Ⅰ. 中甸乌头中生物碱化学成分的研究 Ⅱ. 去甲二萜生物碱转化合成紫杉醇类似物的研究X
摘要
本论文研究内容共分为两个部分。第一部分是中甸乌头(Aconitum pieounense)的生物碱成分研究，之前尚未见到该植物化学成分研究的相关报道。第二部分是去甲二萜生物碱转化合成紫杉醇类似物的研究，该部分研究以deltaline(3)为原料，在参照本课题组前期研究工作的基础上，利用10-OH的特点提出了一个新的结构转化路线，即经C环semipinacol重排构建[6+8+6]环系，并对之进行了系统研究。还尝试了经B环羟醛缩合反应构建[6+8+6]环系。此外，还进行了滇乌碱Acyloin重排以及牛扁碱N-C_((19))键裂解的研究。
一、中甸乌头的生物碱成分研究
从中甸乌头(Aconitum pieounense)中分离得到17个单体化合物，并应用光谱(1D-，2D-NMR和HR-MS)及化学方法对其中16个化合物的结构进行了鉴定。化合物类型涉及C_(18)-、C_(19)-和C_(20)-三种类型的二萜生物碱，其中7个为新化合物。包括3个C_(19)-二萜生物碱，分别命名为piepunensine A、piepunensine B和18-acetylcammaconine；3个C_(18)-二萜生物碱，分别命名为piepunendine A、piepunendine B和piepunendine C；以及一个C_(20)—二萜生物碱，命名为piepunine。9个已知化合物分别是塔拉萨敏(talatisamine)、滇乌碱(yunaconitine)、pengshenine B、阿克诺辛(aconosine)、talatizidine、deltaline、19-one talatisamine、甲基牛扁碱(methyllycaconitine)和德尔色明甲(delsemine A)。另外，通过混合光谱鉴定了2个新二萜生物碱piepunensine D和piepunendine D的结构。
本研究首次发现了同时具有19-羟基和氮乙酰基的乌头碱型二萜生物碱，另外还发现了一个新颖的阿替生-光翠雀碱型双二萜生物碱。
二、去甲二萜生物碱转化合成紫杉醇类似物的研究
1．C环semipinacol重排构建[6+8+6]三坏体系
我们依次尝试了CAB路线和ABC路线(按环系修饰次序)。分别以化合物10、39、43、44和52为底物进行semipinacol重排尝试，结果均未得到目标化合物。1α-OCH_3参与反应可能是致使期望的semipinacol重排难以发生的主要原因。在尝试先修饰C环再进行Grob裂解时发现，C-12上引入含氧基团会妨碍10-OH的氯代反应；而当C-14上取代基发生变化时，并不影响Grob裂解(N-C_((17))／C_((11))-C_((17))次裂化)的发生。
2．经B环羟醛缩合反应构建[6+8+6]三环体系
51经NBS氧化-水解的方法消除O，O-去次甲二氧基得到化合物82。这是一个新的脱次甲二氧基的方法。之后，顺利合成了C_((7))-C_((8))键裂解的化合物85、89和90。并分别以之为底物进行羟醛缩合反应，结果仅得六元B环化合物92和93。反应结果表明，由于双键△~(5(11)的存在，7-酮的α-碳(C-6)更易烯醇化进攻8-酮基。而多方尝试均未能还原双键△~(5(11))。
3．去甲二萜生物碱的其他反应
1)化合物36、51和9与Boc_2O／DMAP反应分别得到10，12-碳酸酯基化合物97、98和99。该反应的过程可能是经酯交换反应形成碳酸酯基。
2)化合物106和105经dioxane／H_2O回流-NaBH_4还原分别得到7，17-次裂化合物109和111。这是一个新的C_((7))-C_((17))键次裂化的方法。该反应表明，四氢呋喃环(C_6-C_5-C_4-C_(18)-O)的形成有利于C_((7))-C_((17))键的裂解。
3)亚胺季胺盐化合物119与浓氨水反应66h，得到一个N-C_((19))键裂解的化合物122。这是一种新的裂解牛扁碱型C_(19)-去甲二萜生物碱的N-C_((19))键的方法。
4．本部分研究共制备了90个去甲二萜生物碱，其中82个为新的人工产物。新化合物中多数结构复杂，且颇具新颖性。对所制备的新化合物应用光谱(IR，MS，HR-MS，~1H-和~(13)C-NMR，DEPT，NOEDS，~1H-~1H COSY，HMQC以及HMBC)和化学方法确定了结构。
5．本部分研究极大丰富了10-OH去甲二萜生物碱化学的研究，并发展了很多优异的化学反应。提出了新的去甲二萜生物碱转化合成紫杉醇类似物的战略，并进行了大量的探索，为课题组以后构建[6+8+6]三环体系打下坚实的基础。
In this dissertation the following two sections are included.
