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Principles and Applications of Asymmetric Synthesis

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190 ALDOL AND RELATED REACTIONS

1991, 113, 9365. (e) Kiyooka, S.; Kaneko, Y.; Komura, M.; Matsuo, H.; Nakano,

M. J. Org. Chem. 1991, 56, 2276.

29.(a) Furuta, K.; Maruyama, T.; Yamamoto, H. J. Am. Chem. Soc. 1991, 113, 1041.

(b) Furuta, K.; Maruyama, T.; Yamamoto, H. Synlett 1991, 439.

30.Carreira, E. M.; Singer, R. A.; Lee, W. J. Am. Chem. Soc. 1994, 116, 8837.

31.Mukaiyama, T. Org. React. 1982, 28, 203.

32.(a) Helmchen, G.; Leikauf, U.; Taufer-KnoÈpfel, I. Angew. Chem. Int. Ed. Engl. 1985, 24, 874. (b) Oppolzer, W.; Marco-Contelles, J. Helv. Chim. Acta 1986, 69, 1699.

33.Oppolzer, W.; Lienard, P. Tetrahedron Lett. 1993, 34, 4321.

34.Enders, D.; Lohray, B. B. Angew. Chem. Int. Ed. Engl. 1988, 27, 581.

35.Meyers, A. I.; Temple, D. L.; Nolen, R. L.; Mihelich, E. D. J. Org. Chem. 1974, 39, 2778.

36.Meyers, A. I.; Knaus, G.; Kamata, K.; Ford, M. E. J. Am. Chem. Soc. 1976, 98, 567.

37.Meyers, A. I.; Yamamoto, Y. J. Am. Chem. Soc. 1981, 103, 4278.

38.Meyers, A. I.; Yamamoto, Y. Tetrahedron 1984, 40, 2309.

39.Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. J. Am. Chem. Soc. 1989, 111, 5493.

40.Corey, E. J.; Lee, D.; Sarshar, S. Tetrahedron Asymmetry 1995, 6, 3.

41.Corey, E. J.; Yu, C. M.; Kim, S. S. J. Am. Chem. Soc. 1989, 111, 5495.

42.Paterson, I.; Mansuri, M. M. Tetrahedron 1985, 41, 3569.

43.Masamune, S.; Sato, T.; Kim, B.; Wollmann, T. A. J. Am. Chem. Soc. 1986, 108, 8279.

44.Duthaler, R. O.; Herold, P.; Lottenbach, W.; Oertle, K.; Riediker, M. Angew. Chem. Int. Ed. Engl. 1989, 28, 494.

45.Mukaiyama, T.; Uchiro, H.; Kobayashi, S. Chem. Lett. 1989, 1001.

46.(a) Kobayashi, S.; Mukaiyama, T. Chem. Lett. 1989, 297. (b) Kobayashi, S.; Uchiro, H.; Shiina, I.; Mukaiyama, T. Tetrahedron 1993, 49, 1761.

47.(a) Iwasawa. N.; Mukaiyama, T. Chem. Lett. 1982, 1441. (b) Mukaiyama, T.; Iwasawa, N.; Stevens, R. W.; Haga, T. Tetrahedron 1984, 40, 1381.

48.Hannun, Y. A.; Loomis, C. R.; Merrill, A. H.; Bell, R. M. J. Biol. Chem. 1986, 261, 12604.

49.(a) Kiso, M.; Nakamura, A.; Tomita, Y.; Hasegawa, A. Carbohydr. Res. 1986, 158, 101. (b) Herold, P. Helv. Chim. Acta 1988, 71, 354. (c) Garner, P.; Park; J. M.; Malecki, E. J. Org. Chem. 1988, 53, 4395. (d) Julina, R.; Herzig, T.; Bernet, B.; Vasella, A. Helv. Chim. Acta 1986, 69, 368. (e) Ito, Y.; Sawamura, M.; Hayashi, T.

Tetrahedron Lett. 1988, 29, 239. (f ) Sugawara, T.; Narisada, M. Carbohydr. Res.

