Synthesis of a sialyl Lewis x mimic with fixed carboxylic acid group: Chemical approach toward the elucidation of the bioactive conformation of sialyl Lewis x

Article abstract of DOI:10.1021/jo951067l

The relation of the solution and bioactive conformation of sialyl Lewis x (sLe(x)) has been addressed by chemical means. To mimic the preferred solution conformation of sLe(x) 1, the more rigid analog 2 has been designed and synthesized. The sialic acid r

Full text of DOI:10.1021/jo951067l

514
J . Org. Chem. 1996, 61, 514-524
Syn th esis of a Sia lyl Lew is x Mim ic w ith F ixed Ca r boxylic Acid
Gr ou p : Ch em ica l Ap p r oa ch tow a r d th e Elu cid a tion of th e
Bioa ctive Con for m a tion of Sia lyl Lew is x
Gebhard Thoma,* Franz Schwarzenbach, and Rudolf O. Duthaler
Central Research Laboratories, CIBA, Postfach, CH-4002 Basel, Switzerland
Received J une 13, 1995X
The relation of the solution and bioactive conformation of sialyl Lewis x (sLex) has been addressed
by chemical means. To mimic the preferred solution conformation of sLex 1, the more rigid analog
2 has been designed and synthesized. The sialic acid residue of 1 was replaced by a carboxylic
acid function which is fixed in the equatorial position of a six membered ring acetal fused to
galactose. Due to entropic considerations, an increased biological activity could be expected if the
preferred solution conformation and bound form of sLex were similar. Since mimic 2 was found to
be inactive in an E-selectin binding assay, the bound form of sLex most probably differs from the
prevailing solution conformation.
Ch a r t 1
In tr od u ction
The recruitment of leukocytes to sites of inflammation
is a protective response of the organism. This crucial
process is mediated by multiple adhesion molecules such
as integrins and super-immunoglobulins which interact
on the basis of protein-protein recognition.1 A third
family of leukocyte adhesion receptors, the selectins,2 is
involved in an early state of the leukocyte recruitment
cascade, the so-called rolling.3 Contrary to integrins and
super-immunoglobulins, the selectins recognize complex
carbohydrate structures in a Ca2+-dependent manner.
Three members have been reported to date. L-Selectin
is expressed constitutively on leukocytes and mediates
their migration from the bloodstream to the lymphatic
system.4 P-Selectin is stored in secretory granules of the
endothelium and, upon activation, transported to the cell
surface, inducing leucocyte rolling.5 E-Selectin is de
novo-synthesized following stimulation by cytokines and
also expressed on endothelial cells.6 The interaction of
E-selectin with complex carbohydrates is of pharmaceuti-
cal interest since cronic expression occurs in certain
inflammatory conditions, such as psoriasis and rheuma-
toid arthritis. In addition, acute disorders like reperfu-
sion injury or asthma caused by excessive leucocyte
recruitment represent an important target.
recently, the amino acid sequence has been determined.8
The carbohydrate part which is crucial for binding has
not been fully elucidated,9 but the sialyl Lewis x (sLex)
epitope 1 appears to be an important feature and is
known to be a weak ligand itself.10 The conformation of
sLex 1 is of great interest and has been investigated by
both NMR and computational means.11 Accordingly, the
Lewis x trisaccharide core is rather rigid, whereas the
sialic acid shows more flexibility. Among several low
energy conformations, structure 1 (Chart 1) is most
consistent with computational and NMR data.11c
A variety of sLex analogs has already been synthe-
sized.12 Whereas substitution of GlcNAc by glucose is
beneficial to E-selectin binding, modifications of the
fucose residue are generally deleterious. Interestingly,
replacement of the sialic acid residue by lactic acid or
A major E-selectin ligand on murine myeloid cells has
been identified to be a 150 kD glycoprotein.7 Very
X Abstract published in Advance ACS Abstracts, J anuary 1, 1996.
(1) Lobb, R. R. In Adhesion. Its Role in Inflammatory Disease;
Harlan, J . M., Liu, D. Y., Eds.; W. H. Freeman: New York, 1992;
Chapter 1, p 1.
(2) Paulson, J . C. In Adhesion. Its Role in Inflammatory Disease;
Harlan, J . M., Liu, D. Y., Eds.; W. H. Freeman: New York, 1992;
Chapter 2, p 19.
(3) Spertini, O.; Luscinskas, F. W.; Gimbrone, M. A., Tedder, T. F.
J . Exp. Med. 1992, 175, 1789.
(4) (a) Gallatin, M.; Weissman, I.; Butcher, E. Nature 1983, 303,
30. (b) Siegelman, M. H.; van de Rijn, M.; Weissman, I. L. Science 1989,
243, 1165. (c) Siegelman, M. H.; Weissman, I. L. Proc. Natl. Acad. Sci.
U.S.A. 1989, 86, 5562.
(7) (a) Levinovitz, A.; Muehlhoff, J .; Isenman, S.; Vestweber, D. J .
Cell Biol. 1993, 121, 449. (b) Lenter, M.; Levinovitz, A.; Isenman, S.;
Vestweber, D. J . Cell Biol. 1994, 125, 471.
(8) Steegmaier, M.; Levinovitz, A.; Isenman, S.; Borges, E.; Lenter,
M.; Kocher, H. P.; Kleuser, B.; Vestweber, D. Nature 1995, 373, 615.
(9) Patel, T. P.; Goelz, S. E.; Lobb, R. R.; Parekh, Raj. B. Biochem-
istry 1994, 33, 14815.
(10) (a) Phillips, M. L.; Nudelman, E.; Gaeta, F. C. A.; Perez, M.;
Singhal, A. K.; Hakomori, S.; Paulson, J . C. Science 1990, 250, 1130.
(b) Walz, G.; Aruffo, A.; Kolanus, W.; Bevilacqua, M.; Seed, B. Science
1990, 250, 1132. (c) Lowe, J . B.; Stoolman, L. M.; Nair, R. P.; Larsen,
R. D.; Berhend, T. L.; Marks, R. M. Cell 1990, 63, 475. (d) Tiemyer,
M.; Swiedler, S. J .; Ishihara, M.; Moreland, M.; Schweingruber, H.;
Hirtzer, P.; Brandley, B. K. Proc. Natl. Acad. Sci. U.S.A. 1991, 88,
1138.
(5) (a) J ohnston, G. I.; Cook, R. G.; McEver, R. P. Cell 1989, 56,
1033. (b) Butcher, E. C. Cell 1991, 67, 1033. (c) Lawrence, M. B.;
Springer, T. A. Cell 1991, 65, 859. (d) Ley, K.; Gaethgens, P.; Fennie,
C.; Singer, M.; Lasky, L. A.; Rosen, S. Blood 1991, 77, 2553. (e)
Shimizu, Y.; Shaw, S.; Graber, N.; Gopal, T. V.; Horgan, K. J .; Van
Seventer, G. A.; Neuwman, W. Nature 1991, 349, 799.
(6) (a) Bevilacqua, M. P.; Prober, J . S.; Mendrick, D. L.; Cotran, R.
S.; Gimbrone, M. A., J r. Proc. Natl. Acad. Sci. U.S.A. 1987, 84, 9238.
(b) Luscinskas, F. W.; Brock, A. F.; Arnaout, M. A.; Gimbrone; M. A.
J . Immunol. 1989, 142, 2257. (c) Kuijpers, T. W.; Hakkert, B. C.;
Hoogerwerf, M.; Leuuwenberg, J . F. M.; Roos, D. J . Immunol. 1991,
147, 1369.
0022-3263/96/1961-0514$12.00/0 © 1996 American Chemical Society

Synthesis of a Rigid Mimic of Sialyl Lewis x
J . Org. Chem., Vol. 61, No. 2, 1996 515
Sch em e 1
acetic acid decreases binding but does not completely
abolish biological activity. On the other hand, removal
of the carboxylic acid function results in inactivity. A
negative charge in the appropriate position seems to be
a requirement for E-selectin recognition. Knowledge of
the bioactive conformation of sLex could support the
rational design of potent analogs. The more rigid sLex
analog 2, matching the preferred solution conformation
1, was designed to probe a possible resemblance of the
bioactive form (Chart 1). The sialic acid residue is
replaced by a carboxylic acid group which is fixed in the
equatorial position of a six-membered ring acetal fused
to galactose. Since compound 2 mimics sLex conforma-
tion 1, an enhancement of the binding to E-selectin would
be expected on entropic grounds if bioactive and solution
conformations were similar. A drop in activity would
indicate different conformations of sLex in solution and
bound form. In the course of our work, bioactive sLex
conformations have been proposed on the basis of trans-
ferred nuclear Overhauser enhancements, studying the
sLex-E-selectin complex by high-field NMR spectro-
scopy.13ab Accordingly, the torsion angle of the glycosidic
link between the sialyl and galactosyl residue of sLex
changes upon binding.13a Interestingly, the bioactive
conformation resembles one of the less preferred local
minima. Therefore, it has been suggested that E-selectin
recognizes only one of several sLex conformers present
in solution and that binding causes only minor structural
changes concerning the fucose residue.13b A third report
describes deviating results13c by implying that the bio-
active and solution conformations are similar.
