Asymmetric Hydrogenation and Other Related Reactions

Office:731E-mail: chenjiarong@mail.ccnu.edu.cn

陈加荣化学学院

2016年04月26日

第10次课

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OUTLINE

1. Introduction

2. Asymmetric Hydrogenations of C=C Double Bonds

3. Asymmetric Reductions of Carbonyl Groups

4. Asymmetric Hydrogenations of Imines

5. Asymmetric Transfer Hydrogenation Reactions

6. Direct Reductive Amination Reactions

7. Asymmetric Hydroformylation Reactions

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1. Introduction –The History of Asymmetric Hydrogenation

是目前在工业上应用最多的不对称催化反应！

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1. Introduction – The Nobel Prize in Chemistry 2001

W. S. Knowles, Angew. Chem., Int. Ed., 2002, 41, 1998-2007. R. Noyori, Angew. Chem., Int. Ed., 2002, 41, 2008-2022.

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1. Introduction – Asymmetric Hydrogenation

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1. Introduction –不对称氢化反应的发现:科学和机遇

Knowles, W. S. et al. JCS Chem. Commun. 1968, 1445.Horner, Angew Chem. Int. Ed. 1968, 7, 942.

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1. Introduction – 不对称氢化的开创性工作

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1. Introduction – 手性膦配体的设计合成

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1. Introduction –不对称氢化反应的催化体系

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1. Introduction –第一个工业化的不对称氢化反应

Knowles, W. S., et al., J. Chem. Soc. Chem. Commun. 1972, 10. Knowles, W. S., et al., Acc. Chem. Res. 1983, 16, 106.

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1. Introduction

The minor diastereomeric intermediate is more reactive！Chan, A. S. C.; J. Halpern, et al. JACS 1980, 102, 5952; Halpern J. Science, 1982, 217, 401.

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不对称催化氢化：最大的工业化例子（>10,000 吨/年）

除草剂金朵尔的不对称合成（Metolachlor, Novartis 1996）

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1. Introduction - Chiral Phosphorus-based Ligands

Tang, W.-J.; Zhang, X.-M. Chem. Rev. 2003, 103, 3029.

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1. Introduction - Chiral Phosphorus-based Ligands

Tang, W.-J.; Zhang, X.-M. Chem. Rev. 2003, 103, 3029.

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2.1 Asymmetric Hydrogenation of C=C bonds –Examples: Unsaturated Acids and Derivatives

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2.1 Asymmetric Hydrogenation of C=C bonds –Examples: Unsaturated Acids and Derivatives

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2.1 Asymmetric Hydrogenation of C=C bonds –Examples: Unsaturated Acids and Derivatives

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2.1 Asymmetric Hydrogenation of C=C bonds –Examples: Unsaturated Acids and Derivatives

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2.1 Asymmetric Hydrogenation of C=C bonds –Examples: Unsaturated Acids and Derivatives

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2.1 Asymmetric Hydrogenation of C=C bonds –Examples: Unsaturated Acids and Derivatives

ACIE 1999, 38, 179.

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2.1 Asymmetric Hydrogenation of C=C bonds –Examples: Unsaturated Acids and Derivatives

The methoxyl groups can block the pyridyl N atoms.

Better performance than BINAP. Stable to air and moisture.

Chan, A.S.C. JACS 2000, 122, 11513.

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2.2 Asymmetric Hydrogenation of C=C bonds –Examples: Unfunctionalized Olefins

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3. Asymmetric Reduction of C=O Bonds

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3.1 Asymmetric Reduction of C=O Bonds -Examples: Metal Hydride Reductions

Good results can be obtained when one π-system is attached to the carbonyl group.

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3.1 Asymmetric Reduction of C=O Bonds -Examples: Metal Hydride Reductions

Dialkyl ketones are not good substrates.

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3.1 Asymmetric Reduction of C=O Bonds -Examples: Metal Hydride Reductions

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3.1 Asymmetric Reduction of C=O Bonds -Examples: Metal Hydride Reductions

Compared with BINAL-H, the amount of chiral CBS catalyst can be reduced to 10 mol%.

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3.2 Asymmetric Reduction of C=O Bonds -Examples: Asymmetric Hydrogenation of C=O Bonds

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3.2 Asymmetric Reduction of C=O Bonds -Examples: Asymmetric Hydrogenation of C=O Bonds

Monohydride mechanism The oxidation state of Ru center is +2 throughout the catalytic cycle.

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3.2 Asymmetric Reduction of C=O Bonds -Examples: Asymmetric Hydrogenation of C=O Bonds

The additional functional group in the substrate is critical for the highenantioselectivity since it can coordinate to the metal center to form a five- toseven-membered-ring intermediate.

Simple ketones are not suitable substrates in the asymmetric hydrogenationreactions using BINAP-Ru system.

