Synthesis and comparative study on the reactivity of peptidyl-type phosphinic esters: Intramolecular effects in the alkaline and acidic cleavage of methyl beta-carboxyphosphinates

Using the phosphinic analogue of Cbz-Phe-Gly-OEt 1a as a template for this study, several phosphinic esters (2a-g) were prepared, employing an efficie nt method for each case. The reactivity of these derivatives under conventi onal deprotection conditions was studied, and the results are listed compar atively. The effect of steric hindrance as well as the contribution of neig hboring groups in the rate of hydrolysis of suitably selected beta -carboxy phosphinates under acidic and alkaline deprotection conditions was examined . The results clearly demonstrate that a significant acceleration of phosph inate cleavage occurs due to the intermediacy of a five-membered, mixed anh ydride-type species. This was supported by the observation that similar int eractions were not observed in the case of hindered alpha -carboxyphosphina te homologous derivatives.