Enantioselective Functionalizations of Azomethines and Alkenes

甲亚胺和烯烃的对映选择性官能化

• 批准号: 8697731
• 负责人: Jeffrey Nicholas Johnston
• 金额: $ 27.84万
• 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/8697731
• 关键词: Acids; Acute; Alkenes; Amidines; Amines; Area; Biological Factors; 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; Oxygen; Pharmaceutical Preparations; Population; Preparation; Production; Protons; Reaction; Reagent; Resources; Stereoisomer; Therapeutic; 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; 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 Bronsted 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）：该提案的总体目标是开发新反应以及控制它们的试剂，以生成对映体富集的有机化合物。这些产品是更精细的小分子的有价值的前体，这些小分子是药剂和/或更复杂的生物活性天然产物。所提出的方法专门针对仲胺、叔胺和邻二胺作为单一立体异构体的简洁合成。这些方法基于双（脒）试剂的开发，当添加强酸或与酸性底物一起使用时，双（脒）试剂会形成手性质子复合物（极性离子氢键）。还描述了对新变体的探索，当从同一手性支架投射时，该变体包含与氢键供体（极性共价氢键）非常接近的单个脒。这些研究继续成功地将双功能有机催化剂应用于结构和功能基序的立体控制创建，这些基序虽然很常见，但使用传统替代品很难制备。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。将使用手性质子催化作为控制对映体选择的手段来开发一系列创新的多组分偶联反应。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，这些方法能够无金属生产功能密集的单一对映体（和非对映体）有机化合物。