Bifunctional para-quinone methides in organocatalytic [3+2]-annulation with nitroalkenes: enantio- and diastereoselective assembly of nitrogen-functionalized cyclopentanes

Abstract

Densely substituted nitrogen-functionalized cyclopentanes are ubiquitous structural motifs in many bioactive compounds, yet their synthesis remains challenging due to inherent molecular complexity. Asymmetric organocatalytic domino reactions can provide direct access to these scaffolds through quick and effective construction of several bonds in one operational step. Herein, we report an enantio- and diastereoselective [3+2]-annulation of bifunctional malonate-possessing para-quinone methides and nitroalkenes, leading to nitro-substituted cyclopentanes with three contiguous stereocenters. This reaction proceeds under mild conditions, tolerates a wide range of functionalities, and allows an efficient gram scale synthesis. The developed strategy introduces a novel reactivity pattern for stable quinone methides, based on their use as three-carbon synthons. Telescopic one-pot synthesis of nitrocyclopentanes from simple starting materials was achieved through an effective catalytic cyclopropanation/annulation sequence. Chemoselective modifications of the obtained products led to the chiral cyclopentene derivatives and 2-azabicyclo[2.2.1]heptane, a privileged scaffold for medicinal chemistry.