New Dynamic Processes for the Preparation of Biologically Active Small Molecules

创造下一代小分子的重大障碍 治疗学是缺乏通用和有效的方法来获得某些特定的 立体化学致密结构，包含对生物活性重要的功能。 该项目寻求提供一系列新的功能化小型 基于新反应实现的分子积木。这项建议 重点介绍D-酮酸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 在有机合成中未得到充分利用。外消旋E-酮的对映体选择性还原 ESTERS是典型的动态动力学拆分，以吨为单位执行 每年一次。与之形成鲜明对比的是，外消旋D-酮的互补动态还原 酯是未知的，尽管这种方法在创造 生物活性天然产物和医药制剂。我们将开发广泛的新产品 外消旋底物经过催化剂介导的去消旋转化为 提供对映体丰富、增值的产品。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，以及完全 取代的乙醇酸盐。访问这些化合物将通过新的动态 合理构型外消旋D-酮酸酯和D-羟基的动力学拆分 醋酸膦。这项研究提案的具体目标是：(I)开发 D-酮酸酯及其衍生物的动态动力学拆分 开发新型加氢催化剂；(Ii)实现新的碳-碳键 利用羟基磷酸盐的DKRs进行结构；(Iii)开发有用的新 非天然D-二氢呋喃绿色制备的仿生动态动力学变换 氨基酸。

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.