http://orcid.org/0000-0002-7261-8454
Figures
Abstract
A novel approach to the production of chiral 1,3-cyclohexadienals has been developed. The organocatalysed asymmetric reaction of different β-disubstituted-α,β-unsaturated aldehydes with a chiral α,β-unsaturated aldehyde in the presence of a Jørgensen-Hayashi organocatalyst provides easy and stereocontrolled access to the cyclohexadienal backbone. This method allows for the synthesis of potential photoprotective chiral 1,3-cyclohexadienals and extra extended conjugation compounds in a simple manner.
Citation: Urosa A, Tobal IE, de la Granja ÁP, Capitán MC, Moro RF, Marcos IS, et al. (2018) Diastereoselective synthesis of chiral 1,3-cyclohexadienals. PLoS ONE 13(2): e0192113. https://doi.org/10.1371/journal.pone.0192113
Editor: Andrew C. Marr, Queen's University Belfast, UNITED KINGDOM
Received: May 12, 2017; Accepted: January 18, 2018; Published: February 13, 2018
Copyright: © 2018 Urosa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper.
Funding: Financial support for this work was provided by the Ministry of Economy and Competitiveness (MINECO) CTQ2015-68175-R, the European Regional Development Fund (FEDER), the Regional Government of Castile & Leon (BIO/SA59/15, UIC21) and the Universidad de Salamanca. AU thanks the Regional Government of Castile & Leon-European Social Fund (JCyL-FSE), IET thanks the Regional Government of Castile & Leon and MCC thanks the Universidad de Salamanca for their fellowships.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Organocatalysis is one of the fastest growing areas in organic chemistry [1–4]. The enantioselective organocatalytic Diels-Alder reaction from the seminal communication of Prof. MacMillan et al. [5] constitutes one of the most interesting research areas. The synthesis of enantiomerically enriched building blocks is an important task in organic synthesis, where cyclohexadienes [6–11] are of special interest due to their reactivity. Although the use of monosubstituted α,β-unsaturated aldehydes is more extended, in the last few years the use of β-disubstituted-α,β-unsaturated aldehydes has become more prevalent in this area. There are numerous examples of asymmetric synthesis by using organocatalysis, as shown by the work of Professor Serebryakov et al. in the synthesis of cyclohexa-1,3-dienes from prenal and unsaturated esters or derivatives, [12–16] Professor Hong et al. for the synthesis of aromatic aldehydes by organocatalytic [4+2] or [3+3] cycloaddition of α,β-unsaturated aldehydes [17–19] and Professor Watanabe et al. in citral, 1, dimerization. [20–25] The cyclohexadienal scaffold has been shown to be bioactive in numerous cases throughout the literature. For example, the citral dimer shows antibiotic activity [26] and the retinal dimer could contribute to macular degeneration. [27] As chiral aldehyde 2 has been intensively used as a synthetic building block in the synthesis of bioactive natural products, [28–33] this study sought to obtain chiral cyclohexadienals using 2 in combination with different β-methyl disubstituted-α,β-unsaturated aldehydes in the presence of different catalysts (5–10), which avoid the dimerization of these compounds (Fig 1).
In the last few decades the potentially dangerous effects of UV radiation exposure have been extensively demonstrated [34–36]. While UVC light is filtered by the upper atmospheric layers, UVB and UVA light penetrate the upper layers of the atmosphere and reach the Earth’s surface. Photoprotection against this radiation can prevent skin damage and deleterious effects on DNA. However, it is important not to overdo protection against UVB as this can reduce the biosynthesis of vitamin D[37,38]. Therefore, photoprotective agents that selectively absorb UVB and UVA radiation are the UV-filters needed for developing effective and safe sunscreens.
There are two groups of UV filters: inorganic and organic compounds. The inorganic filters scatter, reflect or absorb UV radiation, however, only TiO2 and ZnO are FDA approved. The organic UV filters consist of structurally simple aromatic molecules that absorb in UVA and UVB. The organic UV filters used in sunscreens, and approved by the FDA (Fig 2)[39] can be classified as cinnamates, benzophenones, PABA and salicilate derivatives and others. Despite their use in sunscreens, there are several studies regarding the toxicity, and especially the phototoxicity, of these compounds [40–46].
The main UV filters structurally related to cinnamate esters, benzophenone, p-aminobenzoic acid (PABA) and salicilate derivatives, and two additional structures that can be found in ensulizole and bemotrizinol.
In this work, cyclohexadienals containing different substitutions have been synthesized as easily accessible high-conjugated compounds with interesting UV-Vis properties, making them suitable for use as photoprotective UV-filters.
Materials and methods
All reactions were performed in oven-dried glassware under positive Ar pressure with magnetic stirring, unless otherwise noted. Air and moisture-sensitive liquids and solutions were transferred via a syringe or a stainless-steel cannula. TLC was performed on 0.25 mm E. Merck silica gel 60 F254 plates and visualized under UV light (λ = 254 nm) or by staining with potassium permanganate. Flash chromatography was performed on E. Merck 230–400 mesh silica gel 60. All reagents were purchased from commercial suppliers, and used without further purification unless otherwise noted. Solvents were distilled from suitable drying agents (CaH2 or Na wire) under an Ar atmosphere at 760 mmHg. All moisture- and/or oxygen-sensitive solids were handled and stored in a glove box under N2. The NMR spectra were recorded on Bruker AVANCE 400 MHz DRX and Varian Mercury 200 MHz using CDCl3 as solvent. NMR data is reported as follows: chemical shift (δ) (parts per million, ppm); multiplicity: s (singlet), d (doublet), t (triplet), q (quartet) and br (broad); coupling constants (J) are given in Hertz (Hz). 1H NMR chemical shifts were calibrated with respect to residual chloroform in CDCl3 centered at 7.26 ppm, whereas for 13C NMR, the center peak for CDCl3, centered at 77.0 ppm, was used for the calibration. The IR spectra were obtained on a Shimadzu IR Affinity-1 (film over NaCl). All NMR and IR spectra can be found in S1 File. The HRMS spectra were obtained on an Applied Biosystems QSTAR XL mass spectrometer. The optical rotation was performed on a Perkin-Elmer 241 digital polarimeter using cuvette with l = 1 dm and CHCl3 as the solvent. Absorbance measures were determined in 200–700 nm region using iPrOH as the solvent and an UV quartz cuvette (l = 1 cm) in a Shimadzu UV-2401PC spectrophotometer with thermostatic system at 20°C. The UV-Vis spectra can be found in S4 File.
Results and discussion
First, the synthesis of chiral cyclohexadienals (Fig 3) with citral, 1, and aldehyde, 2, obtained from D-mannitol in the usual conditions was tested. [20–25].
