Transaminases have
attracted considerable interest in their use
as biocatalysts for the synthesis of compounds containing chiral amine
units, which are widespread within the pharmaceutical, agrochemical,
and fine chemical industry. Recent developments in enzyme- and process-engineering
have expedited their use in asymmetric synthesis; however, industrial
applications are still hindered by a number of factors, including
equilibrium thermodynamics, product inhibition, and poor substrate
tolerance. Detailed and comprehensive approaches to each of these
challenges have been reported during the last two decades; the most
representative enzyme discovery and screening strategies, protein
and equilibrium engineering, and immobilization techniques are reviewed
herein. Furthermore, we present a detailed look into the applications
of transaminases for the synthesis of a variety of amine-containing
compounds and the integration of transaminases into multienzymatic
systems that allow access to a variety of highly complex products
for the end user.
Biocatalytic retrosynthetic analysis of dibenz[c,e]azepines has highlighted the use of imine reductase (IRED) and ω-transaminase (ω-TA) biocatalysts to establish the key stereocentres of these molecules. Several enantiocomplementary IREDs were identified for the synthesis of (R)- and (S)-5-methyl-6,7-dihydro-5H-dibenz[c,e]azepine with excellent enantioselectivity, by reduction of the parent imines. Crystallographic evidence suggests that IREDs may be able to bind one conformer of the imine substrate such that, upon reduction, the major product conformer is generated directly. ω-TA biocatalysts were also successfully employed for the production of enantiopure 1-(2-bromophenyl)ethan-1-amine, thus enabling an orthogonal route for the installation of chirality into dibenz[c,e]azepine framework.
Putrescine transaminase (pATA; EC 2.6.1.82) catalyzes the transfer of an amino group from terminal diamine donor molecules to keto acid acceptors by using pyridoxal‐5′‐phosphate as a cofactor. The ygjG genes from Escherichia coli K12, Bacillus megaterium, and Bacillus mycoides were successfully cloned and expressed in E. coli BL21(DE3) cells. The three putrescine transaminases were all shown to prefer diaminoalkanes as substrates and thereby generated cyclic imines from the ω‐amino aldehyde intermediates. The addition of a mild chemical reducing agent rapidly reduced the imine intermediate in situ to furnish a range of N‐heterocycle products. We applied pATA in a biomimetic synthesis of 2,3‐dihydro‐1H‐indolizinium‐containing targets, notably the bioactive alkaloid ficuseptine.
A multi‐enzymatic cascade process involving transaminases (TAs) and reductive aminases (RedAms) to produce enantiomerically pure 2,5‐disubstituted pyrrolidine alkaloids from their respective 1,4‐diketones is reported. Several TAs were screened and the best results for diketone monoamination were obtained with an R‐selective TA from Mycobacterium chlorophenicum and with an S‐selective TA from Bacillus megaterium. Pyrroline reduction was best performed by a reductive aminase from Ajellomyces dermatitidis (AdRedAm). Finally, a biocatalytic one‐pot cascade was implemented using the aforementioned enzymes and a variety of 2‐methyl‐5‐alkylpyrrolidines were produced with high (>99 %) conversion, diastereomeric and enantiomeric excess values.
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