Stereoselective synthesis of 2-C-Acetonyl-2-deoxy-D-galactosides using 1,2-Cyclopropaneacetylated sugar as novel glycosyl donor

Article abstract of DOI:10.1021/ol902732w

[Chemical equation presented] 1,2-Cyclopropaneacetylated sugar is an effective glycosyl donor, which reacted with various glycosyl acceptors including monosaccharides, amino acids and other alcohols In the presence of BF₃·OEt₂ or TMS

Full text of DOI:10.1021/ol902732w

ORGANIC
LETTERS
2010
Vol. 12, No. 3
540-543
Stereoselective Synthesis of
2-C-Acetonyl-2-Deoxy-D-Galactosides
using 1,2-Cyclopropaneacetylated Sugar
as Novel Glycosyl Donor
Qiang Tian,† Liyan Xu,† Xiaofeng Ma,† Wei Zou,‡ and Huawu Shao*,†
Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of
Sciences, Chengdu 610041, China, Institute for Biological Sciences, National Research
Council of Canada, 100 Sussex DriVe, Ottawa, Ontario K1A 0R6, Canada and
Graduate School of Chinese Academy of Sciences, China
shaohw@cib.ac.cn
Received November 26, 2009
ABSTRACT
1,2-Cyclopropaneacetylated sugar is an effective glycosyl donor, which reacted with various glycosyl acceptors including monosaccharides,
amino acids and other alcohols in the presence of BF3•OEt2 or TMSOTf. The glycosylation is stereoselective in favor of ꢀ-anomeric products
with BF3•OEt2 as catalyst, whereas TMSOTf-catalyzed glycosylation prefers the r-anomeric products. 2-C-Acetonyl-2-deoxy-D-galactosides
were obtained in good yields.
2-Acetamido-2-deoxy-D-glycopyranosides are widely dis-
tributed in living organisms as oligosaccharides and glyco-
conjugates, and play essential roles in a wide range of
biological processes.1 Hence, there is a considerable interest
in glycan and glycoconjugate mimics with modified 2-N-
acetamidosugar residues for further understanding and
modulating the targets of these glycosides.2 Among the
various analogs, 2-acetonyl-2-deoxy-D-galactose (2-keto-Gal)
has gained much attention.3 This substrate can serve as
ketone isostere of GalNAc for cell surface engineering,4
conjugation of nonglycoprotein with biomolecules,5 and
labeling of a single-chain antibody.6 Moreover, 2-keto-Gal
has been taken as a substrate for mutant GalT to detect
O-GlcNAc-glycosylated proteins,7 and the LacNAc moiety
of glycoproteins and glycolipids.8 Notably, it may function
as a linker substrate to assemble glycoconjugates with
therapeutic and diagnostic applications.6,9
† Chengdu Institute of Biology.
‡ National Research Council of Canada.
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10.1021/ol902732w  2010 American Chemical Society
Published on Web 12/30/2009

