Synthesis of axially chiral diaryl ethers via NHC-catalyzed atroposelective esterification

Abstract

Axially chiral diaryl ethers bearing two potential axes find unique applications in bioactive molecules and catalysis. However, only very few catalytic methods have been developed to construct structurally diverse diaryl ethers. We herein describe an NHC-catalyzed atroposelective esterification of prochiral dialdehydes, leading to the construction of enantioenriched axially chiral diaryl ethers. Mechanistic studies indicate that the matched kinetic resolutions play an essential role in the challenging chiral induction of flexible dual-axial chirality by removing minor enantiomers via over-functionalization. This protocol features mild conditions, excellent enantioselectivity, broad substrate scope, and applicability to late-stage functionalization, and provides a modular platform for the synthesis of axially chiral diaryl ethers and their derivatives.

Scheme 1. Catalytic asymmetric construction of diaryl ether-type atropisomers.

Scheme 2. Scope for the desymmetrizing esterification of axially pre-chiral dialdehydes.^{a,b a} Unless otherwise noted, all the reactions were carried out with 1 (0.1 mmol), 2 (0.5 mmol), C1 (15 mol%), DQ (1.2 equiv.), Cs₂CO₃ (1.5 equiv.), and dry DCM (1.0 mL) at 0 °C under a N₂ atmosphere for 72 h. ^b The isolated yield and ee were determined by chiral-phase HPLC analysis. ^c THF was used instead of DCM. ^d Reactions were performed at −20 °C. ^e Reactions were carried out with 2 (3.0 equiv.). ^f Reactions were carried out with C1 (10 mol%).

Scheme 3. Large-scale synthesis and follow-up transformations. Reaction conditions: (a) C1 (15 mol%), Cs₂CO₃ (1.5 equiv.), DQ (1.2 equiv.), dry DCM (0.1 M), −20 °C, N₂, 72 h; (b) P-(1-diazo-2-oxopropyl)-dimethylester (1.5 equiv.), K₂CO₃ (2.0 equiv.), MeOH (1 mL), rt, 12 h; (c) [MePPh₃]⁺Br⁻ (1.2 equiv.), ⁿBuLi (1.2 equiv.), dry THF (0.1 M), 0 °C, 30 min, then 3ar, rt, 12 h; (d) NaBH₄ (1.0 equiv.), THF/CH₃OH = 3 : 1 (0.1 M), 0 °C, 12 h; (e) 4-methoxyaniline (2.0 equiv.), LiHMDS (3.0 equiv.), PhMe (1 mL), rt, 12 h; (f) NaOAc (2.0 equiv.), NH₂OH·HCl (2.0 equiv.), MeOH (0.9 mL), H₂O (0.1 mL), rt, 3 h; (g) NaClO₂ (3.7 equiv.), NaH₂PO₄ (5.0 equiv.), 2-methylbut-2-ene (13.0 equiv.), ^tBuOH (0.15 M), rt, overnight; (h) LiOH·H₂O (4.0 equiv.), THF and H₂O (v/v = 1 : 1), rt, 24 h; (i) diethylamine (1.2 equiv.), EDCl (1.5 equiv.), DMAP (1.5 equiv.), DCM (1.5 mL), rt, 24 h; (j) TsNHNH₂ (1.2 equiv.), 2-bromo-3,3,3-trifluoropropene (2.0 equiv.), DBU (3.0 equiv.), PhMe (1 mL), 60 °C, 6 h.

Scheme 4. Mechanistic studies and proposed mechanism. s = ln[(1 − Conv.)(1 − ee_s)]/ln[(1 − Conv.)(1 + ee_s)].