Photo-induced glycosylation using a diaryldisulfide as an organo-Lewis photoacid catalyst

Article abstract of DOI:10.1039/c9ob02674f

Photo-induced glycosylations of several acceptors with trichloroacetimidate donors using bis(2-naphthyl)disulfide as an organo-Lewis photoacid (LPA) catalyst proceeded effectively to give the corresponding glycosides in good to high yields. In addition, t

Full text of DOI:10.1039/c9ob02674f

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DOI: 10.1039/C9OB02674F
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Photo-induced glycosylation using a diaryldisulfide as an organo-
Lewis photoacid catalyst
Received 00th January 20xx,
Accepted 00th January 20xx
Naoto Iibuchi,a Takahiro Eto,a Manabu Aoyagi,a Reiji Kurinami,a Hayato Sakai,b Taku Hasobe,b
Daisuke Takahashi*a and Kazunobu Toshima *a
DOI: 10.1039/x0xx00000x
Photo-induced glycosylations of several acceptors with addition, after completion of the glycosylation reactions, a
trichloroacetimidate donors using bis(2-naphtyl)disulfide as an neutralization step for terminating the reaction was not
organo-Lewis photoacid (LPA) catalyst proceeded effectively to necessary. Furthermore, 3–5 were recovered in high yields and
give the corresponding glycosides in good to high yields. In could be reused. Recently, Wang and co-workers reported
addition, the grand and excited state absorption spectra of bis(2- visible-light-induced glycosylations of several alcohols with
naphtyl)disulfide with or without NEt3 suggested the Lewis acidity glycals using eosin Y and diphenyldisulfide (PhSSPh) (6a) as a
of bis(2-naphtyl)disulfide upon photo-irradiation.
phenolic BPA catalyst and co-catalyst, respectively, for
synthesis of 2-deoxy-
-glycosides.6a In this method, PhSSPh

A wide variety of glycosides, such as glycoconjugates and
oligosaccharides, are found in many biologically active natural
products and highly functional molecules. To elucidate their
precise biological and/or functional roles, homogeneous and
structurally well-defined synthetic carbohydrates have been
investigated. Thus, considerable effort has been devoted to
developing an efficient glycosylation reaction, and several
glycosylation methods have been reported.1 However, in
general, environmentally hazardous chemicals, such as strong
acids and toxic metal reagents, are still used for most
conventional glycosylation methods.2 Therefore, greener
methods3 for glycosylation4 and conversion5 of carbohydrates
that involve the use of environmentally benign solvents and
catalysts are desired for environmental and energy reasons. In
addition, the use of light as clean energy to promote
glycosylation reactions also would be beneficial.6 Previous
reports have described photo-induced glycosylations7 of
glycosyl trichloroacetimidate donor 1 and several alcohols
using several organo-Brønsted photoacid (BPA) catalysts, 2-
naphthol (3),7a 5,8-dicyano-2-naphthol (4),7a and 1,3-bis[3,5-
bis(trifluoromethyl)phenyl]thiourea (5),7b which possess the
interesting chemical property that their acidity increases in the
photoexcited state. Results showed that glycosylations
proceeded effectively to provide the corresponding glycoside 2
using only long-wavelength of UV light irradiation (Fig. 1A). In
(6a) is proposed to act only as a redox-active catalyst for
regeneration of the BPA catalyst, eosin Y, during the
glycosylation reaction.
The present study focuses on diaryldisulfide 6 as a new
type of organo-Lewis photoacid (LPA) catalyst8 that would
develop sufficient Lewis acidity to activate glycosyl donor 1
due to delocalization of the lone pair electrons on the sulfur
atom into the aromatic ring upon photo-irradiation (Fig. 1B).
aDepartment of Applied Chemistry and bDepartment of Chemistry, Faculty of
Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama
223-8522, Japan. E-mail: dtak@applc.keio.ac.jp and toshima@applc.keio.ac.jp;
Fax: +81 45-566-1576.
Fig. 1. Photo-induced glycosylation using (A) organo-Brønsted
photoacid (BPA) catalysts and (B) an organo-Lewis photoacid (LPA)
catalyst. TCAA = trichloroacetamide.
Electronic
Supplementary
Information
(ESI)
available:
See
DOI: 10.1039/x0xx00000x
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Table 1 Glycosylations of 1a and 8 using a catalytic amount of disulfides.
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DOI: 10.1039/C9OB02674F
Entry
Cat.
Equiv. of cat.
h
Conc. of 1a (M)
Solvent
Time (h)
Yield (%)


