Synthesis of aryl sialosides using Mitsunobu conditions

Article abstract of DOI:10.1016/j.carres.2004.10.003

Mitsunobu conditions for the efficient synthesis of aryl α/β-sialosides were developed. An oxidative work-up procedure was employed to avoid a cumbersome chromatographic separation from the 2,3-dehydro derivative of sialic acid, which is formed as a side-product.

Full text of DOI:10.1016/j.carres.2004.10.003

Carbohydrate
RESEARCH
Carbohydrate Research 339 (2004) 2835–2840
Synthesis of aryl sialosides using Mitsunobu conditions
Ganpan Gao, Oliver Schwardt and Beat Ernst*
Institute of Molecular Pharmacy, Pharmacenter of the University of Basel, Klingelbergstrasse 50, CH-4056Basel, Switzerland
Received 20 September 2004; accepted 3 October 2004
Available online 28 October 2004
Abstract—Mitsunobu conditions for the efficient synthesis of aryl a/b-sialosides were developed. An oxidative work-up procedure
was employed to avoid a cumbersome chromatographic separation from the 2,3-dehydro derivative of sialic acid, which is formed as
a side-product.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Keywords: Mitsunobu conditions; Ketosugars; Glycal; Aryl sialosides, 1H and 13C NMR
1. Introduction
The Mitsunobu reaction7 has been widely used for the
synthesis of aryl glycosides,8–17 acyl glycosides,16–19 alkyl
glycosides,16,20,21 and amino glycosides16,22 by reacting
hemiacetals of aldosugars, predominantly glucose,
galactose, and mannose, with weakly acidic acceptors
in the presence of diethyl azodicarboxylate (DEAD)
and triphenylphosphine (Ph3P). A major advantage of
this direct dehydrative coupling procedure is that acti-
vated glycosyl donors do not need to be isolated and
all reaction steps—anomerization, activation, and gly-
cosidic bond formation—occur in a single series of
events.23 Due to the neutral conditions, the reaction is
compatible with a wide variety of sensitive functionali-
ties, ranging fromepoxides and spiroketals to any of
the commonly utilized protecting groups.12,24 The stereo-
chemical outcome depends on the anomeric ratio pre-
sent in the hemiacetal and its mutarotation occurring
under reaction conditions. Phenolic nucleophiles are
good acceptors for this glycosylation reaction with aldo-
sugars, leading to aryl glycosides.8,13,15
To our knowledge, Mitsunobu conditions have not
been used for the glycosylation with ketosugars such
as sialic acid, probably because their anomeric centers
were regarded as being too sterically hindered.25 How-
ever, since a limited number of successful noncarbohy-
drate cases have been reported, albeit with moderate
yields and stereoselectivities,26–28 we decided to apply
the Mitsunobu reaction to the synthesis of aryl
sialosides.
Aryl a-sialosides are often used as chromogenic sub-
strates for detecting and quantifying sialidase activ-
ity.1–3 Sialidases catalyze the hydrolytic cleavage of
a-glycosidically linked sialic acid fromglycoconjugates
that regulate cell-to-cell, cell-to-microorganism, -toxin,
and -antibody interactions.4,5 In addition, aryl sialo-
sides, such as p-nitrophenyl sialoside, have also found
use as synthetic substrates for sialidases.6
In contrast to aldoglycosides, only few methods for
the stereoselective synthesis of ketoglycosides, such as
aryl sialosides, exist.2 The most frequently used proce-
dure is a Williamson ether synthesis based on phenolates
and 2-halogeno derivatives of sialic acid.1,3 However,
the low solubility of sodiumphenolates drastically limits
the scope of this method. An alternative method utilizes
phase transfer conditions (chloroform–aqueous alkali)
for the sialidation of phenols with 2-chloro derivatives
of sialic acid.2 Both approaches result in complete inver-
sion of the anomeric configuration and give moderate to
good yields. However, side reactions caused by the basic
reaction conditions, for example, hydrolysis of protect-
ing groups or glycal formation by 2,3-elimination, are
inevitable.
*
Corresponding author. Tel.: +41 61 267 15 51; fax: +41 61 267 15 52;
e-mail: beat.ernst@unibas.ch
0008-6215/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2004.10.003

2836
G. Gao et al. / Carbohydrate Research 339 (2004) 2835–2840
2. Results and discussion
participating character in glycosylation reactions,34–36
no improvement of the stereoselectivity could be
detected (entry 3).
To further improve yield and stereoselectivity, other
reaction variables such as temperature, order of addi-
tion, and additives, were investigated.
