Coordinating CMLD methodology with the build/couple/pair strategy to yield comple

将 CMLD 方法与构建/耦合/配对策略相协调，以生成完整的

• 批准号: 8331511
• 负责人: Damian Winston Young
• 金额: $ 40.69万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8331511
• 关键词: Acetylene; Acylation; Alkylation; Characteristics; Chemicals; Collaborations; Collection; Communities; Complex; Copper; Coupling; Cyclization; Descriptor; Development; Drug Industry; FDA approved; Gold; Heterocyclic Compounds; Institutes; Laboratories; Lead; Libraries; Mediating; Methodology; Methods; Molecular Bank; Nitriles; Nitrogen; Outcome; Oxygen; Palladium; Pathway interactions; Pharmaceutical Preparations; Pilot Projects; Production; Pyrones; Reaction; Relative (related person); Role; Screening procedure; Silver; Skeleton; Stereoisomer; Structure; Structure-Activity Relationship; base; catalyst; functional group; insight; novel; novel strategies; pyridine; repository; skeletal; small molecule; small molecule libraries; stereochemistry

This project aims to exploit the Broad Institute CMLD's chemical methodology efforts to drive small-molecule library development using a strategy that evolved from the Broad Institute CMLD community. We will use the simple yet powerful build/couple/pair (B/C/P) strategy to develop two exceptionally short, modular and stereoselective pathways yielding compounds having, relative to Project 1, high sp[2] content in the atoms that define the heterocyclic skeletons of the products. We note that this descriptor is characteristic of many FDA-approved small-molecule drugs or small molecules currently being investigated in the pharmaceutical industry. These pathways illustrate a new approach to synthesizing stereoisomers of such compounds; stereoisomers of drug-like compounds in screening collections such as the Molecular Libraries Small-Molecule Repository (MLSMR) for use by the Molecular Libraries Probe-Production Centers Network ((MLPCN) provide valuable insights into structure/activity relationships not otherwise available from a primary small-molecule screen. Based on recent progress from the Jacobsen laboratory component of the Broad Institute CMLD, we have conceived of a pathway that exploits both highly selective chiral catalysts for the Pictet-Spengler-like reaction and the B/C/P strategy. We will evaluate the role of catalyst and substrate structure on Pictet-Spengler reaction stereochemistry by constructing a range of hydroxylactams as precursors. We aim to prepare all possible stereoisomers of each skeletal type. The outcomes of reactions using this high level of substrate diversity should lead to a far greater understanding of the asymmetric Pictet-Spengler-like reactions developed in the course of our chemical methodology efforts, especially its generality and value in the context of challenging library syntheses. In addition, the studies are expected to yield a rich collection of stereochemically and skeletally diverse heterocyclic compounds suitable for small-molecule screening. We will also explore a second pathway that builds on the principles of the first pathway and that aims to yield a heterocyclic compounds having multiple skeletons, including ones not yet represented in small-molecule screening collections. Based on progress in a current CMLD project on chemical methodology from the Schreiber laboratory, we have conceived of a B/C/P pathway that exploits a cationic gold(l)/silver(l)-mediated isomerization and nucleophilic trapping of easily synthesized substrates having two neighboring acetylenes yielding novel and complex yield a-pyrones, among others. This pathway exploits this new method for a-pyrone synthesis and a new method for intramolecular, functional group-pairing reactions that incorporate nitriles in order to synthesize a library of small molecules having diverse heterocyclic skeletons, including complex pyridine rings. A unifying theme of the two pathways is the application of the B/C/P strategy to synthesize in high yield, and using very few steps, small molecules that possess (relative to Project 1) high sp[2]/sp[3] ratios in ring atoms, a feature reminiscent of many heterocyclic, small-molecule probes and drugs.

该项目旨在利用 Broad Institute CMLD 的化学方法学成果来驱动小分子 使用从 Broad Institute CMLD 社区发展而来的策略进行库开发。我们将使用 简单而强大的构建/耦合/配对 (B/C/P) 策略，用于开发两个非常短的模块化和 相对于项目 1，立体选择性途径产生的化合物在原子中具有高 sp[2] 含量 定义产物的杂环骨架。我们注意到这个描述符是许多 FDA 批准的药物的特征 小分子药物或制药行业目前正在研究的小分子。 这些途径说明了合成此类化合物立体异构体的新方法；的立体异构体 筛选库中的类药化合物，例如分子库小分子存储库 (MLSMR) 供分子图书馆探针生产中心网络 ((MLPCN) 使用) 提供有价值的 对结构/活性关系的深入了解是通过初级小分子筛选无法获得的。 根据布罗德研究所 CMLD 雅各布森实验室部分的最新进展，我们 设想了一种利用高选择性手性催化剂进行类 Pictet-Spengler 反应的途径 以及 B/C/P 策略。我们将评估催化剂和底物结构对 Pictet-Spengler 反应的作用 通过构建一系列羟基内酰胺作为前体来进行立体化学。我们的目标是做好一切可能的准备 每种骨架类型的立体异构体。使用这种高水平底物多样性的反应结果 应该会导致对不对称皮克泰-斯宾格勒反应的更深入的了解 我们的化学方法学工作的过程，特别是其在具有挑战性的背景下的普遍性和价值 文库合成。此外，这些研究预计将产生丰富的立体化学和 适合小分子筛选的骨架多样的杂环化合物。 我们还将探索第二条途径，该途径建立在第一条途径的原则之上，旨在产生 具有多个骨架的杂环化合物，包括尚未以小分子形式表示的杂环化合物 筛选集合。基于当前 CMLD 化学方法学项目的进展 Schreiber 实验室，我们设想了利用阳离子金（l）/银（l）介导的 B/C/P 途径 具有两个相邻乙炔的易于合成的底物的异构化和亲核捕获 产生新颖且复杂的产物a-吡喃酮等。该途径利用了α-吡喃酮的新方法 合成和分子内官能团配对反应的新方法，其中包含 腈以合成具有不同杂环骨架的小分子库，包括 复杂的吡啶环。两种途径的一个统一主题是 B/C/P 策略的应用 使用很少的步骤以高产率合成具有（相对于项目 1）高 环原子中的 sp[2]/sp[3] 比率，这一特征让人想起许多杂环、小分子探针和药物。