Synthesis of t -Boc-aminoacyl-4-OCH~-Pam-resin
J. Org. Chem., Vol. 43, No. 14, I978
2845
A New Synthetic Route to tert-Butyloxycarbonylaminoacyl-4-(oxymethyl)phenylacetamidomethylresin, an Improved Support for Solid-Phase Peptide Synthesis' Alexander R. Mitchell, Stephen B. H. Kent, Martin Engelhard, and R. B. Merrifield* T h e Rockefeller University, New York, N e u York 10021 Received January 30, 1978
The preferred route to the aminoacylated 4-(oxymethyl)phenylacetamidomethyl-resin(-0CH2-Pam-resin)involves the condensation of a Boc-aminoacyl-4-(oxymethyl)phenylacetic acid (Boc = tert -butyloxycarbonyl)with aminomethyl-resin.Aminomethyl-resinwas synthesized by direct amidoalkylation of polystyrene resin t o give the phthalimidomethyl-resin. The extent of reaction was monitored by IR, allowing the reaction to be stopped at any chosen level of substitution. Hydrazinolysis gave aminomethyl-resin.The Boc-aminoacid was converted in solution to a substituted benzyl ester by reaction with 4-(bromomethyl)phenylaceticacid phenacyl ester. Zinc-acetic acid reduction removed the phenacyl group t o give the Boc-aminoacyl-4-(oxymethyl)phenylaceticacid, which was coupled to aminomethyl-resin with DCC. The benzyl ester bond of the resulting aminoacyl-OCH2-Pam-resinswas approximately 100-fold more stable in refluxing trifluoroacetic acid than the aminoacyl-0CH2-resin.Comparison with a solution analogue showed that this was due to the inductive effect of the p-acetamidomethylgroup. Cleavage yields (HF-anisole, 9:l v/v, 30 min, 0 "C) were 82-100% for the aminoacyl-and peptidyl-OCH2-Pam-resins examined. The aminoacyl-OCH2-Pam-resinsshowed resistance to primary amine nucleophiles similar to that of the aminoacyl-OCH2-resin. No racemization (
