A Sunscreen-Based Photocage for Carbonyl Groups

Article abstract of DOI:10.1002/chem.202000123

Photolabile protecting groups (PPGs) have been exploited in a wide range of chemical and biological applications, due to their ability to provide spatial and temporal control over light-triggered activation. In this work, we explore the concept of a new photocage compound based on the commercial UVA/UVB filter oxybenzone (OB; 2-hydroxy-4-methoxybenzophenone) for photoprotection and controlled release of carbonyl groups. The point here is that oxybenzone not only acts as a mere PPG, but also provides, once released, UV photoprotection to the carbonyl derivative. This design points to a possible therapeutic approach to reduce the severe photoadverse effects of drugs containing a carbonyl chromophore.

Full text of DOI:10.1002/chem.202000123

A Journal of
Accepted Article
Title: A Sunscreen-based Photocage for Carbonyl Groups
Authors: Mauricio Lineros-Rosa, Miguel A. Miranda, and Virginie
Lhiaubet-Vallet
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A Sunscreen-based Photocage for Carbonyl Groups
Mauricio Lineros-Rosa, [a] Miguel A. Miranda*, Virginie Lhiaubet-Vallet*
[a]
[a]
[a]
M. Lineros-Rosa, Prof. M. A. Miranda, Dr V. Lhiaubet-Vallet
Instituto Universitario Mixto de Tecnología Química (UPV-CSIC), Universitat Politècnica de València, Consejo Superior de Investigaciones Científicas
Avda de los Naranjos, s/n, 46022 Valencia, Spain
E-mail: mmiranda@qim.upv.es (MAM), lvirgini@itq.upv.es (VLV)
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: Photoremovable protecting groups (PPG) have been
exploited in a large set of chemical and biological applications,
due to their ability to provide spatial and temporal control over
light-triggered activation. In this work, we explore the concept of
a new photocage compound based on the commercial UVA/UVB
filter oxybenzone (OB, 2-hydroxy-4-methoxybenzophenone) for
photoprotection and controlled release of carbonyl groups. The
point here is that oxybenzone not only acts as a mere PPG, but
also provides, once released, UV photoprotection to the carbonyl
derivative. This design points to a possible therapeutic approach
to reduce the severe photoadverse effects of drugs containing a
carbonyl chromophore.
use of the phenacyl-like structure of the avobenzone diketo
tautomer to cage the carboxylic acid group of non-steroidal anti-
inflammatory drugs such as ketoprofen and diclofenac. [34, 35]
In the present work, the commercial UVA/UVB filter oxybenzone
(OB) has been the cornerstone of our new carbonyl photocage
design (Figure 1A). Actually, this solar filter plays a dual role
acting not only as the photoremovable group but also providing
an efficient UV shield effect to protect the carbonyl-derived drug
after its photorelease. We have proven the concept studying
derivative 1 as a new carbonyl photocage for the photorelease of
a water soluble aromatic ketone (4-carboxybenzophenone, CBP)
along with OB (Figure 1A).
Results and Discussion
Introduction
As a first experiment, the UV-Vis absorption spectra of the
carbonyl compound, 4-carboxybenzophenone (CBP), and the
oxybenzone sunscreen (OB) were recorded in H O:MeCN (40:60,
2
v:v) (Figure 1B). The former exhibits a maximum at 257 nm,
whereas the latter, as expected for a UVA/UVB filter, shows a
broad band with maxima at ca. 287 and 325 nm, which should
provide the purported protection to CBP. This was confirmed by
HPLC analysis of simulated solar light irradiations (SSL) of CBP
alone and in the presence of OB (Figure S1).
