Synthesis of a non-charged analogue of guanosyldiphosphofucose

Article abstract of DOI:10.1016/S0040-4039(01)01906-2

Methylene sulfonoamide is used as a non-charged surrogate of the diphosphate moiety to prepare an analogue of the fucosyl donor guanosyldiphosphofucose of potential use as inhibitor of fucosyltransferases.

Full text of DOI:10.1016/S0040-4039(01)01906-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8821–8824
Synthesis of a non-charged analogue of guanosyldiphosphofucose†
Ge´rald Carchon,a Franc¸oise Chre´tien,a Philippe Delannoy,b Andre´ Verbertb,‡ and Yves Chapleura,*
aGroupe S.U.C.R.E.S, UMR 7565 CNRS-Universite´ Henri Poincare´-Nancy 1, INCM, BP 239,
F-54506 Nancy Vandoeuvre, France
bLaboratoire de Chimie Biologique, UMR 8576, CNRS Universite´ des Sciences et Technologies de Lille,
F-59655 Villeneuve d’Ascq, France
Received 20 July 2001; accepted 10 October 2001
Abstract—Methylene sulfonoamide is used as a non-charged surrogate of the diphosphate moiety to prepare an analogue of the
fucosyl donor guanosyldiphosphofucose of potential use as inhibitor of fucosyltransferases. © 2001 Published by Elsevier Science
Ltd.
The inhibition of fucosyltransferases (FucT) has
become of interest since it has been demonstrated that
fucose-containing oligosaccharides are over-expressed
in tumor cells. On the other hand fucosylated oligosac-
charides such as sialyl LewisX are involved in the
inflammatory process.1 Thus, oligosaccharide biosyn-
thesis blockade by inhibition of fucosyltransferases is a
possible strategy for the intervention on these disorders.
Fucosyltransferases have a substrate, guanosyldiphos-
phofucose 1 (GDP-fucose) from which the fucose
residue is transfered in general to an N-acetyl glu-
cosamine residue of the oligosaccharide. Non-func-
tional analogues of this substrate,2,3 transition
state-multisubstrate analogues4 have been proposed as
candidates for the inhibition of FucT. In this context,
we tried to devise new analogues of GDP-fucose in
which the crucial diphospho linkage would be replaced
by a non-charged isostere group,3,5 the non-charged
character being of help to penetrate the cells. Our
attention was attracted by methylene disulfones which
are isosteric of pyrophosphate and are non-charged.6
Nevertheless the partial negative charge located on the
oxygen atoms of the sulfone would allow complexation
of these oxygen atoms with the manganese ion that
FucTs use normally as a cofactor. Sulfur containing
linkages have been used in the synthesis of nucleotide
analogues.7
Compounds such as 2 with methylene disulfone bridge
were therefore good targets,8 but exploratory experi-
ments on model compounds showed that this moiety
was rather difficult to synthesize in an efficient way.
Here we report our preliminary results in the synthesis
of a non functional analogue 3 of GDP-fucose (Scheme
1) in which the diphospho linkage is replaced by a
methylene sulfono amide tether. In order to have a
non-functional analogue of the donor 1 it was necessary
to replace the anomeric oxygen by a carbon atom thus
an efficient synthesis of a C-glycosyl fucose moiety was
O
N
O
P
O
P
NH
NH2
Me
O
O
O
N
O
N
O
OH O-
-O
OH
HO
HO OH
GDP-Fucose (1)
O
O
N
N
O
X
NH
NH2
S
Me
HO
Y
N
O
O
OH O
OH
HO OH
* Corresponding author. Tel.: +33 383 91 23 55; fax: +33 383 91 24
2
X = SO, Y = O, NH
X = C, Y = NH
79; e-mail: yves.chapleur@meseb.uhp-nancy.fr
3
†
Warmly dedicated to Professor Ge´rard Descotes on the occasion of
his retirement.
Deceased on 21st May 2000.
‡
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01906-2

8822
G. Carchon et al. / Tetrahedron Letters 42 (2001) 8821–8824
O
N
N
N
NH
NH2
O
OZ
HS
H2N
OH
Me
O
O
OH
3
+
+
OH
HO
HO OH
HO
HO
ZO
HO
OH
O
OH
O
D-mannose
HO
OH
Me
HO
Scheme 2.
which exhibited a signal at 8.3 ppm corresponding to
the enolic form upon standing in D2O. This should
reinforce our hypothesis of a possible chelation of our
analogue with manganese ions at the active site of
FucT.
needed. This compound should be suitable for the
construction of the carboxy methylene sulfonyl group.
