Fast and efficient preparation of an α-fucosyl building block by reductive 1,2-benzylidene ring-opening reaction

Article abstract of DOI:10.1055/s-2008-1077961

1,2-Benzylidene ring opening on fucose was promoted in the presence of different reducing agents and Lewis acids, providing a fast access to fucosyl building blocks.

Full text of DOI:10.1055/s-2008-1077961

LETTER
1969
Fast and Efficient Preparation of an a-Fucosyl Building Block by Reductive
1,2-Benzylidene Ring-Opening Reaction
Preparationof
an
a
a
-Fucosyl
B
n
uilding Bloc
i
k
el B. Werz,* Heiko J. Schuster, Lutz F. Tietze
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstraße 2, 37077 Göttingen, Germany
Fax +49(551)399476; E-mail: dwerz@gwdg.de
Received 8 May 2008
The fucosyl motif is found to be one of the most redundant
Abstract: 1,2-Benzylidene ring opening on fucose was promoted in
monosaccharide units for the termination of mammalian
the presence of different reducing agents and Lewis acids, provid-
ing a fast access to fucosyl building blocks.
oligosaccharides at their non-reducing end.7 Commonly,
it is linked by an a-glycosidic bond to the adjacent
Key words: carbohydrates, fucose, building block, protecting
monosaccharide moiety (cf. Figure 1).7
group, benzylidene
To create such a linkage one cannot rely on neighboring-
group participation at the C-2 hydroxyl due to the cis ar-
rangement of the two C–O bonds. Thus, an efficient a-fu-
cosyl building block requires a non-participating group
such as a benzyl (Bn) ether at the C-2 hydroxyl. Recent
studies have shown that ester groups such as pivaloyl
(Piv) or benzoyl (Bz) at the C-4 hydroxyl increase the a/b
selectivity during the glycosylation reaction.8 It is as-
sumed that the ester functionality acts as a remote partici-
pating group when the oxocarbenium intermediate is
formed and the attack of the nucleophile occurs only from
the upper (a) face (Figure 2).8 To generate such a protect-
ing-group pattern with an ester functionality in position 4
and an ether moiety in position 2 several synthetic routes
have been developed.9 However, all of them are quite
lengthy and require at least seven steps starting from un-
protected L-fucose.
Fucosylated oligosaccharides are crucial for a variety of
biological processes including tissue development, angio-
genesis, fertilization, inflammation, cell adhesion, and tu-
mor metastasis.1 Among fucosylated carbohydrates,
Lewis X and Lewis Y,2 the ABH-antigens,3 and Globo-H4
are the most prominent structures from the biological as
well as the synthetic point of view. Figure 1 depicts two
examples of fucose-containing oligosaccharides such as
the A antigen (1),3 being responsible for blood group A,
and the tumor-associated antigen Globo-H (2).4 But also
antitumor agents such as the camptothecine derivative5
(3) contain a fucosyl moiety. It is known that abnormal fu-
cosylation occurs in many diseases1 and recently it was
shown that Gal-Fuc derivatives play also an important
role in the nervous system.6
OH
HO
HO
O
OH
OH
OH
OH
O
HO
OH
O
O
O
AcHN
HO
O
O
HO
O
O
O
O
OH
OH
O
NHAc
N
O
Me
O
N
O
OH
O
A antigen (1)
OH
HO
O
HN
S
O
OH
OH
OH
O
HO
HO
HO
HO
O
O
N
N
O
O
H
H
O
Me
HO
O
N
OH
HO
NHAc
O
HN
O
OMe
OH
OH
⋅
HCl
Me
O
O
O
O
HO
OH
HO
O
OH
OH
HO
OH
camptothecine derivative (3)
Globo-H (2)
Figure 1 Fucose-containing antigens such as the blood-group-A antigen and the breast-cancer-associated antigen Globo-H; a fucosylated
camptothecine derivative that is an excellent antitumor agent is also shown
SYNLETT 2008, No. 13, pp 1969–1972
x
x
.x
x
.2
0
0
8
Advanced online publication: 15.07.2008
DOI: 10.1055/s-2008-1077961; Art ID: G16308ST
© Georg Thieme Verlag Stuttgart · New York

