Asymmetric Reactions with Dual-Functional Organocatalysis

描述(申请人提供)：在过去的两个资助周期中，我们的研究计划在不对称碱催化的开发方面取得了重大进展，以及有机催化剂的酸碱和亚胺碱双功能催化作为不对称反应开发的广泛适用概念。在我们以前的研究中，催化剂通过参与立体化学后果的单一过渡态来提供活性、对映体选择性和非对映选择性。我们的研究集中在新型反应级联的发明和开发上。基于初步结果揭示了金鸡纳生物碱作为高效的手性质子供体的能力，不对称双功能合作有机催化的发展成为我们提出的研究的共同主题。在这种催化模式中，有机催化剂充当双功能催化剂，通过激活和定向两个参与反应的反应物或中间体来促进反应级联反应中的两个不同步骤。具体目标是：1)发展不对称合成手性氨基化合物的对映体选择性和非对映选择性的双取代硝基烯烃的共轭加成-质子化反应。2)开发仿生质子转移催化剂，通过串联的去质子化-质子化反应将不饱和羰基对映体选择性异构化为手性不饱和羰基化合物。3)通过与过氧化氢的对映选择性和化学控制的共轭加成-质子化反应发展不对称过氧化反应。通过建立广泛的具有重要合成意义的不对称转化，这些转化目前对现有催化剂来说是尚未解决的挑战，我们的研究将提供独特的入口，并实现具有生物和治疗意义的手性分子的有效不对称合成，这些分子要么无法获得，要么难以用现有的合成方法以简洁和有用的方式制备。 公共卫生相关性：小分子构成了最重要的治疗剂形式之一，并在生物医学研究中发挥着越来越重要的作用。这项工作的目标是开发新的、高效的合成方法，极大地提高我们快速创建具有定义构型的各种结构的分子的能力，从而为生物医学研究人员提供强大的工具，以加速发现具有生物兴趣和治疗理想特性的小分子。这些合成方法还将为可持续生产对公众健康有重大影响的治疗剂开发具有成本效益的工艺奠定基础。

DESCRIPTION (provided by applicant): During the last two funding cycles our research program has made significant progress in the development of asymmetric base catalysis, as well as acid-base and iminium-base bifunctional catalysis by organic catalysts as broadly applicable concepts for the development of asymmetric reactions. In our previous studies the catalysts afford activity, enantioselectivity and diastereoselectivity through their involvement in a single transition state of stereochemical consequences. Our proposed studies focus on the invention and development of new reaction cascades. Building on preliminary results revealing the ability of cinchona alkaloids to serve as efficient chiral proton donors, the development of asymmetric dual-functional cooperative organocatalysis becomes a common theme underlying our proposed studies. In this mode of catalysis the organic catalysts act as a bifunctional catalyst to promote two different individual steps in the reaction cascades by activating and orienting the two participating reactants or intermediates. The specific aims are: 1) Development of enantioselective and diastereoselective conjugate addition-protonation reactions of ???-disubstituted nitroalkenes for asymmetric synthesis of chiral amino compounds. 2) Development of biomimetic proton transfer catalysis for enantioselective isomerizations of ???-unsaturated carbonyl to chiral ???-unsaturated carbonyl compounds via tandem deprotonation-protonation reactions. 3) Development of asymmetric peroxidations via enantioselective and chemo-controlled conjugate addition-protonation reactions with hydroperoxides. By establishing a broad range of synthetically important asymmetric transformations that currently represent unmet challenges for existing catalysts, our studies will provide unique entries into and achieve efficient asymmetric syntheses of chiral molecules of biological and therapeutic interest that are either inaccessible or difficult to prepare in a concise and useful manner by existing synthetic methods. PUBLIC HEALTH RELEVANCE: Small molecules constitute one of the most important forms of therapeutic agents and play an increasingly important role in biomedical research. The goal of this work is to develop new and efficient synthetic methods that will greatly enhance our ability to rapidly create molecules of diverse structures with defined configuration, thereby providing biomedical researchers with powerful tools to accelerate the discovery of small molecules possessing biologically interesting and therapeutically desirable properties. These synthetic methods will also provide the foundation for the development of cost-effective processes for the sustainable manufacturing of therapeutic agents with significant implications to public health.