Synthesis of epothilones, intermediates thereto, analogues and uses thereof

A compound having the structure:

• 64
• wherein R, R0, and R′ are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, alkoxy, carboxy, carboxaldedyde linear or branched alkyl or cyclic acetal, fluorine, NR1R2, N-hydroximino, or N-alkoxyimino, wherein R1 and R2 are independently H, phenyl, benzyl, linear or branched chain alkyl;
• wherein R″ is —CHY═CHX, or H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6-indolyl;
• and wherein X is H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6-indolyl;
• wherein Y is H or linear or branched chain alkyl;
• wherein Z is O, N(OR3) or N—NR4R5, wherein R3, R4 and R5 are independently H or a linear or branched chain alkyl;
• and wherein n is 0, 1, 2, or 3.

A compound having the structure:

• 66
• wherein R, R0, and R′ are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, alkoxy, carboxy, carboxaldedyde linear or branched alkyl or cyclic acetal, fluorine, NR1R2, N-hydroximino, or N-alkoxyimino, wherein R1 and R2 are independently H, phenyl, benzyl, linear or branched chain alkyl;
• wherein R″ is —CHY═CHX, or H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6-indolyl;
• and wherein X is H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6-indolyl;
• wherein Y is H or linear or branched chain alkyl;
• wherein Z is O, N(OR3) or N—NR4R5, wherein R3, R4 and R5 are independently H or a linear or branched chain alkyl;
• and wherein n is 0, 1, 2, or 3.

A compound having the structure:

• 68
• wherein R, R0 and R′ are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, alkoxy, carboxy, carboxaldedyde linear or branched alkyl or cyclic acetal, fluorine, NR1R2, N-hydroximino, or N-alkoxyimino, wherein R1 and R2 are independently H, phenyl, benzyl, linear or branched chain alkyl;
• wherein R″ is —CHY═CHX, or H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6-indolyl;
• and wherein X is H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6-indolyl;
• wherein Y is H or linear or branched chain alkyl;
• wherein Z is O, N(OR3) or N—NR4R5, wherein R3, R4 and R5 are independently H or a linear or branched chain alkyl or alkoxy;
• and wherein n is 0, 1, 2, or 3.

A compound having the structure:

• 70
• wherein R′ and R″ are independently hydrogen, a linear or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;
• wherein X is oxygen, (OR*)2, (SR*)2, —(O—(CH2)n—O)—, —(O—(CH2)n—S)— or —(S—(CH2)n—S)—;
• wherein R* is a linear or branched alkyl, substituted or unsubstituted aryl or benzyl;
• wherein R2B is a linear, branched or cyclic alkyl or substituted or unsubstituted aryl or benzyl boranyl moiety;
• and wherein n is 2, 3 or 4.

A compound having the structure:

• 71
• wherein R′ and R″ are independently hydrogen, a linear or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;
• wherein X is oxygen, (OR*)2, (SR*)2, —(O—(CH2)n—O)—, —(O—(CH2)n—S)— or —(S—(CH2)n—S)—;
• wherein R* is a linear or branched alkyl, substituted or unsubstituted aryl or benzyl;
• wherein R2B is a linear, branched or cyclic alkyl or substituted or unsubstituted aryl or benzyl boranyl moiety;
• wherein Y is OH, linear or branched chain alkoxy, trimethylsilyloxy, t-butyldimethylsilyloxy or methyldiphenysilyloxy;
• and wherein n is 2, 3 or 4.

A compound having the structure:

• 72
• wherein R′ and R″ are independently hydrogen, a linear or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;
• wherein X is oxygen, (OR)2, (SR)2, —(O—(CH2)n—O)—, —(O—(CH2)n—S)— or —(S—(CH2)n—S)—;
• and wherein n is 2, 3 or 4.

A compound having the structure:

• 73
• wherein R is hydrogen, a linear or branched alkyl, alkoxyalkyl, substituted or unsubstituted aryloxyalkyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;
• wherein X is a halogen;
• wherein R″ is H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6-indolyl;
• and wherein Y is H or linear or branched chain alkyl.;
• wherein R′ is H, linear or branched chain alkyl, hydroxymethyl, hydroxypropyl, alkyl carboxaldehyde, alkyl carboxaldehyde linear or cyclic acetal;
• and X is a halide.

