Solid-phase synthesis sf tyrosine peptide aldehydes. Analogues of (S)-MAPI

We report an efficient solid-phase synthesis of C-terminal tyrosine peptide aldehydes based on the HIV protease inhibitors (S)-MAPI and GE 20372 A. Ou r strategy consisted of anchoring the side chain of Dde-Tyrosinol (5) onto the brominated Wang linker derivative ((4-bromomethyl)-phenoxyallyl acetate ) (6) to give after ester hydrolysis the N-alpha-(Dde)-O-(4-methylphenoxyac etic acid)-L-Tyrosinol template (8). This was attached to aminomethyl resin and elongated using standard Fmoc protocols. Importantly there was no evid ence of esterification side reactions. The unsymmetrically substituted urea linkage of the (S)-MAPI family was incorporated using the N-alpha-(4-nitro phenyloxycarbonyl)amino acid tert-butyl esters following which the protecte d tetrapeptide alcohol immobilized on the solid support was oxidized to its corresponding aldehyde using sulfur trioxide-pyridine. The efficiency and reliability of the oxidation step was dramatically improved by the incorpor ation of a small PEG-spacer between the linker and the solid support. The t etrapeptides 12a and 12b were cleaved by acidolysis, purified by RP HPLC, a nd isolated in high yield and purity, demonstrating the success of the whol e synthetic process.