A novel thiochromone-type photolabile protecting group for carbonyl compounds

Article abstract of DOI:10.1016/j.tet.2013.03.022

A novel photolabile protecting group, thiochromone S,S-dioxide, possessing the 1,2-diol group for protection of ketones and aldehydes is described. Photodeprotection of the successfully protected carbonyl derivatives proceeded smoothly under photoirradiation filtered through Pyrex glass (>280 nm) using an ultrahigh-pressure mercury lamp to recover the corresponding carbonyl compounds and the starting protecting group.

Full text of DOI:10.1016/j.tet.2013.03.022

Tetrahedron 69 (2013) 3984e3990
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Tetrahedron
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A novel thiochromone-type photolabile protecting group for
carbonyl compounds
Ryo Sugiura, Rikio Kozaki, Satoru Kitani, Yoshinori Gosho, Hiroki Tanimoto,
*
Yasuhiro Nishiyama, Tsumoru Morimoto, Kiyomi Kakiuchi
Graduate School of Materials Science, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0101, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel photolabile protecting group, thiochromone S,S-dioxide, possessing the 1,2-diol group for pro-
tection of ketones and aldehydes is described. Photodeprotection of the successfully protected carbonyl
derivatives proceeded smoothly under photoirradiation filtered through Pyrex glass (>280 nm) using an
ultrahigh-pressure mercury lamp to recover the corresponding carbonyl compounds and the starting
protecting group.
Received 15 January 2013
Received in revised form 28 February 2013
Accepted 5 March 2013
Available online 13 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Photolabile protecting group
Thiochromone
1,2-Diol
Carbonyl compound
Photodeprotection
1. Introduction
Although a number of reports on PLPGs have already been
published, relatively few PLPGs for ketones and aldehydes have
Protecting groups are essential in organic synthesis, in order to
achieve desired reactions by protecting reactive functional groups
that are not desired in the reaction. However, most protected
compounds are deprotected under acidic or basic conditions, or
require a highly reactive reagent, which sometimes leads to an
undesired reaction or decomposition of the substrates. In this
context, much attention has been paid to photolabile protecting
groups (PLPGs), which can be removed only by irradiation of light
under neutral conditions without any additional reagents.1 Thus,
introducing PLPGs to substrates is a powerful method to perform
desired reactions in organic synthesis. Moreover, since depro-
tection reactions of PLPGs proceed under irradiation with light,
reaction scale can be reduced down to the nanoscale, so that the
PLPGs can be applied in not only organic synthesis, but also in
construction of DNA microarray,2 or in caged compounds.3 Espe-
cially, an application of PLPGs to caged compounds is now exten-
sively studied in order to control biochemical reactions in a cell to
investigate unknown biological phenomena or to remotely control
cell functions, causing a demand for widely applicable and highly-
efficient PLPGs.
been reported compared to those for alcohols, amines, carboxylic
acid, and phosphates, even though there are many biological
effectors, such as drugs possessing carbonyl moieties.4 The first
PLPG for carbonyl compounds was reported by Gravel et al., in
which a diol derivative of a well-known PLPG o-nitrobenzyl group
releases carbonyl compounds and a-hydroxyketone under photo-
irradiation.4a Dore et al. reported a diol coumarin derivative as
a PLPG for ketones and aldehydes, which photodeprotects carbonyl
compound and regenerate starting PLPG.4b They both modified
a linker of typical PLPGs to diol and protected ketones and alde-
hydes as an acetal moiety.
Inspired by their molecular designs, we designed a novel thio-
chromone PLPG 1d possessing diol group as a linker, of which
derivatives 1aec were developed in our laboratory and applied to
the protection and deprotection for alcohols, amines, carboxylic
acids, and phosphates (Fig. 1).5 Herein, we report how this design
was realized, leading to the development of the novel PLPG 1d
possessing the diol group as linker to connect with ketones and
aldehydes.
2. Results and discussion
PLPG 1d was prepared from compound 2, a common starting
* Corresponding author. Tel.: þ81 0743 72 6080; fax: þ81 0743 72 6089; e-mail
address: kakiuchi@ms.naist.jp (K. Kakiuchi).
material for our PLPGs (Scheme 1).5 Introduction of methoxy
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.022

R. Sugiura et al. / Tetrahedron 69 (2013) 3984e3990
3985
Table 1
Protection and photodeprotection of carbonyl compounds 6
Entry
Carbonyl
compound 6
Protection
Time (h)
Photodeprotection
Yielda (%)
Time
Yieldb (%)
Fig. 1. Structures of new PLPGs.
(min)
6
1d
1
2
a
8
95
88
180
180
91
90
b
24
99
70
94
93
3
4
c
8
70
80
180
160
d
36
75
92
5
6
7
8
9
e
f
15
55
8
85c
20c
11c
N.R.
95d
60
89
99
99
d
89
99
89
d
100
120
d
g
h
i
Scheme 1. Synthetic route for PLPG 1d.
