Tuning Diketodioxinone Reactivity: Biomimetic Synthesis of the Resorcylate Antibiotic Fungal Metabolites ent-W1278A, -B, and -C, Using Iterative Aromatization Reactions
IsmaelNavarro,† Christoph P€verlein,† Gerhard Schlingmann,‡ and o Anthony G. M. Barrett*,†
Department of Chemistry, Imperial College, London SW7 2AZ, England, and ‡Wyeth Research, Natural ProductsDiscovery, Middletown Road, Pearl River, New York 10965 firstname.lastname@example.org Received July 22, 2009
The onset temperature of the retro-Diels-Alder reactions of diketo-1,3-dioxin-2-ones to generateR,γ,ε-triketo-ketenes was found to be significantly reduced with 2-phenyl substitution. These ketenes, generated at 78 °C, were trapped with alcohols to provide resorcylate esters followingaromatization by sequential reaction with cesium acetate and trifluoroacetic acid. The methodology was applied iteratively to the total synthesis of the resorcylate antibiotics W1278A, -B, and -C. It isnoteworthy that in this process the linking of the monomer units occurs during construction of the aromatic ring.
Introduction A distinguishing feature of numerous bioactive natural products is the6-alkyl-2,4-dihydroxybenzoic acid unit.1 This unit also serves as the backbone of the oligo-esters W1278A (1a, n = 2), -B (1b, n = 3), and -C (1c, n = 4) (Figure 1), isolated from Ascomycete sp. LL-W1278and determined by hydrolytic degradation to contain (S)-building blocks.2 These compounds possess antibiotic activity, are potent inhibitors in many enzyme-based assays, and are reported to haveantiviral activity against the influenza A virus. In consequence of these activities, we sought to undertake the total synthesis of the reported structures of these unique oligomers. Although a classicalsynthetic approach could be used to assemble the W1278 antibiotics employing stepwise
(1) Winssinger, N.; Barluenga, S. Chem. Commun. 2007, 22. (2) Roll, D. M.; Schlingmann, G. Chirality 2005, 17,...