Chiral gamma-Lactams by Enantioselective Palladium(0)-Catalyzed Cyclopropane Functionalizations

Cyclopropanes fused to pyrrolidines are important structural features found in a number of marketed drugs and development candidates. Typically, their synthesis involves the cyclopropanation of a dihydropyrrole precursor. Reported herein is a complementary approach which employs a palladium(0)-catalyzed C-H functionalization of an achiral cyclopropane to close the pyrrolidine ring in an enantioselective manner. In contrast to aryl-aryl couplings, palladium(0)-catalyzed C-H functionalizations involving the formation of C(sp(3))-C(sp(3)) bonds of saturated heterocycles are very scarce. The presented strategy yields cyclopropane-fused gamma-lactams from chloroacetamide substrates. A bulky Taddol phosphonite ligand in combination with adamantane-1-carboxylic acid as a cocatalyst provides the gamma-lactams in excellent yields and enantioselectivities.