44
8
carbonyl moiety to 2 by LDA and methyl cyanoformate afforded
methyl ester 3 in 68% yield.
using LDA and Davis reagent prepared by a previously reported
procedure gave
-hydroxy methyl ester 4 in 93%.6 Reduction of
a-Hydroxylation of ester moiety in 3
120
58
59
a
ester moiety in 4 to alcohol was achieved in two steps: LAH re-
duction to give aldehyde intermediate as a crude product, followed
by sodium borohydride reduction to give desired diol product 5 in
50% yield. Direct reduction of 4 with LAH or DIBALH did not work
well to give complex mixtures including the desired diol 5. The final
step was carried out by oxidation of the sulfur atom of 5 with m-
CPBA to give target diol PLPG 1d in 85%.
10
j
52
64c
60
79
88
a
Isolated yield.
b
c
Determined by 1H NMR spectroscopy.
Obtained as a diastereomeric mixture.
d
Obtained as a single diastereomer whose stereochemistry is not determined.
The new PLPG was promising in protecting the carbonyl com-
pounds and was further examined with various substrates. Pro-
tection reactions of the ketones 6aee and the aldehyde 6iej were
straight forward, based on the reaction conditions reported by Wang
et al.4e Treatment of carbonyl compounds 6 with 1.1 equiv of 1d in
the presence of 10 mol % of p-toluenesulfonic acid and 0.8 equiv of
copper(II) sulfate in benzene at room temperature afforded the
corresponding compounds 7 in high yield (Table 1, entries 1e5, 9,10).
However, protection reactions for ketones 6feh were not successful,
supposedly due to their steric hindrance (entry 6).
Deprotection of all ketones and aldehydes proceeded smoothly
under photoirradiation using a 500 W ultrahigh-pressure mercury
lamp filtered through Pyrex glass (>280 nm) within 3 h (Table 1),
except for aldehyde 6i in which moderate photodecomposition of
products was observed (entry 9). This decomposition would have
happened because of the unstability of the aldehyde 6i under
photoreaction conditions.
Progress of photodeprotection of acetone protected compound
7a was monitored by 1H NMR spectra (Fig. 2). Before irradiation,
three peaks at 4.8 ppm (Ha, dd, 1H), 4.3 ppm (Hb, dd, 1H) and
4.1 ppm (Hc, dd, 1H) derived from the linker methine and methy-
lene of 7a were observed. After 30 min irradiation, these peaks
diminished and new peaks appeared instead. The peaks observed
at 4.6 ppm (Ha’, dt, 1H), 3.9 ppm (Hb’, m, 1H), and 3.7 ppm (Hc’, m,
1H) correspond to the PLPG 1d. The peak at 2.1 ppm corresponds to
acetone. Further irradiation for 120 min made the peaks of the
substrate disappeared, while the peaks of the PLPG 1d and the
acetone got stronger, proving that the photodeprotection of 7a
proceeds to release both acetone and PLPG 1d quantitatively under
photoirradiation.
The deprotection mechanism was initially studied with TD-DFT
calculations (B3LYP/6e31þg(d)) of the acetone protected com-
pound 7a, of which HOMO and LUMO maps suggested a charge

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R. Sugiura et al. / Tetrahedron 69 (2013) 3984e3990
Fig. 2. Process of photodeprotection monitored by 1H NMR spectra.
transfer from acetal moiety to thiochromone framework through
excitation, resulting in cleavage of a CeO bond of acetal moiety due
to its low electron density (Fig. 3). Considering the selectivity of
either of the four CeO bonds to be cleaved as the initiation of the
photodeprotection, the cleavage of C24eO20 seems to be preferred
due to a generation of stable tertiary carbocation and oxygen anion
which is connected with the primary carbon being more stabilized
compared to that connected with the secondary carbon (Scheme 2).
After the cleavage of C24eO20 bond, nucleophilic addition of water
the carbocation followed by the elimination of the ketone results in
the recovery of corresponding ketone and PLPG 1d. To experi-
mentally determine, which CeO bond initially gets cleaved, we
carried out the photodeprotection reaction using H218O (Fig. 4). If
the oxygen on the ketone comes from the solvent, then the labeled
ketone 6-18O will be formed and the PLPG 1d won’t be labeled, as
we predicted above (Fig. 4a, route A). Alternatively, if unlabeled
ketone 6 is observed while labeled PLPG 1d-18O is observed, then
the source of the oxygen on the ketone would be from the acetal
moiety (Fig. 4a, route B). Compound 7d was chosen for the sub-
strate due to its efficient photodeprotection and cyclopentanone’s
Scheme 2. Possible photodeprotection mechanism.
Fig. 3. HOMO and LUMO map of the acetone protected compound 7a.

R. Sugiura et al. / Tetrahedron 69 (2013) 3984e3990
3987
to 1d-18O. To confirm the reproducibility, another labeling experi-
ment was conducted with compound 7j and the result showed that
56% of the label was incorporated into the benzaldehyde 6j and 39%
of that into the PLPG 1d (see the Supplementary data for MS
spectra). The similar tendency of labeling ratio, higher ratio for
carbonyl compounds, was observed and further supported our
proposed mechanism. This result is interesting because the pro-
posed intermediate of CeO cleaved dioleprotected aldehydes and
ketones reported by Dore et al., is different from ours, although the
structure of their compound and ours resembles each others in
some points.4b
3. Conclusion
A novel PLPG for carbonyl compounds has been developed.
