紫杉醇类似物的合成研究Ⅶ去甲二萜生物碱转化合成紫杉醇类似物的研究
摘要
本论文在前期研究确定C_(19)-二萜生物碱转化合成紫杉醇类似物的CAB合成路线的基础上,对A环修饰中亚胺氧化形成乃春和氧化裂解N-C(19)键的关键反应以及D环芳构化反应进行了深入研究,并首次成功合成了C环重排并彻底完成A环修饰的关键中间体62。
1.C_(19)-二萜生物碱的A环修饰
8-含氧的C-nor去甲二萜生物碱14、24和26与NBS/HOAc反应都可以较高收率的制得亚胺物16、25和27,但是进一步的m-CPBA氧化却未能得到相应的乃春,而是形成了噁氮丙啶18和化合物17。继续用HIO_4或LTA氧化也没有得到断裂N-C(19)键的产物,可能是由于D环α-甲氧基酮结构在该反应条件下氧化断裂而使产物复杂化。
去掉C(8)含氧基团并还原C(13)酮基后,就可以62%的收率制得亚胺40。采用“一锅煮”的方法,用m-CPBA和LTA氧化亚胺幸运地制得了断裂N-C(19)键的产物42。采用经典的Nef反应条件未能得到预期的17-酮,而是生成了C(3)-OH参与反应的产物43。通过光谱数据和化学方法确定了它的结构。将C(3)和C(13)-OH用TBS保护后,用改良的Nef反应条件成功制备了脱胺产物62,从而彻底完成了A环修饰。
2.通过D环芳构化断裂C(12)-C(14)键反应的研究
化合物28与SOCl_2/Pyr、40%HBr和5%NaOH/MeOH反应可分别制得化合物66和67、70以及71,而未能得到断裂C(12)-C(14)键的产物。为了提高芳构化的收率,制备了具有△~(15(16))的C-nor
On the basis of our previous work on the conversion of the norditerpenoid alkaloids into taxoids, the CAB synthesis approach was determined. This dissertation described further research on the key reactions of the nitrone formation and cleavage of N-C(19) bond in the modification of ring A and the CAB synthesis route. 1. Modification of ring A of C_(19)-diterpenoid alkaloidTreatment of C-nor C_(19)-diterpenoid alkaloids 14, 24 and 26 bearing oxygenated group at C-8 with NBS/HOAc led to imines 16, 25 and 27 in high yield, and further oxidation with m-CPBA did not obtained the expected nitrone but the oxaziridine 18 and compound 17. Attempt to cleave N-C(19) bond through HIO)4 or LTA oxidation of 17 failed probably due to easy oxidation of α-methoxylketone moiety.After expulsion of oxygenated group at C-8 and reduction of ketone group at C-13, the imine 40 could be prepared in moderate 62% yield and N-C(19)-seco norditerpenoid alkaloid 42 was obtained from 40 through a "one-pot" method by oxidation with m-CPBA and LTA. Because of the participation of C(3)-OH, treating imine 40 using classic Nef reaction condition did not give the expected product with ketone group at C-17 rather than a novel compound 43 isolated as blue amorphous powder. Its structure was confirmed by spectral data and chemical method. An improved Nef reaction condition was adopted to convert of the nitro compound 60
being protected by TBS to give a key intermediate 62. Thus, we have successfully accomplished the ring A modification of C-nor Cig-diterpenoid alkaloid for the first time using yunaconitine as starting material through 15 steps.2. Cleavage of C(12)-C(14) bond through aromatization of ring DTreatment of compound 28 with SOCl2/Pyr\ 40% HBr and 5% NaOH/MeOH could afforded products 66, 67 > 70 and 71 instead of the expected aromatic product 29. Two C-nor C19-diterpenoid alkaloids 83 and 88 possessing a 15(16) double bond were prepared, and it was found that A 15(16) olefin 82 and 87 were easier to accomplish semipinacol rearrangement than others in which there has not this structural unit.3. Oxidation of lycoctonine-tye Cig-diterpenoid alkaloidTreatment of a lycoctonine-type alkaloid acetyllycoctonine 89 with NBS and m-CPBA at room temperature led to twelve new artificial products 90-95 and 96-101 respectively and the plausible process of the formation of these compounds was described. 4. Ninety-four norditerpenoid alkaloids and its analogues were prepared during our research; eighty-five of them were new artificial compounds. Their structures were determined by spectral data (MS, !H NMR, i3C NMR and 2D NMR) and chemical methods.
