CYCLOPROPANES AS CONFORMATIONALLY RESTRICTED PEPTIDE ISOSTERES - DESIGN AND SYNTHESIS OF NOVEL COLLAGENASE INHIBITORS

The 1,2,3-trisubstituted cyclopropane derivatives 9 and 10 were prepared as conformationally constrained analogues of the known collagenase inhibitor 8. The syntheses of 9 and 10 featured the highly enantioselective Rh2[S-MEPY]4 catalyzed cyclization of the, allylic diazo ester 11 to give the lactone 13. Opening of the lactone ring of 13 with N,O-di-(p-methoxybenzyl)hydroxylamine under Weinreb conditions followed by refunctionalization, coupling of the intermediate acid 16 with 17 and deprotection led to the dipeptide analogue 9. Alternatively, the lactone ring of 13 could be opened with the protected tyrosine 21 by a novel variant of the Weinreb protocol to give directly the dipeptide analogue 22 which was then converted into 10.