Total Synthesis of Hirsutellone B

Abstract

Hirsutellones,[1] pyrrospirones,[2] and pyrrocidines[3] belong to a growing class of fungal secondary metabolites whose biological properties include antifungal and antibiotic activities. Particularly impressive are the activities of hirsutellones A and B (1a and 1b, Figure 1)[1] against Mycobacterium tuberculosis (MIC = 0.78 μg/mL), the causative pathogen of tuberculosis.[4] Isolated from the insect pathogenic fungus Hirsutella nivea BCC 2594, the hirsutellones share a number of unique structural features, including a 6,5,6-fused tricyclic core, a γ-lactam- or succinimide-containing moiety, a 12- or 13-membered p-cyclophane structural motif that encompasses an aryl ether linkage, and ten stereogenic centers. In view of their promising biological properties as lead compounds for new antituberculosis drugs and because of their challenging molecular architectures, the hirsutellones are deemed important synthetic targets.[5] Herein we report the total synthesis of hirsutellone B (1b) in its enantiomerically pure form through a strategy that features a number of novel cascade sequences and chemoselective reactions.