A compound having the structure:

• 74
• wherein R′ and R″ are independently hydrogen, a linear or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;
• wherein X is oxygen, (OR)2, (SR)2, —(O—(CH2)n—O)—, —(O—(CH2)n—S)— or —(S—(CH2)n—S)—;
• and wherein n is 2, 3 or 4.

A compound having the structure:

• 75
• wherein R is hydrogen, a linear or branched alkyl, alkoxyalkyl, substituted or unsubstituted aryloxyalkyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;
• wherein X is a halogen;
• wherein R′ is H, linear or branched chain alkyl, alkyl carboxaldehyde, alkyl carboxaldehyde linear or cyclic acetal;
• wherein R″ is H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6-indolyl;
• and wherein Y is H or linear or branched chain alkyl.

A compound having the structure:

• 76
• wherein R is hydrogen, methyl, ethyl, n-propyl, n-hexyl, CO2Et,
• 77
• CH2OH;
• or (CH2)3—OH;
• wherein R′ and R″ are independently hydrogen, a linear or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;
• and wherein Z is hydrogen, or linear or branched chain alkyl.

A method of preparing a Z-haloalkene ester having the structure:

• 78
• wherein R is hydrogen, a linear or branched alkyl, alkoxyalkyl, substituted or unsubstituted aryloxyalkyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;
• wherein R′is hydrogen, methyl, ethyl, n-propyl, n-hexyl, CO2Et,
• 79
• CH2OH or (CH2)3—OH;
• and wherein X is a halogen, which comprises
• (a) oxidatively cleaving a compound having the structure:
• 80
• under suitable conditions to form an aldehyde intermediate;
• and
• (b) condensing the aldehyde intermediate with a halomethylene transfer agent under suitable conditions to form the Z-haloalkene ester.

A method of preparing an optically pure compound having the structure:

• 81
• wherein R is hydrogen, a linear or branched alkyl, alkoxyalkyl, substituted or unsubstituted aryloxyalkyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl, which comprises:
• (a) condensing an allylic organometallic reagent with an unsaturated aldehyde having the structure:
• 82
• under suitable conditions to form an alcohol, and, optionally concurrently therewith, optically resolving the alcohol to form an optically pure alcohol having the structure:
• 83
• (b) alkylating or acylating the optically pure alcohol formed in step (a) under suitable conditions to form the optically pure compound.

A method of preparing an open-chain aldehyde having the structure:

• 84
• wherein R′ and R″ are independently hydrogen, a linear or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl, which comprises:
• (a) cross-coupling a haloolefin having the structure:
• 85
• wherein R is a linear or branched alkyl, alkoxyalkyl, substituted or unsubstituted aryloxyalkyl, trialkylsilyl, aryidialkylsilyl, diarylalkylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl, and X is a halogen, with a terminal olefin having the structure:
• 86
• wherein (OR′″)2 is (OR0)2, (SR0)2, —(O—(CH2)n—O)—, —(O—(CH2)n—S)— or —(S—(CH2)n—S)— where R0 is a linear or branched alkyl, substituted or unsubstituted aryl or benzyl;
• and wherein n is 2, 3 or 4, under suitable conditions to form a cross-coupled compound having the structure:
• 87
• wherein Y is CH(OR*)2 where R* is a linear or branched alkyl, alkoxyalkyl, substituted or unsubstituted aryloxyalkyl;
• and
• (b) deprotecting the cross-coupled compound formed in step (a) under suitable conditions to form the open-chain compound.

A method of preparing an epothilone having the structure:

• 88
• which comprises:
• (a) deprotecting a cyclized compound having the structure:
• 89
• wherein R′ and R″ are independently hydrogen, a linear or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl, under suitable conditions to form a deprotected cyclized compound and oxidizing the deprotected cyclized compound under suitable conditions to form a desoxyepothilone having the structure:
• 90
• and
• (b) epoxidizing the desoxyepothilone formed in step (a) under suitable conditions to form the epothilone.

A method of preparing an epothilone precursor having the structure:

• 91
• wherein R1 is hydrogen or methyl;
• wherein X is O, or a hydrogen and OR″, each singly bonded to carbon;
• and wherein R0, R′ and R″ are independently hydrogen, a linear or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl, which comprises
• (a) coupling a compound having the structure:
• 92
• wherein R is an acetyl, with an aldehyde having the structure:
• 93
• wherein Y is oxygen, under suitable conditions to form an aldol intermediate and optionally protecting the aldol intermediate under suitable conditions to form an acyclic epthilone precursor having the structure:
• 94
• (b) subjecting the acylic epothilone precursor to conditions leading to intramolecular olefin metathesis to form the epothilone precursor.

