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).