Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06520, USA.
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06520, USA. Department of Pharmacology, Yale University, 333 Cedar Street, New Haven, CT 06520, USA.
Science. 2015 Oct 16;350(6258):294-8. doi: 10.1126/science.aac9655.
Glucosepane is a structurally complex protein posttranslational modification that is believed to exist in all living organisms. Research in humans suggests that glucosepane plays a critical role in the pathophysiology of both diabetes and human aging, yet comprehensive biological investigations of this metabolite have been hindered by a scarcity of chemically homogeneous material available for study. Here we report the total synthesis of glucosepane, enabled by the development of a one-pot method for preparation of the nonaromatic 4H-imidazole tautomer in the core. Our synthesis is concise (eight steps starting from commercial materials), convergent, high-yielding (12% overall), and enantioselective. We expect that these results will prove useful in the art and practice of heterocyclic chemistry and beneficial for the study of glucosepane and its role in human health and disease.
葡萄糖胺是一种结构复杂的蛋白质翻译后修饰物，据信存在于所有生物体中。人类研究表明，葡萄糖胺在糖尿病和人类衰老的病理生理学中起着关键作用，但由于缺乏用于研究的化学均一物质，对这种代谢物的全面生物学研究受到了阻碍。在这里，我们报告了葡萄糖胺的全合成，这得益于开发了一种一锅法制备核心中环的非芳香 4H-咪唑互变异构体的方法。我们的合成方法简洁（从商业原料开始，经过八步反应）、收敛、高产（总收率为 12%）且具有对映选择性。我们预计这些结果将有助于杂环化学的实践和应用，并有益于研究葡萄糖胺及其在人类健康和疾病中的作用。
