铜催化不对称自由基碳−氮交叉偶联研究

  α-手性胺化合物是一类重要的物质，广泛存在于天然产物和药物中，因此实现其不对称催化高效合成，是具有重要的研究意义。在众多合成策略中，铜催化的不对称自由基交叉偶联策略，因其直接高效的优势，引起了广泛的关注。这一合成策略具有以下优势：首先，催化剂铜易得且毒性较低；其次，有机胺和外消旋烷基卤代烃来源丰富；然后，该策略的底物适用范围广泛。然而这一策略仍面临一些挑战：首先，铜的还原能力较弱，从而导致反应启动困难；其次，胺容易与烷基卤代烃发生非立体选择性的背景反应；然后，胺对铜催化剂毒化作用；此外，对于酸性较弱和位阻较大的胺，转金属化难以发生，使得经典的交叉偶联催化循环很难适用等。针对这些挑战，本研究利用一类“铜/手性阴离子配体”催化体系，系统研究了几类具有挑战性的胺，如脂肪胺和大位阻芳香胺等，实现不对称碳−氮交叉偶联反应，以及将该方法应用于能源与环保领域，使得化学合成更加绿色环保，支持国家“碳达峰”和“碳中和”目标。主要内容如下：

  以强亲核性和配位能力的脂肪胺作为亲核试剂，发展了一类新型铜/手性N,N,N-三齿阴离子配体催化体系，实现脂肪胺参与的不对称交叉偶联的研究目标。通过增强铜与配体的螯合能力，抑制了脂肪胺对铜的毒化作用，同时还提高了铜的还原能力，从而启动反应，促进了反应的高效进行。在该催化体系下，在温和的条件下，能够高立体选择性地构建α-手性脂肪胺。该方法适用于广泛的脂肪胺，如链状脂肪胺和环状脂肪胺等。此外，通过初步的机理探究，验证了在核心碳-氮键构建步骤中，可能经历了球外亲核进攻机制，而非经典的金属催化中形成的铜-亲核试剂复合物机理。

  以弱亲核性和大位阻的芳香胺作为亲核试剂，实现不对称交叉偶联为主要研究目标，利用一类新型的球外亲核进攻机制，实现了芳香胺参与的不对称自由基碳-氮交叉偶联反应。由于球外亲核进攻反应机制的独特优势，亲核试剂不需要经过转金属，即可发生反应。而在传统金属催化循环中，需要形成铜-亲核试剂复合物，但对于大位阻芳香胺则不适用。利用α-卤代酰胺作为亲电试剂，在温和的条件下，能够高效构建α-手性芳香胺，具有高立体选择性。该方法具有广泛的底物普适性，包括一级和二级芳香胺。同时对该方法的实用性进行了考察，发现反应产物可以经过简单的转化，得到手性1,2-二胺等手性骨架。

  以炔丙基卤代烃作为亲电试剂，实现芳香胺的不对称交叉偶联为主要研究目标。尽管球外亲核进攻机制已经成功实现了胺与α-卤代酰胺的偶联，但卤代烷烃的底物范围仍然有限，目前仅适用于α-卤代酰胺这类带有导向基团的底物。为了快速合成多样结构的手性胺类化合物，发展了炔丙基溴代烃与芳香胺的不对称交叉偶联反应。此方法能够以较高的产率及立体选择性，合成多种高附加值手性炔丙胺化合物。该研究突破了仅将亲电试剂限于α-卤代酰胺的局限，实现了底物范围的扩展。

  在上述发展的不对称自由基碳-氮交叉偶联方法的基础上，探讨了该方法在能源与环境相关领域的应用潜力，使得合成更加绿色环保，支持我国在有机合成方面应对气候变化问题的“双碳”策略。该方法能够将产量大的工业原料胺，高效转换成经济价值高的手性胺，为手性精细化学品合成提供了高效合成工具。此外，还为药物提供了不对称烷基化修饰的新途径，构建了药物活性分子库，有助于进一步的活性药物筛选工作。通过该简单高效合成，有效地简化了药物的合成步骤，如沙芬酰胺。手性配体在规模化合成的可行性得到了验证，表明该催化体系在工业应用中具有潜在的前景。

  总之，本博士学位论文实现了一类不对称自由基碳-氮交叉偶联反应，通过α-卤代酰胺和炔丙基卤代烃作为亲电试剂，多样的烷基胺和芳香胺作为亲核试剂，可以实现高附加值的α-手性胺的合成。并且通过本论文佐证该有机合成技术在能源与环境相关领域中有一定的潜在应用的价值。

[1] ABBASS K, QASIM M Z, SONG H, et al. A Review of the Global Climate Change Impacts, Adaptation, and Sustainable Mitigation Measures [J]. Environmental Science and Pollution Research, 2022, 29(28): 42539-42559.
[2] HARPER S L, CUNSOLO A, BABUJEE A, et al. Climate Change and Health in North America: Literature Review Protocol [J]. Systematic Reviews, 2021, 10(1): 3-15.
[3] WEI Y-M, CHEN K, KANG J-N, et al. Policy and Management of Carbon Peaking and Carbon Neutrality: A Literature Review [J]. Engineering, 2022, 14(7): 52-63.
