A Synthesis of Alstonlarsine A via Alstolucines B and F Demonstrates the Chemical Feasibility of a Proposed Biogenesis

Abstract

We offer a new biogenetic proposal for the origin of the complex alkaloid alstonlarsine A, through rearrangement of the Strychnos alkaloids alstolucines B and F. Further, we provide evidence of the chemical feasibility of this proposal in the facile conversion of synthetic alstolucines into alstonlarsine A through a short, efficient sequence of N-methylation, β-elimination, and a cascade 1,7-hydride shift/Mannich cyclization. We believe that this is the first biogenetic proposal involving the "tert-amino effect", a hydride-shift-based internal redox trigger of a Mannich cyclization. A further interesting feature of the cascade is that its stereochemical outcome most likely originates in conformational preferences during the hydride shift.

Synthesis of Indoles from o-Haloanilines

“…Our work commenced with the construction of a tricyclic indole nucleus possessing a five-membered or six-membered ring, as this motif is frequently embedded in structurally complex natural products. , The known 2-cyclopentenyl and 2-cyclohexenyl anilines 3a and 3b were prepared in 82–86% yields by the Suzuki coupling reaction according to literature procedures (Scheme A) . When a THF solution of 3a and 3b was next treated with PhI­(OCOCF 3 ) 2 (PIFA) (1 equiv) at rt, oxidative cyclization proceeded cleanly to afford indoles 5a and 5b in 80 and 73% yields, respectively, requiring no N -protection.…”

Intramolecular Dearomative Inverse-Electron-Demand Diels Alder Strategy for the Total Synthesis of (+)-Alstonlarsine A

“…Due to its uniquely intricate and intriguing architecture associated with a specific bioactivity, alstonlarsine A ( 1 ) attracted considerable attention of scientific community. This culminated in two orthogonal enantioselective syntheses of (+)-alstonlarsine A ( 1 ) published almost simultaneously by Zhai and our group in 2022, while shortly after a proposedly biomimetic conversion of Strychnos type alkaloids alstolucines B and F into alstonlarsine A ( 1 ) demonstrated its putative biogenetic origin (Scheme ). Herein, we present a full account of our work, showing in details how the final synthetic route evolved from the initial approaches.…”