Anomeric samarium(III) intermediates of N-acetylneuraminic acid from anomeric 2-pyridylsulfides

Article abstract of DOI:10.3987/COM-08-S(F)118

Treatment of the anomeric 2-thiopyridyl derivative of N-acetylneuraminic acid (sialic acid or Neu5Ac) with samarium diiodide in the presence of aldehydes or ketones provides the corresponding C-sialylated derivatives in excellent yields. The efficiency of

Full text of DOI:10.3987/COM-08-S(F)118

HETEROCYCLES, Vol. 77, No. 2, 2009
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HETEROCYCLES, Vol. 77, No. 2, 2009, pp. 1417 - 1424. © The Japan Institute of Heterocyclic Chemistry
Received, 24th September, 2008, Accepted, 23rd October, 2008, Published online, 27th October, 2008
DOI: 10.3987/COM-08-S(F)118
ANOMERIC
SAMARIUM(III)
INTERMEDIATES
OF
N-ACETYLNEURAMINIC
ACID
FROM ANOMERIC
2-PYRIDYLSULFIDES
Adeline Malapelle, Zouleika Abdallah, Gilles Doisneau, and Jean-Marie
Beau*
Université Paris-Sud 11, Institut de Chimie Moléculaire et des Matériaux associé
au CNRS, Laboratoire de Synthèse de Biomolécules, 91405 Orsay Cedex, France
Fax: (+33) 1-6985-3715. E-mail: jmbeau@icmo.u-psud.fr
Abstract – Treatment of the anomeric 2-thiopyridyl derivative of
N-acetylneuraminic acid (sialic acid or Neu5Ac) with samarium diiodide in the
presence of aldehydes or ketones provides the corresponding C-sialylated
derivatives in excellent yields. The efficiency of the reductive samariation of the
anomeric 2-pyridylsulfide moiety in the Neu5Ac series does not require any
cosolvent or additive. This samarium Reformatsky-like reaction from anomeric
2-pyridylsulfide derivatives of Neu5Ac provides an efficient and highly
stereoselective access to α-2,6-C-disaccharides.
N-Acetylneuraminic acid (Neu5Ac) is the more common nine-carbon member of the ulosonic acids
family, that are important constituents of numerous oligosaccharides and glycoconjugates.1 The terminal
position of the Neu5Ac residues in these conjugates confer a major role to these structures in many
biological processes.2,3 The α-glycosidic linkage of this important structural unit exhibits however poor
chemical and enzymatic hydrolytic stability thus providing unstable tools for biological research. The
replacement of the interglycosidic oxygen by a carbon atom provides carbon-linked analogues
(C-glycosides) that are stable to hydrolysis.4 Based on our previous work on neutral aldoses5 and
2-acetamido-2-deoxy-sugars,6 Linhardt and coworkers7 have reported, over the past years, efficient and
stereoselective access to C-glycosides of Neu5Ac based on the reductive metallation of anomeric aryl
sulfones and chloride. In an effort to further simplify the preparation of the anomeric organometallic
precursor, our laboratory previously reported procedures that rely on the reductive samariation of
standard peracetylated intermediates8 and subsequent coupling with carbonyl electrophiles. Along these
This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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HETEROCYCLES, Vol. 77, No. 2, 2009
lines, and during the course of a synthesis of a carbon-linked mimic of the disaccharidic unit of the
tumor-related sialyl-Tn antigen, we also showed that the use of 2-pyridyl sulfide of N-acetyl neuraminic
acid derivative 3 as the anionic precursor in a samarium-Reformatsky procedure was remarkably
efficient.9 This prompted us to study this coupling reaction with diverse substrates and we report here the
details and the scope of the reaction.
The crystalline sulfide 3 was prepared from commercial Neu5Ac 1 according to the reactions described
in Scheme 1. Commercial Neu5Ac 1 was quantitatively esterified in a methanolic acid solution and the
methyl ester thus obtained was subsequently treated by a 1/1 mixture of acetic acid and acetyl chloride
saturated at 0°C with hydrogen chloride to furnish the chloride 2.10 With 2-thiopyridine as nucleophile
(3.7 equivalents) in biphasic reaction conditions, the anomeric chloride 2 gave 3 in 60% yield. The same
reaction using thiophenol as a nucleophile gave the corresponding anomeric thiophenyl derivative 4 in
68% yield.
+
OH
OAc
1. MeOH, Dowex H
2. HCl, AcOH/AcCl (1/1)
HO
AcO
CO H
2
Cl
O
O
OH
CO Me
2
AcHN
HO
AcHN
AcO
83%
OH
OAc
1
2
OAc
AcO
ArSH, AcOEt/H O
2
NaHCO , NBu SO H
CO Me
2
3
4
3
O
S
AcHN
AcO
X
OAc
3, X= N, 60%
4, X= CH, 68%
Scheme 1
We started our study on the reductive samariation of 3 in the presence of reactive cyclic ketones (2
equivalents). The coupling reaction with cyclobutanone gave the C-sialyl derivative 5 in 96% yield. As
expected and in agreement with previous observations on the reductive coupling from other anomeric
derivatives,7,8 only one diastereomer with an equatorial orientation of the new C-C bond could be detected
1
by H-NMR analysis of the crude product. Reactions with cyclopentanone and cyclohexanone gave with
equal efficiency the corresponding coupling products 6 and 7 in 94% and 82% yields, respectively
(Scheme 2).
OAc
OAc
AcO
AcO
CO Me
2
CO Me
2
SmI THF
2,
( )
n
O
O
S
AcHN
AcO
AcHN
AcO
O
N
OAc
HO
OAc
3
, rt
5, n = 1, 96%
6, n = 2, 94%
7, n = 3, 82%
( )
n
Scheme 2

