title: A robust platform for the synthesis of new tetracycline antibiotics.
abstract: Tetracyclines and tetracycline analogues are prepared by a convergent, single-step Michael-Claisen condensation of AB precursor 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 degrees C, while Claisen cyclization of the enolate produced is rate-determining, typically occurring upon warming to 0 degrees 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 semisynthetic methods (presently the only means of tetracycline production) and provides a powerful engine for the discovery and, perhaps, development of new tetracycline antibiotics.
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Cuixiang
authors.initials: C
authors.lastname: Sun
authors.forename: Qiu
authors.initials: Q
authors.lastname: Wang
authors.forename: Jason D
authors.initials: JD
authors.lastname: Brubaker
authors.forename: Peter M
authors.initials: PM
authors.lastname: Wright
authors.forename: Christian D
authors.initials: CD
authors.lastname: Lerner
authors.forename: Kevin
authors.initials: K
authors.lastname: Noson
authors.forename: Mark
authors.initials: M
authors.lastname: Charest
authors.forename: Dionicio R
authors.initials: DR
authors.lastname: Siegel
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Wang
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Myers
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D016470:Bacteremia / Q000188:drug therapy; D018360:Crystallography, X-Ray; D003500:Cyclization; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects; D013754:Tetracyclines / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D013754:Tetracyclines