Triple Thorpe-Ingold Effect in the Synthesis of 18-Membered C-3 Symmetric Lactams Stacking as Endless Supramolecular Tubes

Three C-3 symmetric macrolactams were very efficiently cyclized from their linear precursors. Adequately located substituents are responsible for the enhancement of reactivity that is not observed in the unsubstituted parent. DFT calculations show that the properly folded cyclization precursor, the reactive conformer, is more populated than other conformers, leading to a decrease of free energy of activation. The crystal structure of the ring substituted with three very bulky esters indicates that tubular stacking is preserved.

Automated summary

Three C-3 symmetric macrolactams were efficiently cyclized from linear precursors by properly locating substituents, resulting in enhanced reactivity compared to the unsubstituted parent. DFT calculations showed that the reactive conformer, the properly folded cyclization precursor, was more populated than other conformers, leading to a decrease in the activation free energy. The crystal structure of the ester-substituted ring with three bulky esters revealed the preservation of tubular stacking.