1. Investigation on the phytoehemistry of the plant Aconitum pieounense To our knowledge, no phytochemical investigation of this plant had been undertaken. Seven new diterpenoid alkaloids, piepunensine A, piepunensine B, 18-acetylcammaconine, piepunendine A, piepunendine B, piepunendine C and piepunine, together with nine known alkaloids, yunaconitine, talatisamine, pengshenine B, aconosine, talatizidine, deltaline, 19-one talatisamine, methyllycaconitine and delsemine A, have been isolated from the roots of Aconitum pieounense. Their structures were elucidated on the basis of spectral data (1D-, 2D-NMR and HR-MS) and chemical methods. Furthermore, two new norditerpenoid alkaloids were identified according the combinated NMR and ESIMS spectrum.
This research has firstly found a new aconitine-type diterpenoid alkaloid containing both 19-OH and N-acetyl groups. And piepunine is a novel atisine-denudatine bisditerpenoid compound.
2. Studies on the conversion of the norditerpenoid alkaloids into taxoids
1) Construction of [6+8+6] ring system using semipinacol rearrangement
In this section, a new conversion approach to toxids using deltaline (3) as the starting material via the semipinacol rearrangement of the ring C was proposed through the routes ABC and CAB. Under the conditions (NaOH/DMF, NaI/DMF), compound 10, 39, 43, 44, and 52 didn't obtain the expected semipinacol rearrangement products, probably due to the special hindrance derived from the 1α-OCH_3. To attempt the Grob fragmentation followed by the modification of ring C showed that it was difficult to chloro-substitute for 10-OH after introducing the 12-hydroxyl group. However, there was no influence on Grob fragmentation when substitutity at C-14 was changed.
2) Construction of [6+8+6] ring system by aldol cendensation
Using a new method developed by us, NBS oxidation-hydrolysis of 51 obtained the O, O-demethenyl compound 82. With compound 85, 89, and 90 as substrate, respectively, aldol condensation under conditions (NaOH/Na_2CO_3, NaOH/MeOH) only led to two six-membered ring B compounds rather than the expected eight-membered ring compound 86 and 91. This illustrated C-6 perferred to emerge negative ion to attack C-8, possibly because of the existence of double bond△~(5(11)).
3) Other reactions concerning norditerpenoild alkaloids
(1) Treatment of 36, 51, and 9 with Boc_2O/Pyr, gave the 10, 12-carbonate compound 97, 98, and 99, respectively, probably due to the intramolecular transesterification process.
(2) When 106 and 105 was refluxed with dioxane/H_2O, the 7, 17-seco norditerpenoid alkaloid 109 and 111 was obtained, respectively. It's a new cleavage of the 7, 17-bond of the aconitine-type diterpenoid alkaloids. This showed that the formation of tetrahydrofuran ring (C_6-C_5-C_4-C_(18)-O) promoted the cleavage of the 7, 17-bond in 105 and 106.
(3) Treatment of 119 with concentrate aqueous ammonia for 66 h, a N, 19-seco compound 122 was obtained. This is a new method to break N-C_(19) bond of the lycoctonine-type diterpenoid alkaloids.
Eighty-two new or novel artificial compounds among total 90 norditerpenoid alkaloids were prepared in the course of this study. Their structures were determined by spectral analysis (IR, MS, HR-MS, ~1H- and ~(13)C-NMR, DEPT, NOEDS, ~1H-~1H COSY, HMQC and HMBC) and chemical methods.
Having greatly enriched the research of chemistry of the 10-OH C_(19)-diterpenoid alkaloids as well as developed several excellent reactions, this dissertation provided a new plan for conversion of the norditerpenoid alkaloids into taxoids with tedious exploratation and a solid foundation for further construction of the [6+8+6] ring system.
