Investigations on New Strategies for the Facile Synthesis of Polyfunctionalized Phosphinates: Phosphinopeptide Analogues of Glutathionylspermidine
journal contributionposted on 22.01.1998 by Shoujun Chen, James K. Coward
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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 α-aminophosphinates. However, polyamine-containing α-(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.