Catalytic glycosylation with glycosyl thioimidate donors

Article abstract of DOI:10.1002/ejoc.200800503

A new class of glycosyl thioimidates, glycosyl N-phenyl- trifluorothioacetimidates, were prepared from the readily available glycosyl thiols in excellent yields. These imidates exhibited very good donor properties under the action of catalytic amounts of BF₃·Et₂O, and the corresponding glycosidation products were formed in very good to excellent yields. Thus, the first catalytic glycosylations with glycosyl thioimidate donors were achieved. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800503

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800503
Catalytic Glycosylation with Glycosyl Thioimidate Donors
Cristina Lucas-Lopez,[a] Niamh Murphy,[a] and Xiangming Zhu*[a,b]
Keywords: Glycosylation / Sulfur / Catalytic activation / Carbohydrates
A new class of glycosyl thioimidates, glycosyl N-phenyl-tri-
products were formed in very good to excellent yields. Thus,
fluorothioacetimidates, were prepared from the readily avail- the first catalytic glycosylations with glycosyl thioimidate do-
able glycosyl thiols in excellent yields. These imidates exhib-
ited very good donor properties under the action of catalytic
amounts of BF3·Et2O, and the corresponding glycosidation
nors were achieved.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
point of performing the glycosidation reaction on an indus-
trial scale. Trichloroacetimidates have thus become one of
the most widely used glycosyl donors in contemporary
carbohydrate chemistry.
Introduction
Glycoside bond formation is often the key step in most
carbohydrate syntheses. Since the first historical glycoside
syntheses by Michael[1] and Fischer,[2] followed by the semi-
nal work of Koenigs and Knorr,[3] a very large number of
glycosylation methods have been reported in the litera-
ture.[4] However, a general glycosylation procedure has not
appeared yet, and even for the construction of a simple gly-
cosidic bond, the optimization of every parameter, such as
leaving group, promoter and glycosidation conditions, is
sometimes crucial for achieving high yield and stereoselecti-
vity. Thus, new glycosylation methods and strategies are
still welcome in carbohydrate chemistry in order to meet
the intrinsic structural diversity of carbohydrates.[5]
Among all the glycosylation methods developed to date,
glycoside synthesis based on glycosyl imidates, particularly
trichloroacetimidates, are probably the most popular and
powerful. Glycosyl trichloroacetimidates,[6] introduced by
Schmidt in 1980, exhibit outstanding donor properties and
usually result in high product yields and high anomeric ste-
reocontrol during glycosidation reactions.[7] In particular,
they exhibit a great advantage in terms of the amount of
the promoter used, as catalytic amounts of a promoter are
usually sufficient to provide their high glycosyl donor prop-
erties, whereas other glycosyl donors, such as glycosyl ha-
lides and thioglycosides, generally require equimolar or
even excess amounts of a promoter system. Needless to say,
this catalytic characteristic is very important from the view-
In 1983, Schmidt reported another type of glycosyl imid-
ates, trifluoroacetimidates,[8] and investigated the glycosylat-
ing properties of a series of different N-substituted glycosyl
trifluoroacetimidates, including the most common glycosyl
N-phenyl-trifluoroacetimidates. As trichloroacetimidate an-
alogues, trifluoroacetimidates could also be activated with
catalytic amounts of promoters, and they have even shown
advantages over trichloroacetimidates in the synthesis of
some specific glycosides.[9] In the course of trichloroacetim-
idate glycosidation, a certain amount of an N-glycoside by-
product is occasionally produced by the glycosylation of tri-
chloroacetamide liberated from the donor.[10] Particularly,
this side reaction takes place when the acceptor is of low
nucleophilicity or sterically hindered; however, this side re-
action is diminished in trifluoroacetimidate glycosidation
due to the lower N basicity and/or the presence of an N
substituent.
With a view to expand the arsenal of catalytic glycosyla-
tion methods, and to carry forward the advantage of tri-
fluoroacetimidate glycosylation, we present here a new class
of glycosyl thioimidates as glycosylating agents, glycosyl tri-
fluorothioacetimidates, which can be activated effectively
with catalytic amounts of a promoter.
