Catalytic synthesis of versatile chiral heterocycles: en route to gamma-Amino Acid derivatives

Despite decades, the synthesis and application of new chiral Amino Acids (AA) and peptides derived from them remain research topics of major importance. Compared with conventional alfa-AA, the introduction of gamma-AA into the corresponding peptides can lead to peptidomimetics with different secondary structures and improved hydrolytic stability towards peptidases, thus enabling better biological properties/activities. Gamma^2,2-AA are useful building blocks for the development of original chiral small molecules and heterocycles, enabling exploration of 3D chemical space in search of selectivity in biological properties, and prevent racemization at the alfa position of the carbonyl functional group.

The catalytic synthesis of versatile chiral heterocycles: en route to gamma-AA derivatives is a project that aims to develop versatile chiral heterocycles as building blocks for access to gamma-AA derivatives, using Meldrum acid chemistry and new developments in Phase Transfer Catalysis (PTC) approaches. Thanks to the Meldrum acid chemistry we succeeded in developing a robust, versatile and efficient synthetic route for the synthesis of pyridazinone derivatives, 6-membered aza-heterocycles considered as masked gamma-AA, as platforms for PT-catalyzed asymmetric Michael additions to obtain pyridazinone derivatives di-substituted on the alfa-carbonyl position. Using this process, we achieved good yields and enantiomeric excesses up to 86%. Finally, by performing synthetic transformations, we obtained the corresponding gamma-AA derivatives.