Resu lts a n d Discu ssion
In order to approach target molecule 2, we decided to
synthesize a galactosyl donor such as 3 which already
contains the fused six-membered ring acetal and subse-
quently link this building block to the GlcNAc-Fuc
glycosyl acceptor 414 (see Scheme 1). The six-membered
ring acetal of donor 3 can be disconnected to an R-keto
acid 5 and a diol 6 which in turn is available via
stereoselective addition of a hydroxymethyl anion syn-
thon 7 to a sugar ketone such as 8. The carbonyl
compound 8 can be obtained by oxidation of a suitably
protected glucose or galactose with a free 4-hydroxyl
group.
The synthesis of a suitable glycosyl donor such as 3
according to the retrosynthetic analysis is depicted in
Scheme 2. The known glucose derivative 915 was deacety-
lated using Amberlite IRA 910 ion exchange resin and
crude 10 treated with benzaldehyde dimethyl acetal to
furnish 4,6-benzylidene derivative 11 in 89% yield. Next,
the free hydroxyl groups of 11 were protected as benzyl
ethers, applying benzyl bromide/NaH in DMF to give 12
(82%). Acidic cleavage of the benzylidene acetal fur-
nished 13, where the primary hydroxyl group was
selectively silylated to give 14. The 4-hydroxyl group of
14 was oxidized using DMSO/acetic anhydride. The
resulting sugar ketone 15 is stable toward chromatog-
raphy but purification did not improve the yield of the
following step.
(11) (a) Ball, G. E.; O’Neill, R. A.; Schultz, J . E.; Lowe, J . B.; Weston,
B. W.; Nagy, J . O.; Brown, E. G.; Hobbs, C. J .; Bednarski, M. D. J .
Am. Chem. Soc. 1992, 114, 5449. (b) Lin, Y.-C.; Hummel, C. W.; Huang,
D.-H.; Ichikawa, Y.; Nicolaou, K. C.; Wong, C.-H. J . Am. Chem. Soc.
1992, 114, 5452. (c) Ichikawa, Y.; Lin, Y.-C.; Dumas, D. P.; Shen, G.-
J .; Garcia-J unceda, E.; Williams, M. A.; Bayer, R.; Ketcham, C.;
Walker, L. E.; Paulson, J . C.; Wong, C.-H. J . Am. Chem. Soc. 1992,
114, 9283. (d) Rutherford, T. J .; Spackman, D. G.; Simpson, P. J .;
Homans, S. W. Glycobiology 1994, 4, 59.
(12) (a) Dasgupta, F.; Rao, B. N. N. Exp. Opin. Invest. Drugs 1994,
3, 709 and references cited therein. (b) Ragan, J . A.; Cooper, K. Bioorg.
Med. Chem. Lett. 1994, 4, 2563. (c) Allensen, N. M.; Davidson, A. H.;
Martin, F. M. Tetrahedron Lett. 1993, 34, 3954. (d) Allensen, N. M.;
Davidson, A. H.; Floyd, C. D.; Martin, F. M. Tetrahedron Asymmetry
1994, 5, 2061. (e) Hasegawa, A.; Ando, T.; Kato, M.; Ishida, H.; Kiso,
M. Carbohydr. Res. 1994, 257, 67. (f) Ramphal, J . Y.; Zheng, Z.-L.;
Perez, C.; Walker, L. E.; DeFrees, S. A.; Gaeta, F. C. A. J . Med. Chem.
1994, 37, 3459. (g) Prodger, J . C.; Bamford, M. J .; Gore, P. M.; Holmes,
D. S.; Saez, V.; Ward, P. Tetrahedron Lett. 1995, 36, 2339. (h) Huang,
H.; Wong, C.-H. J . Org. Chem. 1995, 60, 3100. (i) Uchiyama, T.;
Vassilev, V. P.; Kajimoto, T.; Wong, W.; Huang, H.; Lin, C.-C.; Wong,
C.-H. J . Am. Chem. Soc. 1995, 117, 5395. (j) Sprengard, U.; Kretzschmar,
G.; Bartnik, E.; Hu¨ls, C.; Kunz, H. Angew. Chem. 1995, 21, 2563. (k)
Kaila, N.; Yu, H.-A.; Xiang, Y. Tetrahedron Lett. 1995, 36, 5503.
(13) (a) Cooke, R. M.; Hale, R. S.; Lister, S. G; Shah, G.; Weir, M.
P. Biochemistry 1994, 33, 10591. (b) Scheffler, K.; Ernst, B.; Katopodis,
A.; Magnani, J . L.; Wang, W, T.; Weisemann, R.; Peters, T. Angew.
Chem. 1995, 107, 2034. (c) Hensley, P.; McDevitt, P. J .; Brooks, I.; Trill,
J . J .; Feild, J . A.; McNulty, D. E.; Connor, J . R.; Griswold, D. E.; Kumar,
N. V.; Kopple, K. D.; Carr, S. A.; Dalton, B. J .; J ohanson, K. J . Biol.
Chem. 1994, 269, 23949.
Crude 15 was treated with vinylmagnesium bromide
at low temperature in THF. Branched galactose deriva-
tive 16 was obtained in 72% yield. NMR analysis of the
crude reaction mixture indicated small amounts of the
C-4 epimer of 16 which could be isolated only in trace
amounts. The galactose/glucose selectivity appears to be
better than 10:1. This has been explained for similar
systems by chelation of the magnesium atom of the
Grignard reagent with the C-4 carbonyl oxygen and the
4
C-3 oxygen atom. The chelated oxo sugar adopts a C1-
conformation (Chart 2, A), and equatorial attack of the
nucleophile dominates over the sterically hindered axial
attack.16 Structure 16 was assigned by NOE measure-
(14) A disaccharide such as 4 (R ) Bn, compound 26 in Scheme 4)
was generously provided by Dr. N. Cooke, CIBA-Basel. The synthesis
is not covered in the Experimental Section and will be published
elsewhere.
(15) J ansson, K.; Ahlfors, S.; Frejd, T.; Kihlberg, J .; Magnusson, G.
J . Org. Chem. 1988, 53, 5629.

516 J . Org. Chem., Vol. 61, No. 2, 1996
Thoma et al.
Sch em e 2a
a
Key: (a) Amberlite IRA 910, methanol, rt, 2 h (10); (b) benzaldehyde dimethyl acetal, PTSA, MeCN, rt, 3 h (11, 89% over two steps);
(c) NaH, DMF, rt, 2 h, BnBr, 0 °C, 2 h (12, 82%); (d) HCl/MeOH, rt, 2 h (13); (e) TBDPS, imidazole, DMF, rt, 3 h (14); (f) DMSO/Ac2O,
65 °C, 2 h (15); (g) CH2CHMgBr, THF, -78 °C, 3 h (16, 72% over four steps); (h) (1) O3, MeOH, 78 °C; (2) NaBH4, -78 f rt, 2 h (17, 79%);
(i) Pd/C (10%), MeOH/AcOH (99:1), 45 °C (18, 98%); (k) furaldehyde diethyl acetal (1.5 equiv), PPTS, benzene, 60 °C, 45 min (19a /19b,
(1:1), 81%); (l) furaldehyde diethyl acetal (0.2 equiv), PPTS, benzene, 60 °C, 16 h; (m) Bu4NF, THF, rt, 150 min (22, quant); (n) BzCl, Py,
DMAP (23, 94%); (o) (1) O3, MeOH, -78 °C; (2) H2O2, MeOH, -78 °C f rt, 16 h; (3) CH2N2, ether, 0 °C (24, 80%); (p) (1) TFA, CH2Cl2,
0 °C, 45 min, (2) Cl3CCN, Cs2CO3, CH2Cl2, rt, 16 h (25, 54% over two steps).
Ch a r t 2
Sch em e 3
ments. The internal vinyl proton showed a strong NOE
to H-3 and H-5. Since both H-3 and H-5 are in axial
positions of the six-membered ring, the vinyl group has
to be in the equatorial position to achieve proximity to
these protons.
Ozonolysis of 16 followed by reductive workup gave
alcohol 17 (66%), and subsequent catalytic hydrogenation
furnished 18 in 98% yield. According to the retrosyn-
thetic analysis (Scheme 1), compound 18 was reacted
with glyoxylic acid derivatives in order to form the
desired 1,3-dioxane bearing a carboxylic acid. Since all
direct approaches failed, we decided to introduce an
acetal containing a functionality which could be easily
converted into an acid, such as furan. Thus, reaction of
18 with furaldehyde diethyl acetal and PPTS in benzene
at 60 °C gave a 1:1 mixture of six-membered ring acetal
19a and five-membered ring acetal 19b in 81% yield. The
isomers could easily be separated by flash chromatogra-
phy. Variation of solvent, catalyst, and reaction tem-
perature did not alter the product ratio. Pure five-
membered ring acetal 19b can be equilibrated to a 1:1
mixture of 19a and 19b by applying small amounts of
furaldehyde diethyl acetal and PPTS. Structures 19a
1
and 19b were assigned by H-NOE measurements.
