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.