Synthesis and Study of Cyclotryptamine and Diketopiperazine Alkaloids

描述（由申请人提供）：在基础水平上对复杂天然产物的化学和生物学进行详细研究，为理解其作用模式提供了关键的见解，并使开发治疗各种人类疾病的新方法成为可能。本研究计划的重点是通过系统地发现、开发和应用新的合成策略和方法，开发结构复杂和具有生物活性的天然产物的高效、简洁的全化学合成。计划合成的一个关键特征是高度化学选择性和立体选择性转化的发展，这使得能够实施新的可推广的合成策略，通常受到生物遗传学考虑的启发，以快速产生分子复杂性。开发简洁统一的天然产品系列方法，这是该项目的一个持续主题，需要同时开发新的方法，以便在复杂的环境中实现高级功能。目标的选择是基于分子结构的新颖性，先前合成研究的缺乏，新策略和方法发展的丰富机会，具有重要的生物活性，以及未来化学的潜力

DESCRIPTION (provided by applicant): The detailed study of the chemistry and biology of complex natural products at a fundamental level provides critical insight to understanding their mode of action and enables development of new approaches for treatment of various human ailments. This research program focuses on the development of efficient and concise total chemical syntheses of structurally complex and biologically active natural products through the systematic discovery, development, and application of new synthetic strategies and methodologies. A key feature of the planned syntheses is the development of highly chemoselective and stereoselective transformations that enable the implementation of new generalizable synthetic strategies, often inspired by biogenetic consideration, for the rapid generation of molecular complexity. The development of concise and unified approaches to families of natural products, a continuing theme of this program, requires the concurrent development of new methodologies allowing advanced stage functionalization in complex settings. The targets are selected based on novelty of molecular architecture, paucity of prior synthetic studies, abundance of opportunities for development of new strategies and methodologies, possession of significant biological activity, and the potential for future chemical and biological studies. This program will focus on synthetic studies of the rich family of cyclotryptamine and diketopiperazine alkaloids. Of central interest is the directed, regioselective stereoselective, and efficient adjoining of cyclotryptamine substructures providing late stage unions to secure challenging quaternary stereocenters. With this program's particular focus on the potently bioactive epidithiodiketopiperazine, a concurrent effort is the development of new efficient methodologies to enable regioselective and stereoselective sulfidation of complex diketopiperazines. This program will continue to provide synthetic samples of rare and precious compounds for structure validation and detailed examination of their chemistry and biology. The well recognized biological activity of the entire family of compounds under investigation ensure that the many related intermediates and derivatives accessed through these efforts will also behold great promise both as mechanistic tools and as new bioactive compounds, and thus they will be subject to continuous evaluation through our multidisciplinary and collaborative engagements.