Transfer hydrogenation of cyclopamine analogs

摘要

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.

主权项

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:
R1 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.