1989, 194, 125. (g) Fujita, S.; Sugimoto, M.; Tomita, K.; Nakahara, Y.; Ogawa, T. Agric. Biol. Chem. 1991, 55, 2561. (h) Marukami, T.; Minamikawa, H.; Hato, M.

Tetrahedron Lett. 1994, 35, 745.

50.(a) Kobayashi, S.; Hayashi, T.; Kawasuji, T. Tetrahedron Lett. 1994, 35, 9573.

(b) For more on the synthesis of sphingosine, sphingofungins B and F see: Kobayashi S.; Furuta, T. Tetrahedron 1998, 54, 10275.

51.Nelson, S. G. Tetrahedron Asymmetry 1998, 9, 357.

3.10 REFERENCES 191

52.Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405.

53.(a) Sawamura, M.; Ito, Y.; Hayashi, T. Tetrahedron Lett. 1989, 30, 2247. (b) Ito, Y.; Sawamura, M.; Hayashi, T. Tetrahedron Lett. 1988, 29, 239.

54.Ito, Y.; Sawamura, M.; Hamashima, H.; Emura, T.; Hayashi, T. Tetrahedron Lett. 1989, 30, 4681.

55.(a) Corey, E. J.; Barnes-Seeman, D.; Lee, T. W. Tetrahedron Lett. 1997, 38, 1699.

(b)Corey, E. J.; Rohde, J. J. Tetrahedron Lett. 1997, 38, 37.

56.(a) Keck, G. E.; Krishnamurthy, D. J. Am. Chem. Soc. 1995, 117, 2363. (b) Mikami, K.; Matsukawa, S. J. J. Am. Chem. Soc. 1994, 116, 4077. (c) Corey E. J.; Cywin, C. L.; Roper, T. D. Tetrahedron Lett. 1992, 33, 6907. (d) Parmee, E. R.; Hong, Y.; Tempkin, O.; Masamune, S. Tetrahedron Lett. 1992, 33, 1729. (e) Kiyooka, S.; Kaneko, Y.; Kume, K. Tetrahedron Lett. 1992, 33, 4927. (f ) Yanagisawa, A.; Matsumoto, Y.; Nakashima, H.; Asakawa, K.; Yamamoto, H. J. Am. Chem. Soc. 1997, 119, 9319, and references therein.

57.Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669.

58.Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay S. W. J. Am. Chem. Soc. 1999, 121, 686.

59.(a) KruÈger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120, 837. (b) Pagenkopf, B.; KruÈger, J.; Stojanovic, A.; Carreira, E. M. Angew. Chem. Int. Ed. Engl. 1998, 37, 3124.

60.(a) Pereyre, M.; Quintard, J.; Rahm, A. Tin in Organic Synthesis, Butterworths, London, 1987, p 286. (b) Davies, A. G. Organotin Chemistry, VCH, Weinheim, 1997, p 185.

61.Yanagisawa, A.; Matsumoto, Y.; Asakawa, K.; Yamamoto, H. J. Am. Chem. Soc. 1999, 121, 892.

62.Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew. Chem. Int. Ed. Engl. 1997, 36, 1871.

63.Yamada, Y. M. A.; Shibasaki, M. Tetrahedron Lett. 1998, 39, 5561.

64.Masamune, S.; Kaiho, T.; Garvey, D. S. J. Am. Chem. Soc. 1982, 104, 5521.

65.Masamune, S.; Choy, W.; Kerdesky, F. A. J.; Imperiali, B. J. Am. Chem. Soc. 1981, 103, 1566.

66.Masamune, S.; Ali, S. A.; Snitman, D. L.; Garvey, D. S. Angew. Chem. Int. Ed. Engl. 1980, 19, 557.

67.Short, R. P.; Masamune, S. Tetrahedron Lett. 1987, 28, 2841.