The different experimental conditions of the catalyst, solvent and additives tested are shown in Table 1.
When using a non-chiral organocatalyst, such as pyrrolidine, 5, cyclohexadienal 4 was obtained in low yields, although without diastereoselectivity (entry 1). The use of L-proline, 6 (entries 2–3), using different solvents, or no solvent at all, gave the required cyclohexadienal 4 in very low yields and the citral dimer 3, as a subproduct. Then, MacMillan´s organocatalysts 7 and 8 were tested, but no result was obtained (entries 4–5). In addition, the Jørgensen-Hayashi catalysts 9 and 10 were used in different solvent conditions, obtaining different results depending on the solvent used, ranging from moderate yields of cyclohexadienal 4 (entries 6–9 and 22) to no reaction at all (entries 10–14). As can be seen in Table 1, in some cases the reaction was carried out in presence of additives such as acids (BzOH, o-nitro-BzOH, AcOH, TsOH, (±)-1,19-binaphthyl-2,29-diyl hydrogenphosphate[(±) BINAP-OH] or TFA) and bases (DBU) (entries 15–21) with improved yields. The best result was obtained when the Jørgensen-Hayashi catalyst 9 in CHCl3 as the solvent, was used without any additional additive (entry 8) and produced a moderate yield and a good d.r.
Determination of stereochemistry of stereocenter created by NMR
An extra cycle was made to introduce more conformational rigidity (Fig 4), in order to establish the stereochemistry of cyclohexadienal 4. Aldehyde 4a was oxidized using the usual conditions [47] to obtain the acid 11; deprotection of the acetonide gave the desired lactone ring, 12. After studying the NOE (Nuclear Overhauser Effect) on this compound, the configuration of C-6 in compound 12 was established as S, because of NOE between H1’ and H6 did not appear. Later on, the absolute configuration was confirmed by X-Ray of an analogue (24a).
Reagents: a) NaH2PO4.H2O (2.2 equiv.), NaClO2 (5%, 2.2 equiv.), 2-methyl-2-butene, tBuOH, r.t., 2h, 99%; b) p-TsOH, MeOH, r.t., 30%.
Synthesis of chiral cyclohexadienals with different substituents
The mechanism could be understood by a Diels-Alder reaction, as suggested by Serebryakov et al. [12–16] and Watanabe et al. [20]. Similarly, this will would explain that the stereochemistry obtained in the final product does not depend on the Z or E stereochemistry of the α,β-unsaturation of the aldehyde used in the reaction. The same result was obtained with E-citral or a mixture E/Z-citral. E-citral was obtained from geraniol as described in the literature.[48] Once the conditions for the synthesis of cyclohexadienals were obtained, the generality of the reaction using different β-disubstituted-α,β-unsaturated aldehydes and 2 as starting materials was then observed, Fig 5 and Table 2.
The reaction was initiated using a simple α,β-unsaturated aldehyde such as 13. When catalysts 9 or 10 were used, both produced a good yield and diastereoselection. When catalyst 10 was used, instead of 9, the yield slightly decreased but diastereoselection remained complete. When using aromatic aldehydes, the reaction worked very well, especially with the p-methoxyphenyl group (entries 5–6) which produced excellent yields and diastereoselection with both catalysts 9 and 10. When a bromophenyl group was used (entries 7–10), the yield and diastereoselection decreased but when a p-nitrophenyl group (entries 11–12) was used the yield increased with both catalysts and the diastereoselection was excellent, especially with catalyst 10. When the reaction was run using an aliphatic cyclic aldehyde, such as catalyst 19, the yield was very poor (entry 13) but diastereoselection was complete. As can be seen in Table 2, the reaction proceeded quite well, especially when using aromatic aldehydes.
Crystallographic analysis of cyclohexadienal 24a
Compound 24a was crystallized. In Fig 6, the X-ray crystal structure of compound 24a [49] is shown and confirms the stereochemistry of compound 24a at C-6. The stereochemistry of this compound was previously predicted by the NMR of compound 12, and by analogy, the stereochemistry of compounds 20 to 26 was established.
Displacement ellipsoids are drawn at the 30% probability level. Hydrogen atoms are shown as spheres of arbitrary radius (S3 File).
UV-Vis absorption analysis
The UV-Vis absorbance of different photostable cyclohexadienals was measured (Table 3 and S4 File) in order to test the possible application of these compounds as photoprotective agents.
The majority of the compounds at concentrations in the order of 10−6 absorbed UVA and UVB. Compound 21b exhibited values suitable for photoprotection against UVA owing to the higher area under the curve (AUC) at that particular wavelength region and its molar extinction coefficient (ε = 13200 M-1cm-1). The best results found in the UVB region were shown by compound 23b which had an extinction coefficient of 34700 M-1cm-1 at 288nm. However, the compound that was able to better absorb UVA and UVB was 23a, with molar extinction coefficients of 8000 M-1cm-1 in UVA and 10900 M-1cm-1 in UVB.
A global view of UV absorption of this chiral aromatic cyclohexadienal can be seen in Fig 7.
Amplification of the 200–450 nm region and the delimited UVA and UVB regions (ISO-21348).
Synthesis
General procedure for the optimization of conditions for cyclohexadienals (4a,b).
Catalyst 5–10 (0.5 eq) were added to a solution containing 2 (0.3 mmol, 1 equiv.) and 1 (0.3 mmol, 1 equiv.) in solvent (1.5 mL, 0.2M) at r.t. The reaction mixture was stirred at r.t. for 48h. The solution was concentrated in and the residue was purified by flash column chromatography (EtAcO:hexane) to obtain cyclohexadienals 4a and 4b as a yellow oil and dimer 3 as a colourless oil.
Catalyst 9 (0.5 eq) was added to a solution containing 2 (0.15 mmol, 1 equiv.) and E-citral (0.15 mmol, 1 equiv.) in CHCl3 (0.75 mL, 0.2M) at r.t. The reaction mixture was stirred at r.t. for 48h. The solution was concentrated in vacuum and the residue was purified by flash column chromatography (EtAcO:hexane) to obtain a mixture of cyclohexadienals 4a and 4b as a yellow oil (yield 37%; d.r. 85:15).
6-Methyl-4,6-bis(4-methylpent-3-en-1-yl)cyclohexa-1,3-diencarbaldehyde(3).