9 (/)[1]
10
17
13
5
1a
0
1
6a
6b
6c
7
0.05
0.05
0.05
0.05
−
+
+
+
+
+
−
+
+
+
+
+
+
+
+
+
0.8
0.8
0.8
0.8
0.8
0.8
0.3
1.0
0.8
0.8
0.8
0.8
0.8
0.8
0.8
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Et2O
2
2
2
2
2
2
2
2
2
2
2
2
2
1
4
75 (79/21)
83 (71/29)
86 (70/30)
25 (92/8)
25 (95/5)
6 ( only)
80 (69/31)
82 (75/25)
78 (76/24)
49 (82/18)
68 (81/19)
77 (77/23)
83 (79/21)
23 (96/4)
84 (68/32)
2
0
3
0
4
6
65
60
92
0
5
−
11
0
6
6c
6c
6c
6c
6c
6c
6c
6c
6c
6c
0.05
0.05
0.05
0.01
0.05
0.05
0.05
0.05
0.05
0.05
7
15
11
15
36
23
11
12
22
5
8
0
9
0
10
11
12
13
14
15
13
0
THF
MeCN
0
CH2Cl2
Toluene
Toluene
0
48
0
[1] The / ratios were determined by 1H-NMR analysis.
This present report demonstrates, for the first time, that 6c, solvent, and reaction time) were optimized. Results
certain diaryldisulfides can act as a reusable organo-LPA showed that, although the -stereoselectivity of 9 increased
catalyst to effectively promote photo-induced glycosylation slightly with concentration, the use of 0.8 M of 1aβ gave the
under mild reaction conditions. best yield (entries 3, 7, and 8). When 0.01 equiv. of 6c was
glucosyl used under photo-irradiation, the chemical yield of
6a-c, and decreased compared to that using 0.05 equiv. of 6c (entry 3 vs.

To
investigate
this
hypothesis,
the
9
trichloroacetimidate
1aβ,
diaryldisulfides
bis(cyclohexyl)disulfide (7) were selected as glycosyl donor, 9). In addition, the solvent effect was examined using Et2O,
candidates for organo-LPA, and negative control, respectively. THF, MeCN, and CH2Cl2, and indicated that toluene gave the
Initially, the glycosylation of cyclohexylmethanol (8) (2.0 best yield (entries 3 and 10–13). Furthermore, the reaction
equiv.) with 1aβwas examined using a catalytic amount of time of 2 h was confirmed to be sufficient for this glycosylation
disulfide in the presence of powdered molecular sieves (MS reaction (entries 3, 14, and 15). Therefore, 0.05 equiv. of 6c
5Å) in toluene with irradiation with non-harmful long- used for glycosylation of 1aβ and 8 at 35 °C in toluene under 2-
wavelength UV light (365 nm, 7 mW/cm2) using a Black-ray hr photo-irradiation gave the best results, producing glycoside
100 W lamp.9 The strength of the light was measured using an 9 in high yield.
actinometer, and controlled by the distance between the lamp
Next, mechanistic studies of the present glycosylation were
and reaction mixture. Results are summarized in Table 1. performed. When the single 9α and 9β were treated with 6c
Glycosylations of 1aβ and 8 using diaryldisulfides 6a-c (0.05 without alcohol 8 under the same reaction conditions used for
equiv.) under photo-irradiation provided, for the first time, the photo-induced glycosylation, no isomerization occurred, and
corresponding glycoside 9 in good to high yields with

