Unified Synthetic Strategy for Trichodermamides Based on Oxidative Molecular Construction

Trichodermamides, fungal secondary metabolites, are characterized by their structurally diverse and highly oxidized cis-1,2-oxazadecalin skeletons, which are linked to an aminocoumarin unit via an amide bond. Trichodermamides bearing this unique oxazadecalin framework exhibit pronounced bioactivities, including anti-proliferative and anti-inflammatory activities. However, in-depth bioactivity studies of this class of molecules have been hampered by their limited availability from natural sources and the lack of a reliable asymmetric synthetic method for constructing the characteristic oxazadecalin core. Herein, we describe oxidative dearomatization-based strategies for the construction of enantioenriched cis-1,2-oxazadecalin skeletons and their application to the asymmetric synthesis of trichodermamides A-F. Moreover, our synthetic efforts led to the structural revision of trichodermamide E.