Kibdelone A

The kibdelones are a novel family of bioactive heterocyclic polyketides produced by a rare soil actinomycete, Kibdelosporangium sp. (MST-108465). Complete relative stereostructures were assigned to kibdelones A-C (1-3), kibdelone B rhamnoside (5), 13-oxokibdelone A (7), and 25-methoxy-24-oxokibdelone C (8) on the basis of detailed spectroscopic analysis and chemical interconversion, as well as mechanistic and biosynthetic considerations. Under mild conditions, kibdelones B (2) and C (3) undergo a facile equilibration to kibdelones A-C (1-3), while kibdelone B rhamnoside (5) equilibrates to a mixture of kibdelone A-C rhamnosides (4-6). A plausible mechanism for this equilibration is proposed and involves air oxidation, quinone/hydroquinone redox transformations, and a choreographed sequence of keto/enol tautomerizations that aromatize ring C via a quinone methide intermediate. Kibdelones exhibit potent and selective cytotoxicity against a panel of human tumor cell lines and display significant antibacterial and nematocidal activity.

The total synthesis of kibdelone A has been accomplished via In(III)-catalyzed arylation of a heterocyclic quinone monoketal and iodine-mediated oxidative photochemical electrocyclization for construction of the ABCD ring moiety. Enzymatic dihydroxylation of methyl 2-halobenzoate substrates was employed for synthesis of activated 2-halo-cyclohexene F-ring fragments. A one pot oxa-Michael/Friedel-Crafts process allowed access to the first simplified DEF ring analogues of the kibdelones.