Quimica organica

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Tuning Diketodioxinone Reactivity: Biomimetic Synthesis of the Resorcylate Antibiotic Fungal Metabolites ent-W1278A, -B, and -C, Using Iterative Aromatization Reactions
Ismael Navarro,† 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 agm.barrett@imperial.ac.uk Received July 22, 2009

The onset temperature of the retro-Diels-Alder reactions of diketo-1,3-dioxin-2-ones to generate R,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 is noteworthy 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-W1278 and 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 classical synthetic 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, S48.Roll, D. M.; Schlingmann, G. J. Chromatogr. A 2007, 1156, 256. Nishihara, Y.; Tsujii, E.; Takase, S.; Tsurumi, Y.; Kino, T.; Hino, M.; Yamashita, M.; Hashimoto, S. J. Antibiot. 2000, 53, 1123. Nishihara, Y.; Tsujii, E.; Takase, S.; Tsurumi, Y.; Kino, T.; Hino, M.; Yamashita, M.; Hashimoto, S. J. Antibiot. 2000, 53, 1341.

esterification reactions of suitably protected 6-alkyl-2,4-hydroxybenzoicacid, we considered this approach problematic. Such a strategy would be severely hampered by the need for multiple/selective protecting group manipulations and probable formation of the undesired benzopyranone 6.1 Following our previous report on the biomimetic synthesis of resorcylate natural products including 15G256β (2) and 15G256ι (3),3 we intended to apply a similar late stage aromatizationstrategy to the synthesis of the homologues W1278A (1a), W1278B (1b), and W1278C (1c) (Figure 2). Further, we sought to find a more general route to synthesize the diketo-dioxinone derivatives 7 by using milder thermolytic conditions in order to suppress conversion of the delicate hydroxyl-ester intermediates 5 into the benzopyranone 6. Herein we report a novel synthesis of the dioxinones 7, astudy of the influence of the substituents R3 and R4 on the rate of ketene generation and the application of the methodology to the total synthesis of the oligo-esters
(3) Navarro, I.; Basset, J.-F.; Hebbe, S.; Major, S. M.; Werner, T.; Howsham, C.; Brackow, J.; Barrett, A. G. M. J. Am. Chem. Soc. 2008, 130, 10293.

DOI: 10.1021/jo9015858 r 2009 American Chemical Society

Published on Web10/01/2009

J. Org. Chem. 2009, 74, 8139–8142

8139

JOC Article
SCHEME 1.

Navarro et al. Synthesis of W1278 Monomer Unit 15

FIGURE 1. Biooligomers W1278A (1a, n=2), W1278B (1b, n=3),
and W1278C (1c, n = 4) and the structurally related antifungal resorcylates 15G256β (2) and 15G256ι (3).

presence of alcohol 127 gave triketo-ester 13,8 which was aromatized by sequential reaction with...