A study of the donor properties of sialyl phosphites having an auxiliary 3-(S)-phenylseleno group

Article abstract of DOI:10.1016/S0008-6215(01)00029-5

Two phosphite sialyl donors, each having an auxiliary 3-(S)-phenylseleno group, were prepared and evaluated. The phenylseleno group was introduced via a new mode of generating phenylselenenic acid ('PhSeOH'). Although the sialyl donors provided fair yields (32-76%) of the desired sialosides in glycosylations of the reactive acceptor 1,2;3,4-di-O-isopropylidene-α-D-galactopyranose, no sialylated products could be obtained with less reactive acceptors. The presence of a 5-N-acetylacetamido group on the phosphite sialyl donor did not appear to improve its sialylating capability. The weak C-Se bond, possibly in combination with a steric hindrance, which disfavors α-nitrilium ion formation, seem to explain the unsuccessful sialylations of the less reactive acceptors.

Full text of DOI:10.1016/S0008-6215(01)00029-5

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Carbohydrate Research 331 (2001) 255–263
A study of the donor properties of sialyl phosphites
having an auxiliary 3-(S)-phenylseleno group
Teddy Ercegovic, Ulf J. Nilsson,* Go¨ran Magnusson†
Organic Chemistry 2, Chemical Center, The Lund Institute of Technology, Uni6ersity of Lund, PO Box 124,
S-221 00 Lund, Sweden
Received 2 October 2000; accepted 19 January 2001
Dedicated to the memory of Professor Go¨ran Magnusson
Abstract
Two phosphite sialyl donors, each having an auxiliary 3-(S)-phenylseleno group, were prepared and evaluated. The
phenylseleno group was introduced via a new mode of generating phenylselenenic acid (‘PhSeOH’). Although the
sialyl donors provided fair yields (32–76%) of the desired sialosides in glycosylations of the reactive acceptor
1,2;3,4-di-O-isopropylidene-a-D-galactopyranose, no sialylated products could be obtained with less reactive accep-
tors. The presence of a 5-N-acetylacetamido group on the phosphite sialyl donor did not appear to improve its
sialylating capability. The weak CꢀSe bond, possibly in combination with a steric hindrance, which disfavors
a-nitrilium ion formation, seem to explain the unsuccessful sialylations of the less reactive acceptors. © 2001 Elsevier
Science Ltd. All rights reserved.
Keywords: Sialic acid phosphites; Auxiliary phenylseleno group; Phenylselenenic acid; Long-range coupling
1. Introduction
forming a-sialylations.2 Since it is rather
difficult to accomplish an a-sialylation in high
yield, many researchers have addressed this
problem over the years. In short, donors for
a-sialylation seem to have evolved through
four main stages. The first was the optimiza-
Gangliosides are glycosphingolipids charac-
terized by the presence of sialic acid (N-acetyl-
neuraminic acid, Neu5Ac), which terminates
the saccharide chain via an a-glycosidic bond,
e.g., to a galactose or sialic acid residue.1 No
b-glycosides of sialic acid have been found in
nature. Due to the observed biological impor-
tance of gangliosides inter alia as tumor-asso-
ciated antigens and receptors for various
bacterial and viral pathogens, there is an on-
going demand for powerful methods of per-
* Corresponding author. Tel.: +46-46-2228218; fax: +46-
46-2228209.
E-mail address: ulf.nilsson@orgk2.lth.se (U.J. Nilsson).
† Deceased in June 2000.
Fig. 1. Some typical available sialyl donors.
0008-6215/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(01)00029-5

256
T. Ercego6ic et al. / Carbohydrate Research 331 (2001) 255–263
the removal of an auxiliary phenylthio group
can be rather difficult.9
2. Results and discussion
Preparation of the sialyl donor 9 (Scheme
1).—As starting material the readily available
glycal 610 was used, to which phenylselenenic
acid (‘PhSeOH’) was added via in situ genera-
tion by mixing phenylselenenyl chloride, water
and silver trifluoromethanesulfonate in tetra-
hydrofuran and keeping the reaction mixture
at 0 °C for 7 days. The desired exo adduct 7
was provided in 51% yield and easily sepa-
rated from its diastereomeric endo adduct 8
obtained in 35% yield. The original Sharpless
method of generating phenylselenenic acid in
a neutral equilibrium system by reacting
diphenyl diselenide with hydrogen peroxide11
gave a similar result, although here the addi-
tion reaction was very slow (weeks required at
room temperature). Our method of generating
phenylselenenic acid thus provides a higher
reaction rate than the original method, and it
may serve as an attractive alternative in other
systems. The method generates trifluoro-
methanesulfonic acid, so an obvious proviso is
that a potential substrate should not be too
acid sensitive (but vide infra).
Scheme 1. Synthesis of the sialyl donor 9. Reagents: (a)
PhSeCl, H2O, AgOTf, THF, 0 °C (51% 7 and 35% 8, respec-
tively). (b) ClP(OEt)2, EtN(i-Pr)2, CH3CN, 0 °C (88%).