Protection for carbonyl compounds proceeded successfully, except
for the bulky ones. Photodeprotection of all carbonyl compounds
proceeded smoothly to regenerate corresponding carbonyl com-
pounds and starting PLPG 1d in moderate to high yield. The pho-
todeprotection mechanism was discussed along with the molecular
orbital map obtained from TD-DFT calculation, supporting the hy-
pothesis that the CeO cleavage is caused by a charge transfer from
HOMO to LUMO making the CeO electron density small easily to be
cleaved. Although the 18O labeling experiment conducted for fur-
ther investigation didn’t give clear results, it generally supported
our proposed mechanism. Interestingly, our proposed intermediate
in the photodeprotection reaction was much different from those
reported by Dore et al., and this would give a mechanistic insight
into the photolysis of acetal structure.
4. Experimental section
4.1. General experimental procedures
Air and/or moisture sensitive reactions were carried out under
a nitrogen atmosphere with commercially available anhydrous
solvents. All reagents and solvents were commercially purchased
and further purified according to the standard methods, if neces-
sary. The progress of reactions was monitored by silica gel TLC
ꢀ
plates (mesh size 60 A, MERCK). Products were purified by flash
column chromatography on 40e63 m
m silica gel 60 (MERCK). 1H
NMR were recorded on JEOL JNM-ECP 500 (500 MHz). Chemical
shifts are reported in parts per million relative to TMS (0 ppm) as an
internal standard, or the peak of chloroform-d (7.26 ppm). Data is
reported as follows: chemical shift, integration, coupling constants
(hertz), multiplicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet,
br¼broad, m¼multiplet). 13C NMR were recorded on a JEOL JNM-
ECP 500 instrument (125 MHz). Chemical shifts are reported in
ppm relative to TMS (0 ppm) as an internal standard, or the middle
peak of chloroform-d (77.0 ppm). Melting points were determined
on a Yanaco MP-500D and uncorrected. IR spectra were recorded on
a Jasco FT/IR-4200 spectrometer. MS and HRMS were measured on
a JEOL JMS-700 spectrometer using EI, CI, ESI or FAB. UV/vis spectra
were measured in a quartz cell (10 mm thickness) on a JASCO V-630
spectrometer. DFT calculations were done using the Gaussian 03
program.7
Fig. 4. (a) 18O labeling experiment. (b) MS (CI) spectra of the reaction solution of the
labeled and unlabeled experiment of 7d.
low volatility. A solution of 7d in either H2O or H218O (97% label)
was exposed to >280 nm light until 7d was totally consumed. Then
the reaction solution was analyzed by MS (CI) (Fig. 4b). For the
reaction in H2O, mass spectral analysis of the peak on the chro-
matogram corresponding to cyclopentanone gave exclusively
m/z 85 ([MþH]þ). But the one corresponding to PLPG 7d gave
331 ([MþH]þ) with its unusually high isotope ion peak 333
([Mþ2þH]þ). The reaction in H218O gave strong m/z 87 and 333,
both as labeled peaks. A comparison of the MS data of the labeled
and unlabeled reactions revealed that 64% of the label was in-
corporated into the cyclopentanone 6d and 17% of that into the
PLPG 1d. These results did not let us determine, which specific CeO
bond was to be cleaved since both the ketone and the PLPG were
labeled. However, much higher labeling ratio in ketone 6d-18O
(64%) compared to the PLPG 1d-18O (17%) suggest that the way of
cleavage of a CeO bond are likely to occur as a simple hydrolysis of
an acetal compared to the photolytic cleavage of C18eO21 leading
4.2. Experimental procedures and characterization data for
the synthesis of PLPG 1d
4.2.1. Methyl
2-(4-oxo-3-phenyl-4H-thiochromen-2-yl)
acetate
(3). To a solution of lithium N,N-diisopropylamide in THF (1.0 ml),
prepared from 1.6 M n-BuLi in hexane (0.65 ml, 1.0 mmol) and N,N-
