Transaminase and Norcoclaurine Synthase One‐Pot Cascades Towards (1 <i>S</i> )‐Tetrahydroisoquinolines

Tetrahydroisoquinolines (THIQs) are an important group of alkaloids, and many of these natural products and non-natural analogues are biologically active. For this reason, concise stereochemical synthetic routes are of significant interest. One strategy has been to use the Pictet-Spenglerase enzyme norcoclaurine synthase (NCS) with an arylethylamine and aldehyde in a single step reaction, alternatively enzyme cascades have been developed. The use of a transaminase (TAm) potentially provides efficient access to the aldehyde component required in NCS cascades, but currently suffers from limited substrate tolerance, in part due to potential complexities with the formation of mixed products. Here we present the development of a TAm-NCS cascade using structurally diverse primary amines to form (1S)-6,7-dihydroxy-THIQs via the generation of, in particular, aliphatic aldehyde intermediates in situ. Application of the one-pot cascade with amines successfully generated the corresponding products in up to >99% enantiomeric excess and 83% isolated yields. The cascade was also extended with a tyrosinase to produce a 3-hydroxymethylene substituted THIQ.