A facile and highly stereoselective synthesis of 1-thiotrehalose

Article abstract of DOI:10.1016/j.tetlet.2012.05.159

A facile and highly stereoselective synthesis of 1-thiotrehalose, that is, α,α-S-linked trehalose, is described. Glycosylation of configurationally pure α-glucosyl thiol 5 with glucosyl trichloroacetimidate 6 or glucosyl thioimidate 9 followed by deprotection afforded 1-thiotrehalose in excellent α-stereoselectivity and high yield. A different synthetic route to the key building block, α-glucosyl thiol 5, was also investigated in this report.

Full text of DOI:10.1016/j.tetlet.2012.05.159

Tetrahedron Letters 53 (2012) 4309–4312
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Tetrahedron Letters
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A facile and highly stereoselective synthesis of 1-thiotrehalose
Guohong Xin a, Xiangming Zhu a,b,
⇑
a College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, China
b Centre for Synthesis and Chemical Biology, UCD School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and highly stereoselective synthesis of 1-thiotrehalose, that is, a,a-S-linked trehalose, is described.
Received 29 April 2012
Accepted 31 May 2012
Available online 17 June 2012
Glycosylation of configurationally pure
a
-glucosyl thiol 5 with glucosyl trichloroacetimidate 6 or glucosyl
thioimidate 9 followed by deprotection afforded 1-thiotrehalose in excellent
a
-stereoselectivity and high
yield. A different synthetic route to the key building block,
report.
a-glucosyl thiol 5, was also investigated in this
Keywords:
Trehalose
Ó 2012 Elsevier Ltd. All rights reserved.
1-Thiotrehalose
Thioglycoside
Glycosidation
Trehalose,1 a non-reducing disaccharide consisting of two glu-
copyranose rings connected by an
-(1?10) linkage (Fig. 1), is
Mycobacterium avium, and significant activities were observed for
some derivatives.6e In addition, C-glycoside analogues of trehalose
were also synthesized and tested on porcine kidney trehalase, an
enzyme involved in the catabolism of trehalose into glucose.6g In
carbohydrate chemistry, thiooligosaccharides and S-glycoconju-
gates have often been synthesized as excellent analogues of natu-
rally occurring O-glycosides,7 because of their resistance to
chemical and enzymatic hydrolysis, and their similar solution con-
formations and bioactivities compared to native counterparts.8 In
this context, we have initiated a program to synthesize 1-thiotreha-
lose and its derived glycolipids in order to provide valuable com-
pounds for biological studies. Herein we report a convenient and
highly stereoselective procedure for the synthesis of 1-thiotreha-
a,a
synthesized by many living organisms including plants, insects,
and microorganisms as a response to prolonged periods of desicca-
tion.2 This disaccharide plays an important role in preventing cell
damage upon drying, and its
a,a
-(1?10) glycosidic linkage is key
to anhydrobiotic preservation.3 Trehalose was found to have
important roles as well in protecting cells and their components
against other stresses such as oxidative or freezing conditions.4
On the other hand, in microorganisms such as mycobacteria, treha-
lose exists not only in free form but in various forms of glycolipids
such as trehalose 6,60-dimycolate, acylated trehalose-2-sulfate, and
complex lipooligosaccharides.5 These trehalose-containing glyco-
lipids are mainly present in mycobacterial cell walls and may play
crucial roles in the survival and virulence of mycobacteria.
lose, that is, a,a-S-linked trehalose.
A thorough literature search revealed numerous methods for
the synthesis of (1?10)-S-linked disaccharides.9 For instance, b,
b-(1?10)-S-disaccharides were readily prepared by treatment of
acetylated glycosyl bromides with potassium alkyl xanthates in
acetone without isolation of the corresponding intermediary glyco-
syl xanthates.9a Glycosyl disulfides were treated with P(Et2N)3 to
Due to the significant bioactivities of trehalose and its deriva-
tives, many efforts have been devoted to synthesize trehalose
analogues that may prove useful in biological studies and as poten-
tial therapeutic agents.6 For example, Bertozzi and coworkers
synthesized a series of mono- and dideoxygenated trehalose ana-
logues,6a which were used in biochemical and NMR-based studies
to probe the substrate binding interactions of trehalose with myco-
bacterial sulfotransferase Stf0. A group of trehalosamine analogues
were also synthesized efficiently in sufficient quantities and purities
for different types of assays against various pathogens.6f A range of
6,60-diamino-6,60-dideoxytrehalose derivatives were also synthe-
sized and evaluated for antimycobacterial activity against Mycobac-
terium tuberculosis H37Ra and a panel of clinical isolates of
HO
HO
HO
HO
HO
HO
O
O
HO
HO
O
S
OH
OH
OH
OH
O
O
HO
HO
HO
HO
1-Thiotrehalose (1)
Trehalose
⇑
Corresponding author. Tel.: +353 17162386; fax: +353 17162501.
