Synthesis of a potential “suicide substrate” of the HIV-1 protease, incorporating A 3-acetoxy-Δ-4,5-(L)-pipecolic acid as proline substitute.

Abstract

Coupling of (D,L)-baikiain methyl ester with Boc-(L)-phenylalanine, followed by saponification, idolactonization and aminolysis of the diastereoisomeric iodolactones by (L)-isoleucyl-(L)-valine methyl ester gave two diastereoisomeric peptides incorporating either a 3 S-hydroxy-4 S-iodo-(L)-pipecolic acid or a 3 R-hydroxy-4 R-iodo-(D)-pipecolic acid residue, which were separated by thin layer chromatography. Assignment of configuration was unambiguous when the synthesis was repeated with (L)-baikiain as starting material. All compounds exhibited conformational isomerism in their 1H NMR spectra, attributed to the existence of both s-cis and s-trans configurations of the Phe-NR 2 peptide bond. Acetylation of each of the two separated diastereoisomers gave Boc-(L)-Phe-3 S-OAc-4 S-I-(L)-Pip-(L)-Ile-(L)-Val-OMe and Boc-(L)-Phe-3 R-OAc-4 R-I-(D)-Pip-(L)-Ile-(L)-Val-OMe. N-deprotection and coupling of the former with Boc-(L)-Ser-(L)-Ala-(L)-Ala-OH by the DCC/HOBt method or stepwise elongation of the peptidic chain, gave Boc-(L)-Ser-(L)-Ala-(L)-Ala-(L)-Phe-3 S-OAc-4 S-I-(L)-Pip-(L)-Ile-(L)-Val-OMe. Dehydroiodination of this compound on treatment with DBU gave Boc-(L)-Ser-(L)-Ala-(L)-Ala-(L)-Phe-3 S-OAc-Δ-4,5-(L)-Pip-(L)-Ile-(L)-Val-OMe, a potential “suicide substrate” of the HIV-1 protease.