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

While MTs show much promise for the selective methylation of molecular scaffolds, allylations have been less explored. In this work, we report biocatalytic cascades for the O-allylation of (S)-THIQs by Rattus norvegicus catechol O-MT (RnCOMT) and Myxococcus xanthus SafC-O-MT (MxSafC) from the saframycin biosynthetic pathway, demonstrating successful allylations on these complex motifs.

A key consideration was at what stage in the biocatalytic pathway the allylation should be performed, either before the NCS step to produce (S)-THIQs (Scheme 1: route A) or after (Scheme 1: route B), and the impact of these two routes on the cascade’s stereoselectivity is presented. Additionally, we established that S-allyl-DL-homocysteine (rac-1), which is readily synthesized in one step, can be used as an allyl donor in a MAT-MT-MTAN allylation cascade. Furthermore, we identified that Ureaplasma urealyticum MAT (UuMAT) is highly effective in forming the allyl analogue of SAM, negating the need for higher temperatures, which has been reported with other MATs.