Pergamon Tetrahedron Letters, Vol. 38, No. 51, pp. 8803-8806, 1997 O 1997 Elsevier Science Ltd All fights reserved.Printedin Great Britain PII: S0040-4039(97) 10421-X 0040-4039/97 $17.00 + 0.00 A Convenient Two-Step One-Pot Synthesis of Phosphonamidates Karyn L. Mlodnosky, H. Michael Holmes, Vinh Q. Lain, and Clifford E. Berkman* Department of Chemistry & Biochemistry, San Francisco State University, 1600 Holloway Ave., San Francisco, CA 94132, USA Abstract: Phosphonamidates are formed in high yield from a one-pot sequential reaction of a phosphonyi dichloride with an alcohol and then an amine in the presence of catalytic lH-tetrazole. Undesired disubstitution of the phoshphonyl dichloride by the alcohol or the amine is minimal due to the presence oftetrazole. © 1997 Elsevier Science Ltd. Phosphonamidates are continuing to be increasingly important as mechanistic probes for proteases, ~ potent inhibitors of peptidases as tetrahedral transition-state or high energy intermediate analogs, 2 or as phosphorylating agents of [~-lactamases. a More recently there is increasing interest to pursue peptide-nucleotide adducts possessing a phosphonamidate moiety. 4 The preparations for simple phosphonamidates utilizing a readily available phosphonyl dichloride, require at least two synthetic steps as the phosphorus reagent is treated sequentially with an alcohol and amine. It is common to intercept the reactive monochloridate intermediate from the reaction of the phosphonyl dichloride with an alcohol without significant purification (i.e., f'fltration of salts) and react it immediately with an amine in a second step to generate the desired phosphonamidate) Generally, this approach will provide the desired phosphonamidate, however, often there may be considerable formation of a symmetrically substituted phosphonate diester resulting from overreaction with the alcohol in the first step. Recently Zhao and Landry identified a strategy to minimize the formation of such symmetrically substituted phosphonate diesters during a two-step one-pot catlytic formation of asymmetric phosphonate diesters using 1H-tetrazole rather than other acylating-type catalysts. 6 Based on this success, we have focused on the utility of catalytic 1H-tetrazole in the formation of simple phosphonamidates in a two-step one-pot procedure in order to minimize the formation of symmetrically substituted phosphonate diester side products in the first step. The molecules of interest in this study were phosphonamidates of glutamic acid as potential inhibitors of a glutamyl hydrolase. Therefore, the synthesis of a limited series of phosphonamidate esters with varying alkyl ligands to phosphorus was undertaken. It was also desired to vary the alcohol ligand to phosphorus allowing alternate deprotection strategies to ultimately generate phosphonamidoic acids. Initial attempts at the preparation of phosphonamidate la in ether utilizing a straightforward method 5 (i.e.; phenylphosphonyl dichloride is reacted with benzyl alcohol (BzlOH) in the presence of base, salts filtered, and the intermediate monochloridate is reacted with glutamic acid dibenzyl ester [Glu(OBzl)2]) provided poor yields in addition to extensive formation of dibenzyl phenylphosphonate 2a as observed by ~P NMR in the crude 8803