A method of preparing a Z-iodoalkene ester having the structure:

• 95
• wherein R is hydrogen, a linear or branched alkyl, alkoxyalkyl, substituted or unsubstituted aryloxyalkyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl, which comprises
• (a) coupling a compound having the structure:
• 96
• with a methyl ketone having the structure:
• 97
• wherein R′ and R″ are independently a linear or branched alkyl, alkoxyalkyl, substituted or unsubstituted aryl or benzyl, under suitable conditions to form a compound having the structure:
• 98
• (b) treating the compound formed in step (a) under suitable conditions to form a Z-iodoalkene having the structure:
• 99
• and
• (c) deprotecting and acylating the Z-iodoalkene formed in step (b) under suitable conditions to form the Z-iodoalkene ester.

A method of preparing an open-chain aldehyde having the structure:

• 100
• wherein R is a linear or branched alkyl, alkoxyalkyl, substituted or unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;
• and wherein R′ and R″ are independently hydrogen, a linear or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl, which comprises:
• (a) cross-coupling a haloolefin having the structure:
• 101
• wherein X is a halogen, with a terminal hydroborane having the structure:
• 102
• wherein R12B is a linear, branched or cyclic alkyl or substituted or unsubstituted aryl or benzyl boranyl moiety;
• wherein Y is (OR0)2, (SR0)2, —(O—(CH2)n—O)—, —(O—(CH2)n—S)— or —(S—(CH2)n—S)— where R0 is a linear or branched alkyl, substituted or unsubstituted aryl or benzyl;
• and wherein n is 2, 3 or 4, under suitable conditions to form a cross-coupled compound having the structure:
• 103
• and
• (b) deprotecting the cross-coupled compound formed in step (a) under suitable conditions to form the open-chain aldehyde.

A method of preparing a protected epothilone having the structure:

• 104
• wherein R′ and R″ are independently hydrogen, a linear or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkyl-arylsilyl, alkyldiarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl, which comprises:
• (a) monoprotecting a cyclic diol having the structure:
• 105
• under suitable conditions to form a cyclic alcohol having the structure:
• 106
• and
• (b) oxidizing the cyclic alcohol formed in step (a) under suitable conditions to form the protected epothilone.

A method of preparing an epothilone having the structure:

• 107
• which comprises:
• (a) deprotecting a protected cyclic ketone having the structure:
• 108
• wherein R′ and R″ are independently hydrogen, a linear or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl, under suitable conditions to form a desoxyepothilone having the structure:
• 109
• and
• (b) epoxidizing the desoxyepothilone formed in step (a) under suitable conditions to form the epothilone.

A method of preparing a cyclic diol having the structure:

• 110
• wherein R′ is a hydrogen, a linear or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl, which comprises:
• (a) cyclizing an open-chain aldehyde having the structure:
• 111
• wherein R is a linear or branched alkyl, alkoxyalkyl, substituted or unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;
• and wherein R″ is a hydrogen, a linear or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl under suitable conditions to form an enantiomeric mixture of a protected cyclic alcohol having the structure:
• 112
• said mixture comprising an α- and a β-alcohol component;
• (b) optionally isolating and oxidizing the α-alcohol formed in step (a) under suitable conditions to form a ketone and thereafter reducing the ketone under suitable conditions to form an enantiomeric mixture of the protected cyclic alcohol comprising substantially the β-alcohol;
• and
• (c) treating the protected cyclic alcohol formed in step (a) or (b) with a deprotecting agent under suitable conditions to form the cyclic diol.

A purified compound having the structure:

• 113
• wherein R is hydrogen, methyl, ethyl, propyl, hexyl, hydroxymethyl or hydroxypropyl;
• wherein X is O;
• and wherein R0, R′ and R″ are independently hydrogen or acetyl.

A purified compound having the structure:

• 114
• wherein R1 is hydrogen, methyl, ethyl, propyl, hexyl, hydroxymethyl or hydroxypropyl;
• wherein X is O;
• and wherein R0, R′ and R″ are independently hydrogen or acetyl.