Regioselective synthesis of CCI-779

A compound of formula (I):

• in which R is:
• —O—C═O.CR7R8R9
• wherein:
• R7 is hydrogen, alkyl of 1–6 carbon atoms, alkenyl of 2–7 carbon atoms, alkynyl of 2–7 carbon atoms, —(CR12R13)fOR10, —CF3, —F, or —CO2R10;
• R10 is hydrogen, alkyl of 1–6 carbon atoms, alkenyl of 2–7 carbon atoms, alkynyl of 2–7 carbon atoms, triphenylmethyl, benzyl, alkoxymethyl of 2–7 carbon atoms, chloroethyl, or tetrahydropyranyl;
• R8 and R9 are taken together to form X;
• X is 2-phenyl-1,3,2-dioxaborinan-5-yl or 2-phenyl-1,3,2-dioxaborinan-4-yl,
• wherein the phenyl may be optionally substituted;
• R12 and R13 are each, independently, hydrogen, alkyl of 1–6 carbon atoms, alkenyl of 2–7 carbon atoms, alkynyl of 2–7 carbon atoms, trifluoromethyl, or —F;
• and
• f=0–6.

A compound of formula:

• in which R is:
• —O—C═O.CR7R8R9
• wherein:
• R7 is hydrogen, alkyl of 1–6 carbon atoms, alkenyl of 2–7 carbon atoms, alkynyl of 2–7 carbon atoms, —(CR12R13)fOR10, —CF3, —F, or —CO2R10;
• R10 is hydrogen, alkyl of 1–6 carbon atoms, alkenyl of 2–7 carbon atoms, alkynyl of 2–7 carbon atoms, triphenylmethyl, benzyl, alkoxymethyl of 2–7 carbon atoms, chloroethyl, or tetrahydropyranyl;
• R8 and R9 are taken together to form X;
• X is 2-phenyl-1,3,2-dioxaborinan-5-yl or 2-phenyl-1,3,2-dioxaborinan-4-yl,
• wherein the phenyl may be optionally substituted;
• R12 and R13 are each, independently, hydrogen, alkyl of 1–6 carbon atoms, alkenyl of 2–7 carbon atoms, alkynyl of 2–7 carbon atoms, trifluoromethyl, or —F;
• and
• f=0–6;
• and wherein R′, R″, and R′″ are the same or different and are selected from the group consisting of alkyl of 1–6 carbon atoms, phenyl and benzyl.

A compound of formula:

• HO—C═O.CR7R8R9
• R7 is hydrogen, alkyl of 1–6 carbon atoms, alkenyl of 2–7 carbon atoms, alkynyl of 2–7 carbon atoms, —(CR12R13)fOR10, —CF3, —F, or —CO2R10;
• R10 is hydrogen, alkyl of 1–6 carbon atoms, alkenyl of 2–7 carbon atoms, alkynyl of 2–7 carbon atoms, triphenylmethyl, benzyl, alkoxymethyl of 2–7 carbon atoms, chloroethyl, or tetrahydropyranyl;
• R8 and R9 are taken together to form X;
• X is a 2-phenyl-1,3,2-dioxaborinan-5-yl or a 2-phenyl-1,3,2-dioxaborinan-4-yl, wherein the phenyl may be optionally substituted;
• R12 and R13 are each, independently, hydrogen, alkyl of 1–6 carbon atoms, alkenyl of 2–7 carbon atoms, alkynyl of 2–7 carbon atoms, trifluoromethyl, or —F;
• and
• f=0–6;
• or a mixed 2,4,6-trichlorobenzoyl anhydride thereof.

A process for preparing a 42-ester of rapamycin, which comprises:

• (b) acylating a rapamycin 31-silyl ether with a compound of formula
• HOOC.CR7R8R9
• or a mixed 2,4,6-trichlorobenzoyl anhydride thereof,
• wherein
• R7 is hydrogen, alkyl of 1–6 carbon atoms, alkenyl of 2–7 carbon atoms, alkynyl of 2–7 carbon atoms, —(CR12R13)fOR10, —CF3, —F, or —CO2R10;
• R10 is hydrogen, alkyl of 1–6 carbon atoms, alkenyl of 2–7 carbon atoms, alkynyl of 2–7 carbon atoms, triphenylmethyl, benzyl, alkoxymethyl of 2–7 carbon atoms, chloroethyl, or tetrahydropyranyl;
• R8 and R9 are taken together to form X;
• X is a 2-phenyl-1,3,2-dioxaborinan-5-yl or a 2-phenyl-1,3,2-dioxaborinan-4-yl, wherein the phenyl may be optionally substituted;
• R12 and R13 are each, independently, hydrogen, alkyl of 1–6 carbon atoms, alkenyl of 2–7 carbon atoms, alkynyl of 2–7 carbon atoms, trifluoromethyl, or —F;
• and
• f=0–6;
• to give a 42-ester boronate 31-silyl ether of rapamycin;
• (b) selectively hydrolyzing the 42-ester boronate 31-silyl ether in mild acidic conditions to provide a rapamycin 42-ester boronate;
• and
• (c) treating the rapamycin 42-ester boronate with diethanolamine, solid-supported polystyrene diethanolamine, or a carboxylic acid to provide a 42-ester of rapamycin.