Absolute Stereochemistry of Antifungal Limonene-1,2-diols from Lippia rubella

Abstract

From the active dichloromethane-soluble extract of Lippia rubella (Moldenke) T.R.S. Silva & Salimena, Verbenaceae (MIC = 78 μg/ml against Cryptococcus neoformans), two diastereomers of limonene-1,2-diol were isolated by countercurrent chromatography. An extensive NMR exploration to address the problem of distinguishing and evaluating the stereochemical influences of the C-2 hydroxy substituent on hydrogen and carbon chemical shifts of the natural products confirmed that these natural antifungal monoterpenes are derived from R-(+)-limonene. The absolute stereochemistry for both isolated diols was confirmed by the application of Mosher esters methodology. For the novel synclinal 1,2-diol, its structure was confirmed as (−)-(1S,2R,4R)-1-methyl-4-(prop-1-en-2-yl)cyclohexane-1,2-diol, which displayed a stronger antifungal activity against Crytococcus neoformans (MIC = 31.25 μg/ml; 184 μM) than the trans-diaxial 1,2-diol (2) which corresponded to the (+)-(1S,2S,4R) isomer (MIC = 250 μg/ml; 1470 μM) probably the most frequently distributed stereoisomer in volatile oils. The natural occurrence of 1 and 2 is being reported for the first time. [Figure not available: see fulltext.].