[4] KEMPASIDDAIAH M, SREE RAJ K A, KANDATHIL V, et al. Waste Biomass-Derived Carbon-Supported Palladium-Based Catalyst for Cross-Coupling Reactions and Energy Storage Applications [J]. Applied Surface Science, 2021, 570(1): 151156-151169.
[5] EGOROVA K S, KOLESNIKOV A E, POSVYATENKO A V, et al. Establishing the Main Determinants of the Environmental Safety of Catalytic Fine Chemical Synthesis with Catalytic Cross-Coupling Reactions [J]. Green Chemistry, 2024, 26(5): 2825-2841.
[6] NAGIB D A. Asymmetric Catalysis in Radical Chemistry [J]. Chemical Reviews, 2022, 122(21): 15989-15992.
[7] XIANG S H, TAN B. Advances in Asymmetric Organocatalysis over the Last 10 Years [J]. Nature Communications, 2020, 11(1): 3786-3790.
[8] SCHETTINI R, DELLA SALA G. New Trends in Asymmetric Catalysis [J]. Catalysts, 2021, 11(3): 306-308.
[9] JOHANSSON SEECHURN C C, KITCHING M O, COLACOT T J, et al. Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the 2010 Nobel Prize [J]. Angewandte Chemie International Edition, 2012, 51(21): 5062-5085.
[10] BIFFIS A, CENTOMO P, DEL ZOTTO A, et al. Pd Metal Catalysts for Cross-Couplings and Related Reactions in the 21st Century: A Critical Review [J]. Chemical Reviews, 2018, 118(4): 2249-2295.
[11] ARMIN DE MEIJERE S B, MARTIN OESTREICH. Metal Catalyzed Cross-Coupling Reactions and More [M]. Weinheim: Wiley‐VCH, 2014.
[12] CHOI J, FU G C. Transition Metal-Catalyzed Alkyl-Alkyl Bond Formation: Another Dimension in Cross-Coupling Chemistry [J]. Science, 2017, 356(6334): eaaf7230.
[13] FU G C. Transition-Metal Catalysis of Nucleophilic Substitution Reactions: A Radical Alternative to SN1 and SN2 Processes [J]. ACS Central Science, 2017, 3(7): 692-700.
[14] DONG X Y, LI Z L, GU Q S, et al. Ligand Development for Copper-Catalyzed Enantioconvergent Radical Cross-Coupling of Racemic Alkyl Halides [J]. Journal of the American Chemical Society, 2022, 144(38): 17319-17329.
[15] CHERNEY A H, KADUNCE N T, REISMAN S E. Enantioselective and Enantiospecific Transition-Metal-Catalyzed Cross-Coupling Reactions of Organometallic Reagents to Construct C-C Bonds [J]. Chemical Reviews, 2015, 115(17): 9587-9652.
[16] ZHOU H, LI Z-L, GU Q-S, et al. Ligand-Enabled Copper(I)-Catalyzed Asymmetric Radical C(sp3)–C Cross-Coupling Reactions [J]. ACS Catalysis, 2021, 11(13): 7978-7986.
[17] LI B, LI T, ALIYU M A, et al. Enantioselective Palladium-Catalyzed Cross-Coupling of Alpha-Bromo Carboxamides and Aryl Boronic Acids [J]. Angewandte Chemie International Edition, 2019, 58(33): 11355-11359.
[18] 徐明华. 铜催化的不对称 Sonogashira 碳(sp3)–碳(sp)偶联反应 [J]. 科学通报, 2019, 64(36): 3776-3778.
[19] 程磊, 周其林. 镍催化构筑 C(sp3)— C(sp3)键反应研究进展 [J]. 化学学报, 2020, 78(10): 1017-1029.
[20] 董晓阳. 铜催化末端炔烃的自由基不对称反应研究[D]. 哈尔滨: 哈尔滨工业大学, 2021.
[21] HUANG C, WAN Z, ZHU A, et al. Copper Catalyzed Enantioconvergent Nucleophilic Substitutions [J]. Chinese Journal of Chemistry, 2024, 42: 1161-1174.
[22] 王璐锦, 阴国印. 光镍双催化实现 C(sp)—C(sp3)对映收敛还原交叉偶联反应 [J]. 有机化学, 2023, 43(6): 2264-2266.
[23] TASKER S Z, STANDLEY E A, JAMISON T F. Recent Advances in Homogeneous Nickel Catalysis [J]. Nature, 2014, 509(7500): 299-309.
[24] QUASDORF K W, OVERMAN L E. Catalytic Enantioselective Synthesis of Quaternary Carbon Stereocentres [J]. Nature, 2014, 516(7530): 181-191.
[25] LIU Y, HAN S J, LIU W B, et al. Catalytic Enantioselective Construction of Quaternary Stereocenters: Assembly of Key Building Blocks for the Synthesis of Biologically Active Molecules [J]. Accounts of Chemical Research, 2015, 48(3): 740-751.
[26] ZENG X P, CAO Z Y, WANG Y H, et al. Catalytic Enantioselective Desymmetrization Reactions to All-Carbon Quaternary Stereocenters [J]. Chemical Reviews, 2016, 116(12): 7330-7396.
