NEW DEVELOPMENTS IN ORGANOCOPPER CHEMISTRY

有机铜化学的新进展

• 批准号: 6498703
• 负责人: R Karl KARL DIETER
• 金额: $ 12.93万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6498703
• 关键词: chemical synthesis; copper; nitrogenous heterocyclic compound; organometallic compounds; stereochemistry

The specific aim of the proposed work is to develop the chemistry of alpha-aminoalkylcopper reagents; a type of organocopper reagent that permits functionalization alpha to an amino group using the reactions characteristic of organocopper reagents. The specific objectives are to (1) expand the range of cuprate-electrophile reaction partners, (2) explore the reactivity and thermal stability of these reagents, and the configurational stability of cuprates with a C-Cu stereogenic center, (3) optimize reaction conditions, substrates, and reagents for effecting relative (diastereoselectivity) and absolute (enantioselectivity) asymmetric induction in the characteristic reactions of alpha-aminoalkylcuprates, and (4) develop the synthetic utility of these reagents by developing synthetic strategies for the synthesis of highly substituted 5-membered heterocyclic compounds with a focus on the pyrrolidine aza sugars. The synthetic approach to highly substituted pyrrolines, pyrrolidines, and pyrrolidinones involves the reaction of alpha-aminoalkylcuprates with scalemic propargyl substrates in a controlled anti-SN2' process followed by cyclization of the carbamate nitrogen or free amine onto the resultant allene. The work will extend the scope and synthetic utility of these organocopper reagents. Successful development of alpha-aminoalkylcuprate chemistry will contribute significantly to the synthesis of highly substituted pyrrolidines, piperidines, and their bicyclic analogs (i.e., pyrrolizidines, indolizidines, and quinolizidines). Complex alkaloids and simple nitrogen-containing compounds are biologically active agents representing important classes of antibacterial agents, CSN agents, and antiretroviral compounds. The polyhydroxy analogs (i.e., aza sugars) are an important class of glycosidase inhibitors and immunostimulators and are the focus of intense synthetic activity because of their effects upon glycoprotein processing enzymes. Inhibition of glycoprotein processing is potentially useful against illnesses such as cancers, malaria, diabetes, cystic fibrosis, bacterial, and viral infections including retro-viruses such as the human immunodeficiency virus (HIV). A need exists for a general synthetic approach to the aza sugars that is short, efficient, and which divergently leads to a large number of stereoisomers and analogues from a common intermediate. The proposed synthetic routes to pyrrolidine aza sugars will develop the potential synthetic power of alpha-aminoalkylcuprate chemistry.

拟议工作的具体目标是发展α-氨基烷基铜试剂的化学；这是一种有机铜试剂，允许利用有机铜试剂的反应特性将α官能化为氨基。具体目标是(1)扩大铜酸盐亲电反应伙伴的范围，(2)探索这些试剂的反应性和热稳定性，以及具有C-铜立体中心的铜酸盐的构型稳定性，(3)优化反应条件、底物和试剂，以影响α-氨基烷基铜酸盐特征反应的相对(非对映选择性)和绝对(对映选择性)不对称诱导，以及(4)通过开发合成策略来开发这些试剂的合成用途，以合成以吡咯烷氮杂糖为重点的高取代五元杂环化合物。高取代吡咯烷、吡咯烷和吡咯烷酮的合成方法包括α-氨基烷基铜酸盐与比例丙叉基底物在受控的抗SN2‘过程中的反应，然后氨基甲酸酯氮或游离胺在生成的丙二烯上环化。这项工作将扩大这些有机铜试剂的合成范围和用途。α-氨基烷基铜酸盐化学的成功开发将对合成高取代的吡咯烷类、哌啶类及其双环类似物(即吡咯利氮类、吲哚类和喹啉类)做出重大贡献。复杂生物碱和简单含氮化合物是代表重要的抗菌剂、CSN试剂和抗逆转录病毒化合物的生物活性物质。多羟基类似物(即氮杂糖)是一类重要的糖苷酶抑制剂和免疫刺激剂，由于它们对糖蛋白加工酶的作用而成为强烈合成活性的焦点。抑制糖蛋白加工可能有助于治疗癌症、疟疾、糖尿病、囊性纤维化、细菌和病毒感染等疾病，包括人类免疫缺陷病毒(HIV)等逆转录病毒。存在对氮杂糖的一般合成方法的需要，该方法是短的、有效的，并且以不同的方式从共同的中间体中得到大量的立体异构体和类似物。所提出的合成吡咯烷氮杂糖的路线将开发α-氨基烷基铜酸盐化学的潜在合成能力。