Total Synthesis of Tetracyclic Spirooxindole Alkaloids via a Double Oxidative Rearrangement/Cyclization Cascade

Abstract

Abstract Piperidine and pyridine are the most significant structural components of bioactive molecules. Aza-Achmatowicz rearrangement is a broadly appliable approach to access piperidine or pyridine derivatives owing to the easily adjustable electronic properties of the amino group. When combined with other chemical transformations, such as nucleophilic cyclization or cycloaddition, it provides entries to a variety of polycyclic skeletons present in naturally-derived alkaloids. Herein, we developed a one-pot reaction cascade of double oxidative rearrangement of furan and indole followed by a nucleophilic cyclization that was successfully applied for the formal synthesis of rhynchophylline/isorhynchophylline and the first total synthesis of 7(R)-geissoschizol oxindole/7(S)-geissoschizol oxindole. The reaction cascade has a broad substrate scope, with a variety of substitutions on the indoles and furans. Other innovative features include the chemo-selective dearomatization of the pyridinium moiety to form the C(sp3)-enriched, three-dimensional spiro[indolizidine-1,3´-oxindole] skeleton and a late-stage, regio- and stereoselective carbene insertion into a C(sp3)-H bond that enabled the successful installation of the adjacent carbon functionality for rhynchophylline and isorhynchophylline. In addition, 7(R)-geissoschizol oxindole/7(S)-geissoschizol oxindole were revised to their C-3 epimers and the mechanism for the reversed stereochemistry through the retro-Mannich/Mannich cascade was proposed and supported by the DFT calculations.