Treatment of the glycosyl donor methyl (methyl 5-ace-
tamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-thio-D-gly-
cero-D-galacto-2-nonulopyranosid)onate with 4-phen-
oxy-phenol (2a) in the presence of NIS-TfOH29,30 as pro-
moter did not provide the corresponding aryl sialoside
3a. DMTST31 also gave unsatisfactory results, providing
3a in low yield and with poor stereoselectivity.
Smith et al.18 reported that the anomeric ratio in the
Mitsunobu acylation can be improved by starting the
reaction at ꢀ50ꢁC. However, these conditions led to a
marked decrease in yield and stereoselectivity (entry
4). Also at ꢀ25ꢁC (entry 5) or rt (entry 6) the yield of
sialoside 3a was reduced and the side product 4 was
favored instead.
According to Voyleꢀs report,14 the outcome of the
reaction can be influenced by the order of addition.
However, we were unable to observe an improvement
in yield or stereoselectivity when we allowed the
zwitterionic P–N adduct fromPh 3P and DEAD to form,
before adding the hemiketal and the nucleophile (entries
4 and 7).
Elimination is a common side reaction in Mitsunobu
reactions, especially when the emerging double bond is
conjugated.25 As a consequence, sialic acid poses a
significant challenge, and glycal 4 is formed under
various sialidation conditions. According to Wovkulich
et al.,38 the dehydration pathway in the Mitsunobu
Gratifyingly, standard Mitsunobu conditions32 [i.e.,
addition of DEAD to
a solution of hemiketal
1b,33 2a, and Ph3P in THF (Table 1, entry 1)] provided
an a/b-mixture of sialoside 3a in 43% yield. Glycal 4,
formed by 2,3-elimination, was isolated as a major
side product. In addition, N-sialyl-1,2-diethoxy-
carbonylhydrazine 5, identified by ESIMS [(m/z):
672.1 (M+Na)+], was obtained in small quantity.
Similar adducts of DEAD to aldosugars have been
reported before.21,22 Since the stereoselectivity at the
anomeric center in glycosylation reactions with donors
lacking a participating group is markedly influenced
by solvent effects, toluene and acetonitrile were
examined next. Whereas toluene (entry 2) gave
approximately the same results as THF, dramatically
improved yields of 75% were obtained in acetonitrile.
Surprisingly, although acetonitrile is known for its
Table 1. Exploration of variant reaction conditions for the sialidation under Mitsunobu conditions
OAc
OAc
O
OH
AcO
O
O
COOMe
+
AcHN
HO
AcO
2a
1β
O
OAc
OAc
OAc
OAc
OAc
COOMe
O
COOMe
OAc
AcO
AcO
AcO
COOMe
O
O
N
NHCOOEt
+
+
AcHN
AcHN
AcHN
COOEt
AcO
AcO
AcO
5
4
3a
Entrya
Solvent
Temp (ꢁC)
Time (h)
3a (a:b)b
3a:4:5c
1
THF
0
0
6
3
43% (62:38)
40% (60:40)
75% (64:36)
23% (55:45)
61% (57:43)
62% (63:37)
67% (60:40)
46% (51:49)
1:1:0.3
2
Toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
1:1.2:0.4
1:0.3:0.1
1:1.3:1
3
0
3
4d
5
ꢀ45
ꢀ25
rt
3
16
3
1:0.4:0.2
1:0.5:0.1
1:0.3:0.2
1:0.3:0.1
6
7e
8f
0
3
0
3
a
˚
Standard conditions: 1b (1.0equiv), 2a (2.0equiv), Ph3P (1.5equiv), DEAD (1.5equiv), molecular sieves 3A.
b Isolated yields of product mixture (a and b), ratios of isomers were determined by 1H NMR37a,b of the crude product prior to oxidative treatment
(vide infra).
c Ratios of 3a, 4, and 5 were determined according to 1H NMR of the crude products: [3a-H3e(a,b):4-H3(6.02ppm):5-H3e(a,b:2.55,2.44ppm)].
d To a solution of Ph3P in dry CH3CN at ꢀ45ꢁC, DEAD was added. The mixture was stirred for 10min, then 1b was added, and stirring continued
for 10 min before addition of 2. The mixture was allowed to warm slowly to rt over a period of 3h and kept at rt until TLC indicated complete
consumption of 1b.
e DEAD was dissolved in dry CH3CN, and Ph3P was added, after 5min 2a was added, then 1b.
f The same procedure as (entry 3), except 1.0equiv of pyridine was added to the reaction mixture.