1970
D. B. Werz et al.
LETTER
Br
OBn
R2
O
Me
OH
OH
1) BzCl, py
O
Me
HO
O
Me
O
OR3
H
OBz
2) HBr/AcOH,
CH2Cl2
(63% over 2 steps)
O
O
OH
OBz
BzO
R1
4
5
Figure 2 a-Selectivity in fucosylation by remote participation
NaBH4, KI,
MeCN, r.t.,
5 h
Recent investigations of 1,2-O-benzylidene hexopyra-
noses have shown that this group has the potential for a
carbohydrate protecting group that can be reductively
ring-opened in a regioselective manner to afford either
1-O- or 2-O-substituted monosaccharide units.10,11
Whereas the behavior of 4,6-benzylidene acetals in reduc-
tive ring-opening reactions is known since decades and
has been used as one of the most frequent manipulations
for the syntheses of carbohydrate building-blocks,12 the
nature of the analogous 1,2-benzylidenes is not well in-
vestigated. In the cases described so far, the regioselectiv-
ity of the reductive ring opening strongly depends on the
reducing agent, the Lewis acid that is used to activate the
system, the solvent, and the reaction temperature.10,11
However, in some cases good regioselectivities could be
achieved.
(71%)
OH
Me
O
O
OBn
Ph
reductive
opening
OBz
Me
O
BzO
O
7
(see Table 1)
OBz
BzO
+
6
OBn
Me
O
OH
OBz
BzO
8
Scheme 1 Access to the hemiacetal of fucose with the appropriate
protecting-group pattern via reductive 1,2-benzylidene ring opening
also yielded 8 as the major product (44%); however, sev-
eral further side products were observed. With the mild re-
ducing agent NaBH(OAc)3 in acetonitrile no conversion
was found. The best results in favor of the desired fucose
7 were obtained using BH3⋅THF complex. A variety of
different conditions was tested using this system. The use
of BH3⋅THF (1.5 equiv) in THF as solvent and a catalytic
amount (0.15 equiv) of the Lewis acid Bu2BOTf afforded
the highest amount of isomer 7 (45%) together with 8
(43%) which could easily be separated by column chro-
matography on silica gel.18 Dichloromethane as solvent
showed a slight preference for isomer 8. With decreasing
temperature the regioselectivity of the ring opening could
not be increased, but the total yields became smaller. A
larger amount of Lewis acid did result in significant loss
of the benzylidene moiety leading to the 1,2-diol. In THF
also polymerization of the solvent was observed when us-
ing a high concentration (2.0 equiv) of Bu2BOTf. The use
of the more bulky Lewis acid PhBCl2 gave similar results
in comparison with Bu2BOTf. Finally, we tested silica gel
as Lewis acid, but no conversion at all was observed. With
use of 1,2-bis(trimethylsiloxy)benzene and BF3⋅OEt2 we
envisioned the formation of a chelating bifunctional
Lewis acid system being more selective. However, the re-
action resulted in a complex mixture.
Encouraged by these results, we investigated the reductive
ring-opening reaction of 1,2-benzylidene fucopyranose in
order to design a short and efficient access to a-fucosyl
building blocks.
The 1,2-benzylidene group can be constructed in several
ways, either by acetal-exchange reactions of the corre-
sponding isopropylidene13 or orthoester14 derivatives un-
der acidic conditions or by reaction of a glycosyl halide
with an adjacent trans-configured benzoate under reduc-
tive conditions.15 Of course, for the construction of 1,2-
benzylidene fucose the latter method is the best choice.
