Asymmetric, Phosphine-Catalyzed Synthesis of Thiazolines and Oxazolines

描述(申请人提供)：催化作用为化学家提供了合成具有结构兴趣和生物活性的化合物的强大方法，这些化合物可以用作有效的治疗药物。用简单易得的原料合成结构复杂的化合物的方法使化学家能够合成各种化合物的类似物，这些化合物的生物活性通常可以通过微妙的结构变化来调节。本项目的目标是开发一种高效、不对称地合成噻唑啉和恶唑啉的方法，这两种化合物是生物活性化合物中常见的杂环结构。目前，手性噻唑类化合物和恶唑类化合物的合成主要依赖于氨基硫醇和氨基酸等对映体起始原料。对映体起始材料的可获得性限制了这些杂环的类似物可以有效地制备的数量。我们将开发使用容易获得的非手性起始材料(酰胺、硫代酰胺和烷基诺酸酯)并使用容易获得的手性膦诱导手性的方法。以硫代酰胺和烯醇酸酯为起始原料，用膦催化合成噻唑类化合物已为人所知，但还没有关于使用这种化学方法不对称合成噻唑类化合物的报道。在整个催化循环中，膦与烷基诺酸盐结合在一起，因此，如果选择正确的膦，就有可能开发一种不对称合成噻唑类化合物。我们还将开发一种方法，利用膦催化将酰胺和烷基诺酸酯偶联来生成恶唑啉。最初的恶唑啉方法将与非手性膦一起建立范围，然后手性膦将被研究以开发不对称过程。文献中没有已知的这种催化反应的例子，但对机理的分析表明，这种转化是可能的。这种方法将为化学家提供一条从无手性起始材料中提取恶唑啉对映体的途径。与公共卫生相关：合成化学为药物提供了有效的途径，使其能够治疗许多疾病和感染，这些疾病和感染一度降低了生活质量。重要的是要进一步开发和建立方法学，以方便和快速地合成在有效药物和分离的天然产品中常见的具有生物重要性的结构基序。开发一种不对称催化方法来合成噻唑啉和恶唑啉，将允许快速进入这些生物相关类别的杂环。

DESCRIPTION (provided by applicant): Catalysis has provided chemists with powerful methods to synthesize structurally interesting and biologically active compounds that can be used as effective therapeutics. Methods that generate structurally complex compounds from simple and readily available starting materials allow chemists to synthesize various analogs of compounds, and the biological activity of these compounds can often be tuned by making subtle structural changes. The goal of this project is to develop a highly efficient, asymmetric synthesis of thiazolines and oxazolines, which are common heterocyclic structures found in biologically active compounds. Currently, the syntheses of chiral thiazolines and oxazolines rely on enantiopure starting materials such as amino thiols and amino acids. The availability of enantiopure starting materials limits the number of analogs of these heterocycles that can be made efficiently. We will develop methods that use readily accessible achiral starting materials (amides, thioamides and alkynoates) and induce chirality using readily available chiral phosphines. The phosphine-catalyzed synthesis of thiazolines starting from thioamides and alkynoates is known, but there has been no description of an asymmetric synthesis of thiazolines using this chemistry. The phosphine is bound to the alkynoate throughout the catalytic cycle, so with the correct choice of phosphine, it will be possible to develop an asymmetric synthesis of thiazolines. We will also develop a method that couples amides and alkynoates to yield oxazolines using phosphine-catalysis. The initial oxazoline method will be developed with achiral phosphines to establish the scope, and then chiral phosphines will be investigated to develop an asymmetric process. There are no known examples of this catalytic reaction in the literature, but analysis of the mechanism suggest that this transformation is possible. This method would provide chemists with a route to enantiopure oxazolines from achiral starting materials. PUBLIC HEALTH RELEVANCE: Synthetic chemistry has provided efficient routes to Pharmaceuticals that allow for the treatment of many diseases and infections that, at one time, decreased quality of life. It is important to further develop and create methodologies that allow for the facile and rapid synthesis of biologically important structural motifs that are commonly seen in effective Pharmaceuticals and isolated natural products. Development of an asymmetric catalytic method for the synthesis of thiazolines and oxazolines would allow rapid entry into these biologically relevant classes of heterocycles.