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: 10200330
• 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/10200330
• 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.

项目摘要/摘要 高效、立体选择性地制备手性有机分子对手性有机分子的发展至关重要。 新的治疗药物。然而，尽管取得了重大进展，许多令人满意的2D和3D复杂分子 脚手架仍然很难接近或准备效率低下。因此，新技术的发展 为合成化学家提供战略断键以促进从头开始的转变 有机合成的方法是非常重要的。此外，这种方法应该是健壮、实用、 允许制备有用数量的材料，并理想地使用容易获得的起始材料。这个 这笔Mira赠款的目的是转换由NIGMS资助的项目，其长期目标是广泛寻求 开发和开发新的、实用的、高效的立体选择性有机合成新技术 具有生物重要性的分子支架，否则很难获得，或通过 当前流程。为此，我们感兴趣的是开发利用广泛化学物质的转换 硼稳定的化学合成子在复杂分子合成中的反应性。这种方法很有吸引力。 因为这种中间体的反应允许新的键结构和同时安装 合成的可取的含硼部分。本计划中描述的拟议研究将进一步扩大我们的 有机硼试剂催化立体选择性C-C键形成反应的研究。这些都是现成的 可获得的试剂将强大的成键反应性与广泛的合成用途结合在一起，以提供多功能性 有机化合物对于基于片段的药物发现具有显著的意义。在我们以前工作的基础上， 我们正在开发新的催化C-C、C-N和C-X键形成方法来合成手性胺， 醇和芳香族结构，特别关注含有季碳的例子 立体中心。我们设想手性金属亲核剂可以通过对映体选择性获得。 易得的非手性有机二硼试剂的易金属化。由此产生的亲核物种可以 与不同的C=O，C=N，C-X亲电体进行大量的对映选择性反应。我们的目标还包括 靶向无金属Lewis碱催化合成新型含硼功能化合成子 与亲电体的反应很难通过过渡金属催化实现。重要的是，对映体选择性 本文将探讨这些未知反应的变体。此外，新的亲核芳香族取代 芳香族和杂芳族化合物与有机硼碳亲核剂的反应将得到发展 在无金属的条件下运行。总体而言，通过探索有机硼的合成反应，这些研究 在方法方面，开发将引入新的转变和战略，将简化合成化学家的 对生物医学研究很重要的复杂分子的方法。