Extensive benzoylation of the unprotected fucose 4 in the
presence of pyridine afforded the tetra-O-benzoylfucose
which can be easily converted into the corresponding bro-
mide 5 by the action of hydrobromic acid in acetic acid.16
The benzylidene acetal formation to afford 6 was accom-
plished in 71% yield using NaBH4 as reducing agent in the
presence of KI with acetonitrile as solvent.17 The use of KI
in the reaction is necessary to allow an isomerization of
the anomerically favored a-bromide 5 that is unfavorable
for the course of the transformation. Thus, reaction of a-bro-
mide with the iodide affords the b-iodide that is prone to
be substituted by the trans-orientated benzoate
(Scheme 1).
The 2-O-benzylated fucose hemiacetal 7 was converted to
building block 9 suitable for oligosaccharide synthesis.
Using conditions reported by Schmidt19 compound 7 was
reacted with trichloroacetonitrile and catalytic amounts of
DBU to yield the corresponding trichloroacetimidate 9
With 1,2-benzylidene acetal 6 in hand, we attempted sev-
eral procedures for a selective ring opening under reduc-
tive conditions to afford either the 2-O-benzylated fucose
hemiacetal 7 or the 1-O-benzylated fucose 8 (Table 1)
When Et3SiH was used as reducing agent in the presence
of trifluoroacetic acid (TFA) and trifluoroacetic anhy-
dride (TFAA) in dichloromethane at 0 °C to room temper-
ature fucose derivative 8 was obtained as the major
product (82%). The use of DIBAL-H in dichloromethane
HN
CCl3
O
OH
CCl3CN
DBU
Me
O
Me
O
OBn
OBn
OBz
OBz
BzO
BzO
7
(84%)
9
Scheme 2 Transformation of the fucose hemiacetal 7 into the fuco-
syl trichloroacetimidate 9
Synlett 2008, No. 13, 1969–1972 © Thieme Stuttgart · New York

LETTER
Preparation of an a-Fucosyl Building Block
1971
Table 1 Different Conditions Tested for the Reductive Ring-Opening Reaction of 1,2-Benzylidene Fucose 6 into 7 and 8a
Entry
1
Conditions
Temp (°C)
7 (%)
8 (%)
82
Et3SiH, TFA, TFAA, CH2Cl2
DIBAL-H, CH2Cl2
0 to 25
11
2
0
25
10
44
3
NaBH(OAc)3, MeCN
no conversion
4
BH3·THF, Bu2BOTf, THF
BH3·THF, Bu2BOTf, THF
BH3·THF, Bu2BOTf, THF
BH3·THF, Bu2BOTf, CH2Cl2
BH3·THF, Bu2BOTf, CH2Cl2
BH3·THF, TMSOTf, CH2Cl2
BH3·THF, PhBCl2, CH2Cl2
BH3·THF, PhBCl2, CH2Cl2
BH3·THF, SiO2, CH2Cl2
–30
0
16
30
38
43
46
47
38
41
43
5
33
6
25
45
7
0 to 25
25
44
8
42
9
25
35
10
11
12
13
0
39
25
41
25
no conversion
complex mixture
BH3·THF, BF3·OEt2, 1,2-bis-(trimethylsiloxy)benzene, CH2Cl2
0 to 25
a Isolated yields.
(Scheme 2).20 Recent investigations have already shown
that this fucosyl trichloroacetimidate is a useful building
block for oligosaccharide assembly.21
2001, 40, 1274. (f) Werz, D. B.; Castagner, B.; Seeberger, P.
H. J. Am. Chem. Soc. 2007, 129, 2770.
(5) Lerchen, H. G.; Baumgarten, J.; von dem Bruch, K.;
Lehmann, T. E.; Sperzel, M.; Kempka, G.; Fiebig, H.-H.
J. Med. Chem. 2001, 44, 4186.
(6) Kalovidouris, S.; Gama, C.; Lee, L.; Hsieh-Wilson, L. C.
