Rapid and efficient conversion of sialyl thioglycosides to sialyl esters via NIS/BF3OEt2-promoted glycosylation

Article abstract of DOI:10.1016/j.tetlet.2017.05.011

A rapid and efficient one-step conversion of sialyl thioglycosides to sialyl esters was disclosed. Under the promotion of NIS and BF₃OEt₂, the glycosylation of per-acetylated sialyl thioglycoside with a set of carboxylic acids provid

Full text of DOI:10.1016/j.tetlet.2017.05.011

Accepted Manuscript
Rapid and Efficient Conversion of Sialyl Thioglycosides to Sialyl Esters via
NIS/BF3OEt2-Promoted Glycosylation
Jiazhe Wang, Rongkun Liu, You Yang
PII:
S0040-4039(17)30580-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.011
TETL 48904
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 April 2017
30 April 2017
4 May 2017
Please cite this article as: Wang, J., Liu, R., Yang, Y., Rapid and Efficient Conversion of Sialyl Thioglycosides to
Sialyl Esters via NIS/BF3OEt2-Promoted Glycosylation, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/
j.tetlet.2017.05.011
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Rapid and Efficient Conversion of Sialyl Thioglycosides to
Sialyl Esters via NIS/BF3OEt2-Promoted Glycosylation
Jiazhe Wang, Rongkun Liu, and You Yang*
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University
of Science and Technology, 130 Meilong Road, Shanghai 200237, China. E-mail:
yangyou@ecust.edu.cn
Abstract:
A rapid and efficient one-step conversion of sialyl thioglycosides to sialyl esters was
disclosed. Under the promotion of NIS and BF3OEt2, the glycosylation of per-acetylated sialyl
thioglycoside with a set of carboxylic acids provided β-sialyl esters as the major products in
good to excellent yields within 5 minutes. Compared with the long-chain alkyl-, aryl- and
α,β-unsaturated acids, complete β-selectivities were observed when the short-chain alkyl
acids were selected as the coupling partners. The resultant β-selectivity for the glycosylation
of the per-acetylated sialyl thioglycoside with acetic acid was compromised when the 5-N,4-
O-oxazolidinone protected sialyl thioglycoside was employed as the coupling partner.
Keywords:
Glycosylation; Sialyl esters; Sialyl thioglycosides; Synthetic methods
Sialic acids are a large family of keto acid sugars that mostly locate at the terminal end of cell
surface glycolipids and glycoproteins of vertebrates or serve as essential component of
1

polysialic acids of mammalian tissues and pathogenic bacteria.1 Owing to their outmost
position on the cell surface carbohydrates and the highly functionalized nature with negative
charge under physiological condition, sialic acids are involved in a variety of biological
processes such as cell adhesion, cell signaling, cell differentiation, neural network maturing,
pathogen recognition, viral infection, cancer growth and metastasis.2
To date, considerable efforts have been directed at the glycosylation of a range of
sialic acid donors with alcohols for the synthesis of naturally occurring sialoglycans and
congeners.3,4 Due to the inherent challenging structure of sialic acid with electro-withdrawing
carboxylic group at C-1 and without neighboring participating group at C-3, stereoselective
O-sialylation was extensively investigated by applying various leaving groups at C-2,
auxiliary groups at C-3, amino protecting groups at C-5, neighboring participating groups at
C-1 as well as promoters and solvents.3,5 However, glycosylation of sialic acid derivatives
with carboxylic acids remains scarce. Traditional coupling of sialic acid derivatives with
carboxylic acids mainly relied on the condensation of protected sialyl hemiketals with
carboxylic acids or their activated forms (e.g., anhydrides) in the presence of DMAP/pyridine,
DIC/DMAP, or 2,4,6-trichlorobenzoyl chloride/DMAP/iPr2NH, usually leading to sialyl
esters with the β-anomers as the major products (Scheme 1a).6,7 As revealed in the
literature,3,4 the stable sialyl thioglycosides were frequently utilized synthetic intermediates
for the synthesis of sialic acid-containing saccharides. To convert sialyl thioglycosides into
sialyl esters, a two-step sequence involving cleavage of the sialyl thioglycosides into sialyl
hemiketals using NIS or NBS followed by coupling of the resulting hemiketals with
carboxylic acids or their activated forms is often needed.7 As such, development of a one-step
stereoselective approach for the direct transformation of sialyl thioglycosides to sialyl esters
would improve the synthetic efficiency and avoid the cumbersome purification procedures.
Here, we present a rapid and efficient glycosylation approach utilizing NIS and BF3OEt2 as
2

