5 dated Oct. 29, 2013.
Notification of Grounds for Rejection from the South Korea Patent Office for the counterpart South Korean Application No. 10-2007-7000085 dated Jun. 30, 2013.
Office Action from the Canadian Intellectual Property Office for the counterpart Canadian Application No. 2,567,984, dated Oct. 7, 2011.
Ph.D. Thesis of Thomas Daniel Aicher, "Synthetic Studies towards Halichondrin B," Chapter 4, pp. 35-54, 1990.
Response to Office Action filed in the European Patent Office for the counterpart EP Application No. 05760356.5 dated Sep. 12, 2013,
Result of Consultation from the European Patent Office for the counterpart EP Application No. 05760356.5 dated Oct. 16, 2013.
Ritter, "Synthetic Transformations of Vinyl and Aryl Triflates," Synthesis 8:735-762, 1993.
RN 1 85411-09-0 CN L-arabino-D-allo-Dodeconic acid, 3,7:6, 1 0-dianhydro-8,9-0-cyclohaxylidene-2,4,5-trideoxy-, methyl ester Entry Date: Entered STN: Jan. 28, 1997.
RN 546141-26-8 CN 1 ,2 Propanediol, 3-[(2R,3R,4R,5S)-tetrahydro-3-hydroxy-4-[(phenylsulfonyl)methyl]-5-(2-propen-1-yl)-2-furanyl]-, 1,2-dibenzoate, (2S)—Entry Date: Entered STN: Jul. 11, 2003.
RN 546141-39-3 CN 1 ,2-Propanediol, 3-[(2R,3R,4S,5S)-tetrahydro-3-methoxy-4-[(phenylsulfonyl)methyl]-5-(2-propen-1-yl)-2-furanyl]-, 1,2-dibenzoate, (2S)—Entry Date: Entered STN: Jul. 11, 2003.
RN 546141-40-6 CN 1 ,2-propanediol, 3-[(2R,3R,4S,5S)-tetrahydro-3-methoxy-4-f(phenylsulfonyl)methyl]-5-(2-propen-14)-2-furanvll-, (2S)—ED Entered STN: Jul. 11, 2003.
RN: 185411-09-0; CN: L-arabino-D-allo-Dodeconic acid, 3,7:6, 10-dianhydro-8,9-O-cyclohexylidene-2,4,5-trideoxy-, methyl ester; Entered STN: Jan. 28, 1997.
RN: 546141-26-8; CN: 1,2-Propaneldiol, 3-[(2R,3R,4R,5S)-tetrahydro-3-hydroxy-4-[(phenylsulfony)methyl]-5-(2-propen-1-yl)-2-furanyl]-1,2-dibenzoate, (2S)-; Entered STN: Jul. 11, 2003.
RN: 546141-39-3; CN: 1,2-Propaneldiol, 3-[(2R,3R,4R,5S)-tetrahydro-3-methoxy-4-[(phenylsulfony)methyl]-5-(2-propen-1-yl)-2-furanyl]-,1,2-dibenzoate, (2S); Entered STN: Jul. 11, 2003.
RN: 546141-40-6; CN: 1,2-Propaneldiol, 3-[(2R,3R,4R,5S)-tetrahydro-3-methoxy-4-[(phenylsulfony)methyl]-5-(2-propen-1-yl)-2-furanyl]-, (2S); Entered STN: Jul. 11, 2003.
Sakamoto et al., "Stereoselective Ring Expansion via Bicyclooxonium ion. A Novel Approach to Oxocanes," Org. Lett. 4(5):676-678 (2002).
Schreiber, "Hydrogen Transfer from Tertiary Amines to Trifluorcacetic Anhydride." Tetrahedron Lett. 21:1027-1030 (1980).
Seletsky et al. "Structurally simplified macrolactone analogues of halichondrin B" Bioorg. Med. Chem. Lett. 14:5547 (2004).
Stamos et al., "A Mild Preparation of Vinyliodides from Vinylsilanes," Tetrahedron Lett. 37(48), pp. 8647-8650 (1996).
Stamos et al., "A mild preparation of vinyliodides from vinylsilanes," Tetrahedron Lett. 37(48): 8647-8650 (1996).
Stamos et al., "New Synthetic Route to the C.14-C.38 Segment of Halichondrins," J. Org. Chem. 62:7552-7553(1997).
Stamos et al., "Synthetic Studies on Halichondrins: A Practical Synthesis of the C.1-C.13 Segment" Tetrahedron Lett. 37(48): 8643-8646 (1996).
Stamos, D.P., et al., "Ni(II)/Cr(II)-Mediated Coupling Reaction: Beneficial Effects of 4-Tert-Butylpyridine as an Additive and Development of New and Improved Workup Procedures," Tetrahedron Lett., 38(36): 6355-6358 (1997).
Supporting Information for Choi, Hyeong-Wook, et al., Asymmetric Ni(II)/Cr(II)-Mediated Coupling Reaction: CaLatytic Process, Organic Letters, vol. 4, No. 25, pp. 1-8 (2002).
Supporting information for Kurosu, M., et al., "Fe/Cr- and Co/Cr-Mediated Catalytic Asymmetric 2-Haloallylations of Aldehydes", Journal of the American Chemical Society, vol. 126, No. 39, pp. S-1-5-9, (2004).
