# Transaminase and Norcoclaurine Synthase One‐Pot Cascades Towards (1S)‐Tetrahydroisoquinolines

## TL;DR

Researchers developed a one-pot enzyme cascade to efficiently produce biologically active THIQs from amines with high enantiomeric purity.

## Contribution

A TAm-NCS cascade was developed for in situ aldehyde generation and THIQ synthesis with improved substrate tolerance.

## Key findings

- The cascade produced (1S)-6,7-dihydroxy-THIQs with up to >99% enantiomeric excess and 83% yield.
- The method works with diverse amines, both nonfunctionalized and functionalized.
- A tyrosinase extension enabled the synthesis of 3-hydroxymethylene substituted THIQs.

## Abstract

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.

A TAm‐NCS cascade towards THIQs has been established, starting from amines with the in situ production of aldehydes. The cascade was used with a variety of nonfunctionalized and functionalized amines, and reaction conditions modified to enhance formation of the desired cross‐products. This resulted in an efficient one‐pot approach to THIQs starting from readily available amines.© 2026 WILEY‐VCH GmbH