Catalytic Stereoselective Olefin Metathesis Reactions

 描述(申请人提供)：烯烃存在于大量自然生成的分子中，并用于一些最广泛使用的转化。因此，能够高效、可靠、高选择性和低成本地获得Z或E异构型烯烃的工艺对化学、生物和医学具有重要意义。特别有价值的是立体选择性地形成烯烃的催化程序。拟议的研究集中在钼和钨基催化剂的设计、合成和开发上，这些催化剂可用于促进化学合成中最有效的方法之一：烯烃歧化反应。这些实验室最初构思的各种概念将被用来引入所需的新催化剂。其目标是实现完全遥不可及并将对药物发现和开发产生持久影响的提供反应性和/或选择性水平。将提出催化方法，允许获得广泛的直链Z-a，b-不饱和酯和酰胺，以及各种二烯酸酯。这些实体存在于无数生物活性分子中，是化学合成中用途最广泛的功能单元之一。拟议研究的最关键目标之一将是开发高效的催化过程，以产生Z-烯基氯、溴和碘化合物。这些也是化学中最重要和最广泛使用的实体(例如，催化交叉偶联的底物)；此外，在有机分子中原位和立体选择性地结合F原子的能力将是至关重要的 对未来的药物开发。将设计第一个催化E-选择性烯烃歧化反应的例子；这些过程将产生有价值的E-烯基卤化物。最后，将介绍生成高能三取代烯烃的立体选择性催化交叉歧化反应的第一个案例。新概念、催化剂和方案的特殊用途将通过应用于具有生物意义的分子的简明合成而得到强调，例如抗炎剂皮质酸甲酯、抗增殖剂 六氯磺脂以及多巴胺受体拮抗剂卡麦角林、caspase 3激活剂PAC-1和HMG-C0A还原酶苦马豆素的烯基卤代衍生物。

 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.