E-mail address: Xiangming.Zhu@ucd.ie (X. Zhu).
Figure 1. Structures of trehalose and 1-thiotrehalose.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.159

4310
G. Xin, X. Zhu / Tetrahedron Letters 53 (2012) 4309–4312
generate
a
,b-(1?10)-S-disaccharides stereospecifically.9b,c Re-
stereospecific way, which, in addition to the high configurational
stability of glycosyl thiol,20 ensured one of the two
-glycosidic
cently, a series of b,b-connected thiodigalactoside derivatives was
synthesized as galectin inhibitors by reaction of glycosyl bromides
with the corresponding glycosyl thiols, or by treatment of glycosyl
bromides with dry Na2S.9g More recently, the synthesis of a range
of 1,10-thiodisaccharides was reported, in which per-acetyl sugars
were activated with BF3ꢀEt2O in the presence of the corresponding
a,a
bonds in the target molecule. Thiol 3 was then subjected to
glycosylation with trichloroacetimidate 621 under normal Schmidt
conditions. Surprisingly, 6-O-glycosylation occurred instead of
1-S-glycosylation, presumably due to the lower steric hindrance
of 6-OH, giving rise to the O-linked disaccharide in very good
yield.22 As such, it was necessary to protect the 6-OH group of thiol
3 before the glycosylation. Acetylation was thus performed on
compound 3 to give the fully protected sugar 4 in 98% yield, which
was treated subsequently with 1 equiv of NaSMe23 in MeOH-
glycosyl thiols to give anomeric mixtures of b,b- and a
,b-(1?10)-S-
disaccharides.9h However, to the best of our knowledge, to date
only very few papers describe the synthesis of -connected 1-
a,a
thiotrehalose, which would best mimic trehalose in comparison
to other thiodisaccharides, and allow access to good mimics of tre-
halose-derived glycolipids as well. Most procedures reported in the
literature for the synthesis of 1-thiotrehalose involve the use of
highly reactive b-glycosyl chlorides. For example, in the early
1960s, the synthesis of fully acetylated 1-thiotrehalose was
CH2Cl2 to furnish the 6-O-protected a-glucosyl thiol 5 in very high
yield (87%). Thiol 5 was glycosylated with trichloroacetimidate 621
under the action of 0.2 equiv of TMSOTf in a mixture of solvents,
Et2O and CH2Cl2 at ꢁ78 °C, but unfortunately, the desired fully pro-
tected
a,a-thiotrehalose 7 was produced in relatively low yield
achieved by treatment of 3,4,6-tri-O-acetyl-b-
D
-glucopyranosyl
(32%) with a large amount of unreacted thiol 5 recovered. In spite
chloride with potassium methyl or benzyl xanthate followed by
of the low yield, the reaction was highly a-stereoselective as no
acetylation.10 Later, Driguez and coworkers synthesized 1-thiotre-
b-isomer was detected.24 It is evident that compared with normal
alkyl thiols the anomeric sulfhydryl group is not reactive enough
due to the stereoelectronic effect. More forcing reaction conditions
were then investigated with the hope of driving the reaction to
halose by reaction of 2,3,4,6-tetra-O-acetyl-b-
chloride with Na2S11 or sodium salt of 1-thio- -glucopyranose,12
but small amounts of the ,b-isomer were also isolated in the reac-
D-glucopyranosyl
a-D
a
tions.12 Later, the reaction of the b-chloride with Na2S was im-
proved by using phase-transfer catalysis, and the desired acetyl
1-thiotrehalose was produced in moderate yield.13 Overall, one
great disadvantage of the above procedures is the use of highly
reactive b-chlorides, which render them very technically challeng-
ing for non-specialists. Another strategy for making 1-thiotreha-
lose was reported by Defaye et al.,14 in which a solution of
glucose in anhydrous HF solution was treated with H2S gas to pro-
vide directly 1-thiotrehalose. However, a mixture of three isomers
was generated in the reaction, and the subsequent purification was
troublesome, leading together to a low yield of 1-thiotrehalose.