In order to avoid five-membered ring acetal formation,
we tried to acetylate the free hydroxyl group of 16. The
teriary allylic alcohol was inert toward standard reaction
conditions, but treatment with acetic anhydride and
magnesium iodide17 gave fully protected 20 in almost
quantitative yield. Unfortunately, under the basic condi-
tions applied for the reduction of the ozonide derived from
20, the acetate migrates to the primary hydroxyl group
leading to 21 (Scheme 3).
(16) Miljkovic, M.; Gligorijevic, M.; Satoh, T.; Miljkovic, D. J . Org.
Chem. 1974, 39, 1379.

Synthesis of a Rigid Mimic of Sialyl Lewis x
J . Org. Chem., Vol. 61, No. 2, 1996 517
Sch em e 4
Sch em e 5a
The silyl protecting group of 19a was removed with
fluoride to yield quantitatively triol 22 and subsequently
benzoylated to give 23 in 94% yield. Ozonolysis of the
furan ring followed by treatment with diazomethane
furnished methyl ester 24 in 80% yield. The (trimeth-
ylsilyl)ethyl glycoside was cleaved under acidic conditions
and the intermediate treated with trichloroacetonitrile
and cesium carbonate. The desired glycosyl donor 25
(54% over two steps) was unstable and always ac-
companied by decomposition products which could not
be removed by chromatography. Attempts to further
purify compound 25 gave no improvement but led to a
great loss of material. Therefore, the donor 25 was
immediately used after preparation. The â-epimer of 25
could not be isolated. Using DBU instead of cesium
carbonate offered no improvement. Starting from glucose
derivative 9, the bicyclic galactose derivative 25 could
be prepared in 14 steps in an overall yield of 6.6%.
Next, we attempted to link trichloroacetimidate 25 to
acceptor 26.14 Both TMS triflate and BF3 etherate were
tried as mediators. We observed rapid consumption of
25 but were unable to detect any glycosylation product
such as 27 (Scheme 4). The acceptor 26 could be
recovered. In some cases, when TMS triflate had been
used, we observed silylation of the 4-hydroxyl group of
26. We also synthesized bicyclic glycosyl donors 28 and
29,18 but all attempts to achieve linkage to acceptor 26
failed.19
a
Key: (a) BzCl, DMAP, Py, 0 °C f rt, 2 h (33, 96%); (b)
NaCNBH3, THF; HCl in ether, 0 °C (34, 93%); (c) DMSO, P2O5,
DMF, 50 °C, 2 h (35); (d) CH2CHMgBr, THF, -78 °C (36); (e) (1)
O3, MeOH, -78 °C; (2) NaCNBH3, -78 °C f rt (37); (f) BzCl,
DMAP, Py, 0 °C f rt, 2 h (38, 70% over four steps); (g) (1)
CF3COOH, CH2Cl2, 0 °C, (2) Cl3CCN, Cs2CO3, CH2Cl2, rt, 4 h (32,
81% over two steps).
Hence, we changed our strategy to assemble the target
molecule 2 (see Chart 1). Sterically less hindered
monosaccharide 3020 was used as glycosyl acceptor for
25. The fucose residue should be introduced at a later
stage. Glycosylation furnished a mixture which con-
tained the desired product 31, but due to the very low
yield (>10%) and the demanding purification we aban-
doned this approach as well. We believe that the rigid
bicyclic core of donor 25 renders sp2 hybridization of a
cationic intermediate more difficult, causing the disap-
pointing results in glycosylation reactions.
In order to circumvent these problems, we decided to
link a monocyclic galactose derivative such as 32 to
GlcNAc-Fuc building block 26 (see Scheme 5) prior to
acetal formation. Starting from glucose derivative 11,
the synthesis of C-4-branched galactose 32 has been
accomplished in eight steps in an overall yield of 52%.
First, the hydroxyl groups were protected as benzoates
(f 33, 96%). The benzylidene acetal was selectively
opened under reductive conditions to give 34 (93%).
Oxidation of the 4-hydroxyl group was attempted under
various conditions. In some cases, we observed elimina-
tion to an R,â-unsaturated ketone. Oxosugar 35 could
finally be obtained by applying DMSO and P2O5. Treat-
ment of 35 with a slight excess of vinylmagnesium
bromide at low temperature resulted exclusively in
equatorial attack at the carbonyl function leading to
olefin 36. This Grignard addition has to be monitored
carefully by TLC since excess reagent leads to partial
benzoate cleavage. The galactose configuration of 36 at
C-4 was proven by NOE measurements. The C-4 epimer
of 36 could not be detected by 1H-NMR of the crude
(17) Chowdhury, P. K. J . Chem. Res., Synop. 1993, 338.
(18) The synthesis of 28 and 29 is not covered in the Experimental
Section.
(19) In an earlier attempt toward a bicyclic glycosyl donor such as
3 we had prepared advanced intermediate 46. Unfortunately, we were
unable to remove the axial anomeric benzyl group.
(20) Compound 30 was generously provided by Dr. George Papan-
dreou. The synthesis of 30 is not covered in the Experimental Section
and will be published elsewhere.

518 J . Org. Chem., Vol. 61, No. 2, 1996
Thoma et al.
Sch em e 6a
a
Key: (a) slow addition of a concd CH2Cl2 solution of 32 (2 equiv) to a concd CH2Cl2 solution of 26 and BF3 OEt2, MS 4 Å, rt, 2 h (42,
55%); (b) NaOMe, MeOH, rt, 2 h (43, 84%); (c) furaldehyde diethyl acetal, PPTS, 60 °C, 1 h (44a , 33%; 44b, 41%); (d) (1) O3, -78 °C; (2)
H2O2/THF, rt, 18 h (45, 66%); (e) H2, Pd/C, dioxane/H2O, rt (2, 94%).
Ta ble 1. NMR Da ta of s Lex An a log 2 (500 MHz, D2O)
Gal GlcNAc Fuc
mixture. As in the Grignard addition to 15 (see Chart
2, A), Mg-chelation could be a plausible explanation for
the striking stereoselectivity.16 The ester substituent in
the 3-position of 33 might be an even better ligand than
the ether-oxygen in 15 (see Chart 2, B). Ozonolysis of
36 followed by reductive workup gave diol 37, and
benzoylation of the primary hydroxyl group furnished 38.
The last four steps could be done without chromatogra-
phy of the intermediates in a satisfying overall yield of
70%. Finally, the (trimethylsilyl)ethyl glycoside was
cleaved and the crude material transformed into the
trichloroacetimidate 32 (81%). All attempts to block the
axial 4-hydroxyl group of 36 or 37 as an ether failed.
Glycosylation of GlcNAc-Fuc building block 26 was
carried out in CH2Cl2 with BF3 etherate as mediator (see
Scheme 6). First attempts gave unsatisfying results, but
a detailed study of the side products 39-4121 led to
optimized conditions that furnished 42 in a moderate
yield of 55% (with respect to applied 26). Approximately
40% of acceptor 26 was reisolated unchanged. Complete
consumption of 26 could not be achieved even when 4
equiv of 32 was used. The R-glycoside could not be
detected. Other mediators or solvents gave no improve-
ment. Debenzoylation of 42 (f 43, 84%) and subsequent
reaction with furaldehyde diethyl acetal gave a 1:1.2
mixture of the desired six-membered ring acetal 44a and
the five-membered ring acetal 44b. The selectivity could
not be improved by variation of the reaction conditions.
The structures 44a and 44b were proven by NOE
measurements. Other acetals were not isolated. The
furyl substituent of 1,3-dioxane 44a was transformed into
a carboxylic acid functionality via ozonolysis followed by
assigned
H
C
H
C
H
C
1
2
3
4
5
6
7
4.58
3.68
3.80
103.0 4.56
70.1 3.87
82.7 3.86
69.2 3.93
76.5 3.56
60.8 3.88/3.99
72.7
101.6 5.09 100.2
57.1 3.68
76.4 3.89
74.6 3.79
76.6 4.87
61.0 1.18
69.9
70.6
73.3
68.1
16.6
3.58
3.68/3.68
3.91/3.92
4.99
CHCO
COOH
C(O)CH3
C(O)CH3
OCH2-
-CH2Si
-Si(CH3)3
99.9
173.7
2.02
23.6
175.6
69.8
18.5
-1.1
3.67/4.02
0.87/0.98
0.01
oxidative workup leading to 45 (66%). Hydrogenolysis
furnished the rigid sLex mimic 2 in 94% yield.
The product was characterized unambiguously by
applying various NMR techniques such as H,H-COSY
and TOCSY (H-assignment), inverse H,C-COSY (C-
assignment), and ROESY (assignment of the carboxylic
acid function in the 2-equatorial position of the 1,3-
dioxane). The data are depicted in Table 1.