J. Am. Chem. Soc. 2005, 127, 1340.
(7) Werz, D. B.; Ranzinger, R.; Herget, S.; Adibekian, A.; von
der Lieth, C.-W.; Seeberger, P. H. ACS Chem. Biol. 2007, 2,
685.
In conclusion, we present a fast and efficient protocol for
the preparation of a-fucosyl building blocks in only five
steps. The key step is a reductive 1,2-benzylidene ring-
opening reaction, rendering this route shorter than the
common syntheses of fucosyl building blocks.
(8) (a) Demchenko, A. V.; Rousson, E.; Boons, G.-J.
Tetrahedron Lett. 1999, 40, 6523. (b) Gerbst, A. G.;
Ustuzhanina, N. E.; Grachev, A. A.; Khatuntseva, E. A.;
Tsvetkov, D. E.; Whitfield, D. M.; Berces, A.; Nifantiev, N.
E. J. Carbohydr. Chem. 2001, 20, 821.
(9) (a) Windmüller, R. Diplomarbeit; Universität Konstanz:
Germany, 1990. (b) Windmüller, R.; Schmidt, R. R.
Tetrahedron Lett. 1994, 35, 7927. (c) Rencoursi, A.; Poletti,
L.; Russo, G.; Lay, L. Eur. J. Org. Chem. 2003, 1672.
(d) Love, K. R.; Andrade, R. B.; Seeberger, P. H. J. Org.
Chem. 2001, 66, 8165.
(10) (a) Suzuki, K.; Nonaka, H.; Yamaura, M. Tetrahedron Lett.
2003, 44, 1975. (b) Suzuki, K.; Nonaka, H.; Yamaura, M.
J. Carbohydr. Chem. 2004, 23, 253.
(11) Sakagami, M.; Hamana, H. Tetrahedron Lett. 2000, 41,
5547.
(12) (a) Liptak, A.; Imure, J.; Harangi, J.; Nanasi, P. Tetrahedron
1982, 38, 3721. (b) Galas, J. Adv. Carbohydr. Chem.
Biochem. 1981, 39, 71. (c) Garreg, P. J. Pure Appl. Chem.
1984, 56, 845. (d) Garreg, P. J.; Hultberg, H.; Wallin, S.
Carbohydr. Res. 1982, 108, 97. (e) Oikawa, M.; Liu, W. C.;
Nakai, Y.; Koshida, S.; Fukase, K.; Kusumoto, S. Synlett
1996, 1179. (f) Jiang, L.; Chan, T.-H. Tetrahedron Lett.
1998, 39, 355.
(13) Ress, R. G.; Tatchell, A. R.; Wells, R. D. J. Chem. Soc. C
1967, 1768.
(14) Dick, W. E. Jr.; Weisleder, D.; Hodge, J. E. Carbohydr. Res.
1972, 23, 229.
Acknowledgment
We thank the Deutsche Forschungsgemeinschaft (Emmy Noether
Fellowship to D.B.W.) and the Fonds der Chemischen Industrie
(Liebig Fellowship to D.B.W.) for financial support. H.J.S. thanks
the Friedrich-Ebert-Stiftung for a Ph.D. fellowship.
References and Notes
(1) (a) Ma, B.; Simala-Grant, J. L.; Taylor, D. E. Glycobiology
2006, 16, 158R. (b) Sharon, N.; Lis, H. Science 1989, 246,
227.
(2) (a) Watkins, W. M. Trends Glycosci. Glycotechnol. 1999,
11, 391. (b) Hakomori, S.; Zhang, Y. Chem. Biol. 1997, 4,
97. (c) Brocke, C.; Kunz, H. Bioorg. Med. Chem. 2002, 10,
3085. (d) Deshpande, P. P.; Danishefsky, S. J. Nature
(London) 1997, 387, 164. (e) Love, K. R.; Seeberger, P. H.
Angew. Chem. Int. Ed. 2004, 43, 602.
(3) Watkins, W. M.; Morgan, W. J. M. Vox Sang. 1955, 5, 1.
