New Methods for the Concise Synthesis of Bioactive Polycyclic Molecules

描述（由申请人提供）：人类疾病有效化学疗法的发现和发展受到合成化学缺陷的限制，这些缺陷使得研究重要的化学结构变得困难。特别是，由于缺乏制备方法，许多复杂多环结构的临床潜力尚未得到充分开发。填补这一空白将使许多新结构得以快速合成，从而提高新疗法被发现的速度。我们的长期目标是通过开发通用的合成方法来构建具有生物活性的复杂多环结构，为化学和医学做出重大贡献。我们目前研究的总体目标是发展硅系链烯醇酯的氧化偶联，作为制备包含连续立体中心的复杂结构的有力方法。现有方法的缺乏限制了这种结构在化学文库合成中的使用，并且使得临床相关天然产物的有效制备变得困难。我们研究硅基双烯醇醚的基本原理是它们可以介导两种不同化学片段的耦合，同时控制成键的立体化学结果，从而提供复杂结构的简洁合成。本建议的具体目标是：1。开发和利用硅基双烯醇醚为基础的氧化法制备连续立体中心的新方法；2. 开发多组分偶联工艺，快速生成复杂的生物活性分子；和3。发展新的氧化成键反应，超越烯醇-烯醇偶联。本研究具有创新性，因为硅系链可以控制异偶联和均偶联，以及氧化烯酸酯键形成的立体选择性。形成四元立体中心、相邻立体阵列和串联多组分耦合序列的技术的发展将有效地产生复杂性。对路易斯碱活化的进一步研究将为制备这些结构提供对映选择性方法。新的氧化成键反应的发明将扩大硅系绳概念的实用性，使之适用于大量具有挑战性的化合物。本研究的预期结果将是对当前方法提出重大挑战的许多重要医学结构的简明合成。这项拟议的研究对人类健康具有重要意义，因为它有望提供大量的复杂多环结构，以确保它们在发现新的化学疗法中得到利用。公共卫生相关性：这项拟议的研究将产生新的方法来制备生物学上重要的多环分子。这些未知结构的合成将对人类健康产生重要的积极影响，允许深入的生物学研究，从而发现新的候选药物和对抗癌症等疾病的生物学靶点。

DESCRIPTION (provided by applicant): The discovery and development of effective chemical therapeutics for human disease is limited by the shortcomings of synthetic chemistry that make investigating important chemical structures difficult. In particular, the clinical potential of many complex polycyclic structures is under-explored due to a lack of methods for their preparation. Bridging this gap will allow many new structures to be synthesized rapidly, leading to an increased rate at which new therapeutics are discovered. Our long-term goal is to make significant contributions to both chemistry and medicine by developing general synthetic methods to construct biologically active complex polycyclic structures. The overall objective of our current research is to develop the oxidative coupling of silicon-tethered enolates as a powerful method to prepare complex structures that contain contiguous stereocenters. The paucity of available methods limits the use of such structures in chemical library synthesis and makes the efficient preparation of clinically relevant natural products difficult. Our rationale for investigating silyl bis-enol ethers is that they can mediate the coupling of two different chemical fragments and simultaneously control the stereochemical outcome of bond formation, thereby affording concise syntheses of complex structures. The Specific Aims of this proposal are: 1. Develop and utilize silyl bis-enol ether-based oxidation as a powerful new method to construct contiguous stereocenters; 2. Develop multicomponent coupling processes for rapid generation of complex bioactive molecules; and 3. Develop new oxidative bond-forming reactions that extend beyond enol-enol coupling. This proposed research is innovative because the silicon-tether acts to control both heterocoupling vs. homocoupling, and stereoselectivity for oxidative enolate bond formation. The development of techniques for fashioning quaternary stereocenters, vicinal stereoarrays, and tandem multicomponent coupling sequences will generate complexity efficiently. Additional research into Lewis base activation will provide enantioselective methods for preparing these structures. The invention of new oxidative bond-forming reactions will expand the usefulness of the silicon-tether concept to a wealth of challenging compounds. The expected outcomes of this research will be the concise synthesis of many medicinally important structures that are of significant challenge to current methods. This proposed research is significant for human health because it is expected to provide complex polycyclic structures in quantities that will ensure their utilization in discovering new chemical therapeutics. PUBLIC HEALTH RELEVANCE: This proposed research will generate new methods to prepare biologically important polycyclic molecules. The synthesis of these unexplored structures will have an important positive impact on human health by allowing in-depth biological studies, and thus unearth new drug candidates and biological targets for combating diseases such as cancer.