EAPSI: Development of New Methods for the Synthesis of Organic Compounds

EAPSI：有机化合物合成新方法的开发

• 批准号: 1414616
• 负责人: Samuel Bartlett
• 金额: $ 0.51万
• 依托单位: Bartlett Samuel L
• 依托单位国家: 美国
• 项目类别: Fellowship Award
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1414616&HistoricalAwards=false
• 关键词: EAPSI; Development; New; Methods; Synthesis

The synthesis of organic compounds in enantiopure form is of premiere importance to the discovery and production of new pharmaceuticals. Enantiomers are a set of organic compounds unique because they are non-superimposable mirror images of one another (similar to the way a right-hand and left-hand glove cannot be superimposed on one another). Single-enantiomer therapeutics account for sales of over 200 billion dollars, and comprise a significant portion of pharmaceutical sales worldwide. The increasing dominance of single-enantiomer drugs is partially due to increased awareness of their enhanced biological properties, in addition to regulatory guidelines. Thus, the preparation of organic compounds in enantiopure form directly impacts human health. The most strategic, straightforward method to produce medicinally important organic compounds in enantiopure form is through a process called enantioselective catalysis. In collaboration with Dr. Mikiko Sodeoka, a known expert in the field of asymmetric catalysis, at the RIKEN Institute in Japan, this research will study a method for the synthesis of a specific class of organic compounds that exhibit medicinal potential but lack a direct method for their enantioselective synthesis. The information produced in this study is expected to have broad impact and will contribute to the development of other catalytic asymmetric transformations as well. Specifically, a novel transition metal-catalyzed cycloaddition reaction between alpha-keto esters and nitrile oxides will be investigated. It is anticipated that chiral nickel-diamine complexes will be uniquely effective catalysts in this cycloaddition process due to their proven ability to enolize relatively weakly acidic alpha-keto esters. Initially the effect of solvent, temperature, ligand structure, and counterion identity on rate of conversion and stereoselectivity will be investigated. Next, an array of differentially substituted alpha-keto ester and nitrile oxide substrates, readily synthesized from cheap feedstock chemicals, will be tested under the optimized reaction conditions to evaluate the scope and utility of the proposed method. This NSF EAPSI award is funded in collaboration with the Japan Society for the Promotion of Science.

对映体有机化合物的合成对新药的发现和生产具有重要意义。对映体是一组独特的有机化合物，因为它们是彼此不可重叠的镜像(类似于左右手手套不能相互重叠的方式)。单一对映体疗法的销售额超过2000亿美元，占全球药品销售额的很大一部分。单一对映体药物日益占主导地位的部分原因是，除了监管指南外，人们对其增强的生物学特性的认识也有所提高。因此，对映体有机化合物的制备直接影响人类健康。以对映体形式生产具有重要药用价值的有机化合物的最具战略、最直接的方法是通过一种称为对映体选择性催化的过程。这项研究将与日本理研研究所的不对称催化领域的著名专家Sodeoka Mikiko博士合作，研究一种合成特定类别的有机化合物的方法，这些化合物具有药用潜力，但缺乏直接的对映选择性合成方法。这项研究中产生的信息预计将产生广泛的影响，并将有助于开发其他催化不对称转化。具体地说，我们将研究一种新型的过渡金属催化的α-酮酸酯和氰氧化物之间的环加成反应。预计手性镍-二胺络合物将是这一环加成过程中唯一有效的催化剂，因为它们被证明有能力使相对弱酸性的α-酮酸酯烯醇化。首先考察了溶剂、温度、配体结构和反离子特性对转化率和立体选择性的影响。接下来，将在优化的反应条件下测试一系列容易从廉价原料化学品中合成的不同取代的α-酮酯和氧化腈底物，以评估所提出的方法的范围和实用性。该NSF EAPSI奖是与日本科学促进会合作资助的。