Highly direct α-selective glycosylations of 3,4-o-carbonate-protected 2-deoxy-and 2,6-dideoxythioglycosides by preactivation protocol

Article abstract of DOI:10.1021/ol801190c

(Chemical Equation Presented) A new efficient pre-activation method for the highly α-stereoselective glycosylation of 2-deoxysugars and 2,6-dideoxysugars has been developed using 2-deoxy- and 2,6- dideoxythioglycosides as glycosyl donors. The approach allows a wide range of glycosyl acceptors and donors to be used; the α-selectivity is very good to excellent.

Full text of DOI:10.1021/ol801190c

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3445-3448
Highly Direct r-Selective Glycosylations
of 3,4-O-Carbonate-Protected 2-Deoxy-
and 2,6-Dideoxythioglycosides by
Preactivation Protocol
Yin-Suo Lu, Qin Li, Li-He Zhang, and Xin-Shan Ye*
The State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical
Sciences, Peking UniVersity, Xue Yuan Rd #38, Beijing 100083, China
xinshan@bjmu.edu.cn
Received May 28, 2008
ABSTRACT
A new efficient pre-activation method for the highly r-stereoselective glycosylation of 2-deoxysugars and 2,6-dideoxysugars has been developed
using 2-deoxy- and 2,6-dideoxythioglycosides as glycosyl donors. The approach allows a wide range of glycosyl acceptors and donors to be
used; the r-selectivity is very good to excellent.
2-Deoxyglycosides containing either R- or ꢀ-glycosyl
linkages are frequently found as integral components of many
important natural products, especially antitumor antibiotics.1
The stereoselective assembly of 2-deoxyglycosyl linkages
is more challenging than that of other glycosyl linkages since
2-deoxyglycosyl donors lack a stereodirecting substituent at
the C-2 position and the resulting glycosides are more acid
labile due to the lack of an electron-withdrawing C-2
substituent. Strategies for the synthesis of 2-deoxyglycosides
with good R- or ꢀ-anomeric selectivities rely heavily on
indirect glycosylation. The indirect strategy involves the
installation of a directing group at C-2 which is reductively
removed after the glycosylation step has been completed.2
Indirect approaches to 2-deoxyglycosides mainly exploit 1,2-
migration,3 introduce auxiliary groups at the C-2 position,2
use 2,6-anhydro-2-thio sugars as donors,4 or cyclize acyclic
sulfanyl alkenes.5 In some cases, glycals are used as
donors.6,7 Most of these methods need a subsequent reduction
step which might be not suitable for the construction of some
complex natural products. Therefore, a direct strategy for
the preparation of 2-deoxyglycopyranosyl linkages that uses
2-deoxyglycopyranosyl donors would be more efficient and
practical than the indirect strategies. Although some direct
methods such as glycosylation promoted by silver silicate,8
I2-Et3SiH,9 AgPF6,10 or polymer-bound iodate(I) com-
(3) (a) Nicolaou, K. C.; Ladduwahetty, T.; Randall, J. L.; Chucholowski,
A. J. Am. Chem. Soc. 1986, 108, 2466–2467. (b) Zuurmond, H. M.; van
der Klein, P. A. M.; van der Marel, G. A.; van Boom, J. H. Tetrahedron
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Tatsuta, K. J. Am. Chem. Soc. 1994, 116, 9042–9051.
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1989, 30, 75–78. (c) Roush, W. R.; Bennett, C. E. J. Am. Chem. Soc. 1999,
121, 3541–3542. (d) Blanchard, N.; Roush, W. R. Org. Lett. 2003, 5, 81–
84. (e) Roush, W. R.; Sebesta, D. P.; James, R. A. Tetrahedron 1997, 53,
8837–8852. (f) Thiem, J.; Schottmer, B. Angew. Chem., Int. Ed. 1987, 26,
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10.1021/ol801190c CCC: $40.75
Published on Web 07/17/2008
2008 American Chemical Society

