A one-pot multistep approach to α-azido-phosphonate and phosphonothioate diesters: key intermediates in the synthesis of haptens for the generation of antibody ligases

A four-step, one-pot synthesis of mixed α-azido-phosphonates and phosphonothioates 12a–d is described. This chemistry has provided a facile route to haptens 6a–b and 7 that have been employed for the elicitation of antibody ligases. Five hapten-specific antibodies have been identified as modest catalysts of a model peptide ligation reaction between thioester 1b and thiol 2 to give the amide product 5. Scheme 2. Synthesis of α-azido-phosphonates and phosphonothioates. Reagents and conditions: (i) hydrazoic acid, DEAD, PPh3, (ii) TMSBr, (iii) (COCl)2, DMF (cat), CH2Cl2 (iv) iPr2NEt, 1H-tetrazole (cat), CH2Cl2, RXH, (v) R′OH. Steps (ii)–(v) are carried out in ‘one-pot’. Scheme 1. Substrates 1a–b and 2 and haptens 6a–b and 7 were employed in a catalytic antibody approach to chemical ligation via transesterification.