Pd-Catalyzed Asymmetric Allylic Alkylation of Cyclobutenes: From Double Inversion to Double Retention

The Pd-catalyzed allylic alkylation of 3,4-disubstituted,
racemic
cyclobutene electrophiles exhibits a highly unusual stereoselectivity
that allows for controlling diastereo- and enantioselectivity only
by the choice of ligand and independent of the configuration of the
substrate. In order to shed light on the origin of stereoinduction,
we performed a systematic mechanistic investigation, including preparation
of various putative Pd-allyl intermediates, 1H/31P NMR reaction monitoring, 2H-labeling studies, ESI–HRMS
and 31P NMR analysis of reaction mixtures, and DFT structural
computations. The mechanism disclosed exhibits several steps with
stereospecificities deviating from the commonly accepted “double
inversion rule”: oxidative addition was found to follow a stereoconvergent
course, giving anti-configured η1-Pd-cyclobutene species as detectable on-cycle intermediates irrespective
of the configuration of starting material, while the subsequent nucleophilic
attack features a stereodivergent behavior. In stark contrast to their
highly reactive anti-analogues, syn-Pd-cyclobutene complexes that can be formed as side products are
rendered entirely unreactive by strong internal Pd–O chelation,
preventing the formation of undesired product diastereomers.