Catalytic synthesis of 9-cis-retinoids: Mechanistic insights

Article abstract of DOI:10.1039/c9dt02189b

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.

Full text of DOI:10.1039/c9dt02189b

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Catalytic synthesis of 9-cis-retinoids: mechanistic
insights†
Cite this: DOI: 10.1039/c9dt02189b
Shirin Kahremany,*a,b Adam Kubas, *c Gregory P. Tochtropd and
a,b
Krzysztof Palczewski
*
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 cata-
lytic 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 for-
mation 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.
Received 24th May 2019,
Accepted 10th June 2019
DOI: 10.1039/c9dt02189b
rsc.li/dalton
required for vision via genetic abnormalities in the enzymes
required for either all-trans-retinyl ester formation (lecithin :
Introduction
Retinoids are an essential class of biomolecules1 involved in retinol acyl transferase or LRAT) or isomerization of these
vertebrate growth and development, cell differentiation, esters by a retinoid isomerase, RPE65.12 Although pharmaco-
embryonic development,2 vision,3,4 immunological mecha- logic delivery of 11-cis-retioids is not possible due to their
nisms,5 and reproduction.6 The ability to gain straightforward metabolic instability, 9-cis-retinoids have been delivered effec-
synthetic access to the various cis-isomers of the polyene chain tively to treat this disease.10,11,13 In addition to their use in the
is of utmost translational importance. One example of a clini- treatment of LCA, several retinoids have shown promising
cally important cis-isomer is 13-cis-retinoic acid, which is used activity as antitumor and chemopreventive agents against
clinically to treat a broad number of disorders, including oral cancer by inhibiting carcinogenesis at the initiation, pro-
leukoplakia and severe acne.7–9 While efficient synthetic access motion, and progression stages.3 The anticancer activity of
to 13-cis-retinoids has been established for some time, the retinoids is mainly due to their binding to nuclear receptors
catalytic production of 9-cis-retinoids from their all-trans that act as hormone receptors activating target genes.14,15
counterparts remains elusive. 9-cis-Retiniods are of critical
Several methods for the production of 9-cis-retinoids have
importance due to the clinical utility of 9-cis-retinoids in treat- been reported, including total synthesis,16–19 however these
ing a subset of Leber congenital amaurosis (LCA), an inherited methods are complicated and require multi-step preparations
retinal degenerative disease.10,11 The molecular etiology of LCA with low yield and contamination by several geometric
is the inability to generate the 11-cis-retinoid chromophore isomers. In one example, the synthesis of 9-cis-retinyl acetate
is comprised of several sequential steps: (i) the Reformatsky
reaction between β-cyclocitral and ethyl 4-bromo-3-methylbut-
aGavin Herbert Eye Institute, Department of Ophthalmology, University of California,
2-enoate, (ii) reduction and acidification steps, (iii) the
Irvine, CA, 92697, USA. E-mail: kpalczew@uci.edu, skahrema@uci.edu
bDepartment of Pharmacology, Case Western Reserve University, Cleveland, OH,
Horner–Emmons reaction, (iv) ester reduction to 9-cis-retinol
and (v) esterification to obtain 9-cis-retinyl acetate with an
overall yield of <8%.20
Inspired by the need for more efficient routes to the thermo-
dynamically less stable Z-retinoids, our current investigation
examines the effect of the catalytic Z-isomerization of seven
representative retinoids. In this study, we examine the ability of
44106, USA
cInstitute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52,
01-224 Warsaw, Poland. E-mail: akubas@ichf.edu.pl
dDepartment of Chemistry, Case Western Reserve University, Cleveland, OH, 44106,
USA
†Electronic supplementary information (ESI) available: Experimental details and
characterization data (PDF). See DOI: 10.1039/c9dt02189b
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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 crystalliza-
tion method.
20 commercially available transition metal-based catalysts to were stored in N,N-dimethylformamide under argon at −80 °C.
induce Z-isomerization and describe a method of repetitive Retinoid analysis was performed on an Agilent 1200 series
crystallization to increase the yield to 100%. We subsequently HPLC equipped with a diode array detector and Agilent
perform extensive mechanistic studies to rationalize our catalytic Chemstation A.10.01 software (Agilent, Palo Alto, CA). A
yields and Z-isomer product distribution (Scheme 1).
normal phase column (Beckman Ultrasphere Si 5μ, 4.6 ×
250 mm [Beckman Instruments, Fullerton, CA]) and an iso-
cratic solvent system of 2–10% ethyl acetate in hexane (v/v)
were used at 20 °C and a flow rate of 1.4 ml min−1
.
Materials and methods
Reagents
A reverse phase column (C18 4.6 × 250 mm, 5 μm,
Phenomenex, Torrance, CA) and an isocratic solvent system of
40% (v/v) CH3CN in aqueous 0.1% trifluoroacetic acid (TFA)
were used. For retinal, retinal derivatives, retinol and retinyl
acetate, the analyses were performed at 325 nm. Retinoic acid
analysis was performed at a flow rate of 1 ml min−1 at 20 °C
with detection at 355 nm.
All reagents, catalysts, and standard retinoids were obtained
from commercial suppliers (Sigma Aldrich, St Louis, MO and
Toronto Research Chemical, Toronto, Canada) and used
without any further purification, unless otherwise noted.
Instrumentation
All the HPLC measurements were calibrated using stan-
Nuclear magnetic resonance (NMR) spectroscopy. The NMR dards of all-trans-retinoids, 9-cis-retinoids, 13-cis-retinods and
spectra were recorded on a Bruker 500 MHz and 800 MHz 4-keto-9,13-dicis-retinal.
apparatus at 25 °C, and referenced relative to the residual
Conventional reactions. Reactions were carried out by dissol-
1
proton resonances of C6D6 (δ = 7.16 ppm). H NMR spectra of ving retinoids (0.1 mmol), triethylamine (TEA, 1 mol%), cata-
the compounds were collected with their corresponding 2D lyst (2 mol%) in different solvents for 2–20 h at 65 °C under
nuclear Overhauser effect spectroscopy, and heteronuclear argon atmosphere and dark conditions. After the treatment,
single quantum coherence (HSQC) spectroscopy. Spectra were samples were dissolved in hexane or CH3CN and analyzed by
processed using MestReNova software (Mestrelab Research). reverse phase or normal phase HPLC.
The coupling constants (J) are reported in hertz (Hz).
