Synthesis of (±)‐Tetrapetalone A‐Me Aglycon

Abstract

The first synthesis of (±)-tetrapetalone A-Me aglycon is described. Key bond-forming reactions include Nazarov cyclization, a ring-closing metathesis (RCM) promoted with complete diastereoselectivity by a chiral Mo-based complex, tandem conjugate reduction-intramolecular aldol cyclization, and oxidative dearomatization. KeywordsCross-Coupling; Cyclization; Natural Products; Olefin Metathesis; Polycycles Tetrapetalones (1-4, Figure 1) were isolated by Hirota and co-workers from Streptomyces sp. USF-4727, a strain of bacteria in the soil of Japan. [1] With a core containing four fused rings including a p-quinol, a tetramic acid, and four contiguous stereocenters, these natural products represent a unique synthetic challenge. They also exhibit moderate inhibitory activity (IC 50 = 190-360 µM) against soybean lipoxygenase (SLO). Since human lipoxygenases (HLOs) are implicated in a number of inflammatory diseases, [2] and the catalytic domain of plant and mammalian lipoxygenases is highly conserved, [3] the study of new SLO inhibitors like tetrapetalone could lead to the identification of new HLO inhibitors.