Synthesis of a novel dioxan sialic acid analog

Article abstract of DOI:10.1016/j.tetlet.2004.03.135

A preparative scale synthesis of a dioxan sialic acid analog was achieved from D-mannose. The conformation and the acidic character of this dioxan derivative, closely related to sialic acid, provides a scaffold for drug design.

Full text of DOI:10.1016/j.tetlet.2004.03.135

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4163–4166
Synthesis of a novel dioxan sialic acid analogq
*
ꢀ
Franßcoise M. Perron-Sierra, Mike Burbridge, Christophe Pean,
Gordon C. Tucker and Patrick Casara
Institut de Recherches Servier, 125 chemin de Ronde, 78290 Croissy sur Seine, France
Received 13 February 2004; revised 18 March 2004; accepted 22 March 2004
Abstract—A preparative scale synthesis of a dioxan sialic acid analog was achieved from D-mannose. The conformation and the
acidic character of this dioxan derivative, closely related to sialic acid, provides a scaffold for drug design.
Ó 2004 Elsevier Ltd. All rights reserved.
Cell-surface glycoproteins are involved in a wide variety
of biological cellular events1 such as the specificity of cell
function, cell–cell communication, cell–cell/cell-extra-
cellular matrix recognition, or migration events, as well
as transport mediation.
of 2, incorporating the key structural elements for sialyl-
transferase recognition9 such as the strong acidic char-
acter of anomeric carboxylic acid (pKa ꢀ 3), the glycerol
side chain, the N-acetamide functionality10 and removal
of the nonessential hydroxyl at C4 (Fig. 1).2;7b
Glycoproteins comprising a terminal sialylated tetra-
saccharide (sialyl lewis x or a sialylated epitope) are
implicated in physiological and pathological situations2
such as embryogenesis, cell differentiation, inflamma-
tion3 (recruitment of leukocytes), cancer (metastasis),4
influenza virus mediated infection, or immune-defense
system detoxification.5 Inhibition of adhesion events has
been attempted via the design of selectin or sialyl Lewis
In order to validate this hypothesis, various simplified
monosubstituted cyclic ketals 5 and 6 were synthesized
(Scheme 1).11 Their probable pKa’s were calculated12 and
for the most interesting ones, pKa’s were determined
experimentally13 (Table 1). The various combinations,
dioxane, dithiane, and hemithioacetal ring systems,
appeared to have the lowest pKa values, close to the pKa
of sialic acid. Moreover, the dioxane arrangement
seemed the most appropriate since the cyclization pro-
ceeded in a stereospecific manner, leading solely to the
requisite isomer. The stereoelectronic effect of the two
oxygens, enabling electronic delocalization, favor an
x
antagonists (tetrasaccharides),6 sialyltransferase
inhibitors (bisphosphates),7 and half-chair oxonium
transition state mimics.8 Therefore, we proposed to
construct compound 4, a conformationally stable mimic
OH
HO
OH
CO2H
OH
OCMP
HO
HO
+
O
HO
HO
CO2H
HO
AcHN
O
O-galac-glycoprotein
Cytidine Monophosphate (CMP)
O
CO2H
β
α
AcHN
AcHN
HO
HO
HO
+
1
3
+
2
OH
HO-galac-glycoprotein
HO
H
X
4
HO
AcHN
Y
CO2H
Figure 1. Sialyltransferase transition state.
Keywords: Sialic acid; Sialyltransferase; Sialidase.
q Supplementary data associated with this article can be found, in the online version, at doi: 10.1016/j.tetlet.2004.03.135
* Corresponding author. Tel.: +33-1-55-72-24-86; fax: +33-1-55-72-24-70; e-mail: francoise.perron@fr.netgrs.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.135

