A novel protecting group for constructing combinatorial peptide libraries

3,3,5-Tris(octadecyloxy)benzyl alcohol, HO-Bzl(OC18)(3), was prepared from gallic acid and stearyl bromide. Using conventional step-wise elongation, N ,C-protected peptides. Fmoc-AA(n)-...-AA(l)-OBzl(OC18)(3), were synthesized . The substituted benzyl esters were selectively cleaved by a treatment wit h 4 M hydrogen chloride in ethyl acetate to give Fmoc-AA(n)-...-AA(l)-OH an d HO-Bzl(OC18)(3). Thus, the substituted benzyl group is effective for the protection of C-terminal carboxyl groups in liquid-phase peptide synthesis. Because the substituted benzyl group has a moderately high molecular weigh t, Fmoc-AA(n)-...-AA(l)-OBzl(OC18)(3) can be easily purified by size-exclus ion chromatography; all protected peptides are eluted in the void fraction of a Sephadex LH-20 gel-filtration column. The combination of the carboxyl- protecting group Bzl(OC18)(3) with simple purification by the gel-filtratio n gives a novel route for constructing combinatorial peptide libraries in t he solution phase.