For mechanistic studies, the reaction of all-trans-retinal 0.1
Mass spectroscopy (MS). MS-based detection was performed M with 2 mol% catalyst I, (CH3CN)2PdCl2 in CH3CN at 65 °C
with an LTQ linear ion trap mass spectrometer (ThermoFisher was performed in the presence of TEMPO (2,2,6,6-tetramethyl-
Scientific, Waltham, MA) equipped with an electrospray ionization 1-piperidinyloxy), 1, 5 and 10 mol% and monitored by HPLC
interface operated in the positive ionization mode. Parameters of for 2 h.
ionization and detection were tuned with standards.
Microwave reactions. Reactions were performed for
High performance liquid chromatography (HPLC) analysis. 5–20 min under dark conditions. Retinoids (0.1 mmol) and
Procedures were performed under a dim red light. Retinoids selected catalysts (2 mol%) were dissolved in DMF or CH3CN.
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The samples were then transferred to 10 ml screw-capped crystallization to obtain compound 2d (90%, 40 g). 1H NMR
glass vials, and the headspace was purged with nitrogen gas, (500 MHz, C6D6) δ 7.01 (d, J = 16.1 Hz, 1H), 6.91 (dd, J = 15.1,
and vials were immediately closed to minimize oxygen 11.4 Hz, 1H), 6.33 (d, J = 16.0 Hz, 1H), 6.25 (d, J = 15.1 Hz, 1H),
exposure. Subsequently, the samples were microwave-treated at 6.09 (d, J = 11.3 Hz, 1H), 5.58 (t, J = 6.8 Hz, 1H), 3.96 (d, J =
60–150 °C and 70–150 W power (Biotage LLC, NC, USA). After 6.7 Hz, 2H), 1.94 (s, 5H), 1.87 (d, J = 15.5 Hz, 1H), 1.81 (s, 3H),
the treatment, samples were extracted with 0.4 mL hexane and 1.57 (dd, J = 7.6, 4.3 Hz, 2H), 1.54 (s, 4H), 1.49–1.42 (m, 2H),
analyzed by HPLC.
1.11 (s, 6H).
Kinetic studies. A stock solution of all-trans-retinal 1a, 0.1 M
and catalyst I, 0.01 M were prepared. The reactions were per-
formed in four conditions with 1a and dilution of catalyst
Complete NMR assignment was previously reported22
Synthesis of 9-cis-retinal (2a). To a solution of 2d (20 g,
I (0.95–4 mol%; 0.004–0.00095 M). The reactions were initiated 0.07 mol) in dry methylene chloride (200 ml), manganese
by addition of catalyst I, (CH3CN)2PdCl2 (final concentration of dioxide (170 g, 1.9 mol) was added in the dark and the mixture
0.954, 1.53, 2.44 and 3.91 mM), in CH3CN at 65 °C for 2 h. All was stirred overnight at room temperature. The mixture was
manipulations were done under dim light and the reactions then filtered, and the filtrate was evaporated; both steps were
were performed in amber glass vials. At various times a small conducted under vacuum. The resulting oil was dissolved in
aliquot of 10 µL was removed and added to a mixture of hexane (80 ml) and cooled to −80 °C. Crystals from the oil
100 µL H2O and 50 µL of hexane. After extraction, 10 µL of were filtered by suction using a filter precooled with dry ice to
hexane layer were injected into the HPLC to monitor the obtain compound 2a (80%, 15 g). 1H NMR (400 MHz, CDCl3) δ
change in all-trans-retinal absorbance at λ = 360 nm. The pro- 10.09 (d, J = 8.2 Hz, 1H), 7.22 (dd, J = 15, 11.6 Hz, 1H), 6.66 (d,
cedure was repeated three times.
J = 15.8 Hz, 1H), 6.33 (d, J = 15.8 Hz, 1H), 6.30 (d, J = 15 Hz,
Synthesis of 9-cis-retinyl acetate (2c). All-trans-retinyl acetate 1H), 6.09 (d, J = 11.6 Hz, 1H), 5.97 (d, J = 8.2 Hz, 1H), 2.31 (s,
1c (300 g, 0.91 mol) was dissolved in a solution of hexane 3H), 2.05 (m, 2H), 2.02 (s, 3H), 1.75 (s, 3H), 1.64 (m, 2H), 1.48
(600 ml) and TEA (0.11 ml, 0.83 mmol). After addition of 4 g (m, 2H), 1.04 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 191.4,
(0.018 mol) of (CH3CN)2PdCl2 I, the mixture was stirred over- 155.2, 140.4, 138.2, 134.0, 131.5, 131.3, 130.6, 129.5, 129.2,
night in the dark at 65 °C under nitrogen. The resulting solu- 128.1, 39.64, 34.45 33.28, 29.20, 22.09, 21.21, 19.38, 13.40.
tion was cooled to room temperature for 1 h and then further
NMR assignment was previously reported23
cooled to −80 °C. The all-trans-retinyl acetate that crystallized
was filtered by suction using a filter precooled with dry ice.
Synthesis of 4-keto-retinal (1g). The compounds were pre-
The filtrate was concentrated and further crystallized. pared according to the procedure described in the literature.24
This process was repeated to obtain a 70 : 30 mixture of 9-cis-/ Briefly, to the all-trans-retinal (500 mg, 1.76 mmol) in a
all-trans-retinyl acetate, which mostly was used for the next mixture of CH3CN (34.9 mL) solution, CH2Cl2 (3.5 mL) and
steps without further purification (70%, 80 g).
H2O (3.5 mL), NBS (622.4 mg, 3.49 mmol) was added at
One hundred milligrams of the above mixture were purified −15 °C under a red dim light. After 5 min, N,N-diethylaniline
as a control by HPLC with 2% ethyl acetate : hexane, producing (349.6 µL) was added. The reaction mixture was stirred an
the desired compound, 9-cis-retinyl acetate 2c (65%, 55 mg). additional 5 min, poured into 5% aqueous Na2S2O3 solution
1H NMR (500 MHz, C6D6) δ (ppm) 7.02–6.84 (m, 2H), 6.31(d, and extracted with Diethylether (×3). The combined organic
J = 15.9 Hz, 1H), 6.20 (d, J = 15.1 Hz, 1H), 6.03 (d, J = 11.4 Hz, solution was washed with 1 M aqueous HCl solution, H2O,
1H), 5.61 (t, J = 7.3 Hz, 1H), 4.61 (d, J = 7.3 Hz, 2H), 1.96–1.91 and brine successively. After drying with MgSO4, the extract
(m, 5H), 1.79 (s, 3H), 1.66 (s, 3H), 1.57–1.53 (m, 5H), 1.46–1.43 was concentrated under reduced pressure and purified by
(m, 2H), 1.10 (s, 6H). 13C NMR (126 MHz, C6D6) δ 170.08, HPLC with 10% ethyl acetate : hexane, producing the desired
1
138.94, 138.54, 136.10, 134.97, 130.71, 129.64, 129.61, 128.90, compound, 4-keto-all-trans-retinal 1g (80%, 350 mg). H NMR
125.67, 124.75, 61.14, 39.81, 34.53, 33.26, 29.19, 22.07, 20.53, (800 MHz, C6D6) δ (ppm) 10.00 (d, J = 7.8 Hz, 1H), 6.73 (dd, J =
19.67, 12.53.
