亚胺还原酶在手性胺合成中的应用

doi:10.12211/2096-8280.2021-054

摘要/Abstract

摘要：

手性胺存在于许多生物活性物质中，是重要的手性助剂，同时也是合成天然产物及手性药物的关键中间体。2019年零售额前200名的药物中，含有手性胺结构的药物超过三成，因此发展高效、便捷合成手性胺化合物的方法是研究的重要方向。通过酶催化方法制备手性胺化合物，因具有高效性、环境友好性、经济效率高等优点，获得了学术界及工业界的广泛关注。本文所综述的亚胺还原酶（IREDs）是一类NAD（P）H依赖的氧化还原酶，可催化亚胺的不对称还原合成手性胺。IREDs具有催化效率高、区域及立体选择性强等优异的特性，在众多合成手性胺方法中脱颖而出，吸引了科研工作者的研究目光。近年来，随着生物信息学、结构生物学、高通量筛选方法的飞速发展和数据库的不断扩充，鉴定了许多不同功能的IRED，并在IRED的发现、分子改造、底物谱扩展和多酶级联应用等方面均取得了显著的成果，其中不乏一些具有工业应用价值。本文概述了IRED的结构特征及作用机理，着重介绍了IRED的分子改造和在多酶串联反应中的应用，以及在不对称催化手性胺生物合成中遇到的瓶颈、获得的突破和进展。此外还对酶法合成手性胺化合物实现工业化生产所面临的挑战及巨大潜力，以及新颖的人工生物合成途径设计对克服这些挑战的重要性进行了展望。

关键词: 亚胺还原酶, 手性胺, 生物催化, 酶工程, 生物合成

Abstract:

Chiral amines with bioactivities are important chiral auxiliaries, and also key intermediates for the synthesis of many natural products and chiral drugs. Among the top 200 drugs for market revenues in 2019, more than 30% contain chiral amine structures. Therefore, the development of efficient and effective methods to synthesize chiral amine compounds is of interest for research. Due to its high efficiency, environmental friendliness and economic competitiveness, more attention has been paid on the enzyme-catalyzed production of chiral amines by academia and industry. Imine reductases (IREDs) reviewed in this article are a class of NAD(P) H-dependent oxidoreductases that catalyze asymmetric reduction of imines to chiral amines. The reduction of C $̿$ N bonds constitutes a physiological reaction present in a number of biosynthetic pathways, leading to a variety of metabolites. The imine reductases have excellent characteristics such as high catalytic efficiency, strong regioselectivity and stereoselectivity, etc., which stand out among many other methods for the synthesis of chiral amines, and attract attention and enthusiasm of many researchers. In the past decade, with the rapid development of bioinformatics, structural biology, high-throughput screening approaches and the continuous expansion of the gene databases, many imine reductases with different functions have been identified. Significant achievements have been made in the discovery of IREDs, protein engineering and multi-enzyme cascade applications, among which some successful modification cases have industrial application potentials. This review summarizes the structural characteristics, catalytic mechanisms and applications of IREDs, with emphasis on their protein engineering and applications in multi-enzyme cascade reactions, as well as the bottleneck, breakthrough and progress in asymmetric catalytic chiral amine biosynthesis. In addition, the challenges and potentials of the enzymatic synthesis of chiral amine compounds for industrial production, and the importance of novel artificial biosynthesis pathway design to overcome these challenges are highlighted.

Key words: imine reductase, chiral amine, biocatalysis, protein engineering, biosynthesis

中图分类号:

Q554

杨璐, 瞿旭东. 亚胺还原酶在手性胺合成中的应用[J]. 合成生物学, 2022, 3(3): 516-529.

Lu YANG, Xudong QU. Application of imine reductase in the synthesis of chiral amines[J]. Synthetic Biology Journal, 2022, 3(3): 516-529.

