Title

對exo-glycals的醣加成反應作合成上的探討

DOI

10.6342/NTU.2004.01368

Authors

許勝傑

Key Words

費里爾重排 ; 共軛醣 ; ferrier rearrangement ; glycoconjugate

PublicationName

臺灣大學生化科學研究所學位論文

Volume or Term/Year and Month of Publication

2004年

Academic Degree Category

碩士

Advisor

林俊宏

Content Language

繁體中文

Chinese Abstract

摘 要 Glycals是帶有不飽和官能基之糖分子,依照其雙鍵的位置可分為環外雙鍵:稱為exo-glycals,與環內雙鍵:稱為endo-glycals。就醣類化學的研究而言,edno-glycals已被開發出多種的反應用來合成包括了路易斯和血型抗原、神經節醣、與腫瘤抗原有關的醣共軛分子。所以結構上類似的exo-glycals應具有相當的應用性,但迄今甚少有文獻提及。本實驗室先前曾製備延伸基團為羥基或醋酸根之exo-glycals,以外加的醇類化合物作為親核劑,進行高度立體選擇性的醣加成反應,成它a合成雙醣、醣胜肽與醣脂質之類的醣類分子衍生物,並且有相當不錯的產率,初步証實exo-glycals的反應性並不亞於endo-glycals。因產物皆有雙鍵位移的現象,所以這個加成反應屬於費里爾 (Ferrier) 型式的重排。 本論文的研究主題在於探討exo-glycals以不同的條件進行費里爾重排反應所造成的影響,以擴大在合成化學上的應用性,並進而製備具有生理義意醣類分子。我們將特別深入研究分子間與分子內的醣加成反應。 在分子間醣加成反應部份,本論文合成延伸基團為第三丁氧羰基 (t-Boc) 之exo-glycal,以外加的醇類化合物作為親核劑,進行重排反應。在此,對於影響反應性的四個因素加以探討,包括:溫度、溶劑、路易士酸與親核劑。我們首先要探討以不加入路易士酸加熱方式能否驅動重排反應,再與路易士酸存在下加熱方式相比較,觀測反應效益是否有所提升。接著選取不同種類的溶劑進行實驗,嘗試找出可將重排反應的效能發揮至最大的溶劑。再來以IIA族、IIIA族、IVA族、過渡金屬與後過渡金屬元素之路易士酸催化反應,觀察重排反應是否可用不同類型的路易士酸催化反應,並尋找出較適合重排反應之路易士酸。最後,將多種親核劑(如:單醣分子、胺基酸、立障大之醇類分子) 以較適合之溶劑與路易士酸進行重排反應,並將數據與之前本實驗室的成果比較之。 於分子內重排方面,我們將exo-glycals的延伸基團連接不同的醇類分子,包括:正丁醇、正戊醇、苯甲醇、甲氧乙醇、單醣分子。以加熱反應與路易士酸 (BF3.OEt2、TMSOTf)催化二種方式比較其加成的反應性,探討分子內醣加成反應的可行性,並且將所得之結果與上述分子間醣加成反應的對照之。 由分子間醣加成反應的實驗資料顯示,硝基烷類與二氯甲烷皆為加成反應的最佳溶劑。在路易士酸方面,加成反應對路易士酸並無太高的偏好。A族、過渡金屬與後過金屬元素之路易士酸大都可驅動重排反應,並且有相當不錯的產率。以多種親核劑與exo-glycals反應亦大都有不錯的反應性。在分子內醣加成的部份,熱裂解與路易士酸均尚未找到最佳的條件,而無法得到令人滿意產率。