Results and Discussion
[a] Centre for Synthesis and Chemical Biology, UCD School of
Chemistry and Chemical Biology,
Glycosyl thioimidates are a class of glycosides bearing a
SCR1=NR2 aglycon. Their preparation dates back to over
40 years ago,[11] and their use as glycosyl donors may date
back to the early 1980s when Woodward et al. employed N-
heterocyclic thioglycosides as glycosylating agents in the to-
tal synthesis of erythromycin.[12] Recently, the glycosyl do-
nor properties of glycosyl thioimidates have been investi-
gated extensively, most notably by Demchenko and cowork-
University College Dublin, Belfield, Dublin 4, Ireland
[b] Zhejiang Key Laboratory for Reactive Chemistry on Solid Sur-
faces, College of Chemistry and Life Sciences, Zhejiang Normal
University,
Jinhua 321004, P. R. China
Fax: +353 17162501
E-mail: Xiangming.Zhu@ucd.ie
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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C. Lucas-Lopez, N. Murphy, X. Zhu
SHORT COMMUNICATION
ers.[13] For instance, S-benzoxazolyl glycosides were em- acetone following the previous procedure[17] to give the de-
ployed as donors and activated with an excess amount of sired glycosyl N-phenyl-trifluorothioacetimidates, such as
MeOTf or AgOTf in the synthesis of both 1,2-trans and 1,2- compound 6, in excellent yields. It is important to note that
cis glycosides.[14] S-Thiazolyl glycosides have also proved to many glycosyl thiols are commercially available, or can be
be efficient glycosyl donors under the activation of different easily prepared by different procedures.[18] Moreover, both
promoter systems, providing the corresponding glycosides α- and β-glycosyl thiols are available;[19] they are quite
with various acceptors in high yields.[15] In addition, stable and do not mutarotate even under basic conditions.
thioimidates have been utilized to develop rapid synthetic Therefore, both α- and β-thioimidates could be readily pre-
routes to oligosaccharides by incorporating different syn- pared in this way. This will be conducive to future studies
thetic strategies, such as chemoselective activation and con- on the reactivity differences between α- and β-donors, and
ventional armed–disarmed strategies.[16] As such, thioimid- also to some specific cases in which only anomerically pure
ate donors hold great promise in carbohydrate chemistry. α- or β-donors can be used.
However, in all the reported thioimidate glycosidations,
stoichiometric amounts of promoters were absolutely neces- erties were then investigated. As anticipated, activation of
sary. The common thiophilic reagents, NIS/catalytic TfOH, galactosyl thioimidate with catalytic amounts of
With the thioimidates in hand, their glycosylation prop-
6
could not even initiate the glycosidation of S-thiazolyl do- BF3·Et2O (0.1 equiv.) in the presence of methyl 2,3,4-tri-O-
nors, and the reaction could only be driven to completion benzoyl-α--glucopyranoside (11) gave rise to disaccharide
by NIS/stoichiometric TfOH.[15] Therefore, it is of great 12 in 67% yield (Table 2, Entry 1). Glycosylation of 11 with
interest to develop a new class of thioimidate donors that glucosyl thioimidate 7 with promotion by catalytic amounts
are readily activated by catalytic amounts of promoters.
of BF3·Et2O (0.1 equiv.) also generated desired disaccharide
Considering the above-mentioned advantage of trifluo- 13 smoothly in very good yield. The complete 1,2-trans ster-
roacetimidate donors, we speculated that glycosyl trifluoro- eoselectivity observed in all the glycosidation reactions in
thioacetimidates may be activated in the presence of cata- this report is attributed to the assistance of the participating
lytic amounts of a Lewis acid, because the strong electron- acetyl group at the C-2 position. The ready formation of 12
withdrawing trifluoromethyl group could reduce the nucleo- and 13 offered a preliminary suggestion that the present
philicity of the liberated thioamide during activation. To thioimidates may be another type of catalytically activated
verify this, we prepared a range of glycosyl N-phenyl-tri- glycosylating agent. Indeed, all other investigated thioimid-
fluorothioacetimidates 6–10, as shown in Table 1, from the ates 8–10 could be activated effectively under the same con-
corresponding glycosyl thiols 1–5. In practice, the thiols, ditions, and the corresponding glycosidation products 13–
such as galactosyl thiol 1 (Table 1, Entry 1), were treated
with N-phenyl trifluoroacetimidoyl chloride and K2CO3 in
Table 2. Catalytic glycosidations of thioimidates 6–10 with acceptor
11.[a]
Table 1. Preparation of glycosyl N-phenyl-trifluorothioacetimida-
tes.[a]
[a] All reactions were conducted under the same conditions; see
Supporting Information for details. [b] Isolated yield following
chromatography. [c] Yield of pure α-anomer.