一、中甸乌头的生物碱成分研究
从中甸乌头(Aconitum pieounense)中分离得到17个单体化合物，并应用光谱(1D-，2D-NMR和HR-MS)及化学方法对其中16个化合物的结构进行了鉴定。化合物类型涉及C_(18)-、C_(19)-和C_(20)-三种类型的二萜生物碱，其中7个为新化合物。包括3个C_(19)-二萜生物碱，分别命名为piepunensine A、piepunensine B和18-acetylcammaconine；3个C_(18)-二萜生物碱，分别命名为piepunendine A、piepunendine B和piepunendine C；以及一个C_(20)—二萜生物碱，命名为piepunine。9个已知化合物分别是塔拉萨敏(talatisamine)、滇乌碱(yunaconitine)、pengshenine B、阿克诺辛(aconosine)、talatizidine、deltaline、19-one talatisamine、甲基牛扁碱(methyllycaconitine)和德尔色明甲(delsemine A)。另外，通过混合光谱鉴定了2个新二萜生物碱piepunensine D和piepunendine D的结构。
本研究首次发现了同时具有19-羟基和氮乙酰基的乌头碱型二萜生物碱，另外还发现了一个新颖的阿替生-光翠雀碱型双二萜生物碱。
二、去甲二萜生物碱转化合成紫杉醇类似物的研究
1．C环semipinacol重排构建[6+8+6]三坏体系
我们依次尝试了CAB路线和ABC路线(按环系修饰次序)。分别以化合物10、39、43、44和52为底物进行semipinacol重排尝试，结果均未得到目标化合物。1α-OCH_3参与反应可能是致使期望的semipinacol重排难以发生的主要原因。在尝试先修饰C环再进行Grob裂解时发现，C-12上引入含氧基团会妨碍10-OH的氯代反应；而当C-14上取代基发生变化时，并不影响Grob裂解(N-C_((17))／C_((11))-C_((17))次裂化)的发生。
2．经B环羟醛缩合反应构建[6+8+6]三环体系
51经NBS氧化-水解的方法消除O，O-去次甲二氧基得到化合物82。这是一个新的脱次甲二氧基的方法。之后，顺利合成了C_((7))-C_((8))键裂解的化合物85、89和90。并分别以之为底物进行羟醛缩合反应，结果仅得六元B环化合物92和93。反应结果表明，由于双键△~(5(11)的存在，7-酮的α-碳(C-6)更易烯醇化进攻8-酮基。而多方尝试均未能还原双键△~(5(11))。
3．去甲二萜生物碱的其他反应
1)化合物36、51和9与Boc_2O／DMAP反应分别得到10，12-碳酸酯基化合物97、98和99。该反应的过程可能是经酯交换反应形成碳酸酯基。
2)化合物106和105经dioxane／H_2O回流-NaBH_4还原分别得到7，17-次裂化合物109和111。这是一个新的C_((7))-C_((17))键次裂化的方法。该反应表明，四氢呋喃环(C_6-C_5-C_4-C_(18)-O)的形成有利于C_((7))-C_((17))键的裂解。
3)亚胺季胺盐化合物119与浓氨水反应66h，得到一个N-C_((19))键裂解的化合物122。这是一种新的裂解牛扁碱型C_(19)-去甲二萜生物碱的N-C_((19))键的方法。
4．本部分研究共制备了90个去甲二萜生物碱，其中82个为新的人工产物。新化合物中多数结构复杂，且颇具新颖性。对所制备的新化合物应用光谱(IR，MS，HR-MS，~1H-和~(13)C-NMR，DEPT，NOEDS，~1H-~1H COSY，HMQC以及HMBC)和化学方法确定了结构。
5．本部分研究极大丰富了10-OH去甲二萜生物碱化学的研究，并发展了很多优异的化学反应。提出了新的去甲二萜生物碱转化合成紫杉醇类似物的战略，并进行了大量的探索，为课题组以后构建[6+8+6]三环体系打下坚实的基础。
In this dissertation the following two sections are included.
1. Investigation on the phytoehemistry of the plant Aconitum pieounense To our knowledge, no phytochemical investigation of this plant had been undertaken. Seven new diterpenoid alkaloids, piepunensine A, piepunensine B, 18-acetylcammaconine, piepunendine A, piepunendine B, piepunendine C and piepunine, together with nine known alkaloids, yunaconitine, talatisamine, pengshenine B, aconosine, talatizidine, deltaline, 19-one talatisamine, methyllycaconitine and delsemine A, have been isolated from the roots of Aconitum pieounense. Their structures were elucidated on the basis of spectral data (1D-, 2D-NMR and HR-MS) and chemical methods. Furthermore, two new norditerpenoid alkaloids were identified according the combinated NMR and ESIMS spectrum.
This research has firstly found a new aconitine-type diterpenoid alkaloid containing both 19-OH and N-acetyl groups. And piepunine is a novel atisine-denudatine bisditerpenoid compound.
2. Studies on the conversion of the norditerpenoid alkaloids into taxoids
1) Construction of [6+8+6] ring system using semipinacol rearrangement
In this section, a new conversion approach to toxids using deltaline (3) as the starting material via the semipinacol rearrangement of the ring C was proposed through the routes ABC and CAB. Under the conditions (NaOH/DMF, NaI/DMF), compound 10, 39, 43, 44, and 52 didn't obtain the expected semipinacol rearrangement products, probably due to the special hindrance derived from the 1α-OCH_3. To attempt the Grob fragmentation followed by the modification of ring C showed that it was difficult to chloro-substitute for 10-OH after introducing the 12-hydroxyl group. However, there was no influence on Grob fragmentation when substitutity at C-14 was changed.
