Highly efficient α-C-sialylation promoted by (p-Tol) 2SO/Tf2O with N-acetyl-5-N,4-O-oxazolidione protected thiosialoside as donor

Article abstract of DOI:10.1039/c3ob40876k

Based on a preactivation protocol with (p-Tol)₂SO/Tf ₂O, a practical, straightforward, and high-yielding synthesis of α-sialyl C-glycosides was accomplished by coupling N-acetyl-5-N,4-O- oxazolidione protected thiosialoside with various trimethylsilyl enol ethers and allyltrimethylsilanes. High yields and excellent α-selectivities were obtained for the strong π-nucleophiles with large nucleophilicity values (N = 4.4-9.0), irrespective of whether silyl enol ethers, silyl ketene acetals or allyltrimethylsilanes were used for the electrophilic C-sialylation.

Full text of DOI:10.1039/c3ob40876k

Organic &
Biomolecular Chemistry
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Highly efficient α-C-sialylation promoted by
(p-Tol)2SO/Tf2O with N-acetyl-5-N,4-O-oxazolidione
Cite this: Org. Biomol. Chem., 2013, 11,
5017
protected thiosialoside as donor†
Zhen-yuan Gu, Xiao-tai Zhang, Jia-xin Zhang and Guo-wen Xing*
Based on a preactivation protocol with (p-Tol)2SO/Tf2O, a practical, straightforward, and high-yielding
synthesis of α-sialyl C-glycosides was accomplished by coupling N-acetyl-5-N,4-O-oxazolidione protected
thiosialoside with various trimethylsilyl enol ethers and allyltrimethylsilanes. High yields and excellent
α-selectivities were obtained for the strong π-nucleophiles with large nucleophilicity values (N = 4.4–9.0),
irrespective of whether silyl enol ethers, silyl ketene acetals or allyltrimethylsilanes were used for the elec-
trophilic C-sialylation.
Received 28th April 2013,
Accepted 10th June 2013
DOI: 10.1039/c3ob40876k
www.rsc.org/obc
Introduction
N-Acetylneuraminic acids (Neu5Ac), mostly located at the
terminal end of oligosaccharides and glycoconjugates, have
vital biological functions in higher animals and human
beings.1 Among the types of sialosides, C-glycosides, whose
interglycosidic oxygen atoms are substituted by carbon atoms,
possess exclusive resistance to chemical and enzymatic degra-
dation and display potential applications in the development
of Neu5Ac-containing antiviral drugs and vaccines.2
Due to the requirement of C–C bond formation at a new ter-
tiary carbon atom center, it is more challenging to synthesize
C-sialosides than other C-glycosides. In 1991, three groups of
investigators3 independently reported the formation of simple
allyl and hydroxymethyl C-glycosides of Neu5Ac, but with poor
α-selectivity or low reaction yield. Over the years, a few glycosy-
lation strategies, especially the SmI2-mediated reductive coup-
ling reactions with appropriate Neu5Ac donors such as sialyl
sulfones,4a chlorides,4b sulfides5a and acetates,5b have been
developed for efficient α-C-sialylation to provide novel series of
catabolically stable C-sialoside analogues of glycoconjugates.4–6
It is reported that C-glycosides can be obtained from silyl enol
ethers with high stereoselectivity in Sakurai/Mukayiama-type
reactions.7 For electrophilic α-C-sialylation with silyl enol
ethers, very recently, N-acetyl-5-N,4-O-oxazolidione-protected
sialyl phosphate (2) was found to be an efficient sialyl donor
for the construction of α-C-sialosides in the presence of tri-
methylsilyl trifluoromethanesulfonate.8a It is noted that donor
Fig. 1 Structures of N-acetyloxazolidinone protected sialyl donors.
2 is, in fact, derived from the corresponding N-acetyloxazolidi-
none protected thiosialoside 18b (Fig. 1), which was first pre-
pared by our laboratory and has proven to be an excellent
O-sialylation donor to couple with various alcohol receptors.9a
In an effort to simplify the synthetic sequence of C-sialosides
and avoid the preparation of complex samarium(III) organome-
tallic species, herein we report that donor 1 is truly a practical
C-sialyl donor. The reaction, promoted by a (p-Tol)2SO/Tf2O
system, occurs with a wide variety of silyl enol ethers as accep-
tors in high α-selectivity and good isolated yield.
