Catalytic Stereoselective Olefin Metathesis Reactions

催化立体选择性烯烃复分解反应

• 批准号: 9029019
• 负责人: AMIR H HOVEYDA
• 金额: $ 54.53万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9029019
• 关键词: Acids; Alkenes; Amides; Anti-Inflammatory Agents; Antifungal Agents; Biology; Bromides; CASP3 gene; Carbon; Chemistry; Chloride Ion; Chlorides; Complex; Coupling; Development; Dopamine Antagonists; Esters; Fluorides; Future; Goals; Healthcare; Human; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Investigation; Iodides; Isomerism; Laboratories; Lead; Ligands; Medicine; Methods; Molybdenum; Oxidoreductase; PAC1 phosphatase; Preparation; Procedures; Process; Protocols documentation; Reaction; Reagent; Research; Site; Structure; Tungsten; antiproliferative agents; base; cabergoline; carbonyl compound; catalyst; chemical synthesis; cost; cost effective; design; diene; drug development; drug discovery; public health relevance

 DESCRIPTION (provided by applicant): Alkenes are found in a great number of naturally occurring molecules and are employed in some of the most widely used transformations. Processes that allow access to Z or E isomeric forms of olefins efficiently, reliably, with high selectivity and cost- effectively are therefore of great importance to chemistry, biology and medicine. Especially valuable are the catalytic procedures that form alkenes stereoselectively. The proposed studies focus on the design, synthesis and development of molybdenum- and tungsten-based catalysts that can be utilized to facilitate one of the most powerful methods in chemical synthesis: olefin metathesis. A variety of concepts, originally conceived in these laboratories, will be used to introduce the needed new catalysts. The goal is to achieve furnish reactivity and/or selectivity levels that remain entirely out of reach and will have a lasting impat on drug discovery and development. Catalytic methods will be put forth that allow access to a wide range of linear Z- a,b-unsaturated esters and amides, as well as various dienoates. Such entities reside in a myriad of biologically active molecules, and are among the most versatile functional units in chemical synthesis. One of the most critical objectives of the proposed investigations will be the development of efficient catalytic processes that will generate Z-alkeny chloride, bromide, and iodide compounds. These are, again, among the most important and widely used entities in chemistry (e.g., substrates for catalytic cross- coupling); moreover, the ability to incorporate F atoms within organic molecules site- and stereoselectively will be crucial to future drug development. The first examples of catalytically E-selective olefin metathesis reactions will be designed; these processes will deliver valuable E-alkenyl halides. Finally, the first cases of stereoslective catalytic cross-metathesis reactions that generate high-energy trisubstituted alkenes will be introduced. The special utility of the new concepts, catalysts and protocols will be underscored through applications to concise syntheses of biologically significant molecules such as anti-inflammatory agent coriolic acid methyl ester, antiproliferative agent hexachlorosulfolipid as well as alkenyl halide derivatives of dopamine receptor antagonist cabergoline, caspase 3 activator PAC-1, and HMG-C0A reductase swertiamarin.

 描述（由申请人提供）：烯烃存在于大量天然存在的分子中，并被用于一些最广泛使用的转化过程中，这些过程允许高效、可靠、高选择性地获得烯烃的 Z 或 E 异构体形式。因此，成本效益对于化学、生物学和医学非常重要，特别有价值的是立体选择性形成烯烃的催化过程。钼基和钨基催化剂可用于促进化学合成中最强大的方法之一：烯烃复分解。这些实验室最初设想的各种概念将用于引入所需的新催化剂。为了达到完全无法达到的反应性和/或选择性水平，将对药物发现和开发产生持久影响，将提出允许获得广泛的线性Z-的催化方法。 a,b-不饱和酯和酰胺以及各种二烯酸酯存在于无数生物活性分子中，是化学合成中最通用的功能单元之一。开发可生成 Z-烯基氯化物、溴化物和碘化物化合物实体的有效催化过程，这些也是化学中最重要和最广泛使用的物质（例如催化交叉反应的底物）。此外，将 F 原子位点选择性和立体选择性结合到有机分子中的能力也至关重要。 将设计催化E-选择性烯烃复分解反应的第一个例子；这些过程将产生有价值的E-烯基卤化物，最后，将产生产生高能三取代烯烃的第一个立体选择性催化交叉复分解反应。将通过对具有生物学意义的分子（例如抗炎剂）的简明合成的应用来强调新概念、催化剂和方案的特殊用途。科里奥酸甲酯，抗增殖 六氯硫脂以及多巴胺受体拮抗剂卡麦角林的烯基卤衍生物、半胱天冬酶 3 激活剂 PAC-1 和 HMG-C0A 还原酶獐牙菜苦苷。