Analog 2 was found to be inactive in a competitive
E-selectin binding assay up to 10 mM concentration,
whereas sLex derivative 1b showed an IC50 of ap-
proximately 1 mM.22 Therefore, we assume that the
position of the carboxylic acid in the bioactive sLex
conformation differs decisively from the preferred solu-
tion conformation. Our results support the findings by

Synthesis of a Rigid Mimic of Sialyl Lewis x
J . Org. Chem., Vol. 61, No. 2, 1996 519
transfer NOE measurements.13a,b The design of new rigid
sLex analogs should therefore be based on the bioactive
conformation as determined by NMR.
approximately 20 °C. The suspension was stirred for 2 h and
then cooled to 0 °C. A solution of benzyl bromide (13.2 g, 77.2
mmol) in 30 mL of DMF was added within 2 h. The mixture
was stirred for 2 h at 25 °C. Additional benzyl bromide (1.38
g, 8.05 mmol) was added and stirring continued for 1 h. The
reaction mixture was quenched at 0 °C with 30 mL of
methanol/water 2:1. Water (150 mL) was added and the
mixture extracted with ethyl acetate (3 × 150 mL). The
organic layer was washed with water (3 × 100 mL) and dried
over Na2SO4. The solvent was evaporated and the residue
subjected to flash chromatography (SiO2, eluted with diethyl
ether/hexane 1:9 f 1:5) to yield 14.5 g (82%) of 12 as a colorless
solid.
Exp er im en ta l Section
Gen er a l.23 Solvents were purified and dried according to
standard procedures.24 All reactions were carried out under
an atmosphere of dry argon. The 1H and 13C NMR spectra
were recorded at 298 K. The multiplicity of 13C NMR spectra
was determined by DEPT measurements. HR FAB mass
spectometry was performed by adding lithium ions in the form
of lithium chloride or lithium carbonate.
1
12: H-NMR (250 MHz, CDCl3) δ 0.02 (9 H, s, -Si(CH3)3),
2-(Tr im eth ylsilyl)eth yl â-D-Glu cop yr a n osid e (10). To
a solution of 915(10.0 g, 22.3 mmol) in 200 mL of methanol
was added 45 mL of Amberlite IRA 910 (Fluka). After the
mixture was stirred for 2 h at 25 °C, the ion exchange resin
was filtered off and the solvent evaporated. Crude 10 (6.30 g,
quant) was used without purification: 1H-NMR (250 MHz,
D2O) δ 0.00 (9 H, s, -Si(CH3)3), 1.00 (2 H, m, OCH2CH2Si-
(CH3)3), 3.21 (1 H, t, 8.5 Hz, H-2), 3.31 (3 H, m, H-3, H-4, H-5),
3.69 (1 H, dd, 12.0/5.0 Hz, H-6a), 3.73 (1 H, ddd, 12.0/10.0/6.0
Hz, OCHaHbCH2Si(CH3)3), 3.89 (1 H, dd, 12.0/1.5 Hz, H-6b),
4.01 (1 H, ddd, 12.0/10.0/6.0 Hz, OCHaHbCH2Si(CH3)3), 4.44
(1 H, d, 8.5 Hz, H-1); 13C-NMR (62.5 MHz, D2O) δ 0.0 (3 C, p),
20.1 (s), 63.2 (s), 70.9 (s), 72.1 (t), 75.7 (t), 78.4 (2 C, t), 104.1
(t).
1.01 (2 H, m, OCH2CH2Si(CH3)3), 3.32-3.44 (2 H, m, H-2, H-5),
3.60 (1 H, td, 9.5/8.0 Hz, OCHaHbCH2Si(CH3)3), 3.65-3.80 (3
H, m, H-3, H-4, H-6a), 3.97 (1 H, m, OCHaHbCH2Si(CH3)3),
4.33 (1 H, dd, 11.0/4.5 Hz, H-6b), 4.48 (1 H, d, 8.0 Hz, H-1),
4.74 (1 H, d, 11.0 Hz, CH2Ph), 4.77 (1 H, d, 11.0 Hz, CH2Ph),
4.88 (2 H, d, 11.0 Hz, CH2Ph), 5.54 (1 H, CHPh), 7.22-7.48
(15 H, m, ArH); 13C-NMR (62.5 MHz, CDCl3) δ -1.4 (3 C, CH3),
18.6 (CH3), 66.0 (CH), 68.1 (CH2), 68.8 (CH2), 75.1 (CH2), 75.4
(CH2), 80.9 (CH), 81.5 (CH), 82.3 (CH), 101.1 (CH), 103.7 (CH),
126.0-128.9 (9 signals, CH), 137.3 (C), 129.3 (CH), 138.4 (C),
138.5 (C); MS (CI) 566 (M + NH4+).
2-(Tr im eth ylsilyl)eth yl 2,3-Di-O-ben zyl-â-D-glu cop yr a -
n osid e (13). A suspension of 12 (14.5 g, 26.4 mmol) in 200
mL of methanol and 71 mL of 0.5 M HCl was heated under
reflux for 2 h. The clear solution was diluted with 250 mL of
methanol and cooled to 0 °C followed by the slow addition of
NaHCO3 (9.0 g). The solvent was removed in vacuo and the
residue partitioned in CHCl3/water (500 mL/250 mL). The
aqueous layer was extracted with chloroform (2 × 150 mL),
and the combined organic extracts were washed with brine
(200 mL) and dried over Na2SO4. After removal of the solvent,
13 (12.1 g, quant) was isolated as a colorless solid. The crude
material was used without further purification.
2-(Tr im eth ylsilyl)eth yl 4,6-O-Ben zylid en e-â-D-glu cop y-
r a n osid e (11). A suspension of 10 (20.3 g, 72.5 mmol),
benzaldehyde dimethyl acetal (14.7 g, 96.6 mmol), and p-
toluenesulfonic acid (0.70 g, 4.05 mmol) in 270 mL of aceto-
nitrile was stirred for 1 h at 25 °C. Additional benzaldehyde
dimethyl acetal (2.20 g, 14.5 mmol) was added and stirring
continued for 2 h. TLC (ether/methanol 99:1) indicated almost
complete consumption of 10. Chloroform (400 mL) was added
followed by extraction with saturated NaHCO3 (3 × 150 mL)
and brine (2 × 100 mL). The organic layer was dried with
Na2SO4 and the solvent evaporated. The residue was sus-
pended in pentane (600 mL) and stirred for 15 min. The
solvent was filtered off and the residue washed carefully with
additional pentane. The remaining colorless solid (11, 23.6 g,
89%) was used without further purification.
1
13: H-NMR (250 MHz, CDCl3) δ 0.02 (9 H, s, -Si(CH3)3),
1.00 (2 H, m, OCH2CH2Si(CH3)3), 2.03 (1 H, t, 6.5 Hz, C6-OH),
2.27 (1 H, s (br), C4-OH), 3.25-3.98 (8 H, m), 4.43 (1 H, d, 7.5
Hz, H-1), 4.63 (1 H, d, 11.0 Hz, CH2Ph), 4.70 (1 H, d, 11.0 Hz,
CH2Ph), 4.94 (2 H, d, 11.0 Hz, CH2Ph), 7.25-7.37 (10 H, m,
ArH); 13C-NMR (62.5 MHz, CDCl3) δ -1.5 (3 C, CH3), 18.6
(CH3), 62.7 (CH3), 67.9 (CH2), 70.4 (CH), 74.7 (CH2), 74.7 (CH),
75.2 (CH2), 82.0 (CH), 83.9 (CH), 103.4 (CH), 127.8-128.6 (five
signals, CH), 138.4 (C), 138.5 (C); MS (CI) 478 (M + NH4+).
2-(Tr im eth ylsilyl)eth yl 2,3-Di-O-ben zyl-6-O-(ter t-bu tyl-
d ip h en ylsilyl)-â-D-glu cop yr a n osid e (14). To a solution of
13 (12.0 g, 26.1 mmol) and imidazole (3.92 g, 57.6 mmol) in
80 mL of DMF was added at 25 °C tert-butyldiphenylsilyl
chloride (7.14 g, 26.0 mmol) in 20 mL of DMF within 10 min.
The mixture was stirred for 4 h followed by the addition of
further tert-butyldiphenylsilyl chloride (0.50 g, 1.82 mmol) in
2 mL of DMF. After being stirred for 1 h, the solution was
diluted with 1 L of ether, washed with water (4 × 400 mL)
and brine (400 mL), and dried over Na2SO4. The solvent was
removed to furnish 14 (18.5 g, quant) as a colorless oil. The
crude material was used without further purification.
