A Ketone‐Accepting Pictet–Spenglerase for the Asymmetric Construction of 1,1‐Disubstituted Tetrahydro‐ß‐carboline Alkaloids

Abstract

Abstract In light of the ubiquity of 1,1′‐disubstituted tetrahydro‐ß‐carboline (THBC) motif in alkaloid natural products, developing asymmetric methodology for its preparation is highly valuable. Despite the immense progress toward achieving stereoselective Pictet–Spengler reaction with aldehydes, the analogous reaction with ketones is still underdeveloped. Exploiting KslB, a Pictet–Spenglerase from the biosynthesis of kitasetaline, we develop a general, diastereoselective, and protecting‐group free method for the construction of densely functionalized THBCs with α‐quaternary center by coupling tryptophan derivatives and α‐keto acids. We determine the stereochemistry of kitasetalic acid, KslB's physiological product and a key biosynthetic intermediate toward kitasetaline, and established that KslB's selectivity is opposite to what is achieved chemically. Our investigations of KslB show its high activity (total turnover number >438000), substrate promiscuity, and tolerance for high substrate concentrations (0.1 M). Additionally, a TrpB‐KslB cascade enables the construction of complex tricyclic products from simple indoles in one‐pot. X‐ray structural characterization of KslB sheds light on potential active site interactions to account for its stereoselectivity and ability to accept ketone substrates.