Photoinduced C-S Bond Cleavage of Thioglycosides and Glycosylation

Article abstract of DOI:10.1021/acs.orglett.5b02823

A glycosyl coupling reaction via photoinduced direct activation of thioglycosides and subsequent O-glycosylation in the absence of photosensitizer was developed for the first time. This reaction underwent a selectively homolytic cleavage of a C-S bond to generate a glycosyl radical, which was oxidized to an oxacarbenium ion by Cu(OTf)₂, and a sequential O-glycosylation. A wide range of glycosides were synthesized in moderate to excellent yield using sugars, amino acids, or cholesterol as the acceptors.

Full text of DOI:10.1021/acs.orglett.5b02823

Letter
pubs.acs.org/OrgLett
Photoinduced C−S Bond Cleavage of Thioglycosides and
Glycosylation
Run-Ze Mao,§,† Fan Guo,§,†,‡ De-Cai Xiong,*,† Qin Li,† Jinyou Duan,‡ and Xin-Shan Ye*,†
†State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Road No.
38, Beijing 100191, China
‡College of Science, Northwest A&F University, Yangling, Shaanxi 712100, China
S
* Supporting Information
ABSTRACT: A glycosyl coupling reaction via photoinduced direct
activation of thioglycosides and subsequent O-glycosylation in the
absence of photosensitizer was developed for the first time. This
reaction underwent a selectively homolytic cleavage of a C−S bond to
generate a glycosyl radical, which was oxidized to an oxacarbenium ion
by Cu(OTf)2, and a sequential O-glycosylation. A wide range of
glycosides were synthesized in moderate to excellent yield using sugars,
amino acids, or cholesterol as the acceptors.
he vital role of carbohydrates in biology has made them
Nevertheless, sugar substrates could not be used as acceptors.13
Tvery popular synthetic targets in modern synthetic Irradiation of a permethylated thioglycoside with a high-
pressure mercury lamp in the presence of 1,4-dicyano-
naphthalene and methanol resulted in the methyl glycoside
and other byproducts in low yields.14 This method was not
compatible with benzyl ether protected substrates and
incapable of activating the disarmed thioglycosides. In addition,
the photoinduced activation of other donors such as phenyl
glycosides,15 selenoglycosides,16 and glycosyl trichloroacetimi-
dates17 also provided good proof-of-concepts for chemical
glycosylation. However, all these photomediated glycosylation
methods lack generality to some extent, either for the donor or
for the acceptor. Improvement of the activation of a donor by
light is still an important issue.
It was found that UV light had the energy capable of breaking
the C−S bond.18 As part of our continuous studies on the
activation of thioglycosides and glycosylation,19 we imagined
that UV light could directly make the C−S bond rupture in
thioglycosides without a photosensitizer. To verify this, β-
thiogalactopyranoside 1 was irradiated for 22 h (Scheme 1).
Indeed, the C−S bond cleavage took place; thus, β-thiogalacto-
pyranoside 1 (48% yield), α-thiogalactopyranoside 2 (26%
yield), 1,5-anhydro-galactitol 3 (25% yield), and TolSSTol (4,
chemistry. The construction of oligosaccharides mainly
depends on the development of glycosylation methods.1
Chemical glycosylation refers to the cleavage of the glycosidic
bond of a donor using chemical or physical means to generate a
glycosyl oxacarbenium species, which undergoes the following
coupling reaction with an acceptor.2 Although many methods
for glycosylation have been reported,3 the development of
universal and efficient approaches for oligosaccharide synthesis
is still highly desirable. In the process of glycosylation,
fragmentation of the glycosidic bond of a donor with high
selectivity and efficiency is of great importance.4 Therefore, the
activation of a donor by chemical or physical means is a subject
of continuous research. Thioglycosides are one of the most
enduring and widely used donors, owing to their stability,
accessibility, and compatibility.5 The sulfur atom in a
thioglycoside is able to selectively react with a soft electrophile.
