Enantioselective Construction of Pyrrolidines by Palladium-Catalyzed Asymmetric [3 + 2] Cycloaddition of Trimethylenemethane with Imines

A protocol for the enantioselective [3 + 2] cycloaddition
of trimethylenemethane
(TMM) with imines has been developed. Central to this effort were
the novel phosphoramidite ligands developed in our laboratories. The
conditions developed to effect an asymmetric TMM reaction using 2-trimethylsilylmethyl
allyl acetate were shown to be tolerant of a wide variety of imine
acceptors to provide the corresponding pyrrolidine cycloadducts with
excellent yields and selectivities. Use of a bis-2-naphthyl phosphoramidite
allowed the successful cycloaddition of the parent TMM with N-Boc imines, and has further permitted the reaction of
substituted donors with N-tosyl aldimines and ketimines
in high regio-, diastereo-, and enantioselectivity. Use of a diphenylazetidine
ligand allows the complementary synthesis of the exocyclic nitrile
product shown, and we demonstrate control of the regioselectivity
of the product based on manipulation of the reaction parameters.