Catalytic Enantioselective Synthesis of N–C Axially Chiral Mebroqualone and Its Derivatives through Reductive Asymmetric Desymmetrization

Abstract

In the presence of (R)-DTBM-SEGPHOS-Pd(OAc) catalyst, treatment of various 3-(2,6-dibromophenyl)quinazolin-4-ones with NaBH gave optically active N-C axially chiral quinazolinone (mebroqualone) derivatives through reductive asymmetric desymmetrization (enantioselective monohydrodebromination) followed by kinetic resolution of the resulting monobromophenyl products (up to 99% ee). The enantioselectivity strongly depended on the substituent (R) at the C4'position, amount of NaBH, and reaction temperature.

Highly atroposelective synthesis of nonbiaryl naphthalene-1,2-diamine N-C atropisomers through direct enantioselective C-H amination

“…Until recently, the preparation of these optically active N-C nonbiaryl atropisomers still depends largely on the chiral resolution and diastereoselective synthesis using chiral pool precursors 15–17 . Only few strategies for catalytic atroposelective construction of N-C nonbiaryl atropisomers exist and mainly consist of enantioselective cyclization 18–20 , N-functionalization 21–27 , and desymmetrization 28–30 of the existing achiral N-C bond. The direct catalytic enantioselective method to build a new chiral N-C bond to form nonbiaryl N-C atropisomers still has significant synthetic challenges and has attracted great interest.

Fig.

…”

Enhanced Reactivity by Torsional Strain of Cyclic Diaryliodonium in Cu-Catalyzed Enantioselective Ring-Opening Reaction

“…[13][14][15] In addition, modification of the existing biaryl structures enables access to enantio-enriched atropisomers via either a desymmetrization reaction or (dynamic) kinetic resolution (Scheme 1D). [16][17][18][19][20][21][22][23][24][25] Furthermore, the construction of benzylic center chirality, followed by center-to-axial chirality transfer aromatization is also an effective approach to access enantio-enriched biaryl atropisomers. 26,27 Recently, there have been a number of reports on organocatalyzed asymmetric atropisomer synthesis.…”

Possible Case of Halogen Bond‐Driven Self‐Disproportionation of Enantiomers (SDE) via Achiral Chromatography

“…With these results in hand, we focused our attention on the structural generality of this approach, studying possible effect of various substituents on the magnitude of the observed SDE and the preparative efficiency in terms of the enantiomeric purifications. To this end, we prepared seven, previously reported derivatives 1 b – d , f , g presented in Figure . All experiments were conducted under the same chromatographic conditions developed for the original mebroqualone 1 a .…”

“…Although direct observation of high‐order species in solution is not possible, it was shown that a very sound idea about a preference for homo‐/heterochiral molecular associations can be obtained by considering the crystallographic structures of racemic and enantiomerically pure compounds . To this end, we performed X‐ray studies of parent compound enantiomerically pure mebroqualone ( P )‐ 1 a (99 % ee ) and its racemic form ( P / M )‐ 1 a ; the data are presented in Figure .…”

“…Mebroqualone 1 a (Figure ), possessing an N−C axially chiral structure, and its analogs present an important family of GABAergic drugs possessing potent sedative, hypnotic, and anticonvulsant properties . Among the recent synthetic methods for preparation of these quinazolinone‐derived drugs, catalytic enantioselective desymmetrization of the corresponding o , o ‐dibromo derivatives represents the most advanced approach allowing for convenient access to various synthesis mebroqualone derivatives . Quite typically for the most of catalytic asymmetric reactions, this method furnishes products with variable enantioselectivity ranging from 29 to 99 % ee , thwarting the study of their biological properties.…”