A series of promoters for the activation of thioglycosides have
been developed, including metal salts,6 halonium reagents,7
organosulfur reagents,8 and single electron transfer (SET)
reagents.9 Thioglycosides could also be electrochemically
activated via the SET mechanism.10
Photoinduced electron transfer is undoubtedly one of the
emerging strategies to meet the increasing demand for more
sustainable chemical processes.11 The activation of thioglyco-
sides by light usually required a photosensitizer or a
photocatalyst. Some methods involving the photoinduced
activation of thioglycosides have been reported. Armed (p-
methoxy)phenyl thioglycosides could undergo a visible light
mediated photoredox O-glycosylation reaction,12 while dis-
armed (p-methoxy)phenyl thioglycosides were unreactive.
Unprotected deoxythioglycosyl donors were able to perform
a reaction with alcohols using 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) in the presence of a boronic acid.
Scheme 1. Irradiation of Thioglycoside 1 with UV Light
Received: September 29, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02823
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Letter
12% yield) were isolated. This suggested a possible homolytic
cleavage of 1 to produce galactosyl radical and p-tolylthiyl
radical, which underwent recombination, dimerization, or
hydrogen atom abstraction to generate the above-mentioned
products. Therefore, we envisaged that the glycosylation of a
thioglycoside with an acceptor would proceed upon ultraviolet
illumination in the presence of a proper oxidant, which oxidizes
a glycosyl radical (II) to a glycosyl oxacarbenium ion (III), as
shown in Scheme 2. This glycosylation protocol would differ
Table 1. Optimization of the Glycosylation Reaction
Conditions
a
a
b
entry
5 (equiv)/6 (equiv)
oxidant (equiv)
solvent
yield (%)
1
1/0.5
1/0.5
1/0.5
1/0.5
1/0.5
1/0.5
1/0.5
1/0.5
1/0.5
1/0.5
1/0.75
1/1
−
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
Et2O
0
Scheme 2. Strategy for Light-Induced Activation of
Thioglycosides and Glycosylation
2
InBr3 (1.0)
13
trace
28
trace
trace
20
75
79
90
80
67
0
3
CuCl2 (1.0)
4
CuSO4 (1.0)
Cu(OAc)2 (1.0)
RuCl3 (1.0)
5
6
7
InCl3 (1.0)
8
Cu(OTf)2 (1.0)
Cu(OTf)2 (1.5)
Cu(OTf)2 (1.7)
Cu(OTf)2 (1.7)
Cu(OTf)2 (1.7)
Cu(OTf)2 (1.0)
Cu(OTf)2 (1.0)
Cu(OTf)2 (1.7)
Cu(OTf)2 (1.7)
9
10
11
12
c
13
1/0.5
1/0.5
1/0.5
1/0.5
d
14
0
15
16
86
62
a
The reactions were carried out with 5 (0.04 mmol), 6, oxidant,
activated 4 Å molecular sieves (200 mg), solvent (2.0 mL) in a quartz
b
flask at room temperature for 22 h under argon atmosphere. Isolated
c
d
yield. No UV irradiation. Reflux in the absence of UV.
from the traditional light-mediated glycosylation involving a S-
radical cation (I). Herein, we report a new O-glycosylation
protocol via photoinduced direct C−S bond cleavage of
thioglycosides and a subsequent oxidation by Cu(OTf)2.