68.(a) For a review about allylation of carbonyl groups by allylic metals as a highly e½cient tool for selective functionalization, see Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207. (b) For a review about the addition of allylic tin reagents to carbonyl compounds, see Marshall, J. A. Chem. Rev. 1996, 96, 31. (c) For a review about the nucleophilic addition of chiral modi®ed allylboron reagents to imines, see Itsuno, S.; Watanabe, W.; Ito, K.; EI-Shehawy, A. A.; Sarhan, A. A. Angew. Chem. Int. Ed. Engl. 1997, 36, 109.

69.Haruta, R.; Ishiguro, M.; Iketa, N.; Yamamoto, H. J. Am. Chem. Soc. 1982, 104, 7667.

70.(a) Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc. 1985, 107, 8186.

(b)Roush, W. R.; Halterman, R. L. J. Am. Chem. Soc. 1986, 108, 294.

192ALDOL AND RELATED REACTIONS

71.Fujita, K.; Schlosser, M. Helv. Chim. Acta 1982, 65, 1258.

72.Roush, W. R.; Hoong, L. K.; Palmer, M. A. J.; Park, J. J. Org. Chem. 1990, 55, 4109.

73.Roush, W. R.; Hoong, L. K.; Palmer, M. A. J.; Straub, J. A.; Palkowitz, A. D.

J.Org. Chem. 1990, 55, 4117.

74.Roush, W. R.; Palkowitz, A. D.; Palmer, M. A. J. J. Org. Chem. 1987, 52, 316.

75.Garcia, J.; Kim, B. M.; Masamune, S. J. Org. Chem. 1987, 52, 4831.

76.Roush, W. R.; Brown, B. B.; Drozda, S. E. Tetrahedron Lett. 1988, 29, 3541.

77.Roush, W. R.; Sciotti, R. J. Tetrahedron Lett. 1992, 33, 4691.

78.(a) Hunt, J. A.; Roush, W. R. Tetrahedron Lett. 1995, 36, 501. (b) Hunt, J. A.; Roush, W. R. J. Org. Chem. 1997, 62, 1112.

79.Brown, H. C.; Phadke, A. S. Synlett 1993, 927.

80.(a) Ho¨mann, R. W.; Herold, T. Chem. Ber. 1981, 114, 375. (b) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401.

81.Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-Streit, P.; Schwarzenbach,

F.J. Am. Chem. Soc. 1992, 114, 2321.

82.(a) Hathaway, S. J.; Paquette, L. A. J. Org. Chem. 1983, 48, 3351. (b) Coppi, L.; Mordini, A.; Taddei, M. Tetrahedron Lett. 1987, 28, 969. (c) Nativi, C.; Ravida, N.; Ricci, A.; Seconi, G.; Taddei, M. J. Org. Chem. 1991, 56, 1951. (d) Chan, T. H.; Wang, D. Tetrahedron Lett. 1989, 30, 3041.

83.(a) Otera, J.; Kawasaki, Y.; Mizuno, H.; Shimizu, Y. Chem. Lett. 1983, 1529. (b) Otera, J. Yoshinaga, Y. Yamaji, T.; Yoshioka, T.; Kawasaki, Y. Organometallics 1985, 4, 1213. (c) Boldrini, G. P.; Tagliavini, E.; Trombini, C.; Umandi-Ronchi, A.

J.Chem. Soc. Chem. Commun. 1986, 685. (d) AugeÂ, J.; Bourleaux, G. J. Organomet. Chem. 1989, 377, 205.

84.Denmark, S. E.; Weber, E. J. Helv. Chim. Acta 1983, 66, 1655.

85.Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 1295.

86.(a) Denmark, S. E.; Almstead, N. G. J. Org. Chem. 1994, 59, 5130. (b) Denmark,

S.E.; Hosoi, S. J. Org. Chem. 1994, 59, 5133.

87.(a) Kobayashi, S.; Nishio, K. Tetrahedron Lett. 1993, 34, 3453. (b) Kobayashi, S.; Nishio, K; Synthesis 1994, 457.

88.Iseki, K.; Mizuno, S.; Kuroki, Y.; Kobayashi, Y. Tetrahedron Lett. 1998, 39, 2767.

