Stereocontrolled Construction of Multi-Chiral [2.2]Paracyclophanes via Cobaltaphotoredox Dual Catalysis

Abstract

Ortho-/pseudo-disubstituted multichiral [2.2]-paracyclophanes (PCPs) represent privileged scaffolds for asymmetric catalysis, finding extensive applications as chiral ligands in organic synthesis and functional materials. However, enantioselective C-H activation strategies for accessing these structurally demanding molecules remain largely underexplored. We report a synergistic strategy combining photoredox catalysis with enantioselective cobalt-catalyzed C-H activation that enables efficient construction of central chiral and planar chiral PCP derivatives through kinetic resolution. This method provides access to diverse disubstituted multichiral PCPs in good yields with exceptional levels of enantioselectivity (>20:1 dr, >99% ee) while simultaneously recovering the unreacted enantiomer in a high optical purity (up to 50% yield, >99% ee). Computational studies reveal the favorable pathway for a single enantiomer of the racemic PCP, rationalizing the observed enantioselectivity in terms of attractive dispersion interactions emerging as key contributors during the enantiodetermining step. The synthetic utility is demonstrated through: (1) gram-scale continuous photoflow synthesis with maintained efficiency and (2) versatile downstream functionalization of the products into valuable PCP-based ligands. Our findings represent a paradigm shift for the synthesis of sterically congested chiral PCP architectures, significantly expanding the toolbox for asymmetric synthesis and chiral material design.

Keywords: C–H activation; [2.2]paracyclophanes; enantioselective cobalt catalysis; flow chemistry; photoredox catalysis.

1

Design blueprint for the assembly of multichiral PCPs via enantioselective C–H activation. (A) Representative chiral ligands and catalysts with PCP skeletons. (B) Strategies for the synthesis of chiral PCPs. (C) Our findings.

2

Optimization of the reaction parameters: ^aReaction conditions: 1a (0.15 mmol, 1.0 equiv),2a (0.15 mmol, 1.0 equiv), PC (0.0075 mmol, 5 mol %), Co­(OAc)₂·4H₂O (0.015 mmol, 10 mol %), L (0.015 mmol, 10 mol %), base (0.15 mmol, 1.0 equiv), TFE (1.0 mL), DCE (0.25 mL), 32–35 °C, 48 h. ^bDimer byproduct: 16% yield. ^cAcyloxylation byproduct: 19% yield. ^dYields were determined by ¹H-NMR using 1,3,5-trimethoxybenzene as the internal standard; isolated yields after column chromatography are shown in parentheses. ^eThe dr value was determined by ¹H-NMR analysis. ^fThe ee value was determined by chiral high-performance liquid chromatography (HPLC) analysis. Q = 8-quinolinyl. PC = photocatalyst. TFE = 2,2,2-trifluoroethanol. DCE = 1,2-dichloroethane. DIPA = diisopropylamine. Calculated conversion, C = ee_SM/(ee_SM + ee_PR); selectivity (S) = ln­[(1 – C)­(1 – ee_SM)]/ln­[(1 – C)­(1 + ee_SM)].

3

Scope of amides with alkenes. Reaction conditions: 1 (0.15 mmol, 1.0 equiv),2 (0.15 mmol, 1.0 equiv), Rhodamine 6G (0.0075 mmol, 5 mol %), Co­(OAc)₂·4H₂O (0.015 mmol, 10 mol %), L (0.015 mmol, 10 mol %), DIPA (0.15 mmol, 1.0 equiv), TFE (1.0 mL), DCE (0.25 mL), 32–35 °C, 24–72 h. ^aCo­(OAc)₂·4H₂O (0.030 mmol, 20 mol %), L (0.030 mmol, 20 mol %).^b 2 (0.075 mmol, 0.5 equiv).

4

(A) Flow photochemistry for the scale-up reaction. (B) Transformations; a: 50% H₂SO₄ (aq.), dioxane at 120 °C for 24 h. b: K₂CO₃ and MeI in MeCN at RT for 16 h. c: DMAP, EDCI, and R-1-(2-naphthyl)­ethylamine in DCM at RT for 24 h. d: DMAP, EDCI, and l -valinol in DCM at RT for 24 h. e: MsCl, DMAP, and NEt₃ in DCM at RT for 16 h.

5

Computational studies. (A) Computed Gibbs free energies (ΔG _308.15) for the elementary steps. (B) Distortion analysis of both enantiomers’ TS1. (C) NICS analysis of the PCP fragment for both enantiomers. Energies reported are in kcal mol^–1, hydrogen atoms from focused PCP fragments were removed for clarity, and the key interatomic distances are labeled in Å.