1.C_(19)-二萜生物碱的A环修饰
8-含氧的C-nor去甲二萜生物碱14、24和26与NBS/HOAc反应都可以较高收率的制得亚胺物16、25和27,但是进一步的m-CPBA氧化却未能得到相应的乃春,而是形成了噁氮丙啶18和化合物17。继续用HIO_4或LTA氧化也没有得到断裂N-C(19)键的产物,可能是由于D环α-甲氧基酮结构在该反应条件下氧化断裂而使产物复杂化。
去掉C(8)含氧基团并还原C(13)酮基后,就可以62%的收率制得亚胺40。采用“一锅煮”的方法,用m-CPBA和LTA氧化亚胺幸运地制得了断裂N-C(19)键的产物42。采用经典的Nef反应条件未能得到预期的17-酮,而是生成了C(3)-OH参与反应的产物43。通过光谱数据和化学方法确定了它的结构。将C(3)和C(13)-OH用TBS保护后,用改良的Nef反应条件成功制备了脱胺产物62,从而彻底完成了A环修饰。
2.通过D环芳构化断裂C(12)-C(14)键反应的研究
化合物28与SOCl_2/Pyr、40%HBr和5%NaOH/MeOH反应可分别制得化合物66和67、70以及71,而未能得到断裂C(12)-C(14)键的产物。为了提高芳构化的收率,制备了具有△~(15(16))的C-nor
On the basis of our previous work on the conversion of the norditerpenoid alkaloids into taxoids, the CAB synthesis approach was determined. This dissertation described further research on the key reactions of the nitrone formation and cleavage of N-C(19) bond in the modification of ring A and the CAB synthesis route. 1. Modification of ring A of C_(19)-diterpenoid alkaloidTreatment of C-nor C_(19)-diterpenoid alkaloids 14, 24 and 26 bearing oxygenated group at C-8 with NBS/HOAc led to imines 16, 25 and 27 in high yield, and further oxidation with m-CPBA did not obtained the expected nitrone but the oxaziridine 18 and compound 17. Attempt to cleave N-C(19) bond through HIO)4 or LTA oxidation of 17 failed probably due to easy oxidation of α-methoxylketone moiety.After expulsion of oxygenated group at C-8 and reduction of ketone group at C-13, the imine 40 could be prepared in moderate 62% yield and N-C(19)-seco norditerpenoid alkaloid 42 was obtained from 40 through a "one-pot" method by oxidation with m-CPBA and LTA. Because of the participation of C(3)-OH, treating imine 40 using classic Nef reaction condition did not give the expected product with ketone group at C-17 rather than a novel compound 43 isolated as blue amorphous powder. Its structure was confirmed by spectral data and chemical method. An improved Nef reaction condition was adopted to convert of the nitro compound 60
being protected by TBS to give a key intermediate 62. Thus, we have successfully accomplished the ring A modification of C-nor Cig-diterpenoid alkaloid for the first time using yunaconitine as starting material through 15 steps.2. Cleavage of C(12)-C(14) bond through aromatization of ring DTreatment of compound 28 with SOCl2/Pyr\ 40% HBr and 5% NaOH/MeOH could afforded products 66, 67 > 70 and 71 instead of the expected aromatic product 29. Two C-nor C19-diterpenoid alkaloids 83 and 88 possessing a 15(16) double bond were prepared, and it was found that A 15(16) olefin 82 and 87 were easier to accomplish semipinacol rearrangement than others in which there has not this structural unit.3. Oxidation of lycoctonine-tye Cig-diterpenoid alkaloidTreatment of a lycoctonine-type alkaloid acetyllycoctonine 89 with NBS and m-CPBA at room temperature led to twelve new artificial products 90-95 and 96-101 respectively and the plausible process of the formation of these compounds was described. 4. Ninety-four norditerpenoid alkaloids and its analogues were prepared during our research; eighty-five of them were new artificial compounds. Their structures were determined by spectral data (MS, !H NMR, i3C NMR and 2D NMR) and chemical methods.
