As with many natural product-derived antibacterials, chemical modification of tetracyclines has generally been accomplished through semisynthesis. A total synthetic approach, however, allows for derivatization at positions of the tetracycline scaffold that are not possible by the traditional route, greatly expanding the scope of chemical space available to the medicinal chemist to modify both biological and ADME properties. Using a tandem Michael-Dieckmann annulation strategy to combine an AB-ring precursor with a D-ring precursor, we have been able to prepare several thousand new tetracycline analogues, most of which are not possible via semisynthesis. Among these, analogues with unique C4 and C8 modifications, as well as C7,8 and C8,9 fused rings, have shown particular promise against Gram-negative bacteria, including Pseudomonas aeruginosa and multidrug-resistant strains such as Carbapenem-resistant Enterobacteriaceae (CRE).

Fully synthetic tetracyclines: Increasing chemical diversity to combat multidrug-resistant bacteria

251st National Meeting (2016)

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