Asymmetric Synthesis of Isotopic Atropisomers based on ortho-CH₃/CD₃ Discrimination and Their Structural Properties

Abstract

N–C axially chiral 3-(2-trideuteriomethyl-4,6-dimethylphenyl)-2-ethylquinazolin-4-ones and 3-(2-trideuteriomethyl-4,6-dimethylphenyl)-2-(1-phenylpropan-2-yl)­quinazolin-4-ones were prepared in high enantio- and diastereomeric purities (98% ee). These quinazolinone derivatives are isotopic atropisomers based on ortho-CH3/CD3 discrimination and were revealed to possess a slight optical rotation and high rotational stability.

Synthesis of Isotopic Atropisomers Based on 12C/13C Discrimination

“…Thus, since the verification of isotopic atropisomerism in 2 was difficult, the conversion to a diastereomeric derivative was subsequently investigated. We previously found that, in the NMR spectra of diastereomeric quinazolinone derivatives ( P,S )- VI and ( P,R )- VI possessing an asymmetric carbon atom and CH 3 /CD 3 isotopic atropisomerism, the chemical shifts of hydrogens and carbon in the ortho -methyl group clearly differ between the diastereomers due to the anisotropic effect by the benzene ring of the benzyl group on the asymmetric carbon . On the basis of this result, diastereomeric quinazolinones ( P,S )- 4 and ( P,R )- 4 were prepared (Scheme ).…”

“…Indeed, in enantioenriched compounds VII – X , their optical rotations were not detected. From the viewpoint of further development of isotopic atropisomeric chemistry based on the N–C axially chiral quinazolinone scaffold, , we were curious about 3-arylquinazolin-4-one derivatives bearing ortho - 12 CH 3 and 13 CH 3 groups. In this paper, we report on the asymmetric synthesis of atropisomeric 3-(2- 13 C-methyl-4,6-dimethylphenyl)­quinazolin-4-ones 2 and 4 , and the verification of their atropisomerism.…”

“…We thought that both enantiomers of isotopic atropisomer (2-ethtylquinazolin-4-one 2 ) based on 12 CH 3 / 13 CH 3 discrimination can be prepared in accordance with the synthetic route of CH 3 /CD 3 -atropisomeric quinazolin-4-one derivative V . V was prepared by the Suzuki–Miyaura cross-coupling of CD 3 B­(OH) 2 (3 equiv) with optically pure ( P )- 1 which was obtained through ( R )-DTBM-SEGPHOS-Pd­(OAc) 2 -catalyzed hydrodebromination (reductive kinetic resolution) with racemic 3-(2-bromo-4,6-dimethylphenyl)-2-ethylquinazolin-4-one rac - 1 , followed by optical purification (self-disproportionation of enantiomers) using medium pressure liquid chromatography (MPLC) …”

“…Meanwhile, since 13 C-methyl boronic acid pinacol ester is very expensive, the optimization of cross-coupling conditions was explored by using inexpensive 12 C-enriched methyl boronic acid pinacol ester. Although an excessive amount (3 equiv) of CD 3 B­(OH) 2 was required in the synthesis of CH 3 /CD 3 derivatives V and VI , after a detailed survey of the coupling conditions, it was found that the coupling product 2 could be obtained by using 1.2 equiv of boronic reagent. That is, when ( P )- 1 was treated with 1.2 equiv of 13 C-methyl boronic acid pinacol ester in the presence of DPPP-Pd­(OAc) 2 catalyst under refluxing 1,4-dioxane–H 2 O (25 h), the coupling product ( P )- 2 was obtained in 53% yield (Scheme ).…”

Synthesis and Chiroptical Properties of a Chiral Isotopologue of syn-Cryptophane-B

“…Several interesting examples have been reported in the literature (compounds A−F in Scheme 1) and different chiroptical tools have been used to characterize them. 5,6 It should be noted that the vast majority of chiral isotopologues studied concern molecules with asymmetric carbons (compounds B, C, D, and F). Conversely, chiral isotopologues with an inherent chiral structure are much less common and only a few examples have been reported so far (see for example compounds A and E).…”