Abstract
Since the beginning of the 20th century, numerous research efforts made elegant use of barbituric acid derivatives as building blocks for the elaboration of more complex and useful molecules in the field of pharmaceutical chemistry and material sciences. However, the construction of chiral scaffolds by the catalytic enantioselective transformation of barbituric acid and derivatives has only emerged recently. The specific properties of these rather planar scaffolds, which also encompass either a high Brønsted acidity concerning the native barbituric acid or the marked electrophilic character of alkylidene barbituric acids, required specific developments to achieve efficient asymmetric processes. This review covers the enantioselective catalytic reactions developed for barbituric acid platforms using an organocatalytic and metal-based enantioselective sequences. These achievements currently allow several unique addition and annulation reactions towards the construction of high valued chiral heterocycles from barbituric acid derivatives along with innovative enantioselective developments.
Highlights
Barbituric acid 1, namely 2,4,6-(lH,3H,5H)-pyrimidinetrione, and derivatives are fascinating building blocks in organic synthesis (Figure 1)
The opportunity afforded by the double functionalization of the C-5 position of barbituric acid allowed the construction of several spiro-compounds and, more rigid architectures highlighted by the development of nucleotide mimics [8], inhibitor of matrix metalloproteinases (MMP) [9] and anticancer agents [10], for example (Figure 1b–d) [11,12]
The same year, Wang and co-workers reported on the enantioselective organocatalytic Michael addition of N,N’-dialkylbarbituric acid derivatives 5 to β-substituted enones 48 making use of chiral bifunctional squaramide catalyst 28b based upon a 9-epi-aminoquinine scaffold (Scheme 10) [34]
Summary
Barbituric acid 1, namely 2,4,6-(lH,3H,5H)-pyrimidinetrione, and derivatives are fascinating building blocks in organic synthesis (Figure 1). Barbituric acid and derivatives be much more prone to deprotonation by soft bases than dimedone 3 or non-cyclic homologues, such as malonate 4, for instance. Mayr and co-workers studied electrophilicity benzylidene barbituric acid derivatives. Mayr and co-workers studied thethe electrophilicity of of benzylidene barbituric acid derivatives [29], which proved a potent electrophile various conjugate addition reactions. Comparison the barbituric benzylidene barbituric acid derivative 8a is a much more potent electrophile than the malonate counterpart 11 and, affords interesting reactivity to be exploited in catalysis. Relies on the modulation of reactivity by moving from barbiturate 8a to thiobarbiturate 9a which displays a derivative 8a is a much more potent electrophile than the malonate counterpart 11 and, affords interesting reactivity to be exploited in catalysis Another important feature, relies on the modulation of.
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