Asymmetric Reactions with Bifunctional Organocatalysis

描述（由申请人提供）：摘要：在过去的几年中，我们的研究计划已经取得了重大进展，在开发和应用金鸡纳生物碱作为广泛有用的手性碱/亲核催化剂的不对称合成和催化剂-底物氢键相互作用的阐明作为基础，有效和一般的不对称催化。本论文的工作重点是设计和开发新型的金鸡纳生物碱作为可调的和实用的酸碱双功能催化剂，用于合成重要的不对称C-C键形成反应。具体目标是：1）开发与三取代碳亲核试剂的催化不对称共轭加成，用于直接和立体控制地构建唯一的全碳取代的季立构中心和相邻的季-叔立构中心; 2）开发用于一步产生1，3-季-叔立体中心的催化、不对称串联共轭加成-质子化反应，生物学上重要的化合物中常见的结构基序，现在通常通过多步过程构建; 3）开发用于构建氧取代的四取代碳立构中心的酮的催化对映选择性亲核加成（O-取代的四元立构中心）; 4）新型C6 ′-OH金鸡纳生物碱衍生物的设计、合成和筛选，用于发现和开发新的和强有力的双功能手性催化剂。为了说明这些反应的合成效用，我们概述了简洁和一般的合成路线，利用这些反应制备各种光学活性的手性积木和生物有趣的化合物。这些新的合成方法为构建所有碳和氧取代的季中心开辟了新的和根本上重要的方法，预计将对生物医学研究产生重大影响，大大促进了许多生物重要化合物的目标导向和多样性导向的合成。

DESCRIPTION (provided by applicant): Abstract: During the last several years our research program has made significant progress in the development and application of cinchona alkaloids as broadly useful chiral base/nucleophilic catalysts for asymmetric synthesis and in the elucidation of catalyst-substrate hydrogen bonding interaction as the basis for efficient and general asymmetric catalysis. The proposed work focuses on the design and development of novel cinchona alkaloids as tunable and practical acid-base bifunctional catalysts for synthetically important asymmetric C-C bond forming reactions. The specific aims are: 1) Development of catalytic asymmetric conjugate additions with trisubstituted carbon nucleophiles for direct and stereocontrolled construction of sole all carbon substituted quaternary stereocenter and adjacent quaternary-tertiary stereocenters; 2) Development of catalytic, asymmetric tandem conjugate addition-protonation reactions for one-step creation of 1,3-quaternary-tertiary stereocenters, a common structural motif in biologically important compounds that are now typically constructed by multistep process; 3) Development of catalytic enantioselective nucleophilic additions to ketones for the construction of oxygen-substituted tetrasubstituted carbon stereocenters (O-substituted quaternary stereocenters); 4) The design, synthesis and screening of novel C6'-OH cinchona alkaloid derivatives for the discovery and development of new and powerful bifunctional chiral catalysts. To illustrate the synthetic utility of these reactions, we outline concise and general synthetic routes which utilize these reactions for the preparation of various optically active chiral building blocks and biologically interesting compounds. Opening new and fundamentally important approaches for the construction of all carbon and oxygen-substituted quaternary centers, these new synthetic methods are expected to have a major impact on biomedical research by greatly facilitating the target-oriented as well as diversity-oriented synthesis of numerous biologically important compounds.