Stereocontrolled Photoinduced Glycosylation Using an Aryl Thiourea as an Organo photoacid

Article abstract of DOI:10.1021/acs.orglett.6b01404

Photoinduced glycosylation of alcohols with α-glucosyl trichloroacetimidates, using aryl urea and thioureas as organo photoacids, was examined under long wavelength UV (ultraviolet) irradiation. The results show, for the first time, that such glycosylatio

Full text of DOI:10.1021/acs.orglett.6b01404

Letter
pubs.acs.org/OrgLett
Stereocontrolled Photoinduced Glycosylation Using an Aryl Thiourea
as an Organo photoacid
Tomoya Kimura, Takahiro Eto, Daisuke Takahashi, and Kazunobu Toshima*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama
223-8522, Japan
S
* Supporting Information
ABSTRACT: Photoinduced glycosylation of alcohols with α-glucosyl trichloroacetimidates, using aryl urea and thioureas as
organo photoacids, was examined under long wavelength UV (ultraviolet) irradiation. The results show, for the first time, that
such glycosylations proceed effectively to give the corresponding glycosides in high yields. In addition, high β-stereoselectivity
was obtained under high concentration conditions, whereas high α-stereoselectivity was realized under low concentration
conditions.
lycomolecules, which include a variety of mono-, oligo-,
trolled in photoinduced glycosylation using naphthol derivatives
Gand polysaccharides such as proteoglycans, glycoproteins, as organo photoacids. Therefore, this study has been focused on
investigating aryl thioureas as organo photoacids for overcoming
these limitations. Aryl thioureas have been used as hydrogen-
bond-donating organocatalysts for many asymmetric syntheses,8
as triplet sensitizers,9 and in glycosylation reactions (for glycal),10
but their usefulness is limited because of their moderate acidity11
(e.g., compound 4 has a pKa value of 8.5 in DMSO). Since a
nitrogen anion can be stabilized through electron delocalization
(resonance effect) over the sulfur atom and the aromatic rings,
the acidity of aryl thioureas should increase significantly upon
photoirradiation. Aryl thioureas inthe excited state wereexpected
to activate glucosyl trichloroacetimidate, which requires a pKa
value less than 5 for activation at room temperature (Figure 1).12
glycolipids, and antibiotics, are important biologically active
substances. A large number of recent molecular-level studies on
these glycomolecules have provided insights into the biological
significance of the carbohydrate (glycon) portion for molecular
recognition during the transmission of biological information.1
Carbohydrates, along with nucleic acids and proteins, play very
important roles in many biological events. Additionally, some
glycomolecules are being used as new functional materials.2 For
example, certain alkyl glycosides have potential as biodegradable
surfactants. Therefore, glycomolecules are worth developing for
applications in chemistry, biology, and materials science.
The efficient synthesis of carbohydrate-containing products is
also of particular interest. Glycosylation, which involves the
attachment of a sugar to other sugar moieties or other molecules
(aglycons), is increasingly important in synthetic organic
chemistry and carbohydrate chemistry, and efforts have been
directed toward the development and efficiency of glycosylation
methods.3 The efficiency of a glycosylation reaction generally is
evaluated using chemical yield, regioselectivity, and α/β-
stereoselectivity. However, little attention has been paid to the
ecological efficiency of glycosylation. In this context, several
redox-type photoinduced glycosylation reactions have been
reported.4 The use of light as clean energy to promote
glycosylation would be advantageous.5 Previously, a type of
photoinduced glycosylation, which uses certain naphthol
derivatives as reusable organo photoacids, has been reported.6
Organo photoacids possess an interesting property7 in that their
acidity increases in the photoexcited state. Therefore, organo
photoacids can be used to control glycosylation by light-
switching, and neutralization is not necessary for terminating
the reaction. However, α/β-stereoselectivity cannot be con-
Figure 1. Photoinduced glycosylation using an aryl thiourea.
