Discovery and enantioselective total synthesis of antitumor agent asperfilasin A via a regio- and diastereoselective Nazarov cyclization

Abstract

Asperfilasin A (1), featuring a unique 5/5 cyclopenta[c]pyrrol-one bicyclic core, represents a newly discovered skeletal cytochalasan isolated from Aspergillus flavipes. The enantioselective total synthesis was efficiently accomplished from the key intermediate (S)-6 with three contiguous stereocenters in 5 steps and the synthetic 1 induced G2/M-phase cell cycle arrest of HT29 cells and apoptosis of HL60 and NB4 cells by activation of caspase-3 and degradation of PARP. (S)-6, bearing three contiguous chiral centers, was efficiently constructed by a novel Nazarov cyclization reaction containing basic nitrogen, which was less developed, primarily due to the incompatibility of basic nitrogen under acidic reaction conditions. This reaction allows a wide range of pentadienone substrates containing basic nitrogen to undergo Nazarov cyclization in a single regioselective and diastereoselective manner and is capable of generating three stereocenters simultaneously. Furthermore, the mechanism of the Nazarov cyclization and the origin of the regio- and diastereoselectivity were elucidated by DFT calculations and deuteration experiments, providing valuable insights into the reaction and serving as a guide for future applications involving substrates containing basic nitrogen.