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Catalytic asymmetric hydrogenation of heterocyclic ketone-derived hydrazones, pronounced solvent effect on the inversion of configuration |
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| Authors: | Nizar Haddad Bo QuSonia Rodriguez Lars van der VeenDiana C. Reeves Nina C. GonnellaHeewon Lee Nelu GrinbergShengli Ma Dhileepkumar KrishnamurthyTobias Wunberg Chris H. Senanayake |
| Affiliation: | a Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., PO Box 368, Ridgefield, CT 06877-0368, USA b Analytical Sciences, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., PO Box 368, Ridgefield, CT 06877-0368, USA c Medicinal Chemistry, Boehringer Ingelheim RCV GmbH & Co. KG, Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria |
| Abstract: | An enantioselective hydrogenation of hydrazones derived from heterocyclic ketones was developed with up to 85% ee. The enantiomeric purity was enriched to >99% ee by crystallization from EtOAc in >80% yield. Optimization studies have revealed a notable solvent effect that resulted in inversion of enantioselectivity from 85% ee in MeOH to −27% ee in DCE. The hydrazone geometry and possible hydrogenation via endocyclic alkene were examined as possible factors for the inversion of enantioselectivity. |
| Keywords: | Hydrazones Chiral hydrazenes Asymmetric hydrogenation Reversed enantioselectivity |
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