tion of the anomeric leaving group, where
b-phosphites and a/b-thioglycosides (1 and 2,
respectively; Fig. 1) gave the most useful re-
sults.3 However, such sialyl donors are prone
to eliminate and form a glycal (6) when unre-
active acceptors are to be sialylated. They also
yield a/b product mixtures.4
The second stage was the introduction of an
auxiliary 3-(S)-substituent to suppress glycal
formation and improve the a/b selectivity.5 In
this respect, the phenylseleno, phenylthio and
thiobenzoyloxy groups gave the best results.6
Although giving fair to good a-sialylation
yields, only halosugars such as 3 were at first
equipped with such auxiliary substituents,
thereby providing some room for continued
development. The logical third stage was then
to combine the best anomeric leaving group
with the best auxiliary substituent, thereby
providing for example the further improved
sialyl donors 4 and 5.7 The fourth stage was
the recent discovery that transformation of the
5-acetamido group of sialyl donors to a 5-N-
acetylacetamido group improves sialylation
yields in general.8
We now report a study of the phosphite
sialyl donors 9 and 17 (Schemes 1 and 3,
respectively) each having an auxiliary 3-(S)-
phenylseleno group. These sialyl donors were
anticipated to have the following properties:
(i) convenient activation by use of a catalytic
amount of an acidic promoter;3a,b (ii)
stereospecific and high-yielding sialylation
also of unreactive acceptors; (iii) easy removal
of the phenylseleno group due to the weak
CꢀSe bond (243 kJ/mol) as compared with the
CꢀS and CꢀO bonds (272 and 336 kJ/mol,
respectively). Aspect (iii) was deemed to be of
considerable importance, particularly because
Direct treatment of the endo adduct 8 with
trifluoromethanesulfonic
acid
in
tetra-
hydrofuran led to partial epimerisation into
the exo adduct 7 (ꢀ25% yield) and formation
of numerous by-products, including the glycal
6. Studies by others have shown that highly
reactive electrophilic species, such as bromine
and (PhS)3SbCl6, prefer endo addition to sialic
acid glycals.5,7b In summary, these observa-
tions support our assumption that the ob-
tained 7/8 ratio is the result of a direct
addition of phenylselenenic acid and not of
any significant epimerisation. A weak buffer-
ing effect may thus be present in our system.
In contrast to the results reported for the
tetra-O-benzylated analogues 21 and 22,6b no
epimerization was observed under basic condi-
tions (DBU).
Treatment of the hemiketal 7 with diethyl
phosphorochloridite in the presence of N-
ethyldiisopropylamine in acetonitrile afforded

T. Ercego6ic et al. / Carbohydrate Research 331 (2001) 255–263
257
the a-phosphite sialyl donor 9 in 88% yield.
Unexpectedly, compound 9 was found to be
stable over several months if stored as an
amorphous powder under argon at −30 °C.
Acceptors used in the present study.—The
study of the sialyl donors 9 and 17 was per-
formed with the acceptors 10,12 1113 and 12,7d
each chosen for a particular reason (Fig. 2).
The diisopropylidenyl galactoside 10 was cho-
sen due to its high reactivity, which should
easily provide a sialylated product. The hex-
abenzyl lactoside 11 and the 9-O-benzylated
sialic acid glycal 12 were chosen due to their
low reactivity and consequent importance in
establishing the full potential of sialyl donors.
Indeed, the usefulness of any sialyl donor is
mainly governed by its ability to a-sialylate
unreactive acceptors. As a general rule, sialyl
donors having an auxiliary group should be
reserved only for cases where low yields of an
a-sialylated product are expected. Sialyl
donors such as 1 and 2 are acceptable in the
a-sialylation of reactive acceptors, such as 10,
whereas their a-sialylation yields are expected
to be impractically low (if any) for the accep-
tors 11 and 12.
either trimethylsilyl trifluoromethanesulfonate
or trifluoromethanesulfonic acid in acetonitrile
or dichloromethane at a temperature between
−40 and −78 °C.3b Hence, our first trial was
to treat the sialyl donor 9 with the galactoside
10 in acetonitrile at −40 °C in the presence
of a catalytic amount of trimethylsilyl tri-
fluoromethanesulfonate, which afforded the
desired b-sialoside 13 in 76% yield (Scheme 2).
The only by-product observed was the glycal
6. This result was promising, particularly in
view of the fact that a tetra-O-benzylated 2-
fluoro analogue of 9 afforded b-sialylated
product in 46% yield with the galactoside 10.6b
However, when the sialyl donor 9 was treated
with the more demanding acceptors 11 and 12
under exactly the same conditions, not even a
trace of b-sialylated product could be ob-
tained. The only products obtained were the
glycal 6, recovered pure acceptor and trace
amounts of trimethylsilyl-O-protected accep-
tor. In contrast to the expected result and
despite several modifications in line with the
optimum conditions referred to above, the
sialyl donor 9 was consistently unable to
provide any glycoside with the acceptors 11
and 12. As a comparison, the available sialyl
donor 4 having an auxiliary 3-(S)-phenylthio
group provided the b-sialylated product in
67% yield with the acceptor 11.7a In summary,
we therefore had to conclude that the sialyl
donor 9 lacks the ability to sialylate unreactive
acceptors.
E6aluation of the sialyl donor 9.—The opti-
mum conditions for activating sialyl phos-
phites are well established, and they normally
involve treatment with a catalytic amount of
The auxiliary phenylseleno group of 13 was
conveniently removed by treatment with
triphenyltin hydride–azoisobutyronitrile in
refluxing toluene for 1 h, thereby providing
the known a-sialoside 1414 in 92% yield
(Scheme 2). Removal of phenylthio groups
under these conditions normally requires
refluxing at least overnight, and a significant
amount of starting material is nevertheless
often recovered.9a,b At least the problem of
easy removal could thereby be well met by the
sialyl donor 9.
Fig. 2. Acceptors used in the evaluation of the sialyl donors 9
and 17.