Results and discussion
In previous reports,9 we have established that both diphenyl
sulfoxide/trifluoromethanesulfonic anhydride (Ph2SO/Tf2O)9d
and N-iodosuccinimide/trifluoromethanesulfonic acid (NIS/
TfOH)9a promotion systems can efficiently activate thiosialo-
side 1α to afford the desired α-O-sialylation products. The
stereoselectivity and yield of the sialylation can be modulated
by carefully changing the added amount of Ph2SO. In the
current study, inspired by above results, we initially attempted
the C-sialylation between 1α and acetophenone trimethylsilyl
enol ether (3) under Ph2SO/Tf2O preactivation conditions in
dichloromethane. To our surprise, the expected C-sialyl deriva-
tive 4 was successfully obtained in 71% yield with exclusive
α-stereoselectivity (Table 1, entry 1). When (p-Tol)2SO was used
Department of Chemistry, Beijing Normal University, Beijing 100875, China.
E-mail: gwxing@bnu.edu.cn
†Electronic supplementary information (ESI) available: Copies of NMR spectra
for all new coupling products. See DOI: 10.1039/c3ob40876k
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sulfoxide bis(triflate) 5 which is generated in situ from the pro-
moter pair (p-Tol)2SO and Tf2O. As proposed by Crich for the
Table 1 Effects of different promoters and amount of (p-Tol)2SO on the
C-sialylation
N,N-diacetyl counterpart10 and our previous studies,9d,e
6
would either rapidly decompose to the 2,3-glycal 7, or be
efficiently trapped by excess (p-Tol)2SO (1–2 equiv.)11 to
provide the N-acetyloxazolidinone protected C2-sialyloxosulfo-
nium salt 8a/8b, which is considered as the second crucial
intermediate for the sialylation and should be more stable
from −70 °C to −50 °C (Table 2). The more reactive β-C2-sialyl-
oxosulfonium intermediate 8b could be quickly attacked by a
nucleophile such as trimethylsilyl enol ether, allyltrimethyl-
silane or alcohol to obtain the α-C- or O-sialyl product. It is
noteworthy that more excess (p-Tol)2SO (3 equiv.) additive led
to a very low C-sialylation yield (Table 1, entry 6) with excellent
α-selectivity. In sharp contrast, the reaction yield of O-sialyla-
tion under similar reaction conditions was extraordinarily
high (96%), but with declined α-selectivity (α/β = 2.7 : 1).9d
Similarly, as described in our previous work, the larger of
excess (p-Tol)2SO (3 equiv.) may produce C2-sialyloxosulfo-
nium supramer 9a/9b,9d the third crucial intermediate, which
accounts for the above experimental results. It is suggested
that the sialyloxosulfonium species have following relative
electrophilicity ranking: 8b > 8a > 9a ≅ 9b. In addition, the
C- and O-nucleophiles should fit the relative nucleophilicity
order: alcohol > trimethylsilyl enol ether or allyltrimethyl-
silane.12 Therefore, alcohol reacts with 9a/9b to give high reac-
tion yield and low α-selectivity; with 8a/8b to afford low
reaction yield and high α-selectivity.9d The nucleophilicity of
trimethylsilyl enol ether is too weak to attack 9a/9b which
could be the major intermediate with 4 equiv. of (p-Tol)2SO
used for the sialylation (Table 1, entry 6), and consequently
the yield of the C-sialylation is poor. Noticeably, with 2–3
equiv. of (p-Tol)2SO (Table 1, entries 4 and 5) trimethylsilyl
enol ether mainly attacks 8a/8b, especially the more reactive
8b, to provide higher product yield and excellent α-selectivity.
To further verify the effectiveness of (p-Tol)2SO/Tf2O as a
promoting system for C-sialylation, a series of trimethylsilyl
enol ethers and allyltrimethylsilanes were applied to the C-gly-
cosylation with thiosialoside 1 as donor under identical con-
ditions (Table 3). All these neutral π-nucleophiles have varying
nucleophilicity values (N = 1.8–9.0) as defined by Mayr and
co-workers.13
Entry
Conditionsa
Yieldb (%)
α : βc
1
2
3
4
5
6
Tf2O/Ph2SO (2.0 equiv.)
71
61
68
82
84
15
α
α
α
α
α
α
Tf2O/(p-Tol)2SO (0.6 equiv.)
