Stereoselective Synthesis of α-Amino-H-phosphinic Acids and Derivatives

Abstract

α-Amino-H-phosphinic acids and derivatives are an important group of compounds of synthetic and pharmacological interest, and particular attention has been dedicated toward their stereoselective synthesis in recent years. While some of these compounds show activity by themselves, they are also valuable starting materials in the synthesis of phosphinic bioisosteres of natural peptides, where the hydrolyzable bond is substituted by a phosphinic functionality that mimics the transition state of peptide hydrolysis, thus acting as efficient enzyme inhibitors in which the molecular stereochemistry is demonstrated to be critical. This review summarizes the latest developments on the asymmetric synthesis of acyclic and phosphacyclic α-amino-Hphosphinic acids and derivatives following an order according to the strategy used; in addition, some implications in medicinal chemistry are disclosed. 1 Introduction 2 Stereoselective Synthesis of Acyclic α-Amino-H-phosphinic Acids and Derivatives 2.1 Stereoselective C-P Bond Formation (Addition of Phosphorus Compounds to Imines) 2.1.1 Chiral Imine Compounds 2.2 Stereoselective C-P Bond Formation (One-Pot, Three-Component Reaction) 2.2.1 Chiral Amino Compounds 2.3 Stereoselective CC Bond Formation 2.3.1 Diastereoselective Alkylations 2.4 Resolution Methodologies 2.5 Conversion from Chiral α-Aminophosphonates 3 Synthesis of Phosphacyclic α-Amino-H-phosphinates 3.1 1,4,2-Oxazaphosphacycles 4 Concluding Remarks

Second Coordination Sphere Effects in an Evolved Ru Complex Based on Highly Adaptable Ligand Results in Rapid Water Oxidation Catalysis

“…The first and second pKa's due to the monodeprotonation of each phosphonic group are expected to occur below pH 1.0. [43][44][45] Further, the pKa for the third and fourth proton loss are labeled, pKa and pKa', and are defined in equations 1 and 2 respectively,…”

Selective and clean synthesis of aminoalkyl-H-phosphinic acids from hypophosphorous acid by phospha-Mannich reaction

“…15 Aminoalkylphosphonic and aminoalkylphosphinic acids are biologically active compounds and there are a number of their applications in biology and medicine as peptidomimetics, enzyme inhibitors, antiviral or antibacterial agents, herbicides, etc. 2,[4][5][6][7][8][9][10] Aminoalkylphosphorus acids are usually prepared by reaction of a precursor with a P(O)-H bond, an aldehyde and a primary/secondary amine. 3,5,16,17 The most common P-H reagents for synthesis of the aminoalkyl-H-phosphinic acids are hypophosphorous acid, its esters or trivalent phosphines derived from the acid.…”

“…2,[4][5][6][7][8][9][10] Aminoalkylphosphorus acids are usually prepared by reaction of a precursor with a P(O)-H bond, an aldehyde and a primary/secondary amine. 3,5,16,17 The most common P-H reagents for synthesis of the aminoalkyl-H-phosphinic acids are hypophosphorous acid, its esters or trivalent phosphines derived from the acid. The esters of hypophosphorous acids are generally not very stable, they are oen prepared in situ and can be used only under very mild conditions.…”

“…The cheapest and the most easily accessible reagent, H 3 PO 2 , has been frequently used as a nucleophile in addition to imines derived from primary amines. 5,16 This approach has been used to obtain many Hphosphinic acid analogues of common amino acids but in variable, and mostly only moderate yields. 12,[25][26][27][28][29][30] The most simple one-pot reaction of an amine, an aldehyde and H 3 PO 2 has been used in the syntheses less frequently.…”