Moisture Stable Promoters for Selective α-Fucosylation Reactions: Synthesis of Antigen Fragments

Article abstract of DOI:10.1055/s-2004-815415

Moisture stable reagents Yb(OTf)₃ and acid washed molecular sieves (AW 300 MS) can act as mild promoters for selective α-fucosylation reactions. Using a combination of Yb(OTf)₃ and AW 300 MS a good stereocontrol is achieved with a pe

Full text of DOI:10.1055/s-2004-815415

LETTER
275
Moisture Stable Promoters for Selective a-Fucosylation Reactions:
Synthesis of Antigen Fragments
Moisture
S
table Promo
a
ters for Sel
t
ective
t
-Fuco
e
sylationRe
o
actions Adinolfi, Alfonso Iadonisi,* Alessandra Ravidà, Marialuisa Schiattarella
Dipartimento di Chimica Organica e Biochimica, Università degli Studi di Napoli Federico II, Via Cynthia 4, I-80126 Napoli, Italy
Fax +39(81)674330; E-mail: iadonisi@unina.it
Received 14 October 2003
highly reactive b-glycosyl halides on which a mechanism
of direct displacement can occur with alcoholic acceptors,
although long reaction times are generally required.7
Abstract: Moisture stable reagents Yb(OTf)3 and acid washed mo-
lecular sieves (AW 300 MS) can act as mild promoters for selective
a-fucosylation reactions. Using a combination of Yb(OTf)3 and
AW 300 MS a good stereocontrol is achieved with a perbenzylated
fucosyl N-phenyl trifluoroacetimidate donor by exploiting the
directing effect of ether solvents. With the AW 300 MS alone the
selectivity can be obtained with partially acetylated donors by
exploiting a long-range participation effect. Both systems proved
suitable for the synthesis of fragments contained in important anti-
gen sequences, included the Lewis X trisaccharide.
Recently, especially mild glycosidation promoters such as
LiClO4 have been tested to modulate the reactivity of
some fucosyl donors (fucosyl trichloroacetimidates or
fluorides). Moderate yields and selectivities were general-
ly observed.4
In pursuing our investigations aimed at developing glyco-
sylation procedures relying on convenient moisture stable
promoters, we have recently reported8 the feasible use of
catalytic Yb(OTf)3 for the activation of both armed and
disarmed glycosyl trichloro-9 and N-phenyltrifluoroace-
timidates.10 A good stereocontrol was achieved even with
a perbenzylated glucosyl donor devoid of neighbouring
participating groups through the appropriate choice of the
reaction solvent. In particular, satisfying a-selectivities
were obtained with secondary acceptors in ternary mix-
tures containing diethyl ether and dioxane.8b,11 Even better
results in terms of stereocontrol (exclusive formation of a-
glucosides) were registered by using these mixtures in
combination with an armed glucosyl trifluoroacetimidate
equipped at 6-OH with the sterically bulky dimethoxytri-
tyl group.8c Unfortunately this strategy cannot be directly
applied to sugars deoxygenated at their primary position
such as fucose. More recently, 4 Å acid washed molecular
sieves (commercially known as AW 300 MS) were also
found to efficiently activate glycosyl trihaloacetimidates,
although in this case glycosidations did not exhibit a sat-
isfying stereocontrol with donors devoid of participating
groups.12
Key words: carbohydrates, synthesis of oligosaccharides, stereo-
selectivity in fucosylation reactions, acid-washed molecular sieves,
ytterbium triflate
L-Fucose residues with a-anomeric configuration are
commonly found in biologically important oligosaccha-
ridic sequences, many antigen domains included.1 Thus, a
wide interest has been elicited toward the development of
methodologies aimed at the a-stereoselective construction
of this glycosidic linkage, a particularly difficult problem
in oligosaccharide synthesis.2 In fact, fucosyl donors are
quite reactive and amenable to decomposition so that ex-
cess amounts are often required to achieve high glycosi-
dation yields, especially with poorly reactive glycosyl
acceptors.2,3,4a In addition, the a-fucosylation reactions
lead to 1,2-cis-glycosides whose stereoselective construc-
tion cannot be guaranteed by an approach as efficient as
the neighboring participation effect exerted by acyl pro-
tecting groups in position 2 in the stereocontrolled synthe-
sis of 1,2-trans-glycosides.
