Unified, Biosynthesis-Inspired, Completely Stereocontrolled Total Synthesis of All Highest-Order [n + 1] Oligocyclotryptamine Alkaloids.

We describe the unified enantioselective total synthesis of the polycyclotryptamine natural products (+)-quadrigemine H, (+)-isopsychotridine C, (+)-oleoidine, and (+)-caledonine. Inspired by our hypothesis for the biogenesis of these alkaloids via an iterative concatenative addition of homochiral cyclotryptamines to a meso -chimonanthine headcap, we leverage the modular, diazene-directed assembly of stereodefined cyclotryptamines to introduce successive C3a-C7' quaternary stereocenters on a heterodimeric meso -chimonanthine surrogate with full stereochemical control at each quaternary linkage. We developed a new strategy for iterative aryl-alkyl diazene synthesis using increasingly complex oligomeric hydrazide nucleophiles and a bifunctional cyclotryptamine bearing a C3a leaving group and a pendant C7 pronucleophile. The utility of this strategy is demonstrated by the first total synthesis of heptamer (+)-caledonine and hexamer (+)-oleoidine. Enabled by our completely stereoselective total syntheses and expanded characterization data sets, we provide the first complete stereochemical assignment of pentamer (+)-isopsychotridine C, provide evidence that it is identical to the alkaloid known as (+)-isopsychotridine B, and report that tetramer (+)-quadrigemine H is identical to the alkaloid called (+)-quadrigemine I, resolving longstanding questions about the structures of the highest-order [n + 1] oligocyclotryptamine alkaloids.