School of Chemistry, University of Bristol, Bristol, UK.
Nature. 2018 Oct;562(7725):105-109. doi: 10.1038/s41586-018-0553-9. Epub 2018 Oct 3.
Quaternary amino acids, in which the α-carbon that bears the amino and carboxyl groups also carries two carbon substituents, have an important role as modifiers of peptide conformation and bioactivity and as precursors of medicinally important compounds. In contrast to enantioselective alkylation at this α-carbon, for which there are several methods, general enantioselective introduction of an aryl substituent at the α-carbon is synthetically challenging. Nonetheless, the resultant α-aryl amino acids and their derivatives are valuable precursors to bioactive molecules. Here we describe the synthesis of quaternary α-aryl amino acids from enantiopure amino acid precursors by α-arylation without loss of stereochemical integrity. Our approach relies on the temporary formation of a second stereogenic centre in an N'-arylurea adduct of an imidazolidinone derivative of the precursor amino acid, and uses readily available enantiopure amino acids both as a precursor and as a source of asymmetry. It avoids the use of valuable transition metals, and enables arylation with electron-rich, electron-poor and heterocyclic substituents. Either enantiomer of the product can be formed from a single amino acid precursor. The method is practical and scalable, and provides the opportunity to produce α-arylated quaternary amino acids in multi-gram quantities.
季铵氨基酸中，α-碳承载着氨基和羧基，还带有两个碳取代基，它们在调节肽构象和生物活性方面具有重要作用，并且是具有药用重要性的化合物的前体。与具有多种方法的这种α-碳的对映选择性烷基化反应不同，一般的α-碳的对映选择性引入芳基取代基在合成上具有挑战性。尽管如此，所得的α-芳基氨基酸及其衍生物是生物活性分子的有价值的前体。在这里，我们描述了通过α-芳基化反应从手性纯氨基酸前体制备季铵α-芳基氨基酸，而不会立体化学完整性。我们的方法依赖于前体氨基酸的咪唑烷酮衍生物的 N'-芳基脲加合物中第二个手性中心的临时形成，并使用易得的手性纯氨基酸作为前体和不对称性的来源。它避免了使用有价值的过渡金属，并能够用富电子、缺电子和杂环取代基进行芳基化。产物的任一对映异构体都可以由单个氨基酸前体制备。该方法具有实用性和可扩展性，为生产多克数量级的α-芳基化季铵氨基酸提供了机会。