Photolabile protecting groups (PPGs) are now integral part
of the organic chemist toolbox. Their removal, which generally
takes place in neutral media and without the addition of any
reagent, makes them appealing alternatives to the conventional
methods employing basic, acidic, reductive or oxidative
conditions. A salient feature relies on the accurate spatial and
temporal control of the photodeprotection process that has been
exploited in advantageous approaches for the release of
chemicals such as acids, bases, oxidants, ions, drugs,
pheromones or fragrances.[1-11] In this context, PPGs have found
a wide range of applications in organic chemistry, biochemistry,
Then, the photolabile compound 1 was synthesized in four steps
(
(
Scheme 1). First, the carboxylic acid of 4-carboxybenzophenone
CBP) was esterified to compound 3, then selective reduction of
[1-
biology, polymer science, lithography, toiletry, pest-control, etc.
1
1]
the ketone was achieved by using NaBH
reacted with oxybenzone (OB) in the presence of
triphenylphosphine (PPh and diisopropyl azodicarboxylate
DIAD) through a Mitsunobu reaction to yield the diaryl ether 5,
which finally gave rise to 1 after basic hydrolysis. The UV-Vis
absorption spectra of photocage 1 displays a long wavelength
band peaking at 310 nm that reaches the UVA region, and making
conceivable the photorelease using SSL.
The progress of steady-state photolysis of 1 (2x10-4 M) in oxygen-
free MeCN:H O (60:40, v:v) was followed by HPLC. It was
2
observed that both OB and CBP are photoreleased together with
other photoproducts (Figure 1C). The peaks corresponding to 1,
OB and CBP were assigned by comparison with standards, and
were quantified along the irradiation to obtain the kinetic curves.
Moreover, peaks eluting at 2.3 and 3.4 min exhibit the kinetic
behavior of an intermediate with an increase of area to a
maximum after 60 min followed by a decrease.
4
. The obtained alcohol
Among the available PPGs, relatively few have found utility
for caging carbonyl functional groups.[6-9] These PPGs are
applicable not only in multi-step organic synthesis, where
carbonyls often require protection against nucleophiles, oxidative
or reductive agents, but also for biological purposes to release
bioactive compounds. Early work on carbonyl caging compounds
was based on acetals from o-nitrophenylethylene glycol.[12, 13]
Later, a series of 1,3-dioxolane and 1,3-dioxane derivatives have
been investigated to optimize the photouncaging process.[8, 14-20]
With this background, our interest was to explore the
concept of sunscreen-based photocages for photoprotection and
controlled release of carbonyl compounds. This is a new PPG
application recently addressed by our group to release a
photosensitive drug together with its UV-protector shield, which
would make special sense for carbonyl compounds in view of their
well-established photoreactivity.[34, 35] Until now, we have made
3
)
(
1
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(
A)
(B)
(
C)
(D)
Figure 1. (A) Photorelease of CBP and OB from new carbonyl photocage 1 (B) UV-Vis absorption spectra in oxygen-containing MeCN:H
2
O (60:40, v:v) of 1, 2,
CBP and OB at same concentration (6.6x10- M), (C) HPLC chromatograms registered at 280 nm for an oxygen-free MeCN:H
5
-4
2
O (60:40, v:v) solution of 1 (2x10
M), upon irradiation at different times with simulated solar light, and (D) kinetic traces of 1, 2, CBP and OB.
These compounds were assigned to the diastereoisomers of
cyclic intermediate 2 (see SI). They are obtained from 1 by an
intramolecular hydrogen abstraction and a subsequent C-C
coupling of the formed biradical (see Scheme 1 for a similar
reaction of the methyl ester 5). Indeed, this intermediate is in turn
a clear photocage for CBP, which is then released together with
OB.
In order to get a deeper understanding about the photorelease
process of OB and CBP from this cyclic intermediate, 2 was
synthesized and used for additional steady-state photolysis
experiments. In a first stage, an oxygen-containing solution of
compound 2 in MeCN:H
confirm the intermediate capacity to photorelease OB and CBP
Figure S3D). Then, to simplify the quantitation process,
experiments were performed using a low pressure Hg lamp with
a monochromatic output at 254 nm under atmosphere of N or air.
