Solid-Phase Synthesis of Tyrosine Peptide Aldehydes. Analogues of (S)-MAPI.

Abstract

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. Our strategy consisted of anchoring the side chain of Dde-Tyrosinol (5) onto the brominated Wang linker derivative ((4-bromomethyl)-phenoxy-allyl acetate) (6) to give after ester hydrolysis the N(alpha)-(Dde)-O-(4-methylphenoxyacetic acid)-L-Tyrosinol template (8). This was attached to aminomethyl resin and elongated using standard Fmoc protocols. Importantly there was no evidence of esterification side reactions. The unsymmetrically substituted urea linkage of the (S)-MAPI family was incorporated using the N(alpha)-(4-nitrophenyloxycarbonyl)amino acid tert-butyl esters following which the protected 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 incorporation of a small PEG-spacer between the linker and the solid support. The tetrapeptides 12a and 12b were cleaved by acidolysis, purified by RP HPLC, and isolated in high yield and purity, demonstrating the success of the whole synthetic process.