OPTICALLY ACTIVE 1-AMINOALKYLPHOSPHONIC ACIDS

Abstract

Abstract 1-Aminoalkylphosphonic acids 1 as analogs of 1-amino-carboxylic acids are important because of their potential biological activity. These act as substrates or inhibitors of enzymes involved in the metabolism of amino acids. Several phosphono dipeptides and oligopeptides are known to repress bacterial growth. Many of these studies have been carried out using racemic l-amino- alkylphosphonic acids 1 although in several cases their activity has been shown to depend upon their absolute c~nfiguration. One such example is the high antibacterial activity of alafosfalin 2, N-(L-alany1)-L-1-aminoethylphosphonic acid, as compared to that of the other diastereoisomers. Alafosfalin 2 has been shown to act by facilitated transport into the bacterial cell wall where it is cleaved enzymatically to L-1-aminoethylphosphonic acid la which inhibits alanine racemase and related processes by simulating L-alanine. The analgesic activity of enkephalin analogs containing aminophosphonic acid residues at C-terminal position has been shown to depend on the configuration of the aminophosphonic acid residue. Of the two diastereoisomeric pentapeptides Tyr-Gly-Gly-Phe-MetP differing only in the configuration at the C-terminal phosphonic analog of methionine, only the one with (-)MetP exhibited significant analgesic activity. Unfortunately, the configuration of the phosphonic analog of methionine was not known. (-)-l-Amino-2-phenylethylphosphonic acid Id, of then unknown con- figuration (now known to be R), was found to interact with rabbit muscle pyruvate kinase. A derivative 4 of racemic 2-phosphonopyrrolidine (phosphonic analog of proline) 3 was found to be an inhibitor of angiotensin-converting enzyme. The active component of 4 was expected to be the R-enantiomer but the study was performed with the racemic 4 presumably for the lack of availability of optically active 2-phosphonopyrrolidine. Thus, there existed an obvious need to have optically active enantiomers of 1-aminoalkylphosphonic acids 1with known absolute configuration, and this need spurred an interest in the last decade in their synthesis. This review surveys the methods developed to prepare optically active 1-aminoalkylphosphonic acids 1 with known absolute configuration. Several excellent reviews on the synthesis and chemistry of l-aminoalkylphos- phonic acids covering the literature to 1975 are available. The chemistry of aminophosphonous and aminophosphinic acids31 has also been reviewed.