To investigate this hypothesis, the glucosyl trichloroacetimi-
date 1, aryl urea 3, and thioureas 2 and 4 were selected as glycosyl
donor and candidates for organo photoacids, respectively (Figure
2). First, the glycosylation reaction of 1 with alcohol 5 (2.0 equiv)
was examined using aryl urea 3 and thioureas 2 and 4 (0.3 equiv)
in the presence of powdered 5 Å molecular sieves (MS) in Et2O.
A Blackray 100 W lamp at 365 nm13 was used because irradiation
Received: May 13, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01404
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Organic Letters
Letter
using 0.5 equiv of thiourea 4 proceeded without photoirradiation,
although the yield of 6 was low (Table 2, entry 1). In addition,
Table 2. Glycosylation of 1 and 5 Using Aryl Thiourea 4 at
High Concentrations
Figure 2. Chemical structures of glycosyl donor 1 and candidates of aryl
urea 3 and thioureas 2 and 4 as organo photoacids.
a
b
c
entry
solv (M)
hν
MS
4 (equiv)
yield (%) (α/β)
at this wavelength is not harmful to humans. The strength of the
light was measured using an actinometer.14 The reaction mixture
in an appropriate size of glassy vessel was stirred at ∼360 rpm.
The results, which are summarized in Table 1, showed that the
1
2
3
4
5
6
7
Et2O (1.0)
Et2O (1.0)
Et2O (1.0)
Et2O (1.0)
Et2O (2.0)
THF (2.0)
MeCN (2.0)
−
+
+
+
+
+
+
+
0.5
0.1
0.3
0.5
0.3
0.3
0.3
31 (22:78)
82 (26:74)
85 (24:76)
87 (25:75)
85 (16:84)
82 (19:81)
+
+
+
−
−
−
Table 1. Glycosylation Reactions of 1 and 5 Using Aryl Urea or
Thiourea 2−4
93 (8:92)
a
b
c
365 nm, 12 mW/cm2. MS 5 Å (100 wt % to donor) was used. α/β
ratios were determined by H NMR analysis.
1
when 0.1−0.5 equiv of 4 was used under photoirradiation, 0.3
equiv of 4 was sufficient and resulted in high reproducibility
(Table 2, entries 2−4). Furthermore, when the concentration of
1 was greater than 1.0 M, the stirring efficiency was low with MS 5
Å. Therefore, glycosylaton reactions were performed using
greater concentrations without 5 Å MS, which resulted in greater
β-stereoselectivity (Table 2, entry 5, 2.0 M 1). In addition, the
solvent effect was examined using THF and MeCN in addition to
Et2O, which revealed that MeCN gave the best yield and β-
stereoselectivity (Table 2, entries 6 and 7). However, this β-
stereoselectivity did not result just from the effect of MeCN
coordination with the generated oxionium intermediate16
because a similar result was obtained when Et2O was used as a
solvent (Table 2, entry 3). The main reason for this high β-
stereoselectivity is the SN2 reaction mechanism of glycosylation
involving 1 and an alcohol by photoactivated 4 using high
concentrations (Scheme 1, path A). However, the effect of the
MeCN may promote β-stereoselectivity.
yield (%)
a
b
entry
cat.
concn of 1 (M)
hν
6 (α/β)
1
7
1
2
3
4
5
6
7
2
3
4
4
0.5
0.5
0.5
0.5
0.5
0.8
+
+
+
19 (33:67)
62 (32:68)
92 (35:65)
0
54
30
0
0
0
0
9
0
0
5
−
+
+
+
84
92
0
0
4
4
87 (30:70)
1.0
b
85 (24:76)
0
a
1
365 nm, 12 mW/cm2. α/β ratios were determined by H NMR
analysis.
