Novel methods for the preparation of taxanes using oxazolidine intermediates

A compound of the following formula I or salt thereof:

• 46
• where
• R1* is hydrogen, arylcarbonyl, alkoxycarbonyl or alkylcarbonyl, with the proviso that R1* is not tert-butoxycarbonyl when R2 is aryl;
• R2 is aryl, heterocyclo or alkyl;
• R4 is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, or heterocyclo;
• and
• R5 and R6 are (a) each independently alkyl;
• or (b) together with the carbon atom to which they are bonded, form a cycloalkyl, cycloalkenyl or heterocyclo group.

A compound of the following formula V or salt thereof:

• 47
• where
• R1* is hydrogen, arylcarbonyl, alkoxycarbonyl or alkylcarbonyl, with the proviso that R1* is not tert-butoxycarbonyl when R2 is aryl;
• R2 is aryl, heterocyclo or alkyl;
• R5 and R6 are (a) each independently alkyl;
• or (b) together with the carbon atom to which they are bonded, form a cycloalkyl, cycloalkenyl or heterocyclo group;
• and
• T is a taxane moiety directly bonded at C-13 of said moiety.

A compound of the following formula iv or salt thereof:

• 48
• where
• R1* is hydrogen, arylcarbonyl, alkoxycarbonyl or alkylcarbonyl, with the proviso that R1* is not tert-butoxycarbonyl when R2 is aryl;
• R2 is aryl, heterocyclo or alkyl;
• R4 is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, or heterocyclo;
• and
• R3P is the group:
• 49
• where
• R5 and R6 are (a) each independently alkyl;
• or (b) together with the carbon atom to which they are bonded, form a cycloalkyl, cycloalkenyl or heterocyclo group;
• and
• R7 is alkyl or aryl.

A method for the preparation of a compound of the following formula VI or a salt thereof:

• 50
• where
• R1 is hydrogen, arylcarbonyl, alkoxycarbonyl or alkylcarbonyl;
• R2 is aryl, heterocyclo or alkyl;
• and
• T is a taxane moiety directly bonded at C-13 of said moiety;
• comprising the steps of:
• (a) contacting a compound of the following formula VII or salt thereof:
• 51
• where
• R1 and R2 are as defined above;
• and
• R8 is alkyl or aryl;
• with a compound of the following formula IV or salt thereof:
• HO—T (IV),
• where T is as defined above, in the presence of a coupling agent, to form a compound of the following formula VIII or salt thereof:
• 52
• where R1, R2, R8 and T are as defined above;
• and
• (b) contacting said compound of the formula VIII or salt thereof with a ring-opening agent, and, optionally, deprotecting one or more protected hydroxyl groups, to form said compound of the formula VI or salt thereof.

A compound of the following formula II or salt thereof:

• 56
• where
• R1 is hydrogen, arylcarbonyl, alkoxycarbonyl or alkylcarbonyl;
• R2 is aryl, heterocyclo or alkyl;
• R4 is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, or heterocyclo;
• and
• R8 is alkyl or aryl.

A compound of the following formula VIII or salt thereof:

• 57
• where
• R1 is hydrogen, arylcarbonyl, alkoxycarbonyl or alkylcarbonyl;
• R2 is aryl, heterocyclo or alkyl;
• R8 is alkyl or aryl;
• and
• T is a taxane moiety directly bonded at C-13 of said moiety.

A compound of the following formula v or salt thereof:

• 58
• where
• R1 is hydrogen, arylcarbonyl, alkoxycarbonyl or alkylcarbonyl;
• R2 is aryl, heterocyclo or alkyl;
• R4 is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, or heterocyclo;
• and
• R8 is alkyl or aryl.