Stereoselective Transaminase‐Mediated Synthesis of Serotonin and Melatonin Receptor Agonists

Abstract

Transaminase enzymes have significant potential for the stereoselective synthesis of drugs or drug precursors. Here, starting from one prochiral β‐tetralone, a short and efficient chemoenzymatic synthesis of four agonists of the serotonin/melatonin receptors have been developed. The key step is the stereoselective transamination of the prochiral ketone to produce both enantiomers of 8‐methoxy‐2‐aminotetraline in high yields and enantiomeric excesses. This was followed by either amidation to give the 8‐methoxy‐2‐acetimidotetralines or several facile chemical steps to the 8‐hydroxy‐2‐aminodipropyltetralines.

Mechanoenzymatic reactions with whole cell transaminases: shaken, not stirred

“…The enantiomeric excesses (ees) were confirmed for 8b , 10b , 11b and 12b via the use of racemic standards and chiral HPLC/GC, with all mechanoenzymatic reaction products found to be a single ( S )-enantiomer (see ESI†). 34–36…”

“…The enantiomeric excesses (ees) were confirmed for 8b, 10b, 11b and 12b via the use of racemic standards and chiral HPLC/GC, with all mechanoenzymatic reaction products found to be a single (S)-enantiomer (see ESI †). [34][35][36] Reactions were also performed to compare mechanoenzymatic whole cell Cv-TAm reactions to reactions under typical enzymatic conditions (with whole cell Cv-TAm), i.e. in a thermomixer.…”

Hot off the Press

“…Transaminases have been used for the stereoselective synthesis of ( R )- or ( S )-8-methoxy-2-aminotetraline from a prochiral β-tetralone (Scheme 4). 30 The synthetic utility of this transformation was demonstrated by the conversion of the products of this process to four agonists of the serotonin and melatonin receptors.…”

A transaminase-mediated aldol reaction and applications in cascades to styryl pyridines

“…Using 5b and 1 again as starting materials, the (R)-selective transaminase from Mycobacterium vanbaalenii (MvTAm) 27 and Arthrobacter sp. (ArRmut11), 15 and (S)selective transaminases from Vibrio fluvialis (Vf TAm), 28 Klebsiella pneumoniae (KpTAm; from UCL plasmid pQR1005) 29,30 and Rhodobacter sphaeroides (RsTAm; from UCL plasmid pQR 1019) 30,31 were selected due to their previous biocatalytic applications. transaminases from a drain metagenome, expressed from plasmids pQR2189, pQR2191, and pQR2208 which have shown good activity towards aromatic amines, were also selected to test in the reaction.…”