Synthesis of 1,2,3-Triazole Peptidomimetics for Antimicrobial Evaluation

Abstract

The scope of this thesis has been to synthesise small cationic amphiphilic 1,2,3-triazoles with multiple lipophilic and cationic groups. These will be tested for antimicrobial activity.

The target compound 7* and 8 were to be obtained from various aromatic aldehydes 1. The preparation of 2d via an aldol reaction was successful, but also gave in some biproduct formation. Aldol adducts 2a and 2d where then reduced to give the alcohols 3a and 3d. Azidation of 3a, 3b and 3d, through the generation of the tosylate 4, gave the azide 5 in good yields.

The azides 5a-d were then coupled with methyl propiolate through a copper-catalysed alkyne-azide cycloaddition. This afforded the key intermediate 1,2,3-triazole methyl esters 6a-d. Amidation of 6a-d afforded the corresponding amines 7a-d. Both of these reactions were done in high yields.

The neutral 1,2,3-triazole amines 7a-d, were then turned into the two target compounds 7* and 8. The cationic ammonium salts 7*b-d were prepared using HCl. This was done with good yields and achieving high purity. Guanidines 8 where prepared using 1H-pyrazole-1-carboxamidine hydrochloride and TEA, affording 8a-c in varying degrees of purity.

The preparation of branched ammonium salt 9*b, via amine 9b, was successful. Both the reactions gave quantitative yields, and 9*b had a HPLC purity of >99%. An attempt to prepare branched ammonium salt 13*a was conducted, but was not effective.