[27] EGOROVA K S, ANANIKOV V P. Which Metals Are Green for Catalysis? Comparison of the Toxicities of Ni, Cu, Fe, Pd, Pt, Rh, and Au Salts [J]. Angewandte Chemie International Edition, 2016, 55(40): 12150-12162.
[28] TRAMMELL R, RAJABIMOGHADAM K, GARCIA-BOSCH I. Copper-Promoted Functionalization of Organic Molecules: From Biologically Relevant Cu/O2 Model Systems to Organometallic Transformations [J]. Chemical Reviews, 2019, 119(4): 2954-3031.
[29] 邓维, 刘磊, 郭庆祥. 铜催化交叉偶联反应研究的新进展 [J]. 有机化学, 2004, 24(2): 150-165.
[30] ZHANG Q, TONG S, WANG M X. Unraveling the Chemistry of High Valent Arylcopper Compounds and Their Roles in Copper-Catalyzed Arene C-H Bond Transformations Using Synthetic Macrocycles [J]. Accounts of Chemical Research, 2022, 55(19): 2796-2810.
[31] XIAO H, ZHANG Z, FANG Y, et al. Radical Trifluoromethylation [J]. Chemical Society Reviews, 2021, 50(11): 6308-6319.
[32] LU F D, CHEN J, JIANG X, et al. Recent Advances in Transition-Metal-Catalysed Asymmetric Coupling Reactions with Light Intervention [J]. Chemical Society Reviews, 2021, 50(22): 12808-12827.
[33] XIONG T, ZHANG Q. Recent Advances in the Direct Construction of Enantioenriched Stereocenters through Addition of Radicals to Internal Alkenes [J]. Chemical Society Reviews, 2021, 50(16): 8857-8873.
[34] WANG F, CHEN P, LIU G. Copper-Catalyzed Radical Relay for Asymmetric Radical Transformations [J]. Accounts of Chemical Research, 2018, 51(9): 2036-2046.
[35] ZHANG C, LI Z L, GU Q S, et al. Catalytic Enantioselective C(sp3)-H Functionalization Involving Radical Intermediates [J]. Nature Communications, 2021, 12(1): 475.
[36] CHEN C, PETERS J C, FU G C. Photoinduced Copper-Catalysed Asymmetric Amidation Via Ligand Cooperativity [J]. Nature, 2021, 596(7871): 250-256.
[37] DONG X Y, ZHANG Y F, MA C L, et al. A General Asymmetric Copper-Catalysed Sonogashira C(sp3)-C(sp) Coupling [J]. Nature Chemistry, 2019, 11(12): 1158-1166.
[38] 李桂根. 手性的控制：不对称有机催化——2021年诺贝尔化学奖成果简析 [J]. 科技导报, 2021, 39(22): 121-130.
[39] TROWBRIDGE A, WALTON S M, GAUNT M J. New Strategies for the Transition-Metal Catalyzed Synthesis of Aliphatic Amines [J]. Chemical Reviews, 2020, 120(5): 2613-2692.
[40] KERRU N, GUMMIDI L, MADDILA S, et al. A Review on Recent Advances in Nitrogen-Containing Molecules and Their Biological Applications [J]. Molecules, 2020, 25(8): 1909-1950.
[41] ALFREDO RICCI L B. Methodologies in Amine Synthesis: Challenges and Applications [M]. Boschstr: WILEY‐VCH, 2021.
[42] Ma D, Yao J. Synthesis of Chiral N-Aryl-α-Amino Acids by Pd-Cu Catalyzed Couplings of Chiral Α-Amino Acids with Aryl Halides [J]. Tetrahedron: Asymmetry, 1996, 7(11): 3075-3078.
[43] 王晔峰, 曾京辉, 崔晓瑞. 铜催化 C-N 交叉偶联反应的研究进展 [J]. 有机化学, 2010, 30(2): 181-199.
[44] UYEDA C, TAN Y, FU G C, et al. A New Family of Nucleophiles for Photoinduced, Copper-Catalyzed Cross-Couplings Via Single-Electron Transfer: Reactions of Thiols with Aryl Halides under Mild Conditions (O °C) [J]. Journal of the American Chemical Society, 2013, 135(25): 9548-9552.
[45] ZIEGLER D T, CHOI J, MUNOZ-MOLINA J M, et al. A Versatile Approach to Ullmann C-N Couplings at Room Temperature: New Families of Nucleophiles and Electrophiles for Photoinduced, Copper-Catalyzed Processes [J]. Journal of the American Chemical Society, 2013, 135(35): 13107-13112.
[46] TAN Y, MUñOZ-MOLINA J M, FU G C, et al. Oxygen Nucleophiles as Reaction Partners in Photoinduced, Copper-Catalyzed Cross-Couplings: O-Arylations of Phenols at Room Temperature [J]. Chemical Science, 2014, 5(7): 2831-2835.
[47] BISSEMBER A C, LUNDGREN R J, CREUTZ S E, et al. Transition-Metal-Catalyzed Alkylations of Amines with Alkyl Halides: Photoinduced, Copper-Catalyzed Couplings of Carbazoles [J]. Angewandte Chemie International Edition, 2013, 52(19): 5129-5133.