Compound 2 (2x10-4 M) dissolved in anhydrous MeCN or in
MeCN:H O (60:40, v:v) was irradiated, and the reaction was
2
O (60:40, v:v) was irradiated with SSL to
(
2
2
followed by UV-Vis absorption spectrophotometry. In all cases, it
was observed an absorption increase as a function of irradiation
time, and a new band peaking at ca. 325 nm appeared, pointing
to OB formation. A similar behavior was observed under the
different conditions (Figure S2).
Scheme 1. Synthesis of compounds 1 and 2
MeCN:H O solution, the peak of compound 2, eluting at 3.4 min,
2
Moreover, to reach a more accurate analysis of the irradiated
samples, aliquots were taken at periodic intervals and analyzed
by HPLC. The compound 2 was consumed during the irradiation
irrespective of the employed conditions, whereas the release of
CBP strongly differed depending on the presence of oxygen
and/or water. As shown in Figure 2 for an oxygen-containing
decreased giving basically rise to the formation of the desired
CBP (at 1.5 min), together with OB (at 3.7 min). The yields of the
photoproducts determined after 60 min of irradiation are
summarized in Table 1. The results were clearly affected by the
presence of O or H O. In oxygen-containing aqueous acetonitrile,
2
2
the yields of CBP and OB were markedly higher and the formation
2
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of undesired byproducts was minimized (Figure S3). Remarkably,
when oxygen and water were present in the solution, CBP yield
Altogether, these results demonstrate that at least part of the
oxygen of CBP arises from water present in the solvent, and
reached 51.7%, whereas the yield of OB grew from 7.6% to 21.1%. supports that in aerobic atmosphere the yield of CBP formation is
A quantum yield of ca. 0.16 was determined for the photoreaction
by means of an established procedure using as standard the
photocyclization of N-methyldiphenylamine to N-methylcarbazole
in oxygen-containing acetonitrile (see Experimental Section).[
enhanced in aqueous acetonitrile. Nonetheless, the reaction still
takes place under aerobic anhydrous conditions, albeit to a lesser
extent, showing that atmospheric oxygen is also capable to trigger
the process. Consequently, the lowest efficiency is observed for
oxygen-free anhydrous acetonitrile.
36]
In order to explain the obtained results and to get insights into the
mechanistic details of the photoprocess, laser flash photolysis
Table 1. Yields of compounds 2, CBP and OB obtained after 60 min of
irradiation under different conditions.
(
LFP) experiments were performed at 266 nm. The transient
absorption spectrum obtained for N -bubbled aqueous solutions
of 2 is shown in Figure 3. It exhibits a maximum at 350 nm
2
Conversion (%)
85.4±0.3
4-CBP (%)
9.1±1.6
OB (%)
together with
a
shapeless band growing until 700 nm
Anhydrous MeCN, N
MeCN/H O, N
Anhydrous MeCN, Air
MeCN/H O, Air
2
7.6±1.2
19.0±0.5
20.6±0.5
21.1±0.4
-
characteristic of hydrated electron (e aq), which was quenched
2
2
89.1±0.7
6.1±0.3
2
under N O atmosphere (Figure 3, top). The linear variation of the
hydrated electron absorbance at 680 nm as a function of the laser
intensity reflected a monophotonic process (Figure 3, bottom).
Furthermore, the log-log representation fitted linearly with a slope
of 1.2 (Figure S5, top) confirming the one-photon nature of the
ionization process, which could thus occur under steady-state
photolysis. Consistently, LFP studies carried out using (2,4-
82.4±1.8
36.3±1.4
51.7±1.2
2
87.8±0.7
dimethoxyphenyl)acetic acid (DMFA) as
a model of the
-
dialkoxyaryl group of 2 also gave rise to e aq (see Figure S5, right).
Interestingly, the 4-carboxyaryl moiety can act as a good electron
acceptor and thus be reduced during the process either through
an intramolecular electron transfer process or through trapping of
hydrated electron.
Figure 2. HPLC chromatograms registered at 280 nm for an oxygen-containing
O (60:40, v:v) solution of 2 (2x10- M), upon irradiation at different
4
MeCN:H
2
times at 254 nm.
