New Cyclization Methods and Multicomponent Couplings

新的环化方法和多组分偶联

• 批准号: 7907102
• 负责人: JOHN MONTGOMERY
• 金额: $ 23.87万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7907102
• 关键词: Active Sites; Alcohols; Aldehydes; Alkynes; Anabolism; Antibiotics; Antineoplastic Agents; Binding; Biological; Biological Factors; Carbohydrates; Collaborations; Coupling; Cyclization; Cytochrome P450; Development; Enzymes; Event; Family; Glucose; Hydroxyl Radical; Iron; Laboratories; Lead; Ligands; Macrolides; Mannose; Methods; Michigan; Nickel; Preparation; Procedures; Process; Reaction; Reporting; Research; Research Personnel; Research Project Grants; Series; Silanes; Silicon; Solutions; Sphingosine; Staging; Structure; Therapeutic Agents; United States National Institutes of Health; Universities; Variant; aigialomycin D; amphidinolide W; appendage; base; desosamine; flexibility; glycosylation; improved; member; molecular recognition; novel; oxidation; programs; silane; sugar

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.

拟议的研究将集中于以开发和应用为中心的一系列广泛目标 镍催化、硅烷促进的醛和炔的还原偶联生成烯丙基 醇类。烯丙醇是许多具有重要生物学和医学意义的常见结构基序 化合物以及用于各种有机反应和催化过程的多功能前体。 基础研究将侧重于理解这种新颖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体。一个重要目标是 拟议的项目期间是开发一种直接组装糖基化的新程序 从简单的无环炔醛中合成大环，这将显着简化碳水化合物的制备 功能化大环化合物。 在天然和非天然大环内酯的合成中的应用将是该研究计划的一个重要重点。 天然存在的大环内酯类构成了一大类具有生物活性的大环天然产物，并且 该组的许多成员都拥有碳水化合物附属物，对分子的影响很大 识别事件是其生物活性的关键。该类别成员的抗生素活性是 已被广泛记录并具有临床重要性，并且许多其他生物活性模式已被 此类化合物的记录。特别针对的结构包括 aigialomycin D、 amphidinolide W 和 7-O-(α-葡萄糖基)-2,3-二氢环霉素 B，以及新型镍催化反应 将用作每个合成中的关键步骤。除了开发一些方法之外 大环内酯天然产物，我们提出的糖基化大环化合物的组装方法将用于 访问新颖的结构，大卫谢尔曼的研究小组将检查这些结构作为底物 细胞色素 P450 催化的氧化。这项合作研究将阐明底物范围 细胞色素 P450 氧化，可能会产生具有治疗药物潜力的新化合物。