New Cyclization Methods and Multicomponent Couplings

描述（由申请人提供）：拟议的研究将集中在一系列广泛的目标上，围绕镍催化、硅烷促进的醛和炔的还原偶联生成烯丙醇的开发和应用。烯丙醇是许多重要的生物和医学化合物的共同结构基序，也是广泛的有机反应和催化过程的通用前体。基础研究将集中于了解这种新型耦合过程的机制和范围，并开发新的区域选择性、非对映选择性和对映选择性变体。本项目的一个重要目标是开发一种从简单的无环环直接组装糖基化大环的新方法，这将大大简化碳水化合物功能化大环的制备。在天然和非天然大环内酯合成中的应用将是研究计划的一个重要重点。天然存在的大环内酯构成了一个具有生物活性的大环天然产物的大家庭，这一群体的许多成员都具有碳水化合物附属物，这极大地影响了分子识别事件，这是其生物活性的关键。这类化合物的抗生素活性被广泛记录并具有重要的临床意义，并且这类化合物的许多其他生物活性模式也被记录下来。特别针对的结构包括aigalomycin D， amphiidinolide W和7-O-（α -葡萄糖基）-2,3-二氢cineromycin B，并且新的镍催化反应将作为每个合成的关键步骤。除了开发几种大环内酯天然产物的方法外，我们提出的糖基化大环组装方法将用于获取新的结构，这些结构将由David Sherman研究小组作为细胞色素p450催化氧化的底物进行研究。这项合作研究将阐明细胞色素P450氧化的底物范围，并可能产生具有潜在治疗剂潜力的新化合物。

DESCRIPTION (provided by applicant): The proposed research will focus on a broad set of aims that center around the development and application of the nickel-catalyzed, silane-promoted reductive coupling of aldehydes and alkynes to generate allylic alcohols. Allylic alcohols are a common structural motif in many biologically and medicinally important compounds as well as versatile precursors for a broad array of organic reactions and catalytic processes. Fundamental studies will focus on understanding the mechanism and scope of this novel coupling process, and on developing new regioselective, diastereoselective, and enantioselective variants. An important aim of the proposed project period is the development of a new procedure for the direct assembly of a glycosylated macrocycle from a simple acyclic ynal, which will significantly simplify the preparation of carbohydrate-functionalized macrocycles. Applications in synthesis of natural and unnatural macrolides will be an important focus of the research plan. Naturally occurring macrolides make up a large family of biologically active macrocyclic natural products, and many members of this group possess carbohydrate appendages that greatly impact the molecular recognition events that are key in their biological activity. The antibiotic activities of members of this class are widely documented and clinically important, and many other modes of biological activity have been documented for this class of compounds. The structures specifically targeted include aigialomycin D, amphidinolide W, and 7-O-(alpha-glucosyl)-2,3-dihydrocineromycin B, and novel nickel-catalyzed reactions will be used as key steps in each of the syntheses. In addition to developing approaches to several macrolide natural products, our proposed method for assembly of glycosylated macrocycles will be used to access novel structures that will be examined by the research group of David Sherman as substrates for cytochrome P450-catalyzed oxidations. This collaborative research will elucidate the substrate scope in cytochrome P450 oxidations and may lead to new compounds with potential as therapeutic agents.