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

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.