Evaluation of thioglycosides of Kdo as glycosyl donors

Article abstract of DOI:10.1016/j.carres.2006.08.021

The use of Kdo thioglycosides as glycosyl donors using DMTST, IBr/AgOTf and NIS/AgOTf as promoters has been evaluated. Activation at low temperature allowed to escape the formation of 2,3-glycal byproducts to give glycosides in high yield and with good β-

Full text of DOI:10.1016/j.carres.2006.08.021

Carbohydrate Research 342 (2007) 631–637
Note
Evaluation of thioglycosides of Kdo as glycosyl donors
Karin Mannerstedt, Kerstin Ekelo¨f and Stefan Oscarson*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden
Received 17 July 2006; accepted 22 August 2006
Available online 9 October 2006
Dedicated to the memory of Professor Nikolay K. Kochetkov
Abstract—The use of Kdo thioglycosides as glycosyl donors using DMTST, IBr/AgOTf and NIS/AgOTf as promoters has been
evaluated. Activation at low temperature allowed to escape the formation of 2,3-glycal byproducts to give glycosides in high yield
and with good b-anomeric selectivity. The use of diethyl ether as solvent and (especially) isopropylidene acetals as protecting groups
improved the a-anomeric selectivity. NIS/AgOTf as promoter surprisingly yielded the 3-iodo-product via the glycal intermediate.
Ó 2006 Elsevier Ltd. All rights reserved.
Keywords: Thioglycoside donors; Kdo glycosides; Thiophilic promoters
3-Deoxy-D-manno-oct-2-ulosonic acid (Kdo) is a mono-
saccharide found in bacterial and plant polysaccharides.
It is an important component of the inner core part of the
lipopolysaccharide structure of Gram-negative bacteria,
where it is found as the a-anomer.1,2 In bacterial cap-
sular polysaccharides, it is found both as the a- and
the b-anomer. Glycosylations with Kdo-donors are
often hampered by the concomitant formation of the
a,b-unsaturated ester through an elimination reaction,3
and, due to the 3-deoxy function, stereochemical control
is a problem. So far, mainly halide donors (especially the
bromide) have been utilized in Kdo glycosylation reac-
tions.4 Surprisingly, there is only one earlier report on
the use of thioglycosides as Kdo glycosyl donors, then
with NIS/TfOH as promoter.5 In contrast, for sialyla-
tion reactions, plagued by the same problems due to
the structural similarities between Kdo and sialic acids,
thioglycosides have been used extensively,6 for example,
O-xanthates promoted by DMTST7 or phenylsulfenyl
triflate8 and alkyl or aryl thioglycosides promoted by
DMTST9 or IBr.10 Herein, we report our findings in
glycosylation with various Kdo thioglycoside donors
promoted with different promoter systems: DMTST,11
IBr/AgOTf10 and NIS/AgOTf.12
The thioglycoside 2 was prepared from the peracetyl-
ated Kdo methyl ester 113 by treatment with EtSH/
ZnCl2 (Scheme 1). The use of BF3-etherate as Lewis acid
is reported to give exclusively the b-glycoside,5 whereas
ZnCl2 gave an a/b-ratio of about 1:5, but the ratio is
quite dependent on the reaction conditions, elevated
temperature and prolonged reaction time giving not only
increased amount of the a-anomer but also a decreased
yield. The a/b-ratio can be changed to around 5:1 by
following anomerization with ZnCl2 in CH3NO2.14
From compound 2, the perbenzoylated analogue 4 as
well as the di-O-isopropylidene derivative 5 were synthe-
sized using known methodology. From 1, the corre-
sponding piperidine N-xanthate 7 was formed, via the
bromo sugar 6, according to the published procedure.15
The glycosylation reactions were performed with the
spacer alcohol 2-(4-trifluoroacetamidophenyl)ethanol (8)
as model acceptor and with different promoter systems,
DMTST, IBr/AgOTf and NIS/AgOTf (Scheme 2), and
the results are summarized in Table 1. To determine
the anomeric configuration of compounds 10 and 11,
which is not trivial since Kdo lacks an anomeric proton,
these derivatives were deprotected and acetylated,
whereafter the NMR spectra of the obtained compounds
were compared to the published spectra of 9a.16
The use of DMTST and the peracetylated donor 2
(a/b 1:5) in CH2Cl2 at ꢀ15 °C (entry 1) gave similar
*
Corresponding author. Tel.: +46 8 16 24 80; fax: +46 8 15 49 08;
e-mail: s.oscarson@organ.su.se
0008-6215/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2006.08.021

632
K. Mannerstedt et al. / Carbohydrate Research 342 (2007) 631–637
DMTST as promoter, experiments proved ꢀ15 °C once
OAc
O
OAc
O
AcO
AcO
AcO
AcO
more to be an optimal reaction temperature to avoid
elimination, while still keeping the glycosylation reac-
tion fast enough (entry 3). A high 84% yield of the
Kdo-glycoside was obtained, mainly as the b-anomer
(a/b 1:2.6). Again the use of diethyl ether as solvent
not only marginally improved the a/b-ratio (a/b 1:1.5)
but also lowered the yield due to competing elimination
reaction at the higher temperature needed (entry 4).