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3.2 Asymmetric Reduction of C=O Bonds -Examples: Asymmetric Hydrogenation of C=O Bonds

Stable to air and moisture The reaction rate and efficiency are both elevated.

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3.2 Asymmetric Reduction of C=O Bonds -Examples: Asymmetric Hydrogenation of C=O Bonds

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3.2 Asymmetric Reduction of C=O Bonds -Examples: Asymmetric Hydrogenation of C=O Bonds

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3.2 Asymmetric Reduction of C=O Bonds -Examples: Asymmetric Hydrogenation of C=O Bonds

summary

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4. Asymmetric Hydrogenation of C=N Bonds

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4. Asymmetric Hydrogenation of C=N Bonds

stronger coordination of the transition metal to the unshared electron to the C=N bond resulting in low catalytic activity/turnover

frequent problems in preparing pure (E) and (Z) imines hydrolytic instability of the imine substrate requirement for H2 at elevated pressure

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4. Asymmetric Hydrogenation of C=N Bonds –Common Imine Substrates

Hydrogen donors: hydrogen gas 2-propanol triethylammonium formate

Additive: Additives (e.g. TBAI, KI, I2) have been found to influence enantioselectivity.

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4.1 Asymmetric Hydrogenation of C=N Bonds –Enantioselective Imine Hydrogenation

JACS 1992, 114, 6266.

OM 1996, 15, 3161.

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4.1 Asymmetric Hydrogenation of C=N Bonds –Enantioselective Imine Hydrogenation

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4.1 Asymmetric Hydrogenation of C=N Bonds –Enantioselective Imine Hydrogenation

金朵尔除草剂

右美沙芬

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4.1 Asymmetric Hydrogenation of C=N Bonds –Enantioselective Imine Hydrogenation

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4.1 Asymmetric Hydrogenation of C=N Bonds –Enantioselective Imine Hydrogenation

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4.2 Asymmetric Hydrogenation of C=N Bonds –不对称硅氢化反应

Buchwald, S. L.; et al JACS (96) 6784.

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4.2 Asymmetric Hydrogenation of C=N Bonds –不对称硅氢化反应

Various cyclic and acyclic imines are viable substrates.

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4.2 Asymmetric Hydrogenation of C=N Bonds –不对称硅氢化反应

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4.2 Asymmetric Hydrogenation of C=N Bonds –不对称硅氢化反应

No additional coordination site is required. The two prochiral face is distinguished only by the shape of the molecules.

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4.2 Asymmetric Hydrogenation of C=N Bonds –不对称硅氢化反应

In some cases where the N-substituted group is large, the Ti–N bond dissociation step becomes very slow.

The reaction can be accelerated by adding some nucleophilic reagent.

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4.2 Asymmetric Hydrogenation of C=N Bonds –不对称硅氢化反应

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5. Asymmetric Transfer Hydrogenation

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5.1 Asymmetric Transfer Hydrogenation–Metal Catalysis

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5.1 Asymmetric Transfer Hydrogenation–Metal Catalysis

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5.1 Asymmetric Transfer Hydrogenation–Metal Catalysis

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5.1 Asymmetric Transfer Hydrogenation –Metal Catalysis

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5.1 Asymmetric Transfer Hydrogenation–Metal Catalysis

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5.1 Asymmetric Transfer Hydrogenation –Metal Catalysis

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5.2 Asymmetric Transfer Hydrogenation –仿生氢转移反应

NADH，烟酰胺腺嘌呤二核苷酸

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5.2 Asymmetric Transfer Hydrogenation –仿生氢转移反应

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5.2 Asymmetric Transfer Hydrogenation –仿生氢转移反应

J. M. Goodman J. Am. Chem. Soc. 2008, 130, 8741.

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5.2 Asymmetric Transfer Hydrogenation –仿生氢转移反应

ACIE 2004, 43, 6660; 2005, 44, 108. JACS, 2005, 127, 32.

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5.2 Asymmetric Transfer Hydrogenation –仿生氢转移反应

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5.2 Asymmetric Transfer Hydrogenation –仿生氢转移反应

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5.2 Asymmetric Transfer Hydrogenation –仿生氢转移反应

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5.2 Asymmetric Transfer Hydrogenation –仿生氢转移反应

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6. Direct Reductive Amination Reactions

MacMillan, D.W.C. JACS 2006, 128, 84.

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6. Direct Reductive Amination Reactions

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7. Asymmetric Hydroformylation Reactions

(S)-布洛芬

(S)-萘普生

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7. Asymmetric Hydroformylation Reactions

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7. Asymmetric Hydroformylation Reactions

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7. Asymmetric Hydroformylation Reactions

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7. Asymmetric Hydroformylation Reactions

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Summary