Racemic and optically active 2-methoxy-4-oxatetradecanoic acids: novel synthetic fatty acids with selective antifungal properties

The unprecedented (+/-)-2-methoxy-4-oxatetradecanoic acid and the optically pure (S)-2-methoxy-4-oxatetradecanoic acid were synthesized in six steps and in 11-14% overall yields starting with either 1,2-O-isopropylidene-rac-glyceroI or 1,2-O-isopropylidene-(S)-glycerol. The key step in the synthesis was the selective monosilylation of a dibutylstannylene intermediate. The title compounds displayed selective fungitoxicity in the range of 0.08-0.22 mM against Cryptococcus neoformans ATCC 66031 and Aspergillus niger ATCC 16404, but no significant activity against C. albicans ATCC 14053 and ATCC 60193 (> 2.6 mM). Albeit being good substrates for N-myristoyltransferases (NMTs), the racemic and the S-enantiomer of the oxygenated 2-methoxylated compounds showed no significant difference in antifungal activity. This finding suggests an alternative mechanism of fungitoxicity other than NMT inhibition. (c) 2005 Elsevier Ireland Ltd. All rights reserved.