89.Furuta, K.; Mouri, M.; Yamamoto, H. Synlett 1991, 561.

90.Costa, A. L.; Piazza, M. G.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A.

J.Am. Chem. Soc. 1993, 115, 7001.

91.Keck, G. E.; Geraci, L. S. Tetrahedron Lett. 1993, 34, 7827.

92.Bedeschi, P.; Casolari, S.; Costa, A. L.; Tagliavini, E.; Umani-Ronchi, A. Tetrahedron Lett. 1995, 36, 7897.

93.Reetz, M. T.; Zierke, T. Chem. Ind. 1988, 663.

94.Roush, W. R.; Ban®, L. J. Am. Chem. Soc. 1988, 110, 3979.

95.Short, R. P.; Masamune, S. J. Am. Chem. Soc. 1989, 111, 1892.

96.Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org. Chem. 1986, 51, 432.

97.Brown, H. C.; Randad, R. S.; Bhat, K. S.; Zaidlewicz, M.; Racherla, U. S. J. Am. Chem. Soc. 1990, 112, 2389.

3.10 REFERENCES 193

98.For a recent review on addition of organometallic reagent to CbN bonds, see Bloch, R. Chem. Rev. 1998, 98, 1407.

99.Watanabe, K.; Ito, K.; Itsuno, S. Tetrahedron Asymmetry 1995, 6, 1531.

100.(a) Nakamura, H.; Iwama, H.; Yamamoto, Y. J. Chem. Soc. Chem. Commun. 1996, 1459. (b) Nakamura, H.; Iwama, H.; Yamamoto, Y. J. Am. Chem. Soc. 1996, 118, 6641.

101.Nakamura, H.; Nakamura, K.; Yamamoto, Y. J. Am. Chem. Soc. 1998, 120, 4242.

102.Park, J. Y.; Park, C. H.; Kadota, I.; Yamamoto, Y. Tetrahedron Lett. 1998, 39, 1791.

103.For other references on the asymmetric allylation of imines, see (a) Yamamoto, Y.; Nishii, S.; Maruyama, K.; Komatsu, T.; Ito, W. J. Am. Chem. Soc. 1986, 108, 7778. (b) Basile, T.; Bocoum, A.; Savoia, D.; Umani-Ronchi, A. J. Org. Chem. 1994, 59, 7766.

104.For review, see, for example, Kleinman, E. F., in Trost, B. M.; Fleming, I. eds. Comprehensive Organic Synthesis, Pergamon Press, New York, 1991, vol. 2, p 893, and references therein.

105.Denmark, S. E.; Nakajima, N.; Nicaise, O. J. J. Am. Chem. Soc. 1994, 116, 8797.

106.(a) Soai, K.; Hatanaka, T.; Miyazawa, T. J. Chem. Soc., Chem. Commun. 1992, 1097. (b) Suzuki, T.; Narisata, N.; Shibata, T.; Soai, K. Tetrahedron Asymmetry 1996, 7, 2519. (c) Anderson, P. G.; Guijarro, D.; Tanner, D. Synlett 1996, 727.

107.Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am. Chem. Soc. 1998, 120, 2474.

108.Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 4548.

109.Ferraris, D.; Young, B.; Cox, C.; Drury, W. J.; Dudding, T.; Lectka, T. J. Org. Chem. 1998, 63, 6090.

110.(a) Howe, R.; Rao, B. S.; Holloway, B. R.; Stribling, D. J. Med. Chem. 1992, 35, 1751. (b) Bloom, J. D.; Dutia, M. D.; Johnson, B. D.; Wissner, A.; Burns, M. G.; Largis, E. E.; Dolan, J. A.; Claus, J. H. J. Med. Chem. 1992, 35, 3081.

111.Askin, D.; Wallace, M. A.; Vacca, J. P.; Reamer, R. A.; Volante, R. P.; Shinkai, I.

J.Org. Chem. 1992, 57, 2771.

112.Ohfune, Y. Acc. Chem. Res. 1992, 25, 360.

