Swapping boron acids for carbon acids Carbon-bound boronic acids and their esters are widely used as coupling partners to make carbon-carbon bonds. More recently, these chemicals have garnered pharmaceutical interest in their own right. Li et al. report a versatile nickel-catalyzed process to replace carboxylic acids with boronate esters by using a phthalimide activator. The reaction is well suited to late-stage modification of complex molecules. The authors used the approach to produce a potent in vitro inhibitor of human neutrophil elastase, a target of interest in treating inflammatory lung diseases. Science, this issue p. eaam7355 Nickel catalyzes replacement of carboxylic acid groups with boronic acids and esters in a wide variety of compounds. INTRODUCTION The boronic acid is a functional group of enormous utility in materials science, chemosensor development, and drug discovery. In medicinal chemistry, boronic acids have been harnessed as a replacement for various structural motifs (a bioisostere) to improve the potency or pharmacokinetic profiles of lead compounds. However, the widespread incorporation of alkyl boronic acids has been largely hampered by the challenges associated with their preparation. Consequently, only two alkyl boronic acids are currently in clinical use, namely Velcade and Ninlaro. Few methods are capable of delivering alkyl boronates from readily available starting materials; most exhibit modest functional group compatibility. Indeed, boronate motifs are often installed at the early stage of a synthesis and thus consume disproportionate effort from the standpoint of planning and manipulation in multistep processes. RATIONALE Alkyl carboxylic acids, as the most variegated chemical building blocks on Earth, are present in a myriad of natural products and medicines. They represent an ideal precursor to boronic acids. Previous efforts from our laboratory revealed that, through the intermediacy of simple redox-active esters (RAEs, e.g., N-hydroxyphthalimide esters), alkyl carboxylic acids could be harnessed as convenient alkyl halide surrogates in metal-catalyzed decarboxylative cross-coupling reactions with carbon nucleophiles, using the same activating principles as amide bond formation. It was therefore surmised that such reactivity could be exploited in a decarboxylative borylation process wherein structurally diverse and ever-present carboxylic acids could be converted directly into high-value boronic acids. RESULTS Through the exclusive use of N-hydroxyphthalimide RAEs, a simple means to convert carboxylic acids into boronate esters was enabled with an inexpensive nickel catalyst. This reaction was broad in scope (>40 examples) and demonstrated excellent functional group compatibility (tolerating alkyl/aryl halides, amides/carbamates, alcohols, ketones, and olefins), and high levels of diastereoselectivity, allowing transformations of densely functionalized drug molecules (e.g., vancomycin and Lipitor) and natural products (e.g., enoxolone) into the analogous boronic acids. This method’s unique capacity to access α-amino boronic acids from native peptides not only allowed the concise syntheses of both Velcade and Ninlaro, it also enabled the expedient discovery of three highly potent human neutrophil elastase (HNE) inhibitors, the most potent of which has shown improved in vitro inhibitory activities (IC50 = 15 pM, Ki = 3.7 pM) relative to leading candidates previously tested in clinical trials. Enzymatic and pharmacokinetic studies indicated high functional stability in physiologically relevant media. CONCLUSION The nickel-catalyzed decarboxylative cross-coupling of RAEs enables substitution of ubiquitous alkyl carboxylic acids with boronate esters using an inexpensive boron source: B2pin2 (Bpin = pinacol boronate). This process provides simple and practical access to complex boronic acids that were heretofore difficult to prepare. The wide diversity of useful reactivity that is exclusive to boronic acids, such as cross-coupling, oxidation, amination, and homologation, will open distinct possibilities in retrosynthetic analysis. This work may also accelerate the discovery and development of new boron-containing therapeutics. Decarboxylative borylation. Decarboxylative borylation replaces alkyl carboxylic acids with boronate esters (top) across a broad range of substrates (middle left), enabling convenient disconnections for synthesis (middle right) and leading to the discovery of potent elastase inhibitors (bottom). The widespread use of alkyl boronic acids and esters is frequently hampered by the challenges associated with their preparation. We describe a simple and practical method to rapidly access densely functionalized alkyl boronate esters from abundant carboxylic substituents. This broad-scope nickel-catalyzed reaction uses the same activating principle as amide bond formation to replace a carboxylic acid moiety with a boronate ester. Application to peptides allowed expedient preparations of α-amino boronic acids, often with high stereoselectivity, thereby facilitating synthesis of the alkyl boronic acid drugs Velcade and Ninlaro as well as a boronic acid version of the iconic antibiotic vancomycin. The reaction also enabled the discovery and extensive biological characterization of potent human neutrophil elastase inhibitors, which offer reversible covalent binding properties.