catalyzed ring-opening of a 1,2-cyclopropaneacetylated sugar
and subsequent glycosylation with various glycosyl acceptors
for stereoselective synthesis of 2-acetonyl-2-deoxy-D-galac-
topyranosyl conjugates.
Scheme 1
.
Synthesis of Glycosyl Conjugates with 2-keto-Gal
Residue3,4
The straightforward synthesis of galactose-derivative cy-
clopropane donor 5 commenced with the known allyl
C-galactoside 1.17 Mild oxidation of 1 with IBX followed
by NaBH4-mediated highly diastereoselective reduction
provided the epimeric allyl C-taloside 2 in excellent yield.
Tosylation of 2′-OH gave 3, and subsequent terminal olefin
oxidation with Hg(OAc)2/Jones reagent afforded 1-C-D-
talosyl acetone 4. Intramolecular SN2 reaction of compound
4 under K2CO3/DMSO conditions produced the desired 1,2-
cyclopropaneacetylated sugar 5 as the main product (Scheme
2). Extensive NMR studies and other analytical methods
confirmed that compound 5 was a pure diastereoisomer with
a trans configuration at bridged C1′ as indicated by the NOEs
between H1′, H3 and H5, which were supported by the
coupling constants (JH1, H1′ ) 2.1 Hz).18,19
Given the complex nature of the chemoenzymatic or
biological synthesis of glycans and glycoconjugates with
2-keto-Gal residuesrelying on the availability of different
wild-type and mutant glycosyltransferases, and UDP-2-keto-
Galsit is not surprising that access to diverse and chemically
defined glycoform mimics through the above the pathways
is difficult (Scheme 1). In this context, we presumed that it
could be a preferred strategy to assemble these modified
glycoforms through chemical glycosylation method. In
addition, as the UDP-2-keto-Gal precursor, peracetylated
2-acetonyl-2-deoxy-galactose,4,10 is not suitable for large-
scale glycosylation reactions as glycosyl donor due to the
synthetic route suffering from poor yield (3 steps, < 10%),
we were therefore attracted to the use of cyclopropanated
sugars as glycosyl donors.
Scheme 2. Synthesis of 1,2-Cyclopropaneacetylated Sugar 5
1,2-Cyclopropanated glycosyl donors have been investi-
gated and employed in the preparation of 2-C-branched
glycosides11 and ring expanded heptanosides12 as a result
of the versatile reactivity of cyclopropyl ring strain. Most
of these unsubstituted, and ester or halo substituted sugar
cyclopropanes are synthesized from glycals through 1,2-
cyclopropanation, and they undergo ring-opening via sol-
volysis, providing anomeric mixtures of 2-C-branched mono-
saccharides,13 or Lewis acid-assisted pyran ring expansion
to oxepanes.14 Unfortunately, only Zeise’s dimer ([Pt(C2H4)-
Cl2]2)15 and NIS/TMSOTf,16 have been found to be effective
for promoting the glycosylation of 1,2-cyclopropanated sugar
donors with sugar alcohols. Herein, we report the Lewis acid-
Unexpectedly, the galactose-derivative cyclopropane 5, in
CDCl3, rapidly generated the hemiacetal 6 as a 2:1 mixture
of R- and ꢀ-isomers (Scheme 3), whereas the structurally
similar glucose cyclopropane existed stably in the same
deuterated solvent.19 This indicated that cyclopropane ring
of 5 was highly reactive and it might be usable as an effective
glycosyl donor.
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from D-galactal as starting material to undergo iodination, Keck radical
(18) Proton-proton coupling constants in a cyclopropane system: J )
0-6 Hz for a trans stereochemistry and J ) 8-10 Hz for a cis
stereochemistry. See: (a) Kawabata, N.; Nakagawa, T.; Nakao, T.; Ya-
mashita, S. J. Org. Chem. 1977, 42, 3031–3035. (b) Wiberg, K. B.; Barth,
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Org. Lett., Vol. 12, No. 3, 2010
541

