Synthesis and Study of Complex Natural Products

描述（由申请人提供）：对复杂分子（包括天然产物和相关衍生物）的基本化学和生物学性质的仔细检查和研究，极大地有助于开发用于治疗人类疾病的疗法。这些研究为理解其作用模式提供了关键见解，并使新治疗方法的开发成为可能。本研究项目旨在发现和开发新的、有效的策略和方法，用于结构复杂和具有生物活性的生物碱的对映选择性全合成。新的合成策略的开发灵感来自生物遗传学的考虑，具有广泛的适用性，复杂的分子合成形成了我们的方法的基础。特别令人感兴趣的是开发新的合成策略，允许快速生成分子复杂性。这些包括级联和串联过程，允许形成具有高水平立体化学控制的多重键。根据分子结构的复杂性、发现新化学转化的前景、开发新策略和方法的机会、具有显著的生物活性以及未来化学和生物机制研究的潜力来选择靶点。以Agelastatin为代表的oroidin生物碱家族是一个丰富和令人兴奋的背景，用于开发快速合成咪唑酮和氨基咪唑杂环的新合成方法，沿着用于构建这些生物碱的复杂成员中所见的多环框架的新级联过程。同样，以aspidophytine为代表的aspidosperma生物碱提供了杰出的架构，激发了新的和高度立体选择性的级联和串联反应的发展，以确保其骨架，除了发展与组装更复杂的铽-吲哚生物碱相关的高度化学和立体选择性转化。该计划将产生大量稀有和珍贵分子的合成样品。这些将包括最终目标和在我们的研究中获得的许多中间体，所有这些都将使我们能够探索它们的化学和生物学。在我们的研究中获得的化合物将通过我们在直接生物活性评价方面的既定合作进行生物学测试，并具有用作化学探针的潜力。 公共卫生相关性：开发用于治疗人类疾病的疗法的重要工具是复杂生物活性化合物（包括天然产物和相关衍生物）的基础化学和生物学研究。目标是根据有趣的分子结构，方法学发展的机会，机制研究，以及未来合作生物机制研究和评估的潜力来选择的。计划中的合成旨在开发新的复杂性生成反应序列，特别是多个立体选择性键形成级联，并挑战现有的合成方法，此外还激发开发新的和广泛适用的方法来合成复杂分子。

DESCRIPTION (provided by applicant): The close examination and study of the fundamental chemical and biological properties of complex molecules, including natural products and related derivatives, significantly contributes to the development of therapeutics for the treatment of human ailments. Such studies provide key insight to understanding their mode of action and enable development of new treatments. This research program aims to discover and develop new and efficient strategies and methodologies for the enantioselective total synthesis of architecturally complex and biologically active alkaloids. The development of new synthetic strategies inspired by biogenetic considerations with broad applicability to complex molecule synthesis forms the basis of our approach. Of particular interest is development of new synthetic strategies allowing rapid generation of molecular complexity. These include cascade and tandem processes that permit the formation of multiple bonds with high levels of stereochemical control. Targets are selected on the basis of the complexity of the molecular architecture, the prospect of discovering new chemical transformations, the opportunities for development of new strategies and methodologies, the possession of significant biological activity, and the potential for future chemical and biological mechanistic studies. The oroidin family of alkaloids, represented by the agelastatins, is a rich and exciting setting for development of new synthetic methodology for rapid synthesis of imidazolone and aminoimidazole heterocycles, along with new cascade processes for construction of polycyclic frameworks seen in complex members of these alkaloids. Likewise, the aspidosperma alkaloids, represented by aspidophytine, offer outstanding architectures that inspire development of new and highly stereoselective cascade and tandem reactions for securing their skeletons, in addition to development of highly chemo- and stereoselective transformations relevant to assembly of more complex terpene-indole alkaloids. This program will result in a vast number of synthetic samples of rare and precious molecules. These will include both the final targets and the great many intermediates that are accessed in the context of our studies, all of which will enable exploration of their chemistry and biology. The compounds accessed in our studies will be subject to biological testing through our established collaborations both in direct bioactivity evaluation and also hold potential for use as chemical probes. PUBLIC HEALTH RELEVANCE: An important tool in the development of therapeutics for the treatment of human ailments is the fundamental chemical and biological study of complex bioactive compounds including natural products and related derivatives. Targets are selected on the basis of interesting molecular architectures, opportunities for methodological developments, mechanistic study, and the potential for future collaborative biological mechanistic studies and evaluation. The planned syntheses are designed to develop new complexity generating sequence of reactions, in particular multiple stereoselective bond-forming cascades, and to challenge existing synthetic methods in addition to inspire the development of new and broadly applicable methodologies for the synthesis of complex molecules.