A Computational Study on the Reaction Mechanism of Stereocontrolled Synthesis of β-Lactam within [2]Rotaxane.

The macrocycle effect of [2]rotaxane on the highly trans -stereoselective cyclization reaction of N -benzylfumaramide was extensively investigated by various computational methods, including DFT and high-level DLPNO-CCSD(T) methods. Our computational results suggest that the most favorable mechanism of the CsOH-promoted cyclization of the fumaramide into trans-β -lactam within [2]rotaxane initiates with deprotonation of a N -benzyl group of the interlocked fumaramide substrate by CsOH, followed by the trans -selective C-C bond formation and protonation by one amide functional group of the macrocycle. Our distortion/interaction analysis further shows that the uncommon trans -stereoselective cyclization forming β-lactam within the rotaxane may be attributed to a higher distortion energy (mainly from the distortion of the twisted cis- fumaramide conformation enforced by the rotaxane). Our systematic study should give deeper mechanistic insight into the reaction mechanism influenced by a supramolecular host.