title: Practical synthesis of 4-hydroxy-3-oxobutylphosphonic acid and its evaluation as a bio-isosteric substrate of DHAP aldolase.
abstract: 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 (Zn2+ catalysis) mechanistic classes were found to catalyze the stereoselective addition of 2 to simple aldehydes to provide bio-isosteric analogs of sugar 1-phosphates in high yields. The lack of acceptance by specific enzymes is discussed with regard to recent protein X-ray data.
authors.affiliation: Institut für Organische Chemie der RWTH Aachen, Germany.
authors.forename: H L
authors.initials: HL
authors.lastname: Arth
authors.forename: W D
authors.initials: WD
authors.lastname: Fessner
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D004099:Dihydroxyacetone Phosphate / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005634:Fructose-Bisphosphate Aldolase / Q000378:metabolism*; D005986:Glyceraldehyde 3-Phosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D063065:Organophosphonates / Q000138:chemical synthesis; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000378:metabolism; D013237:Stereoisomerism; D013379:Substrate Specificity; D013403:Sugar Phosphates / Q000138:chemical synthesis
chemical_list: D000447:Aldehydes; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D013403:Sugar Phosphates; D005986:Glyceraldehyde 3-Phosphate; C008066:4-hydroxy-3-oxobutyl-1-phosphonic acid; D004099:Dihydroxyacetone Phosphate; D005634:Fructose-Bisphosphate Aldolase