- Sep 13, 2018 -
In 1908, A. N. Meldrum condensed malonic acid with acetone to produce a compound he misidentified as a carboxylic acid—hence the name “Meldrum’s acid”. Not until 1948 did D. Davidson and S. A. Bernhard show that the compound has the dioxane-dione structure shown here. Its acidity derives from the lability of the hydrogen atoms between the carbonyl groups. The same authors noted that Meldrum’s acid is a ketene precursor. Recently B. Moon and C. J. Hawker used this property to create polymers with reactive ketene substituents.
The natural environment continues to be an abundant source of biologically active and structurally diverse compounds. Total syntheses of such substances not only provide sufficient amounts of material for biological studies, but also result in novel synthetic methods and strategies. Due to their unique reactivity, Meldrum’s acid and it’s derivatives have proven to be valuable reagents and intermediates in the synthesis of complex organic compounds such as natural products and their analogs. The ability of acyl derivatives of Meldrum’s acid to generate acylketene species under pyrolysis conditions is the most fruitful field of their applications. For example, β-keto thioesters, easily accessible from reaction of thiols with acyl Meldrum’s acids, can be regarded as analogs of acyl-SCoA and have been exploited in biomimetic syntheses of polyketide derived natural products. As demonstrated in the present microreview, cyclic acylals have a potential for application in stereoselective synthesis of complex organic molecules. Another direction in their chemistry is the development of novel multicomponent and domino reactions, producing variously substituted privileged scaffolds. These reactions, along with Meldrum’s acid based solid phase syntheses, are ideally suited for parallel and combinatorial processing. Parallelization techniques provide easy exploration of the chemical space around the biologically active scaffolds, enabling generation of ‘‘natural product-like’’ libraries for biological screening and SAR studies.