Abstract
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.
Highlights
Chemoenzymatic and enzymatic cascade reactions enable the synthesis of complex stereocomplementary 1,3,4trisubstituted tetrahydroisoquinolines (THIQs) with three chiral centers in a step-efficient and selective manner without intermediate purification
Subsequent cyclization catalyzed either enzymatically by a norcoclaurine synthase or chemically by phosphate resulted in opposite stereoselectivities in the products at the C1 position, providing access to both orientations of the THIQ C1 substituent
norcoclaurine synthase (NCS) has been successfully employed in chemoenzymatic cascades.[12,15,16,21]
Summary
Chemoenzymatic and enzymatic cascade reactions enable the synthesis of complex stereocomplementary 1,3,4trisubstituted tetrahydroisoquinolines (THIQs) with three chiral centers in a step-efficient and selective manner without intermediate purification. Modular biocatalytic cascades[23] for the stereoselective production of pharmaceutical compounds are exemplified by the work conducted on phenylpropanolamines.[24,25,26] All four possible isomers of nor(pseudo)ephedrine are available from simple starting materials by one-pot two-enzyme cascades when appropriate biocatalysts are selected.[26] Phenylpropanolamines with an additional 3-hydroxy group on the aromatic ring have been considered to be suitable substrates for cascades including PSRs catalyzed by NCS or phosphate.
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