diisopropylamine (0.14 ml, 1.0 mmol), 2-methyl-3-phenyl-4H-thi-
ochromen-4-one 25 (126 mg, 0.50 mmol) in HMPA (1.0 ml) was
added at ꢀ78 ꢁC. After stirring at ꢀ78 ꢁC for 5 min, a mixture of

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R. Sugiura et al. / Tetrahedron 69 (2013) 3984e3990
methyl cyanoformate (44
m
l, 0.55 mmol) and THF (0.5 ml) was
After stirring at room temperature for 8 h, the reaction was
quenched with satd Na2S2O3 aq and the reaction mixture was
extracted with CH2Cl2. The combined organic extracts were dried
over MgSO4, filtered through filter paper, and evaporated. The
residue was purified by flash chromatography (hexane/EtOAc¼1:1)
to give 1d (280 mg, 0.85 mmol, 85%) as colorless solid. Mp:
68.1e69.9 ꢁC. IR (neat): 3502, 3369, 1662, 1306, 1155, 1049 cmꢀ1. 1H
added. After stirring at ꢀ78 ꢁC for 30 min, the reaction was
quenched with satd NH4Cl aq, and the reaction mixture was
extracted with EtOAc. The combined organic extracts were dried
over MgSO4, filtered through filter paper, and evaporated. The
residue was purified by flash chromatography (hexane/EtOAc¼3:1)
to give 3 (107 mg, 0.34 mmol, 68%) as colorless solid. Mp:
131.5e132.8 ꢁC. IR (neat): 1739, 1618, 1592, 1438, 1343, 1197, 1172,
NMR (CDCl3, 500 MHz,
d
): 8.17 (d, J¼8.0 Hz, 1H), 8.09 (d, J¼8.0 Hz,
1084, 985, 961 cmꢀ1. 1H NMR (CDCl3, 500 MHz,
d
): 8.51 (d, J¼9.5 Hz,
1H), 7.91 (dd, J¼8.0, 8.0 Hz, 1H), 7.80 (dd, J¼8.0, 8.0 Hz, 1H),
7.49e7.47 (m, 3H), 7.29e7.27 (m, 2H), 4.79 (dt, J¼9.0, 7.0 Hz, 1H),
4.11e4.06 (m, 1H), 4.02e3.97 (m, 1H), 3.22 (d, J¼9.0 Hz, 1H), 2.48
1H), 7.65e7.59 (m, 2H), 7.55e7.52 (m, 1H), 7.46e7.43 (m, 2H),
7.40e7.37 (m, 1H), 7.20 (d, J¼7.0 Hz, 2H), 3.67 (s, 3H), 3.56 (s, 2H).
13C NMR (CDCl3, 125 MHz,
d): 179.44, 169.12, 142.64, 138.31, 136.40,
(dd, J¼7.5, 6.0 Hz, 1H). 13C NMR (CDCl3, 125 MHz,
d): 178.63, 148.66,
135.33, 131.50, 131.03, 129.64, 129.48, 128.59, 128.06, 127.66, 125.86,
52.55, 40.87. HRMS (EI) calcd for C18H14O3S: 310.0664; found
310.0675.
143.92, 140.61, 134.69, 133.47, 131.15, 129.53, 129.04, 128.92, 128.61,
122.83, 72.58, 64.46. HRMS (FAB) calcd for C17H14O3S (MþNa)þ:
298.0664; found 298.0669.
4.2.2. Methyl 2-hydroxy-2-(4-oxo-3-phenyl-4H-thiochromen-2-yl)
acetate (4). To a solution of lithium N,N-diisopropylamide in THF
(1.0 ml), prepared from 1.6 M n-BuLi in hexane (0.33 ml, 0.50 mmol)
4.3. General procedure for the synthesis of acetal derivatives 7
To a solution of 2-(1,2-dihydroxyethyl)-3-phenyl-4H-thiochro-
men-4-one 1,1-dioxide 1d (0.070 mmol) in benzene (3 ml), TsOH
(1.2 mg, 0.0070 mmol), CuSO4 (8.9 mg, 0.056 mmol), and carbonyl
compound (0.077 mmol) were added at room temperature and
stirred until 1d was totally consumed. The reaction was quenched
with satd NaHCO3 aq and the reaction mixture was extracted with
EtOAc. The combined organic extracts were dried over MgSO4, fil-
tered through filter paper, and evaporated. The residue was purified
by flash chromatography (hexane/EtOAc¼2:1) to give acetal 7.
and N,N-diisopropylamine (73 ml, 0.50 mmol), methyl 2-(4-oxo-3-
phenyl-4H-thiochromen-2-yl)acetate 3 (81 mg, 0.26 mmol) in
THF (1.0 ml) was added at ꢀ78 ꢁC. After stirring at ꢀ78 ꢁC for
10 min, 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (138 mg,
0.53 mmol) in THF (1.0 ml) was added. After stirring at ꢀ78 ꢁC for
1.5 h, the reaction was quenched with satd NH4Cl aq and the re-
action mixture was extracted with EtOAc. The combined organic
extracts were dried over MgSO4, filtered through filter paper, and
evaporated. The residue was purified by flash chromatography
(hexane/CH2Cl2/EtOAc¼6:3:1) to give 4 (79 mg, 0.24 mmol, 93%) as
colorless solid. Mp: 197.3e199.2 ꢁC. IR (neat): 3350, 1746, 1619,
4.3.1. 2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-3-phenyl-4H-thiochro-
men-4-one 1,1-dioxide (7a). Yellow oil. IR (neat): 2253, 1665, 1317,
1584, 1437, 1213, 1083 cmꢀ1
.