15.1, 11.4 Hz, 1H), 6.21 (d, J = 16.2 Hz, 1H), 6.14 (d, J =
16.2 Hz, 1H), 6.03 (d, J = 15.1 Hz, 1H), 5.95 (dd, J = 21.5,
9.6 Hz, 2H), 2.39 (m, 2H), 2.10 (s, 3H), 1.69 (s, 3H), 1.65
NMR assignment was previously reported21
Synthesis of 9-cis-retinol (2d). To a mixture of 70 : 30 (9-cis- (s, 3H), 1.47 (m, 2H,), 0.91 (s, 6H). 13C NMR (126 MHz, C6D6)
retinyl acetate/all-trans-retinyl acetate) obtained above (50 ml) δ (ppm) 196.82, 189.48, 158.59, 152.16, 139.91, 138.42, 136.80,
in ethanol (180 ml), a solution of NaOH (18 g, 0.45 mol) in 132.56, 130.50, 130.40, 130.03, 127.98, 127.78, 127.59, 126.44,
water (80 ml) was added dropwise at 40 °C under nitrogen in 37.20, 35.19, 34.19, 27.15, 13.85, 12.15.
the dark. After stirring for 30 min, the mixture was cooled to
NMR assignment was previously reported24
0 °C and then extracted with hexanes (3 × 200 ml). The com-
bined organic layers were washed with ice water twice, dried
Synthesis of 4-keto-retinal isomers (2g–4g). 4-Keto-all-trans-
over anhydrous MgSO4, filtered, and the filtrate was concen- retinal (400 mg, 1.34 mmol) was dissolved in a solution of
trated under vacuum. The resultant yellow oil was dissolved in CH3CN (80 ml). After addition of 8 mg (0.03 mmol) of bis
a solution of pyridine (0.18 ml) in methyl formate (90 ml), (benzonitrile)palladium chloride, the mixture was stirred for
stirred at 0 °C for 2 h, and then cooled to −20 °C for overnight 2 h in the dark at 65 °C under nitrogen. The resulting solution
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CBS
HF
def2ꢀTZVPP
was cooled to room temperature, concentrated under reduced polation scheme (this yields
E
,
E(corr)
and
MP2
pressure and purified by HPLC with 10% ethyl acetate : hexane, E(corr)CMBPS2).32 The final DLPNO-CCSD(T)/CBS energy is esti-
producing the desired compounds, 4-keto-9-cis-retinal 2g mated as:38
(20%, 100 mg), 4-keto-13-cis-retinal 3g (30%, 120 mg), and
4-keto-9,13-dicis-retinal 4g (10%, 40 mg).
def2ꢀTZVPP
CBS
EðDLPNO ꢀ CCSDðTÞ=CBSÞ ꢁ E
þ EðcorrÞCC
HF
ꢀ
ꢁ
CBS
def2ꢀTZVPP
4-Keto-9-cis-retinal 2g. 1H NMR (800 MHz, C6D6) δ (ppm)
9.94 (d, J = 7.9 Hz, 1H), 6.95–6.85 (m, 2H), 6.15 (d, J = 16.0 Hz,
1H), 5.97–5.91 (m, 2H), 5.89 (d, J = 11.6 Hz, 1H), 2.37–2.33 (m,
2H), 2.10 (s, 3H),1.75 (s, 3H), 1.59 (s, 3H), 1.49–1.43 (m, 2H),
0.88 (s, 6H).
þ
EðcorrÞMP2 ꢀ EðcorrÞMP2
:
Thermodynamic corrections calculated at the BP86+D3
level were added to the final E(DLPNO-CCSD(T)/CBS) energies
to obtain Gibbs free energies. If not stated otherwise, the final
relative G(DLPNO-CCSD(T)/CBS) values are reported in the
body of the manuscript.
4-Keto-13-cis-retinal 3g. 1H NMR (800 MHz, C6D6) δ (ppm)
10.13 (d, J = 7.2 Hz, 1H), 7.11 (d, J = 14.9 Hz, 2H), 6.66 (dd, J =
15.0, 11.4 Hz, 1H), 6.24 (d, J = 16.2 Hz, 1H), 6.15 (d, J =
16.2 Hz, 1H), 5.97 (d, J = 11.4 Hz, 1H), 5.75 (d, J = 7.3 Hz, 1H),
2.39 (t, J = 6.9 Hz, 2H), 2.12 (s, 3H), 1.65 (s, 3H), 1.56 (s, 3H),
1.49–1.45 (m, 2H), 0.92 (s, 6H).
The resolution of identity (RI)39,40 and chain-of-spheres
(COSX)41 approximations were employed to efficiently evaluate
Coulomb and exchange integrals, respectively. The DFT inte-
gration grid was enlarged to 4 (grid4 in ORCA nomenclature)
while for numerical exchange calculations gridx5 was used.
DLPNO-CCSD(T) calculations were performed with the
NormalPNO settings that were demonstrated to provide excel-
lent balance between calculation time and accuracy.35
Structures of key intermediates, absolute energies used to
compute relative energies and number of imaginary frequen-
cies for all species reported in the manuscript are provided in
the ESI.†
4-Keto-9,13-dicis-retinal 4g. 1H NMR (800 MHz, C6D6)
δ (ppm) 10.08 (d, J = 7.3 Hz, 1H), 7.05 (d, J = 14.2 Hz, 1H),
6.90–6.82 (m, 2H), 6.15 (dd, J = 16.0, 8.4 Hz, 1H), 5.92 (d, J =
11.5 Hz, 1H), 5.70 (d, J = 7.3 Hz, 1H), 2.37–2.33 (m, 2H), 2.10
(s, 3H), 1.77 (s, 3H), 1.47 (s, 3H), 1.45–1.42 (m, 2H), 0.88 (s, 6H).
