A Robust Platform for the Synthesis of New Tetracycline Antibiotics

Abstract

Tetracyclines and tetracycline analogs are prepared by a convergent, single-step Michael-Claisen condensation of the AB precursors 1 or 2 with D-ring precursors of wide structural variability, followed by removal of protective groups (typically in two steps). A number of procedural variants of the key C-ring-forming reaction are illustrated in multiple examples. These include stepwise deprotonation of a D-ring precursor followed by addition of 1 or 2, in situ deprotonation of a D-ring precursor in mixture with 1 or 2, and in situ lithium-halogen exchange of a benzylic bromide D-ring precursor in the presence of 1 or 2, followed by warming. The AB plus D strategy for tetracycline synthesis by C-ring construction is shown to be robust across a range of different carbocyclic and heterocyclic D-ring precursors, proceeding reliably and with a high degree of stereochemical control. Evidence suggests that Michael addition of the benzylic anion derived from a given D-ring precursor to enones 1 or 2 is quite rapid at −78 °C, while Claisen cyclization of the enolate produced is ratedetermining, typically occurring upon warming to 0 °C. The AB plus D coupling strategy is also shown to be useful for the construction of tetracycline precursors that are diversifiable by latter-stage transformations, subsequent to cyclization to form the C ring. Results of antibacterial assays and preliminary data obtained from a murine septicemia model show that many of the novel tetracyclines synthesized have potent antibiotic activities, both in bacterial cell culture and in vivo. The platform for tetracycline synthesis described gives access to a broad range of molecules that would be inaccessible by semi-synthetic methods (presently the only means of tetracycline production), and provides a powerful engine for the discovery and, perhaps, development of new tetracycline antibiotics.

The tetracycline resistome

“…a Promising anticancer drug candidate COL-3, a chemically modified tetracycline. b Recently developed new tetracycline derivatives using the Myers total synthesis approach, which are inaccessible using conventional semi-synthetic approach [71] Resistance to tetracyclines was first reported in 1953, shortly after their first clinical use [17]. In the following decades, resistance increased rapidly in many bacterial species as a result of horizontal exchange of resistance genes on mobile genetic elements such as plasmids and transposons.…”

Antibiotic discovery in the twenty-first century: current trends and future perspectives

“…This synthetic platform gives access to a broad range of tetracyclines that would be inaccessible by semi-synthesis and provides a powerful engine for the discovery of new tetracyclines. 59,60 Even on larger molecules, semi-synthetic and synthetic chemistry has been successfully applied to study and optimize lead compounds. The lipoglycodepsipeptide ramoplanin (Figure 3b) is 2-10 times more active than vancomycin against Gram-positive bacteria and maintains full activity against VRE and all MRSA strains.…”

Biosynthesis of Oxytetracycline by Streptomyces rimosus: Past, Present and Future Directions in the Development of Tetracycline Antibiotics

“…Eravacycline was shown to have a much higher affi nity for the ribosome than tetra cycline; it consistently inhibits in vitro translation more effi ciently than tetracycline. Eravacycline displays similar ribosome binding affi nity to tigecycline (2,6,(16)(17)(18) …”