use of aryl urea or thioureas 2−4 gave the corresponding
glycoside 66 in low to excellent yield (Table 1, entries 1−3) after
photoirradiation. In particular, the corresponding glycoside 6 was
obtained in excellent yield (92%, α/β = 35/65) when aryl
thiourea 4 was used (Table 1, entry 3). In this experiment, donor
1 was not recovered and the hydrolyzed product 7 was also not
produced. In contrast, glycosylation using thiourea 4 without
photoirradiation did not occur, glucoside 6 was not produced,
and a significant amount of 1 was recovered (Table 1, entry 4). In
addition, it was confirmed that only MS 5 Å with photoirradiation
did not promote the reaction, and 1 was recovered in quantitative
yield (Table 1, entry 5). Furthermore, thiourea 4 had an
absorption band near 365 nm (Figure S3). These results clearly
indicate that aryl thiourea 4 promoted glycosylation as an organo
photoacid. In addition, urea 3 was not effective (Table 1, entry 2
vs 3). In addition, the two trifluoromethyl groups of the benzene
substituent, which are electron-withdrawing groups, were
effective for increasing the acidity of the aryl thiourea, even in
the photoexcited state (Table 1, entry 1 vs. 3). Interestingly, β-
stereoselectivity was observed even when Et2O was used as a
solvent, which generally induces α-stereoselectivity.15 Further
results revealed that β-stereoselectivity improved with an increase
in the concentration of 1 in Et2O (Table 1, entries 6 and 7).
On the basis of these results, the reaction conditions were
optimized. Results showed that glycosylation involving 1 and 5
Scheme 1. Proposed Mechanism of Stereocontrolled
Photoinduced Glycosylation Using Aryl Thiourea 4
Based on the reaction mechanism from the results in Table 2
and path A in Scheme 1, this photoinduced glycosylation reaction
under low concentration conditions was expected to produce α-
stereoselective glycosylation using catalyst 4 and Et2O as the
solvent. Therefore, glycosylation was conducted at 0.005 to 0.1 M
1 (Table 3, entries 1−5). The results indicated that the greatest α-
stereoselectivity occurred at 0.01 M 1 in Et2O (Table 3, entry 2).
Furthermore, experiments were performed to optimize the
reaction conditions using 0.1−1.0 equiv of 4 (Table 3, entries 6−
B
DOI: 10.1021/acs.orglett.6b01404
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Letter
Table 3. Glycosylation Reaction of 1 and 5 Using Aryl
Thioureas 4 Under Low Concentration Conditions
Table 4. Glycosylation Reaction of 1 and Alcohols 8−15 Using
Aryl Thiourea 4
a
b
a
entry
solv (M)
4 (equiv)
MS
yield (%) (α/β)
entry
solv (M)
ROH
product
yield (%) (α/β)
b
1
Et2O (0.005)
Et2O (0.01)
Et2O (0.025)
Et2O (0.05)
Et2O (0.1)
0.3
0.3
0.3
0.3
0.3
0.1
0.5
1.0
0.3
0.3
0.3
+
+
+
+
+
+
+
+
+
+
−
73 (83:17)
81 (83:17)
88 (77:23)
89 (67:33)
84 (64:36)
83 (81:19)
78 (80:20)
79 (82:18)
86 (81:19)
51 (41:59)
74 (71:29)
1
Et2O (0.01)
Et2O (0.01)
Et2O (0.01)
Et2O (0.01)
Et2O (0.01)
Et2O (0.01)
Et2O (0.01)
Et2O (0.01)
MeCN (2.0)
MeCN (2.0)
MeCN (2.0)
MeCN (2.0)
MeCN (1.0)
MeCN (1.0)
MeCN (1.0)
MeCN (1.0)
8
16
17
18
19
20
21
22
23
16
17
18
19
20
21
22
23
84 (81:19)
90 (85:15)
85 (84:16)
83 (87:13)
78 (83:17)
75 (81:19)
68 (79:21)
56 (75:25)
90 (9:91)
b
2
2
9
b
3
3
10
11
12
13
14
15
8
b
4
4
b
5
5
b
6
Et2O (0.01)
Et2O (0.01)
Et2O (0.01)
THF (0.01)
MeCN (0.01)
Et2O (0.01)
6
b
7
7
b
8
8
9
9
10
11
10
11
12
13
14
15
16
9
87 (9:91)
10
11
12
13
14
15
87 (12:88)
88 (16:84)
89 (11:89)
85 (12:88)
83 (28:72)
84 (24:76)
a
b
MS 5 Å (100 wt % to donor) was used. α/β Ratios were determined
1
by H NMR analysis.
