NEW DEVELOPMENTS IN ORGANOCOPPER CHEMISTRY

所提出的工作的具体目标是开发α-氨基烷基铜试剂的化学;一种有机铜试剂，其允许使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-亲电试剂反应伙伴的范围，（2）探索这些试剂的反应性和热稳定性，以及具有C-Cu立体异构中心的铜酸盐的构型稳定性，（3）优化反应条件、底物，以及用于实现相对（非对映选择性）和绝对（对映选择性）α-氨基烷基铜酸酯的特征反应中的不对称诱导，和（4）通过开发用于合成高度取代的5元杂环化合物的合成策略（重点是吡咯烷氮杂糖）来开发这些试剂的合成效用。 高度取代的吡咯啉、吡咯烷和吡咯烷酮的合成方法包括α-氨基烷基铜酸酯与成比例炔丙基底物在受控的反SN 2 '过程中反应，然后将氨基甲酸酯氮或游离胺环化到所得的丙二烯上。 该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开发将显著有助于高度取代的吡咯烷、哌啶及其双环类似物（即，吡咯烷、吲嗪和喹嗪）。复杂的生物碱和简单的含氮化合物是代表重要类别的抗菌剂、CSN剂和抗逆转录病毒化合物的生物活性剂。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，并且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。 糖蛋白加工的抑制对于疾病如癌症、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免疫缺陷病毒（HIV））是潜在有用的。 需要一种氮杂糖的通用合成方法，该方法短、有效，并且从共同的中间体发散地产生大量的立体异构体和类似物。 所提出的吡咯烷氮杂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.