图/表 8

图1 含有手性胺结构的药物

Fig. 1 Pharmaceuticals containing chiral amine motifs

图2 天然代谢过程中的亚胺还原过程

Fig. 2 Imine reduction in the biosynthesis of natural products

图3 R-IRED Q1EQE0的同源二聚体的结构

Fig. 3 Structure of the R-IRED Q1EQE0

图4 HIBDH、R-IRED和S-IRED催化机理

Fig. 4 Catalytic mechanisms of HIBDH, R-IRED and S-IRED

表1 亚胺还原酶改造实例

Tab. 1 Examples of imine reductase modifications

Entry	Enzyme	Source	ee/%	Reference
1	IR2	Actinomaduramadurae	99 ^R	[24]
2	IR45	Streptomyces aurantiacus	99 ^S	[8]
3	IR46	Saccharothrixespanaensis	99 ^R	[66]
4	IR1	Leishmania major	99 ^R	[67]
5	AoIRED	Amycolatopsisorientalis	40 ^R	[68]

图5 R-IRED及突变体与NADH的对接模型

Fig. 5 Docking models of R-IRED and its mutants with NADH

图6 一锅法多酶串联合成哌啶和吡咯烷

Fig. 6 One-pot cascade synthesis of piperidines and pyrrolidines

图7 化学-酶法高效合成四氢异喹啉生物碱

Fig. 7 High efficient synthesis of tetrahydroisoquinoline alkaloids by the chemo-enzymatic method

