Process Development of the Novel LpxC Inhibitor T-1228. Part 1: Synthesis of the Diol Fragment

The novel LpxC inhibitor T-1228 is a candidate drug molecule for multidrug-resistant Gram-negative bacterial infection. This report describes the synthesis of the diol unit of T-1228, (S)-1-(4-ethynylphenyl)ethane-1,2-diol, from commercially available 2-bromo-1-(4-iodophenyl)ethan-1-one, achieved in 5 steps and 4 isolations. The stereogenic center of the diol unit was created by means of a highly scalable form of the Corey–Bakshi–Shibata reduction; process parameters were optimized using the Design of Experiments methodology. Using this newly developed process chemistry route, we successfully synthesized 12.5 kg of (S)-1-(4-ethynylphenyl)ethane-1,2-diol in 60% total yield and optical purity >99% ee.