Finally a suitable derivative of the guanosine residue
was required which would allow the formation of a
stable amide linkage with the fucosyl residue. A ret-
rosynthetic analysis of compound 3, depicted on
Scheme 2, shows three different building blocks. The
synthetic plan was thus: (i) construction of the C-glyco-
syl moiety, (ii) coupling of this moiety with the mer-
capto acetic acid and (iii) coupling of the resulting
fucosyl part with 5%-amino-guanosine.
The guanosine part was prepared using modifications
of the procedures developed by Sasaki for 8-bromo-
guanosine.14 The diol function was first protected as an
acetal and the guanidine group was protected as an
amidine to provide 14.
Introduction of a nitrogen atom at C-5% by nucleophilic
substitution required protection of the second nitrogen
group at N-1 with a MOM group by treatment with
Instead of starting from
syl derivative like 7, we tried to exploit the strong
analogy between -fucose and
-mannose.9 Thus, it
L-fucose to prepare a C-glyco-
L
D
turned out that branching an anomeric methyl group
on a mannose derivative should provide a straightfor-
ward solution to our problem. Moreover we had previ-
ously described a short method for the synthesis of
1-C-methyl glycosyl derivatives by using the Wittig
olefination of sugars.10
HO
HO
O
iv
i, ii, iii
O
O
HO
HO
O
O
O
OH
Z
D-mannose
4 Z = O
5 Z = CCl2
The known 2,3:4,6-di-O-isopropylidene manno deriva-
tive11 was oxidized with CrO3–pyridine into the
lactone 4 in 70% yield (Scheme 3). Treatment of 4
according to our reported procedure gave the
dichloroolefin 5 in 75% yield.12 Hydrogenation of 5
gave the expected C-glycosyl derivative 6 as the single
compound in 65% yield, the methyl group being in a cis
relationship (J2,3 2.4 Hz) with the neighboring acetal
group. Selective removal of the six-membered acetal of
O
O
R2
v
Me
O
O
O
Me
OR1
O
OR1
R1O
6
7 R1 =H, R2 = OH
8 R1 = H, R2 = OTs
9 R1 = Bz, R2 = OTs
10 R1 = Bz, R2 = I
vi
vii
viii
the
L
-C-fucosyl derivative 6 proved unsuccessful and
led mainly to the free tetrahydroxy compound 7. This
compound was then selectively tosylated at the primary
position to give 8, which was subsequently acylated to
give 9 in 80% overall yield. Substitution of the tosylate
by iodide gave the iodo derivative 10 in 98% yield. The
spacer was then grafted to the fucose unit by treatment
of 10 with methyl mercaptoacetate in the presence of
cesium carbonate to give almost quantitatively the ester
11. The sulfone 12 was obtained from mCPBA oxida-
tion in 92% yield. Finally saponification of all the ester
groups with sodium methoxide in methanol gave the
expected free acid 13 after acidification.13 It is worthy
of note, that the proton of the methylene group are
X
COOR2
Me
O
ix
OR1
OR1
R1O
11 X = S, R1 = Bz, R2 = Me
12 X = SO2, R1 = Bz, R2 = Me
13 X = SO2, R1 = R2 = H
x
xi
Scheme 3. Reagents: (i) methoxypropene, DMF, PTSA; (ii)
CrO3, pyridine; (iii) PPh3, CCl4, THF; (iv) Raney Ni, EtOAc;
(v) AcOH, H2O; (vi) TsCl, pyridine; (vii) BzCl, pyridine; (viii)
NaI, butanone; (ix) HSCH2COOMe, CsCO3, DMF; (x)
mCPBA, EtOAc; (xi) MeONa, MeOH.
1
relatively acidic as shown on the H NMR spectrum

G. Carchon et al. / Tetrahedron Letters 42 (2001) 8821–8824
8823
methoxymethyl chloride in the presence of sodium
hydride (1 equiv.) to give 15. Finally the azido group
was introduced at position 5% using standard activation
by a mesyl group. Reduction of the azido group using
Staudinger conditions or better by catalytic hydrogena-
tion with Pd/C 5% provided 18 in 65% yield. The last
steps of the synthesis consisted in the coupling of the
acid 13 with amine 18 using BOP to provide the
protected derivative 19 in 48% yield. Silylation of the
free OH groups of the fucose residue gave the less polar
20 which can be purified by standard column chro-
matography.15 Final removal of all protecting group
was achieved by treatment with trifluoroacetic acid
gave the fully deprotected compound 3.16 Purification
by column chromatography on reverse phase gave pure
compound 317 (Scheme 4).
absence of formal negative charges like in the phos-
phate group. Moreover, the presence of an amide func-
tion in the tether used is this work may induce an
improper spatial arrangement of the fucose and the
guanosine residue. Compounds with significant affinity
should be obtained by mimicking the transition state of
the enzymatic reaction, tacking into account the pres-
ence of the acceptor and/or the planar geometry of the
intermediate glycosyl cation.19 This approach is cur-
rently under investigation in our group.