Computational study
Geometry optimizations were carried out within the density
functional theory (DFT) framework using BP86 functional25,26
and def2-TZVP basis set27 along with the corresponding def2-
ECP effective core potential assigned for metals (Pd – 28 elec-
trons replaced, Pt – 60 electrons replaced). The description of
dispersion interactions was improved with the Grimme’s D3BJ
Results and discussion
Condition optimization and screening of inorganic catalysts
correction.28,29 This DFT set-up is abbreviated as BP86+D3. In the search for an optimal catalyst, we performed the above
The obtained structures were subjected to numerical second reactions with twenty transition metal catalyst complexes (all
derivative calculations – energy minima had only positive including ruthenium, rhodium, palladium, iridium, platinum,
normal modes, while transition states had exactly one imagin- or gold) and investigated their effects on the Z-isomerization
ary mode. To check which minima were connected to a given of seven retinoid molecules. The rationale behind the utiliz-
transition state, we performed steepest descent geometry mini- ation of these metals as catalyst complexes is their ability to
mizations in forward and backward directions of the transition catalyze reactions under milder conditions with higher selecti-
mode (this procedure is known as intrinsic-reaction coordinate vity as compared to other metals.42–44
scan, IRC). All calculations were performed with the ORCA 4.1
suite of programs.30
Our list of transition metal catalysts consists of Pd metal-
based catalysts with small/labile and bulky/rigid ligands, Pt
To avoid uncertainties associated with common density metal-based catalysts with small and bulky ligands, and Ru, Ir,
functional theory approximations, we re-calculated all single- Au and Rh metal-based catalysts (Fig. 1).
point energies using a high-level wave-function-based domain-
First, we performed the catalysis reaction on seven biologi-
based local pair natural orbital-coupled cluster method with a cally relevant retinoid molecules, extensively optimizing the
single, double and perturbative triple excitations method31 at reaction conditions across different solvents and reaction
the complete basis set limit (DLPNO-CCSD(T)/CBS). The times (ESI Table S5†). We found that replacement of non-polar
method was extensively benchmarked recently in various appli- solvent (hexane) with polar, aprotic solvents (CH3CN or
cations and showed excellent accuracy with respect to experi- acetone) reduced the reaction time from 20 h to 2 h while
mental data.32–35
maintaining a favorable ratio between the cis isomers.
The complete basis set limit (CBS) was estimated in the
For example, the optimal conditions for heat-induced iso-
following way: the DLPNO-CCSD(T) calculations were carried merization of all-trans-retinyl acetate 1c with (CH3CN)2PdCl2 I
out with the def2-TZVPP basis set to obtain coupled cluster in non-polar solvent (hexane – this hydrophobic solvent was
def2ꢀTZVPP
correlation energy values, E(corr)
. Subsequently, more used because of the propensity of retinoids to convert to
CC
economic MP2 calculations36,37 were performed using def2- anhydro-vitamin A in nucleophilic or acidic solvents) and a
TZVPP and def2-QZVPP basis sets. The two calculations were mildly basic environment (triethylamine, TEA), at 65 °C for
used to obtain a Hartree–Fock reference and MP2 correlation 20 h (standard conditions), produced a 17% conversion of
energies at the CBS limit using a well-known two-point extra- 9-cis isomer 2c (Fig. 2 and ESI Table S5†). While the same reac-
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Fig. 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 rep-
resented 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.
tion in CH3CN produced a 20% conversion of 9-cis after 2 h. (Fig. 2C). Further experiments using heat as an energy source
This observation might be explained by the greater solubility were conducted at 65 °C.
of the compounds and the catalysts in this solvent. For all-
Screening using conventional heat-induced isomerization
trans-retinal 1a with the palladium catalyst I in CH3CN solvent
containing TEA at 65 °C, this yielded 38% conversion to cis We first tested heat-induced isomerization with four represen-
isomers 13-cis : 9-cis (3a : 2a) ratio of 1.3 : 1, respectively, in tative retinoids (all-trans-retinal 1a, all-trans-retinoic acid 1b,
2 hours, as determined by HPLC (ESI Table S5†).
We also observed that as the reaction temperature lysts I–XX under standard conditions. As shown in Table 1, the
increased, yields of 1c increased, reaching maximum Z-isomerization mostly occurred in the presence of Pd-based
between 65–75 °C before the retinoid levels decreased catalysts. Reaction of all-trans-retinal 1a yielded a range of
all-trans-retinyl acetate 1c and all-trans-retinol 1d) and the cata-
a
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Fig. 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.
Table 1 Transition metal-catalyzed Z-isomerization of all-trans-retinoids using traditional heat treatmenta,b
Entry
Sub
Solvent
Time
Conversionc (%)
Selectivity of 9-cis d (%)
Product (3 : 2)
Ratio range
Effective cat
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
C6H14
C6H14
C6H14
C6H14
CH3CN
CH3CN
CH3CN
20 h
20 h
20 h
20 h
2 h
2 h
2 h
33–39
15–34
18–24
16–21
24
37–44
21–98
85–90
77–94
83
39–45
45–55
13-cis : 9-cis
13-cis : 9-cis
13-cis : 9-cis
13-cis : 9-cis
12-cis : 8-cis
13-cis : 9-cis
13-cis : 9-cis
1.2–1.6 : 1
0–3.9 : 1
0.1–5.6 : 1
0.1–0.6 : 1
0.2 : 1
0–3 : 1
0–1.05 : 1
I–V, VII
I, III–V, VII
I–V, VII
II, IV, VII
I
I–V, XIX
I–XI
43–44
1g
33–46e
a Reactions were carried out with all-trans-retinoid (0.1 mmol), catalyst (2 mol%), and TEA (0.2 µmol) at 65 °C under N2. b E/Z ratios reported are
the average of two experiments and were determined by HPLC analysis. c Conversion to Z-isomer of the most effective catalysts. d Yields of 9-cis
isomer for the most effective catalysts. e 4.4% of 9,13-dicis was detected. No reaction occurred without a catalyst for all substrates.
