Glycosylation with 2′-thio-S-acetyl participation

Article abstract of DOI:10.1016/j.tetlet.2003.08.063

The reaction of 1,2,3,4,6-penta-O,S,O,O,O-acetyl-2-thio-β -D-glucopyranose with glycosyl acceptors in the presence of trimethylsilyl triflate leads to the β-disaccharides exclusively, owing to especially avid anchimeric assistance by the 2-thio-S-acetyl group. Optional reductive removal of -SAc with Ra-Ni gives the corresponding 2′-deoxy-β -disaccharides.

Full text of DOI:10.1016/j.tetlet.2003.08.063

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7601–7605
Glycosylation with 2%-thio-S-acetyl participation
Spencer Knapp* and Brian A. Kirk
Department of Chemistry & Chemical Biology, Rutgers–The State University of New Jersey, 610 Taylor Road, Piscataway,
NJ 08854-8087, USA
Received 10 July 2003; revised 13 August 2003; accepted 15 August 2003
Abstract—The reaction of 1,2,3,4,6-penta-O,S,O,O,O-acetyl-2-thio-b-D-glucopyranose with glycosyl acceptors in the presence of
trimethylsilyl triflate leads to the b-disaccharides exclusively, owing to especially avid anchimeric assistance by the 2-thio-S-acetyl
group. Optional reductive removal of ꢀSAc with Ra–Ni gives the corresponding 2%-deoxy-b-disaccharides.
©
2003 Elsevier Ltd. All rights reserved.
5
The stereochemistry of disaccharide formation can be
effectively controlled by a participating group located
Pure b-donor 2 was prepared efficiently in two steps
6
from 1,3,4,6-tetra-O-acetyl-b-
triflation at O-2, and then replacement of triflate by
reaction with potassium thioacetate (Scheme 1). Glyco-
D
-mannopyranose 1 by
1–3
7
near C-1 of the glycosylation donor.
For example,
8
2-O-acetyl-, 2-acetamido-2-deoxy-, and 2-deoxy-2-
phthalimido glucopyranosyl donors are commonly
observed to give b-disaccharide products by way of
presumed cyclized intermediates. Subsequent transfor-
mation of the participating group can give rise to
sylation of three acceptors was examined. The primary
9
alcohol 3 was selected because it gives a mixture of
a/b-disaccharides when steric and/or conformational
10,11
effects determine the donor stereoselectivity,
and thus
2
%-modified disaccharides, including 2%-amino, 2%-deoxy,
and others. We report some glycosylations with the new
-thio-S-acetyl glucopyranosyl donor 2, which evidently
might be used as an indicator of participation. The
12
secondary alcohol 4 is more hindered than 3, and reacts
1
3
2
very slowly with weak donor species. The commercially
available and commonly used galactose-derived acceptor
5 was tried because it would lead to the known 2%-deoxy
disaccharide 10 upon reductive removal of the participat-
ing group.
4
reacts by participation of the thioester carbonyl oxygen,
and provides 2%-thio-S-acetyl b-disaccharides that have
potential for further transformation to the corresponding
2%-deoxy, 2%-thio, and 2%-thio-S-substituted derivatives.
Scheme 1.
*
0
Corresponding author.
040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.063

