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.