8) and THF and MeCN as solvents (Table 3, entries 9−10) at a
low concentration of 0.01 M 1. However, no better result than
that listed in Table 3, entry 3, was observed. The high α-
stereoselectivity was due to the SN1 reaction mechanism of
glycosylation involving 1 and an alcohol by photoactivated 4 via
the oxionium cation intermediate under low concentration
conditions (Scheme 1, path B). Surprisingly, addition of 5 Å MS
was very effective (Table 3, entry 11); the weak acidity of the 5 Å
MS may assist path B, although the reason is not totally
understood. Finally, glycosylation using 0.3 equiv of thiourea 4
(0.01 M in Et2O) in the presence of 5 Å MS produced the best
results with high α-stereoselectivity in high yield (Table 3, entry
2). When the single α-glycoside 6α and β-glycoside 6β were
treated with only thiourea 4 without alcohol 5 under the same
conditions used for photoinduced glycosylation, no isomer-
ization occurred, and 6α and 6β were recovered quantitatively
under both high and low concentration conditions. These results
indicate that α/β-stereoselectivity was determined by the
reaction kinetics.
a
b
α/β ratios were determined by 1H NMR analysis. MS 5 Å (100 wt %
to donor) was used.
Table 5. Glycosylation Reaction of 24 or 25 and Alcohol 5
Using Aryl Thiourea 4
Next, the scope and limitations of the glycosylation method
were examined using the alcohols 8−15. As shown in Table 4, the
photoinduced glycosylation of alcohols 8−15 using thiourea 4 in
Et2O in the presence of 5 Å MS at low concentrations proceeded
smoothly to give the corresponding glycosides 16−18,6 19,17
20,6 21,18 22,19 and 2320 in good to high yield with α-
stereoselectivity (Table 4, entries 1−8). In contrast, high
concentrations without 5 Å MS produced the corresponding
glycosides 16−23 in high yield with β-stereoselectivity (Table 4,
entries 9−16).
a
entry
donor
product
solv (M)
yield (%) (α/β)
b
1
24
25
24
24
25
25
26
27
26
26
27
27
Et2O (0.01)
Et2O (0.01)
Et2O (2.0)
82 (α only)
81 (α only)
94 (12:88)
90 (10:90)
87 (49:51)
88 (48:52)
b
2
3
4
5
6
MeCN (2.0)
Et2O (2.0)
MeCN (2.0)
a
b
α/β ratios were determined by 1H NMR analysis. MS 5 Å (100 wt %
to donor) was used.
The generality of the glycosylation method was also
investigated using alcohol 5 and the glycosyl donors galactosyl
and mannosyl trichloroimidates 24 and 25. The results are
summarized in Table 5. Under low concentration conditions with
5 Å MS, glycosylation proceeded smoothly to give the
corresponding glycosides 266 and 276 in high yields with
complete α-stereoselectivity (Table 5, entries 1 and 2). In
addition, high β-stereoselectivity was observed with high yields,
even when galactosyl trichloroimidate 24 was used as the glycosyl
donor under high concentration conditions without 5 Å MS
C
DOI: 10.1021/acs.orglett.6b01404
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Organic Letters
Letter
(Table 5, entries 3 and 4). However, this method was not
applicable to mannosyl trichloroimidate 25 (Table 5, entries 5
and 6). This switch in α/β-stereoselectivity was not observed in
photoinduced glycosylations using 2-naphtol and 5,8-dicyano-
naphtol (Table S1).6
Finally, the reusability of organo photoacid 4 was investigated
(Table 6). Glycosylation resulted in the recovery of ∼90% 4 via
Ministry of Education, Culture, Sports, Science and Technology
of Japan (MEXT).
