1. Organocatalytic Oxidation Catalytic Asymmetric Epoxidation of Olefins with Chiral Ketones and Synthetic Applications
Frédéric Vallée
Prof. Charette’s laboratories
Literature Meeting
20th January 2009

2. Outline -Introduction -Chiral Ketone-Catalyzed Epoxidation
-Carbohydrate-Based and Related Ketones
-Synthetic Applications

3. Introduction
 Optically active epoxides are highly useful intermediates and building blocks for the total synthesis of biologically active compounds.

4. Introduction
 Various effective systems have been developed over the years for enantioselective epoxidations.
Sharpless (epoxidation of allylic alcohols with chiral titanium catalyst)
VO(acac)2 (epoxidation of allylic and homoallylic alcohols)
Jacobsen (epoxidation of unfunctionalized, cis and terminal olefins)
Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I. Ed.; VCH: New York, 2000; Chapter 6A.
Hoshino, Y.;Yamamoto, H. J. Am. Chem. Soc. 2000, 122,
Zhang, W.;Basak, A.; Kosugi, Y.; Hoshino, Y.; Yamamoto, H. Angew. Chem.,Int. Ed. 2005, 44, 4389.
Makita, N.; Hoshino, Y.; Yamamoto, H. Angew. Chem., Int. Ed. 2003, 42, 941.
Zhang, W.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 286.
Jacobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima, I.Ed.; VCH: New York, 1993; Chapter 4.2.
Collman, J. P.; Zhang, X.; Lee, V. J.; Uffelman, E. S.; Brauman, J. I. Science 1993, 261, 1404.

5. Introduction
 Among the many powerful methods for the epoxidation of olefins, three-membered ring compounds containing two heteroatoms are very versatile oxidation reagents.
Murray, R. W. Chem. Rev. 1989, 89, 1187.
Adam, W.; Curci, R.; Edwards, J. O. Acc. Chem. Res. 1989, 22, 205.
Adam, W.; Saha-Moller,C. R.; Ganeshpure, P. A. Chem. Rev. 2001, 101, 3499.

6.  More rencently asymmetric epoxidations catalyzed by chiral ketones
have received much attention.
 Significant progress has been made in this field towards the epoxidation of various types of olefins such as
Introduction

7. Introduction Ketone-Catalyzed Epoxidation of Olefins
The dioxiranes are generated in situ from ketone and Oxone
(2KHSO5  KHSO4  K2SO4)
Edwards, J. O.; Pater, R. H.; Curci, R.; Di Furia, F. Photochem. Photobiol. 1979, 30, 63.
Curci, R.; Fiorentino, M.; Troisi, L.; Edwards, J. O.; Pater, R. H. J. Org. Chem. 1980, 45, Gallopo, A. R.; Edwards, J. O. J. Org. Chem. 1981, 46, 1684.

8. Outline -Introduction -Chiral Ketone-Catalyzed Epoxidation
-Carbohydrate-Based and Related Ketones
-Synthetic Applications

9. Early Ketones 1984 Curci and co-workers Yields from 60-92%
Up to 12% ee (2, 50 mol%)
1995 Curci and co-workers
Yields from 80-82%
Up to 20% ee (4, 1 equiv.)
Curci, R.; Fiorentino, M.; Serio, M. R. Chem. Commun. 1984, 155.
Curci, R.; D’Accolti, L.; Fiorentino, M.; Rosa, A. Tetrahedron Lett. 1995, 36, 5831.

10. C2-Symmetric Binap-Based Ketones
1996 Yang and co-workers
Yields from 70-95%
Up to 95% ee
Best results
Catalyst 8d, 10 mol%
Substrate (E)-Stilbene
Note : As the X going larger from H (47% ee),
to Cl (76% ee), to Br (75% ee), to I (32%ee).
Yang, D.; Yip, Y.-C.; Tang, M.-W.; Wong, M.-K.; Zheng, J.-H.; Cheung, K.-K. J. Am. Chem. Soc. 1996, 118, 491.
Yang, D.; Wang, X.-C.; Wong, M.-K.; Yip, Y.-C.; Tang, M.-W. J. Am. Chem.Soc. 1996, 118,
Yang, D.; Wong, M.-K.; Yip, Y.-C.; Wang, X.-C.; Tang, M.-W.; Zheng, J.-H. J. Am. Chem. Soc. 1998, 120, 5943.

