Enzymatic and Chemoenzymatic Three‐Step Cascades for the Synthesis of Stereochemically Complementary Trisubstituted Tetrahydroisoquinolines

• Published in: Angewandte Chemie International Edition Vol. 56; no. 41; pp. 12503 - 12507
• Main Authors: Erdmann, Vanessa, Lichman, Benjamin R., Zhao, Jianxiong, Simon, Robert C., Kroutil, Wolfgang, Ward, John M., Hailes, Helen C., Rother, Dörte
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 02-10-2017; John Wiley and Sons Inc
• Edition: International ed. in English
• Subjects: Acetolactate Synthase - chemistry; asymmetric catalysis; Biocatalysis; Biocatalysts; Carbon-Nitrogen Ligases - chemistry; Carbonyls; Cascade chemical reactions; Catalysis; Chemical synthesis; Chemistry Techniques, Synthetic; chemoenzymatic cascades; Chromobacterium - enzymology; Communication; Communications; Escherichia coli - enzymology; Hydroxybenzaldehydes; norcoclaurine synthase; Phosphates; Purification; Pyruvic acid; Stereoisomerism; Substrates; Tetrahydroisoquinolines - chemical synthesis; Tetrahydroisoquinolines - chemistry; Thalictrum - enzymology; Transaminase; transaminases; Transaminases - chemistry; transaminases; norcoclaurine synthase; chemoenzymatic cascades; asymmetric catalysis; biocatalysis
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201705855

Chemoenzymatic and enzymatic cascade reactions enable the synthesis of complex stereocomplementary 1,3,4‐trisubstituted tetrahydroisoquinolines (THIQs) with three chiral centers in a step‐efficient and selective manner without intermediate purification. The cascade employs inexpensive substrates (3‐hydroxybenzaldehyde and pyruvate), and involves a carboligation step, a subsequent transamination, and finally a Pictet–Spengler reaction with a carbonyl cosubstrate. Appropriate selection of the carboligase and transaminase enzymes enabled the biocatalytic formation of (1R,2S)‐metaraminol. Subsequent cyclization catalyzed either enzymatically by a norcoclaurine synthase or chemically by phosphate resulted in opposite stereoselectivities in the products at the C1 position, thus providing access to both orientations of the THIQ C1 substituent. This highlights the importance of selecting from both chemo‐ and biocatalysts for optimal results.
Diverging possibilities: Tetrahydroisoquinolines can be produced by enzymatic and chemoenzymatic three‐step cascade reactions with a combination of carboligases, transaminases, and norcoclaurine synthases (NCSs) or, alternatively, phosphate as the catalyst. With NCS and phosphate, products with opposite stereoselectivity are obtained.