Excellent results considering both the yields and stere-
oselectivity for the a-anomer have been reported using
neuraminic thioglycoside donors in IBr/AgOTf pro-
moted glycosylations.10 Using this promoter system, it
is possible to activate thioglycosides at very low temper-
ature (ꢀ70 °C). This promoter was tried with the per-
benzoylated donor 4. To improve solubility at this low
temperature, a 3:2 MeCN–CH2Cl2 solvent system was
utilized. Glycosylation with donor 4 gave a one-spot
TLC reaction, from which 81% of the spacer glycoside
could be isolated (entry 5). The reaction proceeded with
excellent stereoselectivity, giving exclusively the b-glyco-
side as the product. Thus, as with neuraminic acid
donors, these coupling conditions preferentially yield the
product with an axial carboxyl group and an equatorial
aglycon (although the ring conformations are different:
vi
COOMe
N
COOMe
AcO
AcO
S
7 (79%)
Br
6
S
v
OAc
O
AcO
AcO
COOMe
COOMe
AcO
1
OAc
i
OAc
OH
O
AcO
HO
HO
AcO
ii
O
COOMe
SEt
AcO
HO
SEt
3 (91%)
2 (85%)
iii
iv
OBz
BzO
BzO
O
O
O
O
COOMe
SEt
O
BzO
COOMe
SEt
O
4 (97%)
5 (93%)
4
1C4 as compared to C1). Performing this reaction at
Scheme 1. Synthesis of the thioglycoside donors. Reagents and
conditions: (i) EtSH, ZnCl2, CH2Cl2; (ii) NaOMe, MeOH; (iii) BzCl,
Pyridine; (iv) dimethoxypropane, p-TSOH, DMF; (v) HBr/HOAc; (vi)
piperidine, NaH, CS2.
room temperature resulted in decreased stereocontrol
and increased elimination as expected (entry 6).
Obviously, in these glycosylation reactions, the
control of stereoselectivity is the major problem. To
improve the a-selectivity it has been proposed by Imoto
et al.19 to use isopropylidene acetal protected Kdo
donors. The 4,5-O-isopropylidene acetal force the ring
to change from a chair to a boat conformation opening
up the a-side for attack of an acceptor. In MeCN/
CH2Cl2, glycosylation with donor 5 gave even at
ꢀ70 °C, a considerable amount of the elimination prod-
uct (14, 26%) together with the spacer glycoside product
(11, 70%) but the a/b-ratio was much improved as
compared to the perbenzoylated donor (entry 7).
Surprisingly, the same yields were obtained at room
temperature, but now with a 2:1 a/b-ratio (entry 8).
With diethyl ether as solvent, the elimination reaction
was once again more or less completely suppressed at
low temperature. This also increased the a/b-ratio to
results as those reported with NIS/TfOH as promoter,5
that is, high yield of the spacer glycoside but with low
stereoselectivity and with a preponderance for the b-
anomer. Attempts to increase the amount of the a-
anomer by performing the coupling reaction in diethyl
ether17 required a higher temperature with concomitant
increase of elimination and other side products and
severe decrease in yield and only minor increase in the
a/b-ratio (entry 2).
In glycosylation reactions with neuraminic acid do-
nors, good results have been obtained using O-xanthate
donors at low temperature.7,8,18 We have earlier synthe-
sized anomeric piperidine N-xanthate derivatives of var-
ious hexoses and found that they functioned well as
glycosyl donors.15 With the Kdo N-xanthate 7 using
OR1
R1O
RO
OR
O
R1O
RO
RO
RO
RO
HO
O
O
O
R1O
COOMe +
+
COOMe
OSp
RO
RO
COOMe
N
H
CF3
SR2
2 R1 = Ac, R2 = Et
12 R = Ac
13 R = Bz
9 R = Ac
8 (= SpOH)
4 R1 = Bz, R2 = Et
10 R = Bz
14 R,R = C(CH3)2
11 R,R = C(CH3)2
5 R1,R1 = C(CH3)2, R2 = Et
7 R1 = Ac, R2 = C(S)piperidine
Scheme 2. Glycosylation reactions performed, for conditions, see Table 1.