Preparation of the sialyl donor 17 (Scheme
3).—In our attempts to synthesize an im-
proved analogue of 9, we observed that the
5-acetamido group of the hemiketal 7 could be
selectively acetylated before its anomeric hy-
droxyl group. Treating the hemiketal 7 with
Scheme 2. Evaluation of sialyl donor 9 with the acceptors
10–12. Reagents: (c) Me3SiOTf (cat.), MeCN, AW 300, −
40 °C (76%). (d) Ph3SnH, AlBN, C6H5CH3, reflux (92%). (e)
Me3SiOTf (cat.) or TfOH (cat.), MeCN or CH2Cl2 or
MeCN–CH2Cl2, AW 300 (if any), −78“ −40 °C.

258
T. Ercego6ic et al. / Carbohydrate Research 331 (2001) 255–263
forth above. This type of selective acetylation
may perhaps be observed in other 3-(S)-sub-
stituted Neu5Ac derivatives, but this remains
to be tested.
Treatment of the 5-N-acetylacetamido
hemiketal 15 with diethyl phosphorochloridite
in the presence of N-ethyldiisopropylamine in
acetonitrile then gave the corresponding a-
phosphite sialyl donor 17 in 85% yield. This
compound was very acid-sensitive and re-
quired the presence of a base, such as triethy-
lamine, during work-up in order not to
hydrolyze into the hemiketal 15.
Scheme 3. Synthesis of the 5-N-acetylacetamido sialyl donor
17. Reagents: (f) CH3(CH2ꢁ)COAc, TsOH·H2O, 65 °C (66%
15 and 19% 16, respectively). (g) ClP(OEt)2, EtN(i-Pr)2,
CH3CN, 22 °C then work-up in the presence of Et3N (85%).
E6aluation of the 5-N-acetylacetamido sialyl
donor 17.—When the sialyl donor 17 was
treated with the galactoside 10 under the same
conditions as those used for the sialyl donor 9,
the desired b-sialoside 18 was obtained in
1
about 50% yield. However, H NMR analysis
revealed that the product 18 was no more
than 80% pure and contaminated inter alia by
the corresponding 5-N-acetylacetamido glycal
20 (Scheme 4). Since we failed to obtain even
a trace of pure 18 by conventional chromatog-
raphy, the crude product 18 was subjected to
deacetylation by treatment with sodium
methoxide in dichloromethane–methanol,
whereby the deacetylated b-sialoside 19 could
be obtained pure in a total yield of 32%
(calculated from 17). In view of this result, it
was not surprising that compound 17 was
incapable of sialylating the acceptors 11 and
12 in the presence of trimethylsilyl trifluoro-
methanesulfonate in acetonitrile at −40 °C,
but instead provided only the glycal 20 and
recovered acceptor as main products. Clearly,
the 5-N-acetylacetamido group of 17 did not
confer any improved sialylating power as
compared with donor 9.
Scheme 4. Evaluation of the 5-N-acetylacetamido sialyl donor
17 with the acceptors 10–12. Reagents: (h) Me3SiOTf (cat.),
MeCN, −40 °C (ꢀ50% crude 18). (i) NaOMe, 1:1 MeOH–
CH2Cl2, 22 °C (32% from 17). (j) Me3SiOTf (cat.), MeCN,
AW 300 (if any), −40 °C. (k) CH3(CH2ꢁ)COAc, TsOH·H2O,
65 °C (90%).
isopropenyl acetate in the presence of a cata-
lytic amount of p-toluenesulfonic acid mono-
hydrate at 65 °C overnight thus gave the
desired 5-N-acetylacetamido hemiketal 15 in
66% yield, together with the peracetylated
1
analogue 16 in 19% yield. H NMR analysis
of an aliquot of the reaction mixture con-
firmed that the 15/16 ratio formed was 3:1.
We also noticed that it was necessary to keep
the concentrations of both the hemiketal 7
and the catalyst at a fairly low level (below
0.08 and 0.016 M, respectively) in order to
avoid uncontrollable formation of 16. Careful
attempts to selectively remove the anomeric
O-acetyl group of 16 under acidic conditions
(heating in 500:200:1 toluene–acetic acid–
water) were unsuccessful and primarily led to
N-deacetylation. We therefore concluded that
the anomeric (tertiary) hydroxyl group of 7 is
indeed very sterically hindered and quite unre-
active under the acetylating conditions set
We also prepared the 5-N-acetylacetamido
glycal 20 in 90% yield directly from the glycal
6 by treating the latter with isopropenyl ace-
tate under standard conditions (Scheme 4).
General obser6ations regarding the 3-(S)-
phenylseleno group.—The main reason for the
results above is probably the weak CꢀSe bond,
but we also believe that steric hindrance was
of some importance. The latter consideration
is supported by the unexpected long-range J
1
couplings of 1.0–1.9 Hz observed in the H
NMR analysis of the 3-(S)-phenylseleno com-

T. Ercego6ic et al. / Carbohydrate Research 331 (2001) 255–263
259
ity beyond what is expected purely on the
pounds 7, 9, 15 and 17 (Table 1). Such long-
range J couplings have been observed in other
carbohydrates,15 where they are considered in-
dicative of a so-called ‘W-conformation’, in
this case for the atom sequence H-3ꢀC-3ꢀC-
2ꢀOꢀR (R=H or P(OEt)2). We have found
no reports in the literature of such long-range
J couplings in other Neu5Ac hemiketals or
phosphites carrying a 3-(S)-bromine, iodine,
phenylthio (compound 22) or thiobenzoyloxy
(compound 5) substituent.5,6b,7d However, a
long-range J coupling of 1.5 Hz was reported
for the tetra-O-benzylated hemiketal 21, which
carries a 3-(S)-phenylseleno substituent.6b
These NMR results show that a 3-(S)-
phenylseleno group confers a fairly rigid ‘W-
conformation’ in Neu5Ac derivatives. The
rotation around the C-2ꢀOR bond thus ap-
pears to be restricted, probably due to steric
interference from the phenylseleno group. For
compound 15, this steric effect may explain
the selective N-acetylation of the 5-acetamido
group over the anomeric hydroxyl group. It
appears likely that the phenylseleno group
also sterically disfavors the formation of an
a-nitrilium ion in a nitrile solvent,17 and this
would in turn reduce the b-sialylating capabil-
basis of the weak CꢀSe bond.