With 1,2-cyclopropaneacetylated sugar donor 5 in hand,
we focused our attention on exploring its Lewis acid-
catalyzed glycosylation with the primary alcohol of 7 as a
model reaction (Table 1). Upon treatment of 5 and 7 with
Lewis acid-catalyzed glycosylation reactions by TLC, the
anomerization of ꢀ- to R-O-glycoside was not detected
through prolonging reaction time. These results clearly
demonstrated the similar efficiency of both BF3·OEt2 and
TMSOTf in promoting the ring-opening of 1,2-cyclopropa-
neacetylated sugar donor and the contrast in diastereoselec-
tive glycosylation.
Considering the potential application of R- and ꢀ-2-keto-
galactosides in assembling special glycans and glycoconju-
gates, the scope of both Lewis acids-catalyzed coupling
methods was further examined with a number of monosac-
charides, amino acids and other alcohols 9-15 (Table 2).
Scheme 3. Hydrolysis of 1,2-Cyclopropaneacetylated Sugar 5
10 mol % of BF3·OEt2 under an inert atmosphere, the reaction
proceeded sluggishly at -78-0 °C and gave the desired
disaccharide 8 in 58% yield with R/ꢀ ) 1:4 (Table 1, entry
1). Increasing the amount of BF3·OEt2 to 20 mol % and
warming the reaction to -20 °C-rt successfully improved
the yield to 84%, obtaining slightly higher ꢀ-selectivity
(Table 1, entry 2). A variety of other Lewis acids were then
screened (Table 1, entries 3-10). AlCl3, BiCl3, and ZnCl2
were found to be less effective for O-glycosylation than
BF3·OEt2 (Table 1, entries 3-5). The use of InCl3 and PdCl2
Table 2. Glycosylation of 1,2-Cyclopropaneacetylated Sugar
Donor 5
Table 1. Lewis Acid Catalyzed Glycosylation of Glycosyl
Donor 5 and Acceptor 7a
entry
catalyst
condition
yieldc (%)
R/ꢀd
1b
2
3
4
5
6
7
8
9
BF3·Et2O
BF3·Et2O
AlCl3
BiCl3
ZnCl2
InCl3
PdCl2
AgOTf
TMSOTf
TMSOTf
-78-0 °C, 3 h
-20 °C-rt, 2 h
-20 °C-rt, 2 h
-20 °C-rt, 2 h
-20 °C-rt, 2 h
-20 °C-rt, 16 h
-20 °C-rt, 16 h
-20 °C-rt, 16 h
-20 °C-rt, 2 h
0 °C-rt, 1.5 h
58
84
76
80
1:4
1:5
1:3
1:4
1:2
/
73
trace
trace
0
87
86
/
/
a Reactions were carried out using 20 mol % BF3·OEt2 at -20 °C to rt.
b Reactions were carried out using 20 mol % TMSOTf at 0 °C to rt.
c Reactions were carried out using 40 mol % TMSOTf at rt. d Isolated yield.
2:1
7:1
10
e
1
Values were determined by H NMR.
a Reactions were performed with 1.1 equiv of acceptor in CH2Cl2 (0.1
M). b Ten mol % catalyst was employed. c Isolated yield. d Values were
1
determined by H NMR.
To our delight, using monosaccharides 9-11 as nucleo-
philes, the desired 2-keto-galactosyl disaccharides 16 r/ꢀ,
17 r/ꢀ, and 18 r/ꢀ were formed in 71-89% yield with
moderate to good ꢀ-selectivity under BF3·OEt2-catalyzed
conditions, in contrast to TMSOTf-catalyzed glycosylation
which gave good to high R-selectivity (Table 2, entries 1-6).
When serine and threonine derivatives 12 and 13 were
employed as glycosyl acceptors, 2-keto-galactosides 19 r/ꢀ,
and 20 r/ꢀ were afforded in 71-78% yield (Table 2, entries
7-10). In addition, coupling of the hindered secondary 3-OH
of cholesterol 14 with 5 under both conditions gave good to
excellent R- or ꢀ-selectivity respectively (Table 2, entries
resulted in only a trace amount of the desired disaccharide
8 and the reaction did not even occur in the presence of
AgOTf as a promoter (Table 1, entries 6-8).
Interestingly, we found that by replacing BF3·OEt2 with
the more reactive Lewis acid, TMSOTf, the glycosylation,
under otherwise similar conditions, exhibited modest R-se-
lectivity (Table 1, entry 9). Warming the reaction to near
room temperature resulted in the diastereoselectivity improv-
ing to R/ꢀ ) 7:1 and the same yield (Table 1, entry 10). It
is notable that during the course of monitoring the above
542
Org. Lett., Vol. 12, No. 3, 2010

