Synthesis of Oligopeptides Containing an Oxirane Ring in the Place of a Peptidic Bond

Oligopeptides containing an oxirane ring have recently been identified as inhibitors of a variety of proteases ( 1 – 3 ). These peptidomimetics have the potential to coordinate with metal present in the active site and, after nucleophilic ring opening, irreversibly blocking the enzyme. For this reason, oxirane containing peptidomimetics are good candidates to became transition states analogs or suicide inhibitors with long term efficacy in vivo ( 3 ). Synthetic routes to a variety of terminal ( 4 – 8 ) and internal epoxide peptidomimetics ( 9 – 11 ) have been reported but there are no examples of incorporation of such epoxides into oligopeptides. The focus of this chapter will be on the preparation of oligopeptides (up to a three-peptide) containing an epoxide in the place of the peptide bond. The structures prepared here can be identified, using the notation suggested by Spatola ( 12 ) as AAxψ[ traws -epoxy]-AAy. The general synthetic approach described in this chapter is based on the aldol type reaction of a silylketene thioacetal and a β-amino α-selenyl aldehyde derived from an oligopeptide. This reaction stereoselectively generates a vicinal hydroxy selenide which can be further oxidized to epoxide (Fig. 1 ).   Fig. 1.  Retrosynthetic analysis of oxirane peptidomimetrics.