参考文献 91

1	GHISLIERI D, TURNER N J. Biocatalytic approaches to the synthesis of enantiomerically pure chiral amines[J]. Topics in Catalysis, 2014, 57(5):284-300.
2	SCHRITTWIESER J H, VELIKOGNE S, KROUTIL W. Biocatalytic imine reduction and reductive amination of ketones[J]. Advanced Synthesis & Catalysis, 2015, 357(8):1655-1685.
3	GUO F, BERGLUND P. Transaminase biocatalysis: optimization and application[J]. Green Chemistry, 2017, 19(2):333-360.
4	MATHEW S, YUN H. ω-Transaminases for the production of optically pure amines and unnatural amino acids[J]. ACS Catalysis, 2012, 2(6):993-1001.
5	KOHLS H, STEFFEN-MUNSBERG F, HÖHNE M. Recent achievements in developing the biocatalytic toolbox for chiral amine synthesis[J]. Current Opinion in Chemical Biology, 2014, 19: 180-192.
6	JIANG J J, CHEN X, ZHANG D L, et al. Characterization of (R)-selective amine transaminases identified by in silico motif sequence blast[J]. Applied Microbiology and Biotechnology, 2015, 99(6):2613-2621.
7	JIANG J J, CHEN X, FENG J H, et al. Substrate profile of an ω-transaminase from Burkholderia vietnamiensis and its potential for the production of optically pure amines and unnatural amino acids[J]. Journal of Molecular Catalysis B: Enzymatic, 2014, 100: 32-39.
8	YANG L, ZHU J M, SUN C H, et al. Biosynthesis of plant tetrahydroisoquinoline alkaloids through an imine reductase route[J]. Chemical Science, 2019, 11(2): 364-371.
9	KIM Y, PARK J, KIM M J. Dynamic kinetic resolution of amines and amino acids by enzyme-metal cocatalysis[J]. ChemCatChem, 2011, 3(2):271-277.
10	NUGENT T C, EL-SHAZLY M. Chiral amine synthesis-recent developments and trends for enamide reduction, reductive amination, and imine reduction[J]. Advanced Synthesis & Catalysis, 2010, 352(5):753-819.
11	CHENG F, ZHU L L, SCHWANEBERG U. Directed evolution 2.0: improving and deciphering enzyme properties[J]. Chemical Communications, 2015, 51(48):9760-9772.
12	RAMSDEN J I, HEATH R S, DERRINGTON S R, et al. Biocatalytic N-alkylation of amines using either primary alcohols or carboxylic acids via reductive aminase cascades[J]. Journal of the American Chemical Society, 2019, 141(3):1201-1206.
13	CHENG F, CHEN X L, XIANG C, et al. Fluorescence-based high-throughput screening system for R-ω-transaminase engineering and its substrate scope extension[J]. Applied Microbiology and Biotechnology, 2020, 104(7): 2999-3009.
14	BALKENHOHL F, DITRICH K, HAUER B, et al. Optically active amines via lipase-catalyzed methoxyacetylation[J]. Journal Fur Praktische Chemie-Chemiker-Zeitung, 1997, 339(4):381-384.
15	AHN Y, KO S B, KIM M J, et al. Racemization catalysts for the dynamic kinetic resolution of alcohols and amines[J]. Coordination Chemistry Reviews, 2008, 252(5/6/7): 647-658.
16	SAVILE C K, JANEY J M, MUNDORFF E C, et al. Biocatalytic asymmetric synthesis of chiral amines from ketones applied to sitagliptin manufacture[J]. Science, 2010, 329(5989):305-309.
17	KELLY S A, POHLE S, WHARRY S, et al. Application of ω-transaminases in the pharmaceutical industry[J]. Chemical Reviews, 2018, 118(1):349-367.
18	MUTTI F G, FUCHS C S, PRESSNITZ D, et al. Stereoselectivity of four (R)-selective transaminases for the asymmetric amination of ketones[J]. Advanced Synthesis & Catalysis, 2011, 353(17):3227-3233.
19	GOMM A, O'REILLY E. Transaminases for chiral amine synthesis[J]. Current Opinion in Chemical Biology, 2018, 43: 106-112.
20	ALEXEEVA M, ENRIGHT A, DAWSON M J, et al. Deracemization of α-methylbenzylamine using an enzyme obtained by in vitro evolution[J]. Angewandte Chemie International Edition, 2002, 41(17):3177-3180.
21	CARR R, ALEXEEVA M, ENRIGHT A, et al. Directed evolution of an amine oxidase possessing both broad substrate specificity and high enantioselectivity[J]. Angewandte Chemie International Edition, 2003, 42(39):4807-4810.
22	MUTTI F G, KNAUS T, SCRUTTON N S, et al. Conversion of alcohols to enantiopure amines through dual-enzyme hydrogen-borrowing cascades[J]. Science, 2015, 349(6255):1525-1529.
23	ALEKU G A, FRANCE S P, MAN H, et al. A reductive aminase from Aspergillus oryzae [J]. Nature Chemistry, 2017, 9(10):961-969.
24	ZHU J M, TAN H Q, YANG L, et al. Enantioselective synthesis of 1-aryl-substituted tetrahydroisoquinolines employing imine reductase[J]. ACS Catalysis, 2017, 7(10): 7003-7007.