3. Concluding remarks
In general, reactive acceptors tend to give
lower a/b ratios than less reactive acceptors
when sialylated with a donor lacking an auxil-
iary 3-(S) group.18 Hence, in the not too
uncommon situation where a reactive acceptor
yields an undesired a/b mixture, our donor 9
might provide an alternative due to its conve-
nient preparation, high b-stereoselectivity and
easy phenylseleno group removal.
4. Experimental
General methods.—NMR spectra were
recorded at 400 or 500 MHz. Assignment of
1H NMR spectra was achieved using 2D
methods (COSY, HETCOR). Optical rota-
tions were measured at 22 °C. Chemical shifts
are expressed in ppm using residual CHCl3,
C6HD5 or CHD2OD as reference. Reactions
were monitored by thin-layer chromatography
(TLC) using alumina plates coated with Silica
Gel 60 F254 (E. Merck) and visualized using
either UV light or by charring with H3PO4 (aq
5% dip solution). Preparative chromatography
was performed with Amicon silica gel (35–70
Table 1
NMR analysis of long-range J couplings in 3-(S)-SePh substi-
tuted Neu5Ac derivatives
,
mm, 60 A). Tetrahydrofuran (THF) was soni-
Compound JC-1,H-3 JH-3,OH JH-3,P Configuration b
cated and filtered through a column of Al2O3
(activity I, E. Merck) immediately before use.
Dichloromethane, toluene and EtN(i-Pr)2
(Hz) a
(Hz)
(Hz)
7
9
15
17
21
2.3 c 1.6 d
–
a
a
a
a
a
B1.0 e
–
1.1 e
–
,
,
were stored over 4 A molecular sieves (3 A for
MeCN) and filtered through a column of
Al2O3 as above. Compounds obtained as
white powders were precipitated with n-hex-
ane from a ꢀ1:2 chloroform–diethyl ether
solution. All reactions were carried out under
an Ar atmosphere. Anomeric configurations
of Neu5Ac residues were determined in accor-
dance with Ref. 16.
1.5 c 1.9 d
1.5 e
–
–
1.0 e
–
1.5 d
a Measured according to Ref. 16.
b Anomeric (non-carboxyl) substituent.
c In CD3OD.
d In CDCl3.
e In C6D6.
–: Inaccessible or not measured.
Methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-
3,5 - dideoxy - 3 - phenylseleno -
D
- erythro - h - -
L
gluco-2-nonulopyranosonate (7) and methyl
5 - acetamido - 4,7,8,9 - tetra - O - acetyl - 3,5-
dideoxy-3-phenylseleno-
D
-erythro-h-
L
a
-manno-
stirred,
2-nonulopyranosonate (8).—To
ice-cooled solution of methyl 5-acetamido-

260
T. Ercego6ic et al. / Carbohydrate Research 331 (2001) 255–263
4,7,8,9-tetra-O-acetyl-2,3,5-trideoxy-
ero- -galacto-non-2-enopyranosonate (6, 264
D
-glyc-
sonate (9).—To a stirred, ice-cooled solution
of compound 7 (145 mg, 0.224 mmol) in
MeCN (0.50 mL) was added EtN(i-Pr)2 (0.12
mL, 0.70 mmol) followed by dropwise addi-
tion of ClP(OEt)2 (0.070 mL, 0.49 mmol).
After 4 h, t-BuOH (0.035 mL) was added
dropwise under ice-cooling, after which the
reaction mixture was concentrated.
D
mg, 0.558 mmol) in THF (1.40 mL) was
added PhSeCl (192 mg, 1.11 mmol) immedi-
ately followed by water (22 mg, 1.22 mmol)
and AgOTf (257 mg, 1.12 mmol). The reac-
tion mixture was stirred vigorously for an
additional 5 min, and then kept dark at 2 °C.
After 7 days, Et3N (0.30 mL) was added under
ice-cooling, after which the reaction mixture
was filtered (Celite), washed with 1:1 toluene–
acetone (4×10 mL) and concentrated. The
residue was chromatographed (4:1“3:1 tolu-
ene–acetone, gradient) to give 7 (185 mg,
51%, pure a) and 8 (127 mg, 35%, a/bꢀ12:1),
both as white powders. Data for compound 7:
[h]D +28° (c 0.99, CHCl3). 1H NMR
(CD3OD): l 7.56–7.27 (m, 5 H, SePh), 5.41
(dd, 1 H, J4,5 10.2, J3,4 11.1 Hz, H-4), 5.37 (dd,
1 H, J6,7 2.4, J7,8 6.0 Hz, H-7), 5.12 (ddd, 1 H,
J8,9A 2.6, J8,9B 6.6 Hz, H-8), 4.41 (dd, 1 H,
J9A,9B 12.4 Hz, H-9A), 4.38 (dd, 1 H, J5,6 10.5
Hz, H-6), 4.03 (dd, 1 H, H-9B), 4.01 (bt, 1 H,
H-5), 3.79 (s, 3 H, CO2Me), 3.58 (d, 1 H,
H-3), 2.07, 2.05, 1.99, 1.80, 1.75 (s, 3 H each,
Ac); 13C NMR (CD3OD): l 172.2, 171.4,
170.8, 170.7, 170.6, 168.6 (JC-1,H-3 2.3 Hz, C-1),
133.5, 130.5, 129.2, 127.7, 97.8, 74.7, 70.9,
70.3, 68.3, 62.4, 52.6, 50.8, 50.3, 21.6, 19.8,
19.7, 19.6, 19.5. HR FAB-MS for
C26H33NNaO13Se [M+Na]: Calcd 670.1017.