English Abstract

Abstract Glycals are unsaturated sugars containing the olefin in the anomeric position. endo- or exo-Glycals designate the double bond located inside or outside the sugar ring, respectively. endo-Glycals have been extensively studied to synthesize various biologically significant carbohydrates, including Lewis and blood group determinants, gangliosides and tumor-associated antigens. Consequently it is reasonable to consider analogous exo-glycals as useful and versatile synthons. However, the studies of exo-glycals were not available until recently. Our laboratory developed an expeditious method in the past to prepare exo-glycals that are reactive with various alcohols to proceed glycosyl additions. The reactions were carried out with high yield and exclusive stereoselectivity, to afford a number of disaccaarides, glycopeptides and glycolipid. All of the products had a β-vinyl group resulting from allylic rearrangement, reminiscent of the Ferrier reaction in the glycosylation of endo-glycals. This thesis aims to investigate in detail the Ferrier rearrangement of exo-glycals in order to broaden the synthetic usage for the preparation of various important glycoconjugates. Special emphasis was laid on the inter- and intra-molecular glycosylation. In the study of the former reaction, t-butyl carbonate (t-Boc) is attached to the exo-glycosyl double bond and considered to provide an extra driving force at elevated temperature in the glycosylation. Several factors, including temperature, Lewis acid and solvent were studied to acquire the optimal condition that was further applied for the glycosylation of exo-glycals with a number of monosaccharides, amino acids and alcohols. The latter investigation intended to understand if the Ferrier-type rearrangement is applicable to intramolecular glycosylation. Several exo-glycosyl carbonates were prepared to contain different substituents including n-butanol, benzyl alcohol and protected monosaccharide. The glycosylation was carried out in the existence of Lewis acid (BF3.OEt2 or TMSOTf) or at elevated temperature. So far only moderate yields were obtained.

