New Dynamic Processes for the Preparation of Biologically Active Small Molecules

制备生物活性小分子的新动态工艺

• 批准号: 8730686
• 负责人: Jeffrey S Johnson
• 金额: $ 18.46万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-05 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8730686
• 关键词: Acids; Amino Acids; Architecture; Biological Factors; Biology; Biomimetics; Carbon; Chemicals; Chemistry; Communities; DNA Sequence Rearrangement; Development; Environmental Impact; Essential Amino Acids; Esters; Family; Glycolates; Goals; Hydrogenation; Hydroxy Acids; Keto Acids; Kinetics; Mediating; Methods; Molecular; Natural Product Drug; Organic Chemistry; Organic Synthesis; Pharmaceutical Chemistry; Preparation; Process; Production; Reaction; Research; Research Proposals; Resolution; Role; Route; Scheme; Structure; Therapeutic; Therapeutic Agents; aminoacid biosynthesis; base; catalyst; flexibility; functional group; inorganic phosphate; next generation; novel; novel therapeutics; phosphonate; programs; small molecule; transamination

A significant obstacle to the creation of the next generation of small molecule therapeutics is the lack of general and efficient methods for accessing certain stereochemically dense structures that contain functionality important for bioactivity. This project seeks to provide simple access to a range of new functionalized small molecule building blocks based on the implementation of new reactions. The proposal focuses on new chemistry of D-keto esters and their derivatives. D-Keto acids occupy a central role in biology, for example in the biosynthesis of amino acids, but are underutilized in organic synthesis. The enantioselective reduction of racemic E-keto esters is the archetypal dynamic kinetic resolution and is performed on ton scale annually. In stark contrast, the complementary dynamic reduction of racemic D-keto esters is unknown, despite the enormous potential of this method for the creation of bioactive natural products and medicinal agents. We will develop a broad range of new transformations of racemic substrates that undergo catalyst-mediated deracemization to provide enantiomerically enriched, value-added products. Targeted product structures include D-hydroxy-E-amino acids, D,E-diamino acids, unnatural D-amino acids, and fully substituted glycolates. Access to these compounds will be enabled via new dynamic kinetic resolutions of appropriately configured racemic D-keto esters and D-hydroxy phosphonoacetates. The specific goals of this research proposal are to (i) develop dynamic kinetic resolutions (DKRs) of D-keto esters and their derivatives through the development of novel hydrogenation catalysts; (ii) implement new carbon-carbon bond constructions by using DKRs of hydroxyphosphonates; (iii) develop useful new biomimetic dynamic kinetic transaminations for the green preparation of unnatural D- amino acids.

创造下一代小分子的一个重大障碍 治疗是缺乏一般和有效的方法，以获得某些 立体化学致密的结构包含对生物活性重要的官能度。 该项目旨在提供简单的访问一系列新的功能化小 基于新反应的实施的分子构建块。该提案 重点介绍了D-酮酯及其衍生物的新化学。D-酮酸占据了 在生物学中的中心作用，例如在氨基酸的生物合成中，但 在有机合成中未被充分利用。外消旋E-酮的不对称还原 酯是典型的动态动力学拆分，在吨级上进行 每年。与此形成鲜明对比的是，外消旋D-酮的互补动态还原 酯是未知的，尽管这种方法创造的巨大潜力， 生物活性天然产物和药用制剂。我们将开发一系列新的 进行催化剂介导的去外消旋化的外消旋底物转化为 提供对映体富集的增值产品。目标产品结构 包括D-羟基-E-氨基酸、D，E-二氨基酸、非天然D-氨基酸，且完全 取代的乙醇酸酯。这些化合物的获取将通过新的动态 适当构型的外消旋D-酮酯和D-羟基的动力学拆分 膦酰基乙酸盐。本研究计划的具体目标是：（一）发展 D-酮酯及其衍生物的动态动力学拆分（DKRs） 开发新型加氢催化剂;（ii）实现新的碳-碳键 通过使用羟基膦酸酯的DKR构建;（iii）开发有用的新的 仿生动态动力学转氨用于非天然D-的绿色制备， 个氨基酸