Monte Carlo Simulations on Atropisomerism of Thienotriazolodiazepines Applicable to Slow Transition Phenomena Using Potential Energy Surfaces by <i>ab initio</i> Molecular Orbital Calculations

Abstract

Compounds with a medium-sized flexible ring often show atropisomerism that is caused by the highenergy barriers between long-lived conformers that can be isolated and often have different biological properties to each other. In this study, the frequency of the transition between the two stable conformers, aS and aR, of thienotriazolodiazepine compounds with flexible 7-membered rings was estimated computationally by Monte Carlo (MC) simulations and validated experimentally by NMR experiments. To estimate the energy barriers for transitions as precisely as possible, the potential energy (PE) surfaces used in the MC simulations were calculated by molecular orbital (MO) methods. To accomplish the MC simulations with the MObased PE surfaces in a practical central processing unit (CPU) time, the MO-based PE of each conformer was pre-calculated and stored before the MC simulations, and then only referred to during the MC simulations. The activation energies for transitions calculated by the MC simulations agreed well with the experimental ΔG determined by the NMR experiments. The analysis of the transition trajectories of the MC simulations revealed that the transition occurred not only through the transition states, but also through many different transition paths. Our computational methods gave us quantitative estimates of atropisomerism of the thienotriazolodiazepine compounds in a practical period of time, and the method could be applicable for other slow-dynamics phenomena that cannot be investigated by other atomistic simulations.Key words atropisomerism; Monte Carlo simulation; molecular orbital method; diazepine Stereoisomers often show different biological activity, pharmacokinetics and toxicity profiles because a ligand is threedimensionally recognized by biological receptors. Therefore regulatory guidelines, such as Food and Drug Administration (FDA) guidelines, 1) often request information on the biological properties of each stereoisomer in the drug development process. In addition to classical stereoisomers with chiral centers, much attention has been paid recently to the atropisomer. 2-4)A compound which has axial chiralities caused by hindered rotations about rotatable bonds shows atropisomerism. Compounds showing atropisomerism have long-lived (1000 s or longer) conformers that can be isolated, 5) and, like classical stereoisomers, each long-lived conformer often shows different biological activities. 2,3)Atropisomerism is caused by the high energy barrier between long-lived conformers due to the steric and/or electronic repulsions and is often observed in compounds with bulky substituents in the ortho positions. Half lives (t 1/2 ) of the atropisomers are dependent on the energy barriers, thus the degree of atropisomerism is time-dependent.2-5) For compounds with an energy barrier of 120 kJ/mol or higher, the atropisomers have a t 1/2 of several years at room temperature and behave like classical stereoisomers, but when the energy barrier is lower than 80 kJ/mol, the t 1/2 is less than 10 s and compou...