Central-to-Helical-to-Axial-to-Central Transfer of Chirality with a Photoresponsive Catalyst

Abstract

Recent advances in molecular design have displayed striking examples of dynamic chirality transfer between various elements of chirality, e.g., from central to either helical or axial chirality and vice versa. While considerable progress in atroposelective synthesis has been made, it is intriguing to design chiral molecular switches able to provide selective and dynamic control of axial chirality with an external stimulus to modulate stereochemical functions. Here, we report the synthesis and characterization of a photoresponsive bis(2-phenol)-substituted molecular switch 1. The unique design exhibits a dynamic hybrid central-helical-axial transfer of chirality. The change of preferential axial chirality in the biaryl motif is coupled to the reversible switching of helicity of the overcrowded alkene core, dictated by the fixed stereogenic center. The potential for dynamic control of axial chirality was demonstrated by using ( R)-1 as switchable catalyst to direct the stereochemical outcome of the catalytic enantioselective addition of diethylzinc to aromatic aldehydes, with successful reversal of enantioselectivity for several substrates.

Scheme 1. Isomerization Processes Leading to Unidirectional Rotation in Second Generation Molecular Motor

Four-stage cycle with only two distinct stereoisomers in case of symmetrically substituted lower half (here R = R′). S = stable isomer, MS = metastable isomer.

Scheme 2. Design of Photoswitchable 2,2′-Biphenol-Substituted Overcrowded Alkene 1

The assigned descriptors are based on the structure of compound (R)-1 (for explanation of the chiral descriptors, vide infra). Axial helicity and chirality (green) of the 2,2′-biphenol core are coupled to axial helicity (blue) and point chirality (red) of the molecular switch scaffold. Two diastereomers with opposite coupled helicity can be selectively addressed by irradiation with UV light: (R,P,S_a)-1 (S); (R,M,R_a)-1 (MS).

Figure 1

(a) Example of top-down schematic view and front structural view of (R,P₌,P_a,S_a)-1. Upper half ring (red, methyl substituent omitted); fluorenyl lower half (blue); biaryl moiety (black). Assigned stereodescriptors based on the structure of compound (R)-1 (see main text for details). (b) Depiction of four conformations of the biaryl moiety as viewed from the top along the central double bond and biaryl single bond. (c) Hydrogen-bonding assisted biaryl rotation of 2,2′-biphenol with inversion of stereochemistry. (d) Schematic energy vs biaryl torsional angle profile upon clockwise rotation of lower phenol group around the biaryl single bond in (R)-1.

Scheme 3. Switching Process between the Rotamers of Stable and Metastable Isomers of (R)-1

Proposed ground states of rotamers and transition states (middle) of atropisomerization processes, as viewed from the top along the axis given by the double bond. Top and bottom left: rotamers of stable isomer (R,P,S_a/R_a)-1; top and bottom right: metastable isomer (R,M,R_a/S_a)-1.

Scheme 4. Synthesis and Chiral Resolution of 2,2′-Biphenol Molecular Switch 1

Note on resolution of 1: (i) result from first resolution; (ii) (S,M,R_a/S_a)-1 obtained by second resolution of the solid fraction: (8S,9R)-(−)-N-benzylcinchonidinium chloride 10 (0.9 equiv), 79% yield, > 99% ee (solid); (R,P,S_a/R_a)-1 obtained by second resolution of the residue from solution: 10 (0.3 equiv), 81% ee (residue from solution), followed by recrystallization from EtOH/H₂O = 1:1 of the residue from solution, 15% yield, 96% ee.

Figure 2

(a) X-ray structure of (R,P,S_a)-1. Left: front view; right: top view. Ellipsoids set at 50% probability. Hydrogen bond lengths (intra: H101–O1 1.874 Å, inter: H100–O1′ 1.826 Å) and oxygen–oxygen distances (intra: O1–O2 2.629 Å, inter: O1–O2′ 2.685 Å). (b) Newman projections. Left: top view through overcrowded alkene bond. Right: top view through aryl–aryl bond of biaryl unit. Torsional angles of alkene unit (13.92°) and biaryl unit (55.71°) are shown.

Figure 3

(a) Schematic representation of the photochemical E–Z isomerization of stable atropisomers (R,P,S_a/R_a)-1 to metastable atropisomers (R,M,R_a/S_a)-1. ¹H NMR spectra of (R)-1 (∼5.0 mg, toluene-d₈ (0.7 mL), 25 °C): (b) stable state (R,P,S_a/R_a)-1 (A:B = 67:33); (c) after irradiation with UV light (365 nm) of (R)-1 to the metastable state (R,M,R_a/S_a)-1 (∼65% of MS); (d) metastable state (R,M,R_a/S_a)-1 (C:D = 58:42) isolated by preparative HPLC from the irradiated mixture (see Supporting Information for details).

Scheme 5. Mono- and Bidentate Coordination Equilibrium upon Reaction of (R)-1 with Organozinc Reagents

(a) Depiction of the possible mono- and bidentate coordination species upon reaction of stable isomers of 1 with ZnR₂. (b) Only the isomers with a syn conformation (torsion angle = 0° to ±90°) were expected to efficiently bind a metal center and successfully transfer the chirality within a catalytically active complex. (c) Light-assisted dual stereocontrol could be achieved in a catalyzed organometallic reaction upon photoisomerization of (R)-1 and internal transfer of chirality to the coordinated metal site.

Figure 4

(a) Schematic representation of photochemical E–Z isomerization of stable isomer (R,P,S_a/R_a)-1 to metastable isomer (R,M,R_a/S_a)-1. (b) Experimental UV–vis absorption spectra of stable (R,P,S_a/R_a)-1 (toluene, 4.5 × 10^–5 M, black) and upon irradiation with UV light (365 nm) of (R,P,S_a/R_a)-1 toward the metastable isomer affording a PSS₃₆₅ mixture (S/MS = 17:83, red) with an isosbestic point at 368 nm. (c) Experimental UV–vis absorption spectra after irradiation of the PSS₃₆₅ sample using visible light (420 nm), resulting in reversed E–Z isomerization toward the stable isomer affording a new PSS₄₂₀ mixture (S/MS = 50:50). (d) Irradiation cycles of (R)-1 (toluene, ∼4.0 × 10^–5 M) in the presence of TEMPO (∼10^–5 M) toward opposite PSS mixtures (red: 365 nm, 4 min; blue: 420 nm, 15 min). (e) Experimental and calculated CD spectra of (R)-1 (toluene, 5.0 × 10^–1 M): black, starting stable isomer (R,P,S_a/R_a)-1; red: CD spectra of PSS₃₆₅ mixture; blue: CD spectra of PSS₄₂₀ mixture; cyan: metastable isomer (R,M,R_a/S_a)-1. Note: PSS ratios determined by HPLC analysis of the irradiated solutions via quantitative analysis with PDA detector wavelength set at the isosbestic point (368 nm).