Tf2O/(p-Tol)2SO (1.2 equiv.)
Tf2O/(p-Tol)2SO (2.0 equiv.)
Tf2O/(p-Tol)2SO (3.0 equiv.)
Tf2O/(p-Tol)2SO (4.0 equiv.)
a 1.2 equiv. Tf2O was used for the reactions. b Isolated yields after
column chromatography. c Determined by 1H NMR spectroscopy;
α indicates that no β product was detected.
as additive instead of Ph2SO for the C-sialylation, the reaction
yield was improved from 71% to 82% (Table 1, entry 4), indi-
cating that (p-Tol)2SO is more closely matched with sialyl
donor 1 (containing p-tolyl sulfide as leaving group) than
Ph2SO. The results are also comparable with our previous
observations,9e wherein the (p-Tol)2SO was a superior additive
for O-sialylation with N-acetyl-5-N,4-O-oxazolidione protected
sialyl sulfoxide as donor.
Next, we further probed the influence of different added
amounts of (p-Tol)2SO on the C-sialylation. As shown in
Table 1, when the amount of (p-Tol)2SO was increased from
0.6 equiv. to 4.0 equiv., the optimum amount of (p-Tol)2SO
additive was 2.0–3.0 equiv., with the highest C-sialylation yield
reaching 82–84%. Meanwhile, only the α-C-sialyl product was
obtained in the reaction with different amounts of (p-Tol)2SO.
In addition, the effect of reaction temperature on the model
C-sialylation was also examined. The reaction yields were
closely related to the temperature (Table 2). Ranging the temp-
erature from −70 °C to −20 °C, the yield decreased gradually
from 82% to 68%, suggesting that lower reaction temperature
was more appropriate for the C-glycosylations. Finally, we used
the sialylation conditions described in entry 1 of Table 2 for
the following C-sialylations with silyl enol ethers as acceptors.
With regard to the mechanism of the C-glycosylation
(Scheme 1), the N-acetyl-5-N,4-O-oxazolidione protected oxacar-
benium cation 6 is believed to be the first crucial intermediate,
resulting from the activation of thiosialoside 1 by di-p-tolyl
The nucleophilicity of silyl enol ethers plays an important
role in the C-sialylation. Both high reaction yield and exquisite
α-selectivity were obtained in the C-sialylation of donor 1 with
enoxy silane nucleophiles 3, 10, 12, 14 (N = 5.2–8.2, Table 3,
entries 1, 4–6).13,14 When a weak nucleophile 16 (N = 3.8) was
employed for the electrophilic substitution, the ketone 17 was
obtained in moderate yield, but with low stereoselectivity (α/β
= 2.6 : 1, Table 3, entry 7). Similar results were also reported
during the C-sialylation of N-acetyloxazolidinone protected
sialyl phosphate (2) with 16.8a With strong nucleophiles 18
and 20 (N = 8.2 and 9.0, respectively) derived from esters, only
single α isomers were obtained in 72–84% yields. Application
of this method to the preparation of sialyl aldehyde 23 from
trimethylsiloxyethene (22) gave exclusive α-selectivity and 43%
Table 2 Effect of temperature on the C-sialylationa
Entry
Conditionsb
Yieldc (%)
α : βd
1
2
3
4
5
−70 °C 2.0 h then −50 °C 2.0 h
−50 °C 4.0 h
82
79
75
77
68
α
α
α
α
α
−40 °C 4.0 h
−30 °C 4.0 h
−20 °C 4.0 h
a See Table 1 for reaction scheme. b 1.2 equiv. Tf2O and 2.0 equiv.
(p-Tol)2SO were used for the reactions. c Isolated yields after column
chromatography. d Determined by 1H NMR spectroscopy.