1H NMR (CDCl3, 500 MHz,
d): 8.49
1154, 912 cmꢀ1. 1H NMR (CDCl3, 500 MHz,
d
): 8.13 (d, J¼8.0 Hz, 1H),
(d, J¼8.0 Hz, 1H), 7.63e7.61 (m, 2H), 7.55e7.52 (m, 1H), 7.47e7.44
8.09 (d, J¼8.0 Hz, 1H), 7.88 (dd, J¼8.0, 8.0 Hz, 1H), 7.74 (dd, J¼8.0,
8.0 Hz, 1H), 7.49e7.47 (m, 3H), 7.17 (br, 2H), 4.84 (dd, J¼8.5, 7.0 Hz,
1H), 4.37 (dd, J¼8.5, 8.5 Hz, 1H), 4.08 (dd, J¼8.5, 7.0 Hz, 1H), 1.53
(m, 2H), 7.42e7.39 (m, 1H), 7.30 (br, 2H), 5.24 (d, J¼3.5 Hz, 1H), 3.80
(s, 3H), 3.64 (d, J¼3.5 Hz, 1H). 13C NMR (CDCl3, 125 MHz,
d): 179.70,
171.85, 147.74, 137.85, 136.02, 135.02, 131.66, 130.89, 129.36, 128.12,
127.66, 126.57, 71.47, 53.76. HRMS (EI) calcd for C18H14O4S:
326.0613; found 326.0619.
(s, 3H), 1.32 (s, 3H). 13C NMR (CDCl3, 125 MHz,
d): 179.28, 152.59,
136.99, 135.70, 135.18, 131.32, 130.96, 129.09, 128.75, 128.09, 127.55,
126.77, 111.19, 75.73, 70.53, 25.69, 25.29. HRMS (FAB) calcd for
C20H18O5S (MþNa)þ: 393.0773; found 393.0773.
4.2.3. 2-(1,2-Dihydroxyethyl)-3-phenyl-4H-thiochromen-4-one
(5). To a solution of LiAlH4 (23.2 mg, 0.90 mmol) in THF (5.0 ml),
methyl 2-hydroxy-2-(4-oxo-3-phenyl-4H-thiochromen-2-yl)ace-
tate 4 (200 mg, 0.61 mmol) in THF (8.0 ml) was added at ꢀ78 ꢁC.
After stirring at ꢀ78 ꢁC for 4 h, the reaction was quenched with 1 N
HCl aq and the reaction mixture was extracted with CH2Cl2. The
combined organic extracts were dried over MgSO4, filtered through
filter paper, and evaporated. To the obtained residue dissolved in
MeOH (1.0 ml), NaBH4 (24 mg, 0.63 mmol) was added at 0 ꢁC. After
stirring at 0 ꢁC for 1 h, the reaction was quenched with satd NH4Cl
aq and the reaction mixture was extracted with EtOAc. The com-
bined organic extracts were dried over MgSO4, filtered through
filter paper, and evaporated. The residue was purified by flash
chromatography (CH2Cl2/EtOAc¼5:3) to give 5 (91 mg, 0.31 mmol,
50% within two steps) as colorless solid. Mp: 128.0e128.8 ꢁC. IR
(neat): 3346, 2927, 1727, 1581, 1437, 1340, 1263, 1072 cmꢀ1. 1H NMR
4.3.2. 2-(2,2-Diethyl-1,3-dioxolan-4-yl)-3-phenyl-4H-thiochromen-
4-one 1,1-dioxide (7b). Yellow oil. IR (neat): 2253, 1666, 1317, 1157,
911 cmꢀ1. 1H NMR (CDCl3, 500 MHz,
d
): 8.13 (d, J¼8.0 Hz, 1H), 8.09
(d, J¼8.0 Hz, 1H), 7.87 (dd, J¼8.0 Hz, 1H), 7.74 (dd, J¼8.0 Hz, 1H),
7.48e7.47 (m, 3H), 7.19 (br, 2H), 4.76 (dd, J¼8.5, 8.5 Hz, 1H), 4.40
(dd, J¼8.5, 8.5 Hz, 1H), 4.05 (dd, J¼8.5, 8.5 Hz, 1H), 1.82 (q, J¼8.0 Hz,
2H), 1.58 (q, J¼8.0 Hz, 2H), 0.99 (t, J¼8.0 Hz, 3H), 0.78 (t, J¼8.0 Hz,
3H). 13C NMR (CDCl3, 125 MHz,
d): 178.31, 147.36, 143.26, 142.26,
134.73, 132.89, 131.71, 129.42, 128.64, 128.58, 128.51, 122.94, 115.85,
74.93, 69.06, 29.01, 28.43, 8.44, 7.77. HRMS (EI) calcd for C22H22O5S:
398.1188; found 398.1184.