Under these circumstances, the development of a convenient
and stereoselective synthesis of 1-thiotrehalose would seem to
be of interest. Apparently, the major challenge associated with
completion and maintaining the excellent a-stereoselectivity as
well. Hence, the amount of TMSOTf was increased to 1.0 equiv in
the same solvent system at the same temperature. As expected,
this time 7 was isolated in very good yield (75%) without loss of
the a-stereoselectivity. A major side reaction was the decomposi-
tion of the donor 6 due to the harsh conditions. We speculated that
the relatively large amounts of TMSOTf may react with the thiol to
generate in situ the glucosyl silyl sulfide which possessed higher
reactivity than the thiol, thereby facilitating the glycosidation reac-
tion.25 To corroborate this, 1.0 equiv of TfOH was used instead of
TMSOTf to promote the above reaction with other conditions un-
changed, not surprisingly, the yield dropped dramatically to
ꢂ30%. This result indicates clearly that glycoside bond formation
is still by no means routine, albeit significant advances in the past
decades and optimization of reaction conditions could be crucial
for the reaction to proceed in high yield.
Recently, we reported a new type of glycosyl thioimidates as
glycosylating agents, which could be readily prepared from glyco-
syl thiols and which exhibited greater stability in comparison to
Schmidt donors.26 These thioimidates are thus less prone to
decomposition under Lewis acid conditions, and as such, could
possibly further improve the yield of the above glycosidation reac-
tion. Hence, as shown in Scheme 2, thioimidate donor 9 was pre-
pared in good yield by treatment of thiol 827 with N-phenyl
trifluoroacetimidoyl chloride in the presence of K2CO3 in acetone.
the synthesis of 1-thiotrehalose is how to introduce the two
a,
a
-anomeric linkages. In spite of the advances made recently in car-
bohydrate synthesis,15 there is still no general procedure for the
stereoselective synthesis of 1,2-cis glycosides.16 Seeing that the
Schmidt donor usually exhibits a high glycosylating property and
anomeric stereocontrol,17 it was chosen to construct the desired
a,a
-linkage. To carry out the synthesis, a suitably derivatized
a
-glycosyl thiol was also needed as the glycosyl acceptor. Hence,
as shown in Scheme 1,
a
-glucosyl thiol 318 was first prepared from
1,6-anhydrosugar 219 following the procedure developed in our
laboratory.18 It is worth mentioning that 3 was produced in a
O
OH
OAc
Ref. 18
90%
OBn
O
O
Ac2O, Py
98%
O
BnO
BnO
BnO
BnO
BnO
3
BnO
4
SH
SAc
BnO
OBn
2
OBn
NaSMe
CH2Cl2
MeOH
O
87%
BnO
BnO
BnO
BnO
BnO
O
BnO
O
CCl3
NH
6
BnO
OAc
S
O
OAc
OBn
75%
BnO
O
BnO
BnO
7
1.0 eq TMSOTf
Et2O-CH2Cl2
BnO
SH
OBn
5
Scheme 1. Synthesis of 1-thiotrehalose 7.

G. Xin, X. Zhu / Tetrahedron Letters 53 (2012) 4309–4312
4311
OBn
OBn
CF3C(=NPh)Cl
O
O
BnO
BnO
BnO
BnO
SH
S
CF3
NPh
K2CO3
60%
OBn
OBn
8
9
1.0 eq TMSOTf
AcO
AcO
AcO
5
O
Et2O-CH2Cl2
81%
AcO
S
Ac2O, Py
Na, NH3 (l)
90%
OAc
OAc
7
1
O
95%
AcO
OAc
10
Scheme 2. Synthesis of 1-thiotrehalose 1.
The subsequent glycosidation of 9 with 5 occurred smoothly under
the above-mentioned conditions (1.0 equiv of TMSOTf), and led to
the desired thiotrehalose 7 in slightly better yield (81%). To access
the target molecule, removal of the benzyl groups from 7 was con-
ducted by Birch reduction, and not unexpectedly, the acetyl group
was also cleaved under the conditions, and 1-thiotrehalose 1 was
produced in 90% yield. The NMR data of 1 were in good agreement
with those reported in the literature.28 To confirm the structure, 1
was subsequently converted into octaacetate 10 by acetylation in
95% yield. Compound 10 was then characterized unambiguously
by spectroscopic (1H, 13C, and MS) and X-ray diffraction analysis
(Fig. 2).