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Scheme 1 Three proposed crucial intermediates in the sialylation of thiosialoside 1 with (p-Tol)2SO/Tf2O.
yield. Comparing the glycosylations with 16 and 22 as nucleo-
philes, the yields are comparative, but glycal 7 was obtained in
Conclusion
lower yield in the case of 22 than that of 16, suggesting that In summary, in spite of the development of a few C-sialylation
aldehyde 23 was partially decomposed during flash chromato- strategies in sialic acid chemistry, herein is described the first
graphy due to its instability to silica gel.
direct C-sialylation of N-acetyloxazolidinone17 protected thio-
With allyltrimethylsilane 24 as a sialyl acceptor with a poor sialoside based on a preactivation protocol with (p-Tol)2SO/
N value (N = 1.8), the coupling reaction provided 25 in 50% Tf2O. The efficiency of the C-sialylation is not only regulated
yield and very low stereoselectivity (α/β = 1 : 1.2, Table 3, entry by the reaction conditions, especially the added amount of
12). However, in the case of 26 with a higher N value (N = 4.4), (p-Tol)2SO, but also dependent on the reactivity of the nucleo-
the C-sialylation yield jumped to 86%, and the stereoselectivity philes. High reaction yield and excellent α-selectivity were
was also significantly improved from α/β = 1 : 1.2 to α only obtained for strong π-nucleophiles with large nucleophilicity
(Table 3, entry 14). The results further illustrated that the values (N = 4.4–9.0), irrespective of whether silyl enol ethers,
C-sialylation is sensitive to the nucleophilicity values, and silyl ketene acetals or allyltrimethylsilane were used for the
strong nucleophiles (either trimethylsilyl enol ethers or allyltri- electrophilic C-sialylation. The C-sialylation methodology de-
methylsilane) give both higher yields and α-selectivities.
veloped in this study simplifies the existing synthetic route to
The β-anomer 1β15 was also examined for the C-sialylation build sialyl C-glycosides and affords a powerful tool to explore
with trimethylsilyl enol ethers 3 and 22, and allyltrimethylsi- the syntheses of complex C-sialylconjugates and glycomimetics.
lane 24 as nucleophiles (Table 3, entries 3, 11 and 13). Similar
reaction yields and stereoselectivities were obtained compared
with the corresponding reactions with 1α as donor (Table 3,
Experimental
General
entries 1, 10 and 12). The results are different from the C-sialy-
lation reported by Crich and co-workers,8a wherein the reac-
tion yield or α-selectivity was highly dependent on the anomer All chemicals were purchased as reagent grade and used
configuration of sialyl phosphate donor 2, and 2α was more without further purification. Dichloromethane was distilled
favorable for C-sialylation than 2β. Because the preactivation over calcium hydride (CaH2). The reactions between donor 1
protocol was utilized for the glycosylation in this study, with and different acceptors were carried out under anhydrous con-
anomer 1α as donor the crucial intermediates 6, 8a/8b and 9a/ ditions (argon atmosphere) with anhydrous solvent. Reactions
9b and their equilibrium concentrations should be nearly the were monitored by analytical thin-layer chromatography on
same as those with anomer 1β as donor (Scheme 1). As a silica gel F254 glass plates. Spots were detected under UV
result, donors 1α and 1β have no distinguishable effects on (254 nm) or by staining with a solution of acidic ceric
the C-sialylation. In addition, to demonstrate the practicality ammonium molybdate and EtOH–H2SO4 (3%). Flash column
of the current C-sialylation strategy, the model C-sialylation was chromatography was performed on silica gel (200–300 mesh).
successfully scaled up from the preparation of ∼35 mg of 1H NMR spectra were recorded with a 400 MHz NMR spectro-
ketone 4 (Table 3, entry 1) to ∼140 mg (Table 3, entry 2) in high meter at 20 °C. Chemical shifts (in ppm) were referenced to
yields (82–88%). The anomeric stereochemistry of all new coup- tetramethylsilane (δ = 0 ppm) in deuterated chloroform. 13C
3
ling products was assigned on the basis of JC1,H3ax coupling NMR spectra were recorded with a 400 MHz NMR spectro-
constants.5c,16 Generally, the α isomers of the C-sialylations meter (100 MHz) and calibrated with CDCl3 (δ = 77.23 ppm).
have higher 3JC1,H3ax coupling constants varying from 6.6 to 7.6, High-resolution mass spectra were recorded using electrospray
which are consistent with the data described in literature.5c
ionization (ESI).
