CONFORMATIONAL MIMICRY .3. SYNTHESIS AND INCORPORATION OF 1,5-DISUBSTITUTED TETRAZOLE DIPEPTIDE ANALOGS INTO PEPTIDES WITH PRESERVATION OF CHIRAL INTEGRITY - BRADYKININ

New synthetic procedures for preparing 1,5-disubstituted tetrazole dipeptide analogues, which are a conformational mimic of the cis amide bond, and incorporating these analogues into longer peptides, such as bradykinin, while maintaining chiral integrity are presented. The simple addition of the organic base, quinoline, to the reaction with PCl5 when generating an imidoyl chloride from the amide was effective in reducing racemization of the N-terminal amino acid residue of the protected tetrazole dipeptide to minimal levels. The resulting tetrazole dipeptide is quite sensitive to base, and the normal procedures of solid-phase synthesis for neutralization were sufficient to cause racemization of the alpha carbon on the C-terminal side of the tetrazole ring. The use of Z for amino protection and benzyl ester for carboxyl protection with differential removal of the Z group by HBr/HOAc has proven a practical route to a wide variety of tetrazole dipeptides. Immediate acylation of the tetrazole dipeptide with a Boc amino acid was necessary to prevent formation of the diketopiperazine, which is favored because of the cis conformation of the amide bond surrogate. Three bradykinin analogues, [L-Pro2-psi[CN4]-L-Ala3]-BK, [L-Ala6-psi[CN4]-L-Ala7]-BK, and [L-Ala6-psi[CN4]-D-Ala7]-BK, in which the peptide bond of a proline residue was replaced with the tetrazole surrogate, were prepared to illustrate the synthetic procedures. The availability of these procedures should increase the use of the tetrazole dipeptide analogue in molecular recognition studies.