plexes11 have been used, other approaches have been
explored including the conformational assistance approach12
and the use of S-(2-deoxyglycosyl) phosphorodithioates and
2-pyridylthioglycosides as donors.13 Phosphites, phosphora-
midites, and (2-carboxy)benzyl have also been examined as
leaving groups in the 2-deoxy systems.14 Lewis acid- or
metal-catalyzed syntheses of 2-deoxyglycosides from gly-
cals15 have additionally been developed. However, the direct
synthesis of 2-deoxyglycopyranosides from 2-deoxyglycosyl
donors, with high stereoselectivity, still remains a difficult
task. For instance, for the synthesis of 2-deoxy-R-glycopy-
ranosides, good R-selectivity is usually obtained when the
galactose-type 2-deoxy sugars are used as glycosyl donors,
but the selectivity is not good when the glucose-type 2-deoxy
sugars are used. Another weak point of current methods is
the relatively narrow window of glycosyl acceptors that
perform with good stereoselectivity. Thus, we wanted to
develop a direct R-selective glycosylation method for the
construction of 2-deoxyglycopyranosides with wide donor
and acceptor applicability.
In recent years, “pre-activation” as a new glycosylation
approach has generated considerable interest.16 “Pre-activa-
tion” was developed as an effective method for the iterative
one-pot synthesis of oligosaccharides in Huang’s laboratory
as well as in our own group.17 Very recently, when this
protocol was applied to the glycosylation of oxazolidinone-
protected glucosamine donors, either R- or ꢀ-selective
glycosyl coupling reactions were realized.18 Enlightened by
this work, we applied the “pre-activation” protocol to the
direct synthesis of 2-deoxyglycopyranosides and herein report
that high R-selectivity results from the use of carbonate-
protected 2-deoxythioglycosides as glycosyl donors.
The “pre-activation” approach was conducted in a manner
where the glycosyl donor was completely activated and
consumed (by TLC detection) prior to the addition of a
glycosyl acceptor. First, the glucose-type 2-deoxysugar
donors were examined. Inspired by the results of oxazoli-
dinone-protected glucosamines,18 we used the carbonate
group to mask the hydroxyls at the C-3 and C-4 positions
of 2-deoxyglucosides in order to get similar results to those
as the conformation-constrained donors.18,19 The C-6 hy-
droxyl was protected by a benzoyl group. The combination
of benzenesulfinyl morpholine (BSM)20 and triflic anhydride
(Tf2O) was used as the promoter system in the preactivation
operations. Thus, the carbonate-protected thioglycoside 1a
was preactivated at -72 °C in anhydrous dichloromethane
using BSM-Tf2O. After disappearance of donor 1a (TLC
detection in around 5 min) the acceptor 2a was added to the
reaction mixture. Very fortunately, the coupling reaction of
1a and 2a exhibited complete R-selectivity and proceeded
as shown in Table 1 (entry 1). Next, our investigation was
expanded to other glycosyl acceptors 2b-g, and the results
are listed in Table 1. As displayed, all the glycosylations
proceeded very smoothly in high yields with excellent
1
R-selectivity. The R-anomers were identified by their H
NMR coupling constants for the anomeric protons or the
coupling constants for the axial protons at the C-2 position
of deoxysugars (J1,2 ) 3.0-4.0 Hz). It was found that donor
1a coupled with diverse glycosyl acceptors, including
pyranosides as well as furanosides. It was shown that the
R-selectivity of acceptor 2b was better than acceptor 2c
(Table 1, entry 2 vs entry 3); one might therefore conclude
that higher reactivity acceptors can improve the stereose-
lectivity of these glycosylations.21 The glycosyl acceptors
2e and 2f, which differ only in their anomeric configurations,
provided the same excellent R-stereoselectivity during the
glycosylations (Table 1, entry 5 vs entry 6). On the other
hand, when ꢀ-thioglycoside 1b was used as the glycosyl
donor instead of 1a, under the same preactivation conditions,
the stereochemical outcome of glycosylation was almost the
same (Table 1, entry 8 vs entry 4), which means that
the anomeric configuration of donors has no influence on
the stereoselectivity of these glycosyl coupling reactions.
The R-selectivity of 2-deoxygalactopyranosyl donors has
already been recognized in the literature.12,13b,14b To extend
the scope of our methodology, thiogalactoside donor 1c was
synthesized. Methyl glycosides 2a, 2b, 2d, and 2f, in which
the 6-OH, 4-OH, 3-OH, and 2-OH were exposed, respec-
tively, were again used as the glycosyl acceptors. Under the
above-mentioned preactivation glycosylation conditions, all
(10) Lear, M. J.; Yoshimura, F.; Hirama, M. Angew. Chem., Int. Ed.
2001, 40, 946–949.
(11) Jaunzems, J.; Sourkouni-Argirusi, G.; Jesberger, M.; Kirschning,
A. Tetrahedron Lett. 2003, 44, 637–639.
(12) Toshima, K.; Nozaki, Y.; Tatsuta, K. Tetrahedron Lett. 1991, 32,
6887–6890.
(13) (a) Bielawska, H.; Michalska, M. J. Carbohydr. Chem. 1991, 10,
107–112. (b) Laupichler, L.; Sajus, H.; Thiem, J. Synthesis 1992, 1133–
1136. (c) Mereyala, H. B.; Kulkarni, V. R.; Ravi, D.; Sharma, G. V. M.;
Rao, B. V.; Reddy, G. B. Tetrahedron 1992, 48, 545–562.
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Li, H.; Chen, M.; Zhao, K. Tetrahedron Lett. 1997, 38, 6143–6144. (c)
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Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4510–4511.
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D.; Sun, S. J. Org. Chem. 1997, 62, 1198–1199. (c) Code´e, J. D. C.; Van
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Int. Ed. 2001, 40, 414–417. (f) Huang, L.; Wang, Z.; Li, X.; Ye, X.-S.;
Huang, X. Carbohydr. Res. 2006, 341, 1669–1679. (g) Huang, L.; Huang,
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Ed. 2004, 43, 5221–5224.
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7–599, and references therein. (b) Geng, Y.; Zhang, L.-H.; Ye, X.-S.
Tetrahedron 2008, 64, 4949–4958. For the use of oxazolidinone functional-
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3446
Org. Lett., Vol. 10, No. 16, 2008

