Meldrum’s Acids and 5-Alkylidene Meldrum’s Acids in Catalytic Carbon−Carbon Bond-Forming Processes

摘要

Meldrum’s acid (2,2-dimethyl-1,3-dioxane-4,6-di-none) is a molecule with a unique history, owingnto its originally misassigned structure, as well as anunique place among acylating agents, owing to its highnacidity and remarkable electrophilicity. In this Account, wenoutline the work of our group and others toward harness-ning the reactivity of Meldrum’s acid derivatives in catalyticnC C bond-forming reactions.nTaking advantage of the ability of Meldrum’s acidnto decompose to CO2 and acetone following acyl sub-nstitution, we have shown that intramolecularnFriedel Crafts acylations can be performed undernmild Lewis acidic conditions to yield a variety of ben-nzocyclic ketones. In a further expansion of thisnmethod, a domino Friedel Crafts acylation/ -tert alkylation reaction was used to complete the first total synthesis of ( )-ntaiwaniaquinol B.nThe unique characteristics of Meldrum’s acid extend to its alkylidene derivatives, which have also proven exceptionally usefulnfor the development of new reactions not readily accessible from other unsaturated carbonyl electrophiles. By combining the elec-ntrophilicity and dienophilicity of alkylidene Meldrum’s acid with our Friedel Crafts chemistry, we have demonstrated new dom-nino syntheses of coumarin derivatives and tetrahydrofluorenones by conjugate additions, Diels Alder cycloadditions, and C Hnfunctionalizations. Additionally, we have used these powerful acceptors to allow conjugate alkenylation with functionalized orga-nnostannanes, and conjugate allylation under very mild conditions. We have also shown that these molecules permit the asym-nmetric formation of all-carbon quaternary stereocenters via enantioselective conjugate additions. These reactions employ dialkylzincnnucleophiles, maximizing functional group compatibility, while the presence of a Meldrum’s acid moiety in the product allows anvariety of postaddition modifications. A full investigation of this reaction has determined the structural factors of the alkylidenenthat contribute to optimal enantioselectivity. We have also used these acceptors to form tertiary propargylic stereocenters in verynhigh enantiomeric excess by an extremely mild, Rh(I)-catalyzed addition of TMS-acetylene.nOverall, we demonstrate that Meldrum’s acid and its derivatives provide access to a broad range of reactivities that, com-nbined with their ease of handling and preparation, make them ideal electrophiles.