A Novel Protecting Group for Constructing Combinatorial Peptide Libraries

Abstract 3,4,5-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–AAn–...–AA1–OBzl(OC18)3, were synthesized. The substituted benzyl esters were selectively cleaved by a treatment with 4 M hydrogen chloride in ethyl acetate to give Fmoc–AAn–...–AA1–OH and 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 weight, Fmoc–AAn–...–AA1–OBzl(OC18)3 can be easily purified by size-exclusion 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-filtration gives a novel route for constructing combinatorial peptide libraries in the solution phase.