Table 1. Glycosylation of Donors 1a and 1b with Various
Acceptors by Preactivation
Table 2. Glycosylation of Donor 1c with Various Acceptors by
Preactivation
excellent R-selectivity. It appears that the R-selectivity of
2,6-dideoxyglycosyl linkages is almost as good as that of
2-deoxyglycosyl linkages when the preactivation glycosy-
lation approach is used. Although the selectivity is a little
lower with the poorly reactive acceptor 2c, it is still very
good (entry 2, Table 3).
In light of the excellent R-selectivity of these glycosyla-
tions, it is natural for us to wonder whether it was achieved
due to the preactivation strategy. So the comparison experi-
ments were performed. The coupling of donors 1a and 1d
with high and low reactivity acceptors, promoted by
BSM-Tf2O, under routine glycosylation conditions (non-
preactivation operations) was examined (Table 4). It was
found that only trace amounts or very small amounts of
disaccharide products were gained when donor 1a reacted
with reactive acceptors 2b and 2d under routine glycosylation
operations (entries 1 and 2, Table 4), whereas 1a reacted
with 2b and 2d under the same conditions in preactivation
manner providing the corresponding disaccharides 3b and
3d in high yields (90% for 3b and 83% for 3d, Table 1) and
with excellent selectivity (R/ꢀ ratio g20:1, Table 1). We
think that highly reactive acceptors might be unstable in the
presence of BSM-Tf2O. When the highly reactive acceptor
2b was added to the BSM-Tf2O mixture in the absence of
the donor, the acceptor almost decomposed. Under routine
BSM-Tf2O activation conditions, the coupling reactions of
donors 1a and 1d with low reactive acceptor 2c occurred
smoothly (entries 3 and 4, Table 4). However, the stereo-
selectivity was lower than that obtained by preactivation
of the coupling reactions proceeded with exclusive R-selec-
tivity and in good yield (Table 2). Therefore, in the
2-deoxygalactose case, our method is at least as good as the
reported approaches to 2-deoxygalactosides.
2,6-Dideoxysugars are also found in a plethora of biologi-
cally important natural products.1 To further verify the
effectiveness of our method, the construction of 2,6-
dideoxyglycosyl linkages was investigated. For this purpose,
thioglycoside donor 1d was synthesized, and monosaccharide
building blocks 2a, 2c, 2d, and 2g were chosen as the
glycosyl acceptors. The glycosyl coupling reactions between
donor 1d and acceptors 2a, 2c, 2d, and 2g by the preacti-
vation protocol were carried out. The results are listed in
Table 3. As shown, all of the reactions displayed good to
Org. Lett., Vol. 10, No. 16, 2008
3447

protocol (in comparison with entry 3, Table 1, and entry 2,
Table 3). It was thus demonstrated that preactivation opera-
tions can greatly influence the outcomes and stereochemistry
of glycosyl coupling reactions.
Table 4. Glycosylations Conducted in Routine Operations
Table 3. Glycosylation of Donor 1d with Various Acceptors by
Preactivation
a Detected by TLC. b The numbers in the parentheses were obtained in
preactivation operations.
ysugars has been uncovered. By comparison with the routine
glycosylation approach, the preactivation method may play
an important role in the outcomes and stereochemistry of
glycosylations of glucose and galactose type donors. The
presence of a 3,4-O-carbonate group in glycosyl donors
appears necessary to enhance R-selectivity; presumably, this
occurs by conformational constraint. This approach enjoys
a large scope in terms of glycosyl acceptors and donors. The
R-stereoselectivity toward glycosyl couplings is very good
to excellent. In addition, the carbonate-protected thioglyco-
side donors are stable and easy to prepare, and the glyco-
sylations are rapid. It is expected that the disclosed protocol
might find widespread applications in the synthesis of
R-linked 2-deoxyglycopyranose-containing complex struc-
tures with important biological functions. Further extension
of this protocol to ꢀ-selective glycosylations is currently
under investigation.
The high R-selectivity observed might originate from the
species formed as intermediates after preactivation. Once
activated, the carbonate protected donor becomes an oxac-
arbenium ion, which can be trapped by triflate anion to give
either R-triflate or ꢀ-triflate intermediate.22 As a result of
the low reactivity of the cyclocarbonated derivatives,23 we
might assume that the acceptor might prefer to undergo an
SN2-like reaction with the more reactive ꢀ-triflate inteme-
diate, resulting in the formation of R-glycosides. This process
might shift the anomerization equilibrium from the R- to
ꢀ-triflate intermediate. This might also explain how the
higher stereoselectivity was achieved when more reactive
acceptors were employed.
Acknowledgment. This work was financially supported
by the National Natural Science Foundation of China, “973”
and “863” grants from the Ministry of Science and Technol-
ogy of China.
In conclusion, a new efficient method for highly R-ste-
reoselective glycosylations of 2-deoxysugars and 2,6-dideox-
Supporting Information Available: All experimental
procedures and data for compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(22) See ref 18b and references therein.
(23) Zhu, T.; Boons, G.-J. Org. Lett. 2001, 3, 4201–4203, and references
therein.
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