Synthesis and Study of Dimeric 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，为理解其作用模式和开发用于治疗各种人类疾病的新疗法提供了关键的见解。本研究项目旨在通过新策略和新方法的发现、开发和应用，开发结构复杂和具有生物活性的天然产物的高效、简洁的全合成。在这个程序中，生物遗传学的考虑为开发新的通用策略提供了灵感，以快速建立分子复杂性。计划合成的一个关键特征是开发新的高化学选择性和立体选择性转化。特别感兴趣的是新方法的发展，允许使用中间体的固有反应性进行高级功能化。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充足机会，具有重要的生物活性，以及未来化学和生物机制研究的潜力。本计划将集中于二聚二酮哌嗪生物碱丰富家族的合成研究。这些生物碱的核心结构是由csp3 -烷基（sp3-sp3）或csp3 -芳基（sp3-sp2）键连接在四元立体中心上。该项目将专注于具有潜在生物活性的附二硫代二酮哌嗪，包括噻菌素生物碱，并将开发可用于快速组装和功能化的二聚二酮哌嗪的通用方法，这些二聚二酮哌嗪含有通过Csp3-Csp3键连接的邻季立体中心。我们还将研究一个晚期高度立体选择性的氧化-迁移序列，利用双吲哚结构来获得各种生物碱中发现的csp3 -芳基（sp3-sp2）键连通性。该计划将产生稀有和珍贵化合物的合成样品，用于结构验证和探索其化学和生物学。鉴于二酮哌嗪和附二硫代二酮哌嗪具有丰富的生物活性，相关的中间体和衍生物也有望作为机制工具和新的生物活性化合物，因此将通过我们的合作活动进行各种测试。

DESCRIPTION (provided by applicant): The detailed study of the chemistry and biology of complex natural products at a fundamental level provides insight that is key to understanding their mode of action and development of new therapeutics for treatment of various human ailments. This research program aims to develop efficient and concise total syntheses of structurally complex and biologically active natural products through the discovery, development, and application of new strategies and methodologies. In this program, biogenetic considerations provide inspiration for development of new generalizable strategies to rapidly build molecular complexity. A key feature of the planned syntheses is the development of new highly chemoselective and stereoselective transformations. Of particular interest is development of new methodologies allowing advanced stage functionalization using the inherent reactivity of intermediates. Targets are selected based on novelty of molecular architecture, paucity of prior synthetic studies, ample opportunities for development of new strategies and methodologies, possession of significant biological activity, and the potential for future chemical and biological mechanistic studies. This program will focus on synthetic studies of the rich family of dimeric diketopiperazine alkaloids. The core structures of these alkaloids are adjoined by either Csp3-alkyl (sp3-sp3) or Csp3-aryl (sp3-sp2) bond connectivity at quaternary stereocenters. The program will focus on potently bioactive epidithiodiketopiperazines, including the verticillin alkaloids, and will develop generalizable methodologies for rapid assembly and functionalization of dimeric diketopiperazines containing vicinal quaternary stereocenters connected via a Csp3-Csp3 bond. We will also study a late stage highly stereoselective oxidation-migration sequence using bisindole structures to access the Csp3-aryl (sp3-sp2) bond connectivity found in a variety of alkaloids. This program will result in synthetic samples of rare and precious compounds for structure validation and exploration of their chemistry and biology. Given the rich biological activity of diketopiperazines and epidithiodiketopiperazines under investigation, related intermediates and derivatives also hold great promise as mechanistic tools and new bioactive compounds, and thus will be subject to various tests through our collaborative activities. PUBLIC HEALTH RELEVANCE: The study of the fundamental chemical and biological mechanism of action of natural products continues to play an important role in the development of new treatments for a variety of human ailments. This program aims to discover, develop, and apply new and unique strategies and methodologies for preparation of bioactive and complex natural molecules and related designed derivatives. While the immediate result is direct access to samples of extremely rare and precious compounds for structure validation, collaborative biological evaluation, and mechanistic studies, the longer term and broader impact of this program is the establishment of precedence for the application of these new chemistries to other targets and potential therapeutics both natural or rationally designed.