Strategies for the Synthesis of Bioactive Molecules

描述（由申请人提供）：吲哚杂环在生物活性分子和原料药中普遍存在。迄今为止，已经发现了1万多种具有生物活性的吲哚衍生物，其中200多种目前已作为药物上市或正在进行临床试验。尽管发展了一系列令人印象深刻的策略来合成功能化吲哚，但选择性替代吲哚苯环的方法是有限的。一项允许同时在吲哚苯环上引入多个官能团和组装立体拥挤键系统的新技术将具有巨大的价值，并最终能够合成大量与生物相关的含吲哚的复杂分子，这些分子是传统方法无法获得的。因此，所提出的研究的长期目标是开发新的策略来合成具有特权吲哚基序的高功能化小分子。我们的方法，以及本提案的重点，涉及合成和研究吲哚的高活性芳基衍生物，或“吲哚”。这些物质将起亲电作用，这与众所周知的吲哚杂环的亲核特性形成对比。我们预计这种罕见的吲哚“umpolung”将为合成功能化的含吲哚天然产物提供非常规的策略，包括许多具有多个苯取代基或空间拥挤框架的有趣靶标。如果这一建议的目标得以实现，制备生物活性分子的新化学方法将被开发出来。最终，这一贡献将有助于发现治疗人类疾病的新药。

DESCRIPTION (provided by applicant): The indole heterocycle is ubiquitous amongst bioactive molecules and drug substances. More than 10,000 biologically active indole derivatives have been discovered to date, of which over two hundred are currently marketed as pharmaceuticals or undergoing clinical trials. Despite the development of an impressive array of strategies to synthesize functionalized indoles, methods to selectively substitute the indole benzenoid ring are limited. A new technology that allows for the simultaneous introduction of multiple functional groups on the indole benzenoid ring and the assembly of sterically congested bond systems would be of tremendous value, and would ultimately enable the synthesis of a host of biologically- relevant indole-containing complex molecules that are not accessible by conventional means. Thus, the long-term goal of the proposed research is to develop new tactics for the synthesis of highly functionalized small molecules that possess the privileged indole motif. Our approach, and the focus of this proposal, involves the synthesis and study of highly reactive aryne derivatives of indoles, or "indolynes". These species would function as electrophiles, which lies in contrast to the well-known nucleophilic character of the indole heterocycle. We anticipate that this rare indole 'umpolung' will provide unconventional strategies for the synthesis of functionalized indole-containing natural products, including a number of intriguing targets that possess multiple benzenoid substituents or sterically congested frameworks. If the goals of this proposal are achieved, new chemical methods for preparing biologically active molecules will be developed. Ultimately, this contribution will facilitate the discovery of new medicinal agents for treating human illnesses. PUBLIC HEALTH RELEVANCE: If the goals of this proposal are achieved, new chemical methods for preparing biologically active molecules will be developed. Ultimately, this contribution will facilitate the discovery of new medicinal agents for treating human illnesses.