The Development of New Stereoselective Organocatalytic Processes

描述(申请人提供)：生命的生物化学中涉及的重要分子的很大一部分具有“惯用手”，即它们主要以一种不可叠加的镜像形式被发现。此外，大多数药物和候选药物也有手性(手性)，这些化合物的所有立体异构体通常都是合成的，并对其生物活性进行评估。由于自然的手性，候选药物的镜像形式可能具有非常不同的生物效应。一种正在稳步增长的合成手性分子的方法是在需要立体控制的关键步骤中应用多功能的立体选择性催化方法。有机催化，即使用有机(非金属)小分子作为催化剂，是传统金属催化的一种有吸引力的替代方案。这一方法最近取得了一些成功，继续评估基于有机催化的化学显然是一项值得努力的工作。自2004年以来，基于手性磷酸的有机催化被证明在越来越多的反应中提供了良好的立体选择性。我们一直致力于手性磷酸立体选择性应用的新方法的开发。这项建议的具体目标分为设计、分析和改进一些新的反应，手性磷酸可以作为高效的、立体选择性的催化剂。在每一项新的反应研究中也描述了新创建的手性产品潜在的与健康相关的用途。与公共健康相关：本提案中描述的化学解决了现代合成的一个基本、重要的方面--三维(3-D)化学结构的控制。绝大多数“生命分子”和大多数药物都有特定的三维结构，必须对其进行控制才能高效、低成本地合成。因此，允许这种控制的方法对公共卫生非常重要。

DESCRIPTION (provided by applicant): Significant portions of important molecules involved in the biochemistry of life have "handedness," i.e. they are primarily found in one nonsuperimposible mirror image form. Additionally, the majority of drugs and drug candidates also have handedness (chirality) and all stereoisomers of these compounds are normally synthesized and evaluated for biological activity. Due to the chirality of nature, the mirror image forms of drug candidates can have vastly differing biological effects. One approach to the synthesis of chiral molecules that is growing steadily in usage is the application of versatile, stereoselective catalytic methodology in key steps where stereocontrol is required. Organocatalysis, the use of small organic (non-metal based) molecules as catalysts is an attractive alternative to traditional metal-based catalysis. This approach has found a number of recent successes and the continued evaluation of organocatalytic-based chemistry is clearly a worthwhile endeavor. Since 2004 the use of chiral phosphoric acid-based organocatalysis has been shown to provide for excellent stereoselectivity in a growing number of reactions. Our efforts have been involved in the development of new methodology where chiral phosphoric acids can be applied stereoselectively. The specific aims of this proposal are divided into the design, analysis, and refinement of a number of new reactions whereby chiral phosphoric acids can be efficient, stereoselective catalysts. The potential health-related utility of the newly created chiral products are also described in each new reaction study. PUBLIC HEALTH RELEVANCE: The chemistry described in this proposal addresses a fundamental, important aspect of modern synthesis -- the control of three-dimensional (3-D) chemical structure. The vast majority of the "molecules of life" and most pharmaceutical drugs have specific 3-D structure that must be controlled for efficient, low cost synthesis. Therefore methods that allow for this control are very important for public health.