Asymmetric Synthesis of Axially Chiral C−N Atropisomers

Abstract

Molecules with restricted rotation around a single bond or atropisomers are found in a wide number of natural products and bioactive molecules as well as in chiral ligands for asymmetric catalysis and smart materials. Although most of these compounds are biaryls and heterobiaryls displaying a CÀ C stereogenic axis, there is a growing interest in less common and more challenging axially chiral CÀ N atropisomers. This review offers an overview of the various methodologies available for their asymmetric synthesis. A brief introduction is initially given to contextualize these axially chiral skeletons, including a historical background and examples of natural products containing axially chiral CÀ N axes. The preparation of different families of CÀ N based atropisomers is then presented from anilides to chiral fiveand six-membered ring heterocycles. Special emphasis has been given to modern catalytic asymmetric strategies over the past decade for the synthesis of these chiral scaffolds. Applications of these methods to the preparation of natural products and biologically active molecules will be highlighted along the text.

Rotational Behavior of N-(5-Substituted-pyrimidin-2-yl)anilines: Relayed Electronic Effect in Two N–Ar Bond Rotations

“…Purification of the residue by column chromatography (hexane/AcOEt = 5) gave 1g (145 mg, total 42%). 1g: yellow solid; mp 104−106 °C; IR (neat) 2926 cm −1 ; 1 H NMR (400 MHz, CDCl 2 −CDCl 2 ) δ: 9.21 (1H,d,J = 3.3 Hz),8.96 (1H,d,J = 3.3 Hz),7.57 (1H,m),m),7.21 (1H,m),4.27 (1H,d,J = 12.3 Hz),4.23 (1H,d,J = 12.3 Hz),3.57 (3H,s), 3.31 (3H, s); 13 C{ 1 H} NMR (100 MHz, CDCl 2 −CDCl 2 ) δ: 162.0, 154. 9, 154.6, 141.9, 135.2, 134.1, 129.5, 129.4, 128.1, 127.1, 70.7, 58.5, 39.6; MS (ESI-TOF) m/z: [M + Na] + 297; HRMS (ESI-TOF) m/z: [M + Na] + Calcd for C 13 H 14 N 4 NaO 3 297.0964; Found 297.0958.…”

“…Purification of the residue by column chromatography (hexane/AcOEt = 5) gave 1b (36 mg, total 32%). 1b: brown oil; IR (neat) 2926 cm −1 ; 1 H NMR (500 MHz, CDCl 2 −CDCl 2 ) δ: 8.11 (2H,s),7.55 (1H,d,J = 7.1 Hz),m),7.21 (1H,d,J = 7.1 Hz),4.29 (2H,s),3.81 (3H,d,s),3.41 (3H,s),3.33 (3H,s); 13 C{ 1 H} NMR (100 MHz, CDCl 2 −CDCl 2 ) δ: 157. 4, 146.3, 144.8, 144.0, 136.4, 128.7, 128.5, 127.7, 126.6, 70.6, 58.4, 56.7, 38.9 N-Methyl-N-(5-methylpyrimidin-2-yl)-2-methoxymethylaniline (1c).…”

“…Purification of the residue by column chromatography (hexane/AcOEt = 10) gave 1f (42 mg, total 14%). 1f: brown oil; IR (neat) 2930, 1711 cm −1 ; 1 H NMR (400 MHz, CDCl 2 −CDCl 2 ) δ: 8.99 (1H, s), 8.75 (1H, s), 7.56 (1H, dd, J = 6.6, 2.4 Hz), 7.37−7.43 (2H, m), 7.21 (1H, dd, J = 6.6, 2.4 Hz), 4.32 (2H, q, J = 7.1 Hz), 4.27 (1H,d,J = 12.3 Hz),4.23 (1H,d,J = 12.3 Hz),3.50 (3H,s),3.31 (3H,s), 1.35 (3H, t, J = 7.1 Hz); 13 C{ 1 H} NMR (100 MHz, CDCl 2 −CDCl 2 ) δ: 164.7, 162.4, 159.8, 159.6, 142.5, 135.8, 129.1, 129.0, 127.50, 127.47, 113.3, 70.6, 60.7, 58.4, 39.0, 14.3…”

Copper- and Chiral Nitroxide-Catalyzed Oxidative Kinetic Resolution of Axially Chiral N-Arylpyrroles

“…Despite their synthetic utility, conventional approaches to synthesize chiral arylpyrroles rely on the optical resolution of racemic substrates using stoichiometric resolving agents . To date, only three catalytic protocols have been developed for the synthesis of axially chiral N -arylpyrroles. − To this end, and inspired by the pioneering work of Bin Tan on the synthesis of axially chiral N -arylpyrroles, we hypothesized that the unique structure of our chiral nitroxide catalyst would allow the OKR of axially chiral compounds such as the N -arylpyrrole alcohol with the general structure 7 allowing access to both the recovered alcohol and the oxidized product in optically pure form (Scheme c).…”

Pd-Catalyzed Dynamic Kinetic Asymmetric Cross-Coupling of Heterobiaryl Bromides with N-Tosylhydrazones

“… 2 Remarkably, an axially chiral (hetero)biaryl constitutes the central core of many privileged chiral ligands, catalysts, and auxiliaries that are routinely employed in asymmetric synthesis. 3 Consequently, a great deal of effort has already been devoted to the efficient preparation 4 of these chiral structures, including the asymmetric coupling of two aryl groups by oxidative dimerization or cross-coupling, 5 asymmetric [2+2+2] cycloadditions, 6 asymmetric ring opening of bridged biaryl lactones, 7 stereoselective functionalization of prochiral biaryls, in particular by C–H functionalization, 8 (dynamic) kinetic resolutions, 9 and a growing number of organocatalytic approaches. 10 Our group reported in 2013 an alternative methodology for the synthesis of heterobiaryls (e.g., 2-arylpyridines or analogues) consisting of Pd-catalyzed dynamic kinetic asymmetric (DYKAT) coupling between aryl boroxines and racemic heterobiaryl triflates.…”