the promoters for the direct conversion of sialyl thioglycosides to sialyl esters in a β-selective
manner (Scheme 1b).
Scheme 1. Coupling strategies of sialic acid derivatives with carboxylic acids or their
activated forms. P = protecting group; Ar = 5-tert-butyl-2-methylbenzene.
At the outset, we turned our attention to the screening of glycosylation conditions for
the conversion of sialyl thioglycoside 1 that could be readily prepared by the modified
literature protocols8 to sialyl ester 3a under the activation of NIS (2 equiv) and Lewis acids in
CH2Cl2 at room temperature (Table 1). The anomeric configuration of the product 3a was
3
determined based on the long-range JC1,H3ax coupling constant and the chemical shift of the
C-1.9 Without the addition of Lewis acid, the glycosylation of 1 with acetic acid 2a (5 equiv)
led to the formation of thermodynamically more stable β-sialyl ester 3a (δC-1 = 165.8 ppm,
3JC1,H3ax = 0 Hz) as the single product in a moderate 60% yield, but traces of starting material
1 remained intact and a significant amount of glycal byproduct was formed (entry 1). Upon
addition of 1–3 equiv of BF3OEt2, the glycosylation yields of β-sialyl ester 3a were slightly
improved (62–75%), in which 2 equiv of BF3OEt2 was found to be better (entries 2–4).
Reducing the amount of acetic acid 2a (5 equiv → 2–3 equiv) while fixing the amount of
BF3OEt2 (2 equiv) could result in a very clean reaction and dramatically increase the yield of
3

3a with the β-anomer as the only product within 5 minutes (3 equiv of acetic acid, 98%, entry
5; 2 equiv of acetic acid, 80%, entry 6), which indicated that combination of suitable amounts
of carboxylic acid and Lewis acid was vital for the glycosylation yield of sialyl thioglycoside
with carboxylic acid. In contrast, the glycosylation employing TMSOTf or AgOTf as Lewis
acid under the similar conditions led to β-sialyl ester 3a as the sole products in moderate
yields (51–62%, entries 7 and 8). Thus, glycosylation of sialyl thioglycoside 1 with acetic acid
2a (3 equiv) promoted by NIS (2 equiv) and BF3OEt2 (2 equiv) for 5 minutes (entry 5) was
chosen as the optimal conditions for this transformation.
Table 1. Screening of glycosylation conditions for the conversion of sialyl thioglycoside 1 to
sialyl ester 3a.
β/αb
Entry
HOAc (equiv) Lewis acid (equiv)
Yielda (%)
1
2
3
4
5
6
7
8
HOAc (5)
HOAc (5)
HOAc (5)
HOAc (5)
HOAc (3)
HOAc (2)
HOAc (3)
HOAc (3)
None
60
71
75
62
98
80
51
62
β only
β only
β only
β only
β only
β only
β only
β only
BF3OEt2 (1)
BF3OEt2 (2)
BF3OEt2 (3)
BF3OEt2 (2)
BF3OEt2 (2)
TMSOTf (2)
AgOTf (2)
a Isolated yield.
b The ratio of β/α was determined by 1H NMR spectroscopy.
4

The scope of the present method was then briefly examined with a series of carboxylic
acids (Table 2). When the six-carbon alkyl carboxylic acids such as n-hexanoic acid 2b and 5-
hexynoic acid 2c were used, the glycosylation with sialyl thioglycoside 1 under the optimal
conditions afforded exclusively β-sialyl esters 3b (δC-1 = 165.8 ppm, 3JC1,H3ax = 0 Hz) and 3c
3
(δC-1 = 165.7 ppm, JC1,H3ax = 0 Hz) in 90% and 83% yield, respectively (entries 1 and 2). In
comparison to 2b and 2c, glycosylation of 1 with 5-hexenoic acid under the same conditions
could not yield the desired sialyl ester probably due to the attack of NIS on the double bond of
5-hexenoic acid.10 With regard to long-chain alkyl acids, high yields and good β-
stereoselectivities of 3d (84%, β : α = 5 : 1; β-anomer: δC-1 = 165.8 ppm, 3JC1,H3ax = 0 Hz) and
3e (79%, β : α = 5 : 1; β-anomer: δC-1 = 165.8 ppm, 3JC1,H3ax = 0 Hz) were still observed when
lauric acid 2d bearing a 12-carbon chain or stearic acid 2e bearing an 18-carbon chain was
employed as the coupling partner, respectively (entries 3 and 4). Coupling of thioglycoside 1
with benzoic acid 2f proceeded smoothly to provide sialyl ester 3f in 82% yield with the β-
3
anomer as the major product (β : α = 5 : 1; β-anomer: δC-1 = 165.8 ppm, JC1,H3ax = 0 Hz;
entry 5). Glycosylation of aspirin 2g and α,β-unsaturated cinnamic acid 2h with thioglycoside
1 afforded sialyl esters 3g (65%, β : α = 3 : 1; β-anomer: δC-1 = 165.7 ppm, 3JC1,H3ax = 0 Hz)
and 3h (87%, β : α = 2.5 : 1; β-anomer: δC-1 = 165.9 ppm, 3JC1,H3ax = 0 Hz) in good yields and
moderate β-selectivities which could be explained by the less nucleophilicity of the
nucleophiles (entries 6 and 7).11
Table 2. Conversion of sialyl thioglycoside 1 to a series of sialyl esters 3b-3h under the
promotion of NIS/BF3OEt2.a
5

