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TUMOR REMISSION--TAXOL AND CLOSE ANALOGS VIA SYNTHESIS

肿瘤缓解——紫杉醇及其类似物的合成

基本信息

批准号：
6628425
负责人：
LEO A PAQUETTE
金额：
$ 27.64万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-03-01 至 2004-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6628425
关键词：
analog bridged cyclic compound chemical synthesis diterpenes oxetane paclitaxel

项目摘要

Paclitaxel and its close structural relatives represent very demanding targets for the implementation of de novo synthetic tactics. This is a consequence of their high structural complexity and abundant stereochemical detail. The routes developed to the present time were designed primarily to demonstrate that paclitaxel can be prepared in the laboratory and cannot be categorized as particularly efficient. The primary goal of the present effort is to develop a more abbreviated route to paclitaxel by addressing at least two central rearrangements, which we have demonstrated in highly functionalized settings to be capable of meeting the stated needs. The approach is therefore one designed around the tactic of elaborating the entire taxane ring system early by submitting simple 1,2-adducts of D-camphor derivatives to sequential charge-accelerated oxy- Cope and alpha-ketol rearrangements alongside new, specifically tailored reactions. A synthesis of taxusin, which takes advantage of some of these concepts, has already been completed. Our protocol will rely on D-camphor, an inexpensive enantiomerically pure commodity chemical, to produce the targeted compounds in their proper absolute configuration. Emphasis is to be placed on brevity; consequently, very reasonable regiocontrol and the minimum number of protection/deprotection maneuvers are to be developed. Flexibility shall also be paramount, such that minor changes in methodology will allow for the adaptation of our intermediates to arrival at several targeted end-products. Our first priority is to arrive at paclitaxel. As the most expeditious route is being made evident, real time will be concurrently devoted to preparing important congeners not available by degradation of the natural product. These include, but are not limited to, the 1-deoxy, D-homo-, 2-desmethyl, and 12-methylene derivatives, in addition to the D-ring invertomer and the C-nor isomer.

太平洋和它的结构上的近亲代表了实施从头合成战术的非常苛刻的目标。这是其高度结构复杂性和丰富的立体化学细节的结果。目前开发的路线主要是为了证明紫杉醇可以在实验室中制备，不能归类为特别有效。目前的努力的主要目标是通过解决至少两个中心重排来开发更简短的紫杉醇途径，我们已经在高度官能化的环境中证明了这能够满足所述需求。因此，该方法是一个设计的策略，制定整个紫杉烷环系统早期提交简单的1，2-加合物的D-樟脑衍生物的顺序电荷加速氧-科普和α-酮醇重排旁边的新的，特别定制的反应。利用其中一些概念的紫杉醇合成已经完成。我们的协议将依赖于D-樟脑，一种廉价的对映体纯的商品化学品，以产生其适当的绝对构型的目标化合物。重点是要放在简洁;因此，非常合理的区域控制和最低数量的保护/去保护演习将被开发。灵活性也是最重要的，这样，在方法上的微小变化将允许我们的中间体适应到达几个目标的最终产品。我们的首要任务是找到紫杉醇。由于最快捷的途径已变得明显，因此将同时投入真实的时间来制备无法通过自然产品降解获得的重要同系物。除了D-环反相异构体和C-nor异构体之外，这些包括但不限于1-脱氧、D-高-、2-去甲基和12-亚甲基衍生物。