Conformational enantiodiscrimination for asymmetric construction of atropisomers

Abstract

Molecular conformations induced by the rotation about single bonds play a crucial role in chemical transformations. Revealing the relationship between the conformations of chiral catalysts and the enantiodiscrimination is a formidable challenge due to the great difficulty in isolating the conformers. Herein, we report a chiral catalytic system composed of an achiral catalytically active unit and an axially chiral 1,1'-bi-2-naphthol (BINOL) unit which are connected via a C-O single bond. The two conformers of the catalyst induced by the rotation about the C-O bond, are determined via single-crystal X-ray diffraction and found to respectively lead to the formation of highly important axially chiral 1,1'-binaphthyl-2,2'-diamine (BINAM) and 2-amino-2'-hydroxy-1,1'-binaphthyl (NOBIN) derivatives in high yields (up to 98%), with excellent enantioselectivities (up to 98:2 e.r.) and opposite absolute configurations. The results highlight the importance of conformational dynamics of chiral catalysts in asymmetric catalysis.

Fig. 1. Rotations about single bonds and conformational enantiodiscrimination.

a C–C bond rotation in ethane. b Restricted rotation about the C–C single bonds in atropisomers. c Rotation about the C–C single bond locked in BINAP-metal complexes and BINOL-based phosphoric acids. d Design of a chiral catalytic system for conformational enantiodiscrimination enabling asymmetric construction of atropisomers with opposite absolute configurations. BINOL, 1,1′-bi-2-naphthol; BINAM, 1,1′-binaphthyl-2,2′-diamine; NOBIN, 2-amino-2′-hydroxy-1,1′-binaphthyl; BINAP, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Ph, phenyl; CPA, chiral phosphoric acids.

Fig. 2. Conformational enantiodiscrimination for the asymmetric cross-coupling of azonaphthalenes with 2-naphthylamines.

a Shield screening (48 h). b Influence of the hydroxy group (48 h). c Substrate scope (60 h). Reaction conditions: 1 (0.10 mmol), 2 (0.12 mmol), 1,2-dichlorobenzene (2.0 mL), under air, 30 °C unless noted otherwise (3n: 40 °C). All yields are isolated. Enantiomeric ratios (e.r.) were determined via HPLC analysis and reported as (R:S). Me, methyl; ⁿPr, n-propyl; Bn, benzyl; Ph, phenyl. The absolute configuration of all the products with blue thick bonds is R.

Fig. 3. Conformational enantiodiscrimination for the asymmetric cross-coupling of azonaphthalenes with 2-naphthols.

a Influence of the conformational equilibrium on enantiodiscrimination. b Substrate scope. Reaction conditions: 1 (0.10 mmol), 4 (0.12 mmol), Cu(acac)₂ (10 mol%), ligand (12 mol%), m-xylene (2.0 mL), under N₂, at 25 °C. All yields are isolated. Enantiomeric ratios (e.r.) were determined via HPLC analysis and reported as (R:S). Me, methyl; ⁿPr, n-propyl; ⁱPr, iso-propyl; Bn, benzyl; Ph, phenyl. The absolute configuration of all the products with red thick bonds is S.

Fig. 4. Determination of the conformers via single-crystal X-ray diffraction.

a Copper complex Cu-1 prepared from L8, Cu(MeCN)₄PF₆ and 2-(anthracen-9-yl)−9-chloro-1,10-phenanthroline (L15). b Copper complex Cu-2 prepared from L13 and CuCl.