Nonenzymatic Formation of Streptoindoles Reveals an Unexplored Chemical Space of Tryptamine-Derived Natural Products

Streptoindoles A and B are enantiomeric alkaloids featuring a novel methylene-bridged dimeric framework, produced by a marine-derived <i>Streptomyces</i> species. Here, we demonstrate their assembly via a nonenzymatic cascade comprising oxidation, intramolecular condensation, and Mannich reaction from <i>N</i>-acetyltryptamine and formaldehyde under mild conditions. Furthermore, we uncover a butane-2,3-dione-promoted reaction manifold that converts either tryptamine or <i>N</i>-acetyltryptamine into diverse alkaloid derivatives. These findings significantly expand the accessible chemical space of tryptamine-derived natural products.