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

描述（由申请人提供）：通过不对称催化开发可靠的、立体控制的小分子合成的有效方法，对于提供制备潜在机械探针和药物的手段至关重要。这些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，发展新的催化不对称反应对NIH的使命具有实际和根本的重要性。手性有机硼烷正被越来越多地用作合成中间体，通过立体特异性官能团相互转化获得其他有用的功能，用于不对称合成的试剂，以及用于制药应用的合成靶标。在金属转化或转化为其他有用的官能团时，碳硼键的立体化学性质得以保留。因此，有机硼烷被视为在天然产物、医药中间体和药物合成中结合具有明确立体化学的各种官能团的重要中间体。近年来，碳-硼立体定向转化为碳-碳键的方法取得了突破性进展，这增加了对合成手性有机硼酸盐的有效方法的需求。虽然化学计量不对称硼化反应在不对称合成中很有用，但它的最终替代品——绿色直接催化不对称硼化反应（CAHB），仍然是不对称催化领域尚未解决的问题之一。尽管近年来使用吡纳科尔二硼烷作为（单）硼烷替代物取得了一系列令人印象深刻的进展，但缺乏一种催化不对称硼氢化的通用直接方法仍然是使用手性有机硼烷的关键障碍。提出的研究建立在催化不对称硼氢化两点结合底物的最新突破。实现提案的具体目标将发展和扩大该方法的普遍性，并通过实验数据支持的计算研究更好地定义机制。计算研究将与普渡大学Calumet化学和物理系的教师和本科生合作进行。

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. PUBLIC HEALTH RELEVANCE: The development of efficient green or greener chemical methods that enable the reliable, stereocontrolled synthesis of small molecule target structures is an important goal relevant to the NIH mission. Asymmetric catalysis plays an important role in achieving that goal, and while tremendous advances have been realized, continued progress relies upon developing innovative, new approaches to the remaining unsolved problems. The proposed research plan develops an innovative approach toward developing greener direct catalytic asymmetric hydroborations, one of the unsolved problems in asymmetric catalysis.