1
11: H-NMR (250 MHz, CDCl3) δ 0.02 (9 H, s, -Si(CH3)3),
0.99 (2 H, m, OCH2CH2Si(CH3)3), 2.58 (1 H, s (br), OH), 2.77
(1 H, s (br), OH), 3.38-3.64 (4 H, m, OCHaHbCH2Si(CH3)3, H-2,
H-4, H-5), 3.75 (1 H, t, 10.0 Hz, H-3), 3.81 (1 H, dd, 11.0/2.0
Hz, H-6a), 3.97 (1 H, m, OCHaHbCH2Si(CH3)3), 4.33 (1 H, dd,
11.0/4.5 Hz, H-6b), 4.38 (1 H, d, 8.0 Hz, H-1), 5.50 (1 H, CH-
Ph), 7.32-7.48 (5 H, m, ArH); 13C-NMR (62.5 MHz, CDCl3) δ
-1.4 (3 C, CH3), 18.3 (CH2), 66.3 (CH), 67.9 (CH2), 68.7 (CH2),
73.1 (CH), 74.6 (CH), 80.6 (CH), 101.9 (CH), 102.6 (CH), 126.2
(2 C, CH), 128.3 (2 C, CH), 129.3 (CH), 136.9 (C); MS/HR calcd
for C18H29O6Si (M + H+) 369.1733, found 369.1706.
2-(Tr im eth ylsilyl)eth yl 2,3-Di-O-ben zyl-4,6-O-ben zyli-
d en e-â-D-glu cop yr a n osid e (12). To a solution of 11 (11.9
g, 32.2 mmol) in 100 mL of DMF was added oilfree NaH (4.63
g, 193 mmol) in small portions. The temperature was kept at
1
14: H-NMR (250 MHz, CDCl3) δ 0.02 (9 H, s, -Si(CH3)3),
(21) In addition to the glycosylation product 42, we isolated unprec-
edented orthoester 39 and 1,4-anhydrogalactose derivative 40. When
BF3 etherate was added to a mixture of donor 32 and acceptor 26 we
also obtained N-glycoside 41 in up to 40% yield and isolated much lower
yields (10 -20%) of glycosylation product 42. A mechanistic analysis
will be published elsewhere.
1.03 (9 H, s, -Si(CH3)3), 1.03 (2 H, m, OCH2CH2Si(CH3)3), 2.59
(1 H, d, 2.0 Hz, C4-OH), 3.33-3.67 (5 H, m, H-2, H-3, H-4,
H-5, OCHaHbCH2Si(CH3)3), 3.81-4.05 (3 H, m, H-6a, H-6b,
OCHaHbCH2Si(CH3)3), 4.41 (1 H, d, 7.0 Hz, H-1), 4.71 (1 H, d,
11.5 Hz, CH2Ph), 4.74 (1 H, d, 11.5 Hz, CH2Ph), 4.92 (1 H, d,
11.5 Hz, CH2Ph), 4.97 (1 H, d, 11.5 Hz, CH2Ph), 7.26-7.71
(20 H, m, ArH); 13C-NMR (62.5 MHz, CDCl3) δ -1.4 (3 C, CH3),
18.6 (CH2), 19.2 (C), 26.8 (3C, CH3), 64.5 (CH2), 65.9 (CH2),
67.4 (CH2), 71.8 (CH), 74.8 (CH), 75.3 (CH), 82.0 (CH), 84.2
(CH), 103.1 (CH), 127.6-135.6 (11 signals, CH), 133.0 (C),
133.1 (C), 138.6 (C), 138.7 (C); MS (CI) 716 (M + NH4+).
2-(Tr im eth ylsilyl)eth yl 2,3-Di-O-ben zyl-6-O-(ter t-bu tyl-
d ip h en ylsilyl)-â-D-xylo-h exop yr a n osid -4-u lose (15). A so-
lution of 14 (18.2 g, 26.0 mmol) in 265 mL of DMSO/acetic
anhydride (10:7) was heated at 65 °C for 2 h. The solvents
were removed in vacuo (0.1 mbar) at 50 °C. The residue was
diluted with 1 L of ether, extracted with water (5 × 500 mL),
and washed with brine (500 mL). The organic layer was dried
(22) The biological testing was done at GlycoTech Corp., Rockville,
MD 20850.
(23) See: Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-
Streit, P.; Schwarzenbach, F. J . Am. Chem. Soc. 1992, 114, 2321.
(24) Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. Purification of
Laboratory Chemicals; Pergamon Press: Oxford, 1980.

520 J . Org. Chem., Vol. 61, No. 2, 1996
Thoma et al.
over Na2SO4 and the solvent removed in vacuo to give 15 (18.3
g, quant) as a colorless oil. The crude material was used
without further purification.
with phosphate buffer (3 × 100 mL), washed with brine (100
mL), and dried over Na2SO4. The solvent was removed and
the residue subjected to flash chromatography (SiO2, ether/
hexane 1:3 f 1:1) to give 17 (3.16 g, 79%) as a colorless oil.
1
15: H-NMR (250 MHz, CDCl3) δ 0.02 (9 H, s, -Si(CH3)3),
1
1.03 (9 H, s, -Si(CH3)3), 1.04 (2 H, m, OCH2CH2Si(CH3)3), 3.61
(1 H, m, OCHaHbCH2Si(CH3)3), 3.70 (1 H, dd, 9.0/7.0 Hz, H-2),
3.87 (1 H, dd, 10.5/7.0 Hz, H-6a), 3.96-4.13 (5 H, m, H-3, H-4,
H-5, H-6b, OCHaHbCH2Si(CH3)3), 4.59 (1 H, d, 11.5 Hz, CH2-
Ph), 4.72 (1 H, d, 11.5 Hz, CH2Ph), 4.75 (1 H, d, 7.0 Hz, H-1),
4.85 (1 H, d, 11.5 Hz, CH2Ph), 4.88 (1 H, d, 11.5 Hz, CH2Ph),
7.25-7.71 (20 H, m, ArH); 13C-NMR (62.5 MHz, CDCl3) δ -1.4
(3 C, CH3), 18.4 (CH2), 19.2 (C), 26.7 (3C, CH3), 62.2 (CH2),
67.5 (CH2), 73.7 (CH2), 74.7 (CH2), 78.1 (CH), 83.3 (CH), 83.6
(CH), 102.4 (CH), 127.7-135.6 (eight signals, CH), 133.0 (C),
133.4 (C), 137.5 (C), 138.1 (C), 201.6 (C); MS (CI) 714 (M +
NH4+).
17: H-NMR (250 MHz, CDCl3) δ 0.02 (9 H, s, -Si(CH3)3),
1.00 (2 H, m, OCH2CH2Si(CH3)3), 1.02 (9 H, s, -Si(CH3)3), 1.55
(1 H, t, 6.5 Hz, C7-OH), 3.28 (1 H, s, C4-OH), 3.38 (1 H, t (br),
6.5 Hz, H-5), 3.50 (1 H, d, 9.5 Hz, H-3), 3.55 (3 H, m, OCHaHb-
CH2Si(CH3)3, H-7a, H-7b), 3.79 (1 H, dd, 9.5/8.0 Hz, H-2), 3.87,
(1 H, dd, 11.5/4.0 Hz, H-6a), 4.00 (1H, m, OCHaHbCH2Si-
(CH3)3), 4.04 (1 H, dd, 11.5/5.0 Hz, H-6b), 4.33 (1 H, d, 8.0 Hz,
H-1), 4.67 (1 H, d, 11.5 Hz, CH2Ph), 4.72 (1 H, d, 11.5 Hz, CH2-
Ph), 4.93 (1 H, d, 11.5 Hz, CH2Ph), 4.98 (1 H, d, 11.5 Hz, CH2-
Ph), 7.25-7.69 (20 H, m, ArH); 13C-NMR (62.5 MHz, CDCl3)
δ -1.4 (3 C, CH3), 18.5 (CH2), 19.0 (C), 26.7 (3C, CH3), 62.8
(CH2), 63.3 (CH2), 67.2 (CH2), 74.3 (CH), 75.0 (CH), 75.1 (C),
75.3 (CH), 78.3 (CH), 81.2 (CH), 103.2 (CH), 127.6-135.7 (11
signals, CH), 132.3 (C), 132.5 (C), 138.1 (C), 138.8 (C); MS
(FAB/EI) 727 (M - H-).
2-(Tr im eth ylsilyl)eth yl 2,3-Di-O-ben zyl-4-C-vin yl-6-O-
(ter t-bu tyld ip h en ylsilyl)-â-D-ga la ctop yr a n osid e (16). To
a solution of 15 (5.71 g, 8.20 mmol) in THF was added at -78
°C within 2 h 32.8 mL of a 0.5 M solution of vinylmagnesium
bromide (16.4 mmol) in THF. The clear solution becomes a
brown suspension. After the mixture was stirred for 2 h at
-78 °C, TLC (ether/hexane 1:3) indicated complete consump-
tion of 15. The reaction was quenched with 30 mL of
phosphate buffer (pH 7), warmed to 25 °C, and diluted with
200 mL of ether. The aqueous layer was extracted with ether
(2 × 100 mL), and the combined organic extracts were washed
with brine (200 mL) and dried over Na2SO4. The solvent was
removed and the residue subjected to flash chromatography
(SiO2, ether/hexane 1:5 f 1-3) to yield the C-4 epimer of 16
(0.20 g) and 16 (4.26 g, 72%).