To face these problems several tactics were described
over the last years such as the use of the inverse procedure
proposed by Schmidt with trichloroacetimidate donors,5
or the adoption of fucosyl donors benzylated at the O-2
and acylated at O-3 and O-4. This latter strategy entails an
increased number of steps for preparing the donor, but
glycosidation yields are generally improved as the partial-
ly acylated donors appear relatively less prone to degrada-
tion than their perbenzylated counterparts,2,6 and
guarantee an improved a-selectivity because of the ability
of O-4 acyl groups to give a long range participation ef-
fect. A good control of stereoselectivity can also be at-
tained by procedures based on the ‘in situ’ generation of
In order to expand the scope of these approaches to bio-
logically relevant oligosaccharide sequences we have
now investigated the feasible application of such promot-
ers in the difficult task of a-fucosylations. For this pur-
pose fucosyl N-(phenyl)trifluoroacetimidates 1 and 2
(Figure 1) were prepared by standard procedures. In order
to reconcile this methodological investigation with the
possibility to prepare useful disaccharide building blocks
to be elaborated into structures of biological interest (such
as the Lewis A, B, X, and Y sequences), secondary model
acceptors 3–5 were chosen. Initial efforts were dedicated
to the feasible synthesis of a-fucosides by adopting the
readily prepared perbenzylated donor 1. In this case the
activation of Yb(OTf)3 was examined in combination
with a-directing solvents. Thus, several conditions were
tested for the coupling of 1 with acceptor 3, starting from
SYNLETT 2004, No. 2, pp 0275–0278
0
2.
0
2.
2
0
0
4
Advanced online publication: 12.01.2004
DOI: 10.1055/s-2004-815415; Art ID: G27803ST
© Georg Thieme Verlag Stuttgart · New York

276
M. Adinolfi et al.
LETTER
those previously8b reported for a perbenzylated glucosyl activation of 2 was initially tested in the attempted fuco-
donor [–10 °C to r.t., 0.1 equiv of Yb(OTf)3, toluene/ sylation of acceptor 4. As a matter of fact the reaction pro-
Et2O/dioxane 4:1:1 as the solvent]. As shown in Table 1 ceeded at room temperature in 24–36 hours to afford the
(entries 1 and 2) fucosyl donor 1 proved to be reactive desired disaccharide 9 in good yield and high a-selectivi-
even at –30 °C in the presence of 0.1 equivalent of ty. Both toluene and dichloroethane proved suitable sol-
Yb(OTf)3 and the ternary mixture dichloromethane/Et2O/ vents for this reaction, comparable results being obtained
dioxane 4:1:1 represented the solvent of choice due to the (entries 5 and 6). The procedure was then tested on accep-
best solubility of the acceptor at low reaction temperature. tors 3 and 5 and afforded the corresponding disaccharides
Under these conditions a good yield was achieved for dis- in good yield and notably high a-selectivity (entries 7 and
accharide 6 together with a good control of stereoselectiv- 8). Having demonstrated the applicability of these alter-
ity. The established conditions of activation were then native fucosylation protocols to the synthesis of several
tested in the a-fucosylation of the glucosamine acceptors disaccharides, their extension to even more complex
4 and 5, and also in these cases synthetically useful results structures, containing less reactive fucosylation sites, was
in terms of both yield and selectivity were smoothly ob- attempted.