[48] DO H Q, BACHMAN S, BISSEMBER A C, et al. Photoinduced, Copper-Catalyzed Alkylation of Amides with Unactivated Secondary Alkyl Halides at Room Temperature [J]. Journal of the American Chemical Society, 2014, 136(5): 2162-2167.
[49] RATANI T S, BACHMAN S, FU G C, et al. Photoinduced, Copper-Catalyzed Carbon-Carbon Bond Formation with Alkyl Electrophiles: Cyanation of Unactivated Secondary Alkyl Chlorides at Room Temperature [J]. Journal of the American Chemical Society, 2015, 137(43): 13902-13907.
[50] AHN J M, PETERS J C, FU G C. Design of a Photoredox Catalyst That Enables the Direct Synthesis of Carbamate-Protected Primary Amines Via Photoinduced, Copper-Catalyzed N-Alkylation Reactions of Unactivated Secondary Halides [J]. Journal of the American Chemical Society, 2017, 139(49): 18101-18106.
[51] HE J, CHEN C, FU G C, et al. Visible-Light-Induced, Copper-Catalyzed Three-Component Coupling of Alkyl Halides, Olefins, and Trifluoromethylthiolate to Generate Trifluoromethyl Thioethers [J]. ACS Catalysis, 2018, 8(12): 11741-11748.
[52] BEAUDELOT J, OGER S, PERUSKO S, et al. Photoactive Copper Complexes: Properties and Applications [J]. Chemical Reviews, 2022, 122(22): 16365-16609.
[53] SONG L, CAI L, GONG L, et al. Photoinduced Copper-Catalyzed Enantioselective Coupling Reactions [J]. Chemical Society Reviews, 2023, 52(7): 2358-2376.
[54] 郭晓宁, 吴骊珠. 中国自由基驱动有机合成领域的发展现状和未来挑战 [J]. 科学观察, 2023, 18(1): 2-6.
[55] WANG D, ZHU N, CHEN P, et al. Enantioselective Decarboxylative Cyanation Employing Cooperative Photoredox Catalysis and Copper Catalysis [J]. Journal of the American Chemical Society, 2017, 139(44): 15632-15635.
[56] CHEN H W, LU F D, CHENG Y, et al. Asymmetric Deoxygenative Cyanation of Benzyl Alcohols Enabled by Synergistic Photoredox and Copper Catalysis [J]. Chinese Journal of Chemistry, 2020, 38(12): 1671-1675.
[57] XIA H D, LI Z L, GU Q S, et al. Photoinduced Copper-Catalyzed Asymmetric Decarboxylative Alkynylation with Terminal Alkynes [J]. Angewandte Chemie International Edition, 2020, 59(39): 16926-16932.
[58] MO X, CHEN B, ZHANG G. Copper-Catalyzed Enantioselective Sonogashira Type Coupling of Alkynes with Alpha-Bromoamides [J]. Angewandte Chemie International Edition, 2020, 59(33): 13998-14002.
[59] GUO R, SANG J, XIAO H, et al. Development of Novel Phosphino‐Oxazoline Ligands and Their Application in Asymmetric Alkynlylation of Benzylic Halides [J]. Chinese Journal of Chemistry, 2022, 40(11): 1337-1345.
[60] LI J, NING L, TAN Q, et al. Asymmetric Sonogashira C(sp3)–C(sp) Bond Coupling Enabled by a Copper(I) Complex of a New Guanidine-Hybrid Ligand [J]. Organic Chemistry Frontiers, 2022, 9(22): 6312-6318.
[61] WANG F L, YANG C J, LIU J R, et al. Mechanism-Based Ligand Design for Copper-Catalysed Enantioconvergent C(sp3)-C(sp) Cross-Coupling of Tertiary Electrophiles with Alkynes [J]. Nature Chemistry, 2022, 14(8): 949-957.
[62] MO X, HUANG H, ZHANG G. Tetrasubstituted Carbon Stereocenters Via Copper-Catalyzed Asymmetric Sonogashira Coupling Reactions with Cyclic Gem-Dihaloketones and Tertiary Α-Carbonyl Bromides [J]. ACS Catalysis, 2022, 12(16): 9944-9952.
[63] JIANG S P, DONG X Y, GU Q S, et al. Copper-Catalyzed Enantioconvergent Radical Suzuki-Miyaura C(sp3)-C(sp2) Cross-Coupling [J]. Journal of the American Chemical Society, 2020, 142(46): 19652-19659.
[64] SU X L, YE L, CHEN J J, et al. Copper-Catalyzed Enantioconvergent Cross-Coupling of Racemic Alkyl Bromides with Azole C(sp2)-H Bonds [J]. Angewandte Chemie International Edition, 2021, 60(1): 380-384.
[65] LI C, CHEN B, MA X, et al. Light-Promoted Copper-Catalyzed Enantioselective Alkylation of Azoles [J]. Angewandte Chemie International Edition, 2021, 60(4): 2130-2134.
