One-Pot Cascade Synthesis of Mono- and Disubstituted Piperidines and Pyrrolidines using Carboxylic Acid Reductase (CAR), ω-Transaminase (ω-TA), and Imine Reductase (IRED) Biocatalysts

被引：141

作者：

France, Scott P. ^{[1
]}

Hussain, Shahed ^{[1
]}

Hill, Andrew M. ^{[1
]}

Hepworth, Lorna J. ^{[1
]}

Howard, Roger M. ^{[2
]}

Mulholland, Keith R. ^{[3
]}

Flitsch, Sabine L. ^{[1
]}

Turner, Nicholas J. ^{[1
]}

机构：

[1] Univ Manchester, Manchester Inst Biotechnol, Sch Chem, 131 Princess St, Manchester M1 7DN, Lancs, England

[2] Pfizer Chem Res & Dev, Discovery Pk House,Ramsgate Rd, Sandwich CT13 9NJ, Kent, England

[3] AstraZeneca, Chem Dev, Silk Rd Business Pk, Macclesfield SK10 2NA, Cheshire, England

来源：

ACS CATALYSIS | 2016年 / 6卷 / 06期

基金：

英国工程与自然科学研究理事会; 英国生物技术与生命科学研究理事会;

关键词：

biocatalysis; carboxylic acid reductase; omega-transaminase; imine reductase; piperidines; pyrrolidines; CATALYTIC KINETIC RESOLUTION; ASYMMETRIC-SYNTHESIS; STEREOSELECTIVE MONOAMINATION; (R)-IMINE REDUCTASE; CHIRAL AMINES; HYDROGENATION; PURIFICATION; TOOLBOX; ENZYME;

D O I：

10.1021/acscatal.6b00855

中图分类号：

O64 [物理化学（理论化学）、化学物理学];

学科分类号：

070304 ; 081704 ;

摘要：

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.

引用

页码：3753 / 3759

页数：7