1H NMR (200 MHz, CDCl3): δ = 9.41 (1H, s), 6.67 (1H, d, J = 5.5 Hz), 5.92 (1H, d, J = 5.5 Hz), 5.10–5.03 (2H, m), 2.38–2.33 (1H, m), 2.19–2.18 (4H, m), 2.04–1.77 (4H, m, H-5), 1.69 (3H, s), 1.65 (3H, s), 1.62 (3H, s), 1.55 (3H, s), 1.41–1.32 (1H, m), 1.19 (3H, s).
(S)-6-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-4-(4-methylpent-3-en-1-yl)cyclohexa-1,3- dien-1-carbaldehyde(4a).
[α]D25 = -43.3 (c = 0.54, CHCl3).
IR (film): 2981, 2929, 1670, 1570, 1379, 1213, 1066, 842 cm-1.
1H NMR (200 MHz, CDCl3): δ = 9.47 (1H, s), 6.81 (1H, d, J = 5.7 Hz), 5.95–5.90 (1H, m), 5.10–5.00 (1H, m), 4.18 (1H, q, J = 6.4 Hz), 3.86 (1H, dd, J = 8.4, 6.4 Hz), 3.67 (1H, dd, J = 8.4, 6.4 Hz), 3.20–3.10 (1H, m), 2.44–2.37 (2H, m), 2.36–1.80 (4H, m), 1.68 (3H, s), 1.61 (3H, s), 1.42 (3H, s), 1.27 (3H, s).
13C NMR (50 MHz, CDCl3): δ = 192.4, 151.8, 145.2, 135.1, 132.8, 123.2, 118.7, 109.0, 75.9, 66.7, 38.0, 31.7, 28.8, 26.4, 25.9 (2), 25.5, 18.0.
HRMS (ESI): Calculated for C18H26O3Na ([M+Na]+): 313.1774; found 313.1775.
(R)-6-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-4-(4-methylpent-3-en-1-yl)cyclohexa-1,3-dien-1-carbaldehyde(4b).
[α]D25 = 33.5 (c = 0.45, CHCl3).
IR (film): 2981, 2929, 1670, 1570, 1379, 1213, 1066, 842cm-1.
1H NMR (200 MHz, CDCl3): δ = 9.46 (1H, s), 6.84 (1H, d, J = 5.7 Hz), 6.00–5.97 (1H, m), 5.13–5.08 (1H, m), 3.92 (1H, q, J = 6.7 Hz), 3.75 (1H, dd, J = 15.6, 8.0 Hz), 3.72 (1H, dd, J = 15.6, 6.7 Hz), 2.94 (1H, t, J = 8.5 Hz), 2.66 (1H, d, J = 18.0), 2.37 (1H, dd, J = 18.0, 8.5 Hz), 2.33–2.10 (4H, m), 1.69 (3H, s), 1.62 (3H, s), 1.54 (3H, s), 1.30 (3H, s).
13C NMR (50 MHz, CDCl3): δ = 192.3, 152.6, 146.5, 134.9, 132.4, 123.1, 118.6, 108.6, 74.8, 68.0, 37.9, 32.2, 29.6, 26.8, 25.8, 25.7, 25.6, 17.7.
HRMS (ESI): Calculated for C18H26O3Na ([M+Na]+): 313.1774; found 313.1775.
6-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-(4-methylpent-3-en-1-yl)cyclohexa-1,3-dien-1-carboxilic acid(11).
2-methyl-2-butene (0.097 mL, 0.92 mmol), a 0.65M solution of NaH2PO4.H2O in H2O (0.97 mL, 0.81 mmol) and 5% NaClO2 in H2O (0.91 mL, 0.72 mmol) were added to a solution containing 4a (105 mg, 0.36 mmol) in tBuOH (3.8 mL). The reaction mixture was stirred at r.t. for 22h. The reaction was quenched with H2O and 1M HCl was added until acid pH was reached. The reaction mixture was extracted with EtOAc (3x10 mL). The combined organic layers were washed with H2O until neutral pH was reached, dried over Na2SO4, filtered and concentrated under vacuum to obtain acid 11 (109 mg, 0.36 mmol, 99%).
[α]D25 = -63.0, (c = 0.684, CHCl3).
IR (film): 2984, 2930, 1678, 1582, 1422, 1260, 1217, 1070, 1049 cm-1.
1H NMR (200 MHz, CDCl3): δ = 7.20 (1H, d, J = 5.8 Hz), 5.82 (1H, d, J = 5.8 Hz), 5.07 (1H, bs), 4.27 (1H, q, J = 6,2 Hz), 3.92 (1H, dd, J = 8.4, 6.2 Hz), 3.72 (1H, dd, J = 8.4, 7.4 Hz), 3.06 (1H, t, J = 8.0 Hz), 2.45 (1H, d, J = 8.0 Hz), 2.37 (1H, bs), 2.17 (4H, bs), 1.68 (3H, s), 1.61 (3H, s), 1.41 (3H, s), 1.31 (3H, s).
13C NMR (50 MHz, CDCl3): δ = 172.6, 148.8, 137.6, 132.7, 132.7, 124.1, 118.3, 109.0, 76.4, 66.9, 37.7, 33.6, 28.8, 26.4, 25.9 (2), 25.5, 18.0.
HRMS (ESI): Calculated for C18H27O4 ([M+H]+): 307.1904; found 307.1908.
(3S,3aR)-3-(Hydroxymethyl)-5-(4-methylpent-3-en-yl)-3a,4-dihydroisobenzofuran-1(3H)-one(12).
p-TsOH (21 mg, 0.11 mmol) was added to a solution containing 11 (35mg, 0.11 mmol) and MeOH (1.5 mL). The reaction mixture was stirred at r.t. for 14h. The reaction was quenched with H2O. The crude mixture was extracted with EtOAc (3x10 mL). The combined organic layers were washed with H2O, sat. NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated under vacuum to yield 12 (8 mg, 0.033 mmol, 30%).
IR (film): 2959, 2924, 1749, 1217, 1030 cm-1.
1H NMR (400 MHz, CDCl3): δ = 6.94 (1H, dd, J = 5.4, 3.3 Hz), 6.02(1H, bs), 5.07 (1H, bs), 4.24 (1H, dt, J = 8.2, 3.9 Hz), 3.98 (1H, d, J = 12.6 Hz), 3.76 (1H, d, J = 12.6 Hz), 2.99 (1H, dtd, J = 17.6, 8.2, 3.9 Hz), 2.36 (2H, dd, J = 17.6, 8.2 Hz), 2.28–2.14 (5H, m), 1.69 (3H, s), 1,61 (3H, s).
13C NMR (50 MHz, CDCl3): δ = 169.3, 147.6, 132.9, 131.1, 124.3, 123.2, 120.3, 85.9, 63.0, 37.8, 35.0, 31.7, 26.3, 25.9, 18.0.