113.Kobayashi, S.; Ishitani, H.; Ueno, M. J. Am. Chem. Soc. 1998, 120, 431, and the references cited therein.

114.Nef, J. U. Liebigs Ann. Chem. 1894, 280, 263.

115.For an introduction to Henry reactions, see Coombes, R. G., in Barton, D.; Ollis,

W.D. eds. Comprehensive Organic Chemistry, Pergamon, Oxford, 1979, Vol. 2, p 303.

116.Sasai, H.; Itoh, N.; Suzuki, T.; Shibasaki, M. Tetrahedron Lett. 1993, 34, 855.

117.Sasai, H.; Suzuki, T.; Ito, N.; Arai, S.; Shibasaki, M. Tetrahedron Lett. 1993, 34, 2657.

118.Sasai, H.; Yamada, Y. M. A.; Suzuki, T.; Shibasaki, M. Tetrahedron 1994, 50, 12313.

119.Sasai, H.; Kim, W.; Suzuki, T.; Shibasaki, M. Tetrahedron Lett. 1994, 35, 6123.

120.Rosini, G.; Ballini, R. Synthesis 1988, 833.

Principles and Applications of Asymmetric Synthesis

Guo-Qiang Lin, Yue-Ming Li, Albert S.C. Chan

Copyright ( 2001 John Wiley & Sons, Inc.

ISBNs: 0-471-40027-0 (Hardback); 0-471-22042-6 (Electronic)

CHAPTER 4

Asymmetric Oxidations

The asymmetric oxidation of organic compounds, especially the epoxidation, dihydroxylation, aminohydroxylation, aziridination, and related reactions have been extensively studied and found widespread applications in the asymmetric synthesis of many important compounds. Like many other asymmetric reactions discussed in other chapters of this book, oxidation systems have been developed and extended steadily over the years in order to attain high stereoselectivity. This chapter on oxidation is organized into several key topics. The ®rst section covers the formation of epoxides from allylic alcohols or their derivatives and the corresponding ring-opening reactions of the thus formed 2,3-epoxy alcohols. The second part deals with dihydroxylation reactions, which can provide diols from ole®ns. The third section delineates the recently discovered aminohydroxylation of ole®ns. The fourth topic involves the oxidation of unfunctionalized ole®ns. The chapter ends with a discussion of the oxidation of enolates and asymmetric aziridination reactions.

4.1 ASYMMETRIC EPOXIDATION OF ALLYLIC ALCOHOLS: SHARPLESS EPOXIDATION

Asymmetric epoxidation of allylic alcohols was once one of the leading areas of investigation in synthetic organic chemistry, mainly due to the fact that very high enantioselective induction for a wide range of substrates is possible using several classes of reagents. In terms of both chemical and optical yields, this procedure allows a chemical reaction to compete with an enzymatic process. Among the reagents serving as an essential element in epoxidation, the Sharpless titanium method needs to be introduced ®rst.

In studies of the asymmetric epoxidation of ole®ns, chiral peroxycarboxylic acid±induced epoxidation seldom gives enantiomeric excess over 20%.1 Presumably, this is due to the fact that the controlling stereocenters in peroxycarboxylic acids are too remote from the reaction site. An enantiomeric excess of over 90% has been reported for the poly-(S)-alanine±catalyzed epoxidation of chalcone.2 The most successful nonmetallic reagents for asymmetric epoxidation have been the chiral N-sulfonyloxaziridines3 until asymmetric epoxidation reactions mediated by chiral ketones were reported. Today, the

195

196 ASYMMETRIC OXIDATIONS

Figure 4±1. The Sharpless epoxidation reaction.

most successful asymmetric epoxidation reaction is the titanate-mediated epoxidation of allylic alcohols, or Sharpless epoxidation, which enables the achievement of an enantiomeric excess of over 90% in most cases.

The development of transition metal±mediated asymmetric epoxidation started from the dioxomolybdenum-N-ethylephedrine complex,4 progressed to a peroxomolybdenum complex,5 then vanadium complexes substituted with various hydroxamic acid ligands,6 and the most successful procedure may now prove to be the tetroisopropoxyltitanium-tartrate±mediated asymmetric epoxidation of allylic alcohols.