HETEROCYCLES, Vol. 77, No. 2, 2009
1419
We were pleased to observe that the Sm(II) reduction of the anomeric 2-thiopyridyl group of the substrate
was instantaneous at room temperature as indicated by the rapid discoloration of the dark blue THF-SmI2
solution. The first electron transfer from Sm(II) to the 2-thiopyridyl group was fast enough to avoid the
addition of cosolvants like HMPA,11 DMPU,12 or other chelating agents.13,14
The reaction leading to α-C-sialosides was then examined with several simple electrophiles including
acyclic ketones or aliphatic aldehydes. The coupling reactions from 3 always proceeded in high yields
with total selectivity in favor of a new equatorial C-C bond. Table 1 lists the results of these reactions.
The products obtained from the coupling with an unsymmetrical ketone (entry 1, Table 1) or from
aldehydes (entries 3-5, Table 1) were isolated as a 1/1 mixture of two diastereoisomers at the exocyclic
asymmetric center. The selective formation of monomeric or dimeric structures could be achieved using
1.4 or 0.45 equivalent of 1,4-cyclohexandione (entries 7-8, Table 1), providing adducts 14 and 15,
respectively. Reactions were strictly conducted under Barbier conditions, due to the instability of the
intermediate organosamarium species, and under an argon atmosphere as samarium diiodide is highly
oxygen sensitive.
Table 1. Reductive samariation of 3 with simple electrophiles
OAc
OAc
AcO
AcO
CO Me
CO Me
2
2
SmI THF
O
2,
1
R
O
+
O
S
AcHN
AcO
AcHN
AcO
1
2
2
rt
R
R
R
N
OAc
HO
OAc
3
8-13
1
2
[a]
Entry
R
R
Product
Yield
[b]
Me
Et
Et
Et
8
9
81%
69%
75%
1
2
[b]
[b]
[b]
10
3
4
5
C H
7 15
H
H
H
11
12
78%
90%
(CH ) OTBS
2 2
Cy
O
13
96%
tBu
6
7
8
[c]
14
89%
96%
O
O
[d]
15
O
O
OAc
OAc
AcO
AcO
OAc
OAc
HO
CO Me
O
2
AcO
CO Me
O
2
NHAc
OAc
O
AcHN
AcO
O
AcHN
AcO
CO Me
OH
2
OAc
OH
OAc
14
15
[a] Yields for isolated products after chromatography on silica gel. [b] As a 1:1 mixture of diastereomers. [c] Reaction in
the presence of 1.4 equiv. of 1,4-cyclohexanedione. [d] Reaction in the presence of 0.45 equiv. of 1,4-cyclohexanedione.
Cy = cyclohexyl.

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HETEROCYCLES, Vol. 77, No. 2, 2009
The high efficiency and selectivity of this reaction was exemplified by the quantitative formation of the
C-sialoside 13 issued from the coupling of 3 with 4-tertbutylcyclohexanone. We assume that this
Reformatsky-like reaction goes through the formation of a samarium enolate which reacts with
electrophiles from its less hindered α-face, leading to the formation of an equatorial carbon-carbon bond.
The two diastereotopic faces of the 4-tert-butylcyclohexanone are also highly discriminated by the
organosamarium intermediate which reacts at its more accessible one leading to a single diastereomer
(Scheme 3).
less hindered face
tBu
AcO
AcO
O
III
Sm
AcO
AcO
CO Me
2
O
tBu
OMe
O
O
coupling
AcHN
AcO
AcHN
AcO
OH
OAc
OAc
13
single diastereomer
less hindered face
Scheme 3
A possible explanation for the formation of a samarium(III) enolate is given in Scheme 4, although no
detailed mechanistic study was undertaken. The reaction proceeds through two successive electron
transfers. With the 2-pyridyl sulfide group, activation of the carbon-nitrogen double bond through a
pre-complexation of the samarium(II) reagent as in complex I (Scheme 4) would precede the first electron
transfer into the pyridyl nucleus. Carbon-sulfur bond cleavage that follows is fast because of the
formation of an anomeric radical III further stabilized by the adjacent methyl ester group. The geometry
of this enolate could be the one shown in V with a coordination of the oxophilic Sm(III) to the adjacent
endocyclic oxygen, leading to the cyclic structure.
MeO
MeO
II
MeO
III
O
O
O
O
O
O
Sm
Sm
N
SmI /THF
2
SmI (SPyr)
2
3
N
reduction
complexation
S
S
I
II
III
O
MeO
III
Sm
O
SmI
III
2
Sm
OMe
O
O
SmI
2
nucleophilic samarium enolate
IV
V
Scheme 4

