This paper evaluates the electronic effects of molecular substituents on the stereoselectivity of the umpolung Staudinger catalytic reaction. This is especially important because experimental studies on constructing the β-lactam ring, a core structure of most antibiotics, through catalyzed Staudinger reactions have been massively progressing over the last century. Yet, there is a necessity for an in-depth understanding of the reaction mechanisms to help chemists, working on the well-established discoveries, improve these to optimize the stereoselectivity and yield of synthetic methods. Access to practical and effective advancements in forming optically pure β-lactam is paramount in the field of medical chemistry. This paper specifically investigates how changing the N-protecting group in the imine fragment can switch the stereoselectivity of the PPY-catalyzed Staudinger reaction. To do so, we employed the density functional theory (DFT) for geometry optimization and electronic analysis at the B3LYP/6-31G(d) level of theory to examine and compare the role of N-tosyl (N-Ts) and N-triflyl (N-Tf) imine on the mechanism pathways, i.e., imine-first or ketene-first, and stereochemistry of the reaction, i.e., cis or trans β-lactam. Our results show that the reaction mechanism pathway cannot be simply switched from ketene-first to imine-first by changing the substituent on the imine nitrogen atom, which is contrary to the reported experimental results, and both imines go through the ketene-first mechanism with different stereochemistries, which is cis selective for imine-Ts and trans selective for imine-Tf. Based on electronic analyses, the reversal in diastereoselectivity in the N-triflyl imine system could be attributed to the charge transfers and electron-density distribution over the transition states. Therefore, the cis/trans selectivity of the PPY-catalyzed Staudinger reaction could be effectively controlled by the electronic characteristics of the molecular substituents in the reactants. A N-protecting group in imine with a more electron-withdrawing nature seems to accelerate the stereo-determining step, ring closure, and increase the stabilization charge transfers in the transition state, leading to a preference for trans β-lactam formation. It seems that using a N-substituent with a higher electron-withdrawing nature can initially activate the imine by the nucleophilic catalyst in competition with ketene, i.e., imine-first versus ketene-first. These results can provide an insight into select proper substituents for the fragments to synthesis β-lactam with a desired stereochemistry. Also, a comprehensive comparison was performed between calculations with and without dispersion.
This journal is © The Royal Society of Chemistry.