I. Second Generation Total Synthesis of (-)-Nakadomarin A

Download or read book I. Second Generation Total Synthesis of (-)-Nakadomarin A written by Kyle William Rugg and published by . This book was released on 2018 with total page 307 pages. Available in PDF, EPUB and Kindle. Book excerpt: "Part I. The Second-Generation Total Synthesis of (-)-Nakadomarin A The second-generation total synthesis of (-)-nakadomarin A (1) has been described. A robust sequence toward the bicyclic lactam has been developed, allowing its production on > 5 g scale. This has been enabled by a number of significant improvements, including increased diastereoselectivity for the key SN2' cyclobutane formation, a scalable cyclobutanecarboximine formation/retro-aza-Claisen sequence, and the removal of a step from the longest-linear sequence by use of isocyanate addition to the bicyclic lactam in lieu of a two-step protocol. The Michael addition/spirocyclization's catalytic potential has been investigated, and a robust and scalable method for the synthesis of the spirocycle has been deployed. After pentacycle formation, macrocyclization, and reduction, (-)-nakadomarin A (1) is afforded with production of the target on over 0.5 g scale. This has resulted in a total synthesis of 1 in 16 steps (longest linear) and 6.5% overall yield. Part II. Studies Toward the Total Synthesis of (-)-Apoptolidin A A route toward the potent and selective apoptosis inducer (-)-apoptolidin A has been outlined. Production of the lactone comprising the southwestern quadrant of the natural product on scale by a previously described route has been investigated. Small-scale success in generating the lactone was ineffective on larger scales using the existing protocol due to the sensitive nature of an intermediate Diels-Alder adduct. Important advancement in material throughput was achieved by implementation of a robust two-step protocol for generating a critical intermediate alcohol on larger scales. Combined with the improvement of a deallylation protocol, a scalable route to the lactone of the southwestern quadrant of (-)-apoptolidin A has been established. With this, the completion of the southern hemisphere and aglycone of (-)-apoptolidin A will be accessible"--Pages x-xi.