The Sharpless epoxidation is a popular laboratory process that is both enantioselective and catalytic in nature. Not only does it employ inexpensive reagents and involve various important substrates (allylic alcohols) and products (epoxides) in organic synthesis, but it also demonstrates unusually wide applicability because of its insensitivity to many aspects of substrate structure. Selection of the proper chirality in the starting tartrate esters and proper geometry of the allylic alcohols allows one to establish both the chirality and relative con®guration of the product (Fig. 4±1).

Since its discovery in 1980,7 the Sharpless expoxidation of allylic alcohols has become a benchmark classic method in asymmetric synthesis. A wide variety of primary allylic alcohols have been epoxidized with over 90% optical yield and 70±90% chemical yield using TBHP (t-BuOOH) as the oxygen donor and titanium isopropoxide-diethyl tartrate (DET, the most frequently used dialkyl tartrate) as the catalyst. One factor that simpli®es the standard epoxidation reaction is that the active chiral catalyst is generated in situ, which means that the pre-preparation of the active catalyst is not required.

The wide scope application of this transformation arises not only from the utility of epoxide compounds but also from the subsequent regiocontrolled and stereocontrolled nucleophilic substitution (ring-opening) reactions of the derived epoxy alcohol. These, through further functionalization, allow access to an impressive array of target molecules in enantiomerically pure form.

Like the vanadium-based epoxidation reaction, the Sharpless reaction in-

4.1 ASYMMETRIC EPOXIDATION OF ALLYLIC ALCOHOLS: SHARPLESS EPOXIDATION

197

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Scheme 4±1. Kinetic resolution of secondary allylic alcohols.

trinsically favors 1,2-anti products. With a racemic allylic alcohol, one of the enantiomers reacts faster, and this rate di¨erentiation step can be used to selectively epoxidize the more reactive enantiomer in the presence of its antipode. In general, by reducing the amount of TBHP to 0.6 equivalent in the reaction system, the same reaction can be used to kinetically resolve secondary allylic alcohols (Scheme 4±1).8

4.1.1The Characteristics of Sharpless Epoxidation

For the asymmetric epoxidation of achiral allyl alcohols, high ee can normally be obtained. For example, in Scheme 4±2, asymmetric epoxidation of the achiral allylic alcohol 5 provides epoxyl alcohol (6) with a selectivity of 99:1.

The idea of double asymmetric induction is also applicable to asymmetric epoxidation (see Chapter 1 for double asymmetric induction). In the case of asymmetric epoxidation involving double asymmetric induction, the enantioselectivity depends on whether the con®gurations of the substrate and the chiral ligand are matched or mismatched. For example, treating 7 with titanium tetraisopropoxide and t-butyl hydroperoxide without (‡)- or (ÿ)-diethyl tartrate yields a mixture of epoxy alcohols 8 and 9 in a ratio of 2.3:1 (Scheme 4±3). In a

Scheme 4±3

Scheme 4±2

198 ASYMMETRIC OXIDATIONS

double asymmetric reaction, asymmetric epoxidation reaction of 7 with (‡)- or (ÿ)-diethyl tartrate proceeds smoothly to provide the epoxides 8 and 9 in ratios of 1:22 and 90:1, referring to the mismatched and matched cases, respectively.

In Sharpless epoxidation reactions, (Z)-substituted allylic alcohols react much more slowly than the corresponding (E )-substituted substrates, and sometimes the reaction is sensitive to the position of preexisting chirality in the selected substrate. For instance, in the presence of (‡)-DET, chiral (E )-allylic alcohol 10 undergoes epoxidation in 15 hours to give product 11 as the major product with a diastereomeric ratio of >20:1. As for reaction with (ÿ)-DET, 12 is then obtained, also with a diastereoselectivity of >20:1 (Scheme 4±4).

