Synthesis of epothilones

A method of synthesizing the C12-C20 epothilone precursor of the formula

• where R8 is selected from the group consisting of H, C1-C4 straight or branched chain alkyl, alkenyl or alkynyl groups, R9 is selected from the group consisting of H, C1-C10 straight and branched chain alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl or hydroxyalkynyl groups, substituted and unsubstituted cyclic, heteroxylic and aryl groups, R12 is selected from the group consisting of H, C1-C10 straight and branched chain alkyl groups, substituted and unsubstituted benzyl groups, and C1-C10 alkoxy groups, X2 is O or S, n is an integer which ranges from 1 to 4, P′ is a protective group and M is either iodine or bromine, wherein an alcohol of the formula
• where R8, R9, X2, n4 are as defined above and P′ is a protective group, is converted to the C12-C20 epothilone segment A, which method comprises the steps of:
• providing an enone compound of the formula
• where R8, R9, X2, P′ and n4 are as defined above;
• and
• asymmetrically reducing said enone compound in the presence of a chiral catalyst to obtain said alcohol.

A method of synthesizing the C12-C20 epothilone precursor of the formula

• where R8 is selected from the group consisting of H, C1-C4 straight or branched chain alkyl, alkenyl or alkynl groups, R9 is selected from the group consisting of H, C1-C10 straight and branched chain alkyl, alkenyl, alkynl, hydroxyalkyl, hydroxyalkenyl and hydroxyalkynl groups, substituted and unsubstituted cyclic, heteroxylic and aryl groups, R12 is selected from the group consisting of H, C1-C10 straight and branched chain alkyl groups, substituted and unsubstituted benzyl groups, and C1-C10 alkoxy groups, X2 is O or S, n is an integer which ranges from 1 to 4, P′ is a protective group and M is either bromine or iodine, said method comprising the steps of:
• providing an aldehyde of the formula
• where R8, R9, and X2 are as defined above;
• reacting said aldehyde with an acetate of the formula
• where R13 is a C1-C4 alkyl group, Z is a C1-C4 straight or branched chain alkyl group or a substituted or unsubstituted benzyl group in a basic reaction mixture to yield a β-hydroxyester of the formula
• where R8, R9, X2, Z and n4 are as defined above;
• oxidizing said β-hydroxyester to the corresponding β-ketoester of the formula
• where R8, R9, X2, Z and n4 are as defined above;
• hydrogenating said β-ketoester to form a chiral alcohol of the formula
• where R8, R9, X2, Z and n4 are as defined above, by reacting the β-ketoester with a hydrogenating agent in the presence of asymmetric organometallic molecular catalyst comprising a metal atom or ion having one or more chiral ligands coupled thereto;
• and
• converting said chiral alcohol to said C12-C20 epothilone precursor.

A method of synthesizing a C1-C6 epothilone precursor of the formula

• where n1 is an integer from 0-4, R4 is selected from the group consisting of H, C1-C10 straight and branched chain alkyl groups, substituted and unsubstituted benzyl groups, and C1-C10 alkoxy groups, R5 and R6 are each individually and respectively selected from the group consisting of H, substituted and unsubstituted aryl and heterocyclic groups, C1-C10 straight and branched chain alkyl groups, and substituted and unsubstituted benzyl groups, R7 is H or straight or branched chain C1-C10 alkyl groups, and P′ is a protective group, comprising the steps of:
• providing a nitrile compound of the formula
• where P′, R5, R6, R7 and n1 are as defined above, and the value of each n1, may be the same or different;
• alkylating said nitrile compound to yield a dialkylated compound of the formula
• where P′, R5, R6, R7, and n1 are as defined above, and the value of each n1 may be the same or different;
• and
• converting said nitrile compound to yield said epothilone precursor.

A method of synthesizing a C1-C6 epothilone precursor of the formula

• where n1 is an integer from 0-4, R4 is selected from the group consisting of H, C1-C10 straight and branched chain alkyl groups, substituted and unsubstituted benzyl groups, and C1-C10 alkoxy groups, R5 and R6 are each individually and respectively selected from the group consisting of H, substituted and unsubstituted aryl and heterocyclic groups, C1-C10 straight and branched chain alkyl groups, and substituted and unsubstituted benzyl groups, R7 is H or straight or branched chain C1-C10 alkyl groups, and P′ is a protective group, said method comprising the steps of:
• providing an ester compound of the formula
• where R1, R5, R6, R7, n1 and P′ are as defined above, and R′ is a C1-C10 striaght or branched chain alkyl group;
• reacting said ester compound with a sulfone to acylate the ester, and thereafter desulfonating the acylated ester to obtain said epothilone precursor.