O
OH
MMTrSH
OBn
O
O
BnO
BnO
TMSOTf
15%
BnO
11
SMMTr
BnO
OBn
2
Ac2O
97%
Py
OAc
OAc
TFA
TESH
O
O
BnO
BnO
BnO
BnO
CH2Cl2
83%
BnO
BnO
12
SH
SMMTr
The ring-opening reaction of 2 with 4-monomethoxytrityl thiol
5
(MMTrSH),29 with a view to acquiring the
a-glucosyl thiol 5 in a
more efficient way was also attempted, but unfortunately, this
turned out to be not very successful. As shown in Scheme 3, 1,6-
anhydrosugar 2 was ring-opened with MMTrSH in the presence
of TMSOTf to afford only a 15% yield of a-thioglucoside 11, which
was converted into the fully protected sugar 12 in 97% yield by
Scheme 3. A different route to
a
-glucosyl thiol 5.
and it could be installed and removed effectively in the presence
of various protecting groups.
In conclusion, glycosylation of readily available
with either the Schmidt donor or a thioimidate donor led to 1-thi-
otrehalose derivatives in excellent -stereoselectivity and very
a-glycosyl thiol
acetylation. Cleavage of the MMTr group with trifluoroacetic acid
(TFA) in the presence of triethylsilane (TESH) led to the
a-thiol 5
a
in 83% yield. Notably, the MMTr group was used previously as an
high yield. Thus, a new and convenient route for the synthesis of
anomeric S-protecting group for the synthesis of glycosyl thiols,30
1-thiotrehalose has been developed, which could also be applied
to the synthesis of other
a,a
-(1?10)-S-linked diglycosides. The
high stereoselectivity, high yields, and the ease of conducting the
reactions are attractive features, compared with previous methods.
Its application toward the synthesis of 1-thiotrehalose-derived gly-
colipids is currently underway.
Acknowledgments
This work was supported by the Natural Science Foundation of
Zhejiang Province (R4110195) and the Research Frontier Program
of Science Foundation Ireland.
Supplementary data
Supplementary data (experimental procedure, characterization
data and X-ray crystallographic data of compound 10, as well as
copies of the 1H and 13C NMR of new compounds) associated with
this article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2012.05.159.
References and notes
1. Pratt, M. R.; Leigh, C. D.; Bertozzi, C. R. Org. Lett. 2003, 5, 3185–3188.
2. Luyckx, J.; Baudouin, C. Clin. Ophthalmol. 2011, 5, 577–581.
3. Albertorio, F.; Chapa, V. A.; Chen, X.; Diaz, A. J.; Cremer, P. S. J. Am. Chem. Soc.
2007, 129, 10567–10574.
4. Ohtake, S.; Wang, Y. J. J. Pharm. Sci. 2011, 100, 2020–2053.
Figure 2. X-ray crystal structure of 1-thiotrehalose octaacetate 10 (CCDC 854209).

4312
G. Xin, X. Zhu / Tetrahedron Letters 53 (2012) 4309–4312
5. Woodruff, P. J.; Carlson, B. L.; Siridechadilok, B.; Pratt, M. R.; Senaratne, R. H.;
Mougous, J. D.; Riley, L. W.; Williams, S. J.; Bertozzi, C. R. J. Biol. Chem. 2004, 279,
28835–28843.
12. Blanc-Muesser, M.; Defaye, J.; Driguez, H. Carbohydr. Res. 1978, 67, 305–328.
13. Chrétien, F.; Cesare, P. D.; Gross, B. J. Chem. Soc., Perkin Trans. 1 1988, 3297–
3300.
6. (a) Lin, F. L.; van Halbeek, H.; Bertozzi, C. R. Carbohydr. Res. 2007, 342, 2014–
2030; (b) Namme, R.; Mitsugi, T.; Takahashi, H.; Ikegami, S. Eur. J. Org. Chem.
2007, 3758–3764; (c) Balamurugan, R.; Pachamuthu, K.; Schmidt, R. R. Synlett
2005, 134–138; (d) Babu, R. S.; O’Doherty, G. A. J. Carbohydr. Chem. 2005, 24,
169–177; (e) Rose, J. D.; Maddry, J. A.; Comber, R. N.; Suling, W. J.; Wilson, L. N.;
Reynolds, R. C. Carbohydr. Res. 2002, 337, 105–120; (f) Hui, Y.; Chang, C.-W. T.