To test the feasibility of our idea, examination and
optimization of the reaction parameters were explored using
the model reaction between perbenzoylated thioglucopyrano-
side 5 and the glucosyl acceptor 6 with the C-6 hydroxyl
exposed by varing different oxidants and conditions. The results
are shown in Table 1. Either photoirradiation in the absence of
oxidants, or oxidants in the absence of photoirradiation,
resulted in no glycosylation, and the glycosyl donor 5 was
recovered quantitatively (entries 1, 13−14). As expected, the
desired disaccharide 7 was obtained by the addition of metal
salts as oxidants (entries 2−7, 0−28% yields). These results
clearly indicated that the combination of an oxidant and
photoirradiation together triggered the glycosylation. Among
the metal salts, Cu(OTf)2 afforded the most remarkable result
(entry 8, 75% yield). The yield of 7 was improved gradually as
the equivalent of Cu(OTf)2 was increased (entries 8−10, 75−
90%). The glycosylation yield decreased when increasing the
amount of glycosyl acceptor 6 (entries 10−12). Dichloro-
methane was the most appropriate solvent (entries 15−16). So
the optimized conditions included a donor (1.0 equiv), an
acceptor (0.5 equiv), Cu(OTf)2 (1.7 equiv), and activated 4 Å
molecular sieves (200 mg), in CH2Cl2 (0.01 M) under the
irradiation of UV light at room temperature for 22 h. The
symmetric bis(p-methylphenyl)disulfide (4) was isolated as
another major product.
2, 88%), or tertiary alcohol 12 (entry 3, 81%) gave the
corresponding glycosides in moderate to excellent yields.
However, in the case of acceptor 14, the desired glycosyl
coupling product 15 was obtained in moderate yield (entry 4,
52%), and a large amount of complicated byproducts was
detected. It was also found that cholesterol 16 (entry 5, 75%)
or the appropriately protected amino acid 18 (entry 6, 86%)
could be employed as glycosyl acceptors. This glycosylation
protocol was compatible with isopropylidene, benzyl, and other
conventional protective groups. Furthermore, the reaction of
the disarmed donor 5 with low-reactive acceptor 20 proceeded
smoothly (entry 7, 55% yield). This is attractive because it is
unable to be achieved by the existing photomediated
glycosylation protocols.
Encouraged by these results, we further evaluated the
reaction between a wide range of thioglycoside donors and
glycosyl acceptors. The glycosylations of the acylated galactosyl
(22 and 24, entries 8−9, 76% and 69%, respectively) or
rhamnosyl donor (27, entry 10, 80%) with the glucosyl
acceptor 6 or 25, having a free hydroxyl group at the C-6 or C-
3 position, proceeded in good yield. The reactions of the
benzylated glucosyl donor 29 with acceptors 6 or 20 afforded
the desired disaccharides in moderate (entry 11, 65%, α/β =
1.2/1) to excellent (entry 12, 95%, α/β = 1.7/1) yields, but
with poor stereoselectivity. The stereoselectivity was shifted
toward the α isomer by the use of ether or toward the β isomer
by the use of acetonitrile as solvent, which might be explained
by the participation of the solvent (entry 12).20 Interestingly,
the α-linked disaccharide 32 was obtained with exceptionally
high α-anomeric selectivity by using the benzylated galactosyl
donor 1 (entry 13, 87%). The activation and O-glycosylation of
ethyl thioglycoside 33 under the same conditions also worked
well (entry 14, 85%).
The scope of glycosylation of the disarmed donor 5 with
various acceptors was next investigated under the optimal
conditions (Table 2, entries 1−7). The reactions of 5 with
primary alcohol 8 (entry 1, 70%), secondary alcohol 10 (entry
B
DOI: 10.1021/acs.orglett.5b02823
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Letter
a
13−14, Table 1). Compounds 2, 3, and 4 could be detected
under the irradiation of UV light, whether in the presence of
Cu(OTf)2 or not. The reaction was almost inhibited by the
addition of 2,2,6,6-tetramethylpiperidinooxy (TEMPO, 3.0
equiv), a radical trapper. These observations indicated the
presence of a glycosyl radical and p-tolylthiyl radical, resulting
from a direct homolytic cleavage of the C−S bond upon UV
irradiation. In the reaction process, the remarkable decrease of
Cu(OTf)2, which was determined by EPR spectroscopy,21
confirmed that the Cu(OTf)2 served as the oxidant (Scheme
3). The overall mechanism differs substantially from other
Table 2. Reactions of Glycosyl Donors and Acceptors
a
Scheme 3. EPR Experiments
a
The reaction was carried out with 1, 6, Cu(OTf)2 (1.7 equiv), and
CH2Cl2 (1.0 M solution) in a quartz capillary tube with UV irradiation
at room temperature. (a) Before and (b) after UV irradiation for 30
min.
photomediated glycosylation reactions that involve a S-radical
cation intermediate, and it is what we imagined (Scheme 2).