4164
F. M. Perron-Sierra et al. / Tetrahedron Letters 45 (2004) 4163–4166
HO
O
R
O
XH
OH
R
H
i
+
R
X
OEt
X
+
YH
O
Y
O
Y
5
6
Scheme 1. Synthesis of various six membered-ring-[1,3]-heterocycles. Reagents and conditions: (i) (a) BF3ÆOEt2, HCOCO2Et, CH2Cl2; (b) LiOH,
H2O, MeOH.
Table 1. Structures and yields of compounds 5 and 6 and pKa for compounds 5
R
X
Y
Yield
(%)
5/622
pKa (5)
Found
Ref.
Calcd
CH3
C3H7
H
O
S
O
75
70
50
50
30
––
100/0
85/15
5 ꢀ 623
100/0
100/0
––
3.07
3.1
3.4
3
24
25
25
26
26
––
O
S
S
3.03
3.88
3.95
2.3
ND
ND
ND
3.2
C2H5
CH3
Sialic acid
NH
O
O
NH
NH
CH2
equatorial conformational of the carboxylic acid sub-
stituent.14 Therefore, compound 4 (X, Y ¼ O) fulfilled
the required electronic elements to mimic the transition
state of sialic acid.
gen dibenzylation gave compound 7a, which was selec-
tively deallylated and reduced at the anomeric position16
to form diol 8a. The primary alcohol was selectively
silylated as 8b, the benzylidene precursor of dioxane ring 4.
The transformation of the remaining secondary
a-hydroxy into the corresponding acetamide with
retention of configuration was achieved in four steps,
involving alcohol oxidation, and oxime formation of the
resulting ketone.17 The oxime reduction proceeded ste-
reospecifically, from the a-face, presumably governed by
steric and stereoelectronic effects and by a possible
To elaborate the five chiral centers on the dioxane
backbone, natural sugars were envisioned as starting
materials (Fig. 2). Starting from D-mannose, the ano-
meric position was first protected as an allyl ether fol-
lowed by sequential 4,6-benzylidene formation,15
masking the dioxane oxygens (Scheme 2). The 2,3-oxy-
H
H
OH
OH
O
O
H
HO
HO
HO
HO
HO
HO
HO
HO
HO
AcHN
O
HO
AcHN
O
4
CO2H
HO
HO
OH
OH
O
OH
OH
NHAc
OH
OH
D-Mannose
OH
OH
Figure 2. Retrosynthesis of compound 4.
HO
HO
OBn
OBn
O
OBn
TBSO
O
HO
HO
O
iii
BnO
HO
O
i
OH
OR
O
O
BnO
O
BnO
O
OH
OR
8b
7a R=Allyl
7b R=H
8a R=H
8b R=TBS
ii
iv
OBn
OBn
BnO
OBn
OBn
BnO
BnO
AcHN
TBSO
BnO
v
vii
vi
viii
OEt
BnO
AcHN
OH
O
OH
OH
9%
BnO
AcHN
O
BnO
AcHN
O
O
O
O
9
EtO
11
10
12
nOe
OBn
Hb
OH
OBn
Ha
O
BnO
OBn
6%
Hc
HO
BnO
BnO
H
ix
BnO
x
OH
xi
OH
OH
H
O
HO
BnO
AcHN
BnO
AcHN
O
O
O
AcHN
AcHN
O
O
O
14
4
13
11
Hd
Scheme 2. Synthesis of compound 4. Reagents and conditions: (i) (a) AcCl, allylOH, pyridine (quant.); (b) PhCH(OMe)2, PTSA (90%); (c) BnBr,
NaH, (90%). (ii) SeO2, AcOH (60%). (iii) (a) NaBH4, MeOH (90%). (iv) TBDMSCl, imidazole (92%). (v) (a) PCC, (90%); (b) NH2OH, (90%); (c)
LiAlH4, Et2O (80%); (d) AcCl, NEt3 (90%). (vi) (a) TBAF, (70%); (b) BnBr, NaH, (90%). (vii) PTSA, MeOH (64%). (viii) BF3ÆOEt2, HCOCO2Et,
CH2Cl2 (70%). (ix) acrolein, nBuSnCl3 (80%). (x) (a) OsO4, NMO, tBuOH, H2O (83%); (b) NaIO4, CH2Cl2 (quant.). (xi) (a) AgO, CH3CN (40%); (b)
H2, Pd/C (90%), (quant.).

F. M. Perron-Sierra et al. / Tetrahedron Letters 45 (2004) 4163–4166
4165
aluminum complexation by the ketal oxygens, yielding
the desired isomer 9 in 72% yield, after acetylation of the
crude amine. Replacement of the O-silyl by a O-benzyl
gave the orthogonally protected intermediate 10, which
was hydrolyzed to the key diol 11 in 20% overall yield
from mannose. When compound 11 was subjected to
diethoxyacetic acid ethyl ester as in the model study, no
cyclization occurred in the various acidic reaction con-
ditions attempted, compatible with the benzyl group
stability. The transient a-carbethoxy oxonium was rap-
idly trapped by the ethoxy counterion, producing the
corresponding mixed acetal 12. To successfully perform
the cyclization, it was necessary to stabilize the oxonium
intermediate via the appropriate introduction of a sub-
stituent, precursor of a carbethoxy functionality and
allowing charge delocalization, such as a vinyl group.
When diol 11 was combined with an excess of acrolein in
the presence of catalytic butyltintrichloride, the cycli-
zation was performed in excellent yield, giving the
desired isomer 13 as a single product.18 Conventional
functional group manipulation involving osmylation of
the exocyclic olefin, sodium periodate-catalyzed bond
breaking to aldehyde 14, and subsequent silver nitrate
acid backbone, reminiscent of CMP-sialic acid sub-
strate, and/or a sugar-like substituent. Incorporation of
the dioxan sialic acid moiety 4 at the terminus of sialyl-
conjugates as new bisubstrate analogs is underway.
Supplementary material: spectroscopic and physical
characterization data for compound 4 (1H, 13C NMR
spectra, IR, CHN, MH, optical rotation).
Acknowledgements
The authors wish to thank Sabine Plantier for her
skillful technical assistance and Solange Huet for the
preparation of the manuscript. We would like also to
acknowledge the analytical department at the Institut de
Recherches Servier for performing all the spectral
analyses.
References and notes
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