33–39% conversion to cis isomers with the effective catalysts by a slow decrease in concentration. On the other hand, the 9-
I–V, and VII with a ratio of 1.2–1.6 : 1 3a : 2a (13-cis : 9-cis). In cis 2a isomer is most probably the thermodynamic product,
addition, the distribution of the cis-isomers 2a and 3a was with a quasi-linear increase in concentration over time (ESI,
monitored over time (ESI Fig. S3†), and showed that 13-cis 3a Fig. S3†).
is the kinetic product as the concentration of this isomer
Retinoid 1b isomerization yielded a range of 15–34% cis
increases quickly in the first 10 min of the reaction followed isomers when catalysts I, III–V and VII were used, and the best
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result was obtained in the presence of catalyst III with 34%
We investigated the effects of representative catalysts (I, V,
conversion to 9-cis isomer. Reaction of all-trans-retinyl acetate XI, XV, and XVIII–XX) on the Z-isomerization of these reti-
1c provided yields ranging from 18–24% in the presence of noids. We also evaluated the effects of solvent, temperature
I–V, and VII with the best ratio 0.1 : 1 for 3c : 2c (13-cis : 9-cis). and reaction time on the Z-isomerization. Time points were
All-trans-retinol 1d was mostly reactive with catalysts II and IV, taken after 5–20 min to investigate the reactions in two
with 19% conversion. This analogue is unstable and has a different solvents (DMF and CH3CN). The optimization indi-
high degradation rate (ESI Tables S1–S4†).
cated a superior 13-cis : 9-cis (3 : 2) ratio in DMF. The efficiency
We further investigated the reaction of three additional reti- of different temperatures and reaction times varied for individ-
noid derivatives (3-dehydro-retinal 1f, 4-keto-retinal 1g and ual retinoid derivatives (ESI Table S11†).
anhydroretinol 1e) in CH3CN for 2 h at 65 °C. The results
The results of the catalyst screen showed that only catalysts
showed that both 1f and 1g displayed the highest conversion I and V were effective for the Z-isomerization (Table 2 and ESI
to 9-cis isomer in the presence of catalysts II and V with 19% Tables S12–S14†). Retinoid 1a Z-isomerization with the active
and 22% of 2f and 2g, respectively. 1f displayed reactivity also catalysts showed that the average of the 9-cis isomer 2a
with catalyst IX (17%). Moreover, slightly lower conversion reached 15% in 5 min of microwave irradiation, when the
values were observed for 1g with XIII–XX catalysts ranging temperature reached 80 °C (ESI Table S1†). 1b isomerization
from 10–16% (ESI Tables S7 and S8†).
showed an average yield of 22% 2b with catalyst I and V, and
We also examined the possibility of synergistic catalysis the reaction of 1c yielded an average of 18% 2c in 15 min (ESI
effects but did not detect higher yields as a result of these Table S14†).
combinations (ESI Table S9†).
Additionally, we performed a time course comparison
Overall, the conventional heating method for the between conventional heating and microwave irradiation treat-
Z-isomerization of retinoids showed that six palladium metal- ment. As shown in Fig. 3, when the conventional heat-induced
based complexes (I–V and VII), all share relatively small and isomerization was conducted at 65 °C for 2 h, the 9-cis isomer
labile ligands, were more active than the rest of the metal cata- of retinoid 1c reached a 15% yield for the effective catalyst V.
lysts. Palladium complexes with bulky ligands were less reac- By microwave treatment, the 9-cis isomer content reached 13%
tive perhaps due to steric hindrances which prevented them after 10 min of irradiation.
from forming dimers (vide infra). Also, catalysts with other
central metals (e.g. Pt or Ru) were dramatically less reactive.
Our findings demonstrate that microwave-induced
Z-isomerization of retinoids is more efficient as compared to
conventional heat-induced isomerization, particularly due to
dramatically decreased reaction time. The most efficient cata-
lysts were found to be Pd-based metal catalysts in both
methods, suggesting that internal and external heat sources
may retain similar mechanisms.
Screening using microwave irradiation-induced isomerization
We subsequently investigated the effect of microwave
irradiation on the formation of Z-isomers based on the pre-
viously reported advantage of combining homogeneous cata-
lysts with microwaves. Microwave irradiation produces efficient
internal heating and dramatically reduces reaction time.45,46
Mechanistic study
Three representative retinoids, (all-trans-retinal 1a, all-trans- To further elucidate the mechanistic details related to for-
retinoic acid 1b and all-trans-retinyl acetate 1c) were chosen for mation of the Z-isomers using the effective palladium metal-
studies of microwave irradiation.
based catalysts, we carried out several experiments. The litera-
Table 2 Transition metal catalyzed Z-isomerization of all-trans-retinoids using microwave irradiationa,b
Entry
Sub
Time
Temp (°C)
Conversionc (%)
Selectivity of 9-cisd (%)
Ratio range (13-cis : 9-cis)
Effective cat
1
2
3
1a
1b
1c
5 min
10 min
15 min
80
100
80
27
24
23–27
58, 60
93
67, 85
0.67 : 1
0.07–0.09 : 1
0.2–0.5 : 1
I, V
I, V
I, V
a Reaction conditions: All-trans-retinoid (0.1 mmol) and catalyst (2 mol%) under N2 as determined by HPLC. b Each yield was averaged from n ≥ 2
reactions. c Conversion to Z-isomer of the most effective catalysts. d Yields of 9-cis-isomer for the most effective catalysts. No reaction occurred
without a catalyst for all substrates.
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does not involve a Pd–H intermediate (Fig. 4C). In light of
these findings, the reaction most likely proceeds through the
non-hydride mechanism first suggested by Tan et al.49
Kinetic study
The kinetics of E/Z interconversion of all-trans-retinal 1a was
studied by variation of the concentration of added
(CH3CN)2PdCl2 I, 0.95 ≤ [catalyst I] ≤ 4 mM. Complete dataset
and fits are shown in Fig. 5A. As illustrated here, addition of
catalyst I to the all-trans-retinal gives rise to kinetic traces that
are described by single-exponential functions. Linear
regression of pseudo first-order afforded kobs values displayed
a positive non-linear deviation for catalyst I.
Moreover, when the observed rate constants are plotted as a
function of concentration of the added catalyst I, a non-linear
dependence is observed. Non-linear regression of kobs × [all-
trans-retinal0] versus [Pd] yielded the relationship kobs × [all-
Fig. 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 con-
ventional heating and microwave irradiation.
trans-retinal0]
=
0.24( 0.16)
×
[Pd]1.71( 0.14) (Fig. 5B).
Consequently, the reaction corresponded to pseudo first order
conversion with dependency on Pd catalyst which is larger
than 1 which implies that palladium may form a dimer in
order to react with all-trans-retinal 1a.
ture suggests that an alkene-transition metal catalyst depen-
dent isomerization can go through two main reaction path-
ways—isomerization via hydride and non hydride
mechanisms.47–50 Hydrogen–deuterium exchange (HDX)
experiments showed no deuterium incorporation by the
Z-retinyl products in the presence of CD3CN or CD3OD, indi-
cating that there is no solvent-dependent behavior necessary
for hydride-based mechanisms (Fig. 4A, B). Moreover, reaction
of all-trans-retinal 1a in the presence of a Pd–H trap, TEMPO,
at several concentrations and time points, indicated that there
is no inhibition of Z-isomerization in the presence of the Pd–H
trap, thereby confirming that the Z-isomerization mechanism
Computational study
To gain insights into the mechanism of Z-isomerization using
metal-based catalysis, we further investigated the reaction
using quantum chemical methods. The E to Z isomerization of
an alkene involves rotation around an otherwise rigid carbon–
carbon double bond. Fig. 6 presents the relaxed potential
energy surface scans for rotations around three selected
Fig. 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.
