Attempted Enantioselective Preparation of ∝-Aminophosphonic Acids and a Mechanistic Investigation of the Coupling Agent Mediated Phosphonamidation Reaction

Abstract

The aim of the study was to advance the chemistry related to aminophosphonic acids. After reviewing the available literature, our attention was drawn towards the preparation of chiral ∝-aminophosphonic acids and derivatives thereof. The first objective was to investigate their preparation, with a special emphasis on enantioselective methods. This investigation prompted us to explore whether chiral phase-transfer catalysis could be used in the key step to prepare chiral ∝-aminophosphonic acids in an enantioselective manner (see Chapter 2). The second objective was to promote a phosphonamidation reaction between monoesters of phosphonic acids and amines via a coupling agent-mediated reaction. Upon the eventual establishment of such a method an extended goal would be to attempt a phosphonamidation reaction on adequately protected aminophosphonic acids attempting to form small peptides (see Chapter 3). The peptides themselves could be interesting targets to study by means of NMR spectroscopy and X-ray crystallography, to investigate how the geometry of the phosphonoamidate groups affects the folding of the peptide. Once a methodology for the synthesis of phosphonamidates had been developed it became an important objective to control the stereochemistry at the phosphorous atom. Different strategies to achieve stereoselective phosphonamidation reaction were investigated. This feature necessitated the development of a new subclass of coupling agents that were themselves chiral (see Chapter 4).