Iriomoteolide-1a and\n-1b: Structure Elucidation by\nIntegrating NMR Spectroscopic Analysis, Theoretical Calculation, and\nTotal Synthesis

The structure of iriomoteolide-1a, a marine macrolide\nwith potent\ncytotoxic activity against human cancer cells, has been under scrutiny\nfor more than a decade since the first total synthesis of the proposed\nstructure was achieved by Horne. Here we disclose the correct structure\nof iriomoteolide-1a. Given a huge number of possible stereoisomers,\nwe adopted an integrated strategy toward the structure elucidation\nof iriomoteolide-1a: (1) NMR spectroscopic analysis/molecular mechanics-based\nconformational analysis for configurational reassignment of the macrolactone\ndomain; (2) model synthesis for validating the reassigned configuration\nof the macrolactone domain; (3) GIAO NMR calculation/DP4+ analysis\nof side chain stereoisomers; and (4) total synthesis of the most likely\nstructure. Moreover, the correct structure of iriomoteolide-1b, a\nnatural congener, was also determined by an integration of NMR spectroscopic\nanalysis, GIAO NMR calculation/DP4+ analysis, and total synthesis.