11. Other C2-Symmetric Ketones
1997 Song and co-workers
Yields from 61-95%
Up to 59% ee (6, 1 equiv)
1997 Adam and co-workers
Yields from 67-80%
Up to 81% ee (8, 1 equiv)
Song, E. C.; Kim, Y. H.; Lee, K. C.; Lee, S.-g.; Jin, B. W. Tetrahedron: Asymmetry 1997, 8, 2921.
Adam, W.; Zhao, C.-G. Tetrahedron: Asymmetry 1997, 8, 3995.

12. Other C2-Symmetric Ketones
1998 Denmark and co-workers
Conversion from 6-100%
Enantioselectivity up to 94% ee (9c, 30 mol%)
And many others….
Denmark, S. E.; Wu, Z. Synlett 1999, 847.
Denmark, S. E.; Matsuhashi, H. J. Org. Chem. 2002, 67, 3479.

13. Bicyclo3.2.1octan-3-ones
1998 Armstrong and co-workers
Conversion from %
Up to 98% ee
Best results
Catalyst 11b, 20 mol%
Substrate
Armstrong, A.; Hayter, B. R. Chem. Commun. 1998, 621.
Armstrong, A.; Ahmed, G.; Dominguez-Fernandez, B.; Hayter, B. R.; Wailes, J. S. J. Org. Chem. 2002, 67, 8610.
Sartori, G.; Armstrong, A.; Maggi, R.; Mazzacani, A.; Sartorio, R.; Bigi, F. J. Org. Chem. 2003, 68, 3232.

14. Outline -Introduction -Chiral Ketone-Catalyzed Epoxidation
-Carbohydrate-Based and Related Ketones (The Work of Shi)
-Synthetic Applications

15. Carbohydrate-Based Ketones
Yian Shi was born in Jiangsu, China, in 1963 and obtained his B.Sc. degree in chemistry from Nanjing University in Upon receiving his M.Sc. degree from University of Toronto with Professor Ian W. J. Still in 1987, he pursued his doctoral studies at Stanford University with Professor Barry M. Trost and obtained his Ph.D. degree in Subsequently, he carried out his postdoctoral studies at Harvard Medical School with
Professor Christopher Walsh from 1992 to He joined Colorado State University as assistant professor in 1995 and was promoted to associate professor in 2000 and professor in 2003.

16. Carbohydrate-Based Ketones
1996 Shi and co-workers
Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806.
Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119,

17. Carbohydrate-Based Ketones
Selectivity and Reactivity; Basic General Considerations
(Catalyst Developement)
1) Stereogenic center must be close to the reacting center which favor the ‘’chiral communication’’ between substrates and catalyst.
Fused ring and/or a quaternary center  to the carbonyl minimizes the epimerization of de stereogenic centers.
C2- or pseudo C2 symmetric element inducing
steric discrimination as olefin approaches to the reacting dioxirane.
4) Inductive activation of the carbonyl with the presence of many closed oxygen atoms.
Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806.
Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119,

18. Catalyst Development Why use carbohydrate-derived ketone ?
(a) Carbohydrates are chiral, readily available and inexpensive.
(b) They are highly substituted with oxygen groups,
(inductive effect of oxygen).
(c) Carbohydrate-derived ketones can have rigid conformations
due to the anomeric effect, which is desirable for selectivity.
Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806.
Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119,

19. Catalyst Development
Impact of the pH on the epoxidation with in situ generated dioxiranes
- At high pH, Oxone autodecomposes rapidly
- At pH 7-8, 16 give high enantioselectivity but… need an excess!
- Raising the pH, to avoid B-V favoring 19 formation and hoping that the
reaction of the ketone with Oxone will be faster than its decomposition
Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806.
Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119,