Found 670.1031.
The residue was chromatographed (6:1 tolu-
ene–acetone) on a short column (B15 cm) to
give 9 (152 mg, 88%) as a white powder. [h]D
1
+22° (c 0.98, C6H6). H NMR (C6D6): l
7.44–6.83 (m, 5 H, SePh), 5.81 (dd, 1 H, J6,7
2.4, J7,8 3.7 Hz, H-7), 5.75 (t, 1 H, J 10.5 Hz,
H-4), 5.59 (m, 1 H, H-8), 5.04 (dd, 1 H, J8,9A
2.2, J9A,9B 12.4 Hz, H-9A), 4.84 (dd, 1 H, J5,6
10.7 Hz, H-6), 4.75 (q, 1 H, J 10.3 Hz, H-5),
4.60 (d, 1 H, J5,NH 10.2 Hz, NH), 4.38 (dd, 1
H, J8,9B 6.9 Hz, H-9B), 4.31–4.07 (m, 4 H,
2OCH2CH3), 4.00 (dd, 1 H, J3,4 10.9, J3,P 1.1
Hz, H-3), 3.32 (s, 3 H, CO2Me), 1.92, 1.88,
1.72, 1.55, 1.44 (s, 3 H each, Ac), 1.33 (t, 3 H,
J 7.1 Hz, OCH2CH3), 1.26 (t, 3 H, J 7.1 Hz,
13
OCH2CH3); C NMR (C6D6): l 170.8, 170.4,
170.3, 170.2, 169.6, 167.2 (JC-1,H-3 B1.0 Hz,
C-1), 133.8, 129.5, 128.7, 127.8, 101.6, 74.2,
73.7, 73.5, 68.6, 63.0, 59.9, 59.8, 58.8, 58.7,
53.1, 51.6, 51.0, 22.8, 21.2, 20.8, 20.6, 20.4,
17.4, 17.4, 17.2, 17.2. HR FAB-MS for
C30H42NNaO15PSe [M+Na]: Calcd 790.1354.
Found 790.1362.
1,2,3,4-Di-O-isopropylidene-6-O-[methyl [5-
acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-
Data for compound 8: [h]D −3.6° (c 1.00,
1
3-phenylseleno-
pyranosyl]onate]-h-
To a mixture of compound 9 (51.8 mg, 0.068
mmol), 1,2;3,4-di-O-isopropylidene-a- -galac-
D
-erythro-i-
L
-gluco-2-nonulo-
CHCl3). H NMR (CDCl3): l 7.87–7.22 (m, 5
D
-galactopyranose (13).—
H, SePh), 6.19 (d, 1 H, J5,NH 9.3 Hz, NH),
5.57 (dd, 1 H, J3,4 4.1, J4,5 10.3 Hz, H-4), 5.35
(dd, 1 H, J6,7 1.8, J7,8 3.0 Hz, H-7), 5.28 (ddd,
1 H, J8,9A 2.4, J8,9B 8.6 Hz, H-8), 4.95 (dd, 1
H, J9A,9B 12.4 Hz, H-9A), 4.44 (q, 1 H, H-5),
4.35 (dd, 1 H, J5,6 10.7 Hz, H-6), 4.17 (dd, 1
H, H-9B), 3.94 (d, 1 H, H-3), 3.82 (s, 3 H,
CO2Me), 2.24, 2.09, 2.03, 1.93, 1.69 (s, 3 H
D
topyranose (74.3 mg, 0.285 mmol) and acti-
vated AW300 molecular sieves (0.30 g) was
added MeCN (0.50 mL), and the mixture was
vigorously stirred at rt for 10 min. The tem-
perature was then lowered to −40 °C, and
Me3SiOTf (5.0 mL, 0.027 mmol) was added.
After 80 min Et3N (0.060 mL) was added,
after which time the reaction mixture was
filtered (Celite), washed with 1:1 CHCl3–ace-
tone (2×10 mL) and concentrated. The
residue was chromatographed (4:1 toluene–
acetone) to give 13 (46 mg, 76%) as a white
13
each, Ac); C NMR (CDCl3): l 172.8, 171.8,
171.0, 170.9, 170.8, 168.8, 134.4, 130.3, 129.5,
128.3, 98.1, 73.8, 72.3, 70.5, 69.5, 63.4, 53.1,
52.1, 47.4, 23.6, 21.6, 21.3, 21.2, 20.7. HR
FAB-MS for C26H33NNaO13Se [M+Na]:
Calcd 670.1017. Found 670.1034.
Methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-
3,5-dideoxy-2-O-(diethylphosphite)-3-phenyl-
1
powder. [h]D −16° (c 1.00, CHCl3). H NMR
(CDCl3): l 7.68–7.24 (m, 5 H, SePh), 5.54 (d,
seleno-
D
-erythro-h- -gluco-2-nonulopyrano-
L

T. Ercego6ic et al. / Carbohydrate Research 331 (2001) 255–263
261
1
1.00, CHCl3). H NMR (CDCl3): l 7.54–7.24
(m, 5 H, SePh), 5.92 (dd, 1 H, J3,4 10.7, J4,5
10.2 Hz, H-4), 5.31–5.26 (m, 2 H, H-6, H-8),
5.11 (dd, 1 H, J6,7 1.7, J7,8 8.1 Hz, H-7), 4.44
(d, 1 H, JOH,3 1.9 Hz, OH-2), 4.33 (t, 1 H, J5,6
10.2 Hz, H-5), 4.18 (dd, 1 H, J8,9A 2.5, J9A,9B
12.5 Hz, H-9A), 4.06 (dd, 1 H, J8,9B 6.0 Hz,
H-9B), 3.83 (5, 3 H, CO2Me), 3.69 (dd, 1 H,
H-3), 2.38, 2.28, 2.12, 2.09, 2.02, 1.76 (s, 3 H
1 H, J1,2 5.0 Hz, H-1), 5.38 (d, 1 H, J5%,NH 9.5
Hz, NH), 5.37–5.31 (m, 2 H, H-4%, H-8), 5.28
(dd, 1 H, J6,7 1.8, J7,8 7.6 Hz, H-7), 4.60 (dd, 1
H, J2,3 2.4, J3,4 7.9 Hz, H-3), 4.31 (dd, 1 H,
H-2), 4.27 (dd, 1 H, J8,9A 2.7, J9A,9B 12.5 Hz,
H-9A), 4.23 (dd, 1 H, J4,5 1.7 Hz, H-4), 4.20–
4.09 (m, 3 H, H-5%, H-6%, H-9B), 4.02 (dd, 1 H,
J5,6A 6.2, J6A,6B 9.0 Hz, H-6A), 3.96 (dt, 1 H,
H-5), 3.88 (dd, 1 H, J5,6B 5.6 Hz, H-6B), 3.85
(s, 3 H, CO2Me), 3.25 (d, 1 H, J3%,4% 11.4 Hz,
H-3%), 2.09, 2.09, 2.04, 2.02, 1.88, 1.51, 1.44,
1.36, 1.33 (s, 3 H each, Ac, C(CH3)2); 13C
NMR (CDCl3): l 171.2, 170.7, 170.4, 170.2,
169.8, 168.3 (JC-1%,H-3% 6.1 Hz, C-1), 134.9,
130.7, 129.2, 128.1, 109.4, 108.7, 101.3, 96.5,
73.5, 72.5, 71.1, 70.9, 70.8, 69.4, 67.5, 67.2,
63.8, 62.3, 52.7, 52.6, 50.3, 26.4, 26.2, 25.2,
24.9, 23.4, 21.1, 21.0, 20.9. HR FAB-MS for
C38H51NNaO18Se [M+Na]: Calcd 912.2169.
Found 912.2157.
13
each, Ac); C NMR (CDCl3): l 174.4, 173.7,
170.9, 170.4, 170.3, 169.9 (JC-1,H-3 1.5 Hz, C-1),
168.6, 133.8, 130.1, 129.3, 127.9, 97.2, 72.0,
69.0, 68.1, 67.4, 62.4, 57.7, 53.9, 50.2, 28.3,
26.6, 21.1, 21.1, 21.0, 20.6. HR FAB-MS for
C28H35NNaO14Se [M+Na]: Calcd 712.1120.
Found 712.1136.
Data for compound 16: [h]D +19° (c 1.0,
CHCl3). H NMR (CDCl3): l 7.56–7.27 (m, 5
1
H, SePh), 5.94 (dd, 1 H, J4,5 9.8, J3,4 10.7 Hz,
H-4), 5.18 (dd, 1 H, J6,7 1.9, J7,8 5.5 Hz, H-7),
5.00 (m, 2 H, H-6, H-8), 4.43 (dd, 1 H, J8,9A
2.6, J9A,9B 12.4 Hz, H-9A), 4.40 (t, 1 H, J5,6
1,2;3,4-Di-O-isopropylidene-6-O-[methyl-
[5 - acetamido - 4,7,8,9 - tetra - O - acetyl - 3,5-
dideoxy-
D
-glycero-h-
D
-galacto-2-nonulopyra-
10.0 Hz, H-5), 4.19 (dd, 1 H, J8,9 6.1 Hz,
B
nosyl]onate]-h-
D
-galactopyranose (14).—To a
H-9B), 3.71 (s, 3 H, CO2Me), 3.35 (d, 1 H,
H-3), 2.38, 2.32, 2.21, 2.13, 2.02, 2.01, 1.89 (s,
3 H each, Ac); 13C NMR (CDCl3): l 174.5,
174.1, 171.0, 170.8, 170.4, 170.3, 168.1, 165.2
(JC-1,H-3 1.5 Hz, C-1), 134.6, 129.6, 129.4,
128.5, 100.6, 71.7, 70.7, 70.1, 68.0, 61.9, 57.5,
53.5, 50.8, 28.5, 26.8, 21.4, 21.3, 21.3, 21.2,
20.9. HR FAB-MS for C30H37NNaO15Se
[M+Na]: Calcd 754.1225. Found 754.1230.
Methyl 4,7,8,9-tetra-O-acetyl-5-(N-acety-
stirred solution of compound 13 (45.1 mg,
0.051 mmol) in toluene (1.0 mL) was added
AlBN (12.5 mg, 0.076 mmol) and Ph3SnH
(0.13 mL, 0.51 mmol). After refluxing for 1 h,
the reaction mixture was allowed to reach rt
and then applied directly to a silica gel column
and chromatographed (30:1“10:1 CHCl3–
acetone, gradient) to give 14 (34.0 mg, 92%) as
1
a white powder. The H NMR data were in
agreement with those reported.14
lacetamido)-3,5-dideoxy-2-O-(diethyl
phite)-3-phenylseleno- -erythro-h-
phos-
Methyl 4,7,8,9-tetra-O-acetyl-5-(N-acety-
D
L
-gluco-2-
lacetamido) - 3,5 - dideoxy - 3 - phenylseleno -
erythro-h-
D
-
nonulopyranosonate (17).—To a stirred, ice-
cooled solution of compound 15 (38.7 mg,
0.056 mmol) in MeCN (0.80 mL) was added
EtN(i-Pr)2 (0.040 mL, 0.23 mmol) and then
ClP(OEt)2 (0.023 mL, 0.16 mmol) dropwise.
