Synthesis of Azabicyclic Isosteres of Piperazine 2S-Carboxylic Acid

Methods have been developed for the stereocontrolled synthesis of bicyclic diaza [3.3.0] octane carboxylic acids as possible isosteres of piperazine 2S-carboxylic acid. In the first approach, l-pyroglutamic acid was functionalized adopting new as well as documented reaction sequences via Michael and aza-Michael reactions, leading to two of the four intended isosteres. An alternative shorter route relying on enolate chemistry starting with N-Pf 4-keto l-proline methyl ester led to two other isosteres. Calculated pK_a values and density functional theory (DFT) calculations have provided some insights into the relative basicities of the nitrogen atoms in these diaza [3.3.0] octane carboxylic acids in relation to piperazine 2S-carboxylic acid.