25	MANGAS-SANCHEZ J, FRANCE S P, MONTGOMERY S L, et al. Imine reductases (IREDs)[J]. Current Opinion in Chemical Biology, 2017, 37:19-25.
26	HEBERLING M M, WU B, BARTSCH S, et al. Priming ammonia lyases and aminomutases for industrial and therapeutic applications[J]. Current Opinion in Chemical Biology, 2013, 17(2):250-260.
27	LOVELOCK S L, LLOYD R C, TURNER N J. Phenylalanine ammonia lyase catalyzed synthesis of amino acids by an MIO- cofactor independent pathway[J]. Angewandte Chemie International Edition, 2014, 53(18):4652-4656.
28	GROGAN G, TURNER N J. InspIRED by nature: NADPH-dependent imine reductases (IREDs) as catalysts for the preparation of chiral amines[J]. Chemistry-A European Journal, 2016, 22(6):1900-1907.
29	POSNER B A, LI L Y, BETHELL R, et al. Engineering specificity for folate into dihydrofolate reductase from Escherichia coli [J]. Biochemistry, 1996, 35(5):1653-1663.
30	MENEELY K M, LAMB A L. Two structures of a thiazolinyl imine reductase from Yersinia enterocolitica provide insight into catalysis and binding to the nonribosomal peptide synthetase module of HMWP₁ [J]. Biochemistry, 2012, 51(44):9002-9013.
31	MENEELY K M, RONNEBAUM T A, RILEY A P, et al. Holo structure and steady state kinetics of the thiazolinyl imine reductases for siderophore biosynthesis[J]. Biochemistry, 2016, 55(38):5423-5433.
32	WINZER T, KERN M, KING A J, et al. Morphinan biosynthesis in opium poppy requires a P450-oxidoreductase fusion protein[J]. Science, 2015, 349(6245):309-312.
33	FARROW S C, HAGEL J M, BEAUDOIN G A W, et al. Stereochemical inversion of (S)-reticuline by a cytochrome P450 fusion in opium poppy[J]. Nature Chemical Biology, 2015, 11(9): 728-732.
34	NARDINI M, RICCI G, CACCURI A M, et al. Purification and characterization of a ketimine-reducing enzyme[J]. European Journal of Biochemistry, 1988, 173(3): 689-694.
35	NARDINI M, RICCI G, VESCI L, et al. Bovine brain ketimine reductase[J]. Biochimica et Biophysica Acta, 1988, 957(2): 286-292.
36	HALLEN A, COOPER A J L, JAMIE J F, et al. Mammalian forebrain ketimine reductase identified as μ-crystallin; potential regulation by thyroid hormones[J]. Journal of Neurochemistry, 2011, 118(3): 379-387.
37	LI H, WILLIAMS P, MICKLEFIELD J, et al. A dynamic combinatorial screen for novel imine reductase activity[J]. Tetrahedron, 2004, 60(3): 753-758.
38	MURAMATSU H, MIHARA H, KAKUTANI R, et al. Enzymatic synthesis of N-methyl-L-phenylalanine by a novel enzyme, N-methyl-L-amino acid dehydrogenase, from Pseudomonas putida [J]. Tetrahedron: Asymmetry, 2004, 15(18): 2841-2843.
39	MURAMATSU H, MIHARA H, KAKUTANI R, et al. The putative malate/lactate dehydrogenase from Pseudomonas putida is an NADPH-dependent Δ¹-piperideine-2-carboxylate/Δ¹-pyrroline-2-carboxylate reductase involved in the catabolism of D-lysine and D-proline[J]. Journal of Biological Chemistry, 2005, 280(7):5329-5335.
40	MURAMATSU H, MIHARA H, GOTO M, et al. A new family of NAD(P)H-dependent oxidoreductases distinct from conventional Rossmann-fold proteins[J]. Journal of Bioscience and Bioengineering, 2005, 99(6):541-547.
41	VAIJAYANTHI T, CHADHA A. Asymmetric reduction of aryl imines using Candida parapsilosis ATCC 7330[J]. Tetrahedron: Asymmetry, 2008, 19(1): 93-96.
42	ESPINOZA-MORAGA M, PETTA T, VASQUEZ-VASQUEZ M, et al. Bioreduction of β-carboline imines to amines employing Saccharomyces bayanus [J]. Tetrahedron: Asymmetry, 2010, 21(16): 1988-1992.
43	MITSUKURA K, SUZUKI M, TADA K, et al. Asymmetric synthesis of chiral cyclic amine from cyclic imine by bacterial whole-cell catalyst of enantioselective imine reductase[J]. Organic & Biomolecular Chemistry, 2010, 8(20):4533-4535.
44	MITSUKURA K, SUZUKI M, SHINODA S, et al. Purification and characterization of a novel (R)-imine reductase from Streptomyces sp. GF₃₅₈₇ [J]. Bioscience, Biotechnology, and Biochemistry, 2011, 75(9): 1778-1782.
45	SLABU I, GALMAN J L, WEISE N J, et al. Putrescine transaminases for the synthesis of saturated nitrogen heterocycles from polyamines[J]. ChemCatChem, 2016, 8(6):1038-1042.
46	HUSSAIN S, LEIPOLD F, MAN H, et al. An (R)-imine reductase biocatalyst for the asymmetric reduction of cyclic imines[J]. ChemCatChem, 2015, 7(4):579-583.
47	LEIPOLD F, HUSSAIN S, GHISLIERI D, et al. Asymmetric reduction of cyclic imines catalyzed by a whole-cell biocatalyst containing an (S)-imine reductase[J]. ChemCatChem, 2013, 5(12): 3505-3508.
