分会

第五十三分会：手性化学

摘要

多肽是一类具有重要生物活性的物质，可用于制作疫苗和药物，其中非天然多肽通常表现出不同于天然多肽的生物活性。用固相合成法制备非天然多肽时，一般要用到N,C端双保护的非天然氨基酸，其中N端保护基最常见的是胺基甲酸酯。α-重氮酯衍生的卡宾和胺基甲酸酯的不对称N-H键插入反应是合成氨基甲酸酯保护的非天然α-氨基酸酯的直接方法，此前人们实现了α-芳基和α-烯基重氮酯衍生卡宾对胺基甲酸酯N-H键的高对映选择性插入反应，但α-烷基重氮酯衍生卡宾的同类反应仍然没有成功的例子。这可能是由于在金属催化下，α-烷基卡宾容易发生β-H迁移反应得到烯烃副产物，而其烷基相较芳基和烯基柔性更高，造成相应N-H键插入反应的对映选择性控制更为困难。我们发展了一种基于催化卡宾对N-H键的插入反应合成非天然氨基酸酯的新方法。该方法以Tp*Cu(I)配合物与手性磷酸为催化剂，α-烷基重氮酯为卡宾前体，氨基甲酸酯为N-H键给体，高收率和高对映选择性地合成了胺基甲酸酯基保护的非天然α-氨基酸酯，具有条件温和、底物适用范围广、官能团耐受性好等特点，丰富了非天然氨基酸的类型。该方法合成的保护的非天然氨基酸具有很好的应用潜力，可对映选择性保持地转化为多种α-氨基酸衍生物，并可直接应用于人工合成多肽。该研究拓展了N-H键插入反应，丰富了非天然氨基酸类型，为非天然多肽的合成应用和功能发现提供了新的物质基础。 Polypeptides are a class of substances with important biological activities that can be used to make vaccines and drugs. Unnatural polypeptides usually exhibit different biological activities from natural polypeptides. When using solid phase synthesis to prepare unnatural polypeptides, it is generally necessary to use N- and C- double protected unnatural amino acids, among which the most common N-terminal protective group is carbamate. The asymmetric N-H bond insertion reaction of carbenes derived from diazoesters with carbamates is the direct method for carbamate-protected unnatural α-amino esters. Although such reactions using α-aryl and α-alkenyl carbenes has previously been realized, there are still no successful examples of similar reactions of α-alkyl carbenes. This may be due to the α-alkyl metal carbene is prone to occur β-H migration side reaction and high flexibility of the alkyl group makes it difficult to control the enantioselectivity. Expanding on our previously reported work on catalytic asymmetric carbene insertion reactions, we have developed a method for highly enantioselective N−H bond insertion reactions of α-alkyl-α-diazoacetates and various carbamates cooperatively catalyzed by Tp*Cu(I), where Tp = (hydrotris(4,5-bromopyrazolyl)borate), and a chiral spiro phosphoric acid. These reactions provide straightforward access to unnatural optically active N-carbonate α-alkyl-α-amino esters, which are widely used in artificial peptide synthesis. This mild method uses readily available starting materials and features a broad substrate scope, good functional group tolerance, good to high yields (58−88%), and high enantioselectivities (90−96% ee). The combination of the neutral copper catalyst Tp*Cu(I) and the chiral spiro phosphoric acid ensures the success of the reaction by inhibiting a β-H migration reaction of a copper carbene intermediate and by promoting enantioselective proton transfer to an enolate intermediate.

关键词

不对称合成;N-H键插入反应;非天然α-氨基酸;肽合成;手性质子梭

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