Transfer hydrogenation of cyclopamine analogs

1. A process for preparing a compound of formula (II):

or a pharmaceutically acceptable form thereof;

from a compound of formula (I):

or a pharmaceutically acceptable form thereof;

wherein:

R 1 is alkyl, alkenyl, alkynyl, aralkyl, C(O)R 16 , CO 2 R 16 , —SO 2 R 16 , —[C(R 23 ) 2 ] q —R 23 , —[(W)—N(R 17 )C(O)] q R 16 , —[(W)—C(O)N(R 17 )] q R 17 , or —[(W)—N(R 17 )] q R 16 , W is (CH 2 ) q and each q is independently 1, 2, 3, 4, 5, or 6;

R 5 and R 6 are each H, or R 5 and R 6 taken together with the carbon to which they are bonded form C═O;

R 11 and R 12 are each H, or R 11 and R 12 taken together form a double bond;

X is a bond or the group —CH 2 —;

R 16 is alkyl, alkenyl, alkynyl, aralkyl, alkoxy, arylalkoxy, or heteroaralkyl;

R 17 is H, alkyl, alkenyl, or alkynyl; and

R 23 is H, alkyl, alkenyl, alkynyl, amido, or amino;

the process comprising reducing a compound of formula (I) or a pharmaceutically acceptable form thereof in the presence of a ruthenium transfer hydrogenation catalyst and a hydrogen donor to thereby preferentially generate a stereoisomer of a compound of formula (II) or a pharmaceutically acceptable form thereof,

wherein the ruthenium transfer hydrogenation catalyst comprises one or more of (iii-a), (iii-i), and (iii-k):

wherein R a and R b are each the same group selected from hydrogen and alkyl;

R c is selected from hydrogen and alkyl;

X a is selected from iodo (I − ), bromo (Br − ), chloro (Cl − ) and fluoro (F−); and

each of R h , R i , R k , R l , and R m is independently selected from hydrogen and alkyl.

2. The process of claim 1 , wherein the compound of formula (I) is a compound of formula (I-AA):

or a pharmaceutically acceptable form thereof,

and the compound of formula (II) is a compound of formula (II-AA):

or a pharmaceutically acceptable form thereof,

wherein X is —(CH 2 )—;

R 1 is benzyl or —CO 2 R 16 , and R 16 is benzyl;

R 2 and R 3 are taken together to form a double bond;

R 5 and R 6 are each hydrogen or R 5 and R 6 taken together with the carbon to which they are bonded form C═O; and

R 10 , R 11 and R 12 are each hydrogen, or R 11 and R 12 taken together, form a double bond.

3. The process of claim 2 wherein the ring carbon atom that is directly attached to the hydroxyl group on the compound of formula (II-AA) has an (S) stereochemical configuration and R 11 is hydrogen in the β-position.

4. The process of claim 1 , wherein R a and R b are both —CH 3 and R c is —CH 2 CH 3 .

5. The process according to claim 1 , wherein the benzene ligand with R h -R m is selected from benzene, mesitylene, p-cymene, and hexamethylbenzene.

6. The process according to claim 5 , wherein the ruthenium transfer-hydrogenation catalyst is generated from (hexamethylbenzene)ruthenium chloride dimer and an achiral amino alcohol.

7. The process according to claim 1 , wherein the ruthenium transfer-hydrogenation catalyst is of formula (iii-a):

wherein:

each R a and R b are the same group selected from hydrogen and alkyl,

R c is selected from hydrogen and alkyl; and

each of R h , R i , R j , R k , R l , and R m is independently selected from hydrogen and alkyl.

8. The process according to claim 7 , wherein the ruthenium transfer-hydrogenation catalyst is of the formula (iii-g):

9. The process of claim 1 , wherein R a and R b are each methyl, R c is ethyl, each of R h , R i , R j , R k , R l , and R m is methyl, and X a is Cl − .

10. The process of claim 1 , wherein the hydrogen donor is an organic alcohol.

11. The process of claim 10 , wherein the reducing is carried out in an ether solvent.

12. The process of claim 11 , wherein the reducing is carried out at a temperature of about 10° C. to about 40° C.

13. The process of claim 11 , wherein the reducing is carried out in the presence of base.