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

该项目旨在利用博德研究所CMLD的化学方法学努力推动小分子 使用从布罗德学院CMLD社区演变而来的战略来开发图书馆。我们将使用 简单而强大的构建/耦合/对(B/C/P)策略，以开发两个非常短、模块化和 立体选择性途径，产生相对于项目1具有较高sp[2]含量的原子中的化合物 定义产品的杂环骨架。我们注意到，该描述符是FDA批准的许多 制药行业目前正在研究的小分子药物或小分子药物。 这些途径展示了一种合成这类化合物的立体异构体的新方法； 类药物化合物在筛选分子文库、小分子文库等文库中的应用 (MLSMR)供分子图书馆探测-生产中心网络(MLPCN)使用，提供有价值的 对结构/活性关系的洞察是从初级小分子屏幕上无法获得的。 根据布罗德研究所CMLD雅各布森实验室部分的最新进展，我们已经 设想了一种利用两种高选择性手性催化剂进行Pictet-Spengler类反应的方法 和B/C/P战略。我们将评估催化剂和底物结构在Pictet-Spengler反应中的作用 通过构建一系列羟基内酰胺作为前体的立体化学。我们的目标是尽一切可能准备好 每种骨骼类型的立体异构体。使用这种高度底物多样性的反应的结果 应该导致对不对称Pictet-Spengler类反应的更好的理解 我们化学方法论工作的进程，特别是它在挑战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性杂环化合物。 我们还将探索第二条途径，它建立在第一条途径的原则基础上，旨在产生 具有多个骨架的杂环化合物，包括小分子中尚未出现的杂环化合物 筛选收藏集。基于目前CMLD化学方法论项目的进展 Schreiber实验室，我们设想了一种B/C/P通路，它利用阳离子金(L)/银(L)介导的 具有两个相邻乙炔的易合成底物的异构化和亲核捕获 产生新的和复杂的产物a-吡喃酮等。这种方法利用了这种新方法来制备α-吡喃酮。 分子内官能团配对反应的合成及新方法 为了合成具有不同杂环骨架的小分子的库，包括 复杂的吡啶环。两条道路的一个统一主题是将B/C/P战略应用于 用很少的步骤高产率地合成具有(相对于项目1)高的小分子 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。

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.