2) Construction of [6+8+6] ring system by aldol cendensation
Using a new method developed by us, NBS oxidation-hydrolysis of 51 obtained the O, O-demethenyl compound 82. With compound 85, 89, and 90 as substrate, respectively, aldol condensation under conditions (NaOH/Na_2CO_3, NaOH/MeOH) only led to two six-membered ring B compounds rather than the expected eight-membered ring compound 86 and 91. This illustrated C-6 perferred to emerge negative ion to attack C-8, possibly because of the existence of double bond△~(5(11)).
3) Other reactions concerning norditerpenoild alkaloids
(1) Treatment of 36, 51, and 9 with Boc_2O/Pyr, gave the 10, 12-carbonate compound 97, 98, and 99, respectively, probably due to the intramolecular transesterification process.
(2) When 106 and 105 was refluxed with dioxane/H_2O, the 7, 17-seco norditerpenoid alkaloid 109 and 111 was obtained, respectively. It's a new cleavage of the 7, 17-bond of the aconitine-type diterpenoid alkaloids. This showed that the formation of tetrahydrofuran ring (C_6-C_5-C_4-C_(18)-O) promoted the cleavage of the 7, 17-bond in 105 and 106.
(3) Treatment of 119 with concentrate aqueous ammonia for 66 h, a N, 19-seco compound 122 was obtained. This is a new method to break N-C_(19) bond of the lycoctonine-type diterpenoid alkaloids.
Eighty-two new or novel artificial compounds among total 90 norditerpenoid alkaloids were prepared in the course of this study. Their structures were determined by spectral analysis (IR, MS, HR-MS, ~1H- and ~(13)C-NMR, DEPT, NOEDS, ~1H-~1H COSY, HMQC and HMBC) and chemical methods.
Having greatly enriched the research of chemistry of the 10-OH C_(19)-diterpenoid alkaloids as well as developed several excellent reactions, this dissertation provided a new plan for conversion of the norditerpenoid alkaloids into taxoids with tedious exploratation and a solid foundation for further construction of the [6+8+6] ring system.
引文
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21 Blagbrough, I. S.; Hardick, D. J.; Wonnacott, S.; Potter,; Barry, V. L. Regioselective demethylation of aconitine. Tetrahedron Lett., 1994, 35, 3367-3370
22 Chen, Q. H.;. Wang, F. P. Further studies on the synthesis of 7, 17-seco-norditerpenoid alkaloids. J. Asia Nat. Prod Res., 2003, 5, 43-48
23 Chen, Q. H.; Xu, L.; Wang, F. P.; Preparation of the N, 19-seco nroditerpenoid alkaloids from norditerpenoid alkaloid yunaconitine. Chin. Chem. Bull., 2003, 14, 147-150
24 Shen, X. L.; Wang, F. P. New products from the reaction of acetyllycoctonine with N-bromosuccinimide (NBS). Chem. Pharm. Bull., 2004, 52, 1095-1097
25 徐亮，硕士学位论文，华西医科大学，2000，pp 15
26 Erman, M. B.; Snow, J. W.; Williams, M. J. Process for obtaining nitriles from aldehydes. CODEN: USXXAM US 6114565 A 20000905, 2000, pp 9
1 Wani, M. C.; Taylor, H. I.; Wall, M. E.; Coggen, P.; Mcphail, A. T. Plant antitumor agents. Ⅵ. The isolation and structure of taxol, a novel antileukemic and antitumor agent from taxus brevifolia. J. Am. Chem. Soc., 1971, 93, 2325-2327
2 Horwitz, S. B.; Fant, J.; Schiff, P. B. The effect mechanism of taxol. Nature, 1979, 277, 665-667
3 Denis, J. N.; Greene, A. E.; Guenard, D.; Francoise, G. V.; Mangatal, L.; Potier, P. A highly efficient, practical approach to natural taxol. J. Am. Chem. Soc., 1988, 110, 5917-5919
4 Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.; Sun, C. M.; Brigaud, T. New and efficient approaches to the semisynthesis of taxol and its C-13 side chain analogs by means of β-lactam synthon method. Tetrahedron, 1992, 48, 6985-7012
