Synthesis and Analysis of Thio-, Thiono-, and Dithio-Derivatives of Whiskey Lactone

Cis- and trans-3-methyl-4-octanolide (1, whiskey lactones) were converted into their thio- (2), thiono- (3), and dithio- (4) derivatives by reaction with phosphorus pentasulfide. The reaction products were characterized by GC−mass spectrometry, 1H NMR spectroscopy, and GC−olfactometry. Two-dimensional NOESY spectra showed that sulfur is incorporated into the ring with reversal of the absolute configuration at C-4, whereas substitution of the keto-oxygen atom by sulfur occurs with retention of ring configuration. The cis- and trans-pairs of 2, 3, and 4 were separated into enantiomers by GC on heptakis(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)-β-cyclodextrin and heptakis(2,3-di-O-acetyl-6-O-tert-butyldimethylsilyl)-β-cyclodextrin as chiral stationary phases. GC−olfactometry revealed a sweet coconut-like odor for the cis-thio- and pleasant mushroom-like flavors for the cis-thiono- and trans-dithio-derivatives of whiskey lactone. Keywords: Whiskey lactone; thio-whiskey lactone; thiono-whiskey lactone; dithio-whiskey lactone; enantioselective GC; GC−MS; 1H NMR