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 Streptomyces species. Here, we demonstrate their assembly via a nonenzymatic cascade comprising oxidation, intramolecular condensation, and Mannich reaction from N-acetyltryptamine and formaldehyde under mild conditions. Furthermore, we uncover a butane-2,3-dione-promoted reaction manifold that converts either tryptamine or N-acetyltryptamine into diverse alkaloid derivatives. These findings significantly expand the accessible chemical space of tryptamine-derived natural products.