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.

该项目旨在利用布罗德研究所CMLD的化学方法学努力来推动小分子 图书馆发展使用的策略，从广泛的研究所CMLD社区演变。我们将使用 简单而强大构建/耦合/配对（B/C/P）策略， 立体选择性途径产生相对于项目1在原子中具有高sp[2]含量的化合物， 定义产物的杂环骨架。我们注意到，该描述符是许多FDA批准的 小分子药物或目前在制药工业中正在研究的小分子。 这些途径说明了合成此类化合物的立体异构体的新方法; 药物样化合物在筛选收藏，如分子图书馆小分子储存库 （MLSMR）供分子文库探针生产中心网络（MLPCN）使用， 对结构/活性关系的深入了解，否则无法从初级小分子筛选中获得。 根据Broad Institute CMLD的Jacobsen实验室组件的最新进展，我们 设想了一种利用两种高选择性手性催化剂进行Pictet-Spengler样反应的途径 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 通过构建作为前体的一系列羟基内酰胺来实现立体化学。我们的目标是准备所有可能的 每种骨架类型的立体异构体。使用这种高水平的底物多样性的反应结果 应该会导致对非对称Pictet-Spengler反应的更深入的理解， 我们的化学方法学努力的过程，特别是它的普遍性和价值的背景下，具有挑战性的 文库合成此外，这些研究预计将产生丰富的立体化学和 适用于小分子筛选的结构多样的杂环化合物。 我们还将探索第二条途径，该途径以第一条途径的原则为基础，旨在产生 具有多个骨架的杂环化合物，包括尚未在小分子中出现的那些 筛选收藏品。根据目前CMLD项目中关于化学方法学的进展， Schreiber实验室，我们已经设想了一个B/C/P途径，该途径利用阳离子金（I）/银（I）介导的 具有两个相邻乙炔的容易合成的底物的异构化和亲核捕获 产生新的和复杂的α-吡喃酮等。这种途径利用了这种新的方法为a-吡喃酮 合成和用于分子内官能团配对反应新方法， 为了合成具有不同杂环骨架的小分子库， 复杂的吡啶环。两种途径的一个统一主题是应用B/C/P战略， 高产率合成，并使用非常少的步骤，小分子具有（相对于项目1）高 环原子中的sp[2]/sp[3]比率，这一特征使人联想到许多杂环、小分子探针和药物。