K. Mannerstedt et al. / Carbohydrate Research 342 (2007) 631–637
633
Table 1.
Entry
Donor
Promoter
Temp (°C)
Solvent
Yield (%)
Product/a:b ratio
Elimination (%)
1
2
3
4
5
6
7
8
9
2
2
7
7
4
4
5
5
5
5
5
2
DMTST
DMTST
DMTST
DMTST
IBr/AgOTf
IBr/AgOTf
IBr/AgOTf
IBr/AgOTf
IBr/AgOTf
IBr/AgOTf
IBr/AgOTf
NIS/AgOTf
ꢀ15
CH2Cl2
Et2O
CH2Cl2
Et2O
3:2 MeCN–CH2Cl2
3:2 MeCN–CH2Cl2
3:2 MeCN–CH2Cl2
3:2 MeCN–CH2Cl2
Et2O
81
29
84
51
81
34
70
70
60
32
78
54
9/1:3
9/1:2
—
15 (12)
—
24 (12)
—
44 (13)
26 (14)
26 (14)
—
0
ꢀ15
0
9/1:2.6
9/1:1.5
10/0:1
10/1:2
11/1:1
11/2:1
11/3:1
11/3.5:1
11/3:1
15/1:0
ꢀ70
rt
ꢀ70
rt
ꢀ70
10
11
12
rt
Et2O
Et2O
CH2Cl2
56 (14)
—
45 (12)
ꢀ30
ꢀ30
Since the mixture of anomers was not separable, the a/b-ratio was determined by integration of the equatorial H-3 in the 1H NMR spectra.
3:1, but slowed down the reaction to yield 60% of product
11 together with still unreacted starting material (entry
9). At room temperature the effect on the a/b-ratio
was small, and elimination was the major reaction (entry
10). With the encouraging results obtained with donor 5
in Et2O at ꢀ70 °C, we reasoned that the amount of
starting material left was due mainly to solubility prob-
lems and, thus, tried the reaction at ꢀ30 °C. Elimination
was still avoided and the a/b-ratio was the same, but the
yield of spacer glycoside was improved to 78% (entry 11).
The use of NIS/AgOTf as promoter together with do-
nor 2 gave results (Scheme 3, entry 12), which were quite
different from those of van Boom et al. using NIS/
TfOH.5 TLC-monitoring of the reaction showed that
at first (after 1 h) the only product formed in almost
quantitative yield was the elimination product 12. If
the reaction was allowed to continue, a new product
increasingly started to appear. When no more of this
new product was formed (18 h), the reaction was
worked up and the new product was identified as the
3-iodo a-linked spacer glycoside 15 (54%). This was
unexpected, since normally the double bond in 12 is
resistant to the commonly used iodonium electrophiles
due to the stabilization by the ester function. We tried
NIS, NIS/AgOTf, iodonium dicollidinium perchlorate
(IDCP) and the corresponding triflate (IDCT) to acti-
vate the glycal 1220 in the presence of the spacer alcohol
to obtain 15, but found, as Brenken21 also reports, no
addition to the double bond. In the above reaction,
however, some iodonium species obviously form
in situ, which is active enough to activate the double
bond. Interestingly, activation of 12 with NIS/TfOH
was found to work and gave 15 in 53% (Scheme 4).22
AcO
AcO
AcO
OAc
O
AcO
AcO
8, NIS
TfOH (4 eq)
R
O
COOMe
OSp
AcO
COOMe
Ph3SnH
AIBN
AcO
15 R = I (53%)
12
9αR = H (86%)
Scheme 4. Activation of the Kdo glycal with NIS/TfOH.
However, in contrast to glycosylation reactions with
thioglycoside donors, where only a catalytic amount of
TfOH is used, the glycal activation required excess of
TfOH (4 equiv). Very recently, Tanaka et al. published
similar findings.23 They used the more activated
4,5,7,8-tetra-O-benzylated Kdo glycal derivative, but
still stoichiometric amounts of TfOH were needed to af-
ford 3-iodo-a-Kdo glycosides in high yields. The iodo
function in 15 could efficiently be reduced by triphenyl-
tin hydride to give 9a in 86% yield.