Topic Category 生命科學院 > 生化科學研究所
生物農學 > 生物科學
Reference
  1. 2. Lindhorst, T. K. Essentials of Carbohydrate Chemistry and Biochemistry, 1st Ed.; Wiley-Vch: Weinheim, 1999; pp 3-31.
    連結:
  2. 6. (a) Itzkowitz, S. H.; Yuan, M.; Montgomery, C. K.; Kjeldsen, T.; Takahashi, H. K.; Bigbee, W. L. Cancer Res. 1989, 49, 197. (b) Itzkowitz, S. H.; Bloom, E. J.; Kokal, W. A.; Modin, G.; Hakomori, S.; Kim, Y. S. Cancer 1990, 65, 1960. (c) Werther, J. L.; Tatematsu, M.; Klein, R.; kurihara, M.; Kumagai, K.; Llorens, P.; Neto, J. G.; Bodian, C.; Pertsemlidis, D.; Yamachika, T.; Kitou, T. Int. J. Cancer 1996, 69, 193. (d) Miyajima, K.; Nekado, T.; Ikeda, K.; Achiwa, K. Chem. Pharm. Bull. 1998, 46, 11, 1676 (e) Miyajima, K.; Nekado, T.; Ikeda, K.; Achiwa, K. Chem. Pharm. Bull. Jpn. 1997, 45, 9, 1544.
    連結:
  3. 8. Raetz, C. R.; Withfield, C. Annu. Rev. Biochem. 2002, 71, 635.
    連結:
  4. 11. Ferrier, R. J. Adv. Carbohydr. Chem. Biochem. 1965, 20, 67.
    連結:
  5. 13. (a) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem. Int. Ed. Engl. 1996, 35, 1380.
    連結:
  6. 14. Ferrier, R. J. Adv. Carbohydr. Chem. Biochem. 1969, 199.
    連結:
  7. 16. Ferrier, R. J. J. Chem. Soc. (C) 1964, 5443
    連結:
  8. 19. Seeberger, P. H.; Danishefsky, S. J. Acc. Chem. Res. 1998, 31, 685.
    連結:
  9. 21. Ciment, D. M.; Ferrier, R. J. J. Chem. Soc. (C) 1966, 441
    連結:
  10. 23. Claude T.; Yves C. Chem. Rev. 2004, 104, 263.
    連結:
  11. 25. Suh, H.; Wilcox, C. S. J. Am. Chem. Soc. 1988, 110, 470.
    連結:
  12. 26. (a) Yang, W. B.; Chang, C. F.; Wang, S. H.; Teo, C. F.; Lin, C. H. Tetrahedron Lett. 2001, 42, 4657. (b) Yang, W. B.; Wu, C. Y.; Chang, C. C.; Wang. S. H.; Teo. C. F.; Lin, C. H. Tetrahedron Lett. 2001, 42, 6907. (c) Yang, W. B.; Yang, Y. Y.; Gu, Y. F.; Wang, S. H.; Chang, C. C.; Lin, C. H. J. Org. Chem. 2002, 67, 3773.
    連結:
  13. 28. Tomooka, K.; Nakamura, Y.; Nakai, T. Synlett 1995, 321.
    連結:
  14. 33. Lin, C. H.; Yang, W. B.; Gu Y. F.; Chen, C. Y.; Wu, C. Y.; Lin C. H. Org. Lett. 2003, 5, 1087.
    連結:
  15. 40. (a) Ho, T.-L. Hard and Soft Acids and Bases Principle in Organic Chemistry, Academic Press: New York, 1977. (b) Ho, T.-L. Tetrahedron 1985, 41, 3. (c) Ralph, G. P. J. Chem. Edu. 1968, 45, 581.
    連結:
  16. 42. Gladding, E. K.; Purves C. B. J. Am. Chem. Soc. 1944, 66, 76.
    連結:
  17. 參考文獻
  18. 1. Varki, A.; Cummings, R.; Esko, J.; Freeze, H.; Hart, G.; Marth, J., Eds.; Essential of Glycology; Cold Spring Harbor: New York, 1999; pp1-57.
  19. 3. Fukuda, M., Ed.; Cell surface Carbohydrate and Cell Development, 1st ed.; CRC: Boca Raton, 2000; pp 1-24.
  20. 4. Galustian C.; Childs, R.A.; Yuen, C. T.; Hasegawa, A.; Kiso, M.; Lubineau, A.; Shaw G.; Feizi, T. Biochemistry 1997, 36, 5260.
  21. 5. (a) Desai, P. R. Transfus. Med. Rev. 2000, 14, 312. (b) Schwartz, B.; Bresalier, R. S.; Kim, Y. S. Int. J. Cancer 1992, 52, 60. (c) Brockhausen, I.; Yang, J.-M.; Burchell, J.; Whitehouse, C.; Taylor-Papadimitriou, J. Eur. J. Biochem. 1995, 233, 307.