tained (entries 3 and 4). Encouraged by these results,
some effort was dedicated to ascertain whether a-selective
We chose the Lewis X trisaccharide as a representative
target to demonstrate the practical applicability of the re-
fucosylations might be achieved with the simple activa-
ported procedures.13 Thus, poorly reactive glucosamine
tion of acid washed molecular sieves taking advantage of
acceptor 5 was initially b-galactosylated with donor 128b
under the exclusive activation of acid washed molecular
a long range participation effect. For this purpose the
AcO
OAc
O
OC(=NPh)CF3
OBn
OC(=NPh)CF3
Ph
O
O
O
O
O
H3C
OBn
OTBDMS
NHTroc
H3C
HO
AcO
OAc
BnO
HO
OAc
2
BnO
OAc
4
1
3
H3C
AcO
OAc
Ph
O
O
BnO
OBn
O
O
O
O
OTBDMS
BnO
AcO
OTBDMS
O
O
AllocO
HO
BnO
OTBDMS
O
O
NHTroc
OBn
AllocO
H3C
OAc
OBn
8
NHTroc
NHTroc
5
O
H3C
BnO
7
BnO
BnO
6
BnO
BnO
OAc
H3C
OAc
Ph
O
O
O
AcO
OBn
O
O
O
AcO
H3C
OTBDMS
O
O
AcO
OTBDMS
OAc
OBn
OAc
NHTroc
OBn
O
AllocO
BnO
H3C
O
NHTroc
9
OAc
OAc
11
10
OAc
Figure 1
Table 1 a-Selective Fucosylation of Acceptors 3–5 under the Agency of Yb(OTf)3 or 4 Å AW 300 MS
Entry
Donor (equiv)
1 (1.4)
Acceptor
Product
Solvent
Procedurea
Yield (%)
a:b
1
2
3
4
5
6
7
8
3
3
4
5
4
4
3
5
6
6
4:1:1 toluene/Et2O/dioxane
4:1:1 CH2Cl2/Et2O/dioxane
4:1:1 CH2Cl2/Et2O/dioxane
4:1:1 CH2Cl2/Et2O/dioxane
Toluene
A
A
A
A
B
B
B
B
66
79
83
75
61
66
78
58
9:1
1 (1.4)
8:1
1 (3.0)
7
> 10:1
> 10:1
10:1
1 (2.5)
8
2 (2.0)
9
2 (2.0)
9
Dichloroethane
10:1
2 (2.0)
10
11
Dichloroethane
only a
only a
2 (2.0)
Toluene
a Procedure A: Yb(OTf)3 (0.1 equiv), 4 Å AW 300 MS, –30 °C, 1–3 h; Procedure B: 4 Å AW 300 MS, from 0 °C to r.t., 24–36 h.
Synlett 2004, No. 2, 275–278 © Thieme Stuttgart · New York

LETTER
Moisture Stable Promoters for Selective a-Fucosylation Reactions
277
BnO
BnO
OBn
O
BnO
BnO
OBn
O
BnO
HO
AllocO
BnO
O
AllocO
O
OTBDMS
O
OTBDMS
+
a
CH3O2CO
TrocHN
CH3O2CO
OC(=NPh)CF3
NHTroc
12
13
5
b
BnO
OBn
O
BnO
O
O
BnO
BnO
OBn
O
O
BnO
OTBDMS
c
BnO
CH3O2CO
H3C
O
NHTroc
O
OTBDMS
NHTroc
OBn
HO
CH3O2CO
O
15 R: Bn
16 R: Ac
RO
14
RO
Scheme 1 a) 4 Å AW 300 MS, dichloroethane, 24 h at 5 °C, 24 h at r.t., 76%; b) Pd(PPh3)4, dimedone, THF, 1.5 h at r.t., 70%; c) for 15: donor
1 (3 equiv), procedure A as in Table 1, 81%; for 16 donor 2 (2.5 equiv), procedure B as in Table 1, 42%.
sieves in good yield (65–76%, Scheme 1). Disaccharide
13 was smoothly deprotected at position 314 of the glu-
cosamine to provide acceptor 14 that was submitted to the
fucosylation procedures previously established. Coupling
with excess of 1 in the presence of catalytic Yb(OTf)3
afforded the trisaccharide 15 in high yield and complete a-
selectivity (81%). Remarkably, the synthesis of the Lewis
X trisaccharide 16 based on the exclusive activation with
AW MS in all the glycosidation steps turned out to be fea-
sible although the final fucosylation proceeded in average
yield (42%) but with complete selectivity.
References
(1) Ernst, B.; Hart, G. W.; Sinaÿ, P. Carbohydrates in Chemistry
and Biology; Wiley-VCH: Weinheim, 2000.
