Catalytic Asymmetric Hydroboration: Uncapping the Potential with Two-Point Bindin

描述(由申请人提供)：开发通过不对称催化可靠的、立体控制的小分子合成的有效方法是提供制备潜在的机械探针和药物的手段的核心。这些都是能够更好地了解和控制与人类健康有关的生物过程的基本工具。因此，开发新的催化不对称反应对美国国立卫生研究院的任务具有重要的现实意义和基础意义。手性有机硼烷作为合成中间体，通过立体定向的官能团相互转化、不对称合成试剂和医药应用的合成靶标，正越来越多地被用作合成中间体。碳-硼键的立体化学在过渡金属或转化为其他有用的官能团时保持不变。因此，有机硼烷被认为是在天然产物、药物中间体和药物合成中结合具有特定立体化学的各种官能团的重要中间体。最近在碳-硼立体定向转化为碳-碳键方法方面的突破增加了对合成手性有机硼化合物的有效方法的需求。虽然化学计量不对称氢化反应在不对称合成中是有用的，但它的最终替代方法--更绿色的直接催化不对称氢化反应(CAHB)仍然是不对称催化领域中尚未解决的问题之一。尽管最近在使用频那醇二硼烷作为(单)硼烷替代品方面取得了一系列令人印象深刻的进展，但缺乏一种通用的直接催化不对称氢化反应的方法仍然是手性有机硼烷使用的关键障碍。拟议的研究建立在两点结合底物的催化不对称氢硼化反应的最新突破的基础上。实现该提案的具体目标将发展和扩大这一方法的一般性，并通过实验数据支持的计算研究更好地确定该机制。计算研究将与普渡大学Calumet大学化学和物理系的教职员工和本科生合作进行。

DESCRIPTION (provided by applicant): Developing efficient methods for the reliable, stereocontrolled synthesis of small molecules via asymmetric catalysis is central to providing the means to prepare potential mechanistic probes and pharmaceuticals. These are essential tools that enable the better understanding and control of biological processes relevant to human health. The development of new catalytic asymmetric reactions is therefore of both practical and fundamental importance to the NIH mission. Chiral organoboranes are finding increasing use as synthetic intermediates en route to other useful functionality via stereospecific functional group interconversion, reagents for asymmetric synthesis, and synthetic targets for pharmaceutical applications. The stereochemistry of carbon-boron bond is retained upon transmetallation or conversion to other useful functional groups. Organoboranes are therefore seen as important intermediates for incorporating a variety of functional groups with defined stereochemistry in natural product, pharmaceutical intermediate, and drug synthesis. Recent breakthroughs in the development of methods for the stereospecific conversion of carbon-boron to carbon-carbon bonds increase the demand for efficient methods to synthesize chiral organoboronates. While stoichiometric asymmetric hydroboration is useful for asymmetric synthesis, its ultimate replacement, the greener direct catalytic asymmetric hydroboration (CAHB), remains as one of the unsolved problems in asymmetric catalysis. Notwithstanding a series of impressive recent advances using pinacol diborane as a (mono)borane surrogate, the lack of a versatile direct method for catalytic asymmetric hydroboration remains a critical barrier to the use of chiral organoboranes. The proposed studies build on recent breakthroughs in the catalytic asymmetric hydroboration of two-point binding substrates. Accomplishing the specific aims of the proposal will develop and expand the generality of that methodology and better define the mechanism through computational studies supported by experimental data. The computational studies will be carried out in collaboration with faculty and undergraduate students from the Department of Chemistry and Physics at Purdue University Calumet.