引文
1. P. B. Schif, J. Fant, S. B. Horwitz, Promotion of microtuble assembly in vitro by taxol. Nature, 1979, 277, 665-667.
2. E. Bralm, C. Tang, M. L. Benquerigo. Regression of collagen-induced arthritis with taxol, a microtuble stabilizer. Arthritis Rheum, 1994, 37, 839-845.
3. B. Pouvelle, P. J. Ferley, C. A. Long. Taxol arrests the development of blood-stage plasmodium falciparum in vitro and plasmodium chahaudi Adami in malaria-infected mice. J Clin. Invest, 1994, 94, 413-417.
4. D. D. L. Woo, S. Y. R Miao, Jc. Pelayo. Taxol inhibits progression of congenital polycytic kidney disease. Nature, 1994, 368, 750-753.
5. W. J. Burke, G. Raghu, R. Strong. Taxol protects against calcium-mediated death of differentiated rat pheochromocytoma cells. Life Sci, 1994, 55, 1313-1319.
6.徐亮,博士论文
7. Y. Ogata, Y. Sawaki. Peracid oxidation of imines. Kinetics and mechanism of competitive formation of nitrones and oxaziranes from cyclic and acyclic imines. J. Am. Chem. Soc., 1976, 95, 4692-4698.
8. Y. Ogata, Y. Sawaki. Peracid oxidation of imines. Kinetics of oxazirane formation from benzylidene-tert-butylamines and perbenzoic acid. J. Am. Chem. Soc., 1976, 95, 4687-4692.
9. W. E. Noland. The Nef reaction, Chem. Rev, 1955, 55, 137-155.
10. H. Vorbrueggen, Carl Djerassi. Alkaloid studies ⅩⅩⅩⅥ. The complete absolute configuration of diterpenoids of the garrya and atisine groups and their direct correlation with the phyllocladene-type diterpenes. J. Am. Chem. Soc, 1962, 84, 2990-2997.
11. R. W. Binkley, D. G. Hehemann. A light initiated process for rapid debenzylation of carbohydrates. J. Org. Chem, 1990, 55, 378-380.
12. J. M. Aizpurua, M. Oiarbide, C. Palomo. The Nef reaction on trialkylsilyl nitronates promoted by m-chloroperbenzoic acid. An efficient route to α-alkoxyketones from nitroalkanes. Tetr. Lett, 1987, 28, 5361-5364.
13. N. Kornblum, A. S. Erickson, W. J. Kelly, B. Henggeler. Conversion of nitro paraffins into aldehydes and ketones. J. Org. Chem, 1982, 47, 4534-4538.
14.陈巧鸿,博士论文,p51.
15. Pelletier, S. W., Mody, N. V., Sawhney, R. S., Bhattacharyya, J. Application of carbon-13 NMR spectroscopy to the structural elucidation of C_(19)-diterpenoid alkaloids from Aconitum and Delphinium species. Heterocycles, 1977, 7, 327-339.
16. M. H. Benn and J. M. Jacyno, in 'The Alkaloids: Chemistry and Biological Perspectives' Vol. 1, ed. by S. W. Pelletier, Wiley & Sons, New York, 1983, pp. 120; F. N. Dzhakhargirov, M. N. Sultankhodzhaev, B. Tashkhodzhaev, and B. T. Silmov. Diterpenoid alkaloids as a new class of antiarrhythmic agents structure-activity relationship. Khim. Prir. Soedin., 1997, 33, 254-270.
17.王锋鹏,S.W.Pelletier.若干非天然产C_(19)-二萜生物碱的结构及其核磁共振谱的研究.华西药学杂志,1989,4,193.