HETEROCYCLES, Vol. 77, No. 2, 2009
1421
Under the same reaction conditions, the anomeric phenyl sulfide 4 does not react with samarium diiodide,
and only 25% of the coupling product can be isolated from the reaction with cyclopentanone in the
presence of 4 equivalents of HMPA (results not shown). This demonstrates the crucial role of the
2-pyridyl moiety in 3 that may act as an external ligand like HMPA, inducing a faster internal electron
transfer and formation of the anomeric radical (Scheme 4). As we suggested earlier,4a the initial homolytic
cleavage of the C-S bond is faster as it leads to a stabilized captodative radical.15 With this very reactive
sulfide derivative, the use of only 2.2 equivalents of samarium diiodide is sufficient enough to achieve the
complete conversion of the starting material.
We then focused on the reaction with more elaborated electrophiles derived from monosaccharides in
order to prepare 2,6-C-disaccharidic derivatives of Neu5Ac. The coupling reactions of 3 with the sugar
aldehyde derivatives 16,16 17,5f and 18 9 gave the corresponding C-dimers 19-21 in high yields, each
isolated as an equimolar mixture of diastereomers (Table 2).
Table 2. Preparation of the carbon-linked disaccharides by reductive samariation of 3
[a]
Electrophile
Product (yield)
Me
Entry
OAc
O
O
O
AcO
O
O
O
O
O
O
O
1
O
O
AcHN
AcO
O
O
OH
OAc
16
19 (82%)
O
OAc
OBn
AcO
AcHN
CO Me
2
OBn
O
O
2
BnO
BnO
OBn
OMe
O
BnO
AcO
OH
OAc
OMe
17
20 (80%)
O
OAc
AcO
TESO
AcHN
CO Me
2
OTES
O
NHAc
OBn
OMe
[b]
O
3
O
AcHN
AcO
BnO
OH
OAc
OMe
18
21 (93%)
[a] Yields for isolated products after chromatography on silica gel. [b] Taken from ref. 9; TES = triethylsilyl.
One should take notice of the remarkable efficiency of the reaction even for the coupling with the
aldehyde derived from a GalNAc unit 18 in which the electrophile also possesses an acidic proton
(NHAc), considering that these coupling reactions process through sensitive organometallic species.8a
In conclusion, the reductive samariation of the acetylated pyridyl sulfide of methyl N-acetyl-neuraminate
in the presence of a variety of carbonyl compounds provides a useful and high yielding approach for