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Fig. 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 (kobs) × [1a0] plotted as a function of Pd1.71. kobs = 0.24[Pd]1.71[1a0]−1
.
was very low (about 30i cm−1). The TS optimizations along
these modes consistently revealed the all-trans minimum
structure. Thus, we were unable to locate true transition states
and decided to accept the highest energy structures from the
relaxed surface scans as the approximate TS. The changes in
Gibbs free energy (ΔGE/Z) values as well as Gibbs free activation
barrier (ΔG‡E=Z) values for the E to Z isomerization of 1a are
presented in Table 3. BP86+D3 and reference DLPNO-CCSD(T)
methods provide a consistent picture for 1a isomerization with
barriers calculated using the latter approach of 33.3, 32.0 and
28.0 kcal mol−1 for all-trans conversion into 9-cis, 11-cis and
13-cis isomers, respectively. Interestingly, the 9-cis and 13-cis
isomers are very close in energy to all-trans 1a irrespective of
the method used in the calculations (ΔGE/Z < 0.5 kcal mol−1).
These calculations demonstrate that 11-cis formation is a
rather thermodynamically unfavorable process with ΔGE/Z
=
5.0 kcal mol−1
.
Monomer mechanism
Fig. 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.
A good catalyst for E to Z isomerization should impact two key
elements of the transformation: (1) weaken the CvC bond
and (2) stabilize the TS structure. One can expect an alkene to
replace a labile ligand of the catalyst. We selected two similar
double bonds of retinal 1a. As expected, in all cases a distinct
maximum is found at the dihedral angle α = 90°. The lowest
electronic barrier of about 26 kcal mol−1 is associated with
trans to 13-cis isomerization while other rotations have barriers
Table 3 Comparison of Gibbs free energies (ΔGE/Z) and approximate
activation Gibbs free energies (ΔG‡E=Z) calculated with BP86+D3 and
DLPNO-CCSD(T) methods for the E to Z isomerization process that
takes place around three key double bonds of 1a. All data in kcal mol−1
of more than 30 kcal mol−1
.
C9–C10
C11–C12
C13–C14
To obtain a better estimate for barrier heights we took
efforts to compute true transition states (TS) for these pro-
cesses. Hessian calculations carried out with the highest
energy structures always yielded a single imaginary mode that
ΔGE/Z ΔG‡E=Z
ΔGE/Z ΔG‡E=Z
ΔGE/Z ΔG‡E=Z
BP86+D3
0.4
31.0
33.3
4.1
5.0
30.1
32.0
0.6
0.5
26.4
28.0
DLPNO-CCSD(T) 0.0
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Table 4 Comparison of Gibbs free energies (ΔGmono-complex) calculated
with BP86+D3 and DLPNO-CCSD(T) methods for the catalyst + 1a →
adduct + CH3CN reaction. The catalyst was chosen as species I or XV
(see Fig. 1). All values in kcal mol−1
Table 5 Comparison of approximate activation Gibbs free energies
(ΔG‡rot) calculated with BP86+D3 and DLPNO-CCSD(T) methods for the
E to Z rotations around C9–C10, C11–C12 and C13–C14 double bonds that
lead to 9-cis, 11-cis and 13-cis 1a isomers, respectively, catalyzed by
complexes I or XV (see Fig. 1). All values in kcal mol−1
C9–C10
C11–C12
C13–C14
C9–C10
C11–C12
C13–C14
Pd(I)
Pt(XV)
Pd(I)
Pt(XV)
Pd(I)
Pt(XV)
Pd(I)
Pt(XV)
Pd(I)
Pt(XV)
Pd(I)
Pt(XV)
BP86+D3
DLPNO-CCSD(T)
−6.3
−1.8
−2.1
−1.4
−0.4
−2.4
−2.9
−2.7
−2.2
3.3
1.6
2.5
BP86+D3
DLPNO-CCSD(T)
34.7
46.2
31.7
45.2
32.5
49.2
37.7
52.1
26.5
32.5
23.8
41.7
catalysts from our screening list (Fig. 1), PdCl2(CH3CN) I and
PtCl2(CH3CN) XV, to explore the Z-isomerization of retinoid 1a.
These two catalysts differ only by the central atom, however
they display dramatically different catalytic behavior with cata-
lyst I the most effective catalyst in the set while catalyst XV is
almost completely inactive. Table 4 shows the calculated Gibbs
free energies (ΔGmono-complex) for the reaction of catalyst (I or
XV) with retinoid 1a. The DLPNO-CCSD(T) numbers suggest
that the complex formation is either mildly exothermic
(complexation via C9–C10 and C11–C12 double bonds) or mildly
Therefore, catalysts I and XV do indeed offer CvC bond weak-
ening (postulate 1 for a good catalyst) but do not provide TS
stabilization (postulate 2). High energy barriers as well as the
absence of pronounced experimental solvent effect (carbo-
cation stabilization), rule out the possibility of the reaction
occurring through
mechanism.
a
simple complexation-and-rotation
Dimer mechanism
endothermic (complexation via C13–C14). According to our Based on the results for monomeric catalysts I and XV we pos-
results, the differences between catalysts I and XV are negli- tulate that the reaction follows the non-hydride binuclear
gible (ΔGmono-complex differences up to 0.4 kcal mol−1). The addition–elimination pathway.49 This pathway involves for-
BP86+D3 method shows significant deviations from the mation of a chloropalladate intermediate in which the exces-
DLPNO-CCSD(T) values of up to 5.1 kcal mol−1 in the case of sive positive charge of one of the carbon atoms is stabilized by
catalyst I interacting via the C13–C14 double bond. Such differ- the chlorine atom. This mechanism requires the catalyst to
ences highlight the complexity of electron correlation effects dimerize prior to complexation with alkene and is consistent
in the examined species.
with the presented kinetic data.