The obtained results are in accordance with the fact that formal
incorporation of an oxygen atom to dyad 2 is required to release
CBP and OB (Figure 1A).
To experimentally settle whether the oxygen comes from H
2
O and
if so where it is finally incorporated, photodeprotection was carried
1
8
out using MeCN:H
containing solution of 2 in either MeCN/H
exposed to 254 nm light, and the reaction mixture was analyzed
by UPLC-HRMS. When H O was used, mass spectra of the CBP
2
O as solvent. In this context, an oxygen-
O or MeCN/H 18O was
2
2
2
and OB peaks were coincident with the expected natural isotopic
+
pattern, with m/z values of 227.0714 and 229.0864 as [M+H ],
respectively. Conversely, for the reaction in H
m/z 229.0743 increased and its exact mass corresponded to that
2
18O a CBP peak at
1
8
of O labeled CBP. By contrast, no significant changes were
observed for OB (see Figure S4). Thus, comparison of the MS
spectra for the CBP peak showed that ratio between the intensity
of the ions at m/z 229.0743 and 227.0706 was higher in the
1
8
presence than in the absence of H
Moreover, no changes in the isotopic pattern were observed for
CBP in H
18O solution left in the dark for hours (see Figure S4).
2
O (1/3 vs 1/33, respectively).
Figure 3. Top: transient absorption spectra of 2 in H
2
O under N
O (black line) 0.04 μs after the 266 nm laser pulse
laser energy: 33 mJ). Bottom: laser energy dependence of the
solution.
2
(
(
red line) or N
2
2
transient absorption intensity at 680 nm of the N
2
3
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Scheme 2. Photorelease mechanism from photocage 2.
Actually, comparison of the kinetic traces of hydrated electron at
sodium bicarbonate. Finally, the organic phase was dried with
anhydrous magnesium sulfate, filtered, and the filtrate was
680 nm revealed a faster decay for 2 (Figure S5, τ∼ 270 ns) than
for DMFA (Figure S5, τ ∼ 400 ns), which is in agreement with
electron trapping by the 4-carboxyaryl moiety of 2.
concentrated in vacuo. The pure product 3 was obtained without
further purification. Yield: 0.421 g (77%). 1H NMR (300 MHz,
On the basis of these data, a possible mechanism is outlined in
Scheme 2. The photorelease process might be triggered by the
photoinduced formation of biradical zwitterion I (Scheme 2). This
intermediate can evolve through two different pathways
depending on the mesolytic cleavage of the benzylic C-O bond
CDCl
3
): δ (ppm) 8.15 (d, J = 8.6 Hz, 2H), 7.82 (m, 4H), 7.68 – 7.57
(
m, 1H), 7.55 – 7.42 (m, 2H), 3.97 (s, 3H). HRMS (ESI-TOF) m/z
+
[
13 3
M+H] calculated for C15H O : 241.0865; found: 241.0859.
(
route i) or C-C bond (route ii). In the former case, the obtained
Methyl 4-[hydroxy(phenyl)methyl]benzoate (4). Compound
0.328 g, 1.36 mmol) was dissolved in a mixture of anhydrous
methanol (5 mL) and anhydrous dichloromethane (2 mL). The
resulting solution was cooled to 0 ºC, and then NaBH (0.072 g,
3
biradical II is trapped by O leading to III, which after dimerization
and subsequent fragmentation yields the desired CBP and OB.
The C-C cleavage, route ii, gives rise to biradical IV that reacts
with O
2
(
to form the cyclic endoperoxide intermediate V. In the
, CBP
4
2
presence of water, it hydrolyzes to yield, after loss of H
2
O
2
1.9 mmol) was added portionwise during 2 h. Subsequently, the
solution was allowed reaching room temperature, and stirred for
and OB. In this context, incorporation of 18O to CBP demonstrates
that water attacks at the benzylic position of the carboxyaryl
moiety, which is actually the most electrophilic carbon.
