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.
For decades, akuammiline alkaloids have attracted synthetic chemists due to their intriguing molecular architecture. Among the different structural elements embedded in their carboskeleton, the methanoquinolizidine system constitutes the signature structural element of this alkaloid family. Herein, we describe a novel synthetic access to this system which relies on a [2,3]-Stevens rearrangement and results in the formal synthesis of strictamine.
To date, more than 100 congeners of the akuammiline alkaloid family have been isolated. Their signature structural element is a methanoquinolizidine moiety, a cage-like scaffold structurally related to adamantane. The structural variations of the family members originate from oxidative processes that mostly trigger rearrangements of the methanoquinolizidine motif. The family of the akuammiline alkaloids is best represented by strictamine. It bears the least functionalized carbon skeleton of all family members without lacking the signature structural motifs. Herein, we report the formal synthesis of strictamine through a Stevens [2,3]-sigmatropic rearrangement as a key step and the synthetic pitfalls related with its synthesis.
Due to their structural diversity, elegant polycyclic molecular architecture, and biological activity, the indole alkaloids have been investigated by organic chemists over the last century. The first akuammiline alkaloid, echitamine, was isolated in 1875 and first described in 1880. Owing to the exceptional structure of akuammiline alkaloids, it was not until 125 years later that the first successful total synthesis was accomplished. This review will give an overview of this class of alkaloids, pinpointing its structural characteristics and showcasing the completed total syntheses. Furthermore, an overview of the structural diversity is given.
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