期刊
ACS CATALYSIS
卷 6, 期 6, 页码 3753-3759出版社
AMER CHEMICAL SOC
DOI: 10.1021/acscatal.6b00855
关键词
biocatalysis; carboxylic acid reductase; omega-transaminase; imine reductase; piperidines; pyrrolidines
资金
- Biotechnology and Biological Sciences Research Council (BBSRC)
- Pfizer
- Engineering and Physical Sciences Research Council (EPSRC)
- AstraZeneca
- Centre of Excellence for Biocatalysis, Biotransformations and Biocatalytic Manufacture (CoEBio3)
- BBSRC sLoLa program [BB/L502005/1]
- Royal Society
- Biotechnology and Biological Sciences Research Council [BB/M006611/1, 1394023, 1782874] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [1273953] Funding Source: researchfish
- BBSRC [BB/L502005/1, BB/M006611/1] Funding Source: UKRI
Access to enantiomerically pure chiral mono- and disubstituted piperidines and pyrrolidines has been achieved using a biocatalytic cascade involving carboxylic acid reductase (CAR), omega-transaminase (omega-TA), and imine reductase (IRED) enzymes. Starting from keto acids or keto aldehydes, substituted piperidine or pyrrolidine frameworks can be generated in high conversion, ee, and de in one pot, with each biocatalyst exhibiting chemo-, regio-, and/or stereoselectivity during catalysis. The study also includes a systematic investigation of the effect of the position of a methyl group ring substituent on the IRED-catalyzed reduction of a chiral imine. Analysis of the selectivity observed in these reactions revealed an interesting balance between substrate versus enzyme control; the configurations of the products obtained were rationalized on the basis of minimizing 1,3- or 1,2-steric interactions with incoming NADPH.
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