Asymmetric Reactions with Bifunctional Organocatalysis

描述(申请人提供)：摘要：在过去的几年里，我们的研究计划在开发和应用金鸡纳生物碱作为广泛应用的手性碱/亲核催化剂方面取得了重大进展，并阐明了催化剂-底物氢键相互作用作为有效和一般不对称催化的基础。我们的工作集中在设计和开发新型金鸡纳生物碱作为可调的、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。其具体目标是：1)开发与三取代碳亲核剂的催化不对称共轭加成反应，用于直接和立体控制地构建唯一的全碳取代的四元立体中心和相邻的四元-三元立体中心；2)开发催化的不对称串联共轭加成-质子化反应，用于一步生成1，3-四元-三元立体中心，这是目前通常通过多步工艺构建的生物重要化合物中的常见结构基元；3)开发酮的催化不对称亲核加成反应，用于构建氧取代的四取代碳立体中心(O-取代四取代碳立体中心)；4)新型C6‘-羟基金鸡纳生物碱衍生物的设计、合成和筛选，为发现和开发新型高效的双功能手性催化剂奠定了基础。为了说明这些反应的合成用途，我们概述了利用这些反应来制备各种光学活性手性构件和具有生物学意义的化合物的简明和一般的合成路线。这些新的合成方法为构建所有碳和氧取代的四元中心开辟了新的和根本上重要的途径，预计将通过极大地促进许多生物重要化合物的靶向和多样性合成，从而对生物医学研究产生重大影响。

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.