Acknowledgements
We thank Dr. J. M. Ziegler for electrospray mass
measurement at the mass spectrometry facilities of the
Institut Nance´ien de Chimie Mole´culaire.
This compound did not show any significant inhibition
of fucosyltransferase using a soluble recombinant form
of human FucT-III.18
References
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logue 3 of the natural fucosyl donor GDP-fucose hav-
ing a methylene sulfono amide as a surrogate of the
diphosphate link. One of the key features of our synthe-
sis is the route developed for the preparation of a
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-mannose. Different explana-
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O
N
NR2
H
R1
N
v
N
N
O
NMe2
O
O
14 R1 =OH, R2 = H
i
15 R1 =OH, R2 = MOM
16 R1 =OMs, R2 = MOM
17 R1 =N3, R2 = MOM
18 R1 =NH2, R2 = MOM
ii
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iv
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H
Me
N
H
O
N
O
O
OR1
NMe2
OR1
R1O
O
O
19 R1 =H, R2 = MOM
20 R1 =TMS, R2 = MOM
vi
vii
Scheme 4. Reagents: (i) NaH, MOMCl; (ii) MsCl, CH2Cl2,
NEt3; (iii) NaN3, DMF; (iv) H2, Pd/C 5%; (v) 13, BOP, NEt3;
(vi) TMSCl, NEt3, CH2Cl2; (vii) TFA/H2O 8/2.
9. For previous uses of this analogy, see: (a) Defaye, J.;
Gadelle, A.; Wong, C. C. Carbohydr. Res. 1981, 95,

8824
G. Carchon et al. / Tetrahedron Letters 42 (2001) 8821–8824
131–141; (b) Gesson, J. P.; Jacquesy, J. C.; Mondon, M.;
Petit, P. Tetrahedron Lett. 1992, 33, 3637–3640.
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Hz), 5.36 (dd, 1H, H-2%, J2%–3% 6.6 Hz), 5.76 (s, 2H, CH2
MOM), 5.94 (d, 1H, H-1%, J1%–2% 3.9 Hz), 7.96 (s, 1H, H-8),
8.08 (broad s, 1H, NH), 8.57 (s, 1H, -NꢀCH-); 13C NMR
(62.9 MHz), CDCl3 l (ppm) 0.4, 0.6, 0.9 [3 Si(CH3)3],
16.7 (C-1%%), 25.1, 27.2 (CH3 isopropylidene), 35.3, 41.4
(N(CH3)2), 40.7 (C-5%), 56.1 (C-7%%), 57.5 (CH3 MOM),
61.2 (C-2), 69.7 (C-6%%), 72.8 (CH2 MOM), 74.9, 75.5,
76.0, 76.2, (C-2%%, C-3%%, C-4%%, C-5%%), 81.3, 83.2, 83.9 (C-3%,
C-2%, C-4%), 88.2 (C-1%), 114.6 (C-isopropylidene), 116.8
(C-5 arom.), 137.4 (C-8 arom.), 148.1 (C-4 arom.), 157.5
(C-2 arom.), 157.9 (-NꢀCH-, C-6), 162.2 (C-1).
13. Selected analytical data of 2,6-anhydro-1-deoxy-7-S-(car-
boxymethyl)-7-sulfonyl-D-glycero-D-galacto-heptitol (13):
[h]D +0.7 (c 0.6, H2O); 1H NMR (400 MHz), D2O l
(ppm): 1.13 (d, 3H, H-1, J1–2=6.7 Hz), 3.39 (dd, 1H,
H-5, J5–6 9.5 Hz), 3.54 (d, 1H, H-7, J7–7% 14.3 Hz), 3.56
(dd, 1H, H-4, J3–4 3.5, J4–5 9.4 Hz), 3.64 (d, 1H, H-7%),
3.65–3.73 (broad m, 3H, H-2, H-3, H-6), 3.98 (dd, 1H,
H-8, J8–8% 15.1, J 1.4 Hz), 4.13 (d, 1H, H-8%) H-8 and H-8%
were shifted to 8.34 (s, 1H, H-8) after 48 h; 13C NMR
(62.9 MHz), D2O l (ppm): 18.5 (C-1), 57.4 (C-7), 71.8
(C-5), 74.5 (C-3), 76.6 (C-4), 77.1 (C-6), 77.3 (C-2), 171.0
(C-9), 172.75 (C-8) after 48 h. Anal. calcd for C9H16O8S:
C, 38.02; H, 5.67; S, 11.27. Found: C, 38.49; H, 5.58; S,
11.43.