  22. 7. (a) Moran, A. P. Aliment Pharmacol. Ther. 1996, 10, 39. (b) Moran, A. P.; Prendergast M. M.; Appelmelk B. J. FEMS Immunol. Med Microbiol. 1996, 16, 105.
  23. 9. (a) Monteiro M. A.; Chan, K.-H.; Rasko, D. A.; Taylor, D.E.; Zheng, P.-Y.; Yang, M.; Blaster, M. J.; Hynes, S. O.; Moran, A. P.; Perry, M. B. J. Biol. Chem. 1998, 273, 11533. (b) Appelmelk B. J.; Negrini, R.; Moran, A. P.; Kuipers, E. J. Trends. Microbiol. 1997, 5, 70.
  24. 10. (a) Barrett, A. G. M.; Pena, M.; Willardsen, J. A. J. Chem. Soc., Chem. Commun. 1995, 1145. (b) Barrett, A. G. M.; Pena, M.; willardsen, J. A. J. Chem. Soc., Chem. Commun. 1995, 1147.
  25. 12. (a) Cavallaro, C. L.; Schwartz, J. J. Org. Chem. 1995, 60, 7055. (b) Spencer, R. P.; Cavallaro, C. L.; Schwartz, J. J. Org. Chem. 1999, 64, 3987. (c) Hansen, T.; Krintel, S. L.; Daasbjerg, K.; Skrydstrup, T. Tetrahedron Lett. 1999, 40, 6087. (d) Pouilly, P.; Chenede, A.; Mallet, J. M.; Sinay, P. Tetrahedron Lett. 1992, 33, 8065. (e) Casillas, M.; Gomez, A. M.; Lopez, J. C.; Valverde, S. Synlett 1996, 628. (f)Diaz, R. R.; Melgarejo, C. R.; Cubero, I. I., Lopez-Espinosa, M. T. P. Carbohydr. Res. 1997, 300, 375. (g) Csuk, R.; Furstner, A.; Glänzer, B. I.; Weidmann, H. J. Chem. Soc., Chem. Commun. 1986, 1149. (h) Walker, J. A.; Chen, J. J.; Wise, D. S.; Townsend, L. B. J. Org. Chem. 1996, 61, 2219. (i) Bravo, F.; Kassou, M.; Castillón, S. Tetrahedron Lett. 1999, 40, 1187.
  26. 15. (a) Thiem, J.; Klaffke, W. J. Org. Chem. 1989, 54, 2006. Lemieux, R. U.; Fraser-Reid, B. Can. J. Chem. 1965, 43, 1460. (b) Lemieux, R.U.; Levine, S. Can. J. Chem. 1964, 42, 1473. (c) Friesen, R.W.; Danishesfky, S. J. Tetrahedron 1990, 46, 103. (d) Lemieux, R. U.; Ratcliffe, R.M. Can. J. Chem. 1979, 57, 1244. (e) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1380. (f) Snider, B. B.; Lin, H. Syn. Commun. 1998, 28, 1913. (g) Rollin, P.; Sinay, P. Carbohydr. Res. 1981, 98, 1913. (h) Czernecki, S. et al. Tetrahedron Lett. 1992, 33, 221. (i) Czernecki, S. et al. Tetrahedron Lett. 1992, 33, 221.
  27. 17. (a)Grzegorz, G.; Waldemar, P.; Aleksander, Z. Carbohydr. Res. 1979, 68, 33. (b) J. Cristobal, L.; Ana, M. G.; Serafin, V.; Bert, F.-R. J. Org. Chem. 1995, 60, 3851. (c) Eusebius, W.; Joachim, T. Carbohydr. Res. 1998, 307, 263. (d) Saibal, K. D.; K. Anantha, R.; Joyita, R. Synlett 2003, 1607. (e) Simon, N. T.; Timothy, G. Synlett 1996, 185. (f) Jean H.; Kipamga, M.; Lotfi, B.; Kostas, A. J. Chem. Soc., Perkin Trans I 1990, 1995. (g) Jhillu, S. Y.; Vhasi, V. S. R. Synthesis 2002, 511. (h) B. K. Bettadaiah; P. Sronivas Tetrahedron Lett. 2003, 44, 7257.
  28. 18. Williams, L. J.; Garbaccio, R. M.; Danishefsky, S. J. In Carbohydrate in Chemistry and Biology; Ernst, B., Hart, G. W., Sinay, P.; Eds.; Wiley–VCH Verlag GmbH: Weinheim, Germany, 2000; Vol. 1, pp 61 -92.
  29. 20. (a) Zheng, C.; Seeberger, P. H.; Danishefsky, S. J. Angew. Chem. Int. Ed. 1998, 37, 786. (b) Zheng, C.; Seeberg, P. H.; Danishefsky, S. J. J. Org. Chem. 1998, 63, 1126. (c) Seeberger, P. H.; Eckhardt, M.; Gutteridge, C. E.; Danishefsky, S. J. J. Am. Chem. Soc. 1994, 119, 10064.