After 30 min the reaction mixture was allowed
to reach rt. After 2.5 h, t-BuOH (0.040 mL)
was added under ice-cooling, and the reaction
mixture was concentrated. The residue was
chromatographed (15:1:0.075 toluene–ace-
tone–Et3N) on a silica gel column, which had
been preconditioned with 200:1 toluene–Et3N,
to give 17 (38.6 mg, 85%) as a white powder.
L
-gluco-2-nonulopyranosonate (15)
and methyl 2,4,7,8,9-penta-O-acetyl-5-(N-
acetylacetamido)-3,5-dideoxy-3-phenylseleno-
D
- erythro - h - - gluco - 2 - nonulopyranosonate
L
(16).—To a stirred solution of compound 7
(50.5 mg, 0.078 mmol) in isopropenyl acetate
(1.0 mL) was added p-TsOH·H2O (3.0 mg,
0.016 mmol) and the reaction mixture was
then stirred at 65 °C. After 14 h Et3N (0.060
mL) was added and the reaction mixture was
concentrated in the presence of toluene. The
residue was chromatographed repeatedly (15:1
toluene–acetone) to give 15 (35.5 mg, 66%)
and 16 (10.9 mg, 19%), both as white pow-
ders. Data for compound 15: [h]D +64° (c
1
[h]D +46° (c 1.00, C6H6). H NMR (C6D6): l
7.47–6.82 (m, 5 H, SePh), 6.49 (t, 1 H, J4,5
10.5 Hz, H-4), 5.97 (dd, 1 H, J6,7 1.7, J5,6 10.2

262
T. Ercego6ic et al. / Carbohydrate Research 331 (2001) 255–263
26.3, 26.2, 25.3, 24.7, 21.2, 21.1, 20.9, 20.8. To
crude compound 18 (22 mg) dissolved in 1:1
CH2Cl2–MeOH (1.0 mL) was then added 1 M
NaOMe in MeOH (0.025 mL, 0.025 mmol) at
rt. After 1.5 h AcOH (0.040 mL) was added,
and the reaction mixture was concentrated.
The residue was chromatographed (10:1“5:1
CHCl3–EtOH, gradient) to give 19 (9.9 mg,
32% from 17) as a white powder. [h]D −75°
(c 0.50, CH3OH). 1H NMR (CD3OD): l
7.77–7.23 (m, 5 H, SePh), 5.46 (d, 1 H, J1,2 5.0
Hz, H-1), 4.58 (dd, 1 H, J2,3 2.5, J3,4 7.9 Hz,
H-3), 4.32 (dd, 1 H, H-2), 4.22 (dd, 1 H, J4,5
1.6 Hz, H-4), 4.05 (dd, 1 H, J3%,4% 10.5, J4%,5% 9.8
Hz, H-4%), 3.99–3.94 (m, 2 H, H-5, H-6A),
3.94 (dd, 1 H, J5%,6% 10.7 Hz, H-5%), 3.81 (s, 3 H,
CO2Me), 3.79 (dd, 1 H, J6%,7 1.4 Hz, H-6%),
3.79–3.71 (m, 3 H, H-6B, H-8, H-9A), 3.62
(dd, 1 H, J8,9B 5.1, J9A,9B 11.0 Hz, H-9B), 3.45
(dd, 1 H, J7,8 9.1 Hz, H-7), 3.08 (d, 1 H, H-3%),
1.99 (s, 3 H, NAc), 1.46, 1.37, 1.32 (3 s, 12 H,
2C(CH3)2); 13C NMR (CD3OD): l 174.9,
169.9, 135.9, 133.1, 130.1, 128.7, 110.5, 110.1,
102.7, 97.9, 74.1, 73.5, 72.6, 72.2, 72.1, 71.8,
70.4, 68.9, 65.2, 64.4, 57.9, 54.2, 52.9, 29.7,
26.7, 26.5, 25.4, 24.9, 22.8. HR FAB-MS for
C30H43NNaO14Se [M+Na]: Calcd 744.1746.
Found 744.1734.
Hz, H-6), 5.73 (dd, 1 H, J7,8 5.3 Hz, H-7), 5.65
(ddd, 1 H, J8,9A 2.5, J8,9B 6.0 Hz, H-8), 4.92 (t,
1 H, H-5), 4.84 (dd, 1 H, J9A,9B 12.5 Hz,
H-9A), 4.57 (m, 1 H, OCH2CH3), 4.43 (dd, 1
H, H-9B), 4.43 (m, 1 H, OCH2CH3), 4.22 (m,
2 H, OCH2CH3), 4.06 (dd, 1 H, J3,P 1.0, J3,4
10.6 Hz, H-3), 3.29 (s, 3 H, CO2Me), 2.07,
1.91, 1.89, 1.77, 1.68, 1.48 (s, 3 H each, Ac),
1.47 (t, 3 H, J 7.0 Hz, OCH2CH3), 1.26 (t, 3
13
H, J 7.0 Hz, OCH2CH3); C NMR (C6D6): l
174.2, 173.7, 170.8, 170.4, 170.4, 169.6, 167.7
(JC-1,H-3 1.5 Hz, C-1), 134.1, 130.9, 129.6,
128.9, 101.7, 72.6, 72.3, 71.1, 68.7, 62.5, 61.1,
60.9, 58.5, 58.3, 53.2, 53.0, 28.3, 26.7, 21.4,
20.9, 20.8, 20.4, 17.5, 17.5, 17.4, 17.4. HR
FAB-MS for C32H44NNaO16PSe [M+Na]:
Calcd 832.1461. Found 832.1441.