REFERENCES
■
(1) (a) Carbohydrates in Chemistry and Biology; Ernst, B., Hart, G. W.,
Sinay, P., Eds.; Wiley−VCH: Weinheim, 2000; Vols. 1−4. (b)
̈
Glycoscience, Chemistry and Chemical Biology; Fraser-Reid, B. O.,
́
Tatsuta, K., Thiem, J., Cote, G. L., Flitsch, S., Ito, Y., Kondo, H.,
Nishimura, S.-i., Yu, B., Eds.; Springer: Berlin, 2008; Vols. 1−3.
(2) Functional Carbohydrates; Biriaderis, C. G., Izydorczyck, M. S., Eds.;
CPC Press: Boca Raton, 2006.
Table 6. Recovery and Reuse of 4 in Glycosylation of 1 and 5
(3) Demchenko, A. V. In Handbook of Chemical Glycosylation: Advances
in Stereoselectivity and Therapeutic Relevance; Demchenko, A. V., Eds.;
Wiley−VCH: Weinheim, 2008; pp 1−27.
(4) (a) Garegg, P. J.; Griffin, G. W.; Bandara, N. C.; Clarke, M. A.;
Tsang, W.-S.; Oscarson, S.; Silwanis, B. A. Heterocycles 1990, 30, 939.
(b) Furuta, T.; Takeuchi, K.; Iwamura, M. Chem. Commun. 1996, 157.
(c) Cumpstey, I.; Crich, D. J. Carbohydr. Chem. 2011, 30, 469.
(d) Wever, W. J.; Cinelli, M. A.; Bowers, A. A. Org. Lett. 2013, 15, 30.
(e) Nakanishi, M.; Takahashi, D.; Toshima, K. Org. Biomol. Chem. 2013,
11, 5079. (f) Mao, R.-Z.; Guo, F.; Xiong, D.-C.; Li, Q.; Duan, J.; Ye, X.-S.
Org. Lett. 2015, 17, 5606. (g) Andrews, R. S.; Becker, J. J.; Gagne,
Angew. Chem., Int. Ed. 2010, 49, 7274. (h) Andrews, R. S.; Becker, J. J.;
́
M. R.
recovery of 4
reaction yield using recovered 4 (%)
a
entry condition
(%)
(α/β)
Gagne,
Gagne,
́
M. R. Org. Lett. 2011, 13, 2406. (i) Andrews, R. S.; Becker, J. J.;
M. R. Angew. Chem., Int. Ed. 2012, 51, 4140.
1
2
A
B
89
91
84 (16:84)
83 (82:18)
́
(5) Albini, A.; Fagnoni, M.; Mella, M. Pure Appl. Chem. 2000, 72, 1321.
(6) Iwata, R.; Uda, K.; Takahashi, D.; Toshima, K. Chem. Commun.
2014, 50, 10695.
a
1
α/β ratios were determined by H NMR analysis.
(7) Tolbert, L. M.; Haubrich, J. E. J. Am. Chem. Soc. 1994, 116, 10593.
(8) For a selected review, see: (a) Fang, X.; Wang, C.-J. Chem. Commun.
2015, 51, 1185. For selected examples, see: (b) Okino, T.; Hoashi, Y.;
Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672. (c) Wittkopp, A.;
Schreiner, P. R. Chem. - Eur. J. 2003, 9, 407. (d) Okino, T.; Hoashi, Y.;
Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119.
(e) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem., Int.
Ed. 2005, 44, 6576. (f) Cao, C.-L.; Ye, M.-C.; Sun, X.-L.; Tang, Y. Org.
Lett. 2006, 8, 2901. (g) Xu, H.; Zuend, S. J.; Woll, M. P.; Tao, Y.;
Jacobsen, E. N. Science 2010, 327, 986. (h) Zhang, Z.; Lippert, K. M.;
Hausmann, H.; Kotke, M.; Schreiner, P. R. J. Org. Chem. 2011, 76, 9764.