(4) (a) Clausen, H.; Levery, S. B.; Kannagi, R.; Hakomori, S.
J. Biol. Chem. 1986, 261, 1380. (b) Lassaletta, J. M.;
Schmidt, R. R. Liebigs Ann. 1996, 1417. (c)Zhu, T.; Boons,
G.-J. Angew. Chem. Int. Ed. 1999, 38, 3495. (d) Allen, J.
R.; Allen, J. G.; Zhang, X. F.; Williams, L. J.; Zatorski, A.;
Ragupathi, G.; Livingston, P. O.; Danishefsky, S. J. Chem.
Eur. J. 2000, 6, 1366. (e) Burkhart, F.; Zhang, Z.;
Wacowich-Sgarbi, S.; Wong, C.-H. Angew. Chem. Int. Ed.
Synlett 2008, No. 13, 1969–1972 © Thieme Stuttgart · New York

1972
D. B. Werz et al.
LETTER
The two products were easily separable (7 is much more
(15) Suzuki, K.; Mizuta, T.; Yamaura, M. J. Carbohydr. Chem.
2003, 22, 143.
polar than 8).
(16) Ichikawa, Y.; Sim, M. M.; Wong, C.-H. J. Org. Chem. 1992,
57, 2943.
Analytical Data of the Anomeric Mixture (1:1) of 7
IR (film): 3434, 2936, 1726, 1602, 1453, 1283 cm–1. 1H
NMR (300 MHz, CDCl3): d = 1.19 (d, J = 6.1 Hz, 3 H), 1.27
(d, J = 6.1 Hz, 3 H), 3.38 (br s, 1 H), 3.84 (m, 2 H), 3.98 (q,
J = 6.1 Hz, 1 H), 4.11 (dd, J = 7.4, 3.3 Hz, 1 H), 4.55 (q,
J = 6.1 Hz, 1 H), 4.72 (d, J = 7.4 Hz, 1 H), 4.86 (d, J = 7.4
Hz, 1 H), 4.90 (m, 1 H), 5.39 (dd, J = 7.4, 3.3 Hz, 1 H), 5.43
(m, 1 H), 5.58 (m, 1 H), 5.64 (m, 1 H), 5.75 (dd, J = 7.4, 3.3
Hz, 1 H), 7.11–7.37 (m, 14 H), 7.40–7.55 (m, 6 H), 7.60 (m,
2 H), 7.81 (m, 4 H), 7.99 (m, 4 H). 13C NMR (75 MHz,
CDCl3): d = 16.1, 16.3, 65.1, 69.5, 70.5, 71.5, 72.3, 73.1,
73.7, 74.6, 77.4, 91.7, 97.5, 127.6, 128.0, 128.1, 128.2,
128.2, 128.3, 128.4, 128.5, 129.6, 129.7, 129.8, 129.9,
133.0, 133.0, 133.2, 133.3, 137.3, 137.8, 165.6, 165.9,
165.9. ESI-HRMS: m/z calcd for C27H26O7Na: 485.15707;
found: 485.15705.
(17) 3,4-Di-O-benzoyl-1,2-O-benzylidene-a-L-fuco-
pyranose (6)
To a stirred solution of fucosyl bromide 5 (16.9 g, 31.3
mmol, 1.00 equiv) in abs. MeCN (106 mL) was added dry KI
(7.46 g, 44.9 mmol, 1.43 equiv) and NaBH4 (1.13 g, 29.9
mmol, 0.96 equiv). The mixture was stirred for 2.5 h. Then
more NaBH4 (1.13 g, 29.9 mmol, 0.96 equiv) was added.
After a total reaction time of 5 h, the solvent was removed.
The residue was dissolved in EtOAc, washed with ice water,
cold sat. NaHCO3 solution, and twice with brine. The
mixture was dried (Na2SO4), concentrated, and the residue
purified by column chromatography (SiO2; pentane–EtOAc,
5:1) to afford 10.2 g (71%) of 6 as a colorless foam.
