Asymmetric Brønsted base-catalyzed aza-Michael addition and [3 + 2] cycloaddition reactions of N-ester acylhydrazones and enones

Abstract

The formation of acyclic azomethine imine 1,3-dipoles via an N,N′-prototropic shift of hydrazones in the presence of Lewis acids, Brønsted acids and hydrogen bonding catalysts is a fundamental and powerful strategy for the assembly of chiral pyrazolidines. Despite the advances made in this realm, the ability to gain precise chemoselective control remains challenging. Herein, we report the first highly enantioselective Brønsted base-catalyzed aza-Michael addition and stepwise cascade [3 + 2] cycloaddition reactions between N-ester acylhydrazones and β-trifluoromethyl-α,β-unsaturated ketones. By employing an L-tert-leucine-derived urea-tertiary amine bifunctional catalyst, the reaction was modulated to generate either chiral acyclic amination products or chiral pyrazolidines bearing vicinal three stereocenters with excellent enantio- and diastereoselectivities. In terms of synthetic utility, the enantio-enriched aza-Michael addition derivatives can be readily transformed into 2-pyrazolines bearing a trifluoromethyl unit in good yields with excellent enantioselectivities. Moreover, the selected chiral linear acylhydrazone derivatives exhibited good biological specificity for the tumor cell line MCF-7.