9α and 9β were recovered in high yields. These results indicate
stereoselectivity (entries 1-3). The bis(2-naphtyl)disulfide (6c) that α/β-stereoselectivity was determined by the reaction
provided the highest yield (entry 3). In contrast, when kinetics (Scheme 1A). Next, glycosylation of 1aα and 8 was
dialkyldisulfide 7, which did not have absorption bands near examined under the same reaction conditions to determine
365 nm, was used, the chemical yield of 9 decreased whether β-stereoselectivity occurred. Results showed that the
dramatically to 25%, and a significant amount of donor 1aβ reaction proceeded smoothly to provide 9 in 89% yield with β-
was recovered (entry 4). In addition, glycosylation was stereoselectivity (α/β=27/73) (Scheme 1B). These results
confirmed to proceed slightly, even in the absence of the suggest that photo-induced glycosylation of 1a and
disulfide catalyst with photo-irradiation, and gave 9 in the proceeded mainly via an SN2-like mechanism (Scheme 1C).
8
same yield (entry 4 vs. 5), indicating that 7 did not enhance
Next, the recovery and reusability of 6c were examined.
reaction conversion. Furthermore, glycosylation using 6c Results showed that 94% of 6c could be recovered via column
without photo-irradiation did not proceed, and 1aβ was chromatography after glycosylation of 1aβ and 8, and could be
recovered in high yield (entry 6). These results suggested that reused without any loss of efficiency, producing 9 in 82% yield
6c significantly promoted glycosylation as an organo-photoacid. with the same α/β-stereoselectivity (α/β=70/30).
Next, the reaction conditions (concentration of 1aβ, equiv. of
2 | J. Name., 2012, 00, 1-3
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Table 2 Photo-induced glycosylations of several donors and acceptors
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DOI: 10.1039/C9OB02674F
using a catalytic amount of 6c.
Scheme 1. (A) Mechanistic study of the glycosylation. (B) Photo-
induced glycosylation of 1aα and using 6c (C) Proposed
using 6c
8
.
mechanism of photo-induced glycosylation of 1aα and
8
.
0.6
0.025
6c
6c + NEt3
0.5
6c
6c + NEt3
0.020
0.4
0.015
0.3
0.010
0.2
0.005
0.1
0
300
0.000
400
0.0
500
600
700
400
500
600
700
Wavelength [nm]
Wavelength [nm]
Fig. 2. (A) UV/Vis spectra of 6c (500 μM) without and with NEt3 (50
mM) in toluene. (B) The excited absorption spectra (355 nm, 3.1
mJ) of 6c (500 μM) without and with NEt3 (50 mM) in toluene at 14
μs.
These results indicated that 6c did not decompose through
radical or non-radical reactions under the photo-irradiation
conditions used for the present glycosylation. Furthermore,
the reaction mixture did not require neutralization or product
extraction after reaction was complete, because turning off
the UV light switch rendered the reaction mixture nearly
neutral. Evaporation of the reaction solvent (toluene) was the
only operation needed for work-up, and the solvent could be
reused.
Next, to confirm the Lewis acidity of 6c upon photo-
irradiation,
ground
and
excited state absorption
measurements of 6c in the absence and presence of NEt3 in
toluene were obtained. Results showed that the ground state
absorption spectrum of 6c in toluene was unaffected by
addition of an excess of NEt3 as shown in Fig. 2A, suggesting no
additional structural formation derived from the dimeric units,
(i.e., charge-transfer complex). Next, to examine the excited-
state dynamics, nanosecond transient absorption (nsTA) was
measured for 6c dissolved in toluene with and without NEt3
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upon excitation at 355 nm. The nsTA spectra in the absence of
NEt3 (i.e., pristine 6c) contained broad absorption bands in the
range from ca. 390 to 500 nm containing the typical triplet-
triplet absorption of naphthalene units.10 In contrast, when
NEt3 (50 mM) was added to 6c, the bands from 390 to 500 nm
decreased, and new bands around 550 to 700 nm clearly
appeared (Fig. 2B). These results suggest the Lewis acidity of
6c under photo-irradiation, resulting in effective formation of
complex 6c-NEt3.
Next, the generality of the glycosylation method was
examined using alcohols 11–17 including secondary alcohols
(Table 2). In all cases, glycosylation with 1aβ using 6c under
photo-irradiation proceeded smoothly to give the
corresponding glycosides 18–24 in good to high yields with
moderate α-stereoselectivities (entries 1–7). Next, the effect
of the type of glycosyl donor was investigated. When α-
galactosyl and α-fucosyl trichloroacetimidates 1bα and 1cα
were used, glycosylations of 8 using 6c under photo-irradiation
proceeded smoothly to give the corresponding glycosides 25
and 26 in high yields with high β-stereoselectivities (entries 8
and 9). In addition, β-stereoselectivity with good yield was
observed, even when 2-deoxy-α-glucosyl trichloroacetimidate
Conclusions
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In conclusion, a novel photo-inducedDgOlyI:c1o0s.1y0l3a9t/ioCn9OmB0e2t6h7o4dF
using a trichloroacetimidate donor and diaryldisulfide 6c as an
organo-Lewis photoacid catalyst was developed. The photo-
induced glycosylations of several trichloroacetimidate donors
and alcohols in the presence of 6c with photo-irradiation
proceeded effectively under mild conditions to provide the
corresponding glycosides in good to high yields. In addition, 6c
could be recovered and reused without any loss of efficiency.
Furthermore, the ground and excited state absorption spectra
of 6c with or without NEt3 in toluene suggested that 6c
possessed Lewis acidity and promoted formation of complex
6c-NEt3
upon
photo-irradiation.
This
useful
and
environmentally benign glycosylation method should find
various applications in the synthesis of not only biologically
active compounds but also highly functional molecules.
Conflicts of interest
There are no conflicts to declare.
1dαwas used (entry 10). Next, to overcome the moderate
Notes and references
α/β-stereoselectivity, neighboring-group-assisted glycosylation
using 1eα, which possesses a Bz group at the C2-position, was
examined. Results showed that the reaction also proceeded to
provide the corresponding β-glycoside 28 in high yield with
complete stereoselectivity (entry 11). In addition, when
disarmed peracetylated glycosyl donor 1fα was used, although
longer reaction time was required, desired β-glycoside 29 was
obtained in 63% yield with complete stereoselectivity (entry
12).
Finally, the present method was applied to the synthesis of
trisaccharide 32. Initially, photo-induced and chemoselective
glycosylation of glycosyl fluoride 30 with 1eα using 6c with
photo-irradiation proceeded effectively to provide 31 in 85%
yield with complete β-stereoselectivity. In addition, a second
glycosylation of 31 and 16 using Cp2HfCl2-AgOTf11 provided 32
effectively in 85% yield as a single isomer.
1
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A Black-ray (B-100A) purchased from UVP, Inc. was used.
Scheme 2. Synthesis of trisaccharide 32 using the present photo-
10 D. P. Craig and I. G. Ross, J. Chem. Soc., 1954, 1589.
induced glycosylation of 1eα and 30
.
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