Progress in the synthesis of mycothiol, its biosynthetic precursors and analogues

The protective role of mycothiol in the Actinomycetes in relation to oxidative stress and detoxification, continues to attract interest, with enzymes implicated in its biosynthesis and processing recognized as potential drug targets for mycobacterial diseases such as tuberculosis. Following the initial work of establishing its structure, considerable effort has been expended in establishing the biosynthetic pathway to mycothiol, with all but one of the key enzymes now fully characterized. This has spawned a range of synthetic endeavours to establish efficient and creative routes to mycothiol itself, as well as its biosynthetic precursors and a range of analogues designed to probe enzyme–substrate interactions and possible roles as inhibitors or drug leads. Progress in the synthesis over the past seven years since the last major review, is reviewed here, revealing advances in resolving many of the key challenges, including efficient preparation and resolution of d-myo-inositol, methodologies for selective formation of the requisite 1,2-cis-glucoside, elaboration of the cysteinyl side chain, and preparation of a range of other creative variations of the core of the mycothiol structure.