Schwieter Kenneth E, Johnston Jeffrey N
Department of Chemistry and Vanderbilt Institute of Chemical Biology Vanderbilt University, Nashville, Tennessee 37235.
Chem Sci. 2015;6(4):2590-2595. doi: 10.1039/C5SC00064E.
Peptides consisting of D-amino amides are highly represented among both biologically active natural products and non-natural small molecules used in therapeutic development. Chemical synthesis of D-amino amides most often involves approaches based on enzymatic resolution or fractional recrystallization of their diastereomeric amine salts, techniques that produce an equal amount of the L-amino acid. Enantioselective synthesis, however, promises selective and general access to a specific α-amino amide, and may enable efficient peptide synthesis regardless of the availability of the corresponding α-amino acid. This report describes the use of a cinchona alkaloid-catalyzed aza-Henry reaction using bromonitromethane, and the integration of its product with Umpolung Amide Synthesis. The result is a straightforward 3-step protocol beginning from aliphatic aldehydes that provides homologated peptides bearing an aliphatic side chain at the resulting D-α-amino amide.
由D-氨基酰胺组成的肽在生物活性天然产物和用于治疗开发的非天然小分子中都有很高的占比。D-氨基酰胺的化学合成通常涉及基于其非对映体胺盐的酶促拆分或分步重结晶的方法，这些技术会产生等量的L-氨基酸。然而，对映选择性合成有望选择性地、普遍地获得特定的α-氨基酰胺，并且无论相应的α-氨基酸是否可得，都可能实现高效的肽合成。本报告描述了使用金鸡纳生物碱催化的、以溴硝基甲烷进行的氮杂-Henry反应，以及将其产物与极性翻转酰胺合成相结合。结果是一个从脂肪醛开始的简单的三步方案，可提供在所得D-α-氨基酰胺处带有脂肪族侧链的同系化肽。