16. Depending on hydrolysis conditions, formation of some
N-formylated compound during formamidine protecting
group removal should be observed. For a thorough study
of this protecting group, see: Vincent, S.; Mioskowski, C.;
Lebeau, L. J. Org. Chem. 1999, 64, 991–997.
17. Analytical data of acetamide-N-{5%-[5%-deoxy-guano-
sine]}-2-{7%%-[2%%,6%%-anhydro-1%%,7%%-dideoxy-D-glycero-D-
galacto-heptitol]}-sulfonyl (3): 1H NMR (400 MHz), D2O
l (ppm) 1.2 (d, 3H, CH3, J1%%–2%% 6.5 Hz), 3.45 (dd, 1H,
H-5%%, J4%%–5%% 9.5, J5%%–6%% 9.3 Hz), 3.6–3.9 (m, 10H, H-3%%,
H-4%%, H-6%%, H-7%%a, H-7%%b, H-5%a, H-5%b, H-2a, H-2b,
H-4%), 4.15 (m, 1H, H-3%) 4.30 (m, 1H, H-2%), 5.75 (d, 1H,
H-1%, J1%–2% 5.1 Hz), 7.95 (s, 1H, H-8), 8.2 (bs, 1H, NH);
13C NMR (62.9 MHz), D2O l (ppm) 18.3 (C-1%%), 37.2
(C-5%), 43.7 (C-7%%), 58.0 (C-2), 61.2 (C-7%%), 71.6 (C-6%%),
73.4, 75.3, 75.8, 76.5, 77.0, 77.3, (C-2%%, C-3%%, C-4%%, C-5%%,
C-2%, C-3%), 85.0 (C-1%), 90.4 (C-4%) 116.8 (C-5 arom.),
137.4 (C-8 arom.), 149.6 (C-4 arom.), 156.4 (C-2 arom.),
160.1 (C-6 arom.) 167.1 (C-1). EIMS: 549.1 (M+H)+
(100), 447.0 (5), 386.9 (10), 323.1 (5).
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3509–3515.
15. Selected analytical data of acetamide-N-{5%-[N2-(N%,N%-
dimethylaminomethylene)-1-methoxymethyl-5%-deoxy-2%,
3%-O-isopropylidene-guanosine]}-2-{7%%-[2%%,6%%-anhydro-1%%,
7%%-dideoxy-3%%,4%%,5%%-tri-O-trimethylsilyl- D -glycero-D-
galacto-heptitol]}-sulfonyl (20): [h]D −17.3 (c 0.6, CHCl3)
1
IR (cm−1) 3254 (NH), 1682 (CO), 1247 (SO2); H NMR
(400 MHz), CDCl3 l (ppm) 0.15 (s, 9H, 3CH3 silyl), 0.16
(s, 9H, 3CH3 silyl), 0.18 (s, 9H, 3CH3 silyl), 1.05 (d, 3H,
CH3, J1%%–2%% 6.1 Hz), 1.37 (s, 3H, CH3 isopropylidene),
1.60 (s, 3H, CH3 isopropylidene), 3.16 (s, 3H, N(CH3)2),
3.23 (s, 3H, N(CH3)2), 3.36 (d, 1H, H%%-7a, Jgem 15.4 Hz),
3.43 (s, 3H, CH3 mom), 3.51 (dd, 1H, H%%-4%%, J3%%–4%% 2.6,
J4%%–5%% 9 Hz), 3.56–3.73 (broad m, 5H, H-2%%, H-3%%, H-6%,
H-7b%%, H-5a%), 3.77–3.86 (broad m, 2H, H-5%%, H-5b%%,
J5%%–6%% 9 Hz), 4.11 (d, 1H, H-2a, Jgem 13.7 Hz), 4.17 (d, 1H,
H-2b), 4.31 (m, 1H, H-4%), 4.98 (dd, 1H, H%-3, J3%–4% 3.4
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