Based on Table 4, we first considered the reaction mecha-
To test our hypothesis regarding the formation of a dimeric
nism that involves simple rotation around selected CvC complex as a critical step in the overall reaction, we calculated
bonds in the complex of the catalyst with substrate 1a. The the dimerization energy of catalyst I and its platinum ana-
CvC bond lengths in the isolated 1a are all equal at 1.38 Å. logue, catalyst XV, according to the general reaction 2× catalyst
They become elongated upon complexation to 1.44 Å (C9–C10 I/XV → dimer + 2CH3CN.
and C13–C14) or 1.42 Å (C11–C12) irrespective of the catalyst
We found that the monomeric catalyst I exists in a thermo-
used. Thus, we expect the double bonds to be weakened when dynamic equilibrium with its dimer (ΔGdimerization = −0.02 kcal
compared to the isolated species. Any attempt to locate the TS mol−1 with the dimer favored). Catalyst XV was used in a cis
structures for rotations around CvC bonds in the complex of form but we expect that at reaction temperatures it will be
1a with catalysts I and XV failed. This finding is consistent present in a thermodynamically more stable trans form,
with the results obtained by Tan and co-workers.49 Thus, we especially when considering an isomerization mechanism via
decided to accept the highest energy structures from the CH3CN loss.51 For the trans form of catalyst XV we found that
relaxed potential energy surface scans along dihedral angles dimerization is highly unfavorable with ΔGdimerization
=
that correspond to rotations around three key double bonds in +12.00 kcal mol−1. We associate such a large difference in
the complexes of 1a with the catalysts. These approximate acti- monomer–dimer preference with the difference in a labile
vation Gibbs free energies (ΔG‡rot) calculated with BP86+D3 ligand (CH3CN) dissociation free energy, which increases by
and DLPNO-CCSD(T) methods are reported in Table 5. It is +5.3 kcal mol−1 when going from palladium to platinum (the
clear that all barriers in the complex are larger than for the dimerization process requires two CH3CN molecules to dis-
rotations in the free molecule 1a. For example, in the case of sociate). While it is known that ligands become less labile
rotation around the C11–C12 double bond catalyzed by XV, the when going down the nickel group,52,53 this effect was not
barrier increased by 20.1 kcal mol−1. This observation could explored in the present case. Platinum is expected to show sig-
be explained by the formation of a Pd/Pt–C bond in the nificant relativistic effects that manifest particularly in low 5d–
complex that is accompanied by a positive charge accumu- 6s/p atomic levels splitting as compared to 4d–5s/p splitting
lation on the proximal carbon atom, which in turn is stabilized found in palladium.54 Thus, in the former case we expect large
by the presence of the transition metal ion in close proximity. 5d–6p hybridization (indirectly also with 6s) that should
In the TS, such stabilization is lost and the quasi-carbocation enhance binding of σ-donating/π-accepting molecules such as
has high relative energy with respect to the substrate. acetonitrile. According to Löwdin population (BP86+D3),55,56
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the effective electron configuration of Pd in catalyst I is [Kr] 2.0 and 6.4 kcal mol−1 for C9, C11 and C13, respectively). The
4d9.055s0.435p0.86 and Pt in catalyst XV is [Xe] reaction proceeds via a six-membered cyclic chloropalladate
4f145d8.935f0.056s0.556p0.61. At the same level of theory the intermediate. In contrast to the mechanism described by
metal–nitrogen Mayer bond orders57 were found to be 0.56 Tan et al., we were able to find only full chair-like chloropalla-
and 0.79 for catalyst I and XV, respectively. Thus, the increased date conformations. For trans to 9-cis and 13-cis isomeriza-
population of 6s in catalyst XV as compared to 5s in catalyst I tions, the intermediates are stable minima at their respective
reflects a stronger σ-bond in the case of the platinum complex. potential energy surfaces, while for trans to 11-cis conversion
These results were obtained at the BP86+D3 level with a the intermediate has a transition state character (TSchloro). The
quasi-relativistic effective core potential (ECP) coupled to stability of the intermediate is dictated by the partial positive
specially optimized def2-TZVP basis set applied for Pd and Pt charge stabilization that is largest for tertiary carbon atoms C9
atoms (see above). The interaction energy of a CH3CN frag- and C13. Thus, in our model, rotations around the C9vC10
ment with MCl2(CH3CN), where M = Pd or Pt, calculated in and C13vC14 double bonds are two-step processes, while
this way yields interaction energies of −39.3 and −52.1 kcal rotation around the C11vC12 bond is a one-step process. We
mol−1, respectively. An alternative way to cover relativistic found that trans to 13-cis isomerization has the lowest energy
effects58 is to use a scalar-relativistic Hamiltonian such as barriers of ΔG‡ = +20.3 kcal mol−1 for chloropalladate inter-
Douglas–Kroll–Hess at second-order (DKH2)59 along with a mediate formation and ΔG‡ = +3.1 kcal mol−1 for the chloro-
specially designed all-electron def2-TZVP basis set (all-electron palladate ring-opening resulting in 13-cis product. These bar-
analogue of ECP-based def2-TZVP).60 We performed such cal- riers for trans to 9-cis isomerization were 2.2 kcal mol−1 and
culations and obtained interaction energies of −37.8 and 0.8 kcal mol−1 higher in energy, respectively. Thus, the cata-
−53.4 kcal mol−1 for Pd and Pt complexes, respectively. The lytic effect of the palladium complex is to decrease the barrier
agreement between quasi-relativistic and scalar-relativistic for the rate-determining step of the reaction by about 10 kcal
approaches is encouraging owing to the simplicity of the mol−1 in these cases. The trans to 11-cis one-step isomerization
former method. However, the key step is to turn off relativistic had a barrier of ΔG‡ = +25.2 kcal mol−1, which is only 6 kcal
effects entirely, i.e. adapt all-electron def2-TZVP basis set for mol−1 below the calculated barrier for uncatalyzed rotation
non-relativistic calculations. In this case the interaction ener- around C11vC12 bond (Table 3). Moreover, the 11-cis adduct
gies were found to be −31.6 and −32.3 kcal mol−1 for catalysts with the catalyst had 9.4 kcal mol−1 higher energy as com-
I and XV, respectively. For both systems studied, relativistic pared to the all-trans adduct due to a steric encumbrance
effects are pronounced – they make the interaction with (Fig. 7). Therefore, we conclude that trans to 11-cis isomeriza-
CH3CN stronger but to different extent. In the case of catalyst tion is both kinetically and thermodynamically less favorable
I, relativistic effects account for 6.2 kcal mol−1 of the total when compared to trans to 9- and 13-cis isomerization.