(2) For a discussion on the problems related to a-fucosylations
and pertinent references see: (a) Plante, O. J.; Palmacci, E.
R.; Andrade, R. B.; Seeberger, P. H. J. Am. Chem. Soc. 2001,
123, 9545. (b) Love, K. R.; Andrade, R. B.; Seeberger, P. H.
J. Org. Chem. 2001, 66, 8165.
(3) For other recent examples see: (a) Manzoni, L.; Lay, L.;
Schmidt, R. R. J. Carbohydr. Chem. 1998, 17, 739. (b)Xia,
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Org. Chem. 2003, 68, 2752.
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(5) Schmidt, R. R.; Toepfer, A. Tetrahedron Lett. 1991, 32,
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(6) Flowers, H. M. Carbohydr. Res. 1983, 119, 75.
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(b) Adinolfi, M.; Barone, G.; Iadonisi, A.; Schiattarella, M.
Tetrahedron Lett. 2002, 43, 5573. (c) Adinolfi, M.;
Iadonisi, A.; Schiattarella, M. Tetrahedron Lett. 2003, 44,
6479.
In conclusion, in this paper we have reported the use of
two alternative moisture stable and mild activating
systems of N-phenyltrifluoroacetimidate donors for the
stereocontrolled synthesis of a-fucosides. In a first ap-
proach catalytic Yb(OTf)3 was found to provide good
yields and a-selectivity in short reaction times when used
in combination with solvent mixtures containing diethyl
ether and dioxane.15 In an alternative approach, syntheti-
cally useful results were achieved by activating a partially
acylated fucosyl donor with AW 300 MS.16 In this case a
high stereocontrol could be obtained exploiting a long-
range participation effect of the acyl groups installed at
the fucose residues. Both these approaches were used in
the synthesis of several fragments17 contained in biologi-
cally interesting sequences, including the Lewis X trisac-
charide. The results reported demonstrate that important
oligosaccharidic sequences can be accessed by using pro-
moters, which – in contrast to those adopted in standard
glycosidation procedures – show moisture stability and
remarkable mildness.
(9) Schmidt, R. R.; Kinzy, W. Adv. Carbohydr. Chem. Biochem.
1994, 50, 21.
(10) Yu, B.; Tao, H. Tetrahedron Lett. 2001, 42, 2405.
(11) For a recent review on the synthesis of 1,2-cis-glycosides:
Demchenko, A. Synlett 2003, 1225.
(12) Adinolfi, M.; Barone, G.; Iadonisi, A.; Schiattarella, M. Org.
Lett. 2003, 5, 987.
Acknowledgment
(13) For some examples of syntheses of Lewis X derivatives see
ref.3a,3e. For further examples see: (a) Jacquinet, J.-C.;
Sinaÿ, P. J. Chem. Soc., Perkin Trans. 1 1979, 314.
(b) Hindsgaul, O.; Norberg, T.; Pendu, J. L.; Lemieux, R. U.
Carbohydr. Res. 1982, 109, 109. (c) Lonn, H. Carbohydr.
Res. 1985, 139, 115. (d) Nillsson, M.; Norberg, T.
This work was supported by MIUR (Programmi di Ricerca di Inter-
esse Nazionale 2001 and 2002) and Regione Campania (L. R. 5, a.
2002). NMR spectra were performed at CIMCF (‘Centro Interdipar-
timentale di Metodologie Chimico-fisiche dell’Università di Napoli
Federico II’).
Synlett 2004, No. 2, 275–278 © Thieme Stuttgart · New York

278
M. Adinolfi et al.
LETTER
Carbohydr. Res. 1988, 183, 71. (e) Sato, S.; Ito, Y.; Ogawa,
T. Tetrahedron Lett. 1988, 29, 5267. (f) Classon, B.;
Garegg, P. J.; Helland, A.-C. J. Carbohydr. Chem. 1989, 8,
543. (g) Nillsson, M.; Norberg, T. J. Carbohydr. Chem.
