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: 8122804
• 负责人: Pamela Michele Tadross
• 金额: $ 4.63万
• 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/8122804
• 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. PUBLIC HEALTH RELEVANCE: This proposal outlines a research plan in organic chemistry aimed at the design and development of a new reaction method that will enable the preparation of medicinally important classes of compounds from simple, readily available starting materials. Implementation of this new process will lead to the rapid and efficient synthesis of a wide variety of bioactive structures that are inaccessible by current methodologies. The application of products generated by this method to the total synthesis of naturally occurring molecules and to the preparation of biologically relevant 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（由申请方提供）：内酯和β-内酰胺是治疗疾病和感染的关键结构基序，其活性与各自存在的高度紧张的4元环直接相关。除了它们在临床环境中的应用之外，这些化合物是用于制备其他医学上重要的结构（例如-氨基酸）的有价值的起始材料。尽管它们的重要性，高度取代的-内酯和-内酰胺的催化对映体选择性的建设的方法是有限的底物范围，催化剂的设计，和一般性。为了解决这些限制，当前的提案提供了一种催化对映选择性方法，用于使用双官能膦基硫脲催化剂，从简单、非手性且易于获得的起始材料一步制备β-内酯和β-内酰胺。具体地，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。通过这个过程，可以产生各种各样的带有邻位立体碳的产物。此外，膦基噻吩催化剂的应用将允许两种反应伴侣的协同活化，以最大收敛的方式在两种大致相等复杂性的化合物之间形成新的C-C和C-杂原子键。通过该方法产生的β-内酯和β-内酰胺产物应用于天然产物的全合成和药用重要衍生物的制备将为开发用于治疗癌症和传染病的新药剂提供重要的先导化合物。 公共卫生相关性：该提案概述了一项有机化学研究计划，旨在设计和开发一种新的反应方法，该方法将能够从简单，易得的起始材料制备具有医学重要性的化合物。这一新工艺的实施将导致快速有效地合成各种各样的生物活性结构，这些结构是目前方法学无法获得的。将通过该方法产生的产物应用于天然存在的分子的全合成和生物学相关衍生物的制备，将为开发用于治疗癌症和传染病的新药剂提供重要的先导化合物。