Asymmetric, Phosphine-Catalyzed Synthesis of Thiazolines and Oxazolines

不对称膦催化合成噻唑啉和恶唑啉

• 批准号: 8050549
• 负责人: Jaclyn Marie Murphy
• 金额: $ 0.51万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-06 至 2011-04-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8050549
• 关键词: Amides; Amino Acids; Anti-Bacterial Agents; Binding; Biological; Biological Factors; Catalysis; Chemistry; Complex; Couples; Coupling; Development; Disease; Goals; Health; Infection; Ligands; Literature; Metals; Methodology; Methods; One-Step dentin bonding system; Pharmacologic Substance; Phosphines; Process; Quality of life; Reaction; Reporting; Research; Route; Structure; Sulfhydryl Compounds; Synthesis Chemistry; System; Therapeutic; Thioamides; Time; Transition Elements; analog; anticancer activity; catalyst; interest; scaffold; stereochemistry; tri-n-butylphosphine; triphenylphosphine

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.

描述（由申请人提供）：催化为化学家提供了合成结构上有趣且具有生物活性的化合物的有力方法，这些化合物可用作有效的治疗剂。从简单且容易获得的起始材料产生结构复杂的化合物的方法允许化学家合成化合物的各种类似物，并且这些化合物的生物活性通常可以通过进行微妙的结构改变来调整。本项目的目标是开发一种高效的，不对称合成噻唑啉和恶唑啉，这是常见的杂环结构中发现的生物活性化合物。目前，手性噻唑啉和恶唑啉的合成依赖于对映体纯的起始原料如氨基硫醇和氨基酸。对映体纯起始材料的可用性限制了可以有效制备的这些杂环的类似物的数量。我们将开发使用容易获得的非手性起始材料（酰胺，硫代酰胺和炔酸酯）和使用容易获得的手性膦诱导手性的方法。从硫代酰胺和炔酸酯开始的噻唑啉的膦催化合成是已知的，但是还没有使用这种化学方法的噻唑啉的不对称合成的描述。膦在整个催化循环中与炔酸酯结合，因此通过正确选择膦，将有可能开发噻唑啉的不对称合成。我们还将开发一种使用膦催化剂偶联酰胺和炔酸酯以产生恶唑啉的方法。最初的恶唑啉方法将开发与非手性膦，以建立范围，然后手性膦将进行研究，以开发一个不对称的过程。在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非手性起始原料制备对映体纯恶唑啉的途径。公共卫生相关性：合成化学为药物提供了有效的途径，可以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创建方法，以方便和快速合成生物学上重要的结构基序，这些结构基序通常见于有效的药物和分离的天然产物中。开发用于合成噻唑啉和恶唑啉的不对称催化方法将允许快速进入这些生物学相关的杂环类。