Solid-phase guanidinylation of peptidyl amines compatible with standard Fmoc-chemistry: Formation of monosubstituted guanidines

Abstract

With the growing importance of peptides and peptidomimetics as potential therapeutic agents, a continuous synthetic interest has been shown for their modification to provide more stable and bioactive analogs. Among many approaches, peptide/peptidomimetic guanidinylation offers access to analogs possessing functionality with strong basic properties, capable of forming stable intermolecular H-bonds, charge pairing, and cation-π interactions. Therefore, guanidinium functional group is considered as an important pharmacophoric element. Although a number of methods for solid-phase guanidinylation reactions exist, only a few are fully compatible with standard Fmoc solid-phase peptide chemistry. In this chapter we summarize the solid-phase guanidinylation methods fully compatible with standard Fmoc-synthetic methodology. This includes use of direct guanidinylating reagents such as 1-H-pyrazole-1-carboxamidine and triflylguanidine, and guanidinylation with di-protected thiourea derivatives in combination with promoters such as Mukaiyama's reagent, N-iodosuccinimide, and N,N′-diisopropylcarbodiimide. © 2013 Springer Science+Business Media New York.