Catalytic synthesis of 9-cis-retinoids: mechanistic insights

Abstract

The regioselective Z-isomerization of thermodynamically stable all-trans retinoids remains challenging, and ultimately limits the availability of much needed therapeutics for the treatment of human diseases. We present here a novel, straightforward approach for the catalytic Z-isomerization of retinoids using conventional heat treatment or microwave irradiation. A screen of 20 transition metal-based catalysts identified an optimal approach for the regioselective production of Z-retinoids. The most effective catalytic system was comprised of a palladium complex with labile ligands. Several mechanistic studies, including isotopic H/D exchange and state-of-the-art quantum chemical calculations using coupled cluster methods indicate that the isomerization is initiated by catalyst dimerization followed by the formation of a cyclic, six-membered chloropalladate catalyst-substrate adduct, which eventually opens to produce the desired Z-isomer. The synthetic development described here, combined with thorough mechanistic analysis of the underlying chemistry, highlights the use of readily available transition metal-based catalysts in straightforward formats for gram-scale drug synthesis.

Figure 1.

The structures of transition metal-based complexes. Pd metal-based catalysts with small/labile and bulky/rigid ligands are represented in blue for the central metal. Pt metal catalysts with small and bulky ligands are represented in purple for the central metal. Ru metal catalysts are represented in green for the central metal and Ir, Au and Rh metal catalysts are represented in red, orange and brown respectively for the central metal.

Figure 2.

Z-isomerization of all-trans-retinyl acetate. A) Palladium chloride diacetonitrile complex-catalyzed isomerization reaction of all-trans-retinyl acetate 1c, producing 9-cis 2c and 13-cis 3c isomers. B) HPLC chromatogram of a mixture of retinyl acetate isomers obtained from traditional heat treatment. C) Temperature effects on isomerization of 1c to 2c.

Figure 3.

Z-isomerization of all-trans-retinyl acetate 1c (0.1 mmol) with catalyst V (2 mol %) in CH₃CN. 9-cis-retinyl acetate 2c yields under conventional heating and microwave irradiation.

Figure 4.

Mechanistic study of Pd-catalyzed retinyl acetate Z-isomerization reaction. A) Reaction of all-trans-retinyl acetate 1c with 2 mol % (CH₃CN)₂PdCl₂ I in CD₃CN or CD₃OD (1) or in the presence of TEMPO (2) at several concentrations. B) LC-MS of retinyl acetate isomers obtained after heat treatment with catalyst I and characteristic MS/MS fragmentation patterns of the parent ion m/z = 269 [M + H]⁺. C) Comparison of 1c yields in the absence and presence of TEMPO, monitored by HPLC.

Figure 5.

Z-isomerization of all-trans-retinal 1a catalyzed by (CH₃CN)₂PdCl₂ I in CH₃CN at 65 °C. A) Concentration change of 1a (0.1 M) as a function of time in different concentrations of catalyst I, 0.95 mM represented by blue, 1.53 mM represented by green, 2.44 mM represented by red and 3.91 mM represented by black. B) Observed pseudo-first-order rate constants (k_obs)*[1a₀] plotted as a function of Pd^1.71. k_obs= 0.24[Pd]^1.71[1a₀]⁻¹.

Figure 6.

Relaxed potential energy surface scans along the dihedral angle (α) that defines the rotations around three key double bonds of 1a. α=0° corresponds to the cis isomer, while α=180° corresponds to the trans conformation. Calculations were performed at the BP86+D3 level of theory.

Figure 7.

DLPNO-CCSD(T) free energy surfaces for all-trans-retinal 1a Z-isomerization reaction catalyzed by a dimeric form of catalyst I.

Scheme 1.

Synthetic strategies for cis-retinoids. A) The E to Z isomerization of retinoids from previous work using multistep total synthesis. B) Our approach illustrating the catalytic synthesis of 9-cis-retinoids using conventional heat and microwave irradiation, followed by a repetitive crystallization method.

Scheme 2.

Large-scale synthesis pathway of 9-cis-retinal 2a. a) (CH₃CN)₂PdCl₂, TFA, hexane at 65 °C, 20 h. b) NaOH, ethanol at 40 °C, 30 min. c) MnO₂, DCM, 24 h.