Hydrogen‐Bond‐Enabled Dynamic Kinetic Resolution of Axially Chiral Amides Mediated by a Chiral Counterion

Abstract

Non-biaryl atropisomers are valuable in medicine, materials,a nd catalysis,b ut their enantioselective synthesis remains ac hallenge.Herein, acounterion-mediated O-alkylation method for the generation of atropisomeric amides with an er up to 99:1 is outlined. This dynamic kinetic resolution is enabled by the observation that the rate of racemization of atropisomeric naphthamides is significantly increased by the presence of an intramolecular OÀH···NCO hydrogen bond. Upon O-alkylation of the H-bond donor,the barrier to rotation is significantly increased. Quantum calculations demonstrate that the intramolecular H-bond reduces the rotational barrier about the aryl-amide bond, stabilizing the planar transition state for racemization by approximately 40 kJ mol À1 ,t hereby facilitating the observed dynamic kinetic resolution.

Organocatalytic Atroposelective Dynamic Kinetic Resolution Involving Ring Manipulations

“…In a study from Smith, Paton and co-workers in 2019, the presence of an intramolecular 6-membered OÀ H•••NCO hydrogen bond in napthamides 44 bearing a 2-hydroxy group was found to be capable of stabilizing the planar transition state for the interconversion of the two enantiomeric forms, which provides an opportunity to carry out an enantioselective synthesis of axially chiral amides 45 via O-functionalization. [47] Actually, the barrier to rotation about the C aryl À C amide bond of 44 a is only 95.4 kJ/mol at 294 K in hexane solution, which is close to the boundary for atropisomerism. However, the resultant amide product 45 a upon O-alkylation of the H-bond donor has a significantly higher barrier to rotation of 131.4 kJ/mol (394 K in m-xylene).…”

“…The use of hydrogen bonding represents an ingenious alternative for manipulating configurational stability around a rotating axis. In a study from Smith, Paton and co‐workers in 2019, the presence of an intramolecular 6‐membered O−H⋅⋅⋅NCO hydrogen bond in napthamides 44 bearing a 2‐hydroxy group was found to be capable of stabilizing the planar transition state for the interconversion of the two enantiomeric forms, which provides an opportunity to carry out an enantioselective synthesis of axially chiral amides 45 via O‐functionalization [47] . Actually, the barrier to rotation about the C aryl −C amide bond of 44 a is only 95.4 kJ/mol at 294 K in hexane solution, which is close to the boundary for atropisomerism.…”

Diversity-Oriented Enantioselective Construction of Atropisomeric Heterobiaryls and N -Aryl Indoles via Vinylidene Ortho -Quinone Methides

“…[50][51][52][53][54] Stereoselective methods toward the preparation of individual compound with multiple stereogenic axes are highly desirable. [55][56][57][58][59][60][61][62][63] As a result, with 5a as the substrate and NIS as the iodation agent, the reaction proceeded smoothly to give the corresponding product 6a bearing both C-C and C-N axes in good yield by using cinchona-squaramide catalysts. After screening reaction conditions, catalyst C was identified as the optimal catalyst and high enantioselectivity was achieved with toluene as the solvent at 25 o C (Table 4a, entry 10), albeit the diastereoselectivity of the transformation was not satisfactory (dr = 7:1) under current reaction conditions.…”

Synthesis of Atropisomeric Triazoles with Vicinal 1,5-Diaxes via Rhodium-Catalyzed Click Chemistry

“…Commercially available reagents and solvents were used without further purification. 1 H nuclear magnetic resonance (NMR) and 13 C NMR 19 F NMR and 31 P NMR spectra were recorded at room temperature in DMSO-d6 or CDCl3 on a 400 MHz instrument. Flash column chromatography was performed on silica gel (200-300 mesh).…”

“…Given the relevance of axial chirality, numerous efforts have been dedicated to the synthesis of atropisomers, and remarkable advances have been achieved during the past few decades [10][11][12][13][14][15][16][17] . Nevertheless, these achievements mainly focus on the preparation of atropisomers with a single axis [18][19][20][21][22][23][24][25][26][27][28][29] , while the synthesis of atropisomers with more than one axes are rarely reported [30][31][32] , probably owing to the formidable challenges in establishing multi-axes with efficient chiral control. Multi-axes are also widely found in biologically valuable molecules (Scheme.…”