We have previously developed a highly stereoselective vinylogous Mukaiyama aldol reaction (VMAR) usin gvinylketene silyl N,O-acetal 1, which provides a unique and remarkable entry to a remote asymmetric induction. From a synthetic point of view, this method can directly afford th anti-δ-hydroxy-α,γ-dimethol-α,β-unsaturated carbonyl unit, which is seen in many naturally occurring products. In fact, VMAR has successfully been utilized in the total syntheses of various biologically active compounds by many groups including us. Se envisioned that the VMAR would be an efficient and powerful methodology for the synthesis of (+)-TMC-151C (2). This compound was isolated from Gliocladium sp. by the research group of Tanabe Seiyaku in 1999, and it shows the cytotoxicity to wide-rangingg tumor cell lines, such as HCT-116, B16 and HeLa. The structural significance as well as the biological property has stimulated the synthesis of TMC-151C (2). Herein, we report the first total synthesis of (+)-TMC-151C (2) using VMAR and Ring-Closing Metathesis (RCM) via a highly convergent synthetic route. Characteristic features of the present synthesis include: 1) the construction of C_1-C_5 segmetn and C_9-C_<13> segment was successfully achieved by VMAR, and 2) the stereoselective formation of C_6-C_7 double bond was accomplished by developing a unique E-olefin forming 8-membered RCM of silicon-tethered diene. Moreover, we observed a unique E-olefin forming 8-memberes ring RCM of silylene acetals, and proposed a plausible transition state as well as the structural requirement for E-olefin forming RCM. Although the E-olefin was produced only in a limited case, this methodology was quite useful for the total synthesis of TMC-151C (2).
