Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Zografou, 15784 Athens, Greece.
Département Médicaments et Technologies pour la Santé (DMTS), CEA, INRAE, SIMoS, Université Paris-Saclay, 91191 Gif-sur-Yvette, France.
Molecules. 2022 Feb 12;27(4):1242. doi: 10.3390/molecules27041242.
In this report, a synthetic protocol for the preparation of phosphinic dipeptides of type is presented. These compounds serve as valuable building blocks for the development of highly potent phosphinopeptidic inhibitors of medicinally relevant Zn-metalloproteases and aspartyl proteases. The proposed method is based on the tandem esterification of α-aminophosphinic and acrylic acids under silylating conditions in order to subsequently participate in a -Michael reaction. The scope of the transformation was investigated by using a diverse set of readily available acrylic acids and ()-α-aminophosphinic acids, and high yields were achieved in all cases. In most examples reported herein, the isolation of biologically relevant (,)-diastereoisomers became possible by simple crystallization from the crude products, thus enhancing the operational simplicity of the proposed method. Finally, functional groups corresponding to acidic or basic natural amino acids are also compatible with the reaction conditions. Based on the above, we expect that the practicality of the proposed protocol will facilitate the discovery of pharmacologically useful bioactive phosphinic peptides.
本报告提出了一种用于制备膦酰二肽的合成方案，类型为。这些化合物可用作开发高效的、与医学相关的锌金属蛋白酶和天冬氨酸蛋白酶的膦肽抑制剂的重要构建块。所提出的方法基于α-氨基膦酸和丙烯酸在硅烷基化条件下的串联酯化，以便随后参与迈克尔加成反应。通过使用多种易得的丙烯酸和（）-α-氨基膦酸来研究转化的范围，在所有情况下都获得了高收率。在本文报道的大多数示例中，通过从粗产物中简单结晶，可以获得生物相关的（，）-非对映异构体，从而提高了所提出方法的操作简单性。最后，与酸性或碱性天然氨基酸相对应的官能团也与反应条件兼容。基于上述内容，我们预计所提出方案的实用性将有助于发现具有药理活性的生物活性膦酰肽。
