DFT Study of Stereoselective Ketene-imine Cycloadditions, Evaluation of Possible Solvent Effects with IEF-PCM

The formal [2+2] cycloaddition of ketenes and imines, also known as Staudinger synthesis, is a facile method for the synthesis of biologically important β-lactam derivatives. In this paper two previously reported stereoselective reactions were investigated with computational methods. Our computations support experimental data that a chiral imine, derived from d-glyceraldehyde reacting with ketenes, yields almost exclusively one out of the possible four diastereomers. The reaction proceeds stepwise, first addition of the imine to the ketene yields an intermediate, then the product is formed in a conrotatory electrocyclization. Results indicate that the electrostatic repulsion of the chiral auxiliary group is the main factor of the stereoselectivity, but solvent and substituent effects are not negligible. Calculations were performed at M06-2X/6-31+G** level of theory combined with IEF-PCM solvation, in common solvents such as toluene, THF, dichloromethane, acetonitrile and water. These results provide useful insight for the development of new chiral auxiliaries and optimizing reaction parameters

Experimental and Computational Study on the Debenzylation of (2,4-dimethoxybenzyl)-protected 1,3-diazaoxindoles

The introduction and removal of the 2,4-dimethoxybenzyl (DMB) moiety was studied in order to use it as a protecting group in the synthesis of diverse drug candidates containing the 1,3-diazaoxindole scaffold. The debenzylation of C(5)-unsubstituted and C(5)-isopropylidene-substituted 1,3-diazaoxindoles was investigated under various conditions. The DMB group could only be removed from the latter derivative using triflic acid. This observation can most likely be explained with electronic effects. In order to get a deeper insight into the reaction mechanism, quantum chemical calculations have been performed