New Cyclization Methods and Multicomponent Couplings

新的环化方法和多组分偶联

• 批准号: 7544489
• 负责人: JOHN MONTGOMERY
• 金额: $ 27.35万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7544489
• 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围绕开发和应用的一系列广泛目标 的镍催化，硅烷促进的醛和炔烃的还原耦合以产生烯丙基 酒精。在许多生物学和医学上，烯丙基醇是一个常见的结构基序 化合物以及多种有机反应和催化过程的多功能前体。 基本研究将着重于理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，非映选择性和对映选择性变体。一个重要的目的 拟议的项目期间是开发直接组装糖基化的新程序 来自简单的无环元的大环，这将显着简化碳水化合物的制备。 功能化的大环。 合成自然和非天然大花环的应用将是研究计划的重要重点。 天然发生的大花环构成了一大批生物活性大环天然产物，并且 该组的许多成员拥有碳水化合物附属物，极大地影响了分子 识别事件是其生物活性的关键。该课程成员的抗生素活动是 广泛记录和临床重要的，许多其他生物学活动的模式已经 记录为这类化合物。专门针对的结构包括雌霉素D， 两栖动物W和7-O-（α-葡萄糖基）-2,3-二氢环霉素B，以及新型的镍催化反应 将用作每个合成中的关键步骤。除了开发几种方法 大环内酯类天然产物，我们提出的用于组装糖基化大环的方法将用于 访问大卫·谢尔曼（David Sherman）研究小组将检查的新颖结构作为基材 细胞色素P450催化的氧化。这项协作研究将阐明底物范围 细胞色素P450氧化，可能导致具有治疗剂潜力的新化合物。