Asymmetric Reactions with Dual-Functional Organocatalysis

双功能有机催化的不对称反应

• 批准号: 8050229
• 负责人: LI DENG
• 金额: $ 33.97万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8050229
• 关键词: Acids; Aldehydes; Biological; Biological Factors; Biomedical Research; Biomimetics; Carbon; Catalysis; Cinchona Alkaloids; Development; Drug Formulations; Esters; Foundations; Funding; Goals; Hydrogen Peroxide; Individual; Methods; Nitrogen; Oxygen; Play; Process; Property; Protons; Public Health; Reaction; Research; Research Personnel; Role; Structure; Sulfhydryl Compounds; Sulfones; Therapeutic; Therapeutic Agents; Validation; Work; analog; base; carbonyl compound; catalyst; chiral molecule; cost effective; deprotonation; design; interest; nitroalkene; peroxidation; programs; protonation; small molecule; tool

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.

描述（由申请人提供）：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发展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，作为广泛适用的概念，用于不对称反应的发展。在我们以前的研究中，催化剂提供的活性，对映体选择性和非对映体选择性，通过他们参与一个单一的过渡态的立体化学后果。我们提出的研究重点是新的反应级联的发明和发展。基于金鸡纳生物碱作为高效手性质子供体的初步研究结果，不对称双功能有机催化的发展成为我们研究的一个共同主题。在这种催化模式中，有机催化剂作为双功能催化剂，通过活化和定向两种参与的反应物或中间体来促进反应级联中的两个不同的单独步骤。具体目标是：1）发展？用于手性氨基化合物的不对称合成的二取代硝基烯烃。2)仿生质子转移催化对映异构化反应的研究进展不饱和羰基对手性？-不饱和羰基化合物通过串联的去质子化-质子化反应。3)通过对映选择性和化学控制的共轭加成-质子化反应与氢过氧化物的不对称过氧化反应的发展。通过建立广泛的合成重要的不对称转化，目前代表了现有催化剂的未满足的挑战，我们的研究将提供独特的入口，并实现有效的不对称合成的手性分子的生物和治疗的利益，要么是不可接近的或难以制备的简洁和有用的方式通过现有的合成方法。 公共卫生相关性：小分子是治疗药物的重要形式之一，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和有效的合成方法，这将大大提高我们的能力，以快速创建具有定义的配置不同结构的分子，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学意义和治疗所需特性的小分子。这些合成方法还将为开发具有成本效益的工艺奠定基础，以可持续地生产对公众健康具有重大影响的治疗剂。