4
3 h. To quench the excess of NaBH , the solution was cooled in
an ice bath, and then water (5 mL) was added. The resulting
mixture was stirred for 30 min. The mixture of solvents were
removed under reduced pressure, then the afforded crude was
redissolved with dichloromethane (20 mL) and washed with
water. Finally, the combined organic extracts were dried with
Conclusion
In summary, the concept of sunscreen-based photocages for
carbonyl compounds has been proven in the present work, using
compounds 1 and 2, which serve as precursors of the target
aromatic ketone along with its UV-filter shield. Further work is in
progress to optimize the yields of the uncaging processes and to
explore the scope of this approach with differently substituted
ketones, such as acetophenone derivatives, and aldehydes.
4
MgSO , filtered, and the solvent was removed under reduced
pressure. The pure product 4 was obtained without further
1
purification. Yield: 0.282 g (85%). H NMR (300 MHz, CDCl
3
): δ
(
ppm) 7.91 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.33 –
7
.11 (m, 5H), 5.79 (d, J = 3.3 Hz, 1H), 3.81 (s, 3H), 2.40 (d, J =
.3 Hz, 1H). HRMS (ESI-TOF) m/z [M+H]+ calculated for
3
15 15 3
C H O : 243.1021; found: 243.1021.
Methyl
methoxyphenoxy)(phenyl)methyl]benzoate (5). To a solution of
compound 4 (0.249 g, 1.03 mmol) and triphenylphosphine (PPh
0.324 g, 1.23 mmol) in anhydrous dioxane (5.5 mL) was added
4-[(2-benzoyl-5-
Experimental Section
3
)
Synthesis.
(
oxybenzone (0.353 g, 1.55 mmol) and diisopropyl
azodicarboxylate (DIAD) (0.350 mL, 2 mmol). The solution was
stirred at room temperature for 4 h. The crude reaction mixture
was concentrated under reduced pressure and purified by column
chromatography (cyclohexane/ethyl acetate, 4:1; silica gel) to
Methyl 4-benzoylbenzoate (3). Concentrated sulfuric acid (0.025
mL, 0.44 mmol) was added to a solution of 4-benzoylbenzoic acid
(
0.5 g, 2.2 mmol) in anhydrous MeOH (15 mL). The solution was
stirred at 75 ºC for 17 h and then cooled to room temperature. The
solvent was removed under reduced pressure. The crude product
was redissolved in dichloromethane and washed with saturated
1
give the pure product 5. Yield: 0.340 g (73%). H NMR (300 MHz,
4
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CDCl
3
): δ (ppm) 7.95 – 7.80 (m, 4H), 7.60 – 7.41 (m, 4H), 7.20
7.21 – 6.88 (m, 10H), 6.84 (d, J = 2.2 Hz, 1H), 6.77 (d, J = 8.3 Hz,
1H), 6.50 (dd, J = 8.3, 2.2 Hz, 1H), 3.86 (s, 3H). 13C NMR (75
MHz, MeOD): δ (ppm) 162.3, 160.1, 146.4, 141.9, 141.6, 128.1,
127.8, 127.5, 126.8, 126.6, 126.5, 126.1, 125.5, 107.4, 99.1, 95.4,
86.9, 54.6. HRMS (ESI-TOF) m/z [M-OH]+ calculated for
(
m, 7H), 6.55 (dd, J = 8.5, 2.0 Hz, 1H), 6.48 (d, J = 2.0 Hz, 1H),
.19 (s, 1H), 3.86 (s, 3H), 3.71 (s, 3H). 13C NMR (75 MHz, CDCl
):
3
6
δ (ppm) 195.9, 166.5, 163.1, 157.2, 145.9, 140.2, 139.5, 132.3,
132.3, 129.8, 129.5, 129.2, 128.6, 128.1, 127.9, 126.1, 125.9,
1
22.4, 105.6, 101.4, 81.8, 55.3, 51.9. HRMS (ESI-TOF) m/z
C
28
H
21
O
4
:
421.1440; found: 421.1439. Molar absorption
+
[
M+H] calculated for C29
H
25
O
5
: 453.1702; found: 453.1713.
coefficient in MeCN:H O (60:40, v:v): log ε = 3.8 (283 nm).
