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Medium sized macrocycles, natural or unnatural, are important synthetic targets because of a wide spectrum of their intriguing biological activity. Various synthetic strategies have been developed, most of which utilize ring closure of α,ω-bifunctional linear precursors. Despite many examples in the literature, the formation of medium sized rings is not a trivial task, owing to the unfavourable entropic change associated with. Moreover, the requisite employment of high dilution conditions renders the preparative scale synthesis arduous. Also reported were various methods based on ring expansion including the Wharton/Grob fragmentation as alternatives. We have previously reported the synthesis of structurally novel tricyclolactones 1 from the Diels-Alder cycloadditions of 3,5-dibromo-2-pyrone with cyclic enol ethers. Envisioning the potency of mesylates 2, readily accessible from 1, for the ensuing the Wharton/Grob type fragmentation, we decided to investigate the synthetic manipulation of 1 to medium sized rings 3 (Scheme 1). The cycloadduct 1a was first converted into triol 4a upon debrominations with 2 equiv of Bu3SnH and reductive opening of the lactone bridge with excess LiAlH4 (Scheme 2). Deprotection of TMS followed by selective protection of the primary alcohol with TBS afforded 5a. Subsequent mesylation of the secondary hydroxyl group of 5a would set the stage for the Wharton/Grob fragmentation reaction. However, the attempted mesylation of 5a furnished aromatized product 6a in quantitative yield instead of the desired ketone 3a. Evidently, the initially formed putative mesylate 2a further underwent β-elimination and dehydration reaction. Running the mesylation reaction at lower temperatures produced similar results. Triol 5a was then hydrogenated into 7a before the mesylation, envisioning the removal of the double bond may suppress the ensuing β-elimination reaction (Scheme 3). Treatment of 7a with MsCl indeed provided mesylate 8a in good yield. However, subjection of mesylate 8a into the Wharton/ Grob fragmentation conditions resulted in the formation of alkene 9a, rather than the fragmentation product (Scheme 3). During the investigation, Marko and coworkers reported an efficient radical fragmentation protocol for the Wharton/ Grob type ring expansion reactions of bicyclic tertiary hydroxyl ketones, providing 9-, 10-, and 11-membered

Synthesis of Medium Sized Rings from the Cycloadducts of 3,5-Dibromo-2-pyrone via a Radical Mediated Fragmentation Reaction