Palladium-Catalyzed Functionalization of Lactones via Their Cyclic Ketene Acetal Phosphates. Efficient New Synthetic Technology for the Construction of Medium and Large Cyclic Ethers

The functionalization of lactones (I, Figure 1) via their corresponding enolate derivatives (II) to afford substituted lactones (III) has been one of the most useful carbon-carbon bond-forming reactions in organic synthesis. In contrast, and despite its rich potential, the alternative mode of lactone functionalization to afford substituted cyclic enol ethers (IV) has only recently been investigated.1 Current methodology for this process involves cyclic ketene acetal triflates (II, X ) SO2CF3), which often suffer from instability and low yields, both in their formation and in their coupling reactions.1 In this paper, we introduce lactone-derived cyclic ketene acetal phosphates2 [II, X ) P(O)(OR)2] as superior substrates for palladium(0)catalyzed carbon-carbon bond-forming reactions. In addition to the lower cost of the reagents involved in their preparation, these substrates enjoy higher stability and efficiency in their formation and coupling reactions than their triflate counterparts. Most importantly, and as demonstrated below, these substrates offer excellent solutions to the well-recognized and challenging problem of constructing medium and large ring systems.3 The cyclic ketene acetal diphenyl phosphate4 2 (Scheme 1) was prepared from the 9-membered ring lactone 15 via its potassium enolate (1.2 equiv of potassium bis(trimethylsilyl)amide, KHMDS, 3.0 equiv of HMPA, 2.0 equiv of (PhO)2P(O)Cl, THF, -78 °C; add lactone to phosphoryl chloride and base) and proved to be quite stable at ambient temperatures and to silica gel flash chromatography. Reaction of 2 with a variety