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Organocatalytic Oxidation Catalytic Asymmetric Epoxidation of Olefins with Chiral Ketones and Synthetic Applications Frédéric Vallée Prof. Charette’s laboratories.

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Presentation on theme: "Organocatalytic Oxidation Catalytic Asymmetric Epoxidation of Olefins with Chiral Ketones and Synthetic Applications Frédéric Vallée Prof. Charette’s laboratories."— Presentation transcript:

1 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

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

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

4 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, 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 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, 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 6 Introduction  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

7 7 Introduction Ketone-Catalyzed Epoxidation of Olefins The dioxiranes are generated in situ from ketone and Oxone (2KHSO 5  KHSO 4  K 2 SO 4 ) 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 8 Outline -Introduction -Chiral Ketone-Catalyzed Epoxidation -Carbohydrate-Based and Related Ketones -Synthetic Applications

9 9 Early Ketones Curci, R.; Fiorentino, M.; Serio, M. R. Chem. Commun. 1984, 155. Curci, R.; D’Accolti, L.; Fiorentino, M.; Rosa, A. Tetrahedron Lett. 1995, 36, 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.)

10 10 C 2 -Symmetric Binap-Based Ketones 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, 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 and co-workers

11 11 Other C2-Symmetric Ketones 1997 Song and co-workers 1997 Adam and co-workers Yields from 61-95% Up to 59% ee (6, 1 equiv) 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, Adam, W.; Zhao, C.-G. Tetrahedron: Asymmetry 1997, 8, 3995.

12 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 13 Bicyclo   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, Sartori, G.; Armstrong, A.; Maggi, R.; Mazzacani, A.; Sartorio, R.; Bigi, F. J. Org. Chem. 2003, 68, 3232.

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

15 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 16 Carbohydrate-Based Ketones 1996 Shi and co-workers Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119,

17 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. 2)Fused ring and/or a quaternary center  to the carbonyl minimizes the epimerization of de stereogenic centers. 3)C 2 - or pseudo C 2 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, Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119,

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

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

20 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, H 2 O-CH 3 CN (1:1.5 v/v) (A) and H 2 O-CH 3 CN-DMM (2:1:2 v/v) (B) Plot of the conversion of trans-  - methylstyrene against pH using acetone (3 equiv) as catalyst in H 2 O- CH 3 CN (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) Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, DMM : Dimethoxymethane

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

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

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

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

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

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

27 27 Scope and Substrates Zhu, Y.; Manske, K. J.; Shi, Y. J. Am. Chem. Soc. 1999, 121, 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, Method Limitation : cis and terminal olefins Enol Esters

28 28 Understanding

29 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 30 Understanding Mechanistic studies of disubstituted olefins Baumstark, A. L.; McCloskey, C. J. Tetrahedron Lett. 1987, 28, Baumstark, A. L.; Vasquez, P. C. J. Org. Chem. 1988, 53, The cis-hexenes is more reactive - The reactivity is dependent on the size of the alkyl groups of the olefin

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

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

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

34 34 Stereochemical analysis Bach, R. D.; Andres, J. L.; Owensby, A. L.; Schlegel, H. B. J. Am. Chem. Soc. 1992, 114, Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, Due to steric repulsion B-C-D-F-G are disfavored (for disubstituted, where R 2 =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 General TS analysis

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

36 36 Steric Effect… Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, Decreasing the size R 1 → high ee (spiro A favored) -Increasing the size of R 3 → high ee (spiro A favored) The case of the trisubstituted olefin

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

38 38 What about cis and Terminal Olefins? Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 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.

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

40 40 Ketone Structures Tu, Y.; Wang, Z.-X.; Frohn, M.; He, M.; Yu, H.; Tang, Y.; Shi, Y. J. Org. Chem. 1998, 63, Wang, Z.-X.; Miller, S. M.; Anderson, O. P.; Shi, Y. J. Org. Chem. 2001, 66, 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).

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

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

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

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

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

46 46 Enantioselective Total Synthesis of (+)-Nigellamine A 2 Bian, J.; Van Wingerden, M.; Ready, J. M. J. Am. Chem. Soc. 2006, 128, 7428.

47 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 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 49 Epoxide-Opening Cascades Promoted by Water Vilotijevic, I.; Jamison, T. F. Science 2007, 317, 1189.

50 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 51 Thank you!


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