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: 6350406
• 负责人: LEO A PAQUETTE
• 金额: $ 25.97万
• 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/6350406
• 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.

紫杉醇及其亲密的结构亲戚代表了实施从头综合策略的苛刻目标。 这是它们高结构复杂性和丰富的立体化学细节的结果。 目前开发的途径主要是为了证明可以在实验室准备紫杉醇，并且不能归类为特别有效。 当前努力的主要目的是通过解决至少两个中央重排来开发更简短的途径到紫杉醇，我们已经在高度功能化的设置中证明了这一点，以便能够满足既定需求。 因此，该方法是一种围绕策略设计的一种方法，即通过将简单的1,2个d-camphor衍生物提交到连续电荷加速的氧气和α-酮重排以及新的，新的，具体定制的反应的策略中。 利用其中一些概念的出租车的合成已经完成。我们的方案将依靠D-Camphor（一种廉价的对映体纯商品化学化学物质）在其适当的绝对构型中产生靶向化合物。 重点是简洁。因此，将开发出非常合理的Regiocontrol和最小的保护/脱保护操作数量。 灵活性也应至关重要，因此方法学的较小变化将允许我们的中间体适应到达多种目标最终产品。我们的首要任务是到达紫杉醇。 由于最迅速的路线已经很明显，因此实时将同时致力于为不降解自​​然产品而无法获得的重要同源物做好准备。 这些包括但不限于1-脱氧，D-HOMO-，2-脱甲基和12-甲基衍生物，此外，除了D环和C-NOR异构体外。