2-(Tr im eth ylsilyl)eth yl 4-C-Hyd r oxym eth yl-6-O-(ter t-
bu tyld ip h en ylsilyl)-â-D-ga la ctop yr a n osid e (18). A solu-
tion of 17 (3.45 g, 4.74 mmol) in 70 mL of methanol containing
three drops of acetic acid was hydrogenated in the presence
of 350 mg of Pd/C (10%) at 50 °C for 24 h. Additional catalyst
(100 mg) and a few drops of acetic acid were added, and the
hydrogenation continued until starting material and monode-
benzylated intermediates were completely transformed into
product 18. The catalyst was filtered off and the solvent
removed in vacuo to yield crude 18 (2.55 g, 98%), which was
used without further purification.
18: 13C-NMR (62.5 MHz, CDCl3) δ -1.4 (3 C, CH3), 18.2
(CH2), 19.0 (C), 26.7 (3C, CH3), 62.9 (CH2), 63.3 (CH2), 67.0
(CH2), 72.3 (CH), 73.3 (CH), 74.7 (C), 75.1 (CH), 102.2 (CH),
127.8 (2 C, CH), 127.9 (2 C, CH), 129.9 (CH), 130.0 (CH), 132.4
(C), 132.6 (C), 135.6 (2 C, CH), 135.7 (2 C, CH).
(2S,5S,6R,8R,9R,10R)-6-[[(ter t-Bu tyld ip h en ylsilyl)oxy]-
m eth yl]-2-(fu r a n -2-yl)-8-[2-(tr im eth ylsilyl)eth oxy]-1,3,7-
tr ioxa bicyclo[4.4.0]d eca n e-5,9-d iol (19a ) a n d (2S,5R,6R,
8R,9R,10R)-6-[[(ter t-Bu t yld ip h en ylsilyl)oxy]m et h yl]-2-
(fu r an -2-yl)-8-[2-(tr im eth ylsilyl)eth oxy]-1,3,7-tr ioxaspir o-
[4.5]d eca n e-9,10-d iol (19b). A solution of 18 (650 mg, 1.19
mmol), furaldehyde diethyl acetal (222 mg, 1.31 mmol), and
pyridinium p-toluenesulfonate (30.0 mg, 0.12 mmol) in 30 mL
of benzene was heated at 60° C for 1 h. TLC (ether/hexane
4:1) indicated complete consumption and formation of two
products. The reaction was quenched with 5 mL of 10%
NaHCO3, the layers were separated, the aqueous layer was
extracted with benzene (10 mL), and the combined organic
layers were washed with brine (15 mL) and dried over Na2-
SO4. The solvent was removed and the residue subjected to
flash chromatography (SiO2, ether/hexane 1:1 f 3:1). Six-
membered ring acetal 19a (298 mg, 40%) eluted first followed
by five-membered ring acetal 19b (297 mg, 40%).
19a : 1H-NMR (500 MHz, CDCl3) δ 0.02 (9 H, s, -Si(CH3)3),
1.00 (2 H, m, OCH2CH2Si(CH3)3), 1.06 (9 H, s, -Si(CH3)3), 2.35
(1 H,s (br), C2-OH), 3.22 (1 H, s, C4-OH), 3.41 (1 H, t (br), 5.5
Hz, H-5), 3.55 (1 H, ddd, 11.5/9.5/5.5 Hz, OCHaHbCH2Si(CH3)3),
3.72 (1 H, d, 10.0 Hz, H-3), 3.76, (1 H, dd, 11.0/4.5 Hz, H-6a),
3.83 (1 H, d, 11.5 Hz, H-7axial), 3.87 (1 H, dd, 10.0/8.0 Hz,
H-2), 3.97 (1 H, ddd, 11.5/9.5/5.5 Hz, OCHaHbCH2Si(CH3)3),
4.09 (1 H, dd, 11.0/7.0 Hz, H-6b), 4.31 (1 H, d, 11.5 Hz,
H-7equatorial), 4.32 (1 H, d, 8.0 Hz, H-1), 5.72 (1 H, s, CH-
Fu), 6.39 (1 H, m, Fu(H-4)), 6.52 (1 H, m, Fu(H-3)), 7.38-7.70
(11 H, ArH, Fu(H-5)); 13C-NMR (62.5 MHz, CDCl3) δ -1.4 (3
C, CH3), 18.2 (CH2), 19.1 (C), 26.8 (3C, CH3), 61.8 (CH2), 67.2
(CH2), 67.9 (C), 69.2 (CH), 72.9 (CH2), 74.9 (CH), 82.8 (CH),
96.6 (CH), 102.5 (CH), 108.5 (CH), 110.3 (CH), 127.8 (4 C, CH),
129.9 (2 C, CH), 132.7 (C), 132.9 (C), 135.6 (4 C, CH), 142.9
(CH), 149.4 (C); MS/HR calcd for C33H46O8Si2Li (M + Li+)
633.2891, found 633.2890.
1
16: H-NMR (500 MHz, CDCl3) δ 0.03 (9 H, s, -Si(CH3)3),
1.05 (9 H, s, -Si(CH3)3), 1.10 (2 H, m, OCH2CH2Si(CH3)3), 3.31
(1 H, s, C4-OH), 3.32 (1 H, dd, 6.0/2.0 Hz, H-5), 3.36 (1 H, d,
9.0 Hz, H-3), 3.66 (1 H, td, 10.0/7.0 Hz, OCHaHbCH2Si(CH3)3),
3.75 (1 H, t, 9.0 Hz, H-2), 3.87, (1 H, dd, 11.0/2.0 Hz, H-6a),
3.95 (1 H, dd, 11.0/6.0 Hz, H-6b), 4.15 (1H, td, 10.0/7.0 Hz,
OCHaHbCH2Si(CH3)3), 4.46 (1 H, d, 9.0 Hz, H-1), 4.62 (1 H, d,
11.0 Hz, CH2Ph), 4.73 (1 H, d, 11.0 Hz, CH2Ph), 4.76 (1 H, d,
11.0 Hz, CH2Ph), 4.99 (1 H, d, 11.0 Hz, CH2Ph), 5.23 (1 H, dd,
10.0/3.0 Hz, -CHdCHaHb), 5.49 (1 H, dd, 17.0/3.0 Hz,
-CHdCHaHb), 5.55 (1 H, dd, 17.0/10.0 Hz, -CHdCHaHb),
7.24-7.72 (20 H, m, ArH); 13C-NMR (62.5 MHz, C6D6) δ -0.4
(3 C, CH3), 19.7 (CH2), 20.3 (C), 27.9 (3C, CH3), 64.3 (CH2),
67.8 (CH2), 75.9 (CH2), 76.7 (CH2), 77.6 (C), 79.0 (CH), 81.6
(CH), 84.2 (CH), 104.5 (CH), 117.2 (CH2), 128.4-140.7 (11
signals, CH), 134.5 (C), 135.0 (C), 139.6 (C), 140.7 (C); MS/
HR calcd for C43H56O6Si2Li (M + Li+) 731.3776, found 731.3776.
The configuration of C-4 was proven by NOE measurements.
2-(Tr im eth ylsilyl)eth yl 2,3-d i-O-ben zyl-4-C-vin yl-6-O-
(ter t-bu tyldiph en ylsilyl)-â-D-glu copyr an oside (C-4 epim er
of 16): 1H-NMR (500 MHz, CDCl3) δ 0.00 (9 H, s, -Si(CH3)3),
1.02 (9 H, s, -Si(CH3)3), 1.05 (2 H, m, OCH2CH2Si(CH3)3), 3.41
(1 H, dd, 10.0/8.0 Hz, H-2), 3.43 (1 H, s, C4-OH), 3.58 (2 H, m,
H-5, OCHaHbCH2Si(CH3)3), 3.64 (1 H, d, 10.0 Hz, H-3), 3.71
(1 H, dd, 11.0/6.0 Hz, H-6a), 3.81 (1 H, dd, 11.0/6.0 Hz, H-6b),
3.96 (1H, td, 9.0/8.0 Hz, OCHaHbCH2Si(CH3)3), 4.49 (1 H, d,
8.0 Hz, H-1), 4.71 (1 H, d, 11.0 Hz, CH2Ph), 4.83 (1 H, d, 11.5
Hz, CH2Ph), 4.87 (1 H, d, 11.0 Hz, CH2Ph), 4.91 (1 H, d, 11.5
Hz, CH2Ph), 5.46 (1 H, dd, 11.0/2.0 Hz, -CHdCHaHb), 5.62 (1
H, dd, 17.5/2.0 Hz, -CHdCHaHb), 6.12 (1 H, dd, 17.5/11.0 Hz,
-CHdCHaHb), 7.28-7.72 (20 H, m, Ar-H); 13C-NMR (62.5
MHz, CDCl3) δ -1.4 (3 C, CH3), 18.6 (CH2), 19.0 (C), 26.7 (3C,
CH3), 63.7 (CH2), 67.7 (CH2), 75.1 (CH2), 75.3 (CH2), 75.5 (CH),
78.3 (C), 81.1 (CH), 86.0 (CH), 103.7 (CH), 117.3 (CH2), 127.5-
135.6 (15 signals, CH), 132.3 (C), 132.4 (C), 138.7 (C), 139.0
(C).