Even so, we could not rule out the possibility that part of the
thioglycosides were activated by a newly generated thioradical,
or copper(II) was involved in the photolytic cleavage of the
thioglycoside bond.
In conclusion, we have shown that the activation of
thioglycosides upon the UV irradiation followed by the
oxidation of Cu(OTf)2 leads to the in situ formation of species
that can undergo glycosylation to afford glycosides in moderate
to excellent yields without the need for a photosensitizer. A
wide range of substrates were tolerated, including sugars, amino
acids, and cholesterol. Acyl, benzyl, benzyloxycarbonyl, and
isopropylidene protective groups and double bond functionality
were compatible with these conditions. Specially, the thorny
reactions of the “disarmed” donors with the low-reactive
acceptors proceeded smoothly. The reaction mechanism via a
homolytic cleavage of a C−S bond and a subsequent oxidation
was supported by analysis of the products and byproducts,
TEMPO-inhibition experiments, and EPR experiments. In
contrast with the existing light-induced glycosylation methods,
this protocol features a broad substrate scope, excellent
functional group compatibility, and a unique mechanism
involving the direct C−S bond cleavage of thioglycosides to
generate a glycosyl radical and a subsequent oxidation by
Cu(OTf)2. The disclosed protocol not only provides a novel
glycosylation method with high generality and applicability but
also paves a new avenue for the reaction via a glycosyl radical.22
Further studies toward this direction are underway in our
laboratory and will be reported in due course.
a
Reaction conditions: donor (0.04 mmol), acceptor (0.5 equiv),
Cu(OTf)2 (1.7 equiv), activated 4 Å molecular sieves (200 mg),
CH2Cl2 (2.0 mL) in a quartz flask at room temperature under argon
b
c
atmosphere. Isolated yield. Acetonitrile as solvent, α/β = 1/2.7.
d
Diethyl ether as solvent, α/β = 2.8/1.
Finally, we probed the mechanism of this new type of
glycosylation protocol using the reaction of 1 with 6. The dark
control experiments showed no conversion of the thioglycoside
either at room temperature or with heating to 40 °C (entries
C
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2860. (d) Burkart, M. D.; Zhang, Z. Y.; Hung, S. C.; Wong, C. H. J.
Am. Chem. Soc. 1997, 119, 11743. (e) Ercegovic, T.; Meijer, A.;
Magnusson, G.; Ellervik, U. Org. Lett. 2001, 3, 913.
(8) For selected examples, see: (a) Crich, D.; Smith, M. Org. Lett.
2000, 2, 4067. (b) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02823.
■
S
9015. (c) Codee
Overkleeft, H. S.; van Boom, J. H.; van der Marel, G. A. Org. Lett.
2003, 5, 1519. (d) Duron, S. G.; Polat, T.; Wong, C.-H. Org. Lett.
́
, J. D. C.; Litjens, R. E. J. N.; den Heeten, R. D.;
Experimental details, characterization data for com-
pounds (PDF)
́
2004, 6, 839. (e) Tatai, J.; Fugedi, P. Org. Lett. 2007, 9, 4647.
(9) For selected examples, see: (a) Mitsudo, K.; Kawaguchi, T.;
Miyahara, S.; Matsuda, W.; Kuroboshi, M.; Tanaka, H. Org. Lett. 2005,
7, 4649. (b) Nokami, T.; Shibuya, A.; Tsuyama, H.; Bowers, A. A.;
Crich, D.; Suga, S.; Yoshida, J. J. Am. Chem. Soc. 2007, 129, 10922.
(10) Marra, A.; Scherrmann, M. C. Carbohydr. Chem. 2014, 40, 160.
(11) (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev.
2013, 113, 5322. (b) Lang, X.; Chen, X.; Zhao, J. Chem. Soc. Rev. 2014,
43, 473. (c) Brimioulle, R.; Lenhart, D.; Maturi, M. M.; Bach, T.
