Solid-Phase Guanidinylation of Peptidyl Amines Compatible with Standard Fmoc-Chemistry: Formation of Monosubstituted Guanidines

With the growing importance of peptides and peptidomimetics as potential therapeutic agents, a continuous synthetic interesthas been shown for their modification to provide more stable and bioactive analogs. Among many approaches, peptide/peptidomimeticguanidinylation offers access to analogs possessing functionality with strong basic properties, capable of forming stableintermolecular H-bonds, charge pairing, and cation-π interactions. Therefore, guanidinium functional group is considered asan important pharmacophoric element. Although a number of methods for solid-phase guanidinylation reactions exist, only afew 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 combinationwith promoters such as Mukaiyama’s reagent,
N
-iodosuccinimide, and
N
,
N′
-diisopropylcarbodiimide.