Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia.
University of Latvia, Department of Chemistry, Jelgavas 1, LV-1004 Riga, Latvia.
Org Lett. 2023 Nov 10;25(44):7958-7962. doi: 10.1021/acs.orglett.3c02687. Epub 2023 Sep 27.
Broad application of α,α-disubstituted cyclic amino acid derivatives in medicinal chemistry urges for analogue design with improved pharmacokinetic properties. Herein, we disclose an electrochemical approach toward unnatural THF- and THP-containing amino acid derivatives that relies on anodic decarboxylation-intramolecular etherification of inexpensive and readily available -acetylamino malonic acid monoesters under Hofer-Moest reaction conditions. The decarboxylative cyclization proceeds under constant current conditions in an undivided cell in an aqueous medium without any added base. A successful bioisosteric replacement of the 1-aminocyclohexane-1-carboxylic acid subunit by the THP-containing amino acid scaffold in cathepsin K inhibitor balicatib helped to reduce lipophilicity while retaining low nanomolar enzyme inhibitory potency and comparable microsomal stability.
广泛应用的α,α-二取代环状氨基酸衍生物在药物化学中促使我们设计具有更好的药代动力学性质的类似物。在此，我们公开了一种电化学方法，用于合成非天然的含有四氢呋喃（THF）和四氢吡喃（THP）的氨基酸衍生物，该方法依赖于在 Hofer-Moest 反应条件下，廉价易得的乙酰氨基丙二酸单酯的阳极脱羧-分子内环醚化反应。在没有添加任何碱的情况下，该脱羧环化反应在一个未分隔的、水溶液中的恒流条件下进行。通过将包含 THP 的氨基酸支架成功地替代组织蛋白酶 K 抑制剂巴利昔替尼中的 1-氨基环己烷-1-羧酸亚基，有助于降低亲脂性，同时保持低纳摩尔级别的酶抑制活性和相当的微粒体稳定性。
