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

Abstract

Quinazolin-4-one derivatives possessing an isotopic atropisomerism (isotopic N–C axial chirality) based on ortho-12CH3/13CH3 discrimination were prepared. The diastereomeric quinazolin-4-ones bearing an asymmetric carbon as well as an isotopic atropisomerism were clearly discriminated by 1H and 13C NMR spectra and revealed to possess high rotational stability and stereochemical purity.

Structural Chemistry of C–N Axially Chiral Compounds

“…33 We investigated the synthesis of quinazolinone-based isotopic atropisomers possessing high rotational stability and stereochemical purity (Scheme 4). 36,37 Key synthetic intermediates (P)-24 and (M)-24 were prepared as optically pure forms through (R)-or (S)-DTBM-SEGPHOS-Pd-catalyzed reductive kinetic resolution with The synthesis of diastereomeric isotopic atropisomers bearing a chiral carbon was further investigated (Scheme 5). Diastereomeric 3-arylquinazolin-4-ones 28 based on ortho-CH 3 /CD 3 discrimination were synthesized by α-benzylation of the enolate prepared from the key synthetic intermediate (P)-24 (99% ee) and diastereomer separation followed by Suzuki− Miyaura coupling of the diastereomers (P,S)-27 and (P,R)-27 with CD 3 B(OH) 3 .…”

“…We investigated the synthesis of quinazolinone-based isotopic atropisomers possessing high rotational stability and stereochemical purity (Scheme ). , Key synthetic intermediates ( P )-24 and ( M )-24 were prepared as optically pure forms through ( R )- or ( S )-DTBM-SEGPHOS-Pd-catalyzed reductive kinetic resolution with racemic 24 followed by SDE using MPLC. Subsequently, Suzuki–Miyaura coupling of ( P )-24 and ( M )-24 with CD 3 B(OH) 2 or 13 CH 3 B(OCMe 2 −) 2 gave isotopic atropisomers ( P )-25 and ( M )-25 or ( P )-26 and ( M )-26 , respectively.…”