Harnessing a Ketone-Accepting Pictet-Spenglerase for the Asymmetric Construction of 1,1-Disubstituted Tetrahydro-ß-Carboline Alkaloids

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 towards 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 towards kitasetaline, and established that KslB’s selectivity is opposite to what is achieved chemically. Our investigations of KslB show its high activity (TTN>438,000), substrate promiscuity, and tolerance for high substrate concentrations (0.1M). 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.