HRMS (ESI): Calculated for C15H21O3 ([M+H]+): 249.1485; found 249.1491.
General procedure for the synthesis of cyclohexadienals (20a,b-26).
Catalyst 9 or 10 (0.5 equiv.) was added to a solution of 2 (1 mmol, 1 equiv.) and aldehyde (1 mmol) in CHCl3 (5 mL) at r.t. The reaction mixture was stirred at r.t. for 48h. The solution was concentrated under vacuum and the residue was purified by flash column chromatography (EtOAc:hexane) to obtain cyclohexadienal as a yellow oil.
(S)-3-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-methylcyclohexa-4,6-dien-4-carbaldehyde(20a).
Catalyst 9 used.
Yield: 60% (133 mg, 0.60 mmol).
[α]D25 = -114.5 (c = 0.53, CHCl3).
IR (film): 2916, 2848, 1672, 1059 cm-1.
1H NMR (200 MHz, CDCl3): δ = 9.48 (1H, s), 6.82 (1H, d, J = 5.6 Hz), 5.92 (1H, d, J = 5.6 Hz), 4.21 (1H, q, J = 6.4 Hz), 3.87 (1H, dd, J = 8.4, 6.4 Hz), 3.68 (1H, dd, J = 8.4, 6.4 Hz), 3.17 (1H, ddd, J = 8.4, 6.4, 3.4 Hz), 2.41 (2H, d, J = 3.4 Hz), 1.91 (3H, s), 1.43 (3H, s), 1.30 (3H, s).
13C NMR (50 MHz, CDCl3): δ = 192.4, 148.6, 145.5, 134.8, 119.3, 109.0, 76.1, 66.6, 31.7, 30.0, 26.4, 25.5, 24.2.
HRMS (ESI): Calculated for C13H18O3Na ([M+Na]+): 245.1148; found 245.1146.
(R)-3-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-methylcyclohexa-4,6-dien-4-carbaldehyde(20b).
Catalyst 10 used.
Yield: 52% (116 mg, 0.52 mmol).
[α]D25 = +12.7 (c = 1.65, CHCl3).
IR (film): 2985, 2933,1666, 1573, 1192, 1155, 1066, 860 cm-1
1H NMR (200 MHz, CDCl3): δ = 9.46 (1H, s), 6.83 (1H, d, J = 5.5 Hz), 6.01–5.95 (1H, m), 4.03–3.88 (1H, m), 3.85–3.65 (2H, m), 2.94 (1H, dt, J = 8.4, 1.7 Hz), 2.61 (1H, dd, J = 18.4, 1.7 Hz), 2.38 (1H, dd, J = 18.4, 8.4 Hz), 1.95 (3H, s), 1.39 (3H, s), 1.31 (3H, s).
13C NMR (50 MHz, CDCl3): δ = 192.6, 149.3, 147.0, 136.5, 119.4, 108.9, 75.5, 68.0, 32.5, 31.0, 27.0, 25.9, 24.3.
HRMS (ESI): Calculated for C13H19O3Na ([M+Na]+): 223.1328; found 223.1326.
(S)-3-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,3-dihydro-[1,1’-biphenyl]-4-carbaldehyde(21a).
Catalyst 9 used.
Yield: 72% (205 mg, 0.72 mmol).
[α]D25 = -34.1 (c = 0.16, CHCl3).
IR (film): 2983, 2931, 1668, 1554, 1172, 756 cm-1.
1H NMR (200 MHz, CDCl3): δ = 9.60 (1H, s), 7.53 (2H, dd, J = 8.0, 1.6 Hz), 7.39 (2H, d, J = 8.0 Hz), 7.41–7.37 (1H, m), 7.01 (1H, d, J = 6.0 Hz), 6.57 (1H, d, J = 6.0 Hz), 4.30 (1H, q, J = 6.4 Hz), 3.90 (1H, dd, J = 8.4, 6.4 Hz), 3.76 (1H, dd, J = 8.4, 6.4 Hz), 3.36–3.27 (1H, m), 2.95–2.86 (2H, m), 1.29 (3H, s), 1,40 (3H, s).
13C NMR (50 MHz, CDCl3): δ = 192.3, 146.4, 144.4, 139.3, 136.2, 129.4, 129.0 (2), 126.0 (2), 119.6, 109.2, 76.0, 66.8, 32.0, 27.3, 26.5, 25.6.
HRMS (ESI): Calculated for C18H20O3Na ([M+Na]+): 307.1305; found 307.1300.
(R)-3-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,3-dihydro-[1,1’-biphenyl]-4-carbaldehyde(21b).
Catalyst 10 used.
Yield: 35% (100 mg, 0.35 mmol).
[α]D25 = -27.3 (c = 0.07, CHCl3).
IR (film): 2985, 2933, 1666, 1548, 1170, 756 cm-1.
1H NMR (200 MHz, CDCl3): δ = 9.56 (1H, s), 7.38 (2H, dd, J = 8.0 Hz, 1.6 Hz), 7.37–7.35 (1H, m), 7.20 (1H, d, J = 9.0 Hz), 7.19 (2H, dd, J = 8.0 Hz, 1.6 Hz), 6.59 (1H, dd, J = 9.0 Hz, 2.2 Hz), 4,07–3.97 (1H, m), 3.86–3.74 (2H, m), 3.25 (1H, d, J = 17.9 Hz), 3.05 (1H, dt, J = 8.4, 1.5 Hz), 2.68 (1H, ddd, J = 17.9, 8.4, 2.9 Hz, H-6), 1.36 (3H, s), 1.28 (3H, s).
13C NMR (50 MHz, CDCl3): δ = 197.3, 192.5, 146.2, 139.7, 136.1, 129.3,128.9 (2), 126.4 (2),119.8, 109.0,75.2, 68.1, 32.8, 27.1, 25.9, 21.4.
HRMS (ESI): Calculated for C18H21O3Na ([M+Na]+):285.1461; found 285.1485.
(S)-3-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-4’-methyl-2,3-dihydro-[1,1’-biphenyl]-4-carbaldehyde(22a).
Catalyst 9 used.
Yield: 99% (295 mg, 0.99 mmol).
[α]D25 = - 51.2 (c = 0.16, CHCl3).
