Investigation into the Energy Requirements for Macrocyclization of Novel Lysine-based Macrocycles through DFT calculations and their Synthesis

Background: Macrocycles have long been on the radar of the drug industry since they bridge the chemical space between small molecules and biologics, offering the oral administration of the former and novel target interactions of the latter. However, their synthesis is renowned for its complexity, hindering their development into drugs and therefore prevalence on the drug market. Aim: The present study investigated the geometric requirements of a palladium-catalysed aminocarbonylation leading to the macrocyclization of lysine with aryl dihalides. Promising aryl dihalides were then to be used in the synthesis of novel lysine-based macrocycles. Methods: Density Functional Theory (DFT) was used to calculate activation energies of the reaction of eight aryl dihalides. Synthesis of a 1,8-diiodoanthracene-based lysine macrocycle was then carried out through palladium-catalysed aminocarbonylation. Results: Transition states for seven of the various substrates were found with activation energies ranging from 7.44 to 138 kJ/mol. In terms of experimental parameters, higher temperatures, as well as lower aryl dihalide concentrations, yielded an increase in macrocycle formation, as opposed to longer reaction times. Optimized conditions for macrocyclization of 1,8-diiodoanthracene with lysine were at 80 °C for 24 h with 17 equivalents of Mo(CO)6 and a 5 mMaryl dihalide concentration, achieving an isolated yield of 19%. Conclusion: Quantum chemical modelling, together with experimental testing has for the first time enabled the synthesis of an aryl dihalide-lysine-based macrocycle.