In conclusion, Kdo thioglycosides are good glycosyl
donors. The competing elimination reaction can effi-
ciently be suppressed by using low temperature in com-
bination with most promoters and solvents. Good to
excellent b-selectivity is obtained with peracylated
donors. To achieve high stereoselectivity for the often
desired a-linkage is a more difficult problem. Diethyl
ether as solvent and/or higher temperature only slightly
increase a/b-ratio and the latter cause severe elimination
to occur, but isopropylidene protecting groups consider-
ably increase the amount of a-anomer. The use of donor
5 promoted by IBr/AgOTf in diethyl ether at low tem-
perature (entry 11) shows promising results, especially
since it can be expected that more hindered saccharide
acceptors will improve the a-selectivity even more.
AcO
OAc
AcO
AcO
8, NIS
AcO
1. Experimental
1.1. General
AcO
AgOTf
I
12
+
O
O
COOMe
COOMe
AcO
AcO
OSp
15
SEt
2
Organic solvents were dried over MgSO4 before concen-
tration, which was performed under diminished pressure
Scheme 3. Glycosylation with NIS/AgOTf as promoter.

634
K. Mannerstedt et al. / Carbohydrate Research 342 (2007) 631–637
at <40 °C (bath temperature). TLC was carried out on
E. Merck precoated 60 F254 plates with detection by
UV-light and/or 8% sulfuric acid. Column chromato-
graphy was performed on silica gel (0.040–0.063 mm,
Amicom). NMR spectra were recorded in CDCl3 at
25 °C on a Varian 300 or 400 MHz instrument. MALDI-
TOF spectra were recorded on a Bruker Biflex III instru-
ment using 20,40,60-trihydroxyacetophenone trihydrate
(THAP) as matrix.
33.2 (C-3), 53.1 (OCH3), 63.3, 65.0, 68.2, 68.7, 73.0 (C-4,
5, 6, 7, 8), 84.6 (C-2), 128.3–133.7 (aromatic C), 165.2,
165.4, 165.5, 166.2, 169.1 (C-1, C@OBz). Anal. Calcd
for C39H36O11S: C, 65.72; H, 5.09. Found: C, 65.08;
H, 5.08.
1.5. Methyl (ethyl 4,5;7,8-di-O-isopropylidene-3-deoxy-2-
thio-D-manno-oct-2-ulopyranosid)onate (5)
Dimethoxypropane (88 lL, 0.72 mmol) and p-TsOH
(cat.) were added to a stirred solution of 3 (53 mg,
0.18 mmol) in DMF. After 2 h, the reaction mixture
was quenched by addition of Et3N, concentrated and
purified by silica gel chromatography (5:1 toluene–
EtOAc) to give 5 (59 mg, 0.16 mmol, 93%); 13C NMR
(a-anomer) d 14.4 (SCH2CH3), 22.7, 25.2, 25.3, 25.7,
27.1 (SCH2CH3, C(CH3)2), 32.8 (C-3), 52.7 (OCH3),
67.4, 70.5, 71.8, 72.6, 73.5 (C-4, 5, 6, 7, 8), 88.6 (C-2),
109.6, 109.9 (C(CH3)2), 170.5 (C-1); (b-anomer) d 14.6
(SCH2CH3), 23.7, 25.4, 26.1, 27.1, 27.6 (SCH2CH3,
C(CH3)2), 34.6 (C-3), 52.7 (OCH3), 67.2, 70.3, 70.8,
73.9, 74.7 (C-4, 5, 6, 7, 8), 82.8 (C-2), 109.5, 109.8
(C(CH3)2), 170.1 (C-1). Anal. Calcd for C17H28O7S: C,
54.24; H, 7.50. Found: C, 53.63; H, 7.59.
