Chemoenzymatic Cascades toward Methylated Tetrahydroprotoberberine and Protoberberine Alkaloids

Tetrahydroprotoberberine and protoberberine alkaloids are a group of biologically active natural products with complex molecular scaffolds. Isolation from plants is challenging stereoselective synthetic routes, particularly methylated compounds limited, reducing the potential use these compounds. In this work, we describe chemoenzymatic cascades toward various 13-methyl-tetrahydroprotoberberbine scaffolds using Pictet-Spenglerase, regioselective catechol O-methyltransferases selective chemical Pictet-Spengler reactions. All reactions could be performed sequentially, without workup or purification any intermediates. Moreover, naturally occurring have (+)-configuration importantly here, strategy to (?)-isomers was developed. A methyl at C-8 also introduced some stereocontrol, influenced by stereochemistry C-13. Furthermore, single step reaction found convert tetrahydroprotoberberine into analogous scaffold, avoiding harsh oxidizing conditions oxidase. This work provides facile, routes novel analogues bioactive alkaloids.