11 and 12), while similar results were also obtained using
adamantanol 15 as an acceptor (Table 2, entries 13 and 14).
Overall, the above examples clearly demonstrate the ef-
fectiveness of BF3·OEt2-catalyzed ꢀ-selective glycosylation
and TMSOTf-catalyzed R-selective glycosylation.
our knowledge, these are the first examples of catalyst-
controlled stereoselective glycosylation of 1,2-cyclopropan-
ated sugar.
Scheme 4. Proposed Mechanism for the BF3·OEt2 and TMSOTf
Catalyzed Ring Opeing of 1,2-Cyclopropaneacetylated Sugar
On the basis of the above result, a plausible mechanism
for the BF3·OEt2-catalyzed ꢀ-selective glycosylation is
outlined in Scheme 4 (path a). Coordination of the oxygen
atom of acetyl with BF3·OEt2 followed by the C1-C1′ bond
cleavage produces the highly reactive ion pair 23, which then
reacts with nucleophile and mainly gives 1,2-cis R-glycoside
24, due to the anomeric effect. Alternatively, 23 might be
equilibrating to a more stable enol ether 25 thanks to
intramolecular neighboring group participation.20 Then Lewis
acid-induced nucleophilic attack by the glycosyl acceptor
from ꢀ face, similar to the glycosylation of enol ether-type
glycosides,21 would form the 1,2-trans ꢀ-glycoside 26.
For the TMSOTf-catalyzed R-selective glycosylation, we
presumed that the tight coordination of the oxygen atom of
carbonyl with TMSOTf, followed by breaking of the C1-C1′
bond, could produce oxocarbenium triflate intermediate 2722
with a 2-C-branched trimethylsilyl enol ether, which has no
neighboring group participation.23 Thus, nucleophilic attack
by an acceptor alcohol at the anomeric carbon atom would
afford R-glycoside 24 as the main product, favored by the
anomeric effect (Scheme 4, path b). The opposite stereose-
lectivity of the glycosylation under BF3·OEt2 and TMSOTf
results mainly from the nature of promoters. To the best of
In conclusion, we have demonstrated that 1,2-cyclopro-
panated galactosugar is a useful glycosyl donor, which
undergo BF3·OEt2 and TMSOTf-catalyzed glycosylation
reaction stereoselectively. The glycosylation favors ꢀ-ano-
meric products under BF3·OEt2 while TMSOTf-catalyzed
glycosylation prefers R-anomers. These novel glycoconju-
gates may serve as building blocks for more complex
glycomimics, and be useful substrates for enzymes.
(20) We considered that this kind of neighboring group participation
could also be defined as intramolecular rearragement.
(21) (a) Vankar, Y. D.; Vankar, P. S.; Behrendt, M.; Schmidt, R. R.
Tetrahedron 1991, 47, 9985–9992. (b) Marra, A.; Esnault, J.; Veyrieres,
A.; Sinay, P. J. Am. Chem. Soc. 1992, 114, 6354–6360. (c) Boons, G. J.;
Isles, S. Tetrahedron Lett. 1994, 35, 3593–3596. (d) Boons, G. J.; Isles, S.
J. Org. Chem. 1996, 61, 4262–4271.
Acknowledgment. We are grateful for the financial
support from the Chinese Academy of Sciences (Hundreds
of Talents Program) and the National Science Foundation
of China (20972151).
(22) Glycosyl triflates or the corresponding oxocarbenium triflates were
used as glycosyl donors. See: (a) Leroux, J.; Perlin, A. S. Carbohydr. Res.
1978, 67, 163–178. (b) Lacombe, J. M.; Pavia, A. A. J. Org. Chem. 1983,
48, 2557–2563. (c) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321–8348.
(23) We hypothesized that trimethylsilyl enol ether 27 could form
temporarily due to the fast coordination between oxygen atom of acetyl
and trimethylsilyl cation, and decompose after nucleophilic attack because
of the free proton. During this process, the trimethylsilyl enol ether 27 can
hardly contribute to the stabilization of the oxocarbenium triflate.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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