Enantioselective Synthesis of α,β-Unsaturated Aryl Lactams by Heck-Matsuda and Heck-Mizoroki Arylations of Enelactams

The chiral aryl lactam nucleus is a common motif present in many bioactive natural products and the development of effective enantioselective methodologies for its preparation is of great interest. In this work, we report the synthesis of several enantioenriched aryl lactams in good yields and enantiomeric ratios using a combined strategy employing arenediazonium salts bearing electron-withdrawing substituents, aryl iodides with electron-donating substituents, and chiral N,N-ligands. The chiral alpha,beta-unsaturated aryl lactams were obtained in yields of up to 78 % and enantiomeric ratios up to 95 : 5. Furthermore, this work demonstrates the use of chiral N,N-ligands as a viable alternative to the phosphine-based ligands in the enantioselective Heck-Mizoroki reactions using aryl iodides. The origins of the enantioselectivity and the full catalytic cycle for the Heck-Matsuda arylation of the enelactams were investigated through DFT calculations.