As part of a program towards the development of novel antibiotics, a convenient method for solid-phase synthesis of the cyclic cationic peptide polymyxin B1 and analogues thereof is described. The methodology, based on cleavage-by-cyclization using Kenner's safety-catch linker, yields crude products with purities ranging from 37-67%. Antibacterial assays revealed that analogues 23-26, in which the (S)-6-methyloctanoic acid moiety is replaced with shorter acyl chains, exhibit distinct antimicrobial activity. The results suggest that the length of the acyl chain is rather critical for antimicrobial activity. On the other hand, substitution of the hydrophobic ring-segment D-Phe-6/Leu-7 in polymyxin B1 with dipeptide mimics (i.e. analogues 27-33) resulted in almost complete loss of antimicrobial activity.

Differently functionalized tetrahydropyran‐based dipeptide isosters have been efficiently synthesized from 3,4,6‐tri‐O‐acetyl‐D‐glucal. Analogues of the hsp65 p2−13 epitope of Mycobacterium tuberculosis and Mycobacterium leprae were prepared by replacement of the Ala−Tyr or Glu−Glu moiety in the native dodecapeptide with the prepared dipeptide isosters. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

A stereoselective synthesis of (2S,5R)‐5‐hydroxylysine (1) and (2R,5R)‐5‐hydroxylysine (17), based on a concept involving Williams glycine template methodology and (R)‐hydroxynitrile lyase for the introduction of chirality at the α‐position and the side‐chain, respectively, is described. This strategy offers an expeditious route towards orthogonally protected 5‐hydroxylysines.

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