Decarboxylative borylation.
Decarboxylative borylation.
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DOI：
10.1126/science.aam7355
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发表时间：
2017-06-09
期刊：
影响因子：
--
通讯作者：
Baran PS
中科院分区：
文献类型：
--
作者：
Li C;Wang J;Barton LM;Yu S;Tian M;Peters DS;Kumar M;Yu AW;Johnson KA;Chatterjee AK;Yan M;Baran PS
硼酸是在材料科学、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（生物电子等排体）的替代品，以改善先导化合物的效力或药代动力学特征。然而，烷基硼酸的广泛引入在很大程度上受到与其制备相关的挑战的阻碍。因此，目前只有两种烷基硼酸在临床上使用，即Velcade和Ninlaro。很少有方法能够从容易获得的起始材料提供烷基硼酸酯;大多数显示出适度的官能团相容性。事实上，硼酸酯基序通常在合成的早期阶段安装，因此从多步骤过程中的计划和操作的角度来看，消耗了不成比例的努力。烷基羧酸作为地球上最多样化的化学结构单元，存在于无数的天然产物和药物中。它们代表硼酸的理想前体。我们实验室以前的努力表明，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），烷基羧酸可以在金属催化的脱羧交叉偶联反应中与碳亲核试剂一起作为方便的烷基卤化物替代物，使用与酰胺键形成相同的活化原理。因此推测，这种反应性可以在脱羧硼化过程中利用，其中结构上不同且一直存在的羧酸可以直接转化为高价值的硼酸。通过专门使用N-羟基邻苯二甲酰亚胺RAE，能够用廉价的镍催化剂将羧酸转化为硼酸酯的简单方法。该反应范围广泛（>40个实施例），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，允许密集官能化的药物分子（例如，万古霉素和立普妥）和天然产物（例如，烯醇酮）转化为类似的硼酸。该方法具有从天然肽中获得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，其中最有效的抑制剂已显示出改善的体外抑制活性（IC50 = 15 pM，Ki = 3.7 pM）。酶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。RAE的镍催化的脱羧交叉偶联使得能够使用廉价的硼源B2 pin 2（Bpin =硼酸频哪醇酯）用硼酸酯取代普遍存在的烷基羧酸。该方法提供了制备迄今难以制备的复合硼酸的简单和实用的途径。硼酸独有的有用反应性的广泛多样性，如交叉偶联、氧化、胺化和同系物化，将在逆合成分析中开辟不同的可能性。这项工作也可能加速新的含硼治疗剂的发现和开发。
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. 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. 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. 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.
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影响因子：
3.4
作者：
Ballatore, Carlo;Huryn, Donna M.;Smith, Amos B., III
通讯作者：
Smith, Amos B., III
影响因子：
15
作者：
Dudnik, Alexander S.;Fu, Gregory C.
通讯作者：
Fu, Gregory C.
影响因子：
2.7
作者：
Kinoshita, T;Nakanishi, I;Tada, T
通讯作者：
Tada, T
DOI：
10.1007/7355_2014_65
发表时间：
2016-01-01
期刊：
ATYPICAL ELEMENTS IN DRUG DESIGN
影响因子：
--
作者：
Draganov, Alexander;Wang, Danzhu;Wang, Binghe
通讯作者：
Wang, Binghe
影响因子：
15
作者：
Cornella J;Edwards JT;Qin T;Kawamura S;Wang J;Pan CM;Gianatassio R;Schmidt M;Eastgate MD;Baran PS
通讯作者：
Baran PS