Bioalkylation Strategies to Synthesize Allylated Tetrahydroisoquinolines by Using Norcoclaurine Synthase and O-Methyltransferases

O-Methyltransferase (O-MT)-mediated alkylations are of growing interest for the regioselective modification of bioactive motifs, although there are still few examples of applications with more structurally complex compounds. In this work, we have used O-MTs for the allylation of various catechol and tetrahydroisoquinoline substrates via a biocatalytic cascade involving additionally methionine adenosyltransferases (MATs) and a methylthioadenosine nucleosidase (MTAN). Furthermore, we have integrated norcoclaurine synthase into this cascade to stereoselectively generate (S)-THIQs in situ as both intermediates and products in the allylation cascade. Notably, a variation in the order in which NCS and MAT-MT-MTAN are added can significantly affect the regioselective outcome, enabling exquisite control of both stereochemistry and regiochemistry in the products. We also identified Ureaplasma urealyticum MAT as an effective enzyme for the formation of the S-adenosyl-S-allyl-L-homocysteine required as the cofactor for the O-MTs and established that the racemate rather than the single isomer of S-allyl-homocysteine can effectively be used in the cascades with MATs.