2
Instrumentation
4-(3-hydroxy-6-methoxy-2,3-diphenyl-2,3-dihydrobenzofuran-2-
yl)benzoic acid (1). Compound 5 (0.191 g, 0.42 mmol) was
dissolved in a mixture of 1 M aq. NaOH (2 mL) and THF (2 mL).
The resulting solution was stirred for 22 h at room temperature.
The mixture was acidified to pH 1 using 1 M aq. HCl, then the
resulting mixture was extracted with dichloromethane (3 x 10 mL),
UV-Vis. The absorption spectra were registered with a simple
beam spectrophotometer (Cary 50) using a quartz cell of 1 cm
optical path.
Steady-State Photolysis. All irradiations were carried out at room
dried over anhydrous MgSO
4
, and rotary evaporated to afford
temperature using 3 mL quartz cuvettes of 1 cm optical path.
1
compound 1 (0.127 g) in a 69% yield. H NMR (300 MHz, CDCl
3
):
Photolysis of compound 2 were run using a Luzchem
δ (ppm) 7.88 (d, J = 8.1 Hz, 2H), 7.80 (d, J = 7.2 Hz, 2H), 7.47 (m,
H), 7.25 – 6.98 (m, 7H), 6.54 (dd, J = 8.7, 1.8 Hz, 1H), 6.41 (d, J
1.8 Hz, 1H), 6.12 (s, 1H), 3.73 (s, 3H). 13C NMR (75 MHz,
CDCl ): δ (ppm) 196.29, 163.29, 157.39, 146.57, 140.29, 139.61,
32.55, 132.51, 130.52, 129.67, 129.27, 128.86, 128.27, 128.09,
photoreactor (model LZC-4V, 8W) with one low pressure Hg lamp
4
with an output at 254 nm. Irradiation of compound 1 was carried
=
out in a mixture of MeCN:H O (60:40, v:v) under oxygen-free
2
3
conditions using a simulated solar light (SSL) obtained from a
Xenon arc lamp solar simulator (Thermo Oriel 91192-1000)
equipped with a AM 1.5 filter Global to better match the solar
1
1
26.33, 126.09, 122.68, 105.85, 101.60, 82.15, 55.54. HRMS
+
2
(
ESI-TOF) m/z [M+H] calculated for C28
H
23
O
5
: 439.1545; found:
O (60:40,
emission spectra, its output was of 86 mW/cm . Solutions of
-4
4
39.1550. Molar absorption coefficients in MeCN:H
2
compound 2 (2 x 10 M) were prepared in anhydrous acetonitrile
v:v): log ε = 3.9 (280 nm), 3.7 (310 nm).
or in MeCN:H O (60:40, v:v) under nitrogen or air, and irradiations
2
were run in quartz cells of 1 cm optical path. The oxygen-free and
anhydrous solution of 2 was prepared in a dry box. The course of
the photoreaction was followed by UV-Vis absorption
spectrometry and HPLC.
Methyl
4-(3-hydroxy-6-methoxy-2,3-diphenyl-2,3-
dihydrobenzofuran-2-yl)benzoate (6). An oxygen-free solution of
compound 5 (0.170 g, 0.376 mmol) in 211 mL cyclohexane and 9
mL dichloromethane was irradiated for 90 min using a Luzchem
photoreactor (model LZC-4V) with 8 lamps with a maximum
output at 355 nm. Then, the solvent was removed under vacuum.
Purification was performed by column chromatography
HPLC. All irradiation mixtures were analyzed by a 1100 Series
Agilent HPLC equipped with a diode array detector (DAD), for all
chromatograms the detection wavelength was 280 nm.