20. Catalyst Development
A dramatic pH effect led to a catalytic asymmetric process
Plot of the conversion of trans--methylstyrene against pH using ketone 16 (0.2 equiv) as catalyst in two solvent systems, H2O-CH3CN (1:1.5 v/v) (A) and H2O-CH3CN-DMM (2:1:2 v/v) (B)
Plot of the conversion of trans--methylstyrene against pH using acetone (3 equiv) as catalyst in H2O-CH3CN (1:1.5 v/v). Samples were taken at different reaction times for the determination of conversion: 0.5 (A), 1.0 (B), 1.5 (C), and 2.0 h (D)
DMM : Dimethoxymethane
Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806.
Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119,

21. Reaction Optimization
Solvent effects
Temperature effects
Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806.
Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119,

22. Scope and Substrates trans and Trisubstituted olefins
Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119,

23. Scope and Substrates 2,2-Disubstituted Vinylsilanes
Warren, J. D.; Shi, Y. J. Org. Chem. 1999, 64, 7675.

24. Scope and Substrates Hydroxyalkenes
Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 3099.

25. Scope and Epoxides Conjugated Dienes
Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 2948.
Cao, G.-A.; Wang, Z.-X.; Tu, Y.; Shi, Y. Tetrahedron Lett. 1998, 39, 4425.
Wang, Z.-X.; Cao, G.-A.; Shi, Y. J. Org. Chem. 1999, 64, 7646.

26. Scope and Substrates Conjugated Enynes
Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 2948.
Cao, G.-A.; Wang, Z.-X.; Tu, Y.; Shi, Y. Tetrahedron Lett. 1998, 39, 4425.
Wang, Z.-X.; Cao, G.-A.; Shi, Y. J. Org. Chem. 1999, 64, 7646.

27. Scope and Substrates Method Limitation : cis and terminal olefins
Enol Esters
Method Limitation : cis and terminal olefins
Zhu, Y.; Manske, K. J.; Shi, Y. J. Am. Chem. Soc. 1999, 121, 4080.
Feng, X.; Shu, L.; Shi, Y. J. Am. Chem. Soc. 1999,121,
Zhu, Y.; Shu, L.; Tu, Y.; Shi, Y. J. Org. Chem. 2001, 66, 1818.

28. Understanding

29. Understanding Two mechanistic extremes for disubstituted olefins
Baumstark, A. L.; McCloskey, C. J. Tetrahedron Lett. 1987, 28,
Baumstark, A. L.; Vasquez, P. C. J. Org. Chem. 1988, 53,

30. Understanding Mechanistic studies of disubstituted olefins
- The cis-hexenes is more reactive
- The reactivity is dependent on the size of the alkyl groups of the olefin
Baumstark, A. L.; McCloskey, C. J. Tetrahedron Lett. 1987, 28,
Baumstark, A. L.; Vasquez, P. C. J. Org. Chem. 1988, 53,

31. Understanding Mechanistic studies disubstituted olefins
- The trans-isomers is slightly more reactive (Ph is planar)
- Calculation show that the Spiro TS is favored for the epoxidation on ethylene
Baumstark, A. L.; McCloskey, C. J. Tetrahedron Lett. 1987, 28, 3311.
Baumstark, A. L.; Vasquez, P. C. J. Org. Chem. 1988, 53, 3437.
Bach, R. D.; Andres, J. L.; Owensby, A. L.; Schlegel, H. B. J. Am. Chem. Soc. 1992, 114, 7207.

32. Understanding Mechanistic studies disubstituted olefins
-The spiro orientation could benefits from a stabilizing interaction of an oxygen
lone pair with the * orbital of the alkene
Bach, R. D.; Andres, J. L.; Owensby, A. L.; Schlegel, H. B. J. Am. Chem. Soc. 1992, 114, 7207.

33. Stereochemical analysis
Bach, R. D.; Andres, J. L.; Owensby, A. L.; Schlegel, H. B. J. Am. Chem. Soc. 1992, 114, 7207.

