Total Synthesis Guided Structure Elucidation of (+)‐Psychotetramine

Polymeric tryptamine-based alkaloids belong to a structurally and biologically fascinating class of natural products.[1] Whereas the vast majority of such molecules are linked through C–C bonds, a small subset are linked from the C3 of one indole nucleus to the N1 of another. Psychotetramine (1, Figure 1A) represents the curious case of a tryptamine tetramer containing both types of connectivity: a C3–C3 linked dimer bonded to a C3–N1 dimer through an unusual C7–N1 linkage. This interesting alkaloid was isolated in 2004,[2] but due to the limited quantity from Nature and its complicated NMR spectra, a final chemical structure including stereochemistry was not determined. In this communication, a joint venture between our groups (H. T. and P. S. B.) is described, leading to the total synthesis and final structure elucidation of 1. The pursuit of this complex natural product also led to an efficient enantioselective synthesis of the related alkaloid (+)-psychotrimine, an improved procedure for direct-indole aniline coupling, and one of the most complex and demanding contexts for a Buchwald-Hartwig amination.