7
602
S. Knapp, B. A. Kirk / Tetrahedron Letters 44 (2003) 7601–7605
Scheme 2.
Reaction of donor 2, as the limiting reagent, with the
acceptors 3–5 was carried out in dichloromethane solu-
tion with 0.5 equiv. of trimethylsilyl triflate as the
activator (Scheme 2). With all three acceptors, reac-
tion commenced at −78°C, but only proceeded about
halfway, according to TLC analysis. Raising the tem-
perature to −30°C led to complete consumption of the
donor 2. Efficient and highly stereoselective glycosyla-
tion of the acceptor took place in each case, affording
after chromatography the respective b-disaccharides 7–
trimethylsilyl triflate activator removes the C-1 acetoxy
by O-silylation at the low temperature to afford the
cyclized intermediate 6, which then kinetically glycosyl-
ates the acceptor at the same temperature. Triflic acid,
which forms as the result of partial glycosylation of the
hydroxyl-bearing acceptor, is then available to serve as
the (somewhat weaker) activator after trimethylsilyl
triflate is consumed, necessitating the increase in bath
temperature to about −30°C. Anomerization of the
1
4
10
donor is not observed. The glycosylation is complete
under conditions that are apparently milder than those
9
in the yields shown. The corresponding a-isomers
19
were not detected by NMR or TLC in the crude
reported for similar donors with 2-acetoxy (12) and
1
13
20
product mixture. Mass spectral and H and C NMR
analysis confirmed the structures, and the anomeric
stereochemistry is indicated by J for H-1%/H-2% (9.0, 9.0,
and 10 Hz, respectively).
2-acetamido-2-deoxy (13) participating substituents.
The reactivity of the three anomeric acetate donors 2,
12, and 13 (see structures below) toward trimethylsilyl
triflate was more directly compared under glycosylation
conditions similar to those used for the formation of
disaccharide 9. Treatment of 11 with 0.5 equiv. of
trimethylsilyl triflate and 1.3 equiv. of acceptor 5 at
−78°C for 0.5 h, and then −30°C for 3 h led to no
detectable disaccharide formation, as determined by
Two of the disaccharides were treated with excess
Raney nickel in ethanol solution at room temperature
to afford the corresponding 2%-deoxy b-disaccharides 10
and 11 in the yields shown. As expected, 11 proved to
1
5
be identical with the literature compound, according
1
1
to its H NMR spectrum at 500 MHz. The structure of
comparison of the H NMR spectrum of the crude
1
the triacetate/tribenzoate 10, whose H NMR spectrum
reaction mixture with the spectrum reported for the
21
closely resembles that of the corresponding disaccharide
authentic expected disaccharide. Furthermore, the
1
6
22
hexaacetate, was further corroborated by conversion
known coupled orthoester, which is isomeric with the
to the hexaacetate itself (NaOMe, MeOH; then Ac O,
disaccharide and might form under these conditions via
a cyclized intermediate, was also not detected (no 3H s
at 1.72 ppm ). Rather, the crude reaction mixture
2
pyridine, DMAP; 90% overall), and then comparison of
1
23
its H NMR spectrum with the reported values.
consisted primarily of unreacted, non-anomerized,
donor and acceptor, according to H NMR and TLC
analysis. Treatment of 13 with 2.0 equiv. of trimethyl-
1
7,18
1
The disarmed
donor 2 exhibits high stereoselectivity
and remarkable reactivity at −78°C. Presumably the

