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化学进展 2020, Vol. 32 Issue (11): 1680-1696 DOI: 10.7536/PC200436 前一篇   后一篇

• 综述 •

二茂铁骨架系列三齿配体的合成及其在铱催化不对称氢化中的应用

林鑫1,2†, 管凡夫3,4†, 温佳琳3, 邵攀霖1,3,**, 张绪穆3,**   

  1. 1. 南方科技大学创新创业学院 深圳 518055
    2. 哈尔滨工业大学 哈尔滨 150001
    3. 南方科技大学化学系 深圳小分子药物发现和合成重点实验室 深圳 518055
    4. 利兹大学化学系 工艺研究与发展中心 英国利兹 LS29JT
  • 收稿日期:2020-04-23 修回日期:2020-07-05 出版日期:2020-11-24 发布日期:2020-09-01
  • 通讯作者: 邵攀霖, 张绪穆
  • 作者简介:

    邵攀霖

    南方科技大学研究副教授,致力于不对称合成方法学的开发及药物绿色合成新工艺的产业化研究,在新催化体系的发展以及具有生理活性的手性杂环化合物和药物合成领域取得一系列成果。

    张绪穆

    南方科技大学教授,南方科技大学生物医药研究院院长,理学院副院长,国家特聘专家,长江学者讲座教授,杰出青年基金(B)获得者,长期致力于膦配体的开发,在不对称氢化和氢甲酰化学术研究及工业化领域具有很高的造诣。

    ** Corresponding author e-mail: (Pan-Lin Shao); (Xumu Zhang)
    † These authors contribute equally.
  • 基金资助:
    深圳市小分子药物发现与合成重点实验室项目(ZDSYS20190902093215877); 深圳市科技创新委员会基础研究面上项目(JCYJ20190809160211372)
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Synthesis of Chiral Tridentate Ligands with a Ferrocene Framework and Their Applications in Ir-Catalyzed Asymmetric Hydrogenation

Xin Lin1,2†, Fanfu Guan3,4†, Jialin Wen3, Pan-Lin Shao1,3,**, Xumu Zhang3,**   

  1. 1. School of Innovation and Entrepreneurship, Southern University of Science and Technology, Shenzhen 518055, China
    2. Harbin Institute of Technology, Harbin 150001, China
    3. Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055, China
    4. Institute of Process Research and Development, School of Chemistry, University of Leeds, Leeds LS29JT, UK
  • Received:2020-04-23 Revised:2020-07-05 Online:2020-11-24 Published:2020-09-01
  • Contact: Pan-Lin Shao, Xumu Zhang
  • Supported by:
    the Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis(ZDSYS20190902093215877); the Science, Technology and Innovation Commission of Shenzhen(JCYJ20190809160211372)

本文主要介绍了一系列基于二茂铁骨架的三齿配体:f-amphox、f-ampha、f-amphol和f-amphamide的合成及其应用。这四类手性膦氮配体的铱络合物可以高活性(TON高达1 000 000)、高转化率(>99%)、高对映选择性(>99% ee)地催化(官能团化)酮等底物的不对称氢化反应。该系列配体成功地应用于地诺帕明、苯福林和沙丁胺醇等手性医药中间体的不对称合成。与传统路线相比,这些合成方法更高效,副产物更少,“三废”排放量更低。

关键词： 二茂铁, f-amphox, f-ampha, f-amphol, f-amphamide, 不对称氢化

In this review, the synthesis and application of a series of tridentate ligands, such as f-amphox, f-ampha, f-amphol and f-amphamide, bearing ferrocene skeleton are introduced. The corresponding iridium complex based on these chiral P-N ligands can catalyze(functionalized) ketones with high TON(up to 1 000 000), excellent conversion(>99%) and enantioselectivity(>99% ee). The application of the f-series ligands has successfully realized the asymmetric synthesis of many chiral pharmaceutical intermediates such as Dinopramine, Phenylephrine and Salbutamol. These approaches are more efficient, generating less by-products and lower industrial emissions compared with the traditional routes.

