Asymmetric, Phosphine-Catalyzed Synthesis of Thiazolines and Oxazolines

描述（由申请人提供）：催化为化学家们提供了强大的方法来合成结构有趣且具有生物活性的化合物，这些化合物可以用作有效的治疗药物。从简单易得的起始材料生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，并且这些化合物的生物活性通常可以通过细微的结构变化来调节。本项目的目标是开发一种高效，不对称合成噻唑啉和恶唑啉的方法，这是生物活性化合物中常见的杂环结构。目前，手性噻唑类和恶唑类化合物的合成依赖于氨基硫醇和氨基酸等对映纯原料。对映纯起始材料的可用性限制了这些杂环类似物的数量，这些类似物可以有效地制造。我们将开发使用易于获得的非手性起始材料（酰胺，硫酰胺和炔酸盐）并使用易于获得的手性膦诱导手性的方法。从硫胺和炔酸盐开始，膦催化合成噻唑类化合物是已知的，但没有使用这种化学方法合成不对称噻唑类化合物的描述。在整个催化循环中，磷化氢都与烷基酸盐结合，因此选择正确的磷化氢，将有可能发展不对称合成噻唑类化合物。我们还将开发一种利用磷化氢催化酰胺和炔酸盐偶联生成恶唑啉的方法。首先以非手性膦为原料建立恶唑啉法，然后以手性膦为原料建立不对称工艺。在文献中没有这种催化反应的已知例子，但对机制的分析表明，这种转化是可能的。这种方法将为化学家们提供一条从非手性起始原料制备对映纯恶唑啉的途径。公共卫生相关性：合成化学为制药提供了有效途径，可用于治疗一度降低生活质量的许多疾病和感染。重要的是要进一步发展和创造方法，以方便和快速地合成在有效药物和分离的天然产物中常见的具有生物学重要性的结构基序。发展不对称催化合成噻唑类和恶唑类化合物的方法将使这些生物相关的杂环化合物能够快速进入。

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.