1989, 8, 613. (h) Nicolaou, K. C.; Hummel, C. W.;
Bockovich, N. J.; Wong, C. H. J. Chem. Soc., Chem.
Commun. 1991, 870. (i) Toepfer, A.; Schmidt, R. R.
Tetrahedron Lett. 1992, 33, 5161. (j) Nicolaou, K. C.;
Bockovich, N. J.; Carcanague, D. R. J. Am. Chem. Soc.
1993, 115, 8843. (k) Numomura, S.; Iida, M.; Numata, M.;
Sugimoto, M.; Ogawa, T. Carbohydr. Res. 1994, 263, C1.
(l) vom de Brook, K.; Kunz, H. Angew. Chem., Int. Ed. Engl.
1994, 33, 101. (m) Jain, R. K.; Vig, R.; Locke, R. D.;
Mohammad, A.; Matta, K. L. Chem. Commun. 1996, 65.
(n) Yan, L.; Kahne, D. J. Am. Chem. Soc. 1996, 118, 9239.
(o) Hummel, G.; Schmidt, R. R. Tetrahedron Lett. 1997, 38,
1173. (p) Figueroa-Perez, S.; Verez-Bencomo, V.
temperature was left to rise spontaneously. After complete
consumption of the donor (24–36 h), the mixture was filtered
through a cotton pad and concentrated. The residue was
purified by silica gel chromatography (eluent: hexane/
EtOAc mixtures).
(17) All compounds were identified by 1H NMR and 13C NMR
analyses. Spectroscopic selected data of representative
compounds are reported. Compound 15: 1H NMR (300
MHz, CDCl3): d = 7.50–7.20 (aromatic protons), 5.10 (1 H,
d, J1,2 = 3.9 Hz, H-1 Fuc), 5.07 (1 H, d, J1,2 = 8.2 Hz, H-1
GlcN), 5.03 (1 H, dd, J1,2 = 7.4 Hz, J2,3 = 10.2 Hz, H-2 Gal),
4.62 (1 H, d, H-1 Gal), 4.90–4.34 (17 H, Troc CH2,
7 × benzyl CH2 and H-5 Fuc), 4.18 (1 H, t, J2,3 = J3,4 = 9.6
Hz, H-3 GlcN), 4.04–3.26 (12 H, H-3 Gal, H-4 Gal, H-5 Gal,
H2-6 Gal, H-4 GlcN, H-5 GlcN, H2-6 GlcN, H-2 Fuc, H-3
Fuc, and H-4 Fuc), 3.81 (3 H, s, -OCH3), 3.03 (1 H, m, H-2
GlcN), 1.13 (3 H, d, J5,6 = 6.2 Hz, H3-6 Fuc), 0.86 [9 H, s, -
SiC(CH3)3], 0.08 and 0.03 [6 H, 2 × s, -Si(CH3)2]. 13C NMR
(50 MHz, CDCl3): d = 155.0 and 153.4 (-NH-CO-
Tetrahedron Lett. 1998, 39, 9143. (q) Ellervik, U.;
Magnusson, G. J. Org. Chem. 1998, 63, 9314. (r) Gege, C.;
Vogel, J.; Bendas, G.; Rothe, U.; Schmidt, R. R. Chem.–Eur.
J. 2000, 6, 111. (s) Gege, C.; Oscarson, S.; Schmidt, R. R.
Tetrahedron Lett. 2001, 42, 377. (t) Majumdar, D.; Zhu, T.;
Boons, G.-J. Org. Lett. 2003, 5, 3591.
OCH2CCl3, -O-CO-OMe), 139.3, 139.2, 138.8, 138.6,
138.4, 137.9, and 137.8 (aromatic C), 128.8–127.0 (aromatic
CH), 99.5, 97.3, and 94.4 (C-1 Gal, GlcN, Fuc), 95.1 (-NH-
CO-OCH2CCl3), 55.0 (-OCH3), 25.6 [-SiC(CH3)3], 17.9 [-
SiC(CH3)3], 16.2 (C-6 Fuc), –4.2 and –5.3 [-Si(CH3)2]; other
signals at d = 80.9, 79.6, 78.8, 76.6, 76.0, 75.4, 75.0, 74.7,
73.8, 73.4, 73.2, 72.8, 72.4, 72.3, 68.2, 67.6, 66.4, 61.8.
