EpoxideinOrganic Synthesis
M1 Yuki HiraoIntroduction

Epoxides are important intermediates in total synthesis.

2Asymmetric Epoxidation

The Nobel Prizein Chemistry 2001

3

Contents
1. Introduction
2. Ring-Opening of Epoxide
・Nucleophilic addition
・Reductive-opening by SET

3. Titanocene-catalyzed Epoxide Opening
4. Recent Achievements
・Isomerization of epoxides to Allylic Alcohols
・Anti-Markovnikov alcohols via epoxidehydrogenation4

Ring-Opening of Epoxide

5Nucleophilic addition

Jacobsen, E, N. et al. J. Org. Chem. 1997, 62, 4197.
Jacobsen, E, N. et al. Tetrahedron Lett. 1997, 38, 773.
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Jacobsen, E, N. et al. Science. 1997, 277, 936.

Reductive-opening by SET
General Ideas
Opening of epoxides with low-valent metal complexes

7Reductive-opening by SET

8

Reductive-opening by SET

9

Contents
1. Introduction
2. Ring-Opening of Epoxide
・Nucleophilic addition
・Reductive-opening by SET

3. Titanocene-catalyzed Epoxide Opening
4. Recent Achievements
・Isomerization of epoxides to Allylic Alcohols
・Anti-Markovnikov alcohols via epoxidehydrogenation
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Titanocene-catalyzed Epoxide Opening

11Titanocene-catalyzed Epoxide Opening

Fürstner, A. et al. J. Am. Chem. Soc. 1995, 117, 4468.
Fürstner, A. et al. J. Am. Chem. Soc. 1996, 118, 2533.
Ikeda, I. et al. J. Org. Chem. 1996, 61, 366.
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Titanocene-catalyzed Epoxide Opening

A. Gansäuer. et al. J. Org. Chem. 1998, 66, 2070.
A. Gansäuer. et al. Eur. J. Org. Chem. 1998, 2673.

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Titanocene-catalyzed Epoxide Opening

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Computational Studies
Favored

DFT calculations (BP86/TZVP)

DisfavoredIn disfavored transition state, the larger CH3 group gets intocloser contact with Cp ligand.
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A. Gansäuer. et al. J. Am. Chem. Soc. 2007, 129, 1359.

Computational Studies DFT calculations (BP86/TZVP)Epoxide opening is exothermic.
 The formation of the higher substituted radicals is thermodynamicallyfavored.
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A. Gansäuer. et al. J. Am. Chem. Soc. 2007, 129, 1359.

Computational Studies

A. Gansäuer. et al. J. Am. Chem. Soc. 1998, 120, 12849.
A. Gansäuer. et al. J. Am. Chem. Soc. 2007, 129, 1359.

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Titanocene-catalyzed Epoxide Opening18

Short Summary

Reductive Opening of Epoxides by SET
Radical Stability
Steric Interactions between R1, R2 and Cp ligand

more highly substituted radical
opposed to SN2 Reaction (from less substituted carbon)
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Contents
4. Recent Achievements

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Purpose

J. Andersson. et al. J. Am. Chem. Soc. 2000, 122, 6610.
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K. Y. Ye, T. M. Callum, S. Lin. J. Am. Chem. Soc. 2019, 141, 9548.

Optimization

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K. Y. Ye, T. M. Callum, S. Lin. J. Am. Chem. Soc. 2019, 141, 9548.

Proposed Catalytic Cycle

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K. Y. Ye, T. M. Callum, S. Lin. J. Am. Chem. Soc. 2019, 141, 9548.

Substrate Scope

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K. Y. Ye, T. M. Callum, S. Lin. J. Am. Chem. Soc. 2019, 141, 9548.

Kinetic Resolution

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K. Y. Ye, T. M. Callum, S. Lin. J. Am. Chem. Soc. 2019, 141, 9548.

Radical Rearrangement

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K. Y. Ye, T. M. Callum, S. Lin. J. Am. Chem. Soc. 2019, 141, 9548.

Asymmetric Reaction

27

K. Y. Ye, T. M. Callum, S. Lin. J. Am. Chem. Soc. 2019, 141, 9548.

Contents
4. Recent Achievements

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Anti-Markovnikov alcohols

C. Yao, T, Dahmen, A. Gansäuer, J. Norton. Science. 2019, 364, 764.

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Previous Work30

This Work

C. Yao, T, Dahmen, A. Gansäuer, J. Norton. Science. 2019, 364, 764.

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Proposed Catalytic Cycle

C. Yao, T, Dahmen, A. Gansäuer, J. Norton. Science. 2019, 364, 764.

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Side Reaction

C. Yao, T, Dahmen, A. Gansäuer, J. Norton. Science. 2019, 364, 764.

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Substrate Scope

C. Yao, T, Dahmen, A. Gansäuer, J. Norton. Science. 2019, 364, 764.

34

Substrate Scope

C. Yao, T, Dahmen, A. Gansäuer, J. Norton. Science. 2019, 364, 764.

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Summary36

Appendix

Titanocene-catalyzed Epoxide Opening

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Unsuccessful Substrates
Isomerization of epoxides to Allylic Alcohols

39Radical Rearrangement

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K. Y. Ye, T. M. Callum, S. Lin. J. Am. Chem. Soc. 2019, 141, 9548.

Cyclic Voltammetry Studies

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Optimization of anti-Markovnikov hydrogenation

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NMR Studies

C. Yao, T, Dahmen, A. Gansäuer, J. Norton. Science. 2019, 364, 764.

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NMR Studies

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NMR Studies

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Cyclic Voltammetry Studies

46