Analytical Data of the exo-Product
IR (KBr): 2985, 1727, 1602, 1452, 1280 cm–1. 1H NMR (300
MHz, CDCl3): d = 1.31 (d, J = 6.2 Hz, 3 H), 4.51 (dd,
J = 6.9, 5.2 Hz, 1 H), 4.53 (m, 1 H), 5.51 (dd, J = 6.8, 3.5 Hz,
1 H), 5.64 (dd, J = 3.4, 1.6 Hz, 1 H), 5.91 (d, J = 5.1 Hz,
1 H), 6.04 (s, 1 H), 7.31–7.65 (m, 11 H), 7.93 (m, 2 H), 8.03
(m, 2 H). 13C NMR (75 MHz, CDCl3): d = 16.4, 67.8, 69.5,
71.9, 72.9, 98.8, 101.9, 126.3, 128.2, 128.6, 129.4, 129.6,
129.7, 133.2, 133.4, 137.7, 165.6, 165.7. ESI-HRMS: m/z
calcd for C27H24O7Na: 483.14142; found: 483.14160.
(18) 3,4-Di-O-benzoyl-2-O-benzyl-a/b-L-fucopyranose (7)
To a stirred solution of benzylidene fucose 6 (161 mg, 0.35
mmol, 1.0 equiv) in abs. THF (2 mL) BH3⋅THF (0.53 mL,
0.53 mmol, 1.5 equiv) was added at r.t., then Bu2BOTf
(52 mL, 0.053 mmol, 0.15 equiv). The mixture was stirred for
1–2 h. Water was added and the reaction mixture was
extracted with EtOAc. The organic phase was dried
(Na2SO4), concentrated, and the residue purified by column
chromatography (SiO2; pentane–EtOAc, 3:1 to 2:1) to afford
72 mg (45%) of 7 and 70 mg (43%) of 8 as a colorless foam.
(19) Schmidt, R. R.; Kinzy, W. Adv. Carbohydr. Chem. Biochem.
1994, 50, 21.
(20) Analytical Data of the a-Anomer
[a]D20 –148.4 (c 1.90, CDCl3). IR (film): 2943, 2867, 1733,
1672, 1464, 1278 cm–1. 1H NMR (300 MHz, CDCl3):
d = 1.24 (d, J = 6.1 Hz, 3 H), 4.29 (dd, J = 7.8, 3.4 Hz, 1 H),
4.55 (m, 1 H), 4.61 (d, J = 7.8 Hz, 1 H), 4.69 (d, J = 7.8 Hz,
1 H), 4.75–5.81 (m, 2 H), 6.68 (d, J = 3.4 Hz, 1 H), 7.23–
7.33 (m, 7 H), 7.43–7.49 (m, 3 H), 7.62 (m, 1 H), 7.80 (m,
2 H), 7.94 (m, 2 H), 8.66 (s, 1 H). 13C NMR (75 MHz,
CDCl3): d = 16.2, 67.8, 70.3, 71.7, 72.3, 72.6, 91.2, 94.5,
127.8, 127.9, 127.9, 128.0, 128.2, 128.3, 128.5, 129.4,
129.5, 129.6, 129.7, 133.0, 133.3, 137.4, 161.4, 165.5,
165.7. ESI-HRMS: m/z calcd for C29H26Cl3NO7Na:
628.06725; found: 628.06734.
(21) Gerbst, A. G.; Grachev, A. A.; Ustyuzhanina, N. E.;
Khatuntseva, E. A.; Tsvetkov, D. E.; Usov, A. I.; Shaskov,
A. S.; Preobrazhenskaya, M. E.; Ushakova, N. A.; Nifantiev,
N. E. Russ. J. Bioorg. Chem. 2004, 30, 137.
Synlett 2008, No. 13, 1969–1972 © Thieme Stuttgart · New York