Mechanistic studies of the molybdenum-catalyzed asymmetric alkylation reaction

doi:10.1073/pnas.0306918101

Mechanistic studies of the molybdenum-catalyzed asymmetric alkylation reaction

^†Department of Process Research, Merck Research Laboratories, Merck and Co., Inc., Rahway, NJ 07065; and ^§School of Chemistry, University of Bristol, Bristol BS8 ITS, United Kingdom

Edited by Barry M. Trost, Stanford University, Stanford, CA, and approved January 7, 2004 (received for review October 25, 2003)

Abstract

Enantiomerically enriched, deuterated branched carbonates (Z)-(S)-PhCH(OCO₂Me)-CH = CHD (1-D), (Z)-(R)-PhCH(OCO₂Me)CH = CHD (2-D), and linear carbonate (E)-(S)-PhCH = CHCHD(OCO₂Me) (3-D) were used as probes in the Mo-catalyzed asymmetric allylic alkylation with sodium dimethyl malonate, catalyzed by ligand-complex 11 derived from the mixed benzamide/picolinamide of (S,S)-transdiaminocyclohexane and (norbornadiene)Mo(CO)₄. The results of these studies, along with x-ray crystallography and solution NMR structural analysis of the π-allyl intermediate, conclusively established the reaction proceeded by a retention–retention pathway. This mechanism contrasts with that defined for Pd-catalyzed allylic alkylations, which proceed by an inversion–inversion pathway. A proposed rationale for the retention pathway for nucleophilic substitution involves CO-coordination to form a tri-CO intermediate, followed by complexation with the anion of dimethyl malonate to produce a seven-coordinate intermediate, which reductively eliminates to afford product with retention of configuration.

Footnotes

↵ ‡ To whom correspondence should be addressed at: Mail Drop R800-B275, Merck and Co., Inc., P.O. Box 2000, Rahway, NJ 07065. E-mail: dave_hughes{at}merck.com.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: ee, enantiomeric excess; er, enantiomeric ratio; THF, tetrahydrofuran; NOE, nuclear Overhauser effect.