Contents

1 Introduction

2 History of tridentate ferrocene ligands

2.1 The development of tridentate ligands

2.2 Special properties of ferrocene skeleton

2.3 Representative ligands containing ferrocene framework

3 f-amphox

3.1 The synthesis of f-amphox

3.2 Application of f-amphox in asymmetric hydrogenation

4 f-amphol

4.1 The synthesis of f-amphol

4.2 Application of f-amphol in asymmetric hydrogenation

5 f-ampha

5.1 The synthesis of f-ampha

5.2 Application of f-amphol in asymmetric hydrogenation

6 f-amphamide

6.1 The synthesis of f-amphamide

6.2 Application of f-amphamide in asymmetric hydrogenation

7 New mechanism insight about asymmetric hydrogenation

7.1 Hydrogenation mechanism of N—H structure

7.2 The chiral sources of f series

7.3 Transition state model of asymmetric hydrogenation

8 Conclusion and outlook

Key words: ferrocene, f-amphox, f-ampha, f-amphol, f-amphamide, asymmetric hydrogenation
()
图式1 Pybox配体[7]
Scheme 1 Pybox ligand[7]
图式2 优势三齿配体及其手性诱导模型[8]
Scheme 2 Dominant tridentate ligands and their chiral induction models[8]
图式3 SpiroPAP配体[9]
Scheme 3 SpiroPAP ligand[9]
表1 Ir/f?amphox催化剂和[RuCl2(BINAP)(diamine)]催化剂的对比
Table 1 Comparison between catalyst Ir/f?amphox and [RuCl2(BINAP)(diamine)]
图式4 首例面手性配体(RC, SFc)-PPFA和(RC, SFc)-BPPFA的合成[10]
Scheme 4 Synthesis of the first planar chiral ligands (RC, SFC)-PPFA and (RC, SFC)-BPPFA[10]
图式5 (R)-Ugi’s amine的非典型SN1反应机理[12]
Scheme 5 Reaction mechanism of atypical SN1 of(R)-Ugi’s amine [12]
图式6 含有二茂铁骨架的手性膦配体[13,14,15,16,17]
Scheme 6 Chiral phosphine ligands with ferrocene framework[13,14,15,16,17]
图式7 优势三齿配体及其手性诱导模型[8, 22]
Scheme 7 Dominant tridentate ligands and their chiral induction models[8, 22]
图1 f-amphox的结构式
Fig.1 The structure of f-amphox
图式8 f-amphox的合成路线[23]
Scheme 8 The synthesis of f-amphox[23]
图式9 Ir/f-amphox催化简单酮的不对称氢化反应[23]
Scheme 9 Asymmetric hydrogenation of simple ketones catalyzed by Ir/f-amphox[23]
图式10 Ir/f-amphox催化卤代酮不对称氢化反应及其关键转化[24]
Scheme 10 Ir/f-amphox-catalyzed asymmetric hydrogenation of halogenated ketones and key transformation[24]
图式11 包含手性α-羟基酰胺结构的药物分子
Scheme 11 Drug molecules containing chiral α-hydroxyamides
图式12 Ir/f-amphox不对称氢化α-酮酰胺[25]
Scheme 12 Ir/f-amphox-catalyzed hydrogenation of α-Keto amide[25]
图式13 Ir/f-amphox不对称氢化β,γ-不饱和α-酮酰胺类化合物[27]
Scheme 13 Ir/f-amphox-catalyzed hydrogenation of β,γ-unsaturated α-ketoamide compounds[27]
图式14 手性高苯丙氨酸衍生物的合成路线[26]
Scheme 14 Synthesis of chiral homophenylalanine derivatives[26]
图式15 贝那普利中间体的合成[27, 30]
Scheme 15 Synthesis of intermediate Benazepril[27, 30]
图式16 含有氨基醇片段的药物分子[32]
Scheme 16 Drug molecules corresponding to hydrogenated products[32]
图式17 Ir/f-amphox不对称氢化α-氨基酮[32]
Scheme 17 Ir/f-amphox-catalyzed hydrogenation of α-imino ketones[32]
图式18 (S)-苯肾上腺素的合成[29, 31]
Scheme 18 The synthetic of (S)-Phenylephrine[29, 31]
图式19 Ir/f-amphox不对称氢化α-氨基芳基烷基酮[33]
Scheme 19 Ir/f-amphox-catalyzed hydrogenation of α-amino arylalkylketone[33]
图式20 临床抗肿瘤药物(S,S)-R116010的关键中间体的合成[33, 35]
Scheme 20 Synthesis of the key intermediate of clinical antitumor drug (S,S)-R116010[33, 35].
图式21 Ir/f-amphox在其他药物合成中的应用[36]
Scheme 21 The application of Ir/f-amphox in the synthesis of other drugs[36]