Angew. Chem., Int. Ed. 2015, 54, 3872.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: decai@bjmu.edu.cn.
*E-mail: xinshan@bjmu.edu.cn.
Author Contributions
§R.-Z.M. and F.G. contributed equally.
(12) Wever, W. J.; Cinelli, M. A.; Bowers, A. A. Org. Lett. 2013, 15,
30.
(13) Nakanishi, M.; Takahashi, D.; Toshima, K. Org. Biomol. Chem.
2013, 11, 5079.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(14) Griffin, G. W.; Bandara, N. C.; Clarke, M. A.; Tsang, W.-S.;
Garegg, P. J.; Oscarson, S.; Silwanis, B. A. Heterocycles 1990, 30, 939.
(15) Hashimoto, S.; Kurimoto, I.; Fujii, Y.; Noyori, R. J. Am. Chem.
Soc. 1985, 107, 1427.
(16) (a) Cumpstey, I.; Crich, D. J. Carbohydr. Chem. 2011, 30, 469.
(b) Furuta, T.; Takeuchi, K.; Iwamura, M. Chem. Commun. 1996, 157.
(17) Iwata, R.; Uda, K.; Takahashi, D.; Toshima, K. Chem. Commun.
2014, 50, 10695.
(18) (a) Morine, G. H.; Kuntz, R. R. Photochem. Photobiol. 1981, 33,
1. (b) Byers, G. W.; Gruen, H.; Giles, H. G.; Schott, H. N.;
Kampmeier, J. A. J. Am. Chem. Soc. 1972, 94, 1016. (c) Benson, S. W.
Chem. Rev. 1978, 78, 23.
(19) (a) Huang, X.; Huang, L.; Wang, H.; Ye, X.-S. Angew. Chem., Int.
Ed. 2004, 43, 5221. (b) Wang, C.; Wang, H.; Huang, X.; Zhang, L.-H.;
Ye, X.-S. Synlett 2006, 2006, 2846. (c) Geng, Y.; Zhang, L.-H.; Ye, X.-
S. Chem. Commun. 2008, 597. (d) Xiong, D.-C.; Zhang, L.-H.; Ye, X.-S.
Adv. Synth. Catal. 2008, 350, 1696. (e) Lu, Y.-S.; Li, Q.; Zhang, L.-H.;
Ye, X.-S. Org. Lett. 2008, 10, 3445. (f) Yang, L.; Zhu, J.; Zheng, X.-J.;
Tai, G.; Ye, X.-S. Chem. - Eur. J. 2011, 17, 14518. (g) Peng, P.; Ye, X.-
S. Org. Biomol. Chem. 2011, 9, 616. (h) Geng, Y.; Qin, Q.; Ye, X.-S. J.
Org. Chem. 2012, 77, 5255. (i) Xu, F.-F.; Wang, Y.; Xiong, D.-C.; Ye,
X.-S. J. Org. Chem. 2014, 79, 797.
■
This work was financially supported by the Grants
(2012CB822100, 2013CB910700) from the Ministry of
Science and Technology of China, the National Natural
Science Foundation of China (Grant Nos. 21232002,
21572012), Beijing Natural Science Foundation (2142015),
and Beijing Higher Education Young Elite Teacher Project
(YETP0063). We thank Prof. Jingfen Lu in Peking University
for EPR experiments.
REFERENCES
■
(1) Varki, A.; Cummings, R. D.; Esko, J. D.; Freeze, H. H.; Stanley,
P.; Bertozzi, C. R.; Hart, G. W.; Etzler, M. E. Essentials of Glycobiology,
2nd ed.; Cold Spring Harbor Laboratory Press; Cold Spring Harbor,
NY, 2009.
(2) (a) Crich, D. Acc. Chem. Res. 2010, 43, 1144. (b) Huang, M.;
Garrett, G. E.; Birlirakis, N.; Bohe,
́
L.; Pratt, D. A.; Crich, D. Nat.
