Asymmetric C–H Functionalization of N-Boc-2,5-dihydro-1H-pyrrole and Its Application as a Key Step in the Synthesis of (−)-Dragocin D

Dirhodium tetracarboxylate-catalyzed reaction of aryldiazoacetates with N-Boc-2,5-dihydro-1H-pyrrole results in a highly enantio- and diastereoselective C-H functionalization exclusively at the α-N C2 position. This result is a sharp contrast to the reaction with ethyl diazoacetate, which results in cyclopropanation of the olefinic site. Rh2(S- or R-PTAD)4 is the optimal chiral catalyst and is capable of generating the C-H functionalization products in up to 87% yield with high levels of diastereoselectivity (>20:1 d.r.) and enantioselectivity (97% ee) with a low catalyst loading (0.05 mol %). Computational studies were conducted to rationalize the reactivity difference between donor/acceptor carbenes and acceptor carbenes. The utility of the C-H functionalization chemistry was illustrated by its application to the synthesis of (-)-dragocin D and a variety of pharmaceutically relevant pyrrolidines.