New Organoboron based Methods and Strategies for Organic Synthesis

基于有机硼的新有机合成方法和策略

• 批准号: 10592378
• 负责人: Simon John Meek
• 金额: $ 36.1万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592378
• 关键词: 3-Dimensional; Alcohols; Amines; Attributes of Chemicals; Biological; Biology; Biomedical Research; Boron; Carbon; Catalysis; Chemicals; Complex; Development; Funding; Future; Generations; Goals; Grant; Medicine; Metals; Methods; Molecular; National Institute of General Medical Sciences; Organic Synthesis; Outcome; Preparation; Process; Reaction; Reagent; Research; Structure; Therapeutic Agents; Transition Elements; Variant; Work; base; biological preparation; drug discovery; interest; method development; new technology; novel; novel therapeutics; programs; scaffold

Project Summary/Abstract The efficient and stereoselective preparation of chiral organic molecules is vitally important to the development of new therapeutic agents. However, despite significant progress, many desirable complex 2D and 3D molecular scaffolds remain difficult to access or are inefficiently prepared. Consequently, development of new transformations that provide synthetic chemists with strategic bond disconnections that facilitate de novo approaches to organic synthesis is of great importance. In addition, such methods should be robust, practical, allow the preparation of useful amounts of material, and ideally employ readily available starting materials. The aim of this MIRA grant is the conversion of an NIGMS funded project with a long-term goal that broadly seeks to develop and exploit new, practical, and efficient stereoselective new technologies for organic synthesis of molecular scaffolds of biological importance that are otherwise difficult to access, or inefficiently prepared via current processes. To this end, we are interested in developing transformations that leverage the broad chemical reactivity of boron-stabilized chemical synthons for complex molecule synthesis. This approach is attractive because reactions of such intermediates permit novel bond constructions and simultaneous installation of a synthetically desirable boron moiety. The proposed studies described in this program will further our expanding studies of catalytic stereoselective C–C bond forming reactions with organoboron reagents. These readily accessible reagents merge powerful bond forming reactivity with broad synthetic utility, to deliver versatile organic compounds of notable significance for fragment-based drug discovery. Building off our previous work, we are developing new catalytic C–C, C–N, and C–X bond forming methods for the synthesis of chiral amines, alcohols, and aromatic structures, with a particular focus on examples that contain quaternary carbon stereogenic centers. We envision that chiral metal nucleophiles can be accessed by enantioselective transmetalation of readily accessible achiral organodiboron reagents. The resultant nucleophilic species can engage in a number of enantioselective reactions with various C=O, C=N, C–X electrophiles. We also aim to target the generation and utility of novel boron-functionalized synthons by metal-free Lewis base catalysis for reactions with electrophiles that are difficult to achieve via transition metal catalysis. Importantly, enantioselective variants of these unknown reactions will herein be explored. Furthermore, new nucleophilic aromatic substitution reactions of aromatic and heteroaromatic compounds with organoboron carbon nucleophiles will be developed that operate under metal-free conditions. Overall, by exploring synthetic reactions of organoborons, these studies in methods development will introduce new transformations and strategies that will streamline synthetic chemists' approaches to complex molecules important to biomedical research.

项目概要/摘要 手性有机分子的高效、立体选择性制备对于发展至关重要 然而，尽管取得了重大进展，但许多理想的复杂 2D 和 3D 分子。 脚手架仍然难以接近或准备不足，新的开发也很困难。 为合成化学家提供战略性键断裂的转化，从而促进从头合成 此外，这些方法应该是稳健的、实用的、 允许制备有用量的材料，并且理想地使用容易获得的起始材料。 MIRA 赠款的目的是转换 NIGMS 资助的项目，其长期目标广泛寻求 开发和探索新型、实用、高效的立体选择性有机合成新技术 具有生物学重要性的分子支架，否则很难获得，或者通过以下方法制备的效率低下 为此，我们有兴趣开发利用广泛化学物质的转型。 硼稳定的化学合成子在复杂分子合成中的反应性很有吸引力。 因为此类中间体的反应允许新颖的键结构并同时安装 该计划中描述的拟议研究将进一步扩大我们的综合范围。 用有机硼试剂进行催化立体选择性 C-C 键形成反应的研究。 易于使用的试剂将强大的成键反应性与广泛的合成实用性相结合，提供多种用途 在我们之前的工作基础上，有机化合物对基于片段的药物发现具有显着意义， 我们正在开发新的催化 C-C、C-N 和 C-X 键形成方法，用于合成手性胺， 醇和芳香族结构，特别关注含有季碳的例子 我们设想可以通过对映选择性获得手性金属亲核试剂。 容易获得的非手性有机二硼试剂的金属转移可以产生亲核物质。 我们还致力于与各种 C=O、C=N、C–X 亲电子试剂进行多种对映选择性反应。 目标是通过无金属路易斯碱催化新型硼功能化合成子的生成和利用 与亲电子试剂的反应很难通过过渡金属催化实现，重要的是，是对映选择性的。 此外，本文还将探索这些未知反应的变体，新的亲核芳香取代。 将开发芳族和杂芳族化合物与有机硼碳亲核试剂的反应 总的来说，通过探索有机硼的合成反应，这些研究在无金属条件下进行。 方法开发中将引入新的变革和策略，从而简化合成化学家的工作 对生物医学研究重要的复杂分子的方法。