Direct Reductive Transformation of Amides: From Methodology Development to Applications in Total Synthesis.

IF 17.7 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Wei Ou,Pei-Qiang Huang
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引用次数: 0

Abstract

ConspectusEfficiency, selectivity, versatility, and practicality are major goals in current organic synthesis. Carboxamides are among the most prevalent and versatile functional groups in organic and medicinal chemistry, prominently featured in pharmaceuticals, natural products, and biomolecules. A large-scale analysis of over 1 million pharmaceutical reactions revealed that amide formation is the most frequently used transformation, and amine synthesis remains a foundational transformation in medicinal chemistry. Among various approaches, the reductive functionalization of amides has emerged as a particularly powerful strategy, especially in the concise synthesis of nitrogen-containing alkaloids with diverse biological activities.However, the exceptional stability of amides, due to resonance delocalization, renders them chemically inert toward nucleophilic addition and thus difficult to transform directly. Traditional strategies often require multistep protocols or harsh reagents, thereby limiting their efficiency, selectivity, and compatibility with sensitive functional groups.Our group has contributed significantly to overcoming these challenges by developing general and chemoselective methods for the direct reductive transformation of amides. Since our initial reports in 2010, we have introduced multiple mechanistic paradigms─including triflic anhydride activation and fully catalytic relay processes─that enable the efficient synthesis of α-functionalized amines and alkaloids. These include direct reductive alkylation, bisalkylation, and more recently, catalytic enantioselective reductive alkynylation and alkylation of both secondary and tertiary amides.In this Account, we summarize over a decade of progress in this area, focusing on the development of new activation strategies (e.g., Ir-Cu relay catalysis, organocatalyst integration, Pd-mediated tandem transformations), mechanistic understanding, and synthetic applications. We highlight how our catalytic asymmetric methodologies have redefined the utility of amides as building blocks, enabling highly efficient and selective construction of complex nitrogen heterocycles and natural products. Moreover, we discuss the broader implications of these advances in medicinal chemistry and process-scale synthesis. The impact of these methodologies is further demonstrated through their adoption by other research groups in total synthesis and drug development, underscoring their generality and transformative potential.
酰胺的直接还原转化:从方法发展到在全合成中的应用。
高效、选择性、通用性和实用性是当前有机合成的主要目标。羧胺是有机化学和药物化学中最普遍、用途最广的官能团之一,在药物、天然产物和生物分子中占有重要地位。对超过100万个药物反应的大规模分析表明,酰胺形成是最常用的转化,胺合成仍然是药物化学的基础转化。在各种方法中,酰胺的还原功能化已成为一种特别有效的策略,特别是在具有多种生物活性的含氮生物碱的简明合成中。然而,由于共振离域,酰胺具有特殊的稳定性,使得它们对亲核加成具有化学惰性,因此难以直接转化。传统的策略通常需要多步骤协议或苛刻的试剂,从而限制了它们的效率,选择性和与敏感官能团的相容性。我们的团队通过开发酰胺直接还原转化的通用和化学选择性方法,为克服这些挑战做出了重大贡献。自2010年首次报道以来,我们已经引入了多种机制范式,包括三酸酐活化和全催化接力过程,这些机制范式使α-功能化胺和生物碱的有效合成成为可能。这些包括直接还原性烷基化,双烷基化,以及最近的催化对映选择性还原性烷基化和仲、叔酰胺烷基化。在这篇文章中,我们总结了十多年来在这一领域的进展,重点是新的激活策略的发展(例如,Ir-Cu继电器催化,有机催化剂集成,pd介导的串联转化),机理理解和合成应用。我们强调了我们的催化不对称方法如何重新定义酰胺作为构建块的效用,使复杂的氮杂环和天然产物的高效和选择性构建成为可能。此外,我们还讨论了这些进展在药物化学和工艺规模合成方面的更广泛意义。其他研究小组在全合成和药物开发方面采用了这些方法,进一步证明了这些方法的影响,强调了它们的通用性和变革潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Accounts of Chemical Research
Accounts of Chemical Research 化学-化学综合
CiteScore
31.40
自引率
1.10%
发文量
312
审稿时长
2 months
期刊介绍: Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.
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