Practical synthesis of 4-hydroxy-3-oxobutylphosphonic acid and its evaluation as a bio-isosteric substrate of DHAP aldolase

An efficient four step synthesis of the title compound 4-hydroxy-3-oxobutylphosphonate (2) has been developed based on inexpensive 4-ethoxy-1-hydroxybutane-2-one using an Arbusow reaction (59% overall yield). Several dihydroxyacetone-dependent aldolases having different stereospecificities were tested for their acceptance of this phosphonomethyl substrate mimic as the aldol donor. Individual enzymes belonging to both type I (Schiff base formation) and type II (Zn(2+) catalysis) mechanistic classes were found to catalyze the stereoselective addition of 2 to simple aldehydes to provide bio-isosteric analogs of sugar l-phosphates in high yields. The lack of acceptance by specific enzymes is discussed with regard to recent protein X-ray data. (C) 1998 Elsevier Science Ltd.