Defining Pathways Of Anaerobic Alkane Oxidation: Synthesis Of Enantiomers Of 4-Methylalkanoic Acids And (2-Methylalkyl)Malonic Acids

The coenzyme A (CoA) esters of 4-methylalkanoic acids are pivotal intermediates in metabolism of alkanes by anaerobic bacteria found in O-2-deprived environments. A generic method for synthesis of either (R)- or (S)-acid in high enantiomeric purity from enantiomers of methyl 3-hydroxy-2-methylpropionate is described for (R)- and (S)-4-methyloctanoic acid and (R)-4-methyldodecanoic acid. In a typical procedure silyl-protection of methyl (S)-3-hydroxy-2-methylpropionate was followed by reduction of the ester to a primary alcohol, which was tosylated. Cu(I)-catalysed cross-coupling of the tosylate with propylmagnesium chloride followed by deprotection, tosylation and base-induced reaction with di-t-butyl malonate, gave di-t-butyl (R)-(2-methylhexyl)malonate. Microwave heating of the diester in 2,2,2-trifluoroethanol gave a 42 % overall yield of (R)-4-methyloctanoic acid, which was shown to be the enantiomer derived by metabolism of hexane by proteobacterium Aromatoleum sp. HxN1. Deprotection of the diester with trifluoroacetic acid gave (R)-2-(2-methylhexyl)malonic acid, which is the biological precursor of (R)-4-methyloctanoic acid (via CoA esters).