1,2;3,4 - Di - O - isopropylidene - 6 - O - [methyl
(4,7,8,9-tetra-O-acetyl-5-N-acetylacetamido-
3,5-dideoxy-3-phenylseleno-
D
-erythro - i-
L
-
gluco-2-nonulopyranosyl)onate]-h-
D
-galacto-
pyranose (18) and 1,2;3,4-di-O-isopropylidene-
6-O-[methyl
(5-acetamido-3,5-dideoxy-3-
-erythro-i- -gluco-2-nonulo-
-galactopyranose (19).—
phenylseleno-
D
L
pyranosyl)onate]-h-
D
To a stirred solution of compound 17 (34.9
mg, 0.043 mmol) and 1,2;3,4-di-O-isopropyli-
dene-a- -galactopyranose (21.5 mg, 0.083
D
mmol) in MeCN (0.40 mL) at −40 °C was
added Me3SiOTf (3.0 mL, 0.017 mmol). After
40 min t-BuOH (0.040 mL) and Et3N (0.060
mL) were added, and the reaction mixture was
concentrated. The residue was chro-
matographed (15:1“8:1 toluene–acetone,
gradient) to give crude 18 (22 mg, 50%) as a
Methyl 4,7,8,9-tetra-O-acetyl-5-(N-acetyl-
acetamido) - 2,3,5 - trideoxy -
D
- glycero -
D
-
galacto-non-2-enopyranosonate (20).—To a
stirred solution of methyl 5-acetamido-4,7,8,9-
tetra - O - acetyl - 2,3,5 - trideoxy -
D
- glycero - -
D
galacto-non-2-enopyranosonate (6, 89.7 mg,
0.189 mmol) in isopropenyl acetate (2.0 mL)
was added p-TsOH·H2O (1.8 mg, 0.010
mmol), and the reaction mixture was then
stirred at 65 °C. After 16 h, Et3N (0.10 mL)
was added and the reaction mixture was con-
centrated in the presence of toluene. The
residue was chromatographed (15:1 toluene–
acetone) to give 20 (88.1 mg, 90%) as a white
1
syrup. H NMR (CDCl3): l 7.73–7.24 (m, 5
H, SePh), 5.92 (t, 1 H, J3%,4%=J4%,5% 9.6 Hz,
H-4%), 5.55 (d, 1 H, J1,2 5.0 Hz, H-1), 5.31 (m,
1 H, H-8), 5.10 (dd, 1 H, J6%,7 1.7, J7,8 7.4 Hz,
H-7), 5.02 (dd, 1 H, J5%,6% 10.2 Hz, H-6%), 4.60
(dd, 1 H, J2,3 2.5, J3,4 7.8 Hz, H-3), 4.32 (dd, 1
H, H-2), 4.15 (dd, 1 H, J8,9B 5.3, J9A,9B 12.5
Hz, H-9B), 3.88 (s, 3 H, CO2Me), 3.25 (d, 1
H, H-3%), 2.38, 2.27 (s, 3 H each, Ac2N), 2.11,
2.08, 2.03, 1.96 (s, 3 H each, 4OAc), 1.49,
1.45, 1.35, 1.33 (s, 3 H each, 2C(CH3)2); 13C
NMR (CDCl3): l 174.6, 173.8, 170.7, 170.2,
170.1, 170.0, 167.4 (JC-1%,H-3% 5.9 Hz, C-1),
135.0, 131.3, 129.3, 128.1, 109.5, 108.8, 101.2,
96.6, 71.9, 71.4, 70.9, 70.8, 70.0, 69.3, 67.6,
67.4, 64.3, 61.9, 57.5, 53.8, 52.7, 28.2, 26.4,
1
powder. [h]D +51° (c 1.0, CHCl3). H NMR
(CDCl3): l 6.08 (dd, 1 H, J3,4 2.8, J4,5 9.3 Hz,
H-4), 5.94 (d, 1 H, H-3), 5.35 (ddd, 1 H, J7,8
6.1, J8,9A 2.9, J8,9B 6.3 Hz, H-8), 5.23 (dd, 1 H,
J6,7 1.7 Hz, H-7), 5.16 (dd, 1 H, J6,7 1.7, J5,6
10.1 Hz, H-6), 4.56 (t, 1 H, H-5), 4.53 (dd, 1
H, J9A,9B 12.5 Hz, H-9A), 4.18 (dd, 1 H,
H-9B), 3.81 (s, 3 H, CO2Me), 2.39 (bs, 6 H,

T. Ercego6ic et al. / Carbohydrate Research 331 (2001) 255–263
263
Schneider, R.; Schmidt, R. R. Tetrahedron Lett. 1997, 38,
6837–6840.
Ac2N), 2.11, 2.07, 2.05, 2.03 (s, 3 H each,
4OAc); 13C NMR (CDCl3): l 170.8, 170.6,
170.2, 170.0, 161.8, 146.6, 109.2, 76.5, 70.4,
68.0, 67.5, 62.1, 55.3, 52.8, 21.0, 21.0, 21.0,
20.9. HR FAB-MS for C22H29NNaO13 [M+
Na]: Calcd 538.1537. Found 538.1528.
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Acknowledgements
This work was supported by the Swedish
Natural Science Research Council.
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