O
NIS (2 equiv),
BF3OEt2 (2 equiv),
4Å MS, CH2Cl2, rt, 5 min
OAc
OAc
OAc
OAc
COOEt
SAr
AcO
O
R
AcO
O
COOEt
O
RCOOH
(3 equiv)
2b-2h
AcHN
AcHN
AcO
1
AcO
3b-3h
COOH
COOH
CH3(CH2)16COOH
CH3(CH2)10COOH
COOH
2b
2d
2e
2c
COOH
COOH
OAc
2h
2g
2f
Entry
RCOOH
2b
Yieldb (%)
β/αc
1
2
3
4
5
6
7
90
83
β only
β only
5 : 1
2c
84
79
82
65
87
2d
2e
2f
5 : 1
5 : 1
3 : 1
2g
2h
2.5 : 1
a For a typical procedure for this glycosylation: To a solution of compound 1 (134 mg, 0.20
mmol) and freshly activated 4Å MS in anhydrous CH2Cl2 at room temperature, was added
n-hexanoic acid 2b (75 µL, 0.60 mmol) under argon. After stirring at room temperature for
15 min, the mixture was added BF3OEt2 (50 µL, 0.40 mmol) and NIS (90 mg, 0.40 mmol).
After stirring at room temperature for 5 min, the mixture was filtered and the filtrate was
washed with saturated aqueous Na2S2O3, saturated aqueous NaHCO3, respectively. The
organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a residue,
which was purified by silica gel column chromatography (petroleum ether/EtOAc: 1/1 →
1/2) to afford 3b (109 mg, 90%) as a pale yellow syrup.
b Isolated yield.
c The ratio of β/α was determined by 1H NMR spectroscopy.
To investigate whether the present method could be utilized for the conversion of 5-
N,4-O-oxazolidinone protected sialyl thioglycoside to sialyl ester under the optimal conditions,
5-N,4-O-oxazolidinone protected sialyl thioglycoside 412 was synthesized (see supporting
information for details) for glycosylation with acetic acid 2a under the promotion of NIS and
6

BF3OEt2 (Scheme 2). As expected, NIS/BF3OEt2-promoted glycosylation of thioglycoside 4
with acetic acid 2a proceeded smoothly to provide sialyl ester 5 in 77% yield within 15
minutes. Also, we found that the complete β-selectivity obtained with N-acetyl sialyl
thioglycoside 1 as donor (Table 1, entry 5) was compromised to the moderate β-selectivity (β :
3
α = 2.3 : 1; β-anomer: δC-1 = 165.4 ppm, JC1,H3ax = 0 Hz) when the glycosylation was
performed with 5-N,4-O-oxazolidinone protected sialyl thioglycoside 4 as donor. The
moderate β-selectivity could be explained by the resultant force of the α-directed effect of the
5-N,4-O-oxazolidinone protecting group and the β-directed effect of the optimal glycosylation
conditions.
Scheme 2. Conversion of 5-N,4-O-oxazolidinone protected sialyl thioglycoside 4 to sialyl
ester 5 under the promotion of NIS and BF3OEt2.
In summary, we have developed a rapid and efficient one-step approach for the
conversion of sialyl thioglycosides to sialyl esters under the promotion of NIS and BF3OEt2.
The complete β-selectivities for the glycosylation of per-acetylated sialyl thioglycoside with
the short-chain alkyl acids were eroded by introducing the long-chain alkyl acids, aryl acid,
α,β-unsaturated acid, or 5-N,4-O-oxazolidinone protected sialyl thioglycoside as the coupling
partner. The present method serves as a useful tool for the direct transformation of sialyl
thioglycosides to sialyl esters in the synthesis of sialoglycans.
7

Acknowledgements
Financial support from the National Thousand Young Talents Program (YC0130518,
YC0140103), the Shanghai Pujiang Program (15PJ1401500), and the Fundamental Research
Funds for the Central Universities (WY1514052), is gratefully acknowledged.
A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/
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Graphical Abstract
11

Highlights：
•
•
A rapid and efficient conversion of sialyl thioglycosides to sialyl esters was developed.
NIS/BF3OEt2-promoted glycosylation mainly provided β-sialyl esters within 5
minutes.
•
Complete β-selectivities were observed with the short-chain alkyl acids.
12