48	SCHELLER P N, FADEMRECHT S, HOFELZER S, et al. Enzyme toolbox: novel enantiocomplementary imine reductases[J]. ChemBioChem, 2014, 15(15):2201-2204.
49	FADEMRECHT S, SCHELLER P N, NESTL B M, et al. Identification of imine reductase-specific sequence motifs[J]. Proteins: Structure, Function, and Bioinformatics, 2016, 84(5): 600-610.
50	LENZ M, SCHELLER P N, RICHTER S M, et al. Cultivation and purification of two stereoselective imine reductases from Streptosporangium roseum and Paenibacillus elgii [J]. Protein Expression and Purification, 2017, 133:199-204.
51	MITSUKURA K, KURAMOTO T, YOSHIDA T, et al. A NADPH-dependent (S)-imine reductase (SIR) from Streptomyces sp. GF3546 for asymmetric synthesis of optically active amines: purification, characterization, gene cloning, and expression[J]. Applied Microbiology and Biotechnology, 2013, 97(18): 8079-8086.
52	LENZ M, BORLINGHAUS N, WEINMANN L, et al. Recent advances in imine reductase-catalyzed reactions[J]. World Journal of Microbiology & Biotechnology, 2017, 33(11): 199.
53	MIRABAL-GALLARDO Y, SORIANO M D P C, SANTOS L S. Stereoselective bioreduction of β-carboline imines through cell-free extracts from earthworms (Eisenia foetida)[J]. Tetrahedron: Asymmetry, 2013, 24(8): 440-443.
54	PENG H D, WEI E M, WANG J L, et al. Deciphering piperidine formation in polyketide-derived indolizidines reveals a thioester reduction, transamination, and unusual imine reduction process[J]. ACS Chemical Biology, 2016, 11(12):3278-3283.
55	LI H, ZHANG G X, LI L M, et al. A novel (R)-imine reductase from Paenibacillus lactis for asymmetric reduction of 3H-indoles[J]. ChemCatChem, 2016, 8(4): 724-727.
56	LI H, TIAN P, XU J H, et al. Identification of an imine reductase for asymmetric reduction of bulky dihydroisoquinolines[J]. Organic Letters, 2017, 19(12):3151-3154.
57	ZHANG Y H, CHEN F F, LI B B, et al. Stereocomplementary synthesis of pharmaceutically relevant chiral 2-aryl-substituted pyrrolidines using imine reductases[J]. Organic Letters, 2020, 22(9):3367-3372.
58	RODRÍGUEZ-MATA M, FRANK A, WELLS E, et al. Structure and activity of NADPH-dependent reductase Q1EQE0 from Streptomyces kanamyceticus, which catalyses the R-selective reduction of an imine substrate[J]. ChemBioChem, 2013, 14(11): 1372-1379.
59	LOKANATH N K, OHSHIMA N, TAKIO K, et al. Crystal structure of novel NADP-dependent 3-hydroxyisobutyrate dehydrogenase from Thermus thermophilus HB8[J]. Journal of Molecular Biology, 2005, 352(4): 905-917.
60	HUBER T, SCHNEIDER L, PRÄG A, et al. Direct reductive amination of ketones: structure and activity of S-selective imine reductases from Streptomyces [J]. ChemCatChem, 2014, 6(8): 2248-2252.
61	MAN H, WELLS E, HUSSAIN S, et al. Structure, activity and stereoselectivity of NADPH-dependent oxidoreductases catalysing the S-selective reduction of the imine substrate 2-methylpyrroline[J]. ChemBioChem, 2015, 16(7):1052-1059.
62	ALEKU G A, MAN H, FRANCE S P, et al. Stereoselectivity and structural characterization of an imine reductase (IRED) from Amycolatopsis orientalis [J]. ACS Catalysis, 2016, 6(6): 3880-3889.
63	MEYER T, ZUMBRÄGEL N, GEERDS C, et al. Structural characterization of an S-enantioselective imine reductase from Mycobacterium smegmatis [J]. Biomolecules, 2020, 10(8):1130-1142.
64	REETZ M T, KAHAKEAW D, LOHMER R. Addressing the numbers problem in directed evolution[J]. ChemBioChem, 2008, 9(11):1797-1804.
65	CURRIN A, SWAINSTON N, DAY P J, et al. Synthetic biology for the directed evolution of protein biocatalysts: navigating sequence space intelligently[J]. Chemical Society Reviews, 2015, 44(5):1172-1239.
66	SCHOBER M, MACDERMAID C, OLLIS A A, et al. Chiral synthesis of LSD1 inhibitor GSK2879552 enabled by directed evolution of an imine reductase[J]. Nature Catalysis, 2019, 2(10):909-915.
67	XU Z F, YAO P Y, SHENG X, et al. Biocatalytic access to 1,4-diazepanes via imine reductase-catalyzed intramolecular asymmetric reductive amination[J]. ACS Catalysis, 2020, 10(15):8780-8787.
68	FRANCE S P, ALEKU G A, SHARMA M, et al. Biocatalytic routes to enantiomerically enriched dibenz[c,e]azepines[J]. Angewandte Chemie International Edition, 2017, 56(49): 15589-15593.
