A Divergent Synthetic Route to the Vallesamidine and Schizozygine Alkaloids: Total Synthesis of (+)‐Vallesamidine and (+)‐14,15‐Dehydrostrempeliopine

• Published in: Angewandte Chemie International Edition 2019-12, Vol.58 (50), p.18040-18045
• Main Authors: Zhang, Xiangyu, Anderson, James C.
• Format: Article
• Language: English
• Subjects: Alkaloids; Allyl compounds; asymmetric synthesis; Chemical reactions; hydride transfer/cyclization; Metathesis; nitro-Mannich reaction; Stereoselectivity; total synthesis
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201910593

The total synthesis of representative members of the schizozygine alkaloids, (+)‐vallesamidine and (+)‐14,15‐dehydrostrempeliopine, were completed from a late‐stage divergent intermediate. The synthesis took advantage of efficient nitro‐group reactions with the A/B/C ring skeleton constructed concisely on a gram scale through an asymmetric Michael addition, nitro‐Mannich/lactamisation, Tsuji–Trost allylation, and intramolecular C−N coupling reaction. Other key features of the synthesis are a novel [1,4] hydride transfer/Mannich‐type cyclisation to build ring E and a diastereoselective ring‐closing metathesis reaction to construct ring D. This approach gave access to a late‐stage C14,C15 alkene divergent intermediate that could be simply transformed into (+)‐vallesamidine, (+)‐14,15‐dehydrostrempeliopine, and potentially other schizozygine alkaloids and unnatural derivatives. Necessity is the mother of invention and never more so than in target synthesis. The total synthesis of (+)‐vallesamidine and (+)‐14,15‐dehydrostrempeliopine was possible from a common intermediate that is related to other alkaloids and necessitated the development of a [1,4] hydride transfer/Mannich cyclisation to build ring E (see scheme).