[66] WANG P F, YU J, GUO K X, et al. Design of Hemilabile N,N,N-Ligands in Copper-Catalyzed Enantioconvergent Radical Cross-Coupling of Benzyl/Propargyl Halides with Alkenylboronate Esters [J]. Journal of the American Chemical Society, 2022, 144(14): 6442-6452.
[67] WANG F L, LIU L, YANG C J, et al. Synthesis of Alpha-Quaternary Beta-Lactams Via Copper-Catalyzed Enantioconvergent Radical C(sp3)-C(sp2) Cross-Coupling with Organoboronate Esters [J]. Angewandte Chemie International Edition, 2023, 62(2): e202214709.
[68] LIPP A, BADIR S O, MOLANDER G A. Stereoinduction in Metallaphotoredox Catalysis [J]. Angewandte Chemie International Edition, 2021, 60(4): 1714-1726.
[69] MAO J, LIU F, WANG M, et al. Cobalt-Bisoxazoline-Catalyzed Asymmetric Kumada Cross-Coupling of Racemic Alpha-Bromo Esters with Aryl Grignard Reagents [J]. Journal of the American Chemical Society, 2014, 136(50): 17662-17668.
[70] JIN M, ADAK L, NAKAMURA M. Iron-Catalyzed Enantioselective Cross-Coupling Reactions of Alpha-Chloroesters with Aryl Grignard Reagents [J]. Journal of the American Chemical Society, 2015, 137(22): 7128-7134.
[71] WANG Z, YIN H, FU G C. Catalytic Enantioconvergent Coupling of Secondary and Tertiary Electrophiles with Olefins [J]. Nature, 2018, 563(7731): 379-383.
[72] WANG Z, YANG Z P, FU G C. Quaternary Stereocentres Via Catalytic Enantioconvergent Nucleophilic Substitution Reactions of Tertiary Alkyl Halides [J]. Nature Chemistry, 2021, 13(3): 236-242.
[73] KAINZ Q M, MATIER C D, BARTOSZEWICZ A, et al. Asymmetric Copper-Catalyzed C-N Cross-Couplings Induced by Visible Light [J]. Science, 2016, 351(6274): 681-684.
[74] BARTOSZEWICZ A, MATIER C D, FU G C. Enantioconvergent Alkylations of Amines by Alkyl Electrophiles: Copper-Catalyzed Nucleophilic Substitutions of Racemic Alpha-Halolactams by Indoles [J]. Journal of the American Chemical Society, 2019, 141(37): 14864-14869.
[75] CHO H, SUEMATSU H, OYALA P H, et al. Photoinduced, Copper-Catalyzed Enantioconvergent Alkylations of Anilines by Racemic Tertiary Electrophiles: Synthesis and Mechanism [J]. Journal of the American Chemical Society, 2022, 144(10): 4550-4558.
[76] ZHANG Y F, DONG X Y, CHENG J T, et al. Enantioconvergent Cu-Catalyzed Radical C-N Coupling of Racemic Secondary Alkyl Halides to Access Alpha-Chiral Primary Amines [J]. Journal of the American Chemical Society, 2021, 143(37): 15413-15419.
[77] ZHANG Y F, WANG J H, YANG N Y, et al. Copper-Catalyzed Enantioconvergent Radical C(sp3)-N Cross-Coupling: Access to α, α-Disubstituted Amino Acids [J]. Angewandte Chemie International Edition, 2023, 62(27): e202302983.
[78] ZUCCARELLO G, BATISTE S M, CHO H, et al. Enantioselective Synthesis of Alpha-Aminoboronic Acid Derivatives Via Copper-Catalyzed N-Alkylation [J]. Journal of the American Chemical Society, 2023, 145(6): 3330-3334.
[79] CHEN C, FU G C. Copper-Catalysed Enantioconvergent Alkylation of Oxygen Nucleophiles [J]. Nature, 2023, 618(7964): 301-307.
[80] TIAN Y, LI X T, LIU J R, et al. A General Copper-Catalysed Enantioconvergent C(sp3)-S Cross-Coupling Via Biomimetic Radical Homolytic Substitution [J]. Nature Chemistry, 2024, 16(3): 466-475.
[81] ZHANG W, TIAN Y, LIU X D, et al. Copper‐Catalyzed Enantioselective C(sp3)−SCF3 Coupling of Carbon‐Centered Benzyl Radicals with (Me4N)SCF3 [J]. Angewandte Chemie International Edition, 2024, 63(11): e2023198.
[82] IWAMOTO H, ENDO K, OZAWA Y, et al. Copper(I)-Catalyzed Enantioconvergent Borylation of Racemic Benzyl Chlorides Enabled by Quadrant-by-Quadrant Structure Modification of Chiral Bisphosphine Ligands [J]. Angewandte Chemie International Edition, 2019, 58(32): 11112-11117.
[83] WANG L-L, ZHOU H, CAO Y-X, et al. A General Copper-Catalysed Enantioconvergent Radical Michaelis–Becker-Type C(sp3)–P Cross-Coupling [J]. Nature Synthesis, 2023, 2(5): 430-438.
[84] KWAN M H T, POKAR N P B, GOOD C, et al. Deactivation Mechanisms of Iodo-Iridium Catalysts in Chiral Amine Racemization [J]. Tetrahedron, 2021, 80: 131823-131827.
