Enantioselective Thiourea-Catalyzed Syntheses of beta-Lactones and beta-Lactams

对映选择性硫脲催化合成 β-内酯和 β-内酰胺

• 批准号: 8386192
• 负责人: Pamela Michele Tadross
• 金额: $ 4.92万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8386192
• 关键词: Address; Aldehydes; Amino Acids; Biological Factors; Capromycin; Carbon; Cephalexin; Clinical; Communicable Diseases; Cyclization; Development; Disease; Goals; Imines; Infection; Ketones; Lactams; Lactones; Lead; Mediating; Methodology; Methods; Organic Chemistry; Penicillins; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Preparation; Process; Reaction; Research; Schering-Plough brand of ezetimibe; Structure; Thiourea; Ubenimex; Ursidae Family; Xenical; beta-Lactams; cancer therapy; catalyst; cycloaddition; design; enolate

DESCRIPTION (provided by applicant): Lactones and -lactams are structural motifs critical to the treatment of disease and infection whose activity is directly related to the highly strained 4-membered ring present in each. Beyond their applications in clinical settings, these compounds are valuable starting materials for the preparation of other medicinally important structures, such as -amino acids. Despite their importance, methods for the catalytic enantioselective construction of highly substituted -lactones and -lactams are limited with regard to substrate scope, catalyst design, and generality. To address these limitations, the current proposal provides a catalytic enantioselective method for the preparation of both -lactones and -lactams in a single step from simple, achiral, and readily available starting materials using a bifunctional phosphinothiourea catalyst. Specifically, the thiourea catalyst will mediate the formal [2+2] cycloaddition reaction between ketenes and aldehydes, ketones, and imines. By this process, a diverse array of products can be generated that bear vicinal stereogenic carbons. Furthermore, the application of a phosphinothiourea catalyst will allow cooperative activation of both reaction partners, forming new C-C and C-heteroatom bonds between two compounds of roughly equal complexity in a maximally convergent fashion. The application of -lactone and -lactam products generated by this method to the total synthesis of natural products and to the preparation of medicinally important derivatives will provide access to important lead compounds for the development of new pharmaceutical agents for the treatment of cancer and infectious disease.

描述（由申请人提供）：内酯和-内酰胺是对治疗疾病和感染至关重要的结构基序，其活性与它们中存在的高度紧张的4元环直接相关。除了临床应用之外，这些化合物是制备其他重要医学结构（如-氨基酸）的有价值的起始材料。尽管它们很重要，高取代-内酯和-内酰胺的催化对映选择性构建方法在底物范围、催化剂设计和通用性方面受到限制。为了解决这些限制，目前的建议提供了一种催化对映选择性方法，使用双功能磷硫脲催化剂，从简单的、非手性的、容易获得的起始材料，一步制备-内酯和-内酰胺。具体来说，硫脲催化剂将介导烯酮与醛、酮和亚胺之间的形式[2+2]环加成反应。通过这一过程，可以产生多种具有邻立体碳的产品。此外，磷硫脲催化剂的应用将允许两个反应伙伴的协同活化，在两个大致相同复杂性的化合物之间形成新的C-C和c -杂原子键，以最大程度的收敛方式。将这种方法产生的-内酯和-内酰胺产品应用于天然产物的全合成和具有重要医学意义的衍生物的制备，将为开发用于治疗癌症和传染病的新型药物制剂提供重要的先导化合物。