Diastereoselective Synthesis of Phosphinic Dipeptide Isosteres: Domino Chirality Transfer during a Stereocontrolled P-Michael Reaction.

A highly diastereoselective P-Michael addition of chiral aminophosphinic acids to achiral acrylates has been developed, leading to phosphinic dipeptide isosteres in high yields and dr of up to >50:1. The method allows for the diastereoselective preparation of target compounds without the need for chiral auxiliaries or P-chiral substrates. A possible mechanistic explanation involves a domino chirality transfer from the aminophosphinic acid to the P center, amplified by a crucial benzhydryl ester group, and then to the α-carbon.

Phosphinic Peptides as Tool Compounds for the Study of Pharmacologically Relevant Zn-Metalloproteases.

Phosphinic peptides constitute an important class of bioactive compounds that have found a wide range of applications in the field of biology and pharmacology of Zn-metalloproteases, the largest family of proteases in humans. They are designed to mimic the structure of natural substrates during their proteolysis, thus acting as mechanism-based, transition state analogue inhibitors. A combination of electrostatic interactions between the phosphinic acid group and the Zn cation as well as optimal noncovalent enzyme-ligand interactions can result in both high binding affinity for the desired target and selectivity against other proteases. Due to these unique properties, phosphinic peptides have been mainly employed as tool compounds for (a) the purposes of rational drug design by serving as ligands in X-ray crystal structures of target enzymes and allowing the identification of crucial interactions that govern optimal molecular recognition, and (b) the delineation of biological pathways where Zn-metalloproteases are key regulators. For the latter objective, inhibitors of the phosphinopeptidic type have been used either unmodified or after being transformed to probes of various types, thus expanding the arsenal of functional tools available to researchers. The aim of this review is to summarize all recent research achievements in which phosphinic peptides have played a central role as tool compounds in the understanding of the mechanism and biological functions of Zn-metalloproteases in both health and disease.

Practical Synthesis of Phosphinic Dipeptides by Tandem Esterification of Aminophosphinic and Acrylic Acids under Silylating Conditions.

In this report, a synthetic protocol for the preparation of phosphinic dipeptides of type 5 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 P-Michael reaction. The scope of the transformation was investigated by using a diverse set of readily available acrylic acids and (R)-α-aminophosphinic acids, and high yields were achieved in all cases. In most examples reported herein, the isolation of biologically relevant (R,S)-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.