Non-Canonical Tryptophan Synthesis Enabled by Larock Umpolung

Tryptophan plays a critical role in diverse natural products, biological processes, and pharmaceutical molecules. Facile access to this amino acid and its analogues from readily available building blocks, however, remains a long-standing challenge. Here, we report a regioselective synthesis of tryptophan and unnatural variants bearing C4-C7 substituents via Rh-catalyzed annulation between structurally diverse tert-butyloxycarbonyl (Boc) protected anilines and a serine derived alkynyl chloride. This transformation features C-H activation directed by a weakly coordinating Boc group, the umpolung reactivity of alkynyl chloride, and acetic acid-mediated reverse C-H rhodation to afford the C2 unsubstituted indole products in a redox-neutral fashion. The wide utility of this chemistry is demonstrated for the synthesis of halogenated, borylated, and poly-oxygenated tryptophans, drug analogues, dipeptides with crosslinks on tryptophan, and heterocycle-containing tryptophan derivatives. This reaction will facilitate preparation of diverse compounds, notably a myriad of bioactive Trp-containing natural products.