G. Gao et al. / Carbohydrate Research 339 (2004) 2835–2840
2837
reaction can be minimized by performing the reaction in
the presence of 1.0equiv of pyridine. However, in our
hands, this additive not only reduced the yield of glycal
4, but also that of the desired product 3a (entry 8).
The often formed glycal side product is especially
aggravating, since it is usually difficult to separate from
the desired product.39,40 One approach to avoid the sep-
aration problem is the chemical transformation of the
side product into a derivative with modified polarity.
Goto and co-workers41 converted glycals into 2-bromo-
3-hydroxy or 2-bromo-3-methoxy sialic acid derivatives
by reaction with NBS in CH3CN–H2O or CH3OH.
However, even though the reaction is mild and high
yielding, the polarity of the products is not changed sig-
nificantly and therefore did not allow a separation from
the sialosides. The conditions for the oxidation of gly-
cals reported by Marra and Sinay33 (NaIO4 in
CH3CN–CCl4–H2O in the presence of a catalytic
amount of RuCl3ÆH2O) are in fact incompatible with a
variety of functional groups such as olefins, alcohols,
aromatic rings, and ethers,42 but allowed when applied
only for 2–5min to selectively oxidize glycal 4 without
affecting the yield of the desired sialosides. The polar
products of the glycal oxidation could then readily be
removed by extraction with water.
With optimized reaction conditions and oxidative
work-up procedure for model compound 3a in hand
(entry 3), we applied the protocol to other phenols. In
most cases, high yields and a/b-selectivities in the range
of 2:1 were obtained (Table 2). It is noteworthy that the
yields correlate with the acidity of the glycosyl accep-
tors. Phenols bearing electron-withdrawing substituents
Table 2. Formation of aryl sialosides 3b–k under Mitsunobu conditions
OAc
OH
OAc
OAc
COOMe
O
R
OAc
AcO
AcO
Ph3P, DEAD
R
+
HO
O
COOMe
O
AcHN
AcHN
Å
CH3CN, MS 3
AcO
AcO
2b-k
3b-k
1β
2b–k
Temp (ꢁC)/time (h)
3b–k (a:b)a
3:4:5b
3b–k (a-H3e,b-H3e) (ppm)
CH O
3
2b
2c
0/3
50% (50:50)
1:0.8:0.1
2.69, 2.65
OH
0/3
0/3
73% (58:42)
76% (59:41)
1:0.3:tr
2.68, 2.64
2.71, 2.65
OH
2d
1:0.3:0.1
OH
Br
2e
0/6
0/3
0/3
0/3
0/3
0/3
0/4
72% (64:36)
90% (55:45)
65% (62:38)c
89% (60:40)d
83% (62:38)
87% (46:54)
76% (74:26)
1:0.2:tr
1:tr:tr
2.67, 2.61
2.75, 2.69
2.70, 2.64
2.73, 2.67
2.73, 2.66
2.70, 2.65
2.76, 2.72
OH
NO2
AcHN
OHC
NC
2f
OH
2g
1:0.3:0.2
1:0.1:tr
1:0.1:tr
1:0.1:tr
1:0.4:tr
OH
2h
OH
2i
OH
H COOC
3
2j
OH
OH
2k
tr = trace.
1
a Isolated yields of product mixture (a and b), ratios of isomers were determined by H NMR37a,b of the crude products before oxidative treatment
(vide infra).
b Ratios of 3, 4, and 5 were determined according to 1H NMR of the crude products: [3-H3e(a,b):4-H3(6.02ppm):5-H3e(a,b:2.55,2.44ppm)].
c Oxidative treatment was not necessary because of the different polarity between glycal and the product.
d According to the mass and 1H NMR spectrum, trace of carboxy acid derivative was formed after oxidative treatment.

2838
G. Gao et al. / Carbohydrate Research 339 (2004) 2835–2840
gave excellent yields [e.g., 4-nitrophenol (2f)], while
phenols substituted with electron-donating groups
resulted in lower yields and increased amounts of side
products (e.g., 2b). Analogous observations were made
when methyl 2,3,4-tri-O-acetyl-D-glucopyranuronate
was reacted with substituted phenols under Mitsunobu
conditions.14 A correlation of the pKa of the acceptor
with the stereochemical outcome of the Mitsunobu reac-
tion, as proposed by Myer et al.,17 was not observed in
our sialidation study.
the low diastereoselectivity is a consequence of the kinet-
ically favored reaction of 1a to the phosphoniumion 6a,
which by SN2 displacement by the nucleophile is then
transformed into the sialoside 8b.
