Nonenzymatic Dynamic Kinetic Resolution of Secondary Alcohols via Enantioselective Acylation: Synthetic and Mechanistic Studies

Because of the ubiquity of the secondary carbinol subunit,
the development of new methods for its enantioselective synthesis
remains an important ongoing challenge. In this report, we describe
the first nonenzymatic method for the dynamic kinetic resolution (DKR)
of secondary alcohols (specifically, aryl alkyl carbinols) through
enantioselective acylation, and we substantially expand the scope
of this approach, vis-à-vis enzymatic reactions. Simply combining
an effective process for the kinetic resolution of alcohols with an
active catalyst for the racemization of alcohols did not lead to DKR,
due to the incompatibility of the ruthenium-based racemization catalyst
with the acylating agent (Ac2O) used in the kinetic resolution.
A mechanistic investigation revealed that the ruthenium catalyst is
deactivated through the formation of a stable ruthenium–acetate
complex; this deleterious pathway was circumvented through the appropriate
choice of acylating agent (an acyl carbonate). Mechanistic studies
of this new process point to reversible N-acylation of the nucleophilic
catalyst, acyl transfer from the catalyst to the alcohol as the rate-determining
step, and carbonate anion serving as the Brønsted base in that
acyl-transfer step.