(i) Lin, S.; Jacobsen, E. N. Nat. Chem. 2012, 4, 817.
(9) (a) Vallavoju, N.; Selvakumar, S.; Jockusch, S.; Sibi, M. P.; Sivaguru,
J. Angew. Chem., Int. Ed. 2014, 53, 5604. (b) Telmesani, R.; Park, S. H.;
Lynch-Colameta, T.; Beeler, A. B. Angew. Chem., Int. Ed. 2015, 54, 11521.
(10) Balmond, E. I.; Coe, D. M.; Galan, M. C.; McGarrigle, E. M. Angew.
Chem., Int. Ed. 2012, 51, 9152.
SiO2 column chromatography, which could be reused without
any loss of efficiency. Further, neither neutralization of the
reaction mixture nor extraction of the product was required after
completion of the reaction because discontinuation of UV light
irradiation rendered the reaction mixture almost neutral. Workup
for the reaction involved only evaporation of the solvents (Et2O
and MeCN), which also could be reused.
In conclusion, a novel glycosylation reaction method has been
developed using thiourea 4 as an organo photoacid under
photoirradiation. This reaction allows for α/β-stereoselectivity
by adjusting the substrate concentration. This useful method
should find a wide range of applications involving syntheses of
carbohydrate-containing products and the development of
organocatalysts for asymmetric organic reactions.
(11) (a) Li, X.; Deng, H.; Luo, S.; Cheng, J.-P. Eur. J. Org. Chem. 2008,
2008, 4350. (b) Jakab, G.; Tancon, C.; Zhang, Z.; Lippert, K. M.;
Schreiner, P. R. Org. Lett. 2012, 14, 1724.
(12) Geng, Y.; Kumar, A.; Faidallah, H. M.; Albar, H. A.; Mhkalid, I. A.;
Schmidt, R. R. Angew. Chem., Int. Ed. 2013, 52, 10089.
(13) A Blak-ray (B-100A) purchased from UVP, Inc., was used.
(14) A radiometer sensor (UVX-36) purchased from UVP, Inc., was
used. UV light at 12 mW/cm2 was obtained using one lamp placed at 5
cm from the reaction mixture. Based on the optimized result in ref 5, we
carried out the reaction for 4 h in this study.
(15) Demchenko, A. V. Synlett 2003, 1225.
(16) Hashimoto, S.; Hayashi, M.; Noyori, R. Tetrahedron Lett. 1984, 25,
1379.
(17) Imagawa, H.; Kinoshita, A.; Fukuyama, T.; Yamamoto, H.;
Nishizawa, M. Tetrahedron Lett. 2006, 47, 4729.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01404.
■
S
Supporting figures, experimental procedures, syntheses,
and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: toshima@applc.keio.ac.jp.
Notes
(18) (a) Chu, A.-H. A.; Nguyen, S. H.; Sisel, J. A.; Minciunescu, A.;
Bennett, C. S. Org. Lett. 2013, 15, 2566. (b) Chao, C.-S.; Lin, C.-Y.;
Mulani, S.; Hung, W.-C.; Mong, K.-K. T. Chem. - Eur. J. 2011, 17, 12193.
(19) Chu, A.-H. A.; Minciunescu, A.; Montanari, V.; Kumar, K.;
Bennett, C. S. Org. Lett. 2014, 16, 1780.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported in part by grants for Scientific
Research on Innovative Areas “Middle Molecular Strategy:
Creation of Higher Bio-function Molecules by Integrated
Synthesis” (No. 16H01161) and the Strategic Research
Foundation at Private Universities, 2012−2016, from the
(20) Hosono, S.; Kim, W.-S.; Sasai, H.; Shibasaki, M. J. Org. Chem.
1995, 60, 4.
D
DOI: 10.1021/acs.orglett.6b01404
Org. Lett. XXXX, XXX, XXX−XXX