The presented procedure for the synthesis of aryl
sialosides expands the existing pool of methods. Fur-
thermore, the employed glycosyl donor is easily synthe-
sized. The reaction conditions are mild and the yields are
good to excellent. The improvement of the stereoselec-
tivity is currently further investigated.
The sialosides can be formed by two mechanistic
pathways of the Mitsunobu reaction.7,25 Firstly,
the reaction of the quaternary phosphoniumsalt,
formed from Ph3P and DEAD in the presence of a
weak acid, with the hemiketal 1a or 1b yields the
3. Experimental
3.1. General methods
corresponding oxophosphoniumspecies
6a or 6b.
The triphenylphosphine oxide leaving group is then
displaced by the weakly acidic nucleophile through a
SN2 mechanism to yield the sialosides 8a or 8b. Alterna-
tively, 8a and 8b can be formed from 6a and 6b in a
SN1-type mechanism by elimination of triphenyl-
phosphine oxide ()7) followed by addition of the
nucleophile.
The best stereoselectivity (a:b ꢁ 3:1) was observed
with 2-naphthol (entry k) as acceptor, while all other
cases gave only modest or no diastereoselectivity (3:2
to 1:1). This low selectivity suggests the partial involve-
ment of a SN1 reaction mechanism via the oxonium ion
7 (Scheme 1). However, the fact that the anomeric ratio
does not significantly improve when CH3CN is used as a
solvent (Table 1, entry 3), compared to THF or toluene
(entries 1 and 2), does not support this reaction path-
way. On the other hand, the stereochemical outcome
does not reflect the anomeric ratio present in hemiketal
1 (a:b ꢁ 5:95 in CH3CN).43 Therefore, it is likely that
NMR spectra were recorded on a Bruker Avance DMX-
500 (500MHz) spectrometer. Assignment of 1H and 13
C
NMR spectra was achieved using 2D methods (COSY,
HSQC). Chemical shifts are expressed in ppm using
residual CHCl3 as references. Optical rotations were
measured using a Perkin–Elmer Polarimeter 241. Reac-
tions were monitored by TLC using glass plates coated
with silica gel 60 F254 (Merck) and visualized by using
UV light and/or by charring with a molybdate solution
(0.02M solution of ammonium cerium sulfate dihydrate
and ammonium molybdate tetrahydrate in aqueous 10%
H2SO4). Column chromatography was performed on sil-
ica gel (Uetikon, 40–60 mesh). Pyridine was freshly dis-
tilled under argon over KOH. Acetonitrile and toluene,
were dried by filtration over Al2O3 (Fluka, type 5016 A
basic). THF was dried by refluxing with sodium, benzo-
phenone and distilled immediately before use. Molecular
˚
sieves (3A) were activated in vacuo at 500ꢁC for 2h
immediately before use.
+
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
COOMe
+
COOMe
OH
OH
OPPh3
AcO
AcO
AcO
AcO
O
OPPh3
O
O
COOMe
O
COOMe
AcHN
AcHN
AcHN
AcHN
AcO
AcO
AcO
AcO
6β
6α
1β
α
1
Nu
OAc
+
AcO
OAc
COOMe
Nu
O
AcHN
AcO
7
OAc
OAc
OAc
ONu
COOMe
COOMe
O ONu
AcO
OAc
AcO
O
AcHN
AcHN
AcO
AcO
8β
8
α
Scheme 1. Postulated mechanistic pathway of sialidation using Mitsunobu conditions.

G. Gao et al. / Carbohydrate Research 339 (2004) 2835–2840
2839
3.2. Representative procedure
(125MHz, CDCl3) d 19.69, 19.75, 19.81. 19.88 (4OAc),
22.13 (NHAc), 37.34 (C-3), 48.12 (C-5), 52.14 (OCH3),
61.17 (C-9), 67.17 (C-7), 67.51 (C-4), 71.21 (C-8),
71.54 (C-6), 98.18 (C-2), 117.21, 117.29, 119.29.
122.01, 128.79 (9C, CH-Ar), 148.44, 151.38, 156.56 (C-
Ar), 166.29, 169.11. 169.28, 169.47, 169.60, 170.03
(6CO); HRMS: Calcd for C32H37NO14+Na 682.2214
[M+Na]+; Found m/z 682.2225.
