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: 10398918
• 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/10398918
• 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; 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.

项目总结/摘要 高效、立体选择性地制备手性有机分子对手性药物的开发具有重要意义 新的治疗剂。然而，尽管取得了显著进展，但许多期望的复杂2D和3D分子 支架仍然难以接近或制备效率低。因此，发展新 这些转化为合成化学家提供了战略性的键断开， 有机合成的方法是非常重要的。此外，这种方法应该是稳健的、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。的 该MIRA赠款的目的是转换NIGMS资助的项目，其长期目标是广泛寻求 开发和利用新型、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，否则难以获得，或者通过 目前的进程。为此，我们有兴趣开发利用广泛的化学物质的转化， 硼稳定的化学试剂用于复杂分子合成的反应性。这种做法很有吸引力 因为这种中间体的反应允许新的键结构和同时安装的 合成所需的硼部分。该计划中描述的拟议研究将进一步扩大我们的研究领域。 有机硼试剂催化立体选择性C-C键形成反应的研究。这些容易 可获得的试剂将强大的成键反应性与广泛的合成实用性相结合， 对基于片段的药物发现具有显著意义的有机化合物。基于我们之前的工作， 我们正在开发用于合成手性胺的新的催化C-C、C-N和C-X键形成方法， 醇和芳族结构，特别关注含有季碳的实例 立体中心我们设想手性金属亲核试剂可以通过对映选择性 容易获得的非手性有机二硼试剂的金属转移。所得亲核物质可 与各种C=O、C=N、C-X亲电体进行许多对映选择性反应。我们还旨在 通过无金属刘易斯碱催化， 通过过渡金属催化难以实现的与亲电试剂的反应。重要的是，对映选择性 本文将探索这些未知反应的变体。此外，新的亲核芳香取代 芳香族和杂芳香族化合物与有机硼碳亲核试剂的反应将得到发展 在无金属的条件下工作。总之，通过探索有机硼的合成反应，这些研究 在方法开发中，将引入新的转换和策略，以简化合成化学家的工作。 研究对生物医学研究很重要的复杂分子的方法。