New Methods for the Concise Synthesis of Bioactive Polycyclic Molecules

项目摘要/摘要 治疗人类疾病的有效化学疗法的发现和发展 受限于合成化学的缺点，使研究成为重要的化学物质 结构困难。特别是，许多复杂的多环结构的临床潜力是 由于缺乏准备方法，开发不足。弥合这一差距将使许多 快速合成新结构，导致新疗法的速度加快 都被发现了。 我们的长期目标是为化学和医学做出重大贡献 通过发展通用的合成方法来构建具有生物活性的多环化合物 结构。我们目前研究的总体目标是发展氧化偶联 硅系联烯醇酸盐是一种制备含有以下物质的复杂结构的有效方法 连续的立体中心。现有方法的缺乏限制了此类结构在 化学文库合成，使临床相关的高效天然制备 产品难做。我们研究硅基双烯醇醚的基本原理是它们可以调节 两种不同化学片段的偶联并同时控制立体化学 键形成的结果，从而提供复杂结构的简明合成。 本建议的具体目的是：1.开发和利用硅基双烯醇醚 氧化作为构建连续立体中心的强有力的新方法；2.发展 用于快速生成复杂生物活性分子的多组分耦合过程； 开发超越烯醇-烯醇偶联的新的氧化键形成反应。 这项拟议的研究是创新的，因为硅系绳起到了控制两者的作用。 异位偶联与同位偶联，以及形成氧化烯醇键的立体选择性。 形成第四级立体中心、邻域立体阵列、 而串联多组分耦合序列将有效地产生复杂性。其他内容 对Lewis碱活化的研究将为制备这些化合物提供不对称的方法 结构。新的氧化键形成反应的发明将扩大 硅系绳的概念带来了大量具有挑战性的化合物。这样做的预期结果是 研究将是许多医学上重要结构的简明合成，这些结构是 对现有方法的重大挑战。这项拟议的研究对人类健康具有重要意义 因为预计它将提供复杂的多环结构，从而确保 它们在发现新的化学疗法方面的应用。

PROJECT SUMMARY/ABSTRACT 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.