Atropisomeric Properties of 7-, 8-, and 9-Membered-Ring Dibenzolactams: Conformation, Thermal Stability, and Chemical Reactivity

Tabata, Hidetsugu; Suzuki, Hiroyuki; Akiba, Kazuto; Takahashi, Hideyo; Natsugari, Hideaki

doi:10.1021/jo1013383

Cited by 56 publications

(42 citation statements)

References 19 publications

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“…These compounds possess a flexible 7-membered ring, thus they were considered to have a possibility of atropisomerism caused by the ring inversion of the 7-membered ring like other compounds with 7-membered rings. 6,7,[10][11][12] Potential Energy Surfaces As shown in Fig. 1, four rotatable torsion angles (ϕ 1 , ϕ 2 , ϕ 3 , and ϕ 4 ) that cause the ring inversion of the 7-membered ring of TTDZ should be considered when evaluating the atropisomerism.…”

Section: Methodsmentioning

confidence: 99%

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

Morikami

Itezono

Nishimoto

et al. 2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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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...

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Section: Methodsmentioning

confidence: 99%

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

Morikami

Itezono

Nishimoto

et al. 2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Notably, the quaternary carbon center induces a chiral biaryl axis and only a single diastereomer is observed. Without the stereocenter at C2, this axis has a rather low inversion barrier 20…”

Section: Optimization Of the Enantioselective Ch Arylation Of 1 A[a]mentioning

confidence: 99%

Enantioselective CH Arylation Strategy for Functionalized Dibenzazepinones with Quaternary Stereocenters

Saget

Cramer

2013

Angewandte Chemie

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“…[14] Although both achiral and point chiral dibenzazepinones with potent biological activity are known ( Figure 1), [15] enantioselective routes towards derivatives bearing exclusively an axis of chirality have yet to be disclosed. [16] Herein we report the realization of such as trategy by ap alladium(0)-catalyzed intramolecular CÀHa rylation of achiral amides. Early scouting experiments in the laboratory were guided by computational prediction of product racemization kinetics.…”

mentioning

confidence: 99%

Axially Chiral Dibenzazepinones by a Palladium(0)‐Catalyzed Atropo‐enantioselective C−H Arylation

et al. 2018

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Atropo-enantioselective C À Hf unctionalization reactions are largely limited to the dynamic kinetic resolution of biaryl substrates through the introduction of steric bulk proximalt ot he axis of chirality.R eported herein is ah ighly atropo-enantioselective palladium(0)-catalyzed methodology that forges the axis of chirality during the C À Hf unctionalization process,e nabling the synthesis of axially chiral dibenzazepinones.C omputational investigations support experimentally determined racemization barriers,w hile also indicating CÀHf unctionalization proceeds by an enantio-determining CMD to yield configurationally stable eight-membered palladacycles.

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Atropisomeric Properties of 7-, 8-, and 9-Membered-Ring Dibenzolactams: Conformation, Thermal Stability, and Chemical Reactivity

Cited by 56 publications

References 19 publications

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

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

Enantioselective CH Arylation Strategy for Functionalized Dibenzazepinones with Quaternary Stereocenters

Axially Chiral Dibenzazepinones by a Palladium(0)‐Catalyzed Atropo‐enantioselective C−H Arylation

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