Investigations on New Strategies for the Facile Synthesis of Polyfunctionalized Phosphinates:  Phosphinopeptide Analogues of Glutathionylspermidine

Abstract

Three possible methods for the facile synthesis of functionalized phosphinates, including the core of complex phosphinopeptide analogues of glutathionylspermidine, were explored. Among these methods, the three-component condensation reaction involving benzyl carbamate, an aldehyde, and a functionalized or nonfunctionalized phosphonite can afford a variety of protected alpha-aminophosphinates. However, polyamine-containing alpha-(aminomethylene)phosphinates can be obtained only by the acid-catalyzed Pudovik-Abramov-type reaction of a polyamine-containing phosphonite with a tritylamine-derived Schiff base. Thus, despite its hydrolytic lability, a Tfa-protected polyamine-containing phosphonite reacts smoothly with tritylmethanimine and affords the corresponding phosphinate, a key intermediate for the synthesis of complex phosphinopeptide inhibitors of glutathionylspermidine synthetase. Elaboration of this intermediate via selective deprotection and coupling to a protected dipeptide provided an alanine-containing phosphinate analogue of glutathionylspermidine. The limitations and scope of the three explored methods are discussed.