Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
J Org Chem. 2017 Oct 6;82(19):10650-10658. doi: 10.1021/acs.joc.7b01684. Epub 2017 Sep 26.
An efficient synthesis protocol is presented for accessing quaternized α-amino acids in chiral, nonracemic form via diastereoselective malonate alkylation followed by C- to N-transposition. The key stereodifferentiating step involves a diastereoselective alkylation of an α-monosubstituted malonate-imidazolidinone, which is followed first by a chemoselective malonate PMB ester removal and then a Curtius rearrangement to provide the transposition. The method demonstrates a high product ee (89-99% for eight cases) for quaternizing a range of proteinogenic α-amino acids. The stereogenicity in targets 5a-i supports previous conclusions that the diastereoselective alkylation step proceeds via an α-substituted malonate-imidazolidinone enolate in its Z-configuration, with the auxiliary in an s-trans conformation.
提出了一种高效的合成方案，通过立体选择性丙二酸单酯烷基化反应，随后进行 C 到 N 的转换，以手性非外消旋形式获得季化的α-氨基酸。关键的立体区分步骤涉及α-单取代丙二酸-咪唑烷酮的立体选择性烷基化，首先进行选择性的丙二酸 PMB 酯去除，然后进行 Curtius 重排以提供转换。该方法对一系列蛋白质氨基酸进行季化时，产物的对映体过量值很高（8 个案例中为 89-99%）。目标物 5a-i 的立体异构性支持了先前的结论，即立体选择性烷基化步骤通过 Z-构型的α-取代丙二酸-咪唑烷酮烯醇化物进行，辅助剂呈 s-反式构象。
