Total Synthesis of the Proposed Structure of Iriomoteolide-1a and Asymmetric Synthesis of the Core Structure of Leucosceptroids A-D

Part I: The first total synthesis of the proposed structure of iriomoteolide-1a has been accomplished. The linear C7-C23 fragment was synthesized via Sakurai reaction followed by B-alkyl Suzuki-Miyaura cross-coupling reaction. Formation of the hemiketal was achieved upon deprotection of the TES group under mild conditions. Yamaguchi esterification between fragment C7-C23 3.2 and Z-alkenoic acid C1-C6 fragment 3.3 gave the desired product in moderate yield after a difficult separation by chromatograph. In order to improve the efficiency of the synthesis, an alternative strategy was investigated. The TES protecting group on C9 was switched to a PMB group and the esterification step was performed prior to the hemiketal ring formation. As anticipated, the yield of Yamaguchi esterification step was improved to 93%. Subsequent global deprotection of PMB groups provided the penultimate intermediate 3.1, common to the previous strategy. The final ring closing metathesis generated the proposed structure of iriomoteolide-1a from which we determined that the structure of the original product was misassigned.;Part II: The asymmetric synthesis of the core structure of leucosceptroids A-D has been achieved. The key steps of the synthesis includes the formation of the cis-2,5-disubstituted THF ring by TPAP catalytic oxidative cyclization followed by a highly diastereoselective intramolecular Diels-Alder reaction to fashion the fused tricyclic hydrindane ring system. This represents the first successful approach to the core system.