5 Ojima, I.; Sun, C. M.; Zucco, M.; Park, Y. H.; Duclos, O.; Kuduk, S. A highlefficient route to taxotere by the β-lactam synthon method. Tetrahedron Lett., 1993, 34, 4149-4152
6 Holton, R. A. Method for preparation of taxol. Eur. Pat. Appl, 1990, EP 400971
7 Arseniyadis, S.; Hemando, J. I. M.; Quilez D. Moral, J.; Yashunsky, D. V.; Potier, P. A concise preparation of an appropriately functionalized B-seco taxane derivative. Synlett, 1998, 9,1010-1012
8 a) Holton, R. A.; Somoza, C.; Kim, H. B.; Liang, F.; Biediger, R. T.; Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, D. S.; Murthi, K. K.; Gentile, L. N.; Liu, J. H. First total synthesis of taxol. Functionalization of the B ring. J. Am. Chem. Sco., 1994, 116, 1597-1598;
b) Holton, R. A.; Kim, H. B.; Somoza, C.; Liang, F.; Biediger, R. T.; Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K. K.; Gentile, L. N.; Liu, J. H. First total synthesis of taxol. Completion of the C and D ring. J. Am. Chem. Sco., 1994, 116, 1599-1600
9 Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy, R. K.; Claibome, C. F.; Renaud, J.; Couladouros, E. A.; Paulvannan, K.; Sorensen, E. I. Total synthesis of taxol. Nature, 1994, 367, 630-634
10 a) Masters, J. J.; Link, J. T.; Snyder, L. B.; Young, W. B.; Danishefsky, S. J. A total synthesis of taxol. Angew. Chem. Int. Ed. Engl, 1995, 34, 1723-1726
b) Danishefsky, S. J.; Masters, J. J.; Young, W. B.; Link, T.; Sngder, L. B.; Magee, T. V.; Jung, D. K.; Isaacs, R. A.; Bornmann,W. G.; Alaimo, C. A.; Coburn, C. A.; Digrandi, M. J. Total synthesis of baccatin III and taxol. J. Am. Chem. Soc, 1996,118,2843-2869
11 Wender, P. A.; Badham, N. F.; Conway, S. P.; Floreancig, P. E.; Glass, T. E.; Granicher, C.; Houze, J. B.; Janichen, J.; Lee, D.; Marquess, D. G; McGrane, P. L.; Meng, W.; Mucciaro, T. P.; Muhlebach, M.; Natchus, M. Paulsen, G; H.; Rawlins, D. B.; Satkotsky, J.; Shuker, A. J.; Suttoon, J. C.; Taylor, R. E.; Tomooka, K. The Pinene path to taxanes, stereocontrolled synthesis of a versatile taxane precursor. J. Am. Chem. Soc., 1997, 119, 2755-2756; Wender, P. A.; Badham, N. F.; Conway, S. P.; Floreancig, P. E.; Glass, T. E.; Houze, J. B.; Krauss, N. E.; Lee, D.; Marquess, D. G.; McGrane, P. L.; Meng, W.; Natchus, M. G.; Shuker, A. J.; Sutton, J. C.; Taylor, R. E. The pinene path to taxanes. A concise stereocontrolled synthesis of taxol. J. Am. Chem. Soc., 1997, 119, 2757-2758
12 a) Mukaiyama, T.; Shiina, I.; Iwadare, H.; Sakoh, H.; Tani, Y. I.; Hasegawa, M.; Saitoh, K. Asymmetric total synthesis of taxol. Proc. Japan Acad, 1997, 73, ser B, 95-100; b) Mukaiyama, T.; Shiina, I.; Iwadare, H.; Saitoh, M.; Nishimura, T.; Ohkawa, N.; Sakoh, H.; Nishimura, K.; Tani, Y. I.; Hasegawa, M.; Yamada, K.; Saitoh, K. Asymmetric total synthesis of taxol. Chem. Eur. J., 1999, 5, 121-161
13 Morihira, K.; Hara, R.; Kawahara, S.; Nishimori, T.; Nakamura, N.; Kusama, H.; Kuwajima, I. Enantioselective Total Synthesis of Taxol. J. Am. Chem. Soc., 1998, 120, 12980-12981
14 Kingston, D. J. I.; Molinero, A. A.; Rimoldi, M. The taxane diterpenoids. Progress in the Chemistry of Organic Natural Products, 1993, 61, 1-205
15 徐亮，王锋鹏，抗癌药紫杉醇的全合成—Nicolaou法全合成紫杉醇的剖析，有机化学，2001，21，493-504
16 陈巧鸿，王锋鹏，抗癌药物紫杉醇的全合成—Holton合成紫杉醇路线的剖析，天然产物研究与开发，2001，13，88-95
17 谢光波，紫杉醇全合成—T．Mukaiyama的合成路线，四川大学博士论文，2005，91—113
18 黄化民，李叶芝，紫杉醇全合成，合成化学，1998，6，238-247
19 Nicolaou, K. C.; Guy, R. K. The conquest of taxol. Angew. Chem. Int. Ed. Engl., 1995，34，2079-2090
20 荣国斌(译)，朱士正(校)，(Li，Jei Jack原著)，有机人名反应及机理，2003，3，华东理工大学出版社