Chem. 2012, 4, 663. (c) Bohe, L.; Crich, D. Carbohydr. Res. 2015, 403,
́
48. (d) Frihed, T. G.; Bols, M.; Pedersen, C. M. Chem. Rev. 2015, 115,
4963.
(3) (a) Seeberger, P. H.; Werz, D. B. Nature 2007, 446, 1046.
(b) Demchenko, A. V. Handbook of Chemical Glycosylation; Wiley−
VCH: Weinheim, 2008. (c) Zhu, X. M.; Schmidt, R. R. Angew. Chem.,
Int. Ed. 2009, 48, 1900. (d) Hsu, C.-H.; Hung, S.-C.; Wu, C.-Y.; Wong,
C.-H. Angew. Chem., Int. Ed. 2011, 50, 11872. (e) Yu, B.; Sun, J. S.;
Yang, X. Y. Acc. Chem. Res. 2012, 45, 1227. (f) Yang, L.; Qin, Q.; Ye,
X.-S. Asian J. Org. Chem. 2013, 2, 30. (g) Seeberger, P. H. Acc. Chem.
Res. 2015, 48, 1450.
(4) (a) Yang, Y.; Zhang, X.; Yu, B. Nat. Prod. Rep. 2015, 32, 1331.
(b) Ranade, S. C.; Demchenko, A. V. J. Carbohydr. Chem. 2013, 32, 1.
(c) Kaeothip, S.; Demchenko, A. V. Carbohydr. Res. 2011, 346, 1371.
(d) McKay, M. J.; Nguyen, H. M. ACS Catal. 2012, 2, 1563.
(20) (a) Lemieux, R. U. Pure Appl. Chem. 1971, 25, 527. (b) Vankar,
D.; Vankar, P. S.; Behrendt, M.; Schmidt, R. R. Tetrahedron 1991, 47,
9985.
(21) Leyva-Perez, A.; Vidal-Moya, J. A.; Cabrero-Antonino, J. R.; Al-
́
Deyab, S. S.; Al-Resayes, S. I.; Corma, A. J. Organomet. Chem. 2011,
696, 362.
(22) (a) Andrews, R. S.; Becker, J. J.; Gagne,
13, 2406. (b) Andrews, R. S.; Becker, J. J.; Gagne,
Int. Ed. 2010, 49, 7274.
́
M. R. Org. Lett. 2011,
́
M. R. Angew. Chem.,
́
(5) (a) Codee, J. D. C.; Litjens, R. E. J. N.; van den Bos, L. J.;
Overkleeft, H. S.; van der Marel, G. A. Chem. Soc. Rev. 2005, 34, 769.
(b) Lian, G.; Zhang, X.; Yu, B. Carbohydr. Res. 2015, 403, 13.
(c) Boltje, T. J.; Buskas, T.; Boons, G.-J. Nat. Chem. 2009, 1, 611.
(6) For selected examples, see: (a) Sato, S.; Mori, M.; Ito, Y.; Ogawa,
T. Carbohydr. Res. 1986, 155, C6. (b) Lear, M. J.; Yoshimura, F.;
Hirama, M. Angew. Chem., Int. Ed. 2001, 40, 946. (c) Dondoni, A.;
Marra, A.; Massi, A. Angew. Chem., Int. Ed. 2005, 44, 1672.
(d) Goswami, M.; Ellern, A.; Pohl, N. L. B. Angew. Chem., Int. Ed.
2013, 52, 8441.
(7) For selected examples, see: (a) Nicolaou, K. C.; Seitz, S. P.;
Papahatjis, D. P. J. Am. Chem. Soc. 1983, 105, 2430. (b) Valerio, S.;
Iadonisi, A.; Adinolfi, M.; Ravida,
(c) Kihlberg, J. O.; Leigh, D. A.; Bundle, D. R. J. Org. Chem. 1990, 55,
̀
A. J. Org. Chem. 2007, 72, 6097.
D
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Org. Lett. XXXX, XXX, XXX−XXX