DKH2 interaction energy (16%). This number increases to
21.1 kcal mol−1 for catalyst XV where relativistic effects are 13-cis 3a isomer is only 0.5 kcal mol−1 higher in energy. The
responsible for 40% of the interaction energy. high relative stability of 9-cis and 13-cis can be explained by
All-trans 1a and 9-cis 2a are virtually isoenergetic, and the
Additionally, we examined another palladium catalyst with the fact that the trans-to-cis rotation swaps the positions of the
bulky ligands and calculated the dimerization energy. Catalyst –CH3 and –C(H)v groups (R1 and R2, respectively) interacting
X, PdCl2(PPh3), is closely related to catalyst I but like catalyst with the H atom attached to the neighboring carbon atom in
XV does not show significant activity in the E to Z isomeriza- the R1(R2)CvC(H)– bonding situation. In the presence of cata-
tion reactions. The calculated dimerization energy for this lyst I, formation of the Pd–C9 bond was favored over Pd–C13
catalyst was 27.1 kcal mol−1, thus it exists mainly in the mono- (Fig. 7). The 9-cis isomer had the lowest absolute energy at the
meric form. Phosphorus-based ligands are not as labile as, for end; thus, at 65 °C, the reaction is largely thermodynamically
example, CH3CN or PhCN and thus do not facilitate dimeriza- controlled.
tion of the parent complexes.
To further confirm that the reaction is thermodynamically
Based on these results, catalysts X and XV do not form a controlled we performed simple kinetic simulations based on
dimer, which explains their lack of reactivity. This also the dimeric mechanism presented in Fig. 7. The changes of
explains the lack of reactivity of most of the catalysts which concentrations of various species involved in E/Z isomerization
contain palladium complexes with bulky ligands that prevent of 1a using catalyst I over time are presented graphically in the
their dimerization.
ESI, Fig. S6.† Obtained curves resemble the shape of experi-
In the following, we decided to focus solely on mental concentration traces (ESI, Fig. S3†): initially, the major
(CH3CN)2PdCl2 catalyst I that can form a dimer, a prerequisite product is 13-cis but its concentration decreases slowly in favor
for the non-hydride binuclear addition–elimination pathway. of the 9-cis product. Although the latter requires that a slightly
The calculations were performed for all-trans-retinal 1a as a larger energetic barrier must be passed, it features the lowest
representative retinoid to study the Z-isomerization reaction energy at the end of the reaction. Thus, based on the compat-
pathway. The free energy profile and key intermediates ibility of experimental and computational results, we conclude
involved in the proposed mechanisms are shown in Fig. 7. that transition metal-based complexes with small, labile
Catalyst I dimer forms a reversible adduct with the all-trans ligands capable of forming dimeric complexes are most
substrate (calculated Pd–C bond formation values are ΔG = 4.7, effective for the Z-isomerization of retinoids.
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Fig. 7 DLPNO-CCSD(T) free energy surfaces for all-trans-retinal 1a Z-isomerization reaction catalyzed by a dimeric form of catalyst I.
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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.
The application
The conventional heating method showed that palladium-
based catalysts, in particular palladium catalysts capable of
dimer formation complexes (I–V, VII), were more catalytically
reactive than the rest of the metal catalysts. Moreover, we have
shown that microwave-induced Z-isomerization of retinoids is
even more efficient, and dramatically alters catalyst efficiency,
decreasing the reaction time as compared to conventional
heat-induced isomerization over 50 times.
In this report, we also presented a thorough mechanistic
study of the catalyst I dimer-catalyzed isomerization of repre-
sentative retinoids, all-trans-retinal to cis-retinal, by means of
state-of-the art quantum chemical calculations and kinetic
simulations to further support our hypothesis. The calcu-
lations explain the catalytic yields, the distribution of
Z-isomers, the rationale behind the reactivity of the catalyst, all
of which may help guide future catalyst selection and
improvement.
Here, we successfully developed a method which overcomes
the obstacles associated with the total synthesis of Z-retinoids
(which result in a relatively low yield of ∼8%), and demonstrate
the application of the current method by synthesizing gram-
scale quantities of 9-cis-retinyl acetate, -retinol, and -retinal
(2c, 2b, and 2a, respectively) (Scheme 2). Such quantities allow
for large-scale tests of their therapeutic capabilities in retinal
degeneration models in murine and canine models as a
prelude to human investigations.61–64 As we have shown pre-
viously, supplementation of 3 mg of 9-cis-retinal 2a in the LCA
dog model, which lacks visual cycle function, showed improve-
ment of 25% in photoreceptor function.61
The presented reaction of all-trans-retinyl acetate 1c that
occurs most favorably in the presence of catalyst I yields an
exceptional 20% of the desired 9-cis isomer. Under these con-
ditions, we enriched the solution to a 70 : 30 mixture of 9-cis/
all-trans by recrystallization and re-use of the parent com-
pound 1c (see Experimental section). Theoretically, the yield of
this reaction could be increased to 100% due to our discovery
of optimal conditions for crystallizing the parent compound
for further loop reactions with the catalyst.
Conflicts of interest
The authors declare no competing financial interests.
Conclusions
Acknowledgements
In this investigation, we developed a novel method for the This work was partially carried out at the Department of
Z-isomerization of retinoids with readily available transition Pharmacology, Case Western Reserve University, Cleveland,
metal catalysts in mild conditions using conventional heating Ohio, USA, and supported in part by grants from the National
or microwave irradiation. We were able to produce the stable Institutes of Health (NIH) (EYR24024864 and R24EY027283 to
9-cis (2a–2g) isomers with a single step in relatively high yields, KP), RPB (Research to Prevent Blindness) to the Department of
16–25%. While it is common for other organic catalytic reac- Ophthalmology at UCI, the Canadian Institute for Advanced
tions to reach even higher yields, the method reported here Research (CIFAR), and the Alcon Research Institute (ARI). K. P.
roughly triples the best yield reported to date and also reduces is the Leopold Chair of Ophthalmology. A. K. acknowledges
the number of reaction steps as well as the time of the support from the National Science Centre, Poland, grant
reaction.18,19 In fact, the yields we report, coupled with the use number 2018/30/E/ST4/00004. Access to high performance
of a crystallization loop technique, suggest that this method computing resources was provided by the Interdisciplinary
could be extremely useful in gram-scale synthesis of 9-cis Centre for Mathematical and Computational Modelling in
isomers for studies on the level of large animals or humans.
Warsaw, Poland, under grants no. G64-9 and GB77-11.
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24 M. Hashimoto and Y. Fujimoto, Synth. Commun., 1999, 29,
3793–3797.
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