Enantioselective Total Synthesis of (−)-Rubriflordilactone B by a Bioinspired Skeletal Reorganization Approach

Abstract

Rubriflordilactone B is a Schisandra bisnortriterpenoid with a unique 5/5/7/6/5/5-hexacyclic framework that includes a characteristic tetrasubstituted aromatic ring. Herein, we report a convergent, enantioselective total synthesis of this natural product by a bioinspired skeletal reorganization approach. Key transformations include a chelation-controlled [2,3]-Wittig–Still rearrangement to assemble the western cyclohexenyl fragment with complete diastereocontrol, a Cu(II)-catalyzed tandem acyloin acylation–Wittig olefin to build the eastern butanolide fragment, a Friedel–Crafts cyclization to construct the seven-membered ring, and an E1cB reaction/transesterification/oxa-Michael addition cascade to forge the pivotal 5/5-fused bicyclic lactone. This work vividly demonstrates that bioinspired skeletal reorganization is a useful strategy for simplifying the retrosynthetic analysis of structurally complex natural products.