2-(Tr im eth ylsilyl)eth yl 2,3-Di-O-ben zyl-4-C-(h ydr oxym -
et h yl)-6-O-(ter t-b u t yld ip h en ylsilyl)-â-D-ga la ct op yr a n o-
sid e (17). Ozone was bubbled through a solution of 16 (3.98
g, 5.50 mmol) in 200 mL of CH2Cl2 at -78 °C until TLC (ether/
hexane 1:3) indicated complete consumption (∼40 min). Ex-
cess ozone was removed by bubbling argon through the
mixture for 1 h. Methanol (15 mL) and NaBH4 (0.42 g, 11.0
mmol) were added and stirring continued at -78 °C for 1 h.
The mixture was quenched with 250 mL of phosphate buffer
(pH 7) and warmed to 25 °C. The organic layer was extracted
19b: 1H-NMR (500 MHz, CDCl3) δ 0.01 (9 H, s, -Si(CH3)3),
1.00 (2 H, m, OCH2CH2Si(CH3)3), 1.05 (9 H, s, -Si(CH3)3), 2.48
(1 H,s (br), C3-OH), 2.65 (1 H, s (br), C3-OH), 3.44 (1 H, d (br),
10.0 Hz, H-3), 3.48 (2 H, m, H-5, H-6a), 3.58 (1 H, m, OCHaHb-
CH2Si(CH3)3), 3.65 (1 H, dd, 10.0/7.5 Hz, H-2), 3.77 (1 H, d,
8.5 Hz, H-7a), 4.05 (2 H,m, H-6b, OCHaHbCH2Si(CH3)3), 4.12
(1 H, d, 8.5 Hz, H-7b), 4.27 (1 H, d, 7.5 Hz, H-1), 5.90 (1 H, s,

Synthesis of a Rigid Mimic of Sialyl Lewis x
J . Org. Chem., Vol. 61, No. 2, 1996 521
CH-Fu), 6.22 (2 H, m, Fu(H-3), Fu(H-4)), 7.19 (1 H, m, Fu (H-
5)), 7.33-7.73 (10 H, ArH); 13C-NMR (62.5 MHz, CDCl3) δ -1.4
(3 C, CH3), 18.2 (CH2), 19.2 (C), 26.8 (3C, CH3), 62.9 (CH2),
67.1 (CH2), 67.6 (CH2), 73.5 (CH), 74.2 (CH), 78.9 (CH), 81.8
(C), 100.0 (CH), 101.8 (CH), 109.9 (CH), 110.0 (CH), 127.7 (4
C, CH), 129.6 (CH), 129.7 (CH), 133.4 (C), 133.9 (C), 135.6 (2
C, CH), 135.7 (2 C, CH), 143.2 (CH), 148.8 (C); MS/HR calcd
for C33H46O8Si2Li (M + Li+) 633.2891, found 633.2901.
(2S,5S,6R,8R,9R,10R)-6-(H yd r oxym et h yl)-2-(fu r a n -2-
yl)-8-[2-(tr im eth ylsilyl)eth oxy]-1,3,7-tr ioxa bicyclo[4.4.0]-
d eca n e-5,9-d iol (22). A solution of 19a (390 mg, 0.62 mmol)
and tetrabutylammonium fluoride (393 mg, 1.25 mmol) in 8
mL of THF was stirred at 25 °C for 3 h. Silica gel (1 g) was
added and the solvent removed in vacuo. The residue was
subjected to flash chromatography (SiO2, ether/methanol 98:
2) to give 22 (240 mg, quant) as a colorless solid.
22: 1H-NMR (250 MHz, CDCl3) δ -0.10 (9 H, s, -Si(CH3)3),
0.90 (2 H, m, OCH2CH2Si(CH3)3), 2.11 (1 H, t, 10.0 Hz, C6-
OH), 2.32 (1 H,s (br), C2-OH), 3.21 (1 H, s, C4-OH), 3.35 (1 H,
dd, 6.5/5.5 Hz, H-5), 3.49 (1 H, ddd, 10.5/9.0/6.5 Hz, OCHaHb-
CH2Si(CH3)3), 3.61 (1 H, d, 9.5 Hz, H-3), 3.65, (1 H, m, H-6a),
3.71 (1 H, d, 11.5 Hz, H-7axial), 3.80 (2 H, m, H-2, H-6b), 3.92
(1 H, d, 11.5 Hz, H-7equatorial), 3.93 (1 H, ddd, 10.5/9.0/6.5
Hz, OCHaHbCH2Si(CH3)3), 4.28 (1 H, d, 7.5 Hz, H-1), 5.58 (1
H, s, CH-Fu), 6.25 (1 H, m, Fu(H-4)), 6.40 (1 H, m, Fu(H-3)),
7.30 (1 H, Fu(H-5)); 13C-NMR (62.5 MHz, CDCl3) δ -1.4 (3 C,
CH3), 18.2 (CH2), 60.6 (CH2), 67.6 (CH2), 68.0 (C), 69.2 (CH),
72.3 (CH2), 74.4 (CH), 82.7 (CH), 96.8 (CH), 102.8 (CH), 108.7
(CH), 110.3 (CH), 143.0 (CH), 149.1 (C).
H, t (br), 6.0 Hz, H-5), 3.87 (1 H, d, 11.5 Hz, H-7axial), 3.96 (1
H, d, 10.0 Hz, H-3), 3.98 (1 H, m, OCHaHbCH2Si(CH3)3), 4.26
(1 H, d, 11.5 Hz, H-7equatorial), 4.62 (2 H, m, H-6a, H-6b),
4.70 (1 H, d, 8.0 Hz, H-1), 5.10 (1 H, s, CHCO2CH3), 5.52 (1 H,
dd, 10.0/8.0 Hz, H-2), 7.40-8.07 (10 H, m, ArH); 13C-NMR (62.5
MHz, CDCl3) δ -1.6 (3 C, CH3), 18.8 (CH2), 52.9 (CH3), 62.0
(CH2), 67.2 (CH2), 68.2 (C), 69.8 (CH), 72.2 (CH2), 72.3 (CH),
81.0 (CH), 97.0 (CH), 100.6 (CH), 128.3 (2 C, CH), 128.5 (2 C,
CH), 129.4 (C), 129.6 (2 C, CH), 129.8 (C), 129.9 (2 C, CH),
133.0 (CH), 133.4 (CH), 164.8 (C), 165.2 (C), 166.2 (C); MS/
HR calcd for C29H36O11SiLi (M + Li+) 595.2187, found 595.2195.
(2S,5S,6R,8R,9R,10R)-2-Ca r boxy-5,9-bis(ben zoyloxy)-6-
[(b e n zoyloxy)m e t h yl]-1,3,7-t r ioxa b icyclo[4.4.0]d e c-8-
yl] Tr ich lor oa cetim id a te (25). A solution of 24 (397 mg,
0.67 mmol) in 12 mL of CH2Cl2/trifluoroacetic acid 1:1 was
stirred at 0 °C for 1 h. TLC (ethyl acetate/hexane 2:1)
indicated complete consumption and the formation of two
products. The mixture was diluted with 25 mL of ethyl acetate
and 40 mL of toluene and evaporated under reduced pressure
(bath temperature 35 °C). The residue was coevaporated with
toluene (5 × 40 mL). The remaining colorless foam was
dissolved in CH2Cl2 (10 mL) followed by the addition of
trichloroacetonitrile (144 mg, 1.00 mmol) and cesium carbonate
(107 mg, 0.33 mmol). The mixture was stirred for 16 h at 25
°C and filtered, the solvent removed in vacuo, and the residue
subjected to flash chromatography (SiO2, ethyl acetate/hexane
1:2) to yield 25 (225 mg, 54%) as a colorless foam.
25: 1H-NMR (250 MHz, CDCl3) δ 3.55 (1 H, s, C4-OH), 3.80
(3 H, s, -CO2CH3), 4.01 (1 H, d, 11.5 Hz, H-7axial), 4.25 (1 H,
d, 11.5 Hz, H-7equatorial), 4.26 (1 H, t (br), 6.0 Hz, H-5), 4.45
(1 H, d, 10.0 Hz, H-3), 4.51 (1 H, dd, 11.5/6.5 Hz, H-6a), 4.63
(1 H, dd, 11.5/6.5 Hz, H-6b), 5.26 (1 H, s, CHCO2CH3), 5.77 (1
H, dd, 10.0/3.5 Hz, H-2), 6.75 (1 H, d, 3.5 Hz, H-1), 7.38-8.06
(10 H, m, ArH), 8.57 (1 H, s, dNH).
2-(Tr im et h ylsilyl)et h yl 2,3-Di-O-b en zoyl-4,6-O-b en -
zylid en e-â-D-glu cop yr a n osid e (33). To a solution of 22
(6.25 g, 17.0 mmol) in 60 mL of pyridine was added at 0 °C
benzoyl chloride (9.56 g, 68.0 mmol) and 4-(dimethylamino)-
pyridine (0.86 g, 6.80 mmol). The mixture was warmed to 25
°C and stirred for 2 h. Ether (1 L) was added followed by
extraction with 0.1 M HCl (5 × 250 mL) and 10% NaHCO3 (3
× 250 mL). The organic layer was washed with brine (500
mL) and dried over Na2SO4. The solvent was removed and
the residue stirred with 500 mL of pentane for 15 min.