21 Masters, J. J.; Jung, D. K.; Bornmann, W. G.; Danishefsky, S. J. A concise synthesis of a highly functionalized C-aryl taxol analog by an intramelecular Heck olefination reaction. Tetrahedron Lett., 1993, 45, 7253-7256
22 Kawada, H.; Iwamoto, M.; Utsugi, M.; Miyano, M.; Nakada, M. Synthetic studies on the taxane skeleton: Construction of eight-membered carbocyclic rings by the intramolecular B-alkyl Suzuki-Miyaura cross-coupling reaction. Org. Lett., 2004, 24, 4491-4494
23 Nicolaou, K. C.; Yang, Z.; Sorensen, E. J.; Nakada, M. Synthesis of ABC taxoid ring systems via a convergent strategy. J. Chem. Soc. Chem. Commu., 1993, 115, 1024-1026
24 Nicolaou, K. C.; Claiborne, C. F.; Nantermet, R G.; Couladourors, E. A.; Sorensen, E. J. Synthesis of Novel Taxoids. J. Chem. Soc. Chem. Commu., 1994, 116, 1591-1592
25 Ettonati, L.; Ahond, A.; Poupan, C.; Potier, P. The first hemisynthesis of an 4(20), 5 oxetane group bearing taxane-type compound, Tetrahedron, 1991, 47, 9823-9838
26 Magee, T. V.; Bornmann, W. G.; Isaacs, R. C. A.; Danishefsky, S. J. A straightforward route to functionalized intermediates containing the CD substructure of Taxol. J. Org. Chem., 1992, 57, 3274-3276
27 Isaacs, R. C. A.; Grandi, M. J.; Danishefsky, S. J. Synthesis of an Enantiomerically Pure Intermediate containing the CD substructure of taxol. J. Org. Chem., 1993, 58, 3938-3941
28 Queneau, Y.; Krol, W. J.; Bornmann, W. G.; Danishefsky, S. J. A ready synthesis of intermediates containing the A-ring substructure of taxol: A Diels-Alder route to the B-seco taxane series. J. Org. Chem., 1992, 57, 4043-4047
29 Grandi, M. J.; Coburn, C. A.; Isaacs, R. C. A.; Danishefsky, S. J. Degradative routes to electrophilic CD-substructures of taxol. J. Org. Chem., 1993, 58, 7728-7731
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1 Wani, M. C.; Taylor, H. I.; Wall, M. E.; Coggen, P.; Mcphail, A. T. Plant antitumor agents. Ⅵ. The isolation and structure of taxol, a novel antileukemic and antitumor agent from taxus brevifolia. J. Am. Chem. Soc., 1971, 93, 2325-2327
2 Horwitz, S. B.; Fant, J.; Schiff, P. B. The effect mechanism of taxol. Nature, 1979, 277, 665-667
3 Denis, J. N.; Greene, A. E.; Guenard, D.; Francoise, G. V.; Mangatal, L.; Potier, P. A highly efficient, practical approach to natural taxol. J. Am. Chem. Soc., 1988, 110, 5917-5919
4 Ojima, I.; Sun, C. M.; Zucco, M. Y.; Park, H.; Duclos, O.; Kuduk, S. A highlefficient route to taxotere by the β-lactam synthon method, Tetrahedron Lett., 1993, 34, 4149-4152
5 季红，博士学位论文，四川大学，2006，pp 69-74
6 陈巧鸿，博士学位论文，四川大学，2002，pp 27-53
7 王建莉，硕士学位论文，四川大学，2004，pp 19-21
8 Srivastava, S. K.; Joshi, B. S.; Newton, M. G.; Lee, D.; Pelletier, S. W. Heterolytic fragmentation of deltaline, a norditerpenoid alkaloid. Tetrahedron Lett., 1995, 36, 519-522
9 Takayama H., Sakai S. I., Yamaguchi K., and Okamoto T.: The partial synthesis of isodelphinine. Chem. Pharm. Bull., 1982, 30, 386-389
10 Nader R. B., Kaloustain M. K. The chemistry of tetrahedral intermediates. Part 3. A synthetic route to five-, six-, and seven-mernbered thionolactones.Tetrahedron Lett., 1979, 17, 1477-1480
11 Albright J. D. Sulfoxonium salts as reagents for oxidation of primary and secondary alcohols to carbonyl compounds. J Org. Chem., 1974, 39, 1977-1979
12 闻韧，药物合成反应，第二版，北京：化学工业出版社，2002，pp306-307
13 谢光波，博士学位论文，四川大学，2005，pp 47-48
14 荣国斌(译)，朱士正(校)，(Li，Jei Jack原著)，有机人名反应及机理，上海：华东理工大学出版社，2003，pp 218
15 Nicolaou, K. C.; Guy, R. K. The conquest of taxol. Angew. Chem. Int. Ed. Engl., 1995, 34, 2079-2090