Org. Lett. 2002, 4, 2245–2248; (g) Lubineau, A.; Grand, E.; Scherrmann, M. C.
Carbohydr. Res. 1997, 297, 169–174.
14. Defaye, J.; Gadelle, A.; Pedersen, C. Carbohydr. Res. 1991, 217, 51–58.
15. Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48, 1900–1934.
16. Handbook of Chemical Glycosylation; Demchenko, A. V., Ed.; Wiley-VCH:
Weinheim, 2008.
17. Schmidt, R. R.; Kinzy, W. Adv. Carbohydr. Chem. Biochem. 1994, 50, 21–123.
18. (a) Dere, R. T.; Wang, Y.; Zhu, X. Org. Biomol. Chem. 2008, 6, 2061–2063; (b) Zhu,
X.; Dere, R. T.; Jiang, J.; Zhang, L.; Wang, X. J. Org. Chem. 2011, 76, 10187–10197.
19. Ruckel, E. R.; Schuerch, C. J. Org. Chem. 1966, 31, 2233–2239.
20. Caraballo, R.; Deng, L.; Amorim, L.; Brinck, T.; Ramström, O. J. Org. Chem. 2010,
75, 6115–6121.
7. Pachamuthu, K.; Schmidt, R. R. Chem. Rev. 2006, 106, 160–187.
8. Driguez, H. ChemBioChem 2001, 2, 311–318.
9. (a) Sakata, M.; Haga, M.; Tejima, S. Carbohydr. Res. 1970, 13, 379–390; (b)
Harpp, D. N.; Gleason, J. G. J. Am. Chem. Soc. 1971, 93, 2437–2445; (c) Ferrier, R.
J.; Furneaux, R. H.; Tyler, P. C. Carbohydr. Res. 1977, 58, 397–404; (d) Fujihira, T.;
Takido, T.; Seno, M. J. Mol. Catal. A: Chem. 1999, 137, 65–75; (e) Tiwari, P.;
Agnihotri, G.; Misra, A. K. J. Carbohydr. Chem. 2005, 24, 723–732; (f) El Ashry, E.
S. H.; Awad, L. F.; Hamid, H. M. A.; Atta, A. I. J. Carbohydr. Chem. 2005, 24, 745–
753; (g) Cumpstey, I.; Salomonsson, E.; Sundin, A.; Leffler, H.; Nilsson, U. J.
Chem. Eur. J. 2008, 14, 4233–4245; (h) Morais, G. R.; Humphrey, A. J.; Falconer,
R. A. Carbohydr. Res. 2009, 344, 1039–1045.
21. Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. 1980, 19, 731–732.
22. Dere, R. T.; Kumar, A.; Kumar, V.; Zhu, X.; Schmidt, R. R. J. Org. Chem. 2011, 76,
7539–7545.
23. Wallace, O. B.; Springer, D. M. Tetrahedron Lett. 1998, 39, 2693–2694.
24. The highly
a-selective glycosidation of 6 with thio-nucleophiles was already
observed in: Schmidt, R. R.; Stumpp, M. Liebigs Ann. Chem. 1983, 1249–1256.
25. Many attempts to isolate the glycosyl silyl sulfide intermediate were made, but
all failed.
26. Lucas-Lopez, C.; Murphy, N.; Zhu, X. Eur. J. Org. Chem. 2008, 4401–4404.
27. Zhu, X.; Jin, Y.; Wickham, J. J. Org. Chem. 2007, 72, 2670–2673.
28. Bock, K.; Defaye, J.; Driguez, H.; Bar-Guilloux, E. Eur. J. Biochem. 1983, 131, 595–
600.
10. (a) Akagi, M.; Tejima, S.; Haga, M.; Sakata, M. Chem. Pharm. Bull. 1963, 11,
1081–1082; (b) Sakata, M.; Haga, M.; Tejima, S.; Akagi, M. Chem. Pharm. Bull.
1964, 12, 652–656.
11. Blanc-Muesser, M.; Defaye, J.; Driguez, H. Tetrahedron Lett. 1976, 47, 4307–
4310.
29. Seio, K.; Sekine, M. Tetrahedron Lett. 2001, 42, 8657–8660.
30. Zhu, X. Tetrahedron Lett. 2006, 47, 7935–7938.