IR (film): 3030, 2985, 2873, 2720, 1675, 1170, 1061, 858, 810 cm-1
1H NMR (200 MHz, CDCl3): δ = 9.58 (1H, s), 7.44 (2H, d, J = 8.0 Hz), 7.21 (2H, d, J = 8.0 Hz), 6.99 (1H, d, J = 5.8 Hz), 6.53 (1H, dd, J = 5.8, 2.5 Hz), 4.28 (1H, q, J = 6.3 Hz), 3.89 (1H, dd, J = 8.2, 6.3 Hz), 3.73 (1H, dd, J = 8.2, 6.3 Hz), 3.31 (1H, ddd, J = 9.2, 6.0, 2.3 Hz), 3.11–2.68 (2H, m), 2.38 (3H, s), 1.40 (2H, s), 1.29 (3H, s).
13C NMR (50 MHz, CDCl3): δ = 192.0, 146.2, 144.4, 139.4, 136.1, 135.7, 129.5 (2), 125.7 (2), 118.5, 108.9, 75.8, 66.6, 31.8, 27.0, 26.3, 25.4, 21.3.
HRMS (ESI): Calculated for C19H23O3 ([M+H]+): 299.1642; found 299.1645.
(R)-3-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-4’-methyl-2,3-dihydro-[1,1’-biphenyl]-4-carbaldehyde(22b).
Catalyst 10 used.
Yield: 83% (248 mg, 0.83 mmol).
[α]D25 = +23.1 (c = 0.08, CHCl3).
IR (film): 3030, 2984, 2873, 2717, 1668, 1170, 1067, 854, 810 cm-1.
1H NMR (200 MHz, CDCl3): δ = 9.55 (1H, s), 7.48 (2H, d, J = 8.0 Hz), 7.21 (2H, d, J = 8.0 Hz), 7.01 (1H, d, J = 5.9 Hz), 6.55 (1H, dd, J = 5.9, 2.8 Hz), 4.02 (1H, q, J = 7.5 Hz), 3.90–3.68 (2H, m), 3.28 (1H, d, J = 17.9 Hz), 3.10 (1H, dt, J = 8.2, 1.4 Hz), 2.71 (1H, ddd, J = 17.9, 8.2, 2.8 Hz), 2.38 (3H, s), 1.37 (3H, s), 1.27 (3H, s).
13C NMR (50 MHz, CDCl3): δ = 192.2, 147.2, 146.2, 139.3, 136.6, 135.6, 129.4 (2), 126.1 (2), 118.8, 108.8, 75.1, 67.9, 32.7, 28.1, 26.8, 25.7, 21.3.
HRMS (ESI): Calculated for C19H23O3 ([M+H]+): 299.1642; found 299.1642.
(S)-3’-bromo-3-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,3-dihydro-[1,1’-biphenyl]-4-carbaldehyde(23a).
Catalyst 9 used.
Yield: 48% (174mg, 0.48 mmol).
[α]D25 = -35.4 (c = 0.38, CHCl3).
IR (film): 2984, 2876, 2814, 2718, 1670, 1551, 1211, 1173, 1069, 847, 781 cm-1.
1H NMR (200 MHz, CDCl3): δ = 9.55 (1H, s), 7.61 (1H, t, J = 1.9 Hz), 7.48–7.34 (2H, m), 7.20 (1H, d, J = 7.9 Hz), 6.95 (1H, d, J = 5.9 Hz), 6.50 (1H, dd, J = 5.9, 2.4 Hz), 4.23 (1H, q, J = 6.3 Hz), 3.86 (1H, dd, J = 8.4, 6.3 Hz), 3.68 (1H, dd, J = 8.4, 6.3 Hz), 3.25 (1H, ddd, J = 9.1, 6.0, 3.1 Hz), 2.95–2.65 (2H, m), 1.36 (3H, s), 1.24 (3H, s).
13C NMR (50 MHz, CDCl3): δ = 192.2, 144.5, 143.7, 141.5, 136.7, 132.0, 130.5, 129.0, 124.5, 123.2, 120.6, 109.1, 78.1, 77.5, 76.8, 76.0, 66.7, 31.9, 27.3, 26.5, 25.5.
HRMS (ESI): Calculated for C18H19O3NaBr ([M+Na]+): 385.0410 and 387.0389; found 385.0405 and 387.0384.
(R)-3’-bromo-3-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,3-dihydro-[1,1’-biphenyl]-4-carbaldehyde(23b).
Catalyst 10 used.
Yield: 50% (192 mg, 0.50mmol).
[α]D25 = -5.7 (c = 0.07, CHCl3).
IR (film): 2984, 2934, 2878, 2815, 1670, 1549, 1169, 1067, 847, 782, 515 cm-1.
1H NMR (400 MHz, CDCl3): δ = 9.56 (1H,s), 7.67 (1H, t, J = 1.9 Hz), 7.46 (1H, dd, J = 8.2, 1.9 Hz), 7.25 (1H, t, J = 8.2 Hz), 7.00 (1H, d, J = 5.8 Hz), 6.55 (1H, dd, J = 5.8, 2.9 Hz), 3.98 (1H, dt, J = 8.4, 6.4 Hz), 3.89–3.70 (2H, m), 3.19 (1H, dd, J = 17.9, 1.5 Hz), 3.08 (1H, dt, J = 8.4, 1.5 Hz), 2.70 (1H, ddd, J = 17.9, 8.4, 2.9 Hz), 1.36 (3H, s), 1.27 (3H, s).
13C NMR (100 MHz, CDCl3): δ = 192.2, 145.3, 145.1, 141.6, 136.5, 131.7, 130.1, 129.1, 124.7, 122.9, 120.5, 108.9, 74.9, 67.8, 32.5, 28.0, 26.7, 25.6.
HRMS (ESI): Calculated for C18H19O3NaBr ([M+Na]+): 385.0410 and 387.0389; found 385.0405 and 387.0386.
(S)-4’-bromo-3-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,3-dihydro-[1,1’-biphenyl]-4-carbaldehyde(24a).
Catalyst 9 used.
Yield: 45% (163 mg, 0.45 mmol).
[α]D25 = -23.1 (c = 1.10, CHCl3), this optical rotation was obtained from chromatographed fraction.
[α]D25 = -23.2 (c = 0.10, CHCl3), this optical rotation was obtained from a solution of crystals.
IR (film): 2987, 2875, 2718, 1668, 1171, 1072, 853, 813 cm-1.
1H NMR (200 MHz, CDCl3): δ = 9.60 (1H, s), 7.53 (2H, d, J = 8.6 Hz), 7.39 (2H, d, J = 8.6 Hz), 6.99 (1H, d, J = 6.0 Hz), 6.54 (1H, dd, J = 6.0, 2.3 Hz), 4.28 (1H, q, J = 6.3 Hz), 3.89 (1H, dd, J = 8.4, 6.3 Hz), 3.71 (1H, dd, J = 8.4, 6.3 Hz), 3.31 (1H, ddd, J = 9.1, 5.9, 3.2 Hz), 3.02–2.66 (2H, m), 1.39 (3H, s), 1.29 (3H, s).