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Table 3 C-Sialylation of thiosialoside donor 1 with various trimethylsilyl enol ethers and allyltrimethylsilanes
Entry
1d
Donor
Nucleophile
N valuea
Product
Yieldb
82%
α : βc
1α
6.2
α
2e
3
4
1α
1β
1α
3
3
6.2
6.2
6.2–8.2
4
4
88%
86%
95%
α
α
α
5
1α
5.4
96%
α
6d
7d
1α
1α
5.2
3.8
71%
α
37% + 54% 7
2.6 : 1
8
1α
1α
1α
8.2
9.0
—
72%
α
α
α
9
84%
10d, f
43% + 26% 7
11f
1β
1α
22
24
—
1.8
23
25
40% + 24% 7
50% + 50% 7
α
12d, f
1 : 1.2
13f
14
1β
1α
1.8
4.4
45% + 49% 7
86%
1 : 1
α
a See ref. 13 and 14. b Yield of isolated products. c Determined by 1H NMR spectroscopy. d The 1H NMR spectroscopic data are consistent with
those reported in ref. 8a. e A large-scale sialylation was carried out with 160 mg of donor 1α used for the reaction. f 10.0 equiv. of acceptor
was used in the reaction.
General coupling protocol for the C-salylation
acceptor (5 equiv.) in anhydrous dichloromethane (1 mL) was
added. The resulting mixture was then stirred for 2.0 hours at
−70 °C then warmed to −50 °C for another 2.0 hours. After
quenching with Et3N (0.1 mL), the mixture was diluted with
dichloromethane (50 mL), filtered through Celite®, washed
with saturated brine (10 mL × 3), dried over anhydrous MgSO4,
A solution of sialyl donor (0.069 mmol, 1 equiv.), (Tol)2SO
(0.138 mmol, 2 equiv.) and activated 4 Å powdered sieves in
anhydrous dichloromethane (2 mL) was stirred for 15 min at
−70 °C under argon, followed by addition of Tf2O (13.4 μL,
1.2 equiv.). After stirring the mixture for 30 min, a solution of and concentrated under reduced pressure. The residue was
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purified by silica gel column chromatography eluting with a J = 9.6, 10.9 Hz, 1H), 3.19 (d, J = 14.8 Hz, 1H), 3.02 (d, J = 14.8
petroleum ether–EtOAc system to give the coupling products. Hz, 1H), 2.87 (dd, J = 3.5, 12.2 Hz, 1H, H-3eq), 2.49 (s, 3H),
Methyl (2-C-(2-oxa-2-p-methoxylphenylethyl)-5-N-acetamido- 2.40 (t, J = 12.7 Hz, 1H, H-3ax), 2.13 (s, 3H), 2.07 (s, 3H),
7,8,9-tri-O-acetyl-5-N,4-O-carbonyl-3,5-dideoxy-D-glycero-α-D- 1.93 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 172.1, 171.0
3
galacto-non-2-ulopyranitol)onate (11). This compound was (C1, JC1,H3ax = 6.8 Hz), 170.6, 170.5, 170.0, 166.6, 153.4, 150.3,
prepared according to the general procedure for C-sialylation 129.4, 126.1, 121.4, 78.1, 76.6, 75.4, 73.0, 70.8, 62.9, 59.3, 53.2,
with a sialyl donor 1α (40.1 mg, 0.069 mmol) and 10 (76.7 mg, 43.7, 35.2, 24.7, 21.1, 20.7 ppm; HRMS(ESI-TOF): m/z calcd for
0.345 mmol). Purification by column chromatography over C27H31NO14Na [M + Na]+ 616.1642, found: 616.1621.
