The Evolved Synthetic Strategy to (+)‐Isostrychnine

Abstract

The intriguing structure of strychnine has continuously inspired the development of novel strategies and methodologies in organic synthesis. We have established a general synthetic platform for constructing the octahydro‐1H‐pyrrolo[2,3‐ d ]carbazole scaffold (A–B–C–E rings) via a sequential catalytic tandem double Michael addition/cyclization process, which enables the collective synthesis of monoterpenoid indole alkaloids. Herein, we detail our evolved strategy toward (+)‐isostrychnine—a key precursor for strychnine synthesis—based on this platform. The total synthesis of (+)‐isostrychnine is characterized by an intramolecular cascade condensation/lactamization reaction, which efficiently constructs both the E‐ and G‐rings in one pot from an enantioenriched spirooxindole synthon. Although the formation of the D‐ring via intramolecular allylic nucleophilic addition of propargyl silane to allylic alcohol was successfully achieved under SnCl 4 promotion, the elaboration of the resulting allene intermediate proved unsuccessful. Eventually, by leveraging an allylic diazene rearrangement followed by an intramolecular Heck reaction, the bridged D‐ring was successfully constructed, culminating in the total synthesis of (+)‐isostrychnine in nine longest linear steps (LLS) with an overall yield of 16%.