Convergent Total Synthesis of (+)-TMC-151C by a Vinylogous Mukaiyama Aldol Reaction and Ring-Closing Metathesis

摘要

Antibiotic agents of the TMC-151 family were originally isolated from the fungus Gliocladium catenulatum Gilman & Abbott TC 1280 by a research group at the pharmaceutical company Tanabe Seiyaku in 1999 as novel polyketides containing β-D-mannoside and D-mannitol groups. A related TMC-171 family of antibiotics and TMC-154 were also isolated. Of these compounds, TMC-151C (1) shows the most significant cytotoxicity against a wide range of tumor cell lines, including HCT-116, B16, and HeLa cells. TMC-151C displays several interesting structural features. Notably, 1) the polyketide moiety contains three contiguous anti homoallylic alcohol motifs in the C1-C13 segment and three methyl-substituted asymmetric carbon centers in the C14-C20 segment, and 2) D-mannose is attached to the C13 hydroxy group as β-D-mannoside, which is still problematic in terms of chemical synthesis (Scheme 1). This combination of significant biological activity and structural complexity encouraged us to attempt the total synthesis of (+)-TMC-151C (1).