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HETEROCYCLES, Vol. 77, No. 2, 2009
stereoselective α-C-sialylation. The reactions are very efficient even for the challenging preparation of
C-disaccharides. This procedure complements the use of the corresponding peracetylated derivatives that
react in excellent yields only with simple and more reactive cyclic carbonyl compounds8 but that are not
efficient enough for the coupling with the more demanding sugar-derived aldehydes.
EXPERIMENTAL
For the general conditions see reference 8b.
Preparation of a 0.1M THF solution of samarium diiodide
Samarium powder (0.190 g, 1.26 mmol) was placed in a dry flask under argon. After stirring for 15 min.,
1,2-diiodoethane (0.280 g, 1.00 mmol) was added and the mixture was stirred for 10 min. Freshly
distilled THF (10 mL) was slowly added and the content of the flask was magnetically stirred for at least
5 h at room temperature to give a deep blue solution.
Two representative procedures for the SmI2 coupling reactions:
C-Dimer 15
A 0.1M solution of SmI2 in THF (4.5 mL, 0.45 mmol of SmI2) was added to a stirred THF (1 mL)
solution of pyridyl sulfide 3 (114 mg, 0.19 mmol) and 1,4-cyclohexanedione (9.6 mg, 0.085 mmol, 0.45
eq) at 20 °C under Ar. After stirring the mixture for 10 min, saturated aqueous NH4Cl was added and the
reaction mixture was extracted 3 times with CH2Cl2. The combined organic phases were washed twice
with water, dried with Na2SO4, evaporated and co-evaporated with toluene. The crude product was
purified by flash chromatography on silica gel (toluene/acetone, 1/1) to yield 15 (88 mg, 0.083 mmol,
98%). Mp 243 °C (toluene/acetone); 1H NMR (CDCl3, 360 MHz): δ (ppm) = 5.42 (ddd, 2 H, J8,7 = 8.2 Hz,
J8,9b = 6.6 Hz, J8,9a = 2.6 Hz, H-8), 5.29 (dd, 2 H, J7,8 = 8.0 Hz, J7,6 = 1.8 Hz, H-7), 5.13 (d, 2 H, JNH,5 = 9.6
Hz, NH), 4.72 (ddd, 2 H, J4,3ax = 11.9 Hz, J4,5 = 9.7 Hz, J4,3eq = 4.6 Hz, H-4), 4.32 (dd, 2 H, J9a,9b = 12.4 Hz,
J9a,8 = 2.6 Hz, H-9a), 4.05-3.95 (m, 6 H, H-6, H-5, H-9b), 3.75 (s, 6H, CO2CH3), 2.77 (br s, 2 H, OH), 2.45
(dd, 2 H, J3eq,3ax = 12.8 Hz, J3eq,4 = 4.6 Hz, H-3eq), 2.16, 2.13, 2.04, 2.00 (4s, 24H, 8 OAc), 1.92 (t, 2 H, ,
J3ax,3eq = 12.8 Hz, J3ax,4 = 11.9 Hz, H-3ax), 1.85 (s, 6H, NAc), 1.75-1.58 (m, 8 H, CH2 of cyclohexyl);13C
NMR (CDCl3, 90 MHz): δ (ppm) = 171.1, 170.8, 170.2, 170.1, 169.9, and 169.8 (8 OCOCH3, 2 NCOCH3,
2 COOCH3), 86.0 (C-2), 74.6 (COH), 73.2, 70.4, 68.6, 67.9 (C-4, C-6, C-7, C-8), 62.8 (C-9), 52.4 (CH3O),
49.4 (C-5), 33.1 (C-3), 27.9-26.6 (4 CH2 of cyclohexyl), 23.2, 21.4, 20.9, 20.8, and 20.7 (8CH3OCO,
2CH3CON); MS (ESI): m/z = 1085.5 [M+Na]+; HR-MS (ES) for C46H66O26N2Na; Calcd: 1085.3796;
Found: 1085.3819. Anal. Calcd for C46H66O26N2: C, 51.97; H, 6.26; N, 2.64; Found: C 51.64; H 6.22; N
2.31.

HETEROCYCLES, Vol. 77, No. 2, 2009
1423
C-Disaccharide 20
A 0.1M solution of SmI2 in THF (1.12 mL, 0.112 mmol of SmI2) was added to a stirred mixture of
pyridyl sulfide 3 (30 mg, 0.051 mmol) and freshly prepared aldehyde 17 (49 mg, 0.103 mmol) at 20 °C
under Ar. After treatment of this reaction mixture as described above, a flash chromatography
(toluene/acetone, 3/1) gave 20 (38.8 mg, 80%) as a 1/1 mixture of isomers. Selected data for (R/S)
mixture: 1H NMR (CDCl3, 360 MHz, atom numbering of the dimer): δ (ppm) = 7.40-7.25 (m, 30 H, Ph),
5.45 (ddd, 2 H, J8,7 = 7.4 Hz, J8,9b= 6.4 Hz, J8,9a = 2.2 Hz, H-8), 5.33-5.29 (m, 2 H, H-7), 4.94 (dd, 1 H, J =
10.8 Hz, J = 1.8 Hz, H-2’), 4.82-4.55 (d, 12 H, J = 11.2 Hz, CH2Ph), 4.31-3.57 (m, 22 H, H-3’, H-4’, H-5’,
2 H-6’, H-4, H-5, H-6, H-9a, H-9b, H-7’), 3.73 (s, 3H, COOMe), 3.65 (s, 3H, COOMe), 3.23 (s, 6 H,
OMe), 2.34 (dd, 2 H, J3eq,3ax = 13.0 Hz, J3eq,4 = 4.8 Hz, H-3eq), 2.12, 2.08, 2.02, 2.01, 2.00, 1.97 (6s, 24 H,
OAc), 1.86 (t, 2 H, J3ax,3eq = 13.0 Hz, J3ax,4 = 12.5 Hz, H-3ax), 1.85 (s, 3 H, NAc), 1.84 (s, 3 H, NAc). MS
(ES): m/z = 974 [M+Na]+; HR-MS (ES) for C49H61O18NNa; Calcd: 974.3786; Found: 974.3798.
ACKNOWLEDGEMENTS
We are grateful to the Ministère de la Recherche for Ph.D grants to A. M. and Z. A. and for the financial
support of this study.
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