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 form thereof;
from a compound of formula (I-a):
or a pharmaceutically acceptable 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 form thereof with a chiral ruthenium transfer-hydrogenation catalyst of formula RuClAr(chiral amino alcohol) or RuHClAr(chiral amino alcohol), wherein Ar represents a substituted benzene ligand selected from mesitylene, cymene and hexamethylbenzene and chiral amino alcohol represents a chiral amino alcohol bidentate ligand selected from ephedrine, pseudoephedrine, 2-methylaminocyclohexanol, propranolol, 1-amino-2-indanol, and prolinol, in the presence of an organic alcohol hydrogen donor selected from the group consisting of methanol, ethanol, isopropanol, and t-butanol under conditions effective to provide a substantially enantiomerically pure compound of formula (II-a) or a pharmaceutically acceptable form thereof in at least about 85% weight percent relative to an enantiomer having an (R)-stereochemical orientation at the ring carbon atom that is directly attached to the hydroxyl group.
2. The process according to claim 1 , effective to form at least about 90% by weight of the compound of formula (II-a) relative to its α- or (R)-isomer.
3. The process according to claim 1 , wherein the ruthenium transfer-hydrogenation catalyst comprises a chiral ephedrine ligand.
4. The process according to claim 1 , wherein the chiral amino alcohol ligand is selected from chiral 2-methylaminocyclohexanol, propranolol, 2-amino-1-indanol, and prolinol.
5. The process of claim 3 , wherein the chiral amino alcohol ligand is (1S,2R)ephedrine, (1R,2S)ephedrine, (+)-(1S,2S)pseudoephedrine, or (31)-(1R,2R) pseudoephedrine.
6. The process according to claim 1 , wherein Ar is hexamethylbenzene.
7. The process according to claim 6 , wherein the ruthenium transfer-hydrogenation catalyst is generated by reaction of (hexamethylbenzene)ruthenium chloride dimer and a chiral amino alcohol selected from ephedrine, pseudoephedrine, 2-methylaminocyclohexanol, propranolol, 1-amino-2-indanol, and prolinol.
8. The process according to claim 1 , wherein the reacting step is carried out in the presence of base.
9. The process according to claim 8 , wherein the base is an alkoxide.
10. The process according to claim 1 , further comprising a ruthenium transfer-hydrogenation catalyst of formula RuAr(chiral amino alcohol), wherein Ar and chiral amino alcohol are as defined in claim 1 .
11. The process according to claim 2 , wherein the ruthenium transfer-hydrogenation catalyst comprises one or more of RuHCl(mesitylene)[(1S,2R)-ephedrine] (10), RuHCl(hexamethylbenzene)[(1R,2S)-ephedrine] (12), RuHCl(hexamethylbenzene)[(1S, 2R)-ephedrine] (13), RuHCl(mesitylene)[(1R,2S)2-methylaminocyclohexanol] (64), RuHCl(hexamethylbenzene)[R-propranolol] (75), RuHCl(hexamethylbenzene)[1S,2R-cis-1-amino-2-indanol] (80), RuHCl(hexamethylbenzene)[(1S,2S)2-methylaminocyclohexanol] (82), RuHCl(hexamethylbenzene)[(1R,2S)2-methylaminocyclohexanol] (83), and RuHCl(hexamethylbenzene)[D-prolinol] (86).
12. The process according to claim 1 , wherein the ruthenium transfer-hydrogenation catalyst is selected from RuHCl(mesitylene)[(1S, 2R)-ephedrine] (10), RuHCl(hexamethylbenzene)[(1S,2R)-ephedrine] (13), RuHCl(hexamethylbenzene)[(1R,2S)-ephedrine] (12), RuHCl(p-cymene)[(1S,2R)-ephedrine] (15), RuHCl(mesitylene)[(1R,2S)2-methylaminocyclohexanol] (64), RuHCl(hexamethylbenzene)[(1R,2S)2-methylaminocyclohexanol] (83), RuHCl(hexamethylbenzene)[(1S,2S)2-methylaminocyclohexanol] (82), RuHCl(hexamethylbenzene)[R-propranolol] (75), RuHCl(hexamethylbenzene)[S-propranolol] (74), RuHCl(hexamethylbenzene)[1R,2S-cis-1-amino-2-indanol] (81), RuHCl(hexamethylbenzene)[D-prolinol] (86), RuHCl(hexamethylbenzene)[1S,2R-cis-1-amino-2-indanol] (80), and RuHCl(hexamethylbenzene)[L-prolinol] (87).
13. The process according to claim 2 ,
where R 1 is selected from H, benzyl, and —CO 2 R 16 where R 16 is selected from t-butyl and benzyl.
14. The process of claim 13 , wherein R 1 is —CO 2 R 16 and R 16 is t-butyl.
15. The process of claim 13 wherein R 1 is —CO 2 R 16 and R 16 is benzyl.
16. The process of claim 1 , where the organic alcohol is isopropanol.
17. The process of claim 1 , wherein the reacting step further includes a solvent.
18. The process of claim 17 , where the solvent is an ether.
19. The process of claim 1 , wherein the compound of formula (II-a) or a pharmaceutically acceptable form thereof is formed in enantiomeric excess of about 80% or more.