16 Madhusudhan, G.; Reddy, G. O.; Ramanatham, J.; Dubey, P. K. Unusual migrations and cyclization in the preparation of β-azido alcohols from β-hydroxy esters. Indian journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry., 2004, 43B, 2719-2723
17 余灵，硕士学位论文，华西医科大学，1992，pp 15
18 Wiesner, K.; Gotz, M.; Simmons, D. L.; Fowler, L. R.; Bachelor, F. W.; Brown, R. F. C.; Buchi, G. Structure of aconitine. Tetrahedron Lett. 1959, 2, 15-24
19 Jacobs, W. A.; Pelletier, S. W. Aconite alkaloids. ⅩⅩⅩⅤ. Structural studies with delphinine derivatives. J. Org. Chem. 1957, 22, 1428-1432
20 申向黎，博士学位论文，四川大学，2004，pp 17，pp 47-51
21 Blagbrough, I. S.; Hardick, D. J.; Wonnacott, S.; Potter,; Barry, V. L. Regioselective demethylation of aconitine. Tetrahedron Lett., 1994, 35, 3367-3370
22 Chen, Q. H.;. Wang, F. P. Further studies on the synthesis of 7, 17-seco-norditerpenoid alkaloids. J. Asia Nat. Prod Res., 2003, 5, 43-48
23 Chen, Q. H.; Xu, L.; Wang, F. P.; Preparation of the N, 19-seco nroditerpenoid alkaloids from norditerpenoid alkaloid yunaconitine. Chin. Chem. Bull., 2003, 14, 147-150
24 Shen, X. L.; Wang, F. P. New products from the reaction of acetyllycoctonine with N-bromosuccinimide (NBS). Chem. Pharm. Bull., 2004, 52, 1095-1097
25 徐亮，硕士学位论文，华西医科大学，2000，pp 15
26 Erman, M. B.; Snow, J. W.; Williams, M. J. Process for obtaining nitriles from aldehydes. CODEN: USXXAM US 6114565 A 20000905, 2000, pp 9
1 Wani, M. C.; Taylor, H. I.; Wall, M. E.; Coggen, P.; Mcphail, A. T. Plant antitumor agents. Ⅵ. The isolation and structure of taxol, a novel antileukemic and antitumor agent from taxus brevifolia. J. Am. Chem. Soc., 1971, 93, 2325-2327
2 Horwitz, S. B.; Fant, J.; Schiff, P. B. The effect mechanism of taxol. Nature, 1979, 277, 665-667
3 Denis, J. N.; Greene, A. E.; Guenard, D.; Francoise, G. V.; Mangatal, L.; Potier, P. A highly efficient, practical approach to natural taxol. J. Am. Chem. Soc., 1988, 110, 5917-5919
4 Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.; Sun, C. M.; Brigaud, T. New and efficient approaches to the semisynthesis of taxol and its C-13 side chain analogs by means of β-lactam synthon method. Tetrahedron, 1992, 48, 6985-7012
5 Ojima, I.; Sun, C. M.; Zucco, M.; Park, Y. H.; Duclos, O.; Kuduk, S. A highlefficient route to taxotere by the β-lactam synthon method. Tetrahedron Lett., 1993, 34, 4149-4152
6 Holton, R. A. Method for preparation of taxol. Eur. Pat. Appl, 1990, EP 400971
7 Arseniyadis, S.; Hemando, J. I. M.; Quilez D. Moral, J.; Yashunsky, D. V.; Potier, P. A concise preparation of an appropriately functionalized B-seco taxane derivative. Synlett, 1998, 9,1010-1012
8 a) Holton, R. A.; Somoza, C.; Kim, H. B.; Liang, F.; Biediger, R. T.; Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, D. S.; Murthi, K. K.; Gentile, L. N.; Liu, J. H. First total synthesis of taxol. Functionalization of the B ring. J. Am. Chem. Sco., 1994, 116, 1597-1598;
b) Holton, R. A.; Kim, H. B.; Somoza, C.; Liang, F.; Biediger, R. T.; Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K. K.; Gentile, L. N.; Liu, J. H. First total synthesis of taxol. Completion of the C and D ring. J. Am. Chem. Sco., 1994, 116, 1599-1600
9 Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy, R. K.; Claibome, C. F.; Renaud, J.; Couladouros, E. A.; Paulvannan, K.; Sorensen, E. I. Total synthesis of taxol. Nature, 1994, 367, 630-634
10 a) Masters, J. J.; Link, J. T.; Snyder, L. B.; Young, W. B.; Danishefsky, S. J. A total synthesis of taxol. Angew. Chem. Int. Ed. Engl, 1995, 34, 1723-1726