[85] CABRE A, VERDAGUER X, RIERA A. Recent Advances in the Enantioselective Synthesis of Chiral Amines Via Transition Metal-Catalyzed Asymmetric Hydrogenation [J]. Chemical Reviews, 2022, 122(1): 269-339.
[86] KOBAYASHI S, MORI Y, FOSSEY J S, et al. Catalytic Enantioselective Formation of C-C Bonds by Addition to Imines and Hydrazones: A Ten-Year Update [J]. Chemical Reviews, 2011, 111(4): 2626-2704.
[87] SHI S L, WONG Z L, BUCHWALD S L. Copper-Catalysed Enantioselective Stereodivergent Synthesis of Amino Alcohols [J]. Nature, 2016, 532(7599): 353-356.
[88] XI Y, MA S, HARTWIG J F. Catalytic Asymmetric Addition of an Amine N-H Bond across Internal Alkenes [J]. Nature, 2020, 588(7837): 254-260.
[89] DAVIES H M, MANNING J R. Catalytic C-H Functionalization by Metal Carbenoid and Nitrenoid Insertion [J]. Nature, 2008, 451(7177): 417-424.
[90] LI M L, YU J H, LI Y H, et al. Highly Enantioselective Carbene Insertion into N-H Bonds of Aliphatic Amines [J]. Science, 2019, 366(6468): 990-994.
[91] ROSSLER S L, PETRONE D A, CARREIRA E M. Iridium-Catalyzed Asymmetric Synthesis of Functionally Rich Molecules Enabled by (Phosphoramidite,Olefin) Ligands [J]. Accounts of Chemical Research, 2019, 52(9): 2657-2672.
[92] LAUDER K, TOSCANI A, SCALACCI N, et al. Synthesis and Reactivity of Propargylamines in Organic Chemistry [J]. Chemical Reviews, 2017, 117(24): 14091-14200.
[93] WANG Y, HAIGHT I, GUPTA R, et al. What Is in Our Kit? An Analysis of Building Blocks Used in Medicinal Chemistry Parallel Libraries [J]. Journal of Medicinal Chemistry, 2021, 64(23): 17115-17122.
[94] THORPE T W, MARSHALL J R, HARAWA V, et al. Multifunctional Biocatalyst for Conjugate Reduction and Reductive Amination [J]. Nature, 2022, 604(7904): 86-91.
[95] BROWN D G, BOSTROM J. Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone? [J]. Journal of Medicinal Chemistry, 2016, 59(10): 4443-4458.
[96] KIM H, HEO J, KIM J, et al. Copper-Mediated Amination of Aryl C-H Bonds with the Direct Use of Aqueous Ammonia Via a Disproportionation Pathway [J]. Journal of the American Chemical Society, 2018, 140(43): 14350-14356.
[97] LEE H, AHN J M, OYALA P H, et al. Investigation of the C-N Bond-Forming Step in a Photoinduced, Copper-Catalyzed Enantioconvergent N-Alkylation: Characterization and Application of a Stabilized Organic Radical as a Mechanistic Probe [J]. Journal of the American Chemical Society, 2022, 144(9): 4114-4123.
[98] FISCHER C, FU G C. Asymmetric Nickel-Catalyzed Negishi Cross-Couplings of Secondary Alpha-Bromo Amides with Organozinc Reagents [J]. Journal of the American Chemical Society, 2005, 127(13): 4594-4595.
[99] HUANG W, WAN X, SHEN Q. Enantioselective Construction of Trifluoromethoxylated Stereogenic Centers by a Nickel-Catalyzed Asymmetric Suzuki-Miyaura Coupling of Secondary Benzyl Bromides [J]. Angewandte Chemie International Edition, 2017, 56(39): 11986-11989.
[100] MU X, SHIBATA Y, MAKIDA Y, et al. Control of Vicinal Stereocenters through Nickel-Catalyzed Alkyl-Alkyl Cross-Coupling [J]. Angewandte Chemie International Edition, 2017, 56(21): 5821-5824.
[101] HARTWIG J F, STANLEY L M. Mechanistically Driven Development of Iridium Catalysts for Asymmetric Allylic Substitution [J]. Accounts of Chemical Research, 2010, 43(12): 1461-1475.
[102] TROST B, SCHULTZ J. Palladium-Catalyzed Asymmetric Allylic Alkylation Strategies for the Synthesis of Acyclic Tetrasubstituted Stereocenters [J]. Synthesis, 2018, 51(01): 1-30.
[103] CHENG Q, TU H F, ZHENG C, et al. Iridium-Catalyzed Asymmetric Allylic Substitution Reactions [J]. Chemical Reviews, 2019, 119(3): 1855-1969.
[104] CHEN J J, FANG J H, DU X Y, et al. Enantioconvergent Cu-Catalysed N-Alkylation of Aliphatic Amines [J]. Nature, 2023, 618(7964): 294-300.
[105] YE C-X, DANSBY D R, CHEN S, et al. Expedited Synthesis of Α-Amino Acids by Single-Step Enantioselective Α-Amination of Carboxylic Acids [J]. Nature Synthesis, 2023, 2(7): 645-652.