1.2. Methyl (ethyl 4,5,7,8-tetra-O-acetyl-3-deoxy-2-thio-
D-manno-oct-2-ulopyranosid)onate (2)
Zinc chloride (1.3 g, 9.5 mmol) was added at 0 °C to a
stirred solution of 113 (2.7 g, 5.8 mmol) and ethanethiol
(0.87 mL, 12 mmol) in CH2Cl2 (25 mL). After 18 h, the
solution was diluted with CH2Cl2, washed with water
and satd aq NaHCO3, filtered and evaporated. The res-
idue was purified by silica gel chromatography (4:1 light
petroleum bp 40–60 °C–EtOAc) to give 2 (2.3 g,
8.1 mmol, 85%) as an a/b-mixture 1:5; [a]D +49 (c 1.5,
CHCl3); NMR data: a-anomer: 13C, d 13.7 (SCH2CH3),
20.5, 20.6 (CH3CO), 22.3 (SCH2CH3), 31.5 (C-3), 52.6
(OCH3), 61.7, 64.2, 66.8, 67.4, 68.2, (C-4, 5, 6, 7, 8),
84.6 (C-2), 168.4–170.5 (C-1, C@OAc); b-anomer: 13C,
d
14.0 (SCH2CH3), 20.5, 20.6 (CH3CO), 23.2
1.6. Methyl (4,5,7,8-tetra-O-acetyl-3-deoxy-2-D-manno-
oct-2-ulopyranosyl bromide)onate (6)3
(SCH2CH3), 32.3 (C-3), 52.6 (OCH3), 62.1, 63.8, 67.0,
67.6, 71.7 (C-4, 5, 6, 7, 8), 83.9 (C-2), 168.4, 169.5,
169.6, 170.3, 170.5 (C-1, C@OAc). Anal. Calcd for
C19H28O11S: C, 49.13; H, 6.08. Found: C, 49.55; H,
5.99.
Compound 1 (200 mg, 0.43 mmol) was dissolved in a
saturated solution of hydrogen bromide in glacial acetic
acid (10 mL). After stirring for 30 min, the solution was
diluted with toluene, concentrated and coevaporated
three times with dry toluene. The glycosyl bromide 6
was used without further purification. 13C NMR: d
20.4, 20.5, 20.6, (CH3CO), 36.6 (C-3), 53.6 (OCH3),
61.9, 63.5, 66.6, 67.1, 72.8, (C-4, 5, 6, 7, 8), 92.6 (C-2),
165.9 (C-1), 169.4, 169.6, 169.9, 170.5 (C@OAc).
1.3. Methyl (ethyl 3-deoxy-2-thio-D-manno-oct-2-ulo-
pyranosid)onate (3)
Compound 2 (65 mg, 0.14 mmol) was dissolved in
MeOH (3 mL) and the pH was adjusted to 11 by treat-
ment with 1 M NaOMe (in MeOH). The mixture was
stirred for 2 h, neutralized with Dowex 50 (H+) ion
exchange resin, filtered and concentrated. Purification
by silica gel chromatography (10:1 CH2Cl2–MeOH)
gave 3 (38 mg, 0.13 mmol, 91%); 13C NMR (a-anomer)
d 14.2 (SCH2CH3), 23.3 (SCH2CH3), 35.6 (C-3), 53.1
(OCH3), 64.4, 65.8, 67.3, 69.5, 76.5 (C-4, 5, 6, 7, 8),
84.0 (C-2), 170.7 (C-1).
1.7. Methyl [(4,5,7,8-tetra-O-acetyl-3-deoxy-D-manno-
oct-2-ulopyranosyl) 2-piperidinecarbodithioate]onate (7)
Piperidine (43 lL, 0.43 mmol) was added at 0 °C to a
stirred mixture of NaH (60%, 16 mg, 0.39 mmol) in
DMF (2 mL). After 10 min, CS2 (31 lL, 0.51 mmol)
was added and the mixture was stirred for another
30 min. The temperature was decreased to ꢀ25 °C and
a solution of 6 (200 mg, 0.41 mmol) in DMF (10 mL)
was added dropwise. After 1 h, the mixture was poured
onto ice and the organic phase was separated, dried and
concentrated. The residue was purified by silica gel chro-
matography (6:1 toluene–EtOAc) to give 7 (185 mg,
0.34 mmol, 79%); 13C NMR (a-anomer): d 20.6, 20.7
(CH3CO), 24.0, 25.6 (piperidine), 32.2 (C-3), 52.5
(CH2N piperidine), 53.3 (OCH3), 62.7, 64.2, 66.6, 67.9,
72.4 (C-4, 5, 6, 7, 8), 88.8 (C-2), 169.5, 169.6, 169.7,
170.3, 170.5 (C-1, C@OAc), 188.2 (CS2). Anal. Calcd
1.4. Methyl (ethyl 4,5,7,8-tetra-O-benzoyl-3-deoxy-2-
thio-D-manno-oct-2-ulopyranosid)onate (4)
Benzoyl chloride (59 lL, 0.51 mmol) was added to a stir-
red solution of 3 (15 mg, 0.051 mmol) in pyridine. The
reaction mixture was stirred at room temperature over-
night, quenched by addition of MeOH and concen-
trated. Purification by silica gel chromatography (10:1
toluene–EtOAc) gave 4 (35 mg, 0.049 mmol, 97%); 13C
NMR (b-anomer) d 14.4 (SCH2CH3), 23.7 (SCH2CH3),

K. Mannerstedt et al. / Carbohydrate Research 342 (2007) 631–637
635
for C23H33O11NS2: C, 49.01; H, 5.90; N, 2.48. Found: C,
48.94; H, 5.78; N, 2.38.