Compound 16: 1H NMR (400 MHz, CDCl3): d = 7.40–7.15
(aromatic protons), 5.27 (1 H, dd, J2,3 = 10.4 Hz, J3,4 = 3.2
Hz, H-3 Fuc), 5.21 (1 H, bd, H-4 Fuc), 5.15 (1 H, d, J1,2 = 3.6
Hz, H-1 Fuc), 5.11 (1 H, d, J1,2 = 7.8 Hz, H-1 GlcN), 5.00–
4.96 (2 H, m, H-2 Gal and H-5 Fuc), 4.59 (1 H, d, J1,2 = 8.0
Hz, H-1 Gal), 4.72–4.40 (12 H, Troc CH2, 5 × benzyl CH2),
4.20 (1 H, t, J2,3 = J3,4 = 9.4 Hz, H-3 GlcN), 3.98–3.28 (10 H,
H-3 Gal, H-4 Gal, H-5 Gal, H2-6 Gal, H-4 GlcN, H-5 GlcN,
H2-6 GlcN, and H-2 Fuc), 3.78 (3 H, s, -OCH3), 2.91 (1 H,
m, H-2 GlcN), 2.09 and 1.98 (6 H, 2 × s, 2 × acetyl CH3),
0.93 (3 H, d, J5,6 = 6.2 Hz, H3-6 Fuc), 0.84 [9 H, s, -
SiC(CH3)3], 0.06 and 0.01 [6 H, 2 × s, -Si(CH3)2]. 13C NMR
(50 MHz, CDCl3): d = 170.4 and 169.4 (2 × -COCH3), 155.1
and 154.0 (-NH-CO-CH2CCl3, -O-CO-OMe), 138.6, 138.3,
138.3, 138.1, and 138.1 (aromatic C), 129.0–127.2 (aromatic
CH), 99.4, 97.5, 93.9 (C-1 Gal, GlcN, and Fuc), 55.0 (-
OCH3), 25.6 [-SiC(CH3)3], 20.9 and 20.7 (2 × -COCH3),
17.9 [-SiC(CH3)3], 15.2 (C-6 Fuc), –4.2 and –5.3 [-
(14) Tanaka, H.; Amaya, T.; Takahashi, T. Tetrahedron Lett.
2003, 44, 3053.
(15) Procedure A: A mixture of acceptor (0.2 mmol) and donor
1 (see Table 1 for relative amounts) were coevaporated three
times in anhyd toluene and the residue was kept under
vacuum for 1 h. Acid washed molecular sieves (4 Å AW 300
MS, pellets, 200 mg) were then added and the mixture was
dissolved at 0 °C with CH2Cl2 (2.8 mL), and Et2O (700 mL).
After cooling at –30 °C, a solution of Yb(OTf)3 (12.5 mg,
0.02 mmol) in dioxane (700 mL) was added drop-wise. The
mixture was kept under stirring at this temperature until
complete consumption of the fucosyl donor (1–3 h, TLC)
and then few drops of Et3N were added. The mixture was
filtered on a short pad of silica gel, concentrated, and the
residue purified by silica gel chromatography (eluent:
hexane/EtOAc mixtures).
(16) Procedure B: A mixture of acceptor (0.2 mmol) and donor
2 (see Table 1 for relative amounts) were coevaporated three
times in anhyd toluene and the residue was kept under
vacuum for 1 h. Acid washed molecular sieves (4 Å AW 300
MS, pellets, 1.5–2 g) were then added and the solvent
(dichloroethane or toluene, 2–4 mL) was added at 0 °C. The
mixture was kept at 0 °C under stirring for 30 min and then
Si(CH3)2]; other signals at d = 80.5, 74.8, 74.6, 74.4, 73.6,
73.2, 73.1, 72.3, 72.0, 71.8, 70.3, 67.9, 67.8, 64.5, 61.8.
Synlett 2004, No. 2, 275–278 © Thieme Stuttgart · New York