[106] LANG K, HU Y, CINDY LEE W C, et al. Combined Radical and Ionic Approach for the Enantioselective Synthesis of Beta-Functionalized Amines from Alcohols [J]. Nature Synthesis, 2022, 1(7): 548-557.
[107] XU P, XIE J, WANG D S, et al. Metalloradical Approach for Concurrent Control in Intermolecular Radical Allylic C-H Amination [J]. Nature Chemistry, 2023, 15(4): 498-507.
[108] DING C H, HOU X L. Catalytic Asymmetric Propargylation [J]. Chemical Reviews, 2011, 111(3): 1914-1937.
[109] EVANS P, GRANGE R, CLIZBE E. Recent Developments in Asymmetric Allylic Amination Reactions [J]. Synthesis, 2016, 48(18): 2911-2968.
[110] ROY R, SAHA S. Scope and Advances in the Catalytic Propargylic Substitution Reaction [J]. RSC Advances, 2018, 8(54): 31129-31193.
[111] ABDINE R A A, HEDOUIN G, COLOBERT F, et al. Metal-Catalyzed Asymmetric Hydrogenation of C═N Bonds [J]. ACS Catalysis, 2020, 11(1): 215-247.
[112] ZHANG X, TAN C-H. Stereospecific and Stereoconvergent Nucleophilic Substitution Reactions at Tertiary Carbon Centers [J]. Chem, 2021, 7(6): 1451-1486.
[113] JIN L M, XU P, XIE J, et al. Enantioselective Intermolecular Radical C-H Amination [J]. Journal of the American Chemical Society, 2020, 142(49): 20828-20836.
[114] LIU Y, DIAO H, HONG G, et al. Iridium-Catalyzed Enantioconvergent Borrowing Hydrogen Annulation of Racemic 1,4-Diols with Amines [J]. Journal of the American Chemical Society, 2023, 145(9): 5007-5016.
[115] LIU B, ZHU S F, ZHANG W, et al. Highly Enantioselective Insertion of Carbenoids into N-H Bonds Catalyzed by Copper Complexes of Chiral Spiro Bisoxazolines [J]. Journal of the American Chemical Society, 2007, 129(18): 5834-5835.
[116] GUO W, LUO Y, SUNG H H, et al. Chiral Phosphoric Acid Catalyzed Enantioselective Synthesis of Alpha-Tertiary Amino Ketones from Sulfonium Ylides [J]. Journal of the American Chemical Society, 2020, 142(33): 14384-14390.
[117] CHEN J J, ZHANG J Y, FANG J H, et al. Copper-Catalyzed Enantioconvergent Radical C(sp3)-N Cross-Coupling of Activated Racemic Alkyl Halides with (Hetero)Aromatic Amines under Ambient Conditions [J]. Journal of the American Chemical Society, 2023, 145(27): 14686-14696.
[118] CHOI S, CHOI Y, KIM Y, et al. Copper-Catalyzed C-C Cross-Couplings of Tertiary Alkyl Halides with Anilines Enabled by Cyclopropenimine-Based Ligands [J]. Journal of the American Chemical Society, 2023, 145(45): 24897-24905.
[119] CHAN J Z, YESILCIMEN A, CAO M, et al. Direct Conversion of N-Alkylamines to N-Propargylamines through C-H Activation Promoted by Lewis Acid/Organocopper Catalysis: Application to Late-Stage Functionalization of Bioactive Molecules [J]. Journal of the American Chemical Society, 2020, 142(38): 16493-16505.
[120] BOURBEAU M P, ASHTON K S, YAN J, et al. Nonracemic Synthesis of Gk-Gkrp Disruptor Amg-3969 [J]. The Journal of Organic Chemistry, 2014, 79(8): 3684-3687.
[121] MORGAN D M, REID C M, GUIRY P J. Enantioselective Copper-Catalyzed Alkynylation of Quinolones Using Chiral P,N Ligands [J]. The Journal of Organic Chemistry, 2024, 89(3): 1993-2000.
[122] LANGSTON J W, IRWIN I, LANGSTON E B, et al. Pargyline Prevents Mptp-Induced Parkinsonism in Primates [J]. Science, 1984, 225(4669): 1480-1482.
[123] CHEN J J, SWOPE D M. Clinical Pharmacology of Rasagiline: A Novel, Second-Generation Propargylamine for the Treatment of Parkinson Disease [J]. The Journal of Clinical Pharmacology, 2005, 45(8): 878-894.
[124] BOLEA I, GELLA A, UNZETA M. Propargylamine-Derived Multitarget-Directed Ligands: Fighting Alzheimer's Disease with Monoamine Oxidase Inhibitors [J]. Journal of Neural Transmission, 2013, 120(6): 893-902.
[125] ARSHADI S, VESSALLY E, EDJLALI L, et al. N-Propargylamines: Versatile Building Blocks in the Construction of Thiazole Cores [J]. The Beilstein Journal of Organic Chemistry, 2017, 13: 625-638.