18. Y. L. Bai, H. K. Desai, S. W. Pelletier. N-oxide of some norditerpenoid alkaloids. J. Nat. Prod., 1995, 58, 929-933.
19. D. Helmlinger, G. Ourisson. Le longifolene-XV. Cyclisation transannularire du bromo-3α-longifolene. Tetrahedron, 1969, 25, 4895-4901.
2. E. Bralm, C. Tang, M. L. Benquerigo. Regression of collagen-induced arthritis with taxol, a microtuble stabilizer. Arthritis Rheum, 1994, 37, 839-845.
3. B. Pouvelle, P. J. Ferley, C. A. Long. Taxol arrests the development of blood-stage plasmodium falciparum in vitro and plasmodium chahaudi Adami in malaria-infected mice. J Clin. Invest, 1994, 94, 413-417.
4. D. D. L. Woo, S. Y. R Miao, Jc. Pelayo. Taxol inhibits progression of congenital polycytic kidney disease. Nature, 1994, 368, 750-753.
5. W. J. Burke, G. Raghu, R. Strong. Taxol protects against calcium-mediated death of differentiated rat pheochromocytoma cells. Life Sci, 1994, 55, 1313-1319.
6.徐亮,博士论文
7. Y. Ogata, Y. Sawaki. Peracid oxidation of imines. Kinetics and mechanism of competitive formation of nitrones and oxaziranes from cyclic and acyclic imines. J. Am. Chem. Soc., 1976, 95, 4692-4698.
8. Y. Ogata, Y. Sawaki. Peracid oxidation of imines. Kinetics of oxazirane formation from benzylidene-tert-butylamines and perbenzoic acid. J. Am. Chem. Soc., 1976, 95, 4687-4692.
9. W. E. Noland. The Nef reaction, Chem. Rev, 1955, 55, 137-155.
10. H. Vorbrueggen, Carl Djerassi. Alkaloid studies ⅩⅩⅩⅥ. The complete absolute configuration of diterpenoids of the garrya and atisine groups and their direct correlation with the phyllocladene-type diterpenes. J. Am. Chem. Soc, 1962, 84, 2990-2997.
11. R. W. Binkley, D. G. Hehemann. A light initiated process for rapid debenzylation of carbohydrates. J. Org. Chem, 1990, 55, 378-380.
12. J. M. Aizpurua, M. Oiarbide, C. Palomo. The Nef reaction on trialkylsilyl nitronates promoted by m-chloroperbenzoic acid. An efficient route to α-alkoxyketones from nitroalkanes. Tetr. Lett, 1987, 28, 5361-5364.
13. N. Kornblum, A. S. Erickson, W. J. Kelly, B. Henggeler. Conversion of nitro paraffins into aldehydes and ketones. J. Org. Chem, 1982, 47, 4534-4538.
14.陈巧鸿,博士论文,p51.
15. Pelletier, S. W., Mody, N. V., Sawhney, R. S., Bhattacharyya, J. Application of carbon-13 NMR spectroscopy to the structural elucidation of C_(19)-diterpenoid alkaloids from Aconitum and Delphinium species. Heterocycles, 1977, 7, 327-339.
16. M. H. Benn and J. M. Jacyno, in 'The Alkaloids: Chemistry and Biological Perspectives' Vol. 1, ed. by S. W. Pelletier, Wiley & Sons, New York, 1983, pp. 120; F. N. Dzhakhargirov, M. N. Sultankhodzhaev, B. Tashkhodzhaev, and B. T. Silmov. Diterpenoid alkaloids as a new class of antiarrhythmic agents structure-activity relationship. Khim. Prir. Soedin., 1997, 33, 254-270.
17.王锋鹏,S.W.Pelletier.若干非天然产C_(19)-二萜生物碱的结构及其核磁共振谱的研究.华西药学杂志,1989,4,193.
18. Y. L. Bai, H. K. Desai, S. W. Pelletier. N-oxide of some norditerpenoid alkaloids. J. Nat. Prod., 1995, 58, 929-933.
19. D. Helmlinger, G. Ourisson. Le longifolene-XV. Cyclisation transannularire du bromo-3α-longifolene. Tetrahedron, 1969, 25, 4895-4901.