S. Knapp, B. A. Kirk / Tetrahedron Letters 44 (2003) 7601–7605
7603
silyl triflate at −78 and −30°C in the absence of accep-
tor led to no reaction, according to TLC analysis.
Further stirring for 1 h at 0°C likewise caused no
cyclization, and after aqueous bicarbonate quench the
starting donor 13 was recovered in high yield. Neither
formation of the known oxazoline nor amide C-
ionization at C-1 were the only consideration. In other
words, ꢀSAc should be the better participating neigh-
boring group (by Lewis basicity), but should ‘disarm’
the donor by induction to an extent similar to ꢀOAc.
The same argument can be used to rule out initial
3
1
formation of an intermediate anomeric triflate. Third,
the ꢀNHAc of 13 is known to cyclize in the presence of
trimethylsilyl triflate to form the stable and characteriz-
able oxazoline. The ꢀSAc of 2 ought to cyclize by an
analogous process, and other carbonyl-bearing donor
2
4
silylation was observed, although transient amide O-
2
5
silylation might have gone undetected.
What is the source of the reactivity of 2 as a glycosyl
donor? Compared with the 2-acetoxy substitutent of 12,
the 2-thio-S-acetyl substituent (ꢀSAc) of donor 2 has
greater electron density on the carbonyl oxygen, as
1
,2
32
2-substituents, including ꢀOCOPh and ꢀOCO -(p-
2
33
ClC H ), are thought to behave in comparable fash-
6
4
ion. Participation by the ꢀSAc sulfur atom to form an
2
6
evidenced by the expected bond length and infrared
S-acetyl-episulfonium intermediate is unlikely due its
2
7
34
stretching frequency of CꢁO. Donor 2 also possesses
poor Lewis basicity.
two considerably longer CꢀS single bonds compared
2
8
with CꢀO of 12. On the other hand, the inductive
2%-Deoxy-b-pyranoside substructures occur within the
oligosaccharide portion of a variety of natural prod-
ucts, and their stereoselective synthesis is of continuing
2
9
effects of ꢀSAc and ꢀOAc substituents are quite simi-
lar, according to their | values. Therefore, greater
I
2,10
electron density on the carbonyl oxygen and greater
CꢀS bond lengths relative to CꢀO may be cited as
possible factors contributing to the reactivity of 2. The
corresponding 2-acetamido donor 13, by contrast,
should benefit from its high amide carbonyl electron
density and lower ꢀNAc inductive effect, and yet is
relatively unreactive. This may be due to competing
interest.
glycosylated
resistant thio analogues of oligosaccharides, among
2%-Thiopyranosides have likewise been S-
35,36 37
and S-alkylated to make enzyme-
38
other applications. The use of 2-thio-S-acetyl as a
participating group in b-glycosylations potentially
expands the range of 2%-thio sugars and S-derivatives
that are easily accessible. Despite the availability of
many alternative b-directing donor 2-substituents, its
use may also offer some advantage in the stereoselective
synthesis of 2%-deoxy-b-disaccharides where, for exam-
ple, one can take advantage of its facile participation at
O-silylation at the NCꢁO6 , its most Lewis basic site,
which might be expected to slow O-cyclization, even in
the presence of 2 equiv. of trimethylsilyl triflate. The
3
0
shorter CꢀN single bond lengths of 13 relative to CꢀS
39
of 2 may also play a role.
low temperature.
Several lines of circumstantial evidence point to actual
participation at C-1 by the carbonyl oxygen of ꢀSAc.
First, the glycosylations of 2 are highly b-stereoselec-
tive, and in no case, including the reaction leading to 7,
could we detect the a-linked disaccharide. Some a-dis-
accharide might have been expected had the reaction
Acknowledgements
We are grateful to Merck & Co. and Vela Pharmaceuti-
cals Inc. for financial support. We thank Etzer Darout
for the control reaction of 13 with trimethylsilyl triflate,
and Professor Joseph A. Potenza for assistance with the
Cambridge Crystallographic Data Base search.
11
proceeded through an oxocarbenium intermediate.
Second, the rapid rate of reaction of the donor 2 at
78°C relative to the 2-O-acetyl version 11 suggests
−
that the cyclization rather than formation of an oxocar-
benium ion is rate-determining, as the respective oxo-
carbenium ions should form at comparable rates if
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6
1
1
1
17.5–118.5°C; H NMR [500 MHz, CDCl , l (multipl.,
3
1
J in Hz, integr.)] 5.79 (d, 9.5, 1H), 5.27 (dd, 9.0, 11.5,
vertently lists H-5% at 5.57 instead of 3.57 ppm.
1
2
1
H), 5.05 (t, 10, 1H), 4.28 (dd, 4.0, 12.5, 1H), 4.06 (dd,
.0, 12.5, 1H), 3.81 (ddd, 2.0, 4.0, 10.0, 1H), 3.69 (dd, 9.5,
1.5, 1H), 2.27 (s), 2.02 (s), 1.98 (s), 1.95 (s); C NMR
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1
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(
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1
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2
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1
531.
9. Activation of anomeric acetates such as 1,2,3,4,6-tetra-O-
-glucopyranose (12) with trimethylsilyl triflate
+
0.68 (2 C’s), 20.53, 20.48; LC–MS m/z 429.0 MNa .
1
1
Compound 7: colorless oil; H NMR 7.94 (d, 7.0, 2H),
acetyl-b-
D
7
7
6
5
4
3
3
1
1
6
2
.90 (d, 7.0, 2H), 7.82 (d, 7.5, 2H), 7.49 (app q, 7.5, 2H),
.39 (t, 7.5, 1H), 7.35 (app q, 7.5, 4H), 7.25 (t, 7.5, 2H),
.14 (t, 9.5, 1H), 5.48 (t, 10.0, 1H), 5.30 (dd, 11.5, 9, 1H),
.23–5.28 (m, 2H), 5.05 (t, 9.5, 1H), 4.73 (d, 9.0, 1H),
.26–4.30 (m, 2H), 4.05–4.11 (m, 2H), 3.71–3.76 (m, 2H),
.61 (dd, 9.0, 11, 1H), 3.50 (s, 3H), 2.36 (s, 3H), 2.04 (s,
typically takes place at room temperature. For example,
see: Rodriguez, E. B.; Stick, R. V. Aust. J. Chem. 1990,
4
3, 665–679.
0. For example, comparable formation of oxazolinium ion
from 2-acetamido-2-deoxy-1,3,4,6-tetra-O-acetyl-b-
2
D
-
glucopyranose (13) with trimethylsilyl triflate as the acti-
vator required 30 min at 50°C. See: Nakabayashi, S.;
Warren, C. D.; Jeanloz, R. W. Carbohydr. Res. 1986, 150,
C7–C10.
13
H), 2.03 (s, 3H), 2.02 (s, 3H); C NMR 133.03, 129.87,
29.77, 129.60, 129.22, 129.01, 128.91, 128.43, 128.37,
28.21, 101.15, 96.84, 71.94, 71.63, 71.03, 70.50, 69.48,
9.36, 68.62, 68.30, 62.00, 55.54, 48.39, 30.63, 20.63,
2
2
2
2
2
2
1. Kreuzer, M.; Thiem, J. Carbohydr. Res. 1986, 149, 347–
+
0.55; LC–MS m/z 875.0 MNa . Compound 8: colorless
1
3
61.
oil; H NMR 7.21–7.39 (m, 15H), 4.90–4.98 (m, 3H), 4.74
2. Banoub, J.; Boulanger, P.; Potier, M.; Descotes, G. Tet-
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3. Sznaidman, M. L.; Johnson, S. C.; Crasto, C.; Hecht, S.
M. J. Org. Chem. 1995, 60, 3942–3943.
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Lett. 1995, 36, 7395–7398.
5. Knapp, S.; Gibson, F. S.; Choe, Y. H. Tetrahedron Lett.
(
d, 11.5, 1H), 4.70 (d, 12.5, 1H), 4.69 (d, 12, 1H), 4.56 (d,
12, 1H), 4.55 (d, 3.5, 1H), 4.48 (d, 9.0, 1H), 4.39 (d, 12.0,
1H), 4.10 (dd, 4.5, 12, 1H), 3.91 (t, 10, 1H), 3.86 (dd, 12,
2.5, 1H), 3.80 (t, 9.5, 1H), 3.79 (dd, 11, 2.5, 1H), 3.62 (br
app t, 9.5, 2H), 3.44–3.49 (m, 2H), 3.34 (s, 3H), 3.26
(ddd, 2.5, 4.5, 13.0, 1H), 2.25 (s, 3H), 1.96 (s, 3H), 1.95
(s, 3H), 1.92 (s, 3H); C NMR 192.38, 170.66, 170.03,
169.46, 139.45, 138.26, 137.69, 128.64, 128.49, 128.29.
128.21, 128.18, 128.06, 128.03, 127.71, 127.32, 127.09,
99.34, 98.35, 80.03, 78.83, 75.91, 74.98, 73.43, 71.63,
13
1
990, 38, 5397–5400.
6. The bond lengths estimated for 2 are those of a carbohy-
drate thio-S-acetate, and are typical for this functional-