中文翻译：

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脱羧硼基化


将硼酸换成碳酸碳键合硼酸及其酯被广泛用作偶联伙伴来形成碳-碳键。最近，这些化学品以其自身的优势引起了制药界的兴趣。李等人。报告了一种多功能镍催化工艺，通过使用邻苯二甲酰亚胺活化剂用硼酸酯取代羧酸。该反应非常适合复杂分子的后期修饰。作者利用该方法生产了一种有效的人中性粒细胞弹性蛋白酶体外抑制剂，该酶是治疗炎症性肺部疾病的一个靶点。科学，本期第 14 页。 eaam7355 镍可催化多种化合物中的羧酸基团被硼酸和酯取代。简介 硼酸是一种在材料科学、化学传感器开发和药物发现中具有巨大用途的官能团。在药物化学中，硼酸已被用作各种结构基序（生物等排体）的替代品，以提高先导化合物的效力或药代动力学特征。然而，烷基硼酸的广泛应用在很大程度上受到与其制备相关的挑战的阻碍。因此，目前临床上使用的烷基硼酸只有两种，即Velcade和Ninlaro。很少有方法能够从容易获得的起始原料中制备硼酸烷基酯；大多数表现出适度的官能团兼容性。事实上，硼酸酯基序通常是在合成的早期阶段安装的，因此从多步骤过程中的规划和操作的角度来看，会消耗不成比例的精力。 基本原理 烷基羧酸是地球上最多样化的化学结构单元，存在于多种天然产品和药物中。它们是硼酸的理想前体。我们实验室之前的研究表明，通过简单的氧化还原活性酯（RAE，例如 N-羟基邻苯二甲酰亚胺酯）的中介作用，烷基羧酸可以在金属催化的与碳的脱羧交叉偶联反应中用作方便的烷基卤化物替代物亲核试剂，使用与酰胺键形成相同的激活原理。因此推测这种反应性可用于脱羧硼化过程，其中结构多样且始终存在的羧酸可直接转化为高价值的硼酸。结果通过独家使用 N-羟基邻苯二甲酰亚胺 RAE，使用廉价的镍催化剂实现了将羧酸转化为硼酸酯的简单方法。该反应范围广泛（> 40 个实例），并表现出优异的官能团相容性（耐受烷基/芳基卤化物、酰胺/氨基甲酸酯、醇、酮和烯烃）和高水平的非对映选择性，允许密集官能化药物分子的转化。例如，万古霉素和立普妥）和天然产物（例如，依诺索酮）转化为类似的硼酸。该方法具有从天然肽中获取 α-氨基硼酸的独特能力，不仅可以简洁地合成 Velcade 和 Ninlaro，还可以方便地发现三种高效的人中性粒细胞弹性蛋白酶 (HNE) 抑制剂，其中最有效的是显示出改善的体外抑制活性（IC50 = 15 pM，Ki = 3。晚上 7 点）相对于之前在临床试验中测试的主要候选人。酶学和药代动力学研究表明在生理相关介质中具有高功能稳定性。结论 RAE 的镍催化脱羧交叉偶联能够使用廉价的硼源 B2pin2（Bpin = 硼酸频哪醇）用硼酸酯取代普遍存在的烷基羧酸。该方法提供了简单而实用的方法来获得迄今为止难以制备的复杂硼酸。硼酸独有的各种有用的反应性，例如交叉偶联、氧化、胺化和同系化，将为逆合成分析带来不同的可能性。这项工作还可能加速新的含硼疗法的发现和开发。脱羧硼化。脱羧硼化在多种底物（左中）中用硼酸酯取代烷基羧酸（上），从而可以方便地断开合成（右中），并导致有效弹性蛋白酶抑制剂的发现（下）。烷基硼酸和酯的广泛使用经常因其制备相关的挑战而受到阻碍。我们描述了一种简单实用的方法，可以从丰富的羧基取代基中快速获得密集官能化的烷基硼酸酯。这种广泛的镍催化反应使用与酰胺键形成相同的活化原理，用硼酸酯取代羧酸部分。 应用于肽可以方便地制备 α-氨基硼酸，通常具有高立体选择性，从而促进烷基硼酸药物 Velcade 和 Ninlaro 以及标志性抗生素万古霉素的硼酸版本的合成。该反应还使得有效的人类中性粒细胞弹性蛋白酶抑制剂的发现和广泛的生物学表征成为可能，该抑制剂具有可逆的共价结合特性。