NEW DEVELOPMENTS IN ORGANOCOPPER CHEMISTRY

提出的工作的具体目的是开发α -氨基烷基铜试剂的化学；一种有机铜试剂，它允许利用有机铜试剂的反应特性将α官能化到氨基。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活性和热稳定性，以及具有C-Cu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。(4)通过发展以吡咯烷偶氮糖为重点的高取代5元杂环化合物的合成策略，开发这些试剂的合成用途。高取代吡咯啉、吡咯烷和吡咯烷酮的合成方法包括α -氨基烷基铜酸盐与尺度丙炔底物在可控的抗sn2 '过程中反应，然后将氨基甲酸酯氮或游离胺环化到合成的烯烯上。这项工作将扩大这些有机铜试剂的范围和合成用途。α -氨基烷基铜酸盐化学的成功发展将对高取代吡咯烷类、哌啶类及其双环类似物（即吡咯烷类、吲哚嘧啶类和喹啉嘧啶类）的合成作出重大贡献。复合生物碱和简单含氮化合物是一类重要的抗菌剂、CSN剂和抗逆转录病毒化合物。多羟基类似物（即aza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影响，是合成活性的焦点。抑制糖蛋白加工对癌症、疟疾、糖尿病、囊性纤维化、细菌和病毒感染（包括逆转录病毒，如人类免疫缺陷病毒（HIV））等疾病有潜在的作用。需要一种短而有效的合成aza糖的通用方法，这种方法可以从一个共同的中间体发散地产生大量的立体异构体和类似物。提出的吡咯烷糖的合成路线将开发α -氨基烷基铜酸盐化学的潜在合成能力。

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.