(aromatic C), 168.3, 169.9, 170.0, 170.5, 170.9 (C-1,
C@OAc); H NMR: d 1.95–2.13 (m, 1H, H-3a), 2.32
1
(dd, 1H, H-3e), 4.12 (dd, 1H, H-6), 4.25 (d, 2H, H-8,
80), 4.86 (ddd, 1H, H-4), 5.00 (dt, 1H, H-7), 5.26 (m,
1H, H-5).
1.8. Glycosylation with DMTST as promoter
1.8.1. Thioglycoside 2 as donor. DMTST (209 mg,
0.81 mmol) was added at ꢀ15 °C to a solution of 2
(94 mg, 0.20 mmol) and 2-(4-trifluoroacetamidophe-
nyl)ethanol (8, 60 mg, 0.30 mmol) in CH2Cl2 (5 mL)
1.10. Glycosylations with IBr/AgOTf as promoter
1.10.1. General procedure. AgOTf (3.0 equiv) in
MeCN (3.0 mL) was added to a stirred solution of 4
or 5 (1.0 equiv), 2-(4-trifluoroacetamidophenyl)ethanol
˚
containing molecular sieves (4 A). The mixture was
stirred at ꢀ15 °C for 4 h and then left to attain room
temperature. After 2 h, Et3N (1 mL) was added and
the stirring was continued for 20 min. The mixture was
filtered, concentrated and the residue was purified by
silica gel chromatography (4:1 toluene–EtOAc) to give
a mixture of 9a and 9b (1:3, 105 mg, 82%).
Following the same procedure as above, but starting
at 0 °C instead of ꢀ15 °C and using diethyl ether as
solvent instead of CH2Cl2 gave a mixture of 9a and 9b
(1:2, 29%) and elimination product 12 (15%).
˚
(8, 1.5 equiv) and 3 A molecular sieves in CH2Cl2
(2.0 mL). The solution was cooled to ꢀ70 °C and IBr
(1 M in CH2Cl2, 2.0 equiv) was added dropwise. The
reaction mixture was stirred at ꢀ70 °C and after 2 h
Et3N (10 equiv) was added, followed by stirring for
another 20 min before filtration and concentration.
1.10.2. Methyl [2-(4-trifluoroacetamidophenyl)ethyl 4,5,
7,8-tetra-O-benzoyl-3-deoxy-D-manno-oct-2-ulopyranosid]-
onate (10) and methyl 4,5,7,8-tetra-O-benzoyl-2,6-anhydro-
3-deoxy-D-manno-oct-2-enonate (13). The compound
was prepared according to the general method, using
4 (100 mg, 0.140 mmol), 8 (50 mg, 0.21 mmol), AgOTf
(110 mg, 0.113 mmol), IBr (1 M in CH2Cl2 0.280 mL,
0.288 mmol) and Et3N (0.195 mL, 1.40 mmol). Purifica-
tion by silica gel chromatography (5:1 toluene–EtOAc)
gave 10b (100 mg, 0.113 mmol, 81%); [a]D ꢀ37 (c 1,
1.8.2. N-Xanthate 7 as donor. DMTST (185 mg,
0.72 mmol) was added at ꢀ15 °C to a solution of 7
(103 mg, 0.18 mmol) and 2-(4-trifluoroacetamidophe-
nyl)ethanol (8, 52 mg, 0.22 mmol) in CH2Cl2 (5 mL)
˚
containing molecular sieves (4 A). The mixture was left
to attain room temperature. After 2 h Et3N (1 mL)
was added and the stirring was continued for 20 min.
The mixture was filtered, concentrated and the residue
was purified by silica gel chromatography (4:1 tolu-
ene–EtOAc) to give a mixture of 9a and 9b (2:5,
98 mg, 0.15 mmol, 84%).
Following the same procedure as above, but starting
at 0 °C instead of ꢀ15 °C and using Et2O as solvent
instead of CH2Cl2 gave a mixture of 9a and 9b (2:3,
51%) and elimination product 12 (24%) was obtained.