图式22 CN1237574 A关于地诺帕明消旋体的制备[37]
Scheme 22 Preparation of racemic Dinopramine in CN1237574A[37]
图式23 田边制药株式会社有机化学研究所开发的地诺帕明的合成方法[38]
Scheme 23 Synthesis of Dinopramine developed by the Institute of Organic Chemistry of Tianbian Pharmaceutical Co., Ltd[38]
图式24 田边三棱制药株式会社有限公司公开的地诺帕明的合成方法[39]
Scheme 24 The synthesis of Dinopramine disclosed by Tianbian Sanling Pharmaceutical Co., Ltd[39]
图式25 张绪穆等公开的不对称氢化法制备地诺帕明的方法[40]
Scheme 25 Zhang et al. published asymmetric hydrogenation method for the preparation of Dinopramine[40]
图式26 通过Ir/f-amphox催化不对称氢化合成地诺帕明[41]
Scheme 26 Synthesis of Dinopramine by asymmetric hydrogenation catalyzed by Ir/f-amphox[41]
图2 f-amphol的结构式
Fig.2 The structure of f-amphol
图式27 f-amphol的合成路线[42]
Scheme 27 The synthesis of f-amphol[42]
图式28 Ir/f-amphol催化芳香酮的不对称氢化反应[43]
Scheme 28 Asymmetric hydrogenation of aromatic ketones catalyzed in situ by Ir/f-amphol[43]
图式29 艾司利卡西平的合成[44, 45]
Scheme 29 Synthesis of Escalicarpine[44, 45]
图式30 Ir/f-amphol不对称氢化α-取代-β-酮酸酯[46]
Scheme 30 Asymmetric hydrogenation of α-substituted β-ketoesters by Ir/f-amphol[46]
图式31 手性四取代四氢吡喃的合成[46]
Scheme 31 synthesis of chiral tetrahydropyrane[46]
图3 f-ampha的结构式
Fig.3 The structure of f-ampha
图式32 f-ampha的合成路线[48]
Scheme 32 The synthsis of f-ampha[48]
图式33 Ir/f-ampha催化芳香酮的不对称氢化反应[6]
Scheme 33 Asymmetric hydrogenation of aromatic ketones catalyzed by Ir/f-ampha[6]
图式34 Ir/f-ampha催化的不对称氢化反应[50]
Scheme 34 Asymmetric hydrogenation catalyzed by Ir/f-ampha[50]
图式35 含有(R)-1-(3,5-双(三氟甲基)-苯基)乙烷-1-醇结构的药物分子
Scheme 35 Drug molecules containing the structure of(R)-1-(3,5-bis(tri?uoromethyl)phenyl)ethanol
图式36 f-amphox, f-amphol, and f-ampha配体合成(R)-1-(3,5-双(三氟甲基-苯基)乙烷-1-醇的路线
Scheme 36 Synthetic route for(R)-1-(3,5-bis(tri?uoromethyl)phenyl)ethanol using f-amphox, f-amphol, and f-ampha ligands
图4 f-amphamide的结构式
Fig.4 The structure of f-amphamide
图式37 f-amphamide的合成路线[51]
Scheme 37 The synthesis of f-amphamide[51]
图式38 Ir/f-amphamide对苯乙酮系列底物的不对称氢化[51]
Scheme 38 Asymmetric hydrogenation of acetophenone series substrates by Ir/f-amphamide[51]
Fig.5 a) Traditional asymmetric hydrogenation mechanism; b) New mechanism of asymmetric hydrogenation[55, 56]
图6 f系列配体在简单酮的不对称氢化中的过渡态模型(X=碱金属离子)[46, 50, 51, 58]
Fig.6 The hypothetical catalytic models of these tridentate ligands for asymmetric hydrogenation of simple ketone(X=H or alkali metal cation)[46, 50, 51, 58]
图7 Ir/(SC, SC, RFC)-f-amphox催化剂还原α-酮酰胺的过渡态模型[58]
Fig.7 Transition state model of reduction of α-ketoamide over Ir/(SC, SC, RFC)-f-amphox[58]
图8 a)TS(S)和TS(R)的计算模型,Ar=3,5-(tBu)2C6H3;b)Ir/f-ampha催化剂过渡态的位阻图(红色为位阻更大;蓝色为位阻更小)[49]
Fig.8 a) Computed structures for TS(S) and TS(R), Ar=3,5-(tBu)2C6H3; b) Potential resistance diagram of Ir/f-ampha catalyst in transition state(red indicates greater potential resistance; blue indicates less potential resistance)[49]
图9 Ir/(SC, SC, RFC)-f-amphol催化剂还原α-取代β-酮酸酯的过渡态模型[46]
Fig.9 Transition state model of reduction of α-substituted β-ketoesters over Ir/(SC, SC, RFC)-f-amphol[46]
图10 Ir/(RC, SP)-f-amphamide还原苯乙酮的过渡态模型[51]
Fig.10 Transition state model for reduction of acetophenone over Ir/(RC, SP)-f-amphamide catalyst[51]
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