Method of acylating maytansinol with chiral amino acids

1. A method of making a compound of formula A:

where:

X is Cl or H, and

R is

R 1 is a naturally-occurring amino acid side chain;

R 2 is hydrogen or a C 1-6 alkyl group;

said method comprising:

(a) providing a mixture comprising

(i) a starting material which has a formula identical to formula A except that R is hydrogen,

(ii) a compound of formula 2:

(iii) a Lewis acid,

(iv) a non-nucleophilic base and

(v) an organic solvent;

(b) allowing the mixture of step (a) to react until some of the starting material is converted to the compound of formula A;

(c) removing crude compound of formula A from the mixture of step (b); and

(d) optionally purifying the compound of formula A obtained in step (c).

2. The method of claim 1 wherein the starting material is maytansinol.

3. The method of claim 2 where R 1 is a C 1-6 alkyl and R 2 is a C 1-6 alkyl.

4. The method of claim 3 wherein 2 is predominantly (S)-isomer.

5. The method of claim 4 wherein 2 is 3,4-dimethyl-oxazolidine-2,5-dione.

6. A method of making a compound of formula II:

wherein:

X is Cl or H;

R 1 is a naturally-occurring amino acid side chain;

R 2 is hydrogen, C 1-6 alkyl, aryl or aralkyl;

L is a C 2-6 alkylene chain having 0-2 substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

R 3 is hydrogen or S—R 4 ; and

R 4 is C 1-6 alkyl, aryl, or aralkyl;

the method comprising:

(a) obtaining a compound of formula I:

 by a coupling reaction of 2 with maytansinol or its analogue where X=H, wherein the coupling reaction is performed in the presence of a Lewis acid, a non-nucleophilic base and an organic solvent;

(b) coupling the compound of formula I obtained from step (a) with R 5 O 2 C—L—S—S—R 4 , where R 5 is hydrogen or an activating group to provide the compound of formula II where R 3 is S—R 4 ; and

(c) optionally treating the compound of formula II obtained in step (b) with a reducing agent to provide a compound of formula II where R 3 is hydrogen.

7. The method of claim 6 where R 2 is hydrogen or C 1-6 alkyl and L is a C 2-3 alkylene chain having 0-2 substituents independently selected from C 1-6 alkyl.

8. The method of claim 7 where L is an alkylene chain substituted by 0-2 methyl groups.

9. The method of claim 8 where R 5 O 2 C—L—S—S—C 1-6 alkyl is:

10. The method of claim 9 wherein the compound of formula II obtained in step (b) is treated with a reducing agent to provide a compound of formula II where R 3 is hydrogen.