silica gel (hexanes–AcOEt = 1 : 1) gave the desired product
Methyl (2-C-(1,1-dimethyl-2-oxa-2-methoxylethyl)-5-N-acet-
(39.8 mg, 95%) as colorless viscous oil. 1H NMR (400 MHz, amido-7,8,9-tri-O-acetyl-5-N,4-O-carbonyl-3, 5-dideoxy-D-glycero-
CDCl3): δ = 7.96 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), α-D-galacto-non-2-ulopyranitol)onate (21). This compound
5.45 (d, J = 6.7 Hz, 1H), 5.17 (dt, J = 2.6, 6.7 Hz, 1H), 4.62 (d, J = was prepared according to the general procedure for C-sialyla-
9.4 Hz, 1H), 4.25 (dd, J = 2.6, 12.2 Hz, 1H), 4.19 (dt, J = 3.3, tion with a sialyl donor 1α (40.1 mg, 0.069 mmol) and 20
12.5 Hz, 1H), 3.88 (s, 3H), 3.86 (dd, J = 6.8, 12.2 Hz, 1H), 3.77 (70.0 μL, 0.345 mmol). Purification by column chromatography
(s, 3H, COOCH3), 3.57 (d, J = 14.8 Hz, 1H), 3.56 (t, J = 9.5 Hz, over silica gel (hexanes–AcOEt = 1 : 1) gave the desired product
1H), 3.30 (d, J = 14.8 Hz, 1H), 2.87 (dd, J = 3.5, 12.4 Hz, 1H, (32.4 mg, 84%) as colorless viscous oil. 1H NMR (400 MHz,
H-3eq), 2.47 (s, 3H), 2.31 (t, J = 12.7 Hz, 1H, H-3ax), 2.13 (s, CDCl3): δ = 5.51 (dd, J = 1.6, 6.5 Hz, 1H), 5.40 (dt, J = 2.7,
3H), 2.03 (s, 3H), 1.93 (s, 3H) ppm; 13C NMR (100 MHz, 6.8 Hz, 1H), 4.50 (dd, J = 1.5, 9.4 Hz, 1H), 4.37 (dd, J = 2.6,
3
CDCl3): δ = 193.9, 172.1, 171.5 (C1, JC1,H3ax = 7.1 Hz), 170.6, 12.2 Hz, 1H), 4.08 (dd, J = 6.9, 12.2 Hz, 1H), 3.85 (dt, J = 3.7,
170.4, 169.8, 164.0, 153.7, 131.1, 130.1, 113.7, 78.5, 75.8, 75.6, 12.7 Hz, 1H), 3.79 (s, 3H, C1OOCH3), 3.73 (s, 3H), 3.57 (dd, J =
72.2, 70.1, 62.7, 59.4, 55.6, 52.9, 46.1, 35.1, 24.7, 21.1, 20.8, 9.6, 11.1 Hz, 1H), 2.79 (dd, J = 3.8, 12.1 Hz, 1H, H-3eq), 2.68 (t,
20.7 ppm; HRMS (ESI-TOF): m/z calcd for C28H33NO14Na J = 12.6 Hz, 1H, H-3ax), 2.47 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H),
[M + Na]+ 630.1799, found: 630.1771.
2.05 (s, 3H), 1.31 (s, 3H), 1.21 (s, 3H) ppm; 13C NMR
Methyl (2-C-(2-oxa-2-methylethyl)-5-N-acetamido-7,8,9-tri-O- (100 MHz, CDCl3): δ = 173.7, 171.6, 170.3, 170.0, 169.9 (C1,
acetyl-5-N,4-O-carbonyl-3,5-dideoxy-D-glycero-α-D-galacto-non- 3JC1,H3ax = 6.8 Hz), 169.4, 153.3, 84.2, 76.1, 75.7, 72.5, 69.8,
2-ulopyranitol)onate (13). This compound was prepared 62.5, 58.7, 52.3, 51.7, 49.1, 31.6, 24.3, 20.9, 20.8, 20.7,
according to the general procedure for C-sialylation with a 20.4 ppm. HRMS(ESI-TOF): m/z calcd for C24H34NO14
sialyl donor 1α (40.1 mg, 0.069 mmol) and 12 (45.0 mg, ([M + H])+ 560.1979, found: 560.1980.
