Enantioselective Total Synthesis of the Proposed Structure of the Endophytic Fungal Metabolite Phomolide G: Structural Revision and Unambiguous Stereochemical Assignment

Abstract A total synthesis of the proposed structure of the natural macrolactone phomolide G ( 1 ) by a bidirectional strategy from L ‐tartaric acid is reported. The ω‐terminus of the molecule was elaborated by nitrile extension, C3‐alkylation and a substrate‐controlled 1,3‐ketone reduction. The α‐terminus was extended by a C 2 aldehyde‐to‐alkenal homologation followed by an auxiliary controlled aldol reaction. Macrolactonization and deprotection yielded compound 1 (confirmed by X‐ray analysis). This putative structure of phomolide G displayed discordant NMR spectroscopic data in comparison with those of the natural product. Detailed inspection of all NMR spectroscopic data available indicated phomolide G to be likely a diastereomer of 1 . The synthetic strategy developed allows control of the absolute stereochemistry at all four chiral secondary alcohol groups. Further manipulation allowed for the preparation of diastereomer 33 , the 1 H and 13 C NMR spectroscopic data of which are in full accord with that reported for the natural product.