A Reactivity Test for HBTU-Activated Carboxylic Acids with Low Reactivity and Competitive Coupling of N-Methylpyrrole Derivatives

N-Methylpyrrole carboxylic acids are building blocks for oligopyrroleamides that bind DNA duplexes via the minor groove. The reactivity of HBTUbased active esters of four methylpyrroles in amide-forming reactions was determined. When assayed against HBTU-activated N-acetylleucine, a 6250-fold lower reactivity was found. When assayed against the NHS ester of Boc-valine, the reactivity was up to 4-fold lower. Despite large differences in reactivity, mixed couplings were successfully performed with all four pyrroles, generating small libraries of modified oligonucleotides suitable for spectrometrically monitored selection experiments. Microwave irradiation accelerated coupling of an Fmoc-protected pyrrole to an amine on solid support.