Total Synthesis of (±)‐Trichodermamide B and of a Putative Biosynthetic Precursor to Aspergillazine A Using an Oxaza‐Cope Rearrangement

Angewandte Chemie International Edition
2008.0

Abstract

Trichodermamides A and B are modified dipeptides recently isolated from the marine-derived fungus Trichoderma virens. Trichodermamide B displays significant in vitro activity against HCT-116 human colon carcinoma (IC50 0.32 μgmL⁻¹) and moderate antimicrobial activity against certain drug-resistant bacterial strains. Aspergillazines A–E, a group of related metabolites, were characterized by Capon and co-workers in 2005, but their biological evaluation was prevented by the lack of material. These natural products are distinguished by a 4H-5,6-dihydro-1,2-oxazine fragment fused with a highly functionalized cyclohexene ring, making them compelling synthetic targets. Due to the lack of mild methods for oxazine ring assembly, the authors developed a tandem reaction sequence integrating nitrosation of ester enolates and a Lewis acid mediated oxaza-Cope rearrangement, which directly provides bicyclic oxazines from esters. Herein, this method is applied to the first total syntheses of (±)-trichodermamide B and the putative biosynthetic precursor of aspergillazine A (2) from a common intermediate. Furthermore, the C5 thiol analog 21, proposed as the biosynthetic precursor of aspergillazine A, was synthesized. However, 21 did not undergo spontaneous cyclization to 2, and no ring closure was detected under various harsh conditions, indicating that the cyclization is not spontaneous or facile.

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