[a] All reactions were conducted under the same conditions; see
Supporting Information for details. [b] Isolated yield following
chromatography.
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Eur. J. Org. Chem. 2008, 4401–4404

Catalytic Glycosylation with Glycosyl Thioimidate Donors
16 were produced in invariably good yields, as indicated in
Table 2. Other common Lewis acids, such as TMSOTf and
AgOTf, were also tested for the activation of all the thioimi-
dates, but so far, BF3·Et2O has given the best results.
To further explore the glycosylating properties of this
new class of thioimidates, we proceeded to use 1,2:3,4-di-
O-isopropylidene-α--galactopyranose (17) as the acceptor
in the glycosidation reactions. Thus, reaction of donor 6
with 17 was conducted with BF3·Et2O (0.1 equiv.) as the
promoter, and not unexpectedly, disaccharide 18 was pro-
duced in excellent yield (Table 3, Entry 1). Similarly, glycos-
idation of thioimidate 7 with 17 under the same conditions
gave also the corresponding disaccharide 19 in almost
quantitative yield (Table 3, Entry 2). In addition, excellent
yields were also achieved for the glycosylation of 17 with
thioimidate donors 8, 9 and 10 under the present condi-
tions, as shown in Table 3. These results, together with
those in Table 2, are encouraging, as they demonstrate the
feasibility of activating glycosyl thioimidates with catalytic
amounts of promoters. Furthermore, the promising results
suggest that these thioimidates could be applicable to more
complex carbohydrate synthesis and may find their utility
in modern carbohydrate chemistry.
Conclusions
A new class of glycosyl thioimidates, glycosyl N-phenyl-
trifluorothioacetimidates, have been developed as glycosyl-
ating agents in this report. These thioimidates can be easily
prepared from readily available glycosyl thiols in excellent
yields and activated effectively with catalytic amounts of
Lewis acid. To the best of our knowledge, this is the first
report on catalytic activation of thioimidate donors. The
availability, high stability and catalytic activation properties
of this type of donor may render them a great use in carbo-
hydrate synthesis. Studies on the application of this new
glycosylation method to specific carbohydrate targets are in
progress.
Supporting Information (see footnote on the first page of this arti-
cle): General experimental procedures, as well as the characteriza-
tion of all new compounds.
Acknowledgments
This work was supported by the Program for Research in Third-
Level Institutions (PRTLI) Cycle 3, administered by the High Edu-
cation Authority (HEA) of Ireland. The authors thank Dr. Dilip
Rai for high-resolution mass spectrometry measurements.
Table 3. Catalytic glycosidations of thioimidates 6–10 with acceptor
17.[a]
[1] A. Michael, Am. Chem. J. 1879, 1, 305–312.
[2] F. Fischer, Ber. Dtsch. Chem. Ges. 1893, 26, 2400–2412.
[3] W. Koenigs, E. Knorr, Ber. Dtsch. Chem. Ges. 1901, 34, 957–
981.
[4] A. V. Demchenko (Ed.), Handbook of Chemical Glycosylation,
Wiley-VCH, Weinheim, 2008.
[5] X. Zhu, R. R. Schmidt, Angew. Chem. Int. Ed., manuscript
submitted.
[6] R. R. Schmidt, J. Michel, Angew. Chem. Int. Ed. Engl. 1980,
19, 731–733.
[7] R. R. Schmidt, W. Kinzy, Adv. Carbohydr. Chem. Biochem.
1994, 50, 21–123.
[8] a) R. R. Schmidt, J. Michel, M. Roos, Liebigs Ann. Chem.
1984, 1343–1357; b) U. Huchel, Dissertation, University of
Konstanz, 1998, Papierflieger, Clausthal-Zellerfeld (ISBN 3–
89720–221–2).
