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

Abstract

Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione) is a molecule with a unique history, owing to its originally misassigned structure, as well as a unique place among acylating agents, owing to its high acidity and remarkable electrophilicity. In this Account, we outline the work of our group and others toward harnessing the reactivity of Meldrum's acid derivatives in catalytic C-C bond-forming reactions. Taking advantage of the ability of Meldrum's acid to decompose to CO(2) and acetone following acyl substitution, we have shown that intramolecular Friedel-Crafts acylations can be performed under mild Lewis acidic conditions to yield a variety of benzocyclic ketones. In a further expansion of this method, a domino Friedel-Crafts acylation/alpha-tert alkylation reaction was used to complete the first total synthesis of (+/-)-taiwaniaquinol B. The unique characteristics of Meldrum's acid extend to its alkylidene derivatives, which have also proven exceptionally useful for the development of new reactions not readily accessible from other unsaturated carbonyl electrophiles. By combining the electrophilicity and dienophilicity of alkylidene Meldrum's acid with our Friedel-Crafts chemistry, we have demonstrated new domino syntheses of coumarin derivatives and tetrahydrofluorenones by conjugate additions, Diels-Alder cycloadditions, and C-H functionalizations. Additionally, we have used these powerful acceptors to allow conjugate alkenylation with functionalized organostannanes, and conjugate allylation under very mild conditions. We have also shown that these molecules permit the asymmetric formation of all-carbon quaternary stereocenters via enantioselective conjugate additions. These reactions employ dialkylzinc nucleophiles, maximizing functional group compatibility, while the presence of a Meldrum's acid moiety in the product allows a variety of postaddition modifications. A full investigation of this reaction has determined the structural factors of the alkylidene that contribute to optimal enantioselectivity. We have also used these acceptors to form tertiary propargylic stereocenters in very high enantiomeric excess by an extremely mild, Rh(I)-catalyzed addition of TMS-acetylene. Overall, we demonstrate that Meldrum's acid and its derivatives provide access to a broad range of reactivities that, combined with their ease of handling and preparation, make them ideal electrophiles.

Synthesis and Characterization of Tricarbastannatranes and Their Reactivity in B(C6F5)3‐Promoted Conjugate Additions

“…Ther eactivity of 8 in the conjugate addition reaction to the Meldrums acid 10 a,w as then investigated. [14] Unexpectedly,inthe presence of one equivalent of 6 and one equivalent of 7,n or eactivity was observed ( Table 3, entry 1), while the reaction displayed full conversion into the product 11 a with two equivalents of 6 and one equivalent of 7 (Table 3, entry 4). By using 0.2 equivalents of 7 less than 20 % conversion into product 11 a resulted (Table 3, entry 5).…”

Synthesis and Characterization of Tricarbastannatranes and Their Reactivity in B(C6F5)3‐Promoted Conjugate Additions

“…[14] Unexpectedly,inthe presence of one equivalent of 6 and one equivalent of 7,n or eactivity was observed ( Table 3, entry 1), while the reaction displayed full conversion into the product 11 a with two equivalents of 6 and one equivalent of 7 (Table 3, entry 4). [14] Unexpectedly,inthe presence of one equivalent of 6 and one equivalent of 7,n or eactivity was observed ( Table 3, entry 1), while the reaction displayed full conversion into the product 11 a with two equivalents of 6 and one equivalent of 7 (Table 3, entry 4).…”

Palladium‐Catalyzed Asymmetric Quaternary Stereocenter Formation

“…Notwithstanding the significant advances in the field of transition‐metal‐catalyzed carbon–carbon bond formation,1 the catalytic asymmetric synthesis of quaternary stereocenters remains a challenge and a crucial area of study in chemistry. Among the handful of methods available for construction of these units by metal catalysis,2 conjugate addition to β,β‐substituted3 enones or Meldrum’s acid derivatives4 is of particular importance. This may be evidenced by the reports of Hoveyda5 and Alexakis,6 in which highly reactive organometallic nucleophiles (organozinc, organoaluminum, and organomagnesium reagents) were employed under copper catalysis, or, alternatively, by the recent studies of Shintani and Hayashi7 on the use of boronates, catalyzed by rhodium.…”