3.2.1. Methyl (p-phenoxyphenyl 5-acetamido-4,7,8,9-
tetra-O-acetyl-3,5-dideoxy-D-glycero-D-galacto-2-nonulo-
pyranosid)onate (3a). DEAD (47.5lL, 0.3mmol) was
added to a stirred solution of compound 1b33 (100mg,
0.2mmol), Ph3P (80mg, 0.3mmol), and compound 2a
(76mg, 0.4mmol) in dry CH3CN (6mL) at 0ꢁC under
argon. The reaction mixture was stirred at 0ꢁC for 3h,
diluted with CH2Cl2 (15mL), and filtrated through a
pad of Celite. The Celite was washed with CH2Cl2 (3–
5mL) and the combined filtrates were concentrated
under reduced pressure, then dried at high vacuum. A
catalytic amount of RuCl3ÆH2O was added to a vigor-
ously stirred biphasic solution of the residue in NaIO4
(ꢂ0.1g), CCl4 (0.8mL), CH3CN (0.8mL), and H2O
(1.2mL). After 2–5min at rt, the thick, yellowish-green
mixture was diluted with CH2Cl2 (25mL), and washed
with H2O (2 · 10mL). The organic layer was dried over
Na2SO4, filtrated, and concentrated under reduced pres-
sure. The residue was purified by flash chromatography
on silica gel (0.25% gradient MeOH in CH2Cl2) to afford
sialoside 3a (101mg, 75%, a:b = 76:24) as a white foam.
The diastereomeric mixtures of 3a could be separated by
flash chromatography on silica gel (5% gradient EtOAc
in toluene), yielding 3a-a (60mg, 45%) and 3a-b (16mg,
Acknowledgements
We thank the Volkswagen Foundation (center project
grant ꢁConformational Control of the Biomolecular
Functionsꢀ) for financial support.
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12%) as white foams.
25
Compound 3a-a: ½aꢃ ꢀ2.2ꢁ (c 1.0, CHCl3); Rf 0.15
D
1
(toluene–EtOAc, 1:3); H NMR (500MHz, CDCl3) d
1.89 (s, 3H, NHAc), 2.01, 2.03, 2.11, 2.12 (4s, 12H,
4OAc), 2.18 (t, 1H, J3a,3e, J3a,4 12.6Hz, H-3a), 2.70
(dd, 1H, J3e,4 4.7Hz, H-3e), 3.68 (s, 3H, OCH3), 4.08
(q, 1H, J4,5, J5,6, J5,NH 10.4Hz, H-5), 4.15 (dd, 1H,
J8,9a 4.7, J9a,9b 12.2Hz, H-9a), 4.30–4.33 (m, 2H, H-6,
H-9b), 4.94 (ddd, 1H, H-4), 5.31 (d, 1H, NH), 5.33–
5.37 (m, 2H, H-7, H-8), 6.91–6.93, 6.95–6.98, 7.02–
7.08, 7.29–7.32 (m, 9H, Ar); 13C NMR (125MHz,
CDCl3) d 20.72, 20.82, 20.94 (4C, 4OAc), 23.17 (NHAc),
37.74 (C-3), 49.31 (C-5), 52.88 (OCH3), 62.04 (C-9),
67.40 (C-7), 68.86 (C-4), 69.31 (C-8), 73.29 (C-6),
100.33 (C-2), 118.28, 119.85, 122.01, 122.95 129.66
(9C, CH-Ar), 149.35, 153.54, 157.80 (C-Ar), 167.77,
169.95, 169.98, 170.25, 170.59, 170.92 (6CO); HRMS:
Calcd for C32H37NO14+Na 682.2214 [M+Na]+; Found
m/z 682.2212.
25
D
1
Compound 3a-b: ½aꢃ ꢀ31.3ꢁ (c 1.0, CHCl3); Rf 0.19
(toluene–EtOAc, 1:3); H NMR (500MHz, CDCl3) d
1.86, 1.87, 1.97, 2.05, 2.15 (5s, 15H, 4OAc, NHAc),
1.99 (m, 1H, H-3a), 2.66 (dd, 1H, J3e,4 4.9, J3a,3e
12.9Hz, H-3e), 3.74 (s, 3H, OCH3), 4.10 (dd, 1H, J6,7
2.3Hz, J5,6 10.6Hz, H-6), 4.14 (dd, 1H, J8,9a 7.1, J9a,9b
12.6Hz, H-9a), 4.22 (q, 1H, J4,5, J5,NH 10.4Hz, H-5),
4.69 (dd, 1H, J8,9b 2.2Hz, H-9b), 4.89 (ddd, 1H, J7,8
3.9Hz, H-8), 5.37 (dd, 1H, H-7), 5.43 (d, 1H, NH),
5.46 (ddd, 1H, J3a,4 11.1Hz, H-4), 6.86–6.90, 6.94–
7.05, 7.06–7.08, 7.29–7.32 (m, 9H, Ar); 13C NMR
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