Description:
<jats:title>Abstract</jats:title><jats:p>The coenzyme A (CoA) esters of 4‐methylalkanoic acids are pivotal intermediates in metabolism of alkanes by anaerobic bacteria found in O<jats:sub>2</jats:sub>‐deprived environments. A generic method for synthesis of either (<jats:italic>R</jats:italic>)‐ or (<jats:italic>S</jats:italic>)‐acid in high enantiomeric purity from enantiomers of methyl 3‐hydroxy‐2‐methylpropionate is described for (<jats:italic>R</jats:italic>)‐ and (<jats:italic>S</jats:italic>)‐4‐methyloctanoic acid and (<jats:italic>R</jats:italic>)‐4‐methyldodecanoic acid. In a typical procedure silyl‐protection of methyl (<jats:italic>S</jats:italic>)‐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‐<jats:italic>t</jats:italic>‐butyl malonate, gave di‐<jats:italic>t</jats:italic>‐butyl (<jats:italic>R</jats:italic>)‐(2‐methylhexyl)malonate. Microwave heating of the diester in 2,2,2‐trifluoroethanol gave a 42 % overall yield of (<jats:italic>R</jats:italic>)‐4‐methyloctanoic acid, which was shown to be the enantiomer derived by metabolism of hexane by proteobacterium <jats:italic>Aromatoleum</jats:italic> sp. HxN1. Deprotection of the diester with trifluoroacetic acid gave (<jats:italic>R</jats:italic>)‐2‐(2‐methylhexyl)malonic acid, which is the biological precursor of (<jats:italic>R</jats:italic>)‐4‐methyloctanoic acid (via CoA esters).</jats:p>