Irradiations were analyzed using a Zorbax Eclipse Plus C18 (4.6
x 100 mm, 3.5 Micron) column, and the chromatographic
conditions were an isocratic mixture of water at pH 3 (35%) and
acetonitrile (65%) at a flow rate of 1 mL/min. The injection volume
was of 10 μL. The areas of the peaks were integrated by using
the “OpenLab CDS ChemStation Edition” software supplied by
Agilent. The percent yields were determined from calibration
curves of pure samples of OB, CBP, 1 and 2.
(
cyclohexane/ethyl acetate, 6:1; silica gel). Product 6 was
obtained by resolution of the diastereoisomeric mixture (0.058 g)
1
in a 34% yield. H NMR (300 MHz, CDCl
3
): δ (ppm) 8.07 – 7.96
(
d, J = 8.7 Hz, 2H), 7.95 -7.83 (d, J = 8.7 Hz, 2H), 7.15 (m, 5H),
7
3
1
1
9
.08 – 6.90 (m, 5H), 6.82 (m, 2H), 6.48 (dd, J = 8.3, 2.2 Hz, 1H),
.88 (s, 3H), 3.86 (s, 3H). 13C NMR (75 MHz CDCl
3
): δ (ppm)
66.9, 162.6, 160.2, 146.0, 140.9, 140.8, 129.2, 129.1, 128.1,
27.8, 127.4, 127.4, 127.3, 127.2, 127.0, 126.5, 125.9, 108.3,
9.5, 96.4, 87.8, 55.8, 52.2. HRMS (ESI-TOF) m/z [M-OH]+
The quantum yield of the photoreaction was established using N-
methyldiphenylamine in MeCN as actinometer (φref
irradiating at 254 nm.[36, 37]
= 0.45)
calculated for C29
H
23
O
4
: 435.1596; found: 435.1595. Based on the
spectroscopic data, this compound has the two phenyl groups in
cis arrangement.
UPLC-HRMS. Exact mass values were determined by using a
QTof spectrometer coupled with a liquid chromatography system.
The separation was carried out by UPLC on a Zorbax Eclipse Plus
C18 column (4.6 x 100 mm, 3.5-micron). The mobile phase was
a gradient prepared from 0.1% aqueous formic acid solution
4-(3-hydroxy-6-methoxy-2,3-diphenyl-2,3-dihydrobenzofuran-2-
yl)benzoic acid (2). Compound 6 (0.057 g, 0.13 mmol) was
dissolved in a mixture of 1 M aq. NaOH (0.56 mL) and THF (0.56
mL). The resulting solution was stirred for 22 h at room
temperature. The mixture was acidified to pH 1 using 1 M aq. HCl,
then the resulting mixture was extracted with dichloromethane (3
(
component A) and 0.1% formic acid in acetonitrile (component
B). The column was equilibrated with A:B (80:20; v:v) as mobile
-1
phase at a flow rate of 0.5 mL min . The amount of component A
was maintained at this composition for 3 min, then decreased
from 80 to 0% in 7 min, kept at 0% for 5 min, restored to the initial
composition in 2 min, and finally maintained at this composition
x 10 mL), dried over anhydrous MgSO
4
, and rotary evaporated to
1
afford compound 2 (0.013 g) in a 23% yield. H NMR (300 MHz,
MeOD): δ (ppm) 7.97 (d, J = 8.5 Hz, 2H), 7.90 (d, J = 8.5 Hz, 2H),
5
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Keywords: Laser spectroscopy • Photocage • Photochemistry •
Photoprotection • Solar filter
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6
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Entry for the Table of Contents
Table of Contents
The design of this novel photocage achieves two main goals: an extension of the organic chemist toolbox providing a new carbonyl
photoprotecting group, and a proof of concept for sunscreen-based photocages for carbonyl-derived drugs allowing a controlled and
simultaneous photorelease of a photosensitive drug and its protecting solar filter.
Institute and/or researcher Twitter usernames: @ITQ_UPVCSIC, @VirLhiaubet, @MauriLR1
7
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