| A practical synthetic route to structurally diverse tetracycline antibiotics has been developed. Previously, enone 76 had been demonstrated to be a key precursor to (--)-6-deoxytetracycline (74) in a three-step sequence involving a Michael-Dieckmann reaction and deprotection. We have now demonstrated that enone 76 can be transformed into a diverse array of new tetracycline antibiotics, several of which (such as 151 and 152) show excellent activity in tetracycline-resistant Gram-positive and Gram-negative organisms.; Further exploration of structure activity relationships in the 6-deoxytetracycline series and, ultimately, clinical development of a drug candidate will require the production of kilogram quantities of enone 76. The previously developed route to 76 proceeded in 11 steps and 10% overall yield. We have now developed a completely different route to 76, which proceeds in 9 steps and 27% overall yield. Key features of the synthesis are the enantioselective addition of divinylzinc to aldehyde 188, the convergent coupling of allylic amine 183 with 3-methoxyfurfural (184), the endo-selective furan Diels--Alder reaction of 182, and the boron tribromide promoted demethylation and ring-opening of the oxabicyclic ring system within 208. Ultimately, the new route was used to produce 40 g of enone 76 in three weeks. While further process development will be necessary, this new route provides an excellent starting point for the kilogram-scale production of enone 76.*; *Please refer to dissertation for diagrams. |