13C NMR (50 MHz, CDCl3): δ = 192.2, 145.0, 144.0, 138.2, 136.5, 132.2, 127.5, 123.5, 119.9, 109.2, 76.0, 66.7, 32.0, 27.2, 26.5, 25.5.
HRMS (ESI): Calculated for C18H20O3Br ([M+H]+): 363.0590 and 365.0570; found 363.0596 and 365.0581.
(R)-4’-bromo-3-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,3-dihydro-[1,1’-biphenyl]-4-carbaldehyde(24b).
Catalyst 10 used.
Yield: 45% (164 mg, 0.45 mmol).
[α]D25 = -27.3 (c = 0.02, CHCl3).
IR (film): 2984, 2872, 2718, 1668, 1169, 1072, 853, 815 cm-1.
1H NMR (200 MHz, CDCl3): δ = 9.56 (1H, s), 7.52 (2H, d, J = 8.6 Hz), 7.41 (2H, d, J = 8.6 Hz), 7.00 (1H, d, J = 5.8 Hz), 6.55 (1H, dd, J = 5.8, 2.8 Hz), 4.11–3.88 (1H, m), 3.79 (2H, dd, J = 6.3, 2.0 Hz), 3.20 (1H, d, J = 17.9 Hz), 3.08 (1H, t, J = 8.2 Hz), 2.70 (1H, ddd, J = 17.9, 8.2, 2.8 Hz), 1.35 (3H, s), 1.27 (3H, s).
13C NMR (50 MHz, CDCl3): δ = 192.5, 146.0, 145.7, 138.6, 136.5, 132.1 (2), 127.9 (2), 123.4, 120.1, 109.1, 75.2, 68.1, 32.8, 28.1, 27.0, 25.8.
HRMS (ESI): Calculated for C18H20O3Br ([M+H]+): 363.0590 and 365.0570; found 363.0594 and 365.0582.
(S)-3-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-4’-nitro-2,3-dihydro-[1,1’-biphenyl]-4-carbaldehyde(25a).
Catalyst 9 used.
Yield: 90% (296 mg, 0.90 mmol).
[α]D25 = -19.5 (c = 0.02, CHCl3).
IR (film): 2983, 2931, 1668, 1554, 1172, 756 cm-1.
1H NMR (200 MHz, CDCl3): δ = 9.64 (1H, s), 8.25 (2H, d, J = 9.1 Hz), 7.66 (2H, d, J = 9.1 Hz), 7.03 (1H, d, J = 5.9 Hz), 6.67 (1H, d, J = 5.9 Hz), 4.33–4.24 (1H, m), 3.92 (1H, dd, J = 8.5, 6.4 Hz), 3.73 (1H, dd, J = 8.5, 6.4 Hz), 3.37–3.28 (1H, m), 2.94–2.90 (2H, m), 1.38 (3H, s), 1.28 (3H, s).
13C NMR (50 MHz, CDCl3): δ = 192.3, 147.9, 145.7, 143.5, 143.0, 137.7, 126.6 (2), 124.3 (2), 122.8, 109.4, 76.1, 66.7, 32.0, 27.4, 26.4, 25.3.
HRMS (ESI): Calculated for C18H19NO5Na ([M+Na]+): 352.1155; found 352.1151.
(R)-3-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-4’-nitro-2,3-dihydro-[1,1’-biphenyl]-4-carbaldehyde(25b).
Catalyst 10 used.
Yield: 88% (290 mg, 0.88 mmol).
[α]D25 = -27.6 (c = 0.04, CHCl3).
IR (film): 2983, 2931, 1668, 1554, 1172, 756 cm-1.
1H NMR (200 MHz, CDCl3): δ = 9.61 (1H, s), 8.25 (2H, d, J = 8.8 Hz), 7.69 (2H, d, J = 8.8 Hz), 7.04 (1H, d, J = 5.8 Hz), 6.69 (1H, dd, J = 5.8, 2.9 Hz), 4.06–3.92 (1H, m), 3.90–3.72 (2H, m), 3.25 (1H, dd, J = 17.7, 1.5 Hz), 3.12 (1H, td, J = 8.1, 1.5 Hz), 2.77 (1H, ddd, J = 17.7, 8.1, 3.0 Hz), 1.35 (3H, s), 1.27 (3H, s).
13C NMR (50 MHz, CDCl3): δ = 192.5, 147.8, 146.1, 144.7, 144.3, 137.7, 127.1 (2), 124.2 (2), 122.9, 109.2, 75.4, 68.0, 32.8, 28.0, 27.0, 25.7.
HRMS (ESI): Calculated for C18H19NO5Na ([M+Na]+): 352.1155; found 352.1150.
(1S)-1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1,5,6,7,8,8a-hexahydronaftalen-2-carbaldehyde(26).
Catalyst 9 used.
Yield: 4% (11 mg, 0.04 mmol).
[α]D25 = -198.5 (c = 0.33, CHCl3).
IR (film): 2930, 2855, 1672, 1582, 1059 cm-1
1H NMR (200 MHz, CDCl3): δ = 9.45 (1H, s), 6.73 (1H, d, J = 5.8 Hz), 5.84 (1H, d, J = 5.8 Hz), 4.34–4.27 (1H, m), 3.83 (1H, dd, J = 8.6, 6.8 Hz), 3.67 (1H, dd, J = 8.6, 6.8 Hz), 2.95–2.85 (1H, m), 2.60–2.40 (1H, m), 2.30–1.27 (8H, m), 1,25 (6H, s).
13C NMR (50 MHz, CDCl3): δ = 193.0, 159.4, 144.9, 133.7, 114.6, 109.0, 66.3, 40.3, 38.5, 38.1, 37.1, 32.0, 29.9, 27.4, 26.4, 25.3.
HRMS (ESI): Calculated for C16H22O3Na ([M+Na]+): 285.1461; found 285.1466.
Conclusions
A new method for the synthesis of photoprotective chiral cyclohexadienals is described. The Jørgensen-Hayashi catalyst produced a good yield of these compounds by using a chiral α,β-unsaturated aldehyde, 2. Further reactivity of the corresponding cyclohexadienals is under study.
According to the UV-Vis spectra of 4a, 20b, 21b, 22b, 22a and 23b it can be concluded that the cyclohexadienals containing systems with upper conjugation (21b, 22b, 23a and 23b) present better absorbance properties than low conjugation cyclohexadienals 4a, 20b. In addition, the influence of the aryl substituent provides an important tool for modulating maximum absorbance. In this work, the influence of p-methylphenyl, m-bromophenyl and phenyl substituent on the cyclohexadienal backbone is shown, where the phenyl and m-bromophenyl substituents prove to be the best choice for UVA-filters and UVB-filters, respectively.