4.3.3. 3-Phenyl-2-(1,4-dioxaspiro[4.5]decan-2-yl)-4H-thiochromen-
4-one 1,1-dioxide (7c). Yellow oil. IR (neat): 2253, 1666, 1317, 1160,
905 cmꢀ1. 1H NMR (CDCl3, 500 MHz,
d
): 8.12 (d, J¼8.0 Hz, 1H), 8.08
(CDCl3, 500 MHz,
d
): 8.48 (d, J¼8.0 Hz, 1H), 7.68e7.61 (m, 2H), 7.53
(d, J¼8.0 Hz, 1H), 7.87 (dd, J¼8.0, 8.0 Hz, 1H), 7.73 (dd, J¼8.0, 8.0 Hz,
1H), 7.47e7.47 (m, 3H), 7.18 (br, 2H), 4.84 (dd, J¼8.0, 8.0 Hz, 1H),
4.36 (dd, J¼8.0, 8.0 Hz, 1H), 4.08 (dd, J¼8.0, 8.0 Hz, 1H), 1.82e1.25
(dd, J¼8.0, 8.0 Hz, 1H), 7.47e7.44 (m, 2H), 7.41e7.38 (m, 1H), 7.19
(br, 2H), 4.90e4.87 (m, 1H), 3.73e3.63 (m, 2H), 2.96 (d, J¼3.0 Hz,
1H), 1.92 (dd, J¼6.0, 6.0 Hz, 1H). 13C NMR (CDCl3, 125 MHz,
d
):
(m, 10H). 13C NMR (CDCl3, 125 MHz,
d): 178.31, 148.13, 142.65,
179.72, 154.33, 137.25, 135.50, 135.11, 131.47, 130.71, 129.00, 128.78,
127.98, 127.65, 126.71, 72.45, 65.72. HRMS (EI) calcd for C17H14O3S:
298.0664; found 298.0669.
142.25, 134.70, 132.85, 131.74, 129.33, 128.66, 128.58, 128.49, 122.91,
112.65, 74.09, 69.24, 34.98, 34.90, 24.95, 23.78. HRMS (FAB) calcd
for C23H22O5S (MþNa)þ: 433.1086; found 433.1085.
4.2.4. 2-(1,2-Dihydroxyethyl)-3-phenyl-4H-thiochromen-4-one 1,1-
dioxide (1d). 2-(1,2-Dihydroxyethyl)-3-phenyl-4H-thiochromen-
4-one 5 (298 mg, 1.0 mmol) and m-CPBA (70% assay) (516 mg,
2.1 mmol) were added to CH2Cl2 (2.0 ml) at room temperature.
4.3.4. 3-Phenyl-2-(1,4-dioxaspiro[4.4]nonan-2-yl)-4H-thiochromen-
4-one 1,1-dioxide (7d). Yellow oil. IR (neat): 1666, 1315, 1156 cmꢀ1
.
1H NMR (CDCl3, 500 MHz,
(d, J¼8.0 Hz, 1H), 7.87 (dd, J¼8.0, 8.0 Hz, 1H), 7.73 (dd, J¼8.0, 8.0 Hz,
d
): 8.12 (d, J¼8.0 Hz, 1H), 8.08

R. Sugiura et al. / Tetrahedron 69 (2013) 3984e3990
3989
1H), 7.48e7.47 (m, 3H), 7.17 (br, 2H), 4.81 (dd, J¼8.0 Hz, 1H), 4.31
(dd, J¼8.0, 8.0 Hz, 1H), 4.04 (dd, J¼8.0, 8.0 Hz, 1H), 2.04e1.98
(m, 1H), 1.92e1.87 (m, 1H), 1.77e1.62 (m, 6H). 13C NMR (CDCl3,
peaks probably due to overlaps of the peaks of each diastereomers.
HRMS (ESI) calcd for C25H20NaO5S: 455.09291; found 455.09249.
125 MHz,
d): 178.31, 148.46, 142.54, 142.12, 134.71, 132.90, 131.71,
4.3.8. 2-(2-Heptyl-1,3-dioxolan-4-yl)-3-phenyl-4H-thiochromen-4-
129.33, 128.69, 128.59, 128.52, 122.93, 121.73, 74.02, 69.58, 36.18,
35.87, 23.46, 23.44. HRMS (EI) calcd for C22H20O5S: 396.1031; found
396.1031.
one 1,1-dioxide (7i). A single isomer whose stereochemistry is not
determined. Yellow oil. IR (neat): 2891, 1663, 1315, 1162 cmꢀ1 1H
.
NMR (CDCl3, 500 MHz,
d
): 8.13 (d, J¼8.0 Hz, 1H), 8.09 (d, J¼8.0 Hz,
1H), 7.87 (dd, J¼8.0, 8.0 Hz, 1H), 7.74 (dd, J¼8.0, 8.0 Hz, 1H),
7.48e7.46 (m, 3H), 7.17 (br, 2H), 4.89e4.85 (m, 2H), 4.33 (dd, J¼7.5,
7.5 Hz, 1H), 3.98 (dd, J¼7.5, 7.5 Hz, 1H), 1.74 (m, 2H), 1.44e1.38
(m, 2H), 1.32e1.26 (m, 8H), 0.88 (t, J¼6.5 Hz, 3H). 13C NMR (CDCl3,
4.3.5. 2-(2-Methyl-2-propyl-1,3-dioxolan-4-yl)-3-phenyl-4H-thio-
chromen-4-one 1,1-dioxide (7e). A 1:1 diastereomeric mixture of 7e
was obtained, which was not separated by column chromatography
and characterized as a mixture. Yellow oil. IR (neat): 1664, 1314,
125 MHz, d): 178.40, 148.58, 142.36, 142.05, 134.72, 132.92, 131.72,
1157 cmꢀ1
.
