New Cyclization Methods and Multicomponent Couplings

拟议的研究将集中在以开发和应用为中心的广泛目标上 在镍催化、硅烷促进的醛和炔的还原偶联反应中生成烯丙基 酒精。烯丙醇是一种常见的结构基元，在许多生物和医学上具有重要意义。 这些化合物以及多种有机反应和催化过程的多用途前体。 基础研究将集中于了解这种新的耦合过程的机制和范围， 以及开发新的区域选择性、非对映选择性和对映选择性变异体。的一个重要目标 拟议的项目期是开发一种新的直接组装糖基化的程序 大环从简单的无环芳醛，这将大大简化碳水化合物的制备- 功能化的大循环。 在天然和非天然大环内酯类化合物的合成中的应用将是该研究计划的重要重点。 天然大环内酯组成了一大类具有生物活性的大环天然产物，以及 这一组的许多成员都有碳水化合物附属物，这些附属物对分子有很大的影响 在它们的生物学活动中起关键作用的识别事件。这门课的成员的抗生素活动是 广泛的文献记载和临床上的重要性，以及许多其他的生物活动模式 关于这类化合物的文件。具体靶向的结构包括青霉素D， 两性内酯W和7-O-(α-葡萄糖基)-2，3-二氢红霉素B和镍催化的新反应 将被用作每个合成的关键步骤。除了开发方法来实现以下几个目标 大环内酯类天然产物，我们提出的糖基化大环组装方法将用于 访问将由David Sherman的研究小组研究的新结构作为底物 细胞色素P450催化的氧化。这项合作研究将阐明底物的范围 细胞色素P450氧化，并可能导致潜在的治疗药物的新化合物。

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 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.