34. Stereochemical analysis
General TS analysis
Due to steric repulsion B-C-D-F-G are disfavored (for disubstituted, where R2=H, B is similar to A and G to H
Favored spiro A and planar H TS result in the opposite stereochemistry
For trans-disubstituted and trisub-stituted olefin the spiro TS is favored since the epoxide I is formed predominately
Bach, R. D.; Andres, J. L.; Owensby, A. L.; Schlegel, H. B. J. Am. Chem. Soc. 1992, 114, 7207.
Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119,

35. Stereoelectronic Effect
The energy difference between the two TS will vary with the substituents, since the energy level of the * is affected by those…
Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119,

36. Steric Effect… The case of the trisubstituted olefin
-Decreasing the size R1 → high ee (spiro A favored)
-Increasing the size of R3 → high ee (spiro A favored)
Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119,

37. Steric Effect…
Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119,

38. What about cis and Terminal Olefins?
For cis, electronic and steric factors should favor the spiro TS
- a and b are the main interaction and furthermore, the ee depends
on the energy difference between them.
- The greater the size difference between R2 and R3
the higher the ee is.
Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119,

39. What about cis and Terminals olefins?
-ee’s up to 97% with great conversions
-The energy difference between these TS seems too small
Shu, L.; Wang, P.; Gan, Y.; Shi, Y. Org. Lett. 2003, 5, 293.
Shu, L.; Shi, Y. Tetrahedron Lett. 2004, 45, 8115.
Wong, O. A.; Shi, Y. J. Org. Chem. 2006, 71, 3973.
Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119,

40. Ketone Structures
The catalytic properties are dependant on the precise nature of
the ketone.
- The pyranose oxygen is beneficial for catalysis (16 vs. 26).
16 is still the best ketone for the epoxidation and for the
enantioselectivity compared to all (TS issues).
Tu, Y.; Wang, Z.-X.; Frohn, M.; He, M.; Yu, H.; Tang, Y.; Shi, Y. J. Org. Chem. 1998, 63, 8475.
Wang, Z.-X.; Miller, S. M.; Anderson, O. P.; Shi, Y. J. Org. Chem. 2001, 66, 521.

41. Ketones Studies
The rigid 5-6 spiro ring of 16, is superior in controlling the enantioselectivity.
16 is also superior with regard to the yield.
16 is more stable under the optimal epoxidation conditions.
Tu, Y.; Wang, Z.-X.; Frohn, M.; He, M.; Yu, H.; Tang, Y.; Shi, Y. J. Org. Chem. 1998, 63, 8475.
Wang, Z.-X.; Miller, S. M.; Anderson, O. P.; Shi, Y. J. Org. Chem. 2001, 66, 521.

42. Pyranose Oxygen Effect
Wang, Z.-X.; Miller, S. M.; Anderson, O. P.; Shi, Y. J. Org. Chem. 2001, 66, 521.

43. Pyranose Oxygen Effect
Tu, Y.; Wang, Z.-X.; Frohn, M.; He, M.; Yu, H.; Tang, Y.; Shi, Y. J. Org. Chem. 1998, 63, 8475.
Wang, Z.-X.; Miller, S. M.; Anderson, O. P.; Shi, Y. J. Org. Chem. 2001, 66, 521.

44. Outline -Introduction -Chiral Ketone-Catalyzed Epoxidation
-Carbohydrate-Based and Related Ketones
-Examples of Synthetic Applications Using 16 as Catalyst

45. First Synthesis of (+)-Aurilol
Morimoto, Y.; Nishikawa, Y.; Takashi, M. J. Am. Chem. Soc. 2005, 127, 5806.

46. Enantioselective Total Synthesis of (+)-Nigellamine A2
Bian, J.; Van Wingerden, M.; Ready, J. M. J. Am. Chem. Soc. 2006, 128, 7428.

47. Total Syntheses of Nakorone, and Abudinol B via Biomimetic Oxa- and Carbacyclizations
Tong, R.; Valentine, J. C.; McDonald, F. E.; Cao, R.; Fang, X.; Hardcastle, K. I. J. Am. Chem. Soc. 2007, 129, 1050.

48. Biomimetic Nakanishi, K. Toxicon 1985, 23, 473.
Shimizu, Y.; Chou, H.-N.; Bando, H.; Van Duyne, F.; Clardy, J. C. J. Am. Chem. Soc. 1986, 108, 514.
Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1996, 35, 588.

49. Epoxide-Opening Cascades Promoted by Water
Vilotijevic, I.; Jamison, T. F. Science 2007, 317, 1189.

50. Conclusion
The Shi’s epoxidation is a powerful selective and efficient way to make enantioselective epoxides and it is a wonderful tool for the synthesis of building blocks involved in modern total synthesis.

51. Thank you!