Jean-François Brière

Organocatalysed decarboxylative protonation process from Meldrum's acid: enantioselective synthesis of isoxazolidinones

An asymmetric organocatalysed decarboxylative protonation reaction allowed a straightforward synthesis of α-substituted isoxazolidin-5-ones from readily available 5-substituted Meldrums acids. This process is initiated by an anionic formal (3+2) cycloaddition-fragmentation, generated in-situ from a sulfone-amide precursor which also served as a latent source of proton.

Highly regio- and diastereoselective anionic [3 + 2] cycloaddition under phase transfer catalytic conditions.

A highly trans and regioselective anionic formal [3 + 2] cycloaddition was achieved with allylic sulfones having an MBH acrylamide backbone under phase transfer organocatalytic conditions giving rise to the formation of unprecedented densely substituted cyclopentene derivatives.

Developments in Meyers' lactamization methodology: en route to bi(hetero)aryl structures with defined axial chirality.

Highly atroposelective Meyers lactamization promoted by pivalic acid under microwave irradiation is reported which allows the construction of nonracemic substituted-dibenzo(di)azepine derivatives through a center to axial chirality transfer principle, controlling the otherwise configurationally labile biaryl axis. This approach provides a straightforward entry to enantioenriched analogues of biorelevant architectures.

Organocatalyzed Multicomponent Synthesis of Isoxazolidin-5-ones.

An unprecedented multicomponent organocatalyzed Knoevenagel-aza-Michael-cyclocondensation reaction between Meldrums acid, hydroxylamines, and aldehydes afforded a straightforward entry to a large array of racemic and syn-diastereoenriched isoxazolidinones as synthetically useful scaffolds. This process revealed a markedly facile aza-Michael-cyclocondensation sequence as a key domino reaction between RCO2NHOH and transient alkylidene Meldrums acid upon Brønsted base catalysis.

Meldrum's Acid: A Useful Platform in Asymmetric Organocatalysis

For more than a hundred years, Meldrums acid and its derivatives have proven their utility and versatility in organic synthesis. Showing very unusual properties and multiple facets of reactivity, this small architecture has become the keystone of numerous synthetic methodologies. In asymmetric organocatalysis, where the catalyst/substrate matching is of upmost importance, Meldrums acid derivatives have slowly but surely emerged as partners of choice over the last decade. This review intends to give a comprehensive state‐of‐the‐art view of the use of Meldrums acid in enantioselective organocatalysis. After discussing the properties of Meldrums acid and alkylidene Meldrums acid derivatives, we will also make a point of highlighting how they allow such a good pairing with organocatalysts.

Organocatalyzed Enantioselective Protonation

This chapter gathers the main organocatalytic processes involving an enantioselective proton transfer. These include decarboxylation of malonates, addition of protic nucleophiles to ketenes and to α,β-unsaturated carbonyl compounds, photodeconjugation of α,β-unsaturated esters, protonation of silyl enol ethers, along with some other miscellaneous chemical transformations. The main purpose is to provide an overall view of what is being done in this field by discussing the scope and limitations, and the mechanism of each organocatalytic process. To account for the catalytic nature of the enantioselective protonation, a special emphasis will be placed on the description of the proton transfer pathway from the achiral proton source to the prochiral substrate.

Modified multicomponent Biginelli–Atwal reaction towards a straightforward construction of 5,6-dihydropyrimidin-4-ones

A straightforward access to 5,6-dihydropyrimidin-4-ones as racemic mixtures or enantiopure diastereoisomers was achieved thanks to a multicomponent Knoevenagel-aza-Michael-Cyclocondensation reaction involving Meldrums acid and isourea derivatives. This constitutes not only a novel MCR of the original Biginelli–Atwal condensation but allows the construction of dihydrouracyl derivatives known as biorelevant diazole architectures.

Scalable asymmetric synthesis of a key fragment of Bcl-2/Bcl-xL inhibitors

The asymmetric synthesis of a 1,3-diamine building block for the elaboration of Bcl-2 and Bcl-xL protein inhibitors is described through two key steps: (1) a highly diastereoselective aza-Reformatsky reaction, and (2) a chemoselective amination under Mitsunobu conditions. This synthetic sequence was also demonstrated to be successfully amenable to a large-scale synthesis.

Concise synthesis of an enantiopure bicyclic pyrazinone as constrained peptidomimetic building block.

A concise synthetic route has been developed for the preparation of a constrained peptidomimetic pyrazinone building block. From hydroxy-L-lysine, the desired pyrazinone is obtained in 43% overall yield (6 steps) via an efficient deprotection-double cyclization sequence.