Scheme 4±4

In the case of (Z)-allylic alcohol 13, however, it takes 2 weeks to get product 14 in a ratio of 14:15 ˆ 30:1 for matched pairs, while the epoxide 14 is obtained in the much lower ratio of 14:15 ˆ 3:2 for mismatched pairs (Scheme 4±5).

Scheme 4±5

4.1 ASYMMETRIC EPOXIDATION OF ALLYLIC ALCOHOLS: SHARPLESS EPOXIDATION

199

In summary, the following characteristics describe the e¨ectiveness of this epoxidation reaction.

. Simplicity: All the ingredients are inexpensive and commercially available.

.Reliability: It succeeds with most allylic alcohols, although bulky substituents at R are deleterious (Fig. 4±1).

.High optical purity: Optical purity of the product is generally >90% ee and usually >95% (99.5% ee is the highest measured accurately to date).

.Predictable absolute stereochemistry: Thus far, when dealing with a prochiral allylic alcohol substrate, no exception to the rules laid down in Figure 4±1 has been observed.

.Relative insensitivity to preexisting chiral centers: In allylic alcohols with preexisting chiral centers, the diastereofacial preference of the chiral tita- nium-tartrate catalyst is often strong enough to override diastereofacial preferences inherent in the chiral ole®nic substrate.

.Versatility of 2,3-epoxy alcohols as intermediates: New selective transformations widen the utility and signi®cance of the reaction.

4.1.2Mechanism

There are several Ti±tartrate complexes present in the reaction system. It is believed that the species containing equal moles of Ti and tartrate is the most active catalyst. It promotes the reaction much faster than Ti(IV) tetraalkoxide alone and exhibits selective ligand-accelerated reaction.9

Sharpless suggested that epoxidation was catalyzed by a single Ti center in a dimeric complex with a C2 symmetric axis. Molecular weight measurement, infrared spectroscopy, and 1H, 13C, and 17O NMR spectrometry all suggest that such a dinuclear structure is dominant in the solution phase (Fig. 4±2).10 As shown in Scheme 4±6, the reaction proceeds via a Ti(IV) mixed-ligand complex A bearing allyl alkoxide and TBHP anions as ligands. The alkyl peroxide is electrophilically activated by bidentate coordination to the Ti(IV) center. Oxygen transfer to the ole®nic bond occurs to provide the complex B, in which Ti(IV) is coordinated by epoxy alkoxide and t-butoxide. In complex B,

Figure 4±2. Structure of dinuclear Ti±tartrate complexes.

200 ASYMMETRIC OXIDATIONS

Scheme 4±6. Mechanism of Ti-catalyzed Sharpless epoxidation.

alkoxide products are replaced by allylic alcohol and TBHP to regenerate A and complete the catalytic cycle. It seems clear that enantioselectivity is controlled by the chiral ligands on Ti(IV), which determines the conformation of the coordinated allylic alcohol. The exact nature of the catalytic species remains only partially understood.

Corey11 also proposed another mechanism for the origin of enantioselectivity in the reaction by suggesting the presence of an ion pair in the reaction pathway. Interested readers are advised to consult the original papers.

4.1.3Modi®cations and Improvements of Sharpless Epoxidation

4.1.3.1 The CaH2/SiO2 System. Almost by chance, Zhou and colleagues found that the reaction time in Sharpless epoxidation could be reduced dramatically by adding a catalytic amount of calcium hydride and silica gel to the reaction system, although the mechanism is not yet clari®ed (Table 4±1).12

Using this modi®cation, Zhou et al.13 succeeded in the kinetic resolution of a-furfuryl amide 16a±f (Scheme 4±7).

Under these oxidation conditions, (S)-16a±f and (R)-16a±f remain as part of the slow reacting enantiomers and can be obtained in high enantiomeric purity (90±100% ee) and 40±50% chemical yield when using the corresponding l-(‡)- and d-(ÿ)-DIPT. It should be pointed out that 2.0±2.5 equivalents of TBHP is required to get @50% conversion. Otherwise, the reaction proceeds extremely

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