Supporting information
S2 File. Experimental procedure for the synthesis of α,β-aldehyde intermediates.
https://doi.org/10.1371/journal.pone.0192113.s002
(DOCX)
Acknowledgments
The authors gratefully acknowledge the help of J. Rodilla from the Universidade da Beira Interior and C. Raposo (MS) from the Universidad de Salamanca and S. S. Serra for her help in writing the manuscript. Financial support for this work was provided by the Ministry of Economy and Competitiveness (MINECO) CTQ2015-68175-R, the European Regional Development Fund (FEDER), the Regional Government of Castile & Leon (BIO/SA59/15, UIC21) and the Universidad de Salamanca. IET thanks the Regional Government of Castile & Leon for his fellowship, MCC thanks the Universidad de Salamanca for her fellowship and AU thanks the Regional Government of Castile & Leon-European Social Fund (JCyL-FSE).
References
- 1. Bertelsen S, Jorgensen KA. Organocatalysis-after the gold rush. Chem Soc Rev. 2009;38(8):2178–89. pmid:19623342
- 2. Mukherjee S, Yang JW, Hoffmann S, List B. Asymmetric Enamine Catalysis. Chem Rev. 2007;107(12):5471–569. pmid:18072803
- 3. Scheffler U, Mahrwald R. Recent Advances in Organocatalytic Methods for Asymmetric C-C Bond Formation. Chem Eur J. 2013;19(43):14346–96. pmid:24115407
- 4. Maruoka K, List B, Yamamoto H, Gong L-Z. Organocatalysis: a web collection. Chem Commun. 2012;48(87):10703– and following articles.
- 5. Ahrendt KA, Borths CJ, MacMillan DWC. New Strategies for Organic Catalysis: The First Highly Enantioselective Organocatalytic Diels−Alder Reaction. J Am Chem Soc. 2000;122(17):4243–4.
- 6. Pezzati B, Chellat MF, Murphy JJ, Besnard C, Reginato G, Stephens JC, et al. Organocatalytic Asymmetric Annulation of 1,3-Bis(alkoxycarbonyl)buta-1,3-dienes and Aldehydes. Org Lett. 2013;15(12):2950–3. pmid:23731393
- 7. Murphy JJ, Quintard A, McArdle P, Alexakis A, Stephens JC. Asymmetric Organocatalytic 1,6-Conjugate Addition of Aldehydes to Dienic Sulfones. Angew Chem Int Ed. 2011;50(22):5095–8.
- 8. Ye L-W, Wang S-B, Wang Q-G, Sun X-L, Tang Y, Zhou Y-G. Asymmetric tandem Michael addition-ylide olefination reaction for the synthesis of optically active cyclohexa-1,3-diene derivatives. Chem Commun. 2009(21):3092–4.
- 9. Chang M-Y, Chan C-K, Lin S-Y, Wu M-H. One-pot synthesis of multifunctionalized m-terphenyls. Tetrahedron. 2013;69(46):9616–24.
- 10. Wang Z-Y, Wong W-T, Yang D. Organocatalyzed Asymmetric Synthesis of Dihydrodibenzofurans Based on a Dienamine Process. Organic Letters. 2013;15(19):4980–3. pmid:24040890
- 11. Loupy A, Maurel F, Sabatié-Gogová A. Improvements in Diels–Alder cycloadditions with some acetylenic compounds under solvent-free microwave-assisted conditions: experimental results and theoretical approaches. Tetrahedron. 2004;60(7):1683–91.
- 12. Serebryakov EP, Shcherbakov MA, Gamalevich GD, Struchkova MI. New ways to determine the absolute configurations of alkyl 6-R-cyclohexa-1,3-dienecarboxylates. Russ Chem Bull. 2003;52(3):734–9.
- 13. Serebryakov EP, Nigmatov AG, Shcherbakov MA, Struchkova MI. The effects of the nature of catalyst and of the solvent on the stereoselectivity in amine-catalyzed asymmetric synthesis of substituted cyclohexa-1,3-dienes from prenal and monoesters of ylidenemalonic acids. Russ Chem Bull. 1998;47(1):82.
- 14. Nigmatov AG, Serebryakov EP. Catalytic asymmetric synthesis of polysubstituted cyclohexa-1,3-dienes from β-branched α,β-alkenals. Russ Chem Bull. 1996;45(3):623–9.
- 15. Nigmatov AG, Kornilova IN, Serebryakov EP. Synthesis of polysubstituted 1,3-cyclohexadienes from β-branched α,β-alkenals and monoesters of ylidenemalonic acids. Russ Chem Bull. 1996;45(1):144–52.
- 16. Nigmatov AG, Serebryakov EP. Catalytic asymmetric synthesis of 6-substituted derivatives of 1,3-cyclohexadienecarboxylic acid. Russ Chem Bull. 1993;42(1):213–.
- 17. Hong B-C, Wu M-F, Tseng H-C, Huang G-F, Su C-F, Liao J-H. Organocatalytic Asymmetric Robinson Annulation of α,β-Unsaturated Aldehydes: Applications to the Total Synthesis of (+)-Palitantin. J Org Chem. 2007;72(22):8459–71. pmid:17919000
- 18. Hong B-C, Tseng H-C, Chen S-H. Synthesis of aromatic aldehydes by organocatalytic [4+2] and [3+3] cycloaddition of α,β-unsaturated aldehydes. Tetrahedron. 2007;63(13):2840–50.
- 19. Hong B-C, Wu M-F, Tseng H-C, Liao J-H. Enantioselective Organocatalytic Formal [3 + 3]-Cycloaddition of α,β-Unsaturated Aldehydes and Application to the Asymmetric Synthesis of (−)-Isopulegol Hydrate and (−)-Cubebaol. Org Lett. 2006;8(11):2217–20. pmid:16706490
- 20. Bench BJ, Liu C, Evett CR, Watanabe CMH. Proline Promoted Synthesis of Ring-Fused Homodimers: Self-Condensation of α,β-Unsaturated Aldehydes. J Org Chem. 2006;71(25):9458–63. pmid:17137373
- 21. Bench BJ, Tichy SE, Perez LM, Benson J, Watanabe CMH. Synthesis and cellular effects of cycloterpenals: Cyclohexadienal-based activators of neurite outgrowth. Bioorg Med Chem. 2008;16(16):7573–81. pmid:18678500
- 22. Yamada S-i, Shibasaki M, Terashima S. A biogenetic-type asymmetric cyclization syntheses of optically active α-cyclocitral and trans-α-damascone. Tetrahedron Lett. 1973;14(5):381–4.
