Total Synthesis of Scholarisines A, I, T, and W and Identification of Scholarisine I as a Lysosome Inhibitor.

Scholarisine A (1) represents a structurally distinct and synthetically intriguing subfamily of the echitamine/akuammiline-type alkaloids. Inspired by its postulated biogenetic logic, we developed a radical cyclization strategy that retains the key bond-forming site while replacing the aldol reaction. This reaction-altering biomimetic strategy, combined with expeditious preparation of a tetracyclic precursor, enabled a 13-step, scalable synthesis of 1. Moreover, facile access to its congeners, scholarisines I, T, and W (2-4), was achieved. Compound 2 impairs lysosomal degradative capacity and thus inhibits late-stage autophagy in cancer cells.