Szcześniak Piotr, Pieczykolan Michał, Stecko Sebastian
Institute of Organic Chemistry , Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland.
J Org Chem. 2016 Feb 5;81(3):1057-74. doi: 10.1021/acs.joc.5b02628. Epub 2016 Jan 12.
An approach to α,α-disubstituted α-amino acids is reported. The key step is allyl cyanate-to-isocyanate rearrangement. As demonstrated, the resultant allyl isocyanates can be directly trapped with various nucleophiles, for instance, alcohols, amines, and organometallic reagents, to provide a broad range of N-functionalized allylamines. The developed method has been successfully applied in the synthesis of two bioactive peptides: 2-aminoadamantane-2-carboxylic acid derived P2X7-evoked glutamate release inhibitor and 4-amino-tetrahydropyranyl-4-carboxylic acid derived dipeptide GSK-2793660, which is currently in clinical trials as cathepsin C inhibitor for the treatment of cystic fibrosis, noncystic fibrosis bronchiectasis, ANCA-associated vasculitis and bronchiectasis.
报道了一种合成α,α-二取代α-氨基酸的方法。关键步骤是烯丙基氰酸酯到异氰酸酯的重排。结果表明，生成的烯丙基异氰酸酯可直接与各种亲核试剂（如醇、胺和有机金属试剂）反应，以提供多种N-官能化烯丙胺。所开发的方法已成功应用于两种生物活性肽的合成：2-氨基金刚烷-2-羧酸衍生的P2X7诱导的谷氨酸释放抑制剂和4-氨基-四氢吡喃基-4-羧酸衍生的二肽GSK-2793660，后者目前作为组织蛋白酶C抑制剂用于治疗囊性纤维化、非囊性纤维化支气管扩张、抗中性粒细胞胞浆抗体相关性血管炎和支气管扩张的临床试验。