Supporting Information for Wan et al., "Asymmetric Ni(II)/Cr(II)-Mediated Coupling Reaction: Stoichiometric Process," Organic Letters 4(25), pp. 4431-4434 (2002).
Sutherland et al., "The Synthesis of 6α- and 6β-Fluoroshikimic Acids," J. Chem. Soc., Chem. Commun. 18:1386-1387, 1989.
Takai et al., "Reactions of Alkenylchromium reagents prepared from alkenyl trifluoromethanesulfonates (triflates) with chromium (II) chloride under nickel catalysis," J. Am. Chem. Soc. 108, pp. 6048-6050 (1986).
Takai et at "Reactions of Alkenylchromium Reagents Prepared from Alkenyl Trifluoromethanesulfonates (Triflates) with Chromium(l1) Chloride under Nickel Catalysis" J. Am. Chem. Soc. 1966, 108:6048.
The AkzoNobel Technical Bulletin. "Diisobutylaluminum hydride (DIBAL-H) and Other Isobutyl Aluminum Alkyls (DIBAL-BOT, TIBAL) as Specialty Organic Synthesis Reagents," 14 pages (2006).
Third Party Observation pursuant to Article 115 EPC relating to counterpart European Application EP 05760356.5, dated Jan. 9, 2013.
Third Party Observation pursuant to Article 115 EPC relating to counterpart European Application EP 05760356.5, dated Mar. 26, 2012.
Tokunaga et al., "Asymmetric Catalysis with Water: Efficient Kinetic Resolution of Terminal Epoxides by Means of Catalytic Hydrolysis," Science 277: 936-938 (1997).
Towle et al. "Halichondrin B Macrocyclic Ketone Analog E7389: Medicinal Chemistry Repair of Lactone Ester Instability Generated During Structural Simplification to Clinical Candidate" Annual Meeting of the American Association for Cancer Research, Apr. 6-1 0. 2002, 5721.
Towle et al. "In Vitro and In Vivo Anticancer Activities of Synthetic Macrocyclic Ketone Analogues of Halichondrin B" Cancer Research 2001, 61:1013.
U.S. Patent and Trademark Office, "Clarification of Criteria for Reissue Error in View of In re Tanaka " dated Aug. 1, 2011.
Uemura et al., "Norhalichondrin A: An Antitumor Polyether Macrolide from a Marine Sponge," J. Am. Chem. Soc. 107: 4796-4798 (1985).
Vahdat et al., "Phase II Study of Eribulin Mesylate, a Halichondrin B Analog, in Patients with Metastatic Breast Cancer Previously Treated with an Anthracycline and a Taxane," J. Clin. Oncol. 27(18): 2964-2961 (2009).
Wan et al., "Asymmetric Ni(II)/Cr(II)-Mediated Coupling Reaction: Stoichiometric Process," Org. Lett. 4(25): 4431-4434 (2002) Supporting Information, 8 pages.
Wan et al., "Asymmetric Ni(II)/Cr(II)-Mediated Coupling Reaction: Stoichiometric Process," Org. Lett. 4(25): 4431-4434 (2002).
Wan et al., "Asymmetric Ni(II)/Cr(II)-Mediated Coupling Reaction: Stoichiometric Process," Organic Letters 4(25), pp. 4431-4434 (2002).
Wang et al. "Structure-Activity Relationships of Halichondrin B Analogues: Modifications at C.30-C.38" Bioorg. Med. Chem. Lett. 2000, 10:1029.
Wang et al., "Facile preparation of peracetates and per-3-bromobenzoates of alpha-mono- and disaccharides," Molecules 1 0:1325-1334, 2005.
Written Amendment and Written Argument filed in the Japanese Patent Office for the counterpart Japanese Application No. 2007-515,643dated Feb. 4, 2013.
Written Opinion from International Application No. PCT/US2005/019669, dated Sep. 7, 2005.
Written Opinion from International Application No. PCT/US2005/019669, mailed Sep. 7, 2005.
Written Submissions filed in the from the European Patent Office for the counterpart EP Application No. 05760356.5 dated Oct. 21, 2013.
Xie, C., et al., "Synthesis of the C20-C26 Building Block of Halichondrins via a Regiospecific and Stereoselective SN2' Reaction," Org. Lett., 4(25):4427-4429 (2002).
Yang et al., "Second Generation Synthesis of C27-C35 Building Block of E7389, a Synthetic Halichondrin Analogue," Org. Lett. 11 (20): 4516-4519 (2009).
Youssefyeh, "Acylatrons of Ketals and Errol Ethers,"J. Am. Chem. Soc., 85:3901-3902, 1963.
Yu et al., Anticancer Agents from Natural Products; CRC Press: Boca Raton, FL, 241-265. (2005).
Yu et al., New Synthetic Route to the C.14-C.21 Fragment of Halichondrin B, Book of Abstracts, 219th ACS National Meeting, San Francisco, CA, Mar. 26-30, 2000 (2000).
Zheng et al., "Macrocyclic Ketone Analogues of Halichondrin B," Bioorg. Med. Chem. Lett. 14: 5551-5554 (2004).
Zheng, W. et al. "Synthetic macrocyclic ketone analogs of halichondrin B: structure-activity relationships" American Association for Cancer Research, San Francisco, CA Apr. 1-5, 2000, 1915.

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