[9] For some recent examples, see: a) S. I. Tanaka, M. Takashina,
H. Tokimoto, Y. Fujimoto, K. Tanaka, K. Fukase, Synlett
2005, 2325–2328; b) H. Tanaka, Y. Iwata, D. Takahashi, M.
Adachi, T. Takahashi, J. Am. Chem. Soc. 2005, 127, 1630–1631;
c) D. Comegna, E. Bedini, A. D. Nola, A. Iadonisi, M. Parrilli,
Carbohydr. Res. 2007, 342, 1021–1029; d) M. Thomas, J. P. Ges-
son, S. Papot, J. Org. Chem. 2007, 72, 4262–4264.
[10] a) G. J. S. Lohman, P. H. Seeberger, J. Org. Chem. 2004, 69,
4081–4093; b) P. Bindschädler, C. Noti, E. Castagnetti, P. H.
Seeberger, Helv. Chim. Acta 2006, 89, 2591–2610.
[11] a) H. Zinner, K. Peseke, Chem. Ber. 1965, 98, 3508–3514; b) P.
Nuhn, G. Wagner, Arch. Pharm. Ber. Dtsch. Pharm. Ges. 1968,
301, 186–200.
[12] R. B. Woodward, E. Logusch, K. P. Nambiar, K. Sakan, D. E.
Ward, B. W. Au-Yeung, P. Balaram, L. J. Browne, P. J. Card,
C. H. Chen, R. B. Chenevert, A. Fliri, K. Frobel, H. J. Gais,
D. G. Garratt, K. Hayakawa, W. Heggie, D. P. Hesson, D.
Hoppe, I. Hoppe, J. A. Hyatt, D. Ikeda, P. A. Jacobi, K. S.
Kim, Y. Kobuke, K. Kojima, K. Krowicki, V. J. Lee, T. Leutert,
S. Malchenko, J. Martens, R. S. Matthews, B. S. Ong, J. B.
Press, T. V. Rajan Babu, G. Rousseau, H. M. Sauter, M. Su-
zuki, K. Tatsuta, L. M. Tolbert, E. A. Truesdale, I. Uchida, Y.
Ueda, T. Uyehara, A. T. Vasella, W. C. Vladuchick, P. A. Wade,
R. M. Williams, H. N. C. Wong, J. Am. Chem. Soc. 1981, 103,
3215–3217.
[a] All reactions were conducted under the same conditions; see
Supporting Information for details. [b] Isolated yield following
chromatography.
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C. Lucas-Lopez, N. Murphy, X. Zhu
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[13] A. Ramakrishnan, P. Pornsuriyasak, A. V. Demchenko, J. Car-
bohydr. Chem. 2005, 24, 649–663.
[14] a) A. V. Demchenko, M. N. Kamat, C. De Meo, Synlett 2003,
1287–1290; b) A. V. Demchenko, N. N. Malysheva, C. De Meo,
Org. Lett. 2003, 5, 455–458.
[15] A. V. Demchenko, P. Pornsuriyasak, C. De Meo, N. N. Malysh-
eva, Angew. Chem. Int. Ed. 2004, 43, 3069–3072.
[16] a) P. Pornsuriyasak, U. B. Gangadharmath, N. P. Rath, A. V.
Demchenko, Org. Lett. 2004, 6, 4515–4518; b) P. Pornsuriya-
sak, A. V. Demchenko, Chem. Eur. J. 2006, 12, 6630–6646.
[17] B. Yu, H. Tao, J. Org. Chem. 2002, 67, 9099–9102.
[18] The preparation of glycosyl thiol dates from nearly half a cen-
tury ago and new preparative procedures are still emerging: a)
ˇ
M. Cerný, J. Vrkocˇ, J. Staneˇk, J. Collect. Czech. Chem. Com-
mun. 1959, 24, 64–69; b) G. J. L. Bernardes, D. P. Gamblin,
B. G. Davis, Angew. Chem. Int. Ed. 2006, 45, 4007–4011.
[19] It is worth mentioning that very recently we developed a stere-
ospecific procedure for the synthesis of α-glycosyl thiols, see:
R. T. Dere, Y. Wang, X. Zhu, Org. Biomol. Chem. 2008, 6,
2061–2063.
Received: May 23, 2008
Published Online: July 29, 2008
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Eur. J. Org. Chem. 2008, 4401–4404