Synthesis of Four Enantiomers of (1-Amino-3-Hydroxypropane-1,3-Diyl)Diphosphonic Acid as Diphosphonate Analogues of 4-Hydroxyglutamic Acid.

All the enantiomers of (1-amino-3-hydroxypropane-1,3-diyl)diphosphonic acid, newly design phosphonate analogues of 4-hydroxyglutamic acids, were obtained. The synthetic strategy involved Abramov reactions of diethyl ( R )- and ( S )-1-( N -Boc-amino)-3-oxopropylphosphonates with diethyl phosphite, separation of diastereoisomeric [1-( N -Boc-amino)-3-hydroxypropane-1,3-diyl]diphosphonates as O -protected esters, followed by their hydrolysis to the enantiomeric phosphonic acids. The absolute configuration of the enantiomeric phosphonates was established by comparing the 31 P NMR chemical shifts of respective ( S )- O -methylmandelic acid esters obtained from respective pairs of syn - and anti -[1-( N -Boc-amino)-3-hydroxypropane-1,3-diyl]diphosphonates according to the Spilling rule.