[126] CARDOSO F S, ABBOUD K A, APONICK A. Design, Preparation, and Implementation of an Imidazole-Based Chiral Biaryl P,N-Ligand for Asymmetric Catalysis [J]. Journal of the American Chemical Society, 2013, 135(39): 14548-14551.
[127] DETZ R J, DELVILLE M M, HIEMSTRA H, et al. Enantioselective Copper-Catalyzed Propargylic Amination [J]. Angewandte Chemie International Edition, 2008, 47(20): 3777-3780.
[128] LIU L, GUO K X, TIAN Y, et al. Copper-Catalyzed Intermolecular Enantioselective Radical Oxidative C(sp3)-H/C(sp)-H Cross-Coupling with Rationally Designed Oxazoline-Derived N,N,P(O)-Ligands [J]. Angewandte Chemie International Edition, 2021, 60(51): 26710-26717.
[129] ZHANG H, CHEN B, ZHANG G. Enantioselective 1,2-Alkylhydroxylmethylation of Alkynes Via Chromium/Cobalt Cocatalysis [J]. Organic Letters, 2020, 22(2): 656-660.
[130] HU B, BEZPALKO M W, FEI C, et al. Origin of and a Solution for Uneven Efficiency by Cinchona Alkaloid-Derived, Pseudoenantiomeric Catalysts for Asymmetric Reactions [J]. Journal of the American Chemical Society, 2018, 140(42): 13913-13920.
[131] WANG Y, YANG L, LIU S, et al. Surgical Cleavage of Unstrained C(sp3)−C(sp3) Bonds in General Alcohols for Heteroaryl C−H Alkylation and Acylation [J]. Advanced Synthesis & Catalysis, 2019, 361(19): 4568-4574.
[132] SARKAR S M, TAIRA Y, NAKANO A, et al. Organocatalytic Asymmetric Synthesis of Quinine and Quinidine [J]. Tetrahedron Letters, 2011, 52(8): 923-927.
[133] LINE N J, WITHERSPOON B P, HANCOCK E N, et al. Synthesis of Ent-
[3]-Ladderanol: Development and Application of Intramolecular Chirality Transfer
[2+2] Cycloadditions of Allenic Ketones and Alkenes [J]. Journal of the American Chemical Society, 2017, 139(41): 14392-14395.
[134] XU Q, XIE H, ZHANG E-L, et al. Selective Catalytic Hofmann N-Alkylation of Poor Nucleophilic Amines and Amides with Catalytic Amounts of Alkyl Halides [J]. Green Chemistry, 2016, 18(14): 3940-3944.
[135] BHATTACHARYYA S, PATHAK U, MATHUR S, et al. Selective N-Alkylation of Primary Amines with R–NH2·HBr and Alkyl Bromides Using a Competitive Deprotonation/Protonation Strategy [J]. RSC Advances, 2014, 4(35): 18229-18233.
[136] LUCAS E L, JARVO E R. Stereospecific and Stereoconvergent Cross-Couplings between Alkyl Electrophiles [J]. Nature Reviews Chemistry, 2017, 1(9): 65-71.
[137] BROOKS W H, GUIDA W C, DANIEL K G. The Significance of Chirality in Drug Design and Development [J]. Current Topics in Medicinal Chemistry, 2011, 11(7): 760-770.
[138] ZHOU Y, WU S, ZHOU H, et al. Chiral Pharmaceuticals: Environment Sources, Potential Human Health Impacts, Remediation Technologies and Future Perspective [J]. Environment International, 2018, 121(1): 523-537.
[139] CERAMELLA J, IACOPETTA D, FRANCHINI A, et al. A Look at the Importance of Chirality in Drug Activity: Some Significative Examples [J]. Applied Sciences, 2022, 12(21): 10909-10932.
[140] NADENDLA R. Molecular Modification: A Strategy in Drug Discovery and Drug Design [J]. Biomedical Journal of Scientific & Technical Research, 2023, 52(2): 43511-43522.
[141] HAO Y, LI R, MIN Y. Platinum-Based Twin Drug Modulates Tumor-Infiltrating Immune Cells to Improve Immune Checkpoint Blockade Therapy [J]. Journal of Medicinal Chemistry, 2023, 66(19): 13607-13621.
[142] GOLDEN D L, SUH S E, STAHL S S. Radical C(sp3)-H Functionalization and Cross-Coupling Reactions [J]. Nature Reviews Chemistry, 2022, 6(6): 405-427.
[143] ZHANG T, WU Y-H, WANG N-X, et al. Advances in C(sp3)–H Bond Functionalization Via Radical Processes [J]. Synthesis, 2019, 51(24): 4531-4548.
[144] JANKOVIC J, TAN E K. Parkinson's Disease: Etiopathogenesis and Treatment [J]. Journal of Neurology, Neurosurgery & Psychiatry, 2020, 91(8): 795-808.
[145] SHARAF J, WILLIAMS K D, TARIQ M, et al. The Efficacy of Safinamide in the Management of Parkinson's Disease: A Systematic Review [J]. Cureus, 2022, 14(9): e29118.
[146] OMORI A T, HIGA V M. A Two Hour Synthesis of the Anti-Parkinson Drug Safinamide Methanesulfonate [J]. Synlett, 2021, 32(14): 1433-1436.