The Double‐Bond Configuration of Corynanthean Alkaloids and Its Impact on Monoterpenoid Indole Alkaloid Biosynthesis

Experimental evidence is provided for the coherence of the double‐bond geometry and the occurrence of “secondary cyclizations” in the biosynthesis of monoterpenoid indole alkaloids. Biosynthetically, akuammiline, C‐mavacurine, and Strychnos alkaloids are proposed to be derived from the corynanthean alkaloid geissoschizine, a key intermediate in the biosynthetic pathway of these monoterpenoid indole alkaloids. This process occurs by so‐called “secondary cyclizations” from geissoschizine or its derivatives. Although corynanthean alkaloids like geissoschizine incorporate E or Z double bonds located at C19–C20, the alkaloids downstream in the biosynthesis exclusively exhibit the E double bond. This study shows that secondary cyclizations preferentially occur with the E isomer of geissoschizine or its derivatives. This is attributed to the flexibility of the quinolizidine system of the corynanthean alkaloids, which can adopt a cis or trans conformation. For the secondary cyclization to take place, the cis‐quinolizidine conformation is required. Experimental evidence supports the hypothesis that the E double bond of geissoschizine induces the cis conformation, whereas the Z double bond induces the trans conformation, which prohibits secondary cyclization of the Z compounds.