Transfer hydrogenation of cyclopamine analogs
Provided herein is a process for the transfer-hydrogenation of ketone analogs of members of the jervine type of Veratrum alkaloids, such as cyclopamine. Also provided herein are novel ruthenium transfer-hydrogenation catalysts.
1. A process for preparing a compound of formula II-a:
or a pharmaceutically acceptable salt form thereof;
from a compound of formula I-a:
or a pharmaceutically acceptable salt form thereof;
wherein:
R 1 is H or a nitrogen protecting group;
the process comprising reacting a compound of formula (I-a) or a pharmaceutically acceptable salt form thereof with a hydrogen donor selected from the group consisting of methanol, ethanol, isopropanol, and t-butanol, in the presence of a ruthenium transfer-hydrogenation catalyst of formula (iii-a):
wherein R a and R b are both either H or methyl; and
R c is either H or C 1-6 alkyl;
to thereby provide a compound of formula (ii-a) or a pharmaceutically acceptable salt form thereof in a diastereomeric excess of greater than about 90% to about 99.5%.
2. The process of claim 1 , wherein R 1 is benzyl or —CO 2 R 16 , and R 16 is benzyl.
3. The process according to claim 1 , wherein R a and R b are both methyl.
4. The process according to claim 1 , wherein R a and R b are both hydrogen.
5. The process according to claim 1 , wherein R c is C 1 -C 6 alkyl.
6. The process according to claim 5 , wherein R c is —CH 2 CH 3 .
7. The process according to claim 1 , wherein the ruthenium transfer-hydrogenation catalyst is generated from (hexamethylbenzene)ruthenium chloride dimer and an achiral amino alcohol having the formula,
where R a , R b and R c are as defined in claim 1 .
8. The process according to claim 1 , wherein the ruthenium transfer-hydrogenation catalyst is of the formula (iii-g):
9. The process according to claim 1 , wherein the ruthenium transfer-hydrogenation catalyst is prepared from a catalyst precursor of formula (iii-i):
wherein X a is selected from the group consisting of iodo (I − ), bromo (Br − , chloro (Cl − ) and fluoro (F—), and R a , R b , and R c are as defined in claim 1 .
10. The process according to claim 9 , wherein X a is chloro.
11. The process according to claim 1 , further comprising a ruthenium transfer-hydrogenation catalyst of formula (iii-k):
wherein R a , R b , and R c are as defined in claim 1 .
12. The process according to claim 1 , wherein the ruthenium transfer-hydrogenation catalyst further comprises one or more ruthenium complexes selected from formulas (iii-i), and (iii-k):
wherein X a is selected from iodo (I − ), bromo (Br − ), chloro (Cl − ) and fluoro (F—) and R a , R b , and R c are as defined in claim 1 .
13. The process of claim 1 , wherein compound (II-a) is formed in greater than 99 percent diastereomeric excess.
14. The process of claim 1 , wherein the reacting step is carried out in the presence of a base.
15. The process of claim 14 , wherein the hydrogen donor is isopropanol.
16. The process of claim 15 , wherein the reacting step further comprises a solvent.
17. The process of claim 16 , wherein the solvent is an ether.
18. The process of claim 16 , wherein the solvent is 2-methyltetrahydrofuran.
19. The process of claim 1 , wherein R a and R b are both hydrogen and R c is methyl.
20. The process of claim 1 , wherein R a and R b are both methyl and R c is selected from hydrogen, isopropyl and n-propyl.
21. The process of claim 20 , wherein R c is hydrogen.
22. The process of claim 20 , wherein R c is isopropyl.
23. The process of claim 20 , wherein R c is n-propyl.
24. The process of claim 8 , wherein the reacting step is carried out in the presence of a base and further comprises a solvent, the hydrogen donor is isopropanol, and the solvent is 2-methyltetrahydrofuran.