S. Knapp, B. A. Kirk / Tetrahedron Letters 44 (2003) 7601–7605
7605
7
2
1.27, 69.45, 69.34, 68.17, 61.87, 55.33, 48.82, 30.67, 20.62,
(m, 10H), 7.74–7.88 (m, 5H), 5.99 (t, 10.0, 1H), 5.50 (t, 10.0,
1H), 5.25 (dd, 4.0, 10.5, 1H), 5.16 (d, 4.0, 1H), 4.98 (ddd,
5.5, 7.5, 13.0, 1H), 4.80 (1H partially obscured by HOD),
4.55 (dd, 2.0, 9.5, 1H), 4.24 (ddd, 2.5, 5.5, 10.0, 1H), 4.16
(dd, 6.4, 11.5, 1H), 3.98 (dd, 2.5, 11.5, 2H), 3.70 (dd, 6.0,
11.5, 1H), 3.61 (ddd, 2.0, 5.0, 10, 1H), 3.45 (s, 3H), 2.26
(ddd, 2.0, 5.0, 12.0, 1H), 1.94 (s, 3H), 1.94 (s, 3H), 1.93 (s,
+
0.57, 20.53; LC–MS m/z 832.9 MNa . Compound 9:
1
colorless oil; H NMR 5.44 (d, 4.5, 1H), 5.20 (dd, 9.0, 11.5,
1H), 5.00 (t, 9, 1H), 4.69 (d, 10.0, 1H), 4.56 (dd, 1.5, 10.0,
1H), 4.23–4.28 (m, 2H), 4.15 (dd, 2.0, 5.0, 1H), 4.09 (dd,
2.0, 11.5, 1H), 3.96 (dd, 1.5, 11.5, 1H), 3.87–3.90 (m, 1H),
3.63–3.68 (m, 2H), 3.55 (dd, 9.0, 11.5, 1H), 2.29 (s, 3H),
2.04 (s, 3H), 1.96 (s, 6H), 1.48 (s, 3H), 1.39 (s, 3H), 1.28
13
3H), 1.57 (app q, 9.5, 1H); C NMR (CD OD) 171.23,
3
13
(s, 6H); C NMR 192.91, 170.63, 170.09, 169.47, 109.23,
170.57, 170.44, 166.12, 165.80, 165.59, 133.57, 133.50,
133.34, 129.59, 129.53, 129.34, 129.18, 129.14, 128.5,
128.41, 128.32, 100.23, 97.22, 71.98, 71.85, 70.99, 70.61,
69.71, 69.45, 68.90, 68.40, 62.42, 54.88, 35.88, 19.61, 19.48
1
6
2
08.56, 101.59, 96.14, 71.52, 71.24, 71.02, 70.56, 70.34,
9.51, 69.32, 67.69, 61.99, 48.35, 30.63, 26.02, 25.86, 24.99,
+
4.26, 20.70, 20.56, 20.54. LC–MS m/z 629.1 MNa .
1
+
Compound 10: colorless oil; H NMR (CD OD) 7.22–7.51
(2 C’s); LC–MS m/z 801.1 MNa .
3