Catalytic Asymmetric Synthesis of Atropisomers Featuring an Aza Axis

Abstract

Metrics & More Article Recommendations CONSPECTUS: Atropisomers bearing a rotation-restricted axis are common structural units in natural products, chiral ligands, and drugs; thus, the prevalence of asymmetric synthesis has increased in recent decades. Research into atropisomers featuring an N-containing axis (N−X atropisomers) remains in its infancy compared with the well-developed C−C atropisomer analogue. Notably, N−X atropisomers could offer divergent scaffolds, which are extremely important in bioactive molecules. The asymmetric synthesis of N−X atropisomers is recognized as both appealing and challenging. Recently, we devoted our efforts to the catalytic asymmetric synthesis of N−X atropisomers, benzimidazole−aryl N−C atropisomers, indole−aryl N−C atropisomers, hydrogen-bond-assisted N−C atropisomers, pyrrole−pyrrole N−N atropisomers, pyrrole−indole N−N atropisomers, and indole−indole N−N atropisomers. To obtain the N−C atropisomers, an asymmetric Buchwald−Hartwig reaction of amidines or enamines was employed. Using a Pd(OAc) 2 /(S)-BINAP or Pd(OAc) 2 /(S)-Xyl-BINAP catalyst system, benzimidazole−aryl N−C atropisomers and indole−aryl N−C atropisomers were readily obtained. To address the issue of the reduced stability of the diarylamine axis, a six-membered intramolecular N−H−O hydrogen bond was introduced into the N−C atropisomer scaffold. A tandem N-arylation/oxidation process was used for the chiral phosphoric acid (CPA)-catalyzed asymmetric synthesis of N-aryl quinone atropisomers. For N−N atropisomers, a copper-mediated asymmetric Friedel−Crafts alkylation/arylation reaction was developed. The desymmetrization process was completed successfully via a Cu(OTf) 2 /chiral bisoxazoline or (CuOTf)•Tol/bis(phosphine) dioxide system, thereby achieving the first catalytic asymmetric synthesis of N/N bipyrrole atropisomers. Asymmetric Buchwald−Hartwig amination of enamines was utilized to provide N−N bisindole atropisomers with excellent stereogenic control. This was the first asymmetric synthesis of N−N atropisomers featuring a bisindole structural scaffold using the de novo indole construction strategy. The asymmetric N−N heterobiaryl atropisomer synthesis was substantially facilitated using palladium-catalyzed transient directing group (TDG)-mediated C−H functionalization. Atropisomeric alkenylation, allylation, or alkynylation was accomplished using the Pd(OAc) 2 /L-tert-leucine system. Herein, we summarize our work on the palladium-, copper-, and CPA-catalyzed asymmetric syntheses of N−C and N−N atropisomers. Furthermore, the application of our work in the synthesis of bioactive molecule analogues and axially chiral ligands is demonstrated. Subsequently, the stability of the chiral N-containing axis is briefly discussed in terms of single crystals and obtained rotational barriers. Finally, an outlook on the asymmetric N−X atropisomer synthesis is provided.

Regio‐ and Atroposelective Ring‐Opening of 1H‐Benzo[4,5]oxazolopyridinones

“…This methodology features regio-and enantioselective CÀ O bond activation/ arylation, facilitated by the use of an inexpensive and airstable nickel salt. The reaction also took an advantage by using readily available starting materials, 1H-benzo [4,5]oxazolopyridinones, which only required heating the two substrates in acetic acid, followed by crystallization from the solvent. Finally, diverse post-functionalizations, such as preparing CÀ N atropisomeric phosphine, were briefly demonstrated.…”

“…The past decade has witnessed significant advancements in the construction of CÀ N axial chirality, owing to the prevalence of this atropisomeric unit in natural products, pharmaceuticals, and chiral ligands. [1][2][3][4][5][6] Several powerful strategies have been established, such as metal-or organocatalyzed enantioselective CÀ N coupling, [7][8][9][10][11] de novo synthesis of arenes or heteroarenes, [12][13][14][15][16][17][18][19][20] desymmetrization process [21][22][23][24][25][26] and dynamic kinetic resolution (DKR). [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] However, there still remains a pressing need to develop new approaches to enhance the diversity of CÀ N atropisomers, especially the biologically active motifs.…”

Regio‐ and Atroposelective Ring‐Opening of 1H‐Benzo[4,5]oxazolopyridinones

“…The past decade has witnessed significant advancements in the construction of C−N axial chirality, owing to the prevalence of this atropisomeric unit in natural products, pharmaceuticals, and chiral ligands [1–6] . Several powerful strategies have been established, such as metal‐ or organocatalyzed enantioselective C−N coupling, [7–11] de novo synthesis of arenes or heteroarenes, [12–20] desymmetrization process [21–26] and dynamic kinetic resolution ( DKR ) [27–41] .…”

Nitro-Enabled Atroposelective Dynamic Kinetic Resolution of 2-Arylindoles by Phase-Transfer Catalysis

“…In particular, indoles bearing an ortho -substituted aromatic ring can exhibit chirality depending on the rotational barrier around a single bond. Because substitutions on indoles are typically concentrated on the N-1, C-2, and C-3 positions, both in nature and in laboratories because of their inherent reactivity, catalytic and atroposelective methods have been developed for synthesizing these arylindoles . Among them, the catalytic and enantioselective synthesis of N -arylindoles and 3-arylindoles have been extensively investigated, even though 2-arylindoles are considered the most privileged scaffolds with broad-ranging pharmacological activities as shown in Figure a …”