  30. 22. (a) Bischofberger, K.; Hall, R. H.; Jordan, A. J. Chem. Soc., Chem. Commun. 1975, 806. (b) Hall, R. H.; Bischofberger, K.; Eitelman, S. J.; Jordan, A. J. Chem. Soc., Perkin Trans I 1977, 743.
  31. 24. (a) Reid, W.; Appel, H. Annalen. 1964, 679, 51. (b) Castro, B.; Burgada, R.; Lavielle, G.; Villieras, J. C. R. Acad. Sci C 1969, 268, 1067. (c) Tronchet, J. M. J.; Baehler, B.; Bonenfant, A. Helv. Chim. Acta 1976, 59, 941. (d) Salmond, W. G. Tetrahedron Lett. 1977, 1239.
  32. 27. (a) Griffin, F. K.; Murphy, P. V.; Paterson, D. E.; Taylor, R. J. K. Tetrahedron Lett. 1998, 39, 8179. (b) Alcaraz, M. L.; Griffin, F. K.; Paterson, D. E.; Taylor, R. J. K. Tetrahedron Lett. 1998, 39, 8183.
  33. 29. (a) Praly, J.-P.; Chen, G.-R.; Gola, J.; Hetzer, G.; Raphoz, C. Trtrahedron Lett. 1997, 38, 8185. (b) Molina, A.; Czernecki, S.; Xie, J. Tetrahedron Lett. 1998, 39, 7507. (c) Griffin, F. K.; Paterson, D. E.; Murphy, P. V.; Taylor, R. J. K. Eur. J. Org. Chem. 2002, 1305. (d) Belica, P. S.; Frank, R. W. Tetrahedron Lett. 1998, 39, 8225. (e) Yang, G.; Frank, R. W.; Bittman, R.; Samadden, P.; Arthur, G. Org. Lett. 2001, 3, 197.
  34. 30. Bartolozzi, A.; Capozzi, G.; Falciani, C.; Menichetti, S.; Nativi, C.; Bacialli, A. P. J. Org. Chem. 1999, 64, 6490.
  35. 31. Capozzi, G.; Bartolozzi, A.; Falciani, C.; Menichetti, S.; Nativi, C. Phosphorus, Sulfur Silicon 1999, 153-154, 309.
  36. 32. 張權發,國防醫學院 博士論文, 民國九十一年
  37. 34. (a) Cheng, M.-C.; Lin, C.-H.; Khoo, K.-H.; Wu, S.-H. Angew. Chem., Int. Ed. 1999, 38, 686. (b) Cheng, M.-C.; Lin, C.-H.; Wang, H.-Y.; Lin, H.-R.; Wu, S.-H. Angew. Chem., Int. Ed. 2000, 39, 772.
  38. 35. (a) Masahiro, w.; Yoshihiko, N.; Koichi, F.; Shoichi, K. Chem. Lett. 1999, 27. (b) Terumki, M.; Yoshinari, W.; Kazuo, M.; Kazuya, T. Chem. Lett. 1999, 933. (c)Alberto, M.; Jacques, E.; Alain, V.; Pierre, V. J. Chem. Soc., Chem. Commun. 1992, 114, 6354.
  39. 36. Steve, P. R.; Nicola J. D. Org. Lett. 1999, 1, 933.
  40. 37. (a) Isao, A.; Toshihir, N.; Masaomi, K.; Takamasa, I.; Shiro, I. Tetrahedron Lett. 1999, 40, 4683. (b) Takamasa I.; Takafumi, S.; Shiro I. Tetrahedron Lett. 1996, 37, 2267. (c) Takamasa, I.; Isao, A.; Takafumi S.; Shiro, I. Heterocycles 1997, 46, 221. (d) Yoshiharu, I.; Shigeru I.; Akira M.; Teruo, Y.; Hideo, U. J. Chem. Soc., Perkin Trans I 1977, 1382. (e) Götz, S.; Richard, S. Tetrahedron Lett. 1997, 38, 2934.
  41. 38. (a) Maria, P. C.; Gal, J. F. J. Phys. Chem. 1985, 89, 1296. (b) Maria, P. C.; Gal, J. F.; Jeanine, D. F.; Evelyne, F. J. Am. Chem. Soc. 1987, 109, 483.
  42. 39. Mark, R. L. The Lewis Acid/Base Reaction Chemistry. Web site: http://www.meta-synthesis.com/index.html.
  43. 41. (a) Stephen, H.; Antonio, U. Carbohydr. Res. 1984, 130, 261. (b) Micheal, D. L.; Jin, K. C.; Yoshito K. J. Am. Chem. Soc. 1982, 104, 4976.
  44. 43. Masaru, H.; Shiro, T. Heterocycles 1998, 47, 59.