Mukaiyama Aldol Reactions Catalyzed by Zirconocene Bis(triflate) Complexes:  Stereochemistry and Mechanisms for C−C Bond Formation

The aldol condensations of α- and β-(benzyloxy) aldehydes with enol silanes, catalyzed by Cp2Zr(OTf)2·THF or Cp2Zr(OTf)2, in a variety of solvents were studied. The simple diastereoselectivity of these reactions is modest and comparable to that observed using simple aldehydes of similar steric requirements. Studies have revealed that TMSOTf is directly produced on reaction with the zirconocene catalyst with the enol silane in nitroalkane solvent or is formed during catalysis in dichloromethane solution. Although TMSOTf is known to catalyze cross-aldol reactions under these conditions, the rate of this process is not always competitive with that observed using the zirconocene catalysts. In particular, sterically unhindered or aromatic aldehydes react via a mechanism that appears to be mainly Zr-catalyzed, based on both the difference in rate between Zr- and Si-mediated reactions as well as differences in enol silane/silyl triflate reactivity in crossover-type experiments. With sterically hindered aldehydes in dichloromethane or nitromethane, catalysis is mediated by Si. The Zr-catalyzed process occurs via formation of a Zr−aldolate complex from aldehyde and enol silane, with liberation of TMSOTf, followed by rate-limiting O-silylation of the metal aldolate by TMSOTf, as revealed by both model studies and in situ monitoring during catalysis.