Synthesis of epothilones, intermediates thereto and analogues thereof

A method of preparing a hydroxy acid desoxyepothilone precursor having the structure:

• wherein R, R0, and R′ are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acet al, fluorine, NR1R2, N-hydroximino, or N-alkoxyimino, wherein R1 and R2 are independently H, phenyl, benzyl, linear or branched chain alkyl;
• wherein R″ is —CY═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;
• wherein X is H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazolyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazolyl, 3-indolyl or 6-indolyl;
• wherein Y is H or linear or branched chain alkyl;
• wherein n is 2 or 3;
• wherein RA 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;
• wherein RB is hydrogen, t-butyloxycarbonyl, amyloxycarbonyl, (trialkylsilyl)alkyloxycarbonyl, (dialkylarylsilyl)alkyloxycarbonyl, benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;
• which comprises selectively etherifying and hydrolyzing a hydroxy ester desoxyepothilone precursor having the structure:
• wherein R, R0, RB, RC, R′, R″ and n are defined as above;
• wherein RC is tertiary-alkyl;
• under suitable conditions to form the hydroxy acid desoxyepothilone precursor.

A method of preparing a hydroxy ester desoxyepothitone precursor having the structure:

• wherein R, R0, and R′ are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, alkoxy, carboxy, carboxaldehyde, 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 —CY═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;
• wherein X is 2-methyl-1,3-thiazolyl;
• wherein Y is H or linear or branched chain alkyl;
• wherein n is 3;
• wherein RB is hydrogen, t-butyloxycarbonyl, amyloxycarbonyl, (trialkylsilyl)alkyloxycarbonyl, (dialkylarylsilyl)alkyloxycarbonyl, benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;
• and wherein RC is tertiary-alkyl;
• which comprises reducing a hydroxy ketoester desoxyepothilone precursor having the structure:
• wherein R, R0, RB, RC, R′, R″, and n are defined as above;
• under suitable conditions to form the hydroxy ester desoxyepothilone precursor.

A method of preparing a hydroxy ester desoxyepothilone precursor having the structure:

• wherein R, R0, and R′ are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acet al, fluorine, NR1R2, N-hydroximino, or N-alkoxyimino, wherein R1 and R2 are independently H, phenyl, benzyl, linear or branched chain alkyl;
• wherein R″ is —CY═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, 1,2-methyl-1,3-oxazolinyl, 3-indolyl, or 6-indolyl;
• wherein X is H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazolyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazolyl, 3-indolyl, or 6-indolyl;
• wherein Y is H or linear or branched chain alkyl;
• wherein n is 2 or 3;
• wherein RB is Troc;
• and wherein RC is tertiary-alkyl;
• which comprises reducing a hydroxy ketoester desoxyepothilone precursor having the structure:
• wherein R, R0, RB, RC, R′, R″, and n are defined as above;
• under suitable conditions to form the hydroxy ketoester desoxyepothilone precursor.

A method of preparing a hydroxy ketoester desoxyepothilone precursor having the structure:

• wherein P is H;
• wherein R, R0, and R′ are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, NR1NR2, N-hydroximino, or N-alkoxyimino, wherein R1 and R2 are independently H, phenyl, benzyl, linear or branched chain alkyl;
• wherein R″ is —CY═CHX, or H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 2-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl, or 6-indolyl;
• wherein X is 2-methyl-1,3-thiazolyl;
• wherein Y is H or linear or branched chain alkyl;
• wherein n is 3;
• wherein RB is hydrogen, t-butyloxycarbonyl, amyloxycarbonyl, (trialkylsilyl)alkyloxycarbonyl, (dialkylarylsilyl)alkyloxycarbonyl, benzyl, trialkylsislyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;
• and wherein RC is tertiary-alkyl;
• which comprises deprotecting a protected ketoester desoxyepothilone precursor having the structure:
• wherein R, R0, RB, RC, R′, R″, and n are defined as above;
• and wherein P is a linear of branched alkyl, alkoxyalkyl, substituted or unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, or triarylsilyl;
• under suitable conditions to form the hydroxy ketoester desoxyepothilone precursor.

A method of preparing a hydroxy ketoester desoxyepothilone precursor having the structure:

• wherein P is H;
• wherein R, R0, and R′ are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acet al, fluorine, NR1NR2, N-hydroximino, or N-alkoxyimino, wherein R1 and R2 are independently H, phenyl, benzyl linear or branched chain alkyl;
• wherein R″ is —CY═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;
• wherein X is H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazolyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazolyl, 3-indolyl, or 6-indolyl;
• wherein Y is H or linear or branched chain alkyl;
• wherein n is 2 or 3;
• wherein RB is Troc;
• and wherein RC is tertiary-alkyl;
• which comprises deprotecting a protected ketoester desoxyepothilone precursor having the structure:
• wherein R, R0, RB, RC, R′, R″, and n are defined as above;
• and wherein P is a linear or branched alkyl, alkoxyalkyl, substituted or unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, or triarylsilyl;
• under suitable conditions to form the hydroxy ketoester desoxyepothilone precursor.

A method of preparing a terminal vinyl enol ether ester having the structure:

• wherein R0 and R′ are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acet al, fluorine, NR1NR2, N-hydroximino, or N-alkoxyimino, wherein R1 and R2 are independently H, phenyl, benzyl, linear or branched chain alkyl;
• wherein m is 0, 1, or 2;
• wherein RB is hydrogen, t-butyloxycarbonyl, amyloxycarbonyl, (trialkylsilyl)alkyl-oxycarbonyl, (dialkylarylsilyl)alkyl-oxycarbonyl, benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;
• wherein RC is tertiary-alkyl;
• and wherein RD is linear or branched alkyl, benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;
• which comprises:
• (a) treating a keto enol ester having the structure:
• with a strong nonnucleophilic base selected from the group consisting of lithium dimethylamide, lithium diethylamide, lithium diisopropylamide, lithium hydride, sodium hydride, potassium hydride, and potassium t-butoxide, to form an enolate ester having the structure:
• wherein M is Li, Na, or K;
• and
• (b) coupling the enolate enol ester with a vinyl aldehyde having the structure:
• wherein m, and R0 and R′ are as defined above;
• under suitable conditions to form the terminal vinyl enol ether ester.

A method of preparing a terminal vinyl enol ether ester having the structure:

• wherein R0 and R′ are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acet al, fluorine, NR1NR2, N-hydroximino, or N-alkoxyimino, wherein R1 and R2 are independently H, phenyl, benzyl, linear or branched chain alkyl;
• wherein m is 0, 1, or 2;
• wherein RB is hydrogen, t-butyloxycarbonyl, amyloxycarbonyl, (trialkylsilyl)alkyl-oxycarbonyl, (dialkylarylsilyl)alkyl-oxycarbonyl, benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;
• wherein RC is tertiary-alkyl;
• and wherein RD is linear or branched alkyl,benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;
• which comprises:
• (a) treating a keto enol ester having the structure:
• under suitable conditions to form an enolate ester having the structure:
• wherein M is Li, Na, or K;
• and
• (b) coupling at a temperature from about −130° C. to about −78° C. the enolate enol ester with a vinyl aldehyde having the structure:
• wherein m, and R0 and R′ are as defined above;
• under suitable conditions to form the terminal vinyl enol ether ester.