b) Danishefsky, S. J.; Masters, J. J.; Young, W. B.; Link, T.; Sngder, L. B.; Magee, T. V.; Jung, D. K.; Isaacs, R. A.; Bornmann,W. G.; Alaimo, C. A.; Coburn, C. A.; Digrandi, M. J. Total synthesis of baccatin III and taxol. J. Am. Chem. Soc, 1996,118,2843-2869
11 Wender, P. A.; Badham, N. F.; Conway, S. P.; Floreancig, P. E.; Glass, T. E.; Granicher, C.; Houze, J. B.; Janichen, J.; Lee, D.; Marquess, D. G; McGrane, P. L.; Meng, W.; Mucciaro, T. P.; Muhlebach, M.; Natchus, M. Paulsen, G; H.; Rawlins, D. B.; Satkotsky, J.; Shuker, A. J.; Suttoon, J. C.; Taylor, R. E.; Tomooka, K. The Pinene path to taxanes, stereocontrolled synthesis of a versatile taxane precursor. J. Am. Chem. Soc., 1997, 119, 2755-2756; Wender, P. A.; Badham, N. F.; Conway, S. P.; Floreancig, P. E.; Glass, T. E.; Houze, J. B.; Krauss, N. E.; Lee, D.; Marquess, D. G.; McGrane, P. L.; Meng, W.; Natchus, M. G.; Shuker, A. J.; Sutton, J. C.; Taylor, R. E. The pinene path to taxanes. A concise stereocontrolled synthesis of taxol. J. Am. Chem. Soc., 1997, 119, 2757-2758
12 a) Mukaiyama, T.; Shiina, I.; Iwadare, H.; Sakoh, H.; Tani, Y. I.; Hasegawa, M.; Saitoh, K. Asymmetric total synthesis of taxol. Proc. Japan Acad, 1997, 73, ser B, 95-100; b) Mukaiyama, T.; Shiina, I.; Iwadare, H.; Saitoh, M.; Nishimura, T.; Ohkawa, N.; Sakoh, H.; Nishimura, K.; Tani, Y. I.; Hasegawa, M.; Yamada, K.; Saitoh, K. Asymmetric total synthesis of taxol. Chem. Eur. J., 1999, 5, 121-161
13 Morihira, K.; Hara, R.; Kawahara, S.; Nishimori, T.; Nakamura, N.; Kusama, H.; Kuwajima, I. Enantioselective Total Synthesis of Taxol. J. Am. Chem. Soc., 1998, 120, 12980-12981
14 Kingston, D. J. I.; Molinero, A. A.; Rimoldi, M. The taxane diterpenoids. Progress in the Chemistry of Organic Natural Products, 1993, 61, 1-205
15 徐亮，王锋鹏，抗癌药紫杉醇的全合成—Nicolaou法全合成紫杉醇的剖析，有机化学，2001，21，493-504
16 陈巧鸿，王锋鹏，抗癌药物紫杉醇的全合成—Holton合成紫杉醇路线的剖析，天然产物研究与开发，2001，13，88-95
17 谢光波，紫杉醇全合成—T．Mukaiyama的合成路线，四川大学博士论文，2005，91—113
18 黄化民，李叶芝，紫杉醇全合成，合成化学，1998，6，238-247
19 Nicolaou, K. C.; Guy, R. K. The conquest of taxol. Angew. Chem. Int. Ed. Engl., 1995，34，2079-2090
20 荣国斌(译)，朱士正(校)，(Li，Jei Jack原著)，有机人名反应及机理，2003，3，华东理工大学出版社
21 Masters, J. J.; Jung, D. K.; Bornmann, W. G.; Danishefsky, S. J. A concise synthesis of a highly functionalized C-aryl taxol analog by an intramelecular Heck olefination reaction. Tetrahedron Lett., 1993, 45, 7253-7256
22 Kawada, H.; Iwamoto, M.; Utsugi, M.; Miyano, M.; Nakada, M. Synthetic studies on the taxane skeleton: Construction of eight-membered carbocyclic rings by the intramolecular B-alkyl Suzuki-Miyaura cross-coupling reaction. Org. Lett., 2004, 24, 4491-4494
23 Nicolaou, K. C.; Yang, Z.; Sorensen, E. J.; Nakada, M. Synthesis of ABC taxoid ring systems via a convergent strategy. J. Chem. Soc. Chem. Commu., 1993, 115, 1024-1026
24 Nicolaou, K. C.; Claiborne, C. F.; Nantermet, R G.; Couladourors, E. A.; Sorensen, E. J. Synthesis of Novel Taxoids. J. Chem. Soc. Chem. Commu., 1994, 116, 1591-1592
25 Ettonati, L.; Ahond, A.; Poupan, C.; Potier, P. The first hemisynthesis of an 4(20), 5 oxetane group bearing taxane-type compound, Tetrahedron, 1991, 47, 9823-9838
26 Magee, T. V.; Bornmann, W. G.; Isaacs, R. C. A.; Danishefsky, S. J. A straightforward route to functionalized intermediates containing the CD substructure of Taxol. J. Org. Chem., 1992, 57, 3274-3276
27 Isaacs, R. C. A.; Grandi, M. J.; Danishefsky, S. J. Synthesis of an Enantiomerically Pure Intermediate containing the CD substructure of taxol. J. Org. Chem., 1993, 58, 3938-3941
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