STRUCTURAL MODIFICATIONS OF THE ACTIVE-SITE IN TEICOPLANIN AND RELATED GLYCOPEPTIDES .1. REDUCTIVE HYDROLYSIS OF THE 1,2-PEPTIDE AND 2,3-PEPTIDE BONDS

Reaction of teicoplanin glycopeptides with sodium borohydride in aqueo us ethanol solutions produced open pentapeptide derivatives in which t he amide bond between amino acids 2 and 3 was hydrolyzed and the carbo xyl group of amino acid 2 was reduced to a primary alcohol. Other glyc opeptides of the dalbaheptide family, such as vancomycin, ristocetin, and A-40,926, underwent selective reductive hydrolysis (RH) of the hep tapeptide backbone at the same position as in teicoplanins, while anti biotic A-42,867 and vancomycin hexapeptide were resistant. Also, teico planin and vancomycin were resistant to RH-treatment when the N-termin us was protected as carbamate. In contrast, open hexapeptides in which the 1,2-peptide bond was hydrolyzed and the carboxyl group of amino a cid 1 was reduced to hydroxymethyl were obtained from carbamate deriva tives of sugar-free compounds deglucoteicoplanin (TD) and vancomycin-a glycon (VA) under RH-conditions. Limited to BOC or CBZ-TD, the 3,4-ami de bond was also affected. A possible RH-mechanism is proposed for nat ural glycopeptides and their derivatives. Teicoplanin-derived RH penta - and hexapeptides maintained residual antibacterial activity. As othe r analogous RH-glycopeptides, they are key intermediates for the synth esis of new members of this family of antibiotics. A synthetic approac h to ring-closed derivatives of TD hexapeptide alcohol (TDHPA) and the ir activities are also reported.