THE SYNTHESIS OF SOME COMPLEX CYTOTOXIC COMPOUNDS

一些复杂细胞毒性化合物的合成

• 批准号: 3168201
• 负责人: RICHARD H SCHLESSINGER
• 金额: $ 15.34万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-04-01 至 1991-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3168201
• 关键词: antineoplastic antibiotics; drug design /synthesis /production; plant extracts

It is our intention to accomplish the following synthetic goals within the time frame requested for this grant application. Firstly, we intend to finish the vertisporin problem, which should only take a year of one graduate student's time. We have invested a lot of time in this problem, but we now know how to do it properly. A major component of this problem, in terms of learning new chemistry, concerns the application of some organotin reagents to reaction with sugar-derived ketones. These reactions yield stereochemistry that is the reverse of the more usual stereochemistry observed with ketones of this type. Thus, along with finishing the synthesis of vertisporin, we intend to examine the stereochemistry of organostannane reagents in reaction with a number of sugar-derived ketones. Secondly, we intend to embark on a rather ambitious project, the total synthesis of okadaic acid. This molecule is a complex cytotoxic ionophore, the structure of which asks many interesting stereochemical questions. Over the past year, we have developed, via a consideration of ionophores in general, new methods, based on the chemistry of vinylogous urethanes, to deal with the intricate stereochemical problems presented by these natural products. Okadaic acid holds within its structural framework a majority of the stereochemical problems presented by ionophores. Since the molecule has the additional virtue of being a known anti-tumor substance, and further since the structure of okadaic acid presents stereochemical problems of current significance, we intend to use this natural product to demonstrate and further develop the efficacy of our new methods.

我们的意图是实现以下综合目标 在本次拨款申请所要求的时间范围内。 首先，我们打算完成Vertisporin问题，它应该 只花一个研究生一年的时间。我们已经投资了 在这个问题上花了很多时间，但我们现在知道如何做了 恰到好处。这个问题的一个主要组成部分，就是 学习新化学，涉及到一些应用 与糖基酮反应的有机锡试剂。这些 反应产生立体化学，这与更多的 用这种类型的酮观察到的通常的立体化学。因此， 在完成Vertisporin的合成的同时，我们打算 检查有机锡试剂的立体化学 与一些糖基酮反应。 其次，我们打算启动一个相当雄心勃勃的项目， 冈田酸的全合成。这种分子是一种络合物 细胞毒性离子载体，其结构令人感兴趣 立体化学问题。在过去的一年里，我们发展了， 通过对一般电离团的考虑，新方法，基于 关于乙烯基氨基甲酸酯的化学，以处理 这些天然的、复杂的立体化学问题 产品。冈田酸在其结构框架内含有一个 电离团带来的大多数立体化学问题。 因为分子还有一个额外的优点，那就是它是一种已知的 抗肿瘤物质，进一步自冈田克的结构 酸提出了具有当前意义的立体化学问题，我们 意在用这一天然产物来展示和进一步 开发我们新方法的有效性。