1
CHCl3); NMR data (CDCl3): H, d 2.36 (m, 1H, J3a,4
12.9 Hz, H-3a), 2.62 (dd, 1H, J3e,3a 12.6 Hz, J3e,4
4.6 Hz, H-3e), 2.94, (t, 2H, ArCH2CH2O), 3.70 (s,
3H, OCH3), 3.82–3.74 (m, 1H, ArCH2CH2O), 4.13–
4.05 (m, 1H, ArCH2CH2O), 4.71–4.54 (m, 3H,
J8;8 12:4 Hz, J8 ;7 2:3 Hz, H-6, 8, 80), 5.35 (br d, 1H,
H-4), 5.45 (m, 1H, H-7), 5.79 (s, 1H, H-5), 8.24–7.16
(m, 24H, Ar–H); 13C, d 32.9 (C-3), 36.0 (ArCH2CH2O),
52.9 (OCH3), 63.4, 65.1, 65.5, 68.1, 68.9, 71.6 (C-4, 5, 6,
7, 8, ArCH2CH2O), 99.4 (C-2), 121.4, 128.3–133.5, 137.5
(aromatic C), 165.4, 165.4, 165.5, 166.3, 168.7 (C-1,
C@OBz). Anal. Calcd for C47H40F3NO13: C, 63.87; H,
4.56. Found: C, 63.68; H, 4.67.
0
0
1.9. Methyl [2-(4-trifluoroacetamidophenyl)ethyl 4,5,7,8-
tetra-O-acetyl-3-deoxy-D-manno-oct-2-ulopyranosid]-
onate (9a,b)
1.9.1. Compound 9a. NMR data were in agreement
with those already published:16 13C, d 20.5, 20.7, 20.7,
20.8, 20.9 (CH3CO), 32.0 (C-3), 35.3 (ArCH2CH2O),
52.8 (OCH3), 62.4, 64.2, 64.5, 66.4, 67.4, 68.4 (C-4, 5,
6, 7, 8, ArCH2CH2O), 98.7 (C-2), 113.7, 118.0 (CF3)
120.9, 129.8, 134.2, 136.5 (aromatic C), 154.7, 155.2
(amide C@O), 167.1, 169.8, 170.2, 170.6, 170.7 (C-1,
C@OAc); H NMR: d 1.96–2.10 (m, 1H, H-3a), 2.16
(dd, 1H, H-3e), 3.57 (dd, 1H, H-6), 4.00 (dd, 1H, H-
8), 4.51 (dd, 1H, H-80), 5.15–5.29 (m, 3H, H-4, 5, 7).
Following the same procedure using 4 (50 mg,
0.070 mmol),
2-(4-trifluoroacetamido-phenyl)ethanol
(7, 30 mg, 0.14 mmol), AgOTf (36 mg, 0.21 mmol), IBr
(1 M in CH2Cl2 0.11 mL, 0.11 mmol) and Et3N
(0.098 mL, 0.70 mmol), but stirring at room temperature
instead of ꢀ70 °C gave a mixture of 10 (a/b 1:2, 21 mg,
0.24 mmol, 34%) and elimination product 13 (20 mg,
1
1
0.031 mmol, 44%); [a]D ꢀ103 (c 1, CHCl3); H NMR:
d 3.86 (s, 3H, OCH3), 4.77 (m, 2H, J6,7 8.5 Hz,
0
J8,7 4.7 Hz, H-6, 8), 4.98 (dd, 1H, J8 ;7 2:7 Hz,
J8 ;8 12:4 Hz, H-80), 5.83 (m, 1H, H-7), 6.00 (m, 1H,
0
1.9.2. Compound 9b. (CDCl3): 13C, d 20.7, 20.8
(CH3CO), 32.3 (C-3), 35.7 (ArCH2CH2O), 52.7
(OCH3), 62.4, 64.0, 65.2, 67.1, 68.0, 70.6 (C-4, 5, 6, 7,
8, ArCH2CH2O), 99.3 (C-2), 120.8, 129.9, 133.6, 136.9
H-5), 6.14–6.13 (m, 3H, H-3, 4), 8.02–7.22 (m, 20H,
Ar–H); 13C, d 52.8 (OCH3), 61.9, 63.0, 65.8, 68.4, 74.5
(C-4, 5, 6, 7, 8), 108.2 (C-3), 120.8, 128.4–133.6 (aro-
matic C), 145.2 (C-2), 161.8, 165.2, 165.6, 165.7, 166.2

636
K. Mannerstedt et al. / Carbohydrate Research 342 (2007) 631–637
(C-1, C@OBz). Anal. Calcd for C37H30O11: C, 68.30; H,
4.65. Found: C, 68.12; H, 4.62.
63.1, 65.3, 66.0, 67.3, 68.2 (C-4, 5, 6, 7, 8, ArCH2-
CH2O), 101.8 (C-2), 113.9, 117.7 (CF3), 122.6–139.5
(aromatic C), 165.9, 169.4, 169.6, 170.2, 170.5 (C-1,
C@OAc).