1H NMR (CDCl3, 500 MHz,
d
): 8.13 (d, J¼7.5 Hz, 1H),
129.32, 128.73, 128.68, 128.62, 128.48, 122.98, 106.97, 74.25, 70.04,
33.04, 31.74, 29.37, 29.13, 24.25, 22.62, 14.09. HRMS (EI) calcd for
C25H28O5S: 440.1657; found 440.1657.
8.17e8.08 (m, 1H), 7.88 (dd, J¼7.5, 7.5 Hz,1H), 7.74 (dd, J¼7.5, 7.5 Hz,
1H), 7.48e7.47 (m, 3H), 7.18 (br, 2H), 4.83 (dd, J¼8.5, 8.5 Hz, 0.5H),
4.77 (dd, J¼8.5, 8.5 Hz, 0.5H), 4.40 (dd, J¼8.5, 8.5 Hz, 0.5H), 4.33
(dd, J¼8.5, 8.5 Hz, 0.5H), 4.06 (ddd, J¼8.5, 8.5, 8.5 Hz, 1H), 1.79e1.73
(m, 1H), 1.56e1.52 (m, 1H), 1.47 (s, 1.5H), 1.33e1.28 (m, 1H), 1.25
(s, 1.5H), 0.96 (dd, J¼7.5, 7.5 Hz, 1.5H), 0.93e0.88 (m, 1H), 0.85
4.3.9. 3-Phenyl-2-(2-phenyl-1,3-dioxolan-4-yl)-4H-thiochromen-4-
one 1,1-dioxide (7j). A 3:1 diastereomeric mixture of 7j was ob-
tained, which was not separated by column chromatography and
characterized as a mixture. Yellow oil. IR (neat): 1664, 1310, 1158,
(dd, J¼7.5, 7.5 Hz,1.5H). 13C NMR (CDCl3,125 MHz,
d): 178.34,147.77,
147.69, 142.98, 142.81, 142.26, 142.14, 134.74, 132.92, 132.88, 131.72,
131.66, 129.41, 129.39, 128.68, 128.61, 128.60, 128.56, 128.53, 128.52,
122.97, 122.95, 113.65, 113.52, 74.73, 74.27, 69.42, 69.19, 41.34, 41.02,
23.55, 23.03, 17.67, 17.20, 14.38, 14.14. Four 13C NMR peaks are
missing apart from equivalent peaks probably due the overlap of
the peaks of each diastereomers. HRMS (EI) calcd for C22H22O5S:
398.1188; found 398.1190.
1088, 1070, 912 cmꢀ1 1H NMR (CDCl3, 500 MHz,
. d): 8.19e8.11
(m, 2H), 7.94e7.87 (m, 1H), 7.78e7.74 (m, 1H), 7.67e7.64 (m, 0.5H),
7.51e7.48 (m, 3H), 7.43e7.40 (m, 2.25H), 7.36e7.37 (m, 2.25H), 7.20
(br, 2H), 6.04 (s, 0.75H), 5.70 (s, 0.25H), 5.05 (dd, J¼8.5, 6.5 Hz,
0.75H), 5.01 (dd, J¼8.5, 6.5 Hz, 0.25H), 4.58 (t, J¼7.5 Hz, 0.25H), 4.41
(t, J¼8.5 Hz, 0.75H), 4.34 (dd, J¼8.5, 6.5 Hz, 0.75H), 4.13 (t, J¼7.5 Hz,
0.25H). 13C NMR (CDCl3, 125 MHz,
d): 69.93, 71.40, 74.39, 75.13,
105.89,105.96,122.94,123.00,126.78,127.59, 218.30,128.37,128.55,
128.64, 218.68, 128.70, 128.74, 128.77, 129.50, 129.54, 129.62,
129.82, 131.48, 131.51, 132.98, 133.07, 134.75, 134.78, 135.21, 136.20,
141.80,142.10,142.54,143.00,147.40,149.38,178.24,178.38. Two 13C
NMR peaks are missing apart from equivalent peaks probably due
to overlaps of the peaks of each diastereomers. HRMS (ESI) calcd for
C24H18NaO5S: 441.07726; found 441.07706.
4.3.6. 2-(2-Decyl-2-methyl-1,3-dioxolan-4-yl)-3-phenyl-4H-thio-
chromen-4-one 1,1-dioxide (7f). A 1:1 diastereomeric mixture of 7f
was obtained, which was not separated by column chromatography
and characterized as a mixture. Yellow oil. IR (neat): 1665, 1314,
1158 cmꢀ1. 1H NMR (CDCl3, 500 MHz,
d): 8.12 (d, J¼8.0 Hz, 1H), 8.09
(d, J¼8.0 Hz, 1H), 7.87 (dd, J¼8.0 Hz, 1H), 7.74 (dd, J¼8.0 Hz, 1H),
7.48e7.47 (m, 3H), 7.19 (br, 2H), 4.83 ( dd, J¼8.0, 6.5 Hz, 0.5H), 4.76
(dd, J¼8.0, 6.5 Hz, 0.5H), 4.40 (dd, J¼8.0, 8.0 Hz, 0.5H), 4.33 (dd,
J¼8.0, 8.0 Hz, 0.5H), 4.06 (ddd, J¼8.0, 6.5, 6.5,1H),1.79e1.74 (m,1H),
1.56e1.53 (m, 1H), 1.47 (s, 1.5H), 1.44e1.39 (m, 1H), 1.30e1.20
4.4. General procedure for photodeprotection reaction
Irradiation reactions were carried out using an ultra-high
pressure mercury lamp (SXeUIe500H, USHIO) as a light source. A
CH3CN (1.0 vol % H2O, 1.0ꢂ10ꢀ2 M) solution of acetal 7 in an NMR
tube was irradiated through Pyrex filter until 7 was totally con-
sumed. The yield was determined by 1H NMR spectroscopy using
1,3,5-trioxane as an internal standard.