- 23. Asato AE, Watanabe C, Li X-Y, Liu RSH. The proline and β-lactoglobulin mediated asymmetric self-condensation of β-ionylideneacetaldehyde, retinal and related compounds. Tetrahedron Lett. 1992;33(22):3105–8.
- 24.
Coran M. H. Watanabe, Bench BJ, inventorsSubstituted Cyclohexadienals—Syntheses and Applications. USA patent US 20070232813 A1. 2007 4 Oct 2007.
- 25. Pena J, Moro RF, Basabe P, Marcos IS, Diez D. Solvent free l-proline-catalysed domino Knoevenagel/6[small pi]-electrocyclization for the synthesis of highly functionalised 2H-pyrans. RSC Advances. 2012;2(21):8041–9.
- 26. Peters L, Wright AD, Kehraus S, Gündisch D, Tilotta MC, König GM. Prenylated Indole Alkaloids from Flustra foliacea with Subtype Specific Binding on NAChRs. Planta Med. 2004;70(10):883–6. pmid:15490312
- 27. Fishkin NE, Sparrow JR, Allikmets R, Nakanishi K. Isolation and characterization of a retinal pigment epithelial cell fluorophore: An all-trans-retinal dimer conjugate. PNAS. 2005;102(20):7091–6. pmid:15870200
- 28. Buchanan GS, Dai H, Hsung RP, Gerasyuto AI, Scheinebeck CM. Asymmetric Aza-[3 + 3] Annulation in the Synthesis of Indolizidines: An Unexpected Reversal of Regiochemistry. Org Lett. 2011;13(16):4402–5. pmid:21786757
- 29. Sydorenko N, Hsung RP, Vera EL. Torquoselective 6π-Electron Electrocyclic Ring Closure of 1-Azatrienes Containing Acyclic Chirality at the C-Terminus. Org Lett. 2006;8(12):2611–4. pmid:16737326
- 30. Deng Y, Salomon RG. Total Synthesis of γ-Hydroxy-α,β-Unsaturated Aldehydic Esters of Cholesterol and 2-Lysophosphatidylcholine. J Org Chem. 1998;63(22):7789–94.
- 31. Gu X, Sun M, Gugiu B, Hazen S, Crabb JW, Salomon RG. Oxidatively Truncated Docosahexaenoate Phospholipids: Total Synthesis, Generation, and Peptide Adduction Chemistry. J Org Chem. 2003;68(10):3749–61. pmid:12737551
- 32. Dunlap NK, Mergo W, Jones JM, Carrick JD. A general procedure for a one-pot oxidative cleavage/Wittig reaction of glycols. Tetrahedron Lett. 2002;43(21):3923–5.
- 33. Díez Martin D, San Feliciano SG, Marcos IS, Basabe P, Garrido NM, Urones JG. On the Stereoselectivity of the Synthesis of 1-Hydroxymethyl-4-phenylsulfonylbuta-1,3-dienes from β,γ-Unsaturated Sulfones. Synthesis. 2001;2001(07):1069–75.
- 34. Schuch AP, Menck CFM. The genotoxic effects of DNA lesions induced by artificial UV-radiation and sunlight. J Photochem Photobiol B. 2010;99(3):111–6. pmid:20371188
- 35. Maciel E, Felgueiras J, Silva EMP, Ricardo F, Moreira ASP, Melo T, et al. Lipid remodelling in human melanoma cells in response to UVA exposure. Photochem Photobiol Sci. 2017;16(5):744–52. pmid:28304067
- 36. He J, Long C, Huang Z, Zhou X, Kuang X, Liu L, et al. PTEN Reduced UVB-Mediated Apoptosis in Retinal Pigment Epithelium Cells. Biomed Res Int. 2017;2017:11.
- 37. Girigalavicius M, Iani V, Juzeniene A. Layer Thickness of SPF 30 Sunscreen and Formation of Pre-vitamin D. Anticancer Res. 2016;36(3):1409–15. pmid:26977044
- 38. Osterwalder U, Herzog B. Sun protection factors: world wide confusion. Br J Dermatol. 2009;161:13–24. pmid:19775352
- 39.
Food and Drugs, Vol. 5 (Rep. num.: 21CRF352), 2016, FDA.
- 40. Freitas JV, Praça FSG, Bentley MVLB, Gaspar LR. Trans-resveratrol and beta-carotene from sunscreens penetrate viable skin layers and reduce cutaneous penetration of UV-filters. Int J Pharm. 2015;484(1):131–7.
- 41. Bos JD, Meinardi MMHM. The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Exp Dermatol. 2000;9(3):165–9. pmid:10839713
- 42. Gustavsson Gonzalez H, Farbrot A, Larkö O. Percutaneous absorption of benzophenone-3, a common component of topical sunscreens. Clin Exp Dermatol. 2002;27(8):691–4. pmid:12472548
- 43. Gonzalez H. Percutaneous absorption with emphasis on sunscreens. Photochem Photobiol Sci. 2010;9(4):482–8. pmid:20354641
- 44. Chrétien MN, Heafey E, Scaiano JC. Reducing Adverse Effects from UV Sunscreens by Zeolite Encapsulation: Comparison of Oxybenzone in Solution and in Zeolites. Photochem Photobiol. 2010;86(1):153–61. pmid:19930122
- 45. Krause M, Klit A, Blomberg Jensen M, Søeborg T, Frederiksen H, Schlumpf M, et al. Sunscreens: are they beneficial for health? An overview of endocrine disrupting properties of UV-filters. Int J Androl. 2012;35(3):424–36. pmid:22612478
- 46. Gong P, Yuan H, Zhai P, Xue Y, Li H, Dong W, et al. Investigation on the degradation of benzophenone-3 by UV/H2O2 in aqueous solution. Chem Eng J. 2015;277:97–103.
- 47. Urosa A, Marcos I, Díez D, Lithgow A, Plata G, Padrón J, et al. Synthesis and Bioactivity of Luffarin I. Marine Drugs. 2015;13(4):2407. pmid:25903281
- 48. Zeng S, Kapur A, Patankar MS, Xiong MP. Formulation, Characterization, and Antitumor Properties of Trans- and Cis-Citral in the 4T1 Breast Cancer Xenograft Mouse Model. Pharm Res. 2015;32(8):2548–58. pmid:25673043
- 49.
Crystal data for 24a: CCDC 976522. See https://www.ccdc.cam.ac.uk/services/structure_deposit/ for crystallographic data in .cif or other electronic format.