Compound 10a: 13C NMR: d 32.8 (C-3), 35.5
(ArCH2CH2O), 52.9 (OCH3), 63.5, 64.8, 65.4, 67.5,
68.5, 69.6 (C-4, 5, 6, 7, 8, ArCH2CH2O), 99.1 (C-1),
121.0, 128.4–133.8, 137.0 (aromatic C), 165.2, 165.5,
165.5, 167.8, 168.7 (C-1, C@OBz).
1.11.2. NIS/TfOH (Glycal activation). TfOH (1.33 mL,
1.99 mmol) was added dropwise to a stirred solution of
methyl 4,5,7,8,-tetra-O-acetyl-2,6-anhydro-3-deoxy-D-
manno-oct-2-enonate20 (12, 200 mg, 0.497 mmol), 2-(4-
trifluoroacetamidophenyl)ethanol (8, 174 mg, 0.746
1.10.3. Methyl [2-(4-trifluoroacetamidophenyl)ethyl 3-
deoxy-4,5;7,8-di-O-isopropylidene-D-manno-oct-2-ulopyr-
anosid]onate (11). Compound 11 was prepared
according to the general method using 5 (175 mg,
0.465 mmol), 2-(4-trifluoroacetamidophenyl)ethanol (8,
169 mg, 0.725 mol), AgOTf (369 mg, 1.45 mmol), IBr
(1M in CH2Cl2 0.966 mL, 0.966 mmol), and triethyl-
amine (0.679 mL, 4.83 mmol) to give a mixture of 11
(a/b 2:1, 162 mg, 0.325 mmol, 70%) and elimination
product 1424 (38 mg, 0.121 mmol, 26%).
Following the same procedure using 5 (50 mg,
0.14 mmol), 8 (64 mg, 0.28 mmol), AgOTf (108 mg,
0.42 mmol), IBr (1M in CH2Cl2 0.21 mL, 0.21 mmol),
and triethylamine (0.2 mL, 1.4 mmol), but with Et2O
as solvent instead of MeCN/CH2Cl2 gave, after purifica-
tion by silica gel chromatography (10:1 toluene–EtOAc),
11 (a/b 3:1, 44 mg, 0.082 mmol, 60%). Compound 11a:
13C NMR: d 25.0, 25.3, 25.5, 26.9, (C(CH3)2), 32.9 (C-
3), 35.6 (ArCH2CH2O), 52.5 (OCH3), 63.7, 67.2, 70.0,
72.0, 72.1, 73.7 (C-4, 5, 6, 7, 8, ArCH2CH2O), 97.5 (C-
2), 109.3, 109.6 (C(CH3)2), 120.7–137.2 (aromatic C),
169.4 (C-1). Compound 11b: 13C NMR: d 25.1, 25.3,
26.6, 27.1 (C(CH3)2), 36.0 (C-3), 38.7 (ArCH2CH2O),
52.5 (OCH3), 63.5, 65.2, 70.1, 71.3, 73.7, 73.9 (C-4,
5, 6, 7, 8, ArCH2CH2O), 98.6 (C-2), 109.4, 109.5,
(C(CH3)2), 120.7–137.2 (aromatic C), 170.4 (C-1). Anal.
Calcd for C25H32F3NO9: C, 54.84; H, 5.89. Found: C,
54.62; H, 5.94.
˚
mmol), NIS (487 mg, 1.99 mmol) and 4 A molecular
sieves in CH2Cl2. The reaction mixture was stirred at
room temperature overnight. Et3N was added and the
reaction mixture was filtered and concentrated. Purifica-
tion by silica gel chromatography (5:1 toluene–EtOAc)
gave 15 (200 mg, 0.263 mmol, 53%).
AIBN (4.3 mg, 0.02 mmol) and Ph3SnH (37 mg,
0.10 mmol) were added to a solution of 15 (35 mg,
0.05 mmol) in toluene (10 mL). The solution was re-
fluxed for 1 h and then concentrated. The residue was
purified by silica gel chromatography (4:1 toluene–
EtOAc) to give 9a (25 mg, 86%).
Acknowledgements
We thank the Swedish Research Council for financial
support.
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