TUMOR REMISSION--TAXOL AND CLOSE ANALOGS VIA SYNTHESIS

肿瘤缓解——紫杉醇及其类似物的合成

• 批准号: 6551975
• 负责人: LEO A PAQUETTE
• 金额: $ 1.75万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/6551975
• 关键词: analog; bridged cyclic compound; chemical synthesis; diterpenes; oxetane; paclitaxel

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.

紫杉醇及其结构上的近亲是实施从头合成战术的非常苛刻的目标。这是由于它们高度的结构复杂性和丰富的立体化学细节造成的。发展到现在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。目前努力的主要目标是通过解决至少两个中心重排来开发一条更短的紫杉醇路线，我们已经在高度功能化的环境中证明了这一点能够满足所述需要。因此，这种方法是围绕这样一种策略设计的，即通过将D-樟脑衍生物的简单1，2-加合物与新的、专门定制的反应一起，进行顺序的电荷加速氧合和α-酮醇重排，从而及早阐述整个紫杉烷环系。紫杉素的合成利用了其中的一些概念，已经完成。我们的方案将依赖于D-樟脑，一种廉价的对映体纯商品化学品，以适当的绝对构型生产目标化合物。强调简明扼要；因此，应制定非常合理的区域控制和最少的保护/解除保护演习次数。灵活性也是最重要的，这样，方法上的微小变化将允许我们的中间体适应几个目标最终产品的到达。我们的首要任务是到达紫杉醇。由于最快捷的路线正在变得明显，实时将同时致力于准备因天然产品降解而无法获得的重要同系物。这些包括但不限于1-脱氧、D-高甲基、2-脱甲基和12-亚甲基衍生物，以及D-环反式异构体和C-NOR异构体。