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

【作者】 蔡乐；

【导师】 王锋鹏；

【作者基本信息】 四川大学 ， 药物化学， 2006， 博士

【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C₁₈-、C₁₉-和C₂₀-三种类型的二萜生物碱，其中7个为新化合物。包括3个C₁₉-二萜生物碱，分别命名为piepunensine A、piepunensine B和18-acetylcammaconine；3个C₁₈-二萜生物碱，分别命名为piepunendine A、piepunendine B和piepunendine C；以及一个C₂₀—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-OCH₃参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Boc₂O／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／H₂O回流-NaBH₄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(C₆-C₅-C₄-C₁₈-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C₁₉-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¹³C-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。更多还原

【Abstract】 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 taxoids1) Construction of [6+8+6] ring system using semipinacol rearrangementIn 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-OCH₃. 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 cendensationUsing 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/Na₂CO₃, 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 Boc₂O/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/H₂O, 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 (C₆-C₅-C₄-C₁₈-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-C₁₉ 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 ¹³C-NMR, DEPT, NOEDS, ¹H-¹H COSY, HMQC and HMBC) and chemical methods.Having greatly enriched the research of chemistry of the 10-OH C₁₉-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.更多还原