Total Synthesis of a Mycolic Acid from Mycobacterium tuberculosis

In Mycobacterium tuberculosis, mycolic acids and their glycerol, glucose, and trehalose esters (“cord factor”) form the main part of the mycomembrane. Despite their first isolation almost a century ago, full stereochemical evaluation is lacking, as is a scalable synthesis required for accurate immunological, including vaccination, studies. Herein, we report an efficient, convergent, gram‐scale synthesis of four stereo‐isomers of a mycolic acid and its glucose ester. Binding to the antigen presenting protein CD1b and T cell activation studies are used to confirm the antigenicity of the synthetic material. The absolute stereochemistry of the syn‐methoxy methyl moiety in natural material is evaluated by comparing its optical rotation with that of synthetic material.
The total synthesis of four methoxy mycolic acid diastereomers is described. Key steps involve a Suzuki–Fu cross‐coupling, an anti‐selective Abiko–Masamune asymmetric aldol reaction, and an enantioselective Charette cyclopropanation. CD1b‐free mycolic acid tetramer staining experiments clearly favoured one diastereomer over the other three.