Journal of the American Chemical Society · 2002 · 109 citations · 20 references
PharmacyChemistryMedicinal ChemistryBioorganic ChemistryOrganic ChemistrySynthetic Medicinal ChemistryBiomimetic SynthesisHeterocycle SynthesisMacrocycle SynthesisNatural Product Drug DiscoveryOrganic SynthesisRetrosynthetic AnalysisMacrocyclic Library SynthesisMild Reaction ConditionsNatural Product Macrocycle SynthesisNatural Product SynthesisRing-forming ReactionsSecondary Metabolite DiscoveryTandem Reactions
An efficient biomimetic synthesis of the reported structure of the hexacyclic, cytotoxic secondary metabolite FR182877 is described. The successful route features the synthesis of a 19-membered ring carbocycle using two pi-allyl palladium(II)-mediated C-C bond-forming reactions. This polyunsaturated macrocycle undergoes tandem transannular Diels-Alder reactions that create five rings and seven stereogenic centers in one operation under mild conditions, representing the first double transannular Diels-Alder reaction. The absolute stereochemistry of the natural product is demonstrated to be opposite of that reported previously. Significant quantities of both enantiomers of this microtubule-stabilizing natural product and related structures are now available via this approach.
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