Total synthesis of (±)-ginkgolide B
Total synthesis of (±)-ginkgolide B
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DOI：
10.1021/ja993013p
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发表时间：
1999-11-03
影响因子：
15
通讯作者：
Wagman, AS
中科院分区：
文献类型：
--
作者：
Crimmins, MT;Pace, JM;Wagman, AS
银杏，被达尔文称为“活化石”，其祖先可以追溯到公元前2.3亿年1银杏提取物，已被用作草药5000年来治疗各种疾病，如咳嗽，哮喘和循环系统疾病，目前正在进行临床评估治疗痴呆症。2银杏内酯B是银杏提取物中最强的血小板活化因子（PAF）拮抗剂，IC 50为0.6 μM。[3]银杏内酯B复杂的分子结构，包括六个环，十一个立体中心，十个含氧碳和四个连续的完全取代的碳，是化学合成的一个艰巨挑战。功能性的恶魔般的处置决定了功能性基团的引入要明智地协调。1967年首次对银杏内酯进行了表征，1988年Corey及其同事报道了银杏内酯A5和B6的合成。相关化合物白果内酯的合成也由Corey组7和我们的实验室完成。8本文报道了银杏内酯B的全合成，采用高烯醇化锌铜9和我们实验室开发的双非对映选择性分子内[2+ 2]光环加成方法。从战略上讲，银杏内酯B的合成被认为是可以从五环前体2实现的，该五环前体2是通过区域选择性环丁烷断裂和进一步官能化从3衍生的。烯酮-呋喃4的立体选择性分子内光环加成产生环加合物3预期提供构建分子的拥挤核心所需的立体化学控制。光环化加成底物4的制备通过我们的用于构建羰基烷氧基环戊烯酮的均烯醇化物技术来完成。9光环化加合物3的合成如方案2所示。使3-（3-呋喃基）丙烯酸乙酯8经受更高级的铜酸盐[t-Bu 2CuCNLi 2，TMSCl，Et 2 O]以引入关键的叔丁基。用i-Bu 2AlH还原所得酯，以95%的总产率提供相应的醛5。将乙炔基溴化镁加入到醛5中，得到1.2：1的产物。
Ginkgo biloba, termed the “living fossil” by Darwin, has ancestors dating to 230 million BC 1 Extracts of Ginkgo biloba, which have been used as herbal medicines for 5000 years to treat a variety of conditions such as coughs, asthma, and circulatory disorders, are currently undergoing clinical evaluation for treatment of dementia. 2 Ginkgolide B is the most potent platelet activating factor (PAF) antagonist of the ginkgo extracts, with an IC50 of 0.6 μM. 3 The complex molecular architecture of ginkgolide B, which includes six rings, eleven stereogenic centers, ten oxygenated carbons, and four contiguous fully substituted carbons, is a daunting challenge for chemical synthesis. The diabolical disposition of functionality dictates that introduction of functional groups be judiciously orchestrated. The ginkgolides were first characterized in 1967, 4 and the syntheses of ginkgolides A5 and B6 were reported by Corey and co-workers in 1988. The synthesis of the related compound, bilobalide, was also achieved by the Corey group7 as well as by our laboratory. 8 Reported herein is the total synthesis of ginkgolide B utilizing the zinc-copper homoenolate9 and double diastereoselective intramolecular [2+ 2] photocycloaddition methodologies developed in our laboratories. 10 Strategically, the synthesis of ginkgolide B was thought to be achievable from the pentacyclic precursor 2 which was to be derived from 3 by a regioselective cyclobutane fragmentation and further functionalization. A stereoselective intramolecular photocycloaddition of the enone-furan 4 to produce cycloadduct 3 was anticipated to provide the stereochemical control required to construct the congested core of the molecule. Preparation of the photocycloaddition substrate 4 was to be accomplished through our homoenolate technology for the construction of carboalkoxycyclopentenones. 9The synthesis of the photocycloadduct 3 is illustrated in Scheme 2. Ethyl 3-(3-furyl) acrylate8 was subjected to the higher order cuprate [t-Bu2CuCNLi2, TMSCl, Et2O] to incorporate the critical tert-butyl group. The resultant ester was reduced with i-Bu2AlH to provide the corresponding aldehyde 5 in 95% overall yield. Addition of ethynylmagnesium bromide to aldehyde 5 gave a 1.2: 1