New Cyclization Methods and Multicomponent Couplings

描述（由申请人提供）：快速可靠地获取合成衍生化学结构在生物医学研究的许多方面起着至关重要的作用。虽然复杂分子合成的进展表明，可以制备出一系列显著的结构，但潜在合成方法的潜在困难往往阻碍了有趣的化学结构被选择用于研究。本提案的潜在目标是为(i)作为许多生物活性天然产物和其他复杂结构的亚基或前体的简单化学亚结构，以及（ii）已知可调节化学实体生物活性的复杂含碳水化合物结构类型提供基本的新条目，但通常通过现有方法有效制备这些结构非常具有挑战性。第一个具体目标侧重于开发一种机械驱动的方法，用于发现高度区域选择性和对映选择性的还原偶联过程。解决区域选择性和对映选择性醛和炔的还原结合的挑战所带来的预期影响将是创造一种被合成化学家广泛采用的工艺。这一结果将具有广泛的意义，因为烯丙醇是许多生物活性化合物中不可或缺的特征，并作为广泛的复杂性构建和非对映选择性或对映选择性转化的通用构建块。此外，对催化操作中区域控制起源的基本理解将有助于在催化插入过程中需要区域选择性的许多其他反应中取得相关进展。第二个具体目标侧重于开发一套正交催化过程，用于复杂分子的化学选择性糖基化。我们努力开发位点选择性糖基化化学方法的预期影响将是，获得复杂糖基化结构的速度、效率和选择性将显著提高。这一结果将允许快速制备特定目标分子或少量非天然或天然产物衍生的糖基化结构，以作为药物化学先导或生化研究的探针分子进行检查。该方法代表了两个不同领域的合并：催化还原偶联技术和碳水化合物化学，这两个领域以前没有被协同研究过。这种独特的视角允许对传统方法无法解决的策略进行检查。本研究使生物医学上重要结构的改进条目成为可能，将使它们的生物学功能和治疗潜力得到更有效的研究。

DESCRIPTION (provided by applicant): Rapid and reliable access to synthetically-derived chemical structures plays an essential role in many aspects of biomedical research. While advances in complex molecule synthesis have illustrated that a remarkable range of structures can be prepared, the underlying difficulties of potential synthetic approaches often prevent interesting chemical structures from being selected for study. The underlying objective of this proposal is to provide fundamentally new entries to (i) simple chemical substructures that serve as subunits or precursors of many bioactive natural products and other complex structures, and (ii) complex carbohydrate- containing structures of the type that are well known to modulate the bioactivity of chemical entities, but that are often exceptionally challenging to prepare efficiently by existing methods. The first specific aim focuses on developing a mechanistically-driven approach for discovery of highly regioselective and enantioselective reductive coupling procedures. The expected impact of solving challenges in the regio- and enantioselective reductive union of aldehydes and alkynes will be the creation of a process that becomes widely adopted by synthetic chemists. This outcome will be broadly significant since allylic alcohols are an integral feature in many bioactive compounds and serve as versatile building blocks for a wide range of complexity-building and diastereoselective or enantioselective transformations. Furthermore, developing a fundamental understanding of the origin of regiocontrol in the catalytic operation will facilitate related advances in many other reactions that require regioselectivity in a catalytic insertion process. The second specific aim focuses on development of a suite of orthogonal catalytic processes for chemoselective glycosylation of complex molecules. The expected impact of our efforts to develop chemical methods for site-selective glycosylation will be that the speed, efficiency, and selectivity with which complex glycosylated structures may be obtained will be significantly improved. This outcome will allow the rapid preparation of either a specific target molecule or small collections of unnatural or natural product-derived glycosylated structures to examine as medicinal chemistry leads or probe molecules for biochemical studies. The approach represents a merger of two distinct fields: catalytic reductive coupling technology and carbohydrate chemistry, which have not previously been examined synergistically. This unique perspective allows examination of strategies that cannot be addressed by conventional approaches. The improved entries to biomedically important structures made possible by this research will enable their biological function and therapeutic potential to be more efficiently studied.