具有生物活性的苯并呋喃类天然产物及其衍生物的合成_硕士学位论文.pdf

米
文
硕士学位论文
摘要
苯并二氧六环类新木脂素和苯并呋喃类新木脂素是两类具有重要生理活性的
天然有机物,是许多药用植物的有效成分。为了满足生理活性物质筛选及研究开
发新药的需要,本文对苯并二氧六环类新木脂素、苯并呋喃类新木脂素进行了全
合成研究,并对苯并呋喃类新木脂素进行了结构修饰和生物活性的研究。
以苯并二氧六环骨架为母核设计反应路线,通过一系列反应过程合成了
两个苯并二氧六环类新木脂素化合物。以3-甲氧基-4-羟基苯甲醛为原料,经过溴
化、水解、诺文葛耳反应、酯化、以氧化银为氧化剂的自由基仿生氧化偶联五步
反应合成了苯并二氧六环结构化合物1,化合物1经氢化铝锂还原得到天然产物
2
ニ、3-甲氧基-4-羟基苯基丙烯酸甲酯和3-甲氧基-4,5-二羟基苯基丙烯酸甲
酯在氧化银催化下发生自由基仿生氧化偶联反应,首次用交叉偶联的方法合成了
苯并二氢呋喃类化合物3,化合物3经氢化铝锂还原得到化合物4。生物活性研
究表明化合物4对HL-60(白血病细胞)具有较好的细胞毒活性。
三、以苯并二氢呋喃环骨架为母核设计反应路线,通过以下反应过程合成了
天然产物XH-14。以3-甲氧基-4-羟基苯甲醛为原料,经过诺文葛耳反应、酯化、
以氧化银为氧化剂的自由基仿生氧化偶联、乙酸酐保护酚羟基、DDQ脱氢、PdC
还原、氢化铝锂还原、活性二氧化锰氧化等反应合成具有良好生物活性的天然产
物10(XH14)。为天然产物XH-14的合成提供了新的路线,整个合成路线的关键
是氧化银作为氧化剂的自由基仿生氧化偶联反应。
四、以合成的苯并呋喃类新木脂素为底物,在无水碳酸钾/无水丙酮的温和碱
性体系下对其4-0位进行一系列的修饰,合成一系列的O-异戊烯基、O-法尼烯
基29-33和乙酰基糖苷类衍生物34-40,乙酰基糖苷类衍生物在弱碱体系中脱乙酰
基得到糖苷类衍生物41-43
五、对合成的化合物用MT法进行了PANC-1(胰腺癌细胞)、SMMC-771(开
癌细胞)、SK-BR-3(乳腺癌细胞)、HL-60(白血病细胞)的生物活性的筛选。
以上所合成的新化合物1-4、29-43的结构均已由质谱(MS)、红外光谱(R)、
核磁共振氢谱(HNMR)所证实。
关键词:苯并二氧六环类;苯并呋喃类;新木脂素;糖苷;仿生氧化偶联;生物
活性
具有生物活性的苯并呋喃类天然产物及其衍生物的合成
Abstract
1, 4-benzodioxane neolignans and benzofuran neolignans are potent ingredients
of many medicinal plants, exhibit important biological activities. In order to meet the
needs for selecting the substances with biological activities and developing new drugs
this thesis aims at the studies on synthesis 1, 4-benzodioxane neolignans and
benzofuran neolignans, structural modification and biological activity screening of
benzofuran neolignan compounds
1. Aiming at constructing 1, benzodioxane skeleton, the synthetic routes were
devised; through the following reaction process two 1, 4-benzodioxane neolignans
have been synthesized. Starting from Vanillin, via bromination reaction, hydrolysi
reactions, Knoevenagel reaction, esterification reaction, Ag2o-catalyzed biomimetic
oxidative coupling reaction in five steps, the compounds 1 containing a
1, 4-benzodioxane skeleton was synthesized. The nature product 2 were synthesized
via reduction of compounds 1 with lithium aluminium hydride.
2. Starting from 3-methoxy-4-dihydroxyphenylmethacrylate and 3-methoxy
-4, 5-dihydroxyphenylmethacrylate, compound 3 containing a dihydro- benzofuran
skeleton was synthesized via Ag Catalyzed biomimetic oxidative coupling reaction
as the key step. Compound 4 were synthesized via reduction of compounds 3 with
lithium aluminium hydride. Compound containing a dihydro-benzofuran skeleton was
synthsized by cross coupling firstly. Compound 4 has an inhibitory effect on the
HL-60
Aiming at constructing dihydrobenzofuran skeleton, the synthetic routes were
devised. Starting from Vanillin, via Knoevenagel reaction, esterification reaction
Ag2o-catal yzed biomimetic oxidative coupling reaction, acetylized reaction, DDQ
dehydrogenate reaction, reduction with H/Pd-c, oxidation with Mno2/Si02, the
nature product 10(xh-14)with biological activities was synthesized, providing new
synthetic routes for XH-14. The key steps was the Ag2o-catalyzed biomimetic
oxidative coupling.
The synthetic benzofuran neolignans as substrate, of which 4-OH were
replaced by a series of other functional group. Benzofuran neolignans with prenyl
bromide or trans, trans-farnesyl bromide and anhydrous potassium carb