Z-isomerization of retinoids through combination of monochromatic photoisomerization and metal catalysis

Abstract

Catalytic Z-isomerization of retinoids to their thermodynamically less stable Z-isomer remains a challenge. In this report, we present a photochemical approach for the catalytic Z-isomerization of retinoids using monochromatic wavelength UV irradiation treatment. We have developed a straightforward approach for the synthesis of Z-retinoids in high yield, overcoming common obstacles normally associated with their synthesis. Calculations based on density functional theory (DFT) have allowed us to correlate the experimentally observed Z-isomer distribution of retinoids with the energies of chemically important intermediates, which include ground- and excited-state potential energy surfaces. We also demonstrate the application of the current method by synthesizing gram-scale quantities of 9-cis-retinyl acetate 9Z-a. Operational simplicity and gram-scale ability make this chemistry a very practical solution to the problem of Z-isomer retinoid synthesis.

Figure 1.

Screening of wavelength bands for the isomerization of E to Z retinyl acetate. A) The yield of 9Z-a using different wavelengths over 4 h. B) HPLC chromatograms of all-trans to 9-cis isomer after 0 (black), 20 min (pink), 1 (green), 2 (purple), and 4 (blue) h irradiation at 385 nm. Peak 13Z-a represents 13-cis, Peak 9Z-a represents 9-cis, Peak 7Z-a represents 7-cis, and Peak E-a represents all-trans.

Figure 2.

A) Reaction progress monitoring the isomerization of all-trans-retinyl acetate to the 9-cis isomer. B) Dose dependency of E retinyl acetate. C) Energy level measurements.

Figure 3.

Relationship between the distribution of cis-retinyl acetate isomers. A) Time course of the reaction from E to Z and backward. B) Absorbance spectra of all-trans E-a and 9-cis 9Z-a isomers.

Figure 4.

Exploring a catalyst effect on the distribution of cis-retinyl acetate isomers.

Figure 5.

Computed Jablonski diagrams of the photochemical isomerizations of (A) retinyl acetate E-a and (B) retinal E-d. Singlet and triplet states are represented with solid and dashed lines. Color code denotes the isomer of interest: all-trans (black), 7-cis (red), 9-cis (green), 11-cis (yellow), 13-cis (violet). Fast processes are represented with solid arrows (absorption, emission, relaxation), while slow processes are depicted with dotted lines (intersystem crossing, ISC) or dot-dash lines (phosphorescence, phosph). T₁^TS denotes transition states for rotations around C=C bonds in the first triplet state and MECP is the minimum energy crossing point that approximates the true conical intersection point between S₀ and S₁ surfaces. Computed absorption wavelength (λ_max) maxima and the fluorescence rates (k_fluor) are provided for all ground state isomers.

Figure 6.

Experimental and calculated UV-VIS spectra for retinyl acetate E-a and in a complex with catalyst III. A) Experimental spectra of the retinyl acetate E-a (black), catalyst III (red) and the complex of the two (magenta). B) Computed spectra of the retinyl acetate E-a. On the right: one-electron orbital picture of two key transitions.

Figure 7.

UV-Vis absorption spectra of opsin (black) and opsin with addition of all-trans-retinal E-a (blue dashed) after irradiation with 395 nm UV light for 5 min, 10 min and 15 min.

Scheme 1.

Photoisomerization of retinoids in two different pathways. Top arrow: isomerization with monochromatic UV light in the presence of catalyst produces mainly 13-cis among the cis isomers. Bottom arrow: isomerization with monochromatic UV light produces mainly the 9-cis among the cis isomers.

Scheme 2.

Theoretical reaction pathway for the Z-isomerization of all-trans-retinyl acetate E-a.

Scheme 3.

Gram-scale synthesis of 9-cis-retinyl acetate 9Z-a.