(m, 16.5H), 0.88 (t, J¼7.0 Hz, 3H). 13C NMR (CDCl3, 125 MHz,
d):
178.34, 178.32, 147.76, 147.72, 143.07, 142.78, 142.26, 142.13, 134.73,
134.70, 132.92, 132.86, 131.74, 131.67, 129.39, 129.38, 128.64, 128.60,
128.58, 128.55, 128.50, 122.98, 122.95, 113.71, 113.67, 74.70, 74.22,
69.41, 69.10, 39.20, 38.85, 31.92, 31.89, 29.84, 29.67, 29.63, 29.59,
29.58, 29.55, 29.51, 29.35, 29.29, 24.38, 23.89, 23.59, 22.98, 22.69,
22.67, 14.12, 14.11. Four 13C NMR peaks are missing apart from
equivalent peaks probably due to overlaps of the peaks of each
diastereomers. HRMS (EI) calcd for C29H36O5S: 496.2283; found
496.2283.
4.5. 18O labeling experiment
As a control, a 1.0ꢂ10ꢀ2 M solution of 7d or 7j in CH3CN/H2O
(99/1 v/v) was irradiated at >280 nm from an ultra-high pressure
mercury lamp until 7d or 7j was totally consumed. For experiment
of 7d, the reaction solution was directly analyzed by MS (CI). For
experiment of 7j, aldehyde 6j, and PLPG 1d were isolated from the
reaction solution and then analyzed by MS (CI), respectively. Next,
a 1.0ꢂ10ꢀ2 M solution of 7d or 7j in CH3CN/H218O (99/1 v/v) was
irradiated. Analysis of each resulting reaction solution was done as
above. The values of label incorporation into the products were
calculated from the comparison of the height of [MþH]þ peak and
[Mþ2þH]þ peak of each labeled and unlabeled products.
4.3.7. 2-(2-Methyl-2-phenyl-1,3-dioxolan-4-yl)-3-phenyl-4H-thio-
chromen-4-one 1,1-dioxide (7g). A 17:3 diastereomeric mixture of
7g was obtained, which was not separated by column chromatog-
raphy and characterized as a mixture. Yellow oil. IR (neat): 2922,
1664, 1442, 1313, 1202, 1150 cmꢀ1 1H NMR (CDCl3, 500 MHz,
. d):
8.03 (dd, J¼8.0,1.5 Hz, 0.15H), 7.90 (dt, J¼7.5, 1.0 Hz, 0.85H), 7.84 (dt,
J¼7.5, 1.5 Hz, 0.15H), 7.76 (dt, J¼7.5, 1.0 Hz, 0.85H), 7.72 (dt, J¼7.5,
1.0 Hz, 0.15H), 7.59e7.57 (m, 0.3H), 7.48e7.36 (m, 5H), 7.31e7.24 (m,
2.7H), 7.17 (br, 2H), 4.97 (dd, J¼9.0, 6.0 Hz, 0.15H), 4.78 (dd, J¼8.5,
6.0 Hz, 0.85H), 4.47 (dd, J¼8.5, 6.0 Hz, 0.85H), 4.29 (dd, J¼9.0,
6.0 Hz, 0.15H), 4.12 (dd, J¼9.0, 6.0 Hz, 0.15H), 3.90 (t, J¼8.5 Hz,
Acknowledgements
0.85H), 1.70 (s, 3H). 13C NMR (CDCl3, 125 MHz,
d): 178.59, 178.30,
148.70, 146.67, 142.59, 142.12, 142.06, 141.87, 134.75, 134.70, 133.00,
132.87, 131.54, 131.47, 129.33, 128.81, 128.75, 128.70, 128.64, 128.61,
128.56,128.54, 128.49,128.43, 128.30, 128.09,127.96,127.87,125.30,
125.06, 123.03, 123.00, 111.89, 111.63, 75.05, 73.67, 69.69, 27.88,
27.20. Three 13C NMR peaks are missing apart from equivalent
This research was supported in part by a Grant-in-Aid for Sci-
entific Research from the Ministry of Education, Culture, Sports,
Science and Technology (MEXT) in Japan, for scientific research
from Nara Institute of Science and Technology (NAIST) and NAIST
Advanced Research Partnership Project, which are gratefully

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R. Sugiura et al. / Tetrahedron 69 (2013) 3984e3990
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Nishiyama for their help in MS measurements.
Supplementary data
Supplementary data related to this article can be found at http://
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