Strategies for the Synthesis of Bioactive Molecules

描述(申请人提供)：吲哚杂环在生物活性分子和药物物质中普遍存在。到目前为止，已经发现了10,000多种具有生物活性的吲哚衍生物，其中200多种目前作为药物上市或正在进行临床试验。尽管已经开发了一系列令人印象深刻的策略来合成功能化吲哚，但选择性取代吲哚苯环的方法仍然有限。一种允许在吲哚苯环上同时引入多个官能团和组装立体致密键体系的新技术将具有巨大的价值，并最终能够合成一系列常规方法无法获得的含有吲哚的生物相关复杂分子。因此，拟议研究的长期目标是开发新的策略来合成具有优先吲哚基序的高度官能化的小分子。我们的方法，也是这项建议的重点，涉及合成和研究吲哚的高活性芳烃衍生物，或“吲哚”。这些物种将作为亲电体发挥作用，这与众所周知的吲哚杂环的亲核特性形成了鲜明对比。我们预计，这种罕见的吲哚‘umpolung’将为合成含有吲哚的官能化天然产物提供非传统的策略，包括一些具有多个苯类取代基或空间稠密骨架的有趣目标。如果这项提议的目标得以实现，将开发新的化学方法来制备生物活性分子。最终，这一贡献将促进发现治疗人类疾病的新药物。 与公共健康相关：如果这项提案的目标得以实现，将开发新的化学方法来制备生物活性分子。最终，这一贡献将促进发现治疗人类疾病的新药物。

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.