0.345 mmol). Purification by column chromatography over
Methyl (2-C-(2-methylallyl)-5-N-acetamido-7,8,9-tri-O-acetyl-
silica gel (hexanes–AcOEt = 1 : 1) gave the desired product 5-N,4-O-carbonyl-3,5-dideoxy-D-glycero-α-D-galacto-non-2-ulo-
(34.1 mg, 96%) as colorless viscous oil. 1H NMR (400 MHz, pyranitol)onate (27). This compound was prepared according
CDCl3): δ = 5.50 (dd, J = 1.5, 6.1 Hz, 1H), 5.30 (dt, J = 2.5, to the general procedure for C-sialylation with a sialyl donor
7.4 Hz, 1H), 4.71 (dd, J = 1.4, 9.4 Hz, 1H), 4.40 (dd, J = 2.5, 1α (40.1 mg, 0.069 mmol) and 26 (61.0 μL, 0.345 mmol). Puri-
12.2 Hz, 1H), 4.13 (dt, J = 3.6, 12.9 Hz, 1H), 3.95 (dd, J = 7.4, fication by column chromatography over silica gel (hexanes–
12.2 Hz, 1H), 3.78 (s, 3H, COOCH3), 3.61 (dd, J = 9.6, 10.9 Hz, AcOEt = 2 : 1) gave the desired product (30.5 mg, 86%) as color-
1
1H), 3.05 (d, J = 15.3 Hz, 1H), 2.85 (d, J = 15.3 Hz, 1H), 2.72 less viscous oil. H NMR (400 MHz, CDCl3): δ = 5.55 (dd, J =
(dd, J = 3.6, 12.3 Hz, 1H, H-3eq), 2.48 (s, 3H), 2.22 (s, 3H), 2.19 1.4, 6.0 Hz, 1H), 5.40 (dt, J = 2.7, 6.9 Hz, 1H), 4.96 (s, 1H), 4.79
(t, J = 12.6 Hz, 1H, H-3ax), 2.14 (s, 3H), 2.11 (s, 3H), 2.05 (s, 1H), 4.50 (dd, J = 2.4, 12.2 Hz, 1H), 4.42 (dd, J = 1.4, 9.4 Hz,
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 203.9, 172.2, 171.4 (C1, 1H), 4.07 (dd, J = 7.0, 12.2 Hz, 1H), 4.00 (dt, J = 3.6, 12.8 Hz,
3JC1,H3ax = 7.6 Hz), 170.8, 170.4, 169.9, 153.6, 77.9, 76.1, 75.3, 1H), 3.77 (s, 3H, COOCH3), 3.60 (dd, J = 9.5, 11.1 Hz, 1H), 2.72
72.7, 70.6, 63.1, 59.3, 53.0, 51.1, 34.9, 31.7, 24.7, 21.1, (dd, J = 3.6, 12.2 Hz, 1H, H-3eq), 2.60 (d, J = 13.8 Hz, 1H), 2.48
20.8 ppm; HRMS(ESI-TOF): m/z calcd for C22H29NO13Na (d, J = 13.8 Hz, 1H), 2.48 (s, 3H), 2.14 (s, 3H), 2.11 (s, 3H), 2.06
[M + Na]+ 538.1537, found: 538.1528.
(t, J = 12.5 Hz, 1H, H-3ax), 2.05 (s, 3H), 1.84 (s, 3H) ppm; 13C
3
Methyl (2-C-(2-oxa-2-phenoxylethyl)-5-N-acetamido-7,8,9-tri- NMR (100 MHz, CDCl3): δ = 172.3 (C1, JC1,H3ax = 6.6 Hz),
O-acetyl-5-N,4-O-carbonyl-3,5-dideoxy-D-glycero-α-D-galacto- 170.4, 170.2, 169.6, 153.5, 139.7, 116.6, 80.9, 76.1, 75.7, 72.5,
non-2-ulopyranitol)onate (19). This compound was prepared 70.6, 62.6, 59.3, 52.5, 46.5, 34.4, 24.5, 23.5, 20.9, 20.5 ppm;
according to the general procedure for C-sialylation with a HRMS(ESI-TOF): m/z calcd for C23H32NO12 ([M + H])+ 514.1925,
sialyl donor 1α (40.1 mg, 0.069 mmol) and 18 (71.9 mg, Found 514.1917.
0.345 mmol). Purification by column chromatography over
silica gel (hexanes–AcOEt = 1 : 1) gave the desired product
(29.5 mg, 72%) as white solid. M.p. 62–63 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.38 (t, J = 7.9 Hz, 2H), 7.24 (t, J = 7.4
Acknowledgements
Hz, 1H), 7.12 (d, J = 7.7 Hz, 2H), 5.48 (dd, J = 1.6, 5.4 Hz, 1H), The project was financially supported by the National Natural
5.40 (dt, J = 2.6, 7.6 Hz, 1H), 4.74 (dd, J = 1.6, 9.3 Hz, 1H), 4.41 Science Foundation of China (21272027, 20502002), Beijing
(dd, J = 2.6, 12.2 Hz, 1H), 4.13 (dt, J = 3.4, 12.9 Hz, 1H), 4.04 Natural Science Foundation (2122031) and Beijing Municipal
(dd, J = 7.4, 12.1 Hz, 1H), 3.83 (s, 3H, COOCH3), 3.72 (dd, Commission of Education.
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5022 | Org. Biomol. Chem., 2013, 11, 5017–5022
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