69	RENATA H, WANG Z J, ARNOLD F H. Expanding the enzyme universe: accessing non-natural reactions by mechanism-guided directed evolution[J]. Angewandte Chemie International Edition, 2015, 54(11):3351-3367.
70	PORTER J L, RUSLI R A, OLLIS D L. Directed evolution of enzymes for industrial biocatalysis[J]. ChemBioChem, 2016, 17(3):197-203.
71	HESTERICOVÁ M, HEINISCH T, ALONSO-COTCHICO L, et al. Directed evolution of an artificial imine reductase[J]. Angewandte Chemie International Edition, 2018, 57(7): 1863-1868.
72	NEWTON C R, GRAHAM A, HEPTINSTALL L E, et al. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS)[J]. Nucleic Acids Research, 1989, 17(7): 2503-2516.
73	MORLEY K L, KAZLAUSKAS R J. Improving enzyme properties: when are closer mutations better?[J]. Trends in Biotechnology, 2005, 23(5):231-237.
74	MINDT M, HANNIBAL S, HEUSER M, et al. Fermentative production of N-alkylated glycine derivatives by recombinant corynebacterium glutamicum using a mutant of imine reductase DpkA from Pseudomonas putida [J]. Frontiers in Bioengineering and Biotechnology, 2019, 7: 232.
75	PAVLIDIS I V, WEIß M S, GENZ M, et al. Identification of (S)-selective transaminases for the asymmetric synthesis of bulky chiral amines[J]. Nature Chemistry, 2016, 8(11): 1076-1082.
76	TANIHARA H, INOUE T, YAMAMOTO T, et al. Intra-ocular pressure-lowering effects of a Rho kinase inhibitor, ripasudil (K-115), over 24 hours in primary open-angle glaucoma and ocular hypertension: a randomized, open-label, crossover study[J]. Acta Ophthalmologica, 2015, 93(4): e254-e260.
77	GARWEG G, REHREN D V, HINTZE U. L-pipecolate formation in the mammalian brain. Regional distribution of Δ¹-Pyrroline-2-carboxylate reductase activity[J]. Journal of Neurochemistry, 1980, 35(3): 616-621.
78	GAND M, THÖLE C, MÜLLER H, et al. A NADH-accepting imine reductase variant: immobilization and cofactor regeneration by oxidative deamination[J]. Journal of Biotechnology, 2016, 230: 11-18.
79	BORLINGHAUS N, NESTL B M. Switching the cofactor specificity of an imine reductase[J]. ChemCatChem, 2018, 10(1):183-187.
80	HEATH R S, PONTINI M, HUSSAIN S, et al. Combined imine reductase and amine oxidase catalyzed deracemization of nitrogen heterocycles[J]. ChemCatChem, 2016, 8(1):117-120.
81	FRANCE S P, HUSSAIN S, HILL A M, et al. 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[J]. ACS Catalysis, 2016, 6(6):3753-3759.
82	HEPWORTH L J, FRANCE S P, HUSSAIN S, et al. Enzyme cascades in whole cells for the synthesis of chiral cyclic amines[J]. ACS Catalysis, 2017, 7(4):2920-2925.
83	MONTGOMERY S L, MANGAS-SANCHEZ J, THOMPSON M P, et al. Direct alkylation of amines with primary and secondary alcohols through biocatalytic hydrogen borrowing[J]. Angewandte Chemie International Edition, 2017, 56(35): 10491-10494.
84	FORD G J, KRESS N, MATTEY A P, et al. Synthesis of protected 3-aminopiperidine and 3-aminoazepane derivatives using enzyme cascades[J]. Chemical Communications, 2020, 56(57):7949-7952.
85	COSGROVE S C, THOMPSON M P, AHMED S T, et al. One-pot synthesis of chiral N-arylamines by combining biocatalytic aminations with Buchwald-Hartwig N-arylation[J]. Angewandte Chemie International Edition, 2020, 59(41):18156-18160.
86	MARSHALL J R, YAO P Y, MONTGOMERY S L, et al. Screening and characterization of a diverse panel of metagenomic imine reductases for biocatalytic reductive amination[J]. Nature Chemistry, 2021, 13(2): 140-148.
87	HOPMANN K H, BAYER A. Enantioselective imine hydrogenation with iridium-catalysts: reactions, mechanisms and stereocontrol[J]. Coordination Chemistry Reviews, 2014, 268:59-82.
88	TANG W J, ZHANG X M. New chiral phosphorus ligands for enantioselective hydrogenation[J]. Chemical Reviews, 2003, 103(8): 3029-3070.
89	RIANT O, MOSTEFAÏ N, COURMARCEL J. Recent advances in the asymmetric hydrosilylation of ketones, imines and electrophilic double bonds[J]. Synthesis, 2004(18): 2943-2958.
90	VILAIVAN T, BHANTHUMNAVIN W, SRITANA-ANANT Y. Recent advances in catalytic asymmetric addition to imines and related C=N systems[J]. Current Organic Chemistry, 2005, 9(14):1315-1392.
91	MUSACCHIO A J, LAINHART B C, ZHANG X, et al. Catalytic intermolecular hydroaminations of unactivated olefins with secondary alkyl amines[J]. Science, 2017, 355(6326):727-730.

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