Enantioselective Functionalizations of Azomethines and Alkenes

甲亚胺和烯烃的对映选择性官能化

• 批准号: 9050686
• 负责人: Jeffrey Nicholas Johnston
• 金额: $ 28.49万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9050686
• 关键词: Acids; Acute; Alkenes; Amidines; Amines; Area; Carbon; Carbon Dioxide; Catalysis; Chagas Disease; Chemistry; Chronic; Collaborations; Communicable Diseases; Complex; Coupling; Cyclization; Development; Diamines; Electronics; Funding; Goals; Halogens; Health; Human; Hydrogen Bonding; Imidazolines; Iodine; MDM2 gene; Malignant Neoplasms; Measures; Mediating; Medicine; Metals; Methods; Natural Products; Oxygen; Pharmaceutical Preparations; Population; Preparation; Production; Protons; Reaction; Reagent; Resources; Stereoisomer; TP53 gene; Therapeutic Agents; Trypanosoma cruzi; Variant; Work; Xenograft procedure; aurora kinase; base; catalyst; cost; enantiomer; improved; innovation; melanoma; milligram; mouse model; nitroalkane; nutlin 3; programs; protein protein interaction; scaffold; small molecule; small molecule therapeutics; tertiary amine; therapeutic development; tool

DESCRIPTION (provided by applicant): The overarching goal of this proposal is the development of new reactions, and the reagents that control them, to generate enantioenriched organic compounds. These products are valuable precursors to more elaborate small molecules that are medicinal agents and/or more complex biologically active natural products. The proposed methods specifically target the concise synthesis of secondary amines, tertiary amines, and vicinal diamines as single stereoisomers. These methods are based on the development of bis (amidine) reagents that form chiral proton complexes (a polar ionic hydrogen bond) when a strong acid is added, or when used with acidic substrates. Exploration of a new variant is also described, which contains a single amidine in close proximity to a hydrogen bond donor (polar covalent hydrogen bond) when projected from the same chiral scaffold. These studies continue the successful application of bifunctional organocatalysts to the stereocontrolled creation of structural and functional motifs that, while common, are otherwise difficult to prepare using conventional alternatives. These studies also explore an entirely new mode of activation that involves chiral Brønsted acid mediated halogen- alkene reactions. A range of innovative multicomponent coupling reactions will be developed using chiral proton catalysis as the means to control enantioselection. These studies have the potential to impact small molecule synthesis, and ultimately the development of therapeutic agents. Moreover, the methods enable the metal-free production of functionally dense, single enantiomer (and diastereomer) organic compounds.

描述（由申请人提供）：本提案的总体目标是开发新反应和控制它们的试剂，以生成对映体富集的有机化合物。这些产物是更精细的小分子的有价值的前体，所述小分子是药剂和/或更复杂的生物活性天然产物。所提出的方法具体针对作为单一立体异构体的仲胺、叔胺和邻二胺的简明合成。这些方法是基于双（脒）试剂的开发，当加入强酸或与酸性底物一起使用时，双（脒）试剂形成手性质子络合物（极性离子氢键）。还描述了一种新的变体的探索，其包含从相同的手性支架投射时靠近氢键供体（极性共价氢键）的单个脒。这些研究继续成功地应用双功能有机催化剂的立体控制创建的结构和功能的图案，虽然常见的，否则难以使用常规的替代品。这些研究还探索了一种全新的活化模式，涉及手性布朗斯台德酸介导的卤素-烯烃反应。一系列创新的多组分偶联反应将开发使用手性质子催化作为手段来控制对映选择。这些研究有可能影响小分子合成，并最终影响治疗药物的开发。此外，所述方法能够无金属地生产功能致密的单一对映异构体（和非对映异构体）有机化合物。