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Frédéric Vallée Prof. Charette’s laboratories Literature Meeting 20 th January 2009

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

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Frédéric Vallée Prof. Charette’s laboratories Literature Meeting 20 th January 2009

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  1. Organocatalytic OxidationCatalytic 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, 10452. 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, 4758. 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, 11311. 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 47-100% 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 1983. 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 1992. Subsequently, he carried out his postdoctoral studies at Harvard Medical School with Professor Christopher Walsh from 1992 to 1995. 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, 11224.

  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, 11224.

  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, 11224.

  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, 11224.

  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, 11224.

  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, 11224.

  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, 11224.

  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 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, 11002. 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, 3311-3314. Baumstark, A. L.; Vasquez, P. C. J. Org. Chem. 1988, 53, 3437-3439.

  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, 3311-3314. Baumstark, A. L.; Vasquez, P. C. J. Org. Chem. 1988, 53, 3437-3439.

  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-Gare 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, 11224.

  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, 11224.

  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, 11224.

  37. Steric Effect… Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224.

  38. What about cis and Terminal Olefins? For cis, electronic and steric factors should favor the spiro TS - aand 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, 11224.

  39. What about cis and Terminals olefins? Terminals olefins -ee’s up to 97% with great conversions -The energy difference between these TS seems too small Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224. 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.

  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 ofSynthetic 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.

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