Filtration followed by pentane washings afforded 33 (9.35 g,
96%) as a clorless solid.
(2S,5S,6R,8R,9R,10R)-6-[(Ben zoyloxy)m eth yl]-2-(fu r a n -
2-yl)-8-[2-(t r im et h ylsilyl)et h oxy]-9-(b en zoyloxy)-1,3,7-
tr ioxa bicyclo[4.4.0]d eca n -5-ol (23). To a solution of 22 (660
mg, 1.70 mmol) in 7 mL of pyridine were added at 0 °C benzoyl
chloride (956 mg, 6.80 mmol) and 4-(dimethylamino)pyridine
(83 mg, 0.68 mmol). The mixture was warmed to 25 °C and
stirred for 16 h. Ether (100 mL) was added followed by
extraction with 0.1 M HCl (5 × 25 mL) and 10% NaHCO3 (3
× 25 mL). The organic layer was washed with brine (50 mL)
and dried over Na2SO4. The solvent was removed and the
residue stirred with 30 mL of pentane for 15 min. Filtration
followed by pentane washings afforded 23 (950 mg, 94%) as a
colorless solid.
1
23: H-NMR (250 MHz, CDCl3) δ 0.01 (9 H, s, -Si(CH3)3),
0.97 (2 H, m, OCH2CH2Si(CH3)3), 3.58 (1 H, d, 0.5 Hz, C4-OH),
3.67 (1 H, td, 10.0/6.5 Hz, OCHaHbCH2Si(CH3)3), 3.93 (1 H, t
(br), 6.0 Hz, H-5), 4.04 (1 H, d, 11.5 Hz, H-7axial), 4.11 (1 H,
td, 10.0/6.5 Hz, OCHaHbCH2Si(CH3)3), 4.12 (1 H, d, 10.0 Hz,
H-3), 4.34 (1 H, d, 11.5 Hz, H-7equatorial), 4.74 (2 H, m, H-6a,
H-6b), 4.81 (1 H, d, 8.0 Hz, H-1), 5.64 (1 H, dd, 10.0/8.0 Hz,
H-2), 5.75 (1 H, s, CH-Fu), 6.40 (1 H, m, Fu(H-4)), 6.54 (1 H,
m, Fu(H-3)), 7.45 (1 H, Fu(H-5)), 7.49-8.17 (10 H, m, Ar-H);
13C-NMR (62.5 MHz, CDCl3) δ -1.4 (3 C, CH3), 18.0 (CH2),
62.3 (CH2), 67.3 (CH2), 68.2 (C), 70.1 (CH), 72.4 (CH2), 72.5
(CH), 81.2 (CH), 96.9 (CH), 100.8 (CH), 108.5 (CH), 110.4 (CH),
128.4 (2 C, CH), 128.7 (2 C, CH), 129.6 (C), 129.7 (2 C, CH),
129.9 (2 C, CH), 130.1 (C), 133.1 (CH), 133.5 (CH), 142.9 (CH),
149.2 (C), 165.2 (C), 166.3 (C); MS/HR calcd for C31H36O10SiLi
(M + Li+) 602.2238, found 603.2224.
33: 1H-NMR (250 MHz, CDCl3) δ -0.10 (9 H, s, -Si(CH3)3),
0.87 (2 H, m, OCH2CH2Si(CH3)3), 3.57 (1 H, m, OCHaHbCH2-
Si(CH3)3), 3.67 (1 H, td, 6.5/5.0 Hz, H-5), 3.86 (1 H, t, 10.0 Hz,
H-6a), 3.89 (1 H, t, 9.5 Hz, H-4), 3.97 (1 H, m, OCHaHbCH2-
Si(CH3)3), 4.74 (1 H, dd, 10.5/5.0 Hz, H-6b), 4.88 (1 H, d, 7.5
Hz, H-1), 5.44 (1 H, dd, 9.5/8.0 Hz, H-2), 5.52 (1 H, s, CH-Ph),
5.74 (1 H, d, 9.5 Hz, H-3), 7.29-8.00 (15 H, m, Ar-H); 13C-
NMR (62.5 MHz, CDCl3) δ -1.5 (3 C, CH3), 18.1 (CH2), 66.6
(CH), 67.3 (CH2), 68.0 (CH2), 68.7 (CH2), 72.2 (CH), 72.6 (CH),
78.9 (CH), 101.2 (CH), 101.4 (CH), 126.1-133.1 (eight signals,
CH, C), 136.8 (C), 165.2 (C), 165.6 (C); MS (CI) 594 (M +
NH4+).
(2S,5S,6R,8R,9R,10R)-6-[(Ben zoyloxy)m eth yl]-2-(m eth -
oxycar bon yl)-8-[2-(tr im eth ylsilyl)eth oxy]-9-(ben zoyloxy)-
1,3,7-tr ioxabicyclo[4.4.0]decan -5-ol (24). Ozone was bubbled
through a solution of 23 (72.0 mg, 0.12 mmol) in 6 mL of
methanol/CH2Cl2 1:1 at -78 °C for approximately 2 min. TLC
(ether/hexane 4:1) indicated complete consumption. Excess
ozone was removed by bubbling argon through the mixture
for 30 min. Then, hydrogen peroxide (0.1 mL of a 30%
solution) was added at -78 °C and the mixture warmed to 25
°C and stirred for 3 h. The solvents were removed in vacuo
and the residue dissolved in ether (10 mL). The mixture was
cooled to 0 °C, and a solution of diazomethane in ether was
added dropwise until the yellow color remained. Stirring was
continued for 1 h at 25 °C. The solvent was removed and the
residue subjected to flash chromatography (SiO2, ether/hexane
2:1) to yield 24 (57.0 mg (80%) as a colorless foam.
2-(Tr im eth ylsilyl)eth yl 2,3-Di-O-ben zoyl-6-O-ben zyl-â-
D-glu cop yr a n osid e (34). Compound 33 (8.06 g, 14.0 mmol),
NaCNBH4 (8.82 g, 140 mmol), and molecular sieves (4 Å,
powdered, 8.0 g) were suspended in 200 mL of THF at 0 °C. A
saturated solution of HCl in ether was added dropwise and
the reaction carefully monitored by TLC (ether/hexane 2:1).
After complete consumption of 33, the mixture was filtered,
the residue was washed with ether (2 × 100 mL), and the
combined organic layers were extracted with phosphate buffer
(pH 7, 2 × 300 mL), washed with brine (300 mL), and dried
over Na2SO4. The solvent was removed in vacuo, and the
residue was subjected to flash chromatography (SiO2, ether/
hexane 1:1) to yield 34 (7.56 g, 93%) as a colorless solid.
34: 1H-NMR (500 MHz, CDCl3) δ -0.04 (9 H, s, -Si(CH3)3),
0.90 (2 H, m, OCH2CH2Si(CH3)3), 3.27 (1 H, d, 3.5 Hz, C4-OH),
3.59 (1 H, m, OCHaHbCH2Si(CH3)3), 3.71 (1 H, dt, 9.0/4.5 Hz,
H-5), 3.87 (2 H, m, H-6a, H-6b), 3.96 (1 H, td, 9.0/3.5 Hz, H-4),
4.03 (1 H, m, OCHaHbCH2Si(CH3)3), 4.62 (1 H, d, 12.0 Hz,
-CH2Ph), 4.66 (1 H, d, 12.0 Hz, -CH2Ph), 4.71 (1 H, d, 7.5
24: 1H-NMR (250 MHz, CDCl3) δ -0.10 (9 H, s, -Si(CH3)3),
0.88 (2 H, m, OCH2CH2Si(CH3)3), 3.48 (1 H, s, C4-OH), 3.56 (1
H, m, OCHaHbCH2Si(CH3)3), 3.76 (3 H, s, -CO2CH3), 3.80 (1

522 J . Org. Chem., Vol. 61, No. 2, 1996
Thoma et al.
Hz, H-1), 5.44 (2 H, m, H-2, H-3), 7.30-8.00 (15 H, m, ArH);
13C-NMR (62.5 MHz, CDCl3) δ -1.5 (3 C, CH3), 18.0 (CH2),
67.5 (CH2), 70.2 (CH2), 71.3 (CH), 71.5 (CH), 73.8 (CH2), 74.5
(CH), 76.9 (CH), 100.5 (CH), 127.7-133.4 (nine signals, CH),
129.0 (C), 129.6 (C), 137.7 (C), 165.2 (C), 167.3 (C); MS (CI)
613 (M + Cl-), 578 (M-).
4.76 (1 H, d, 8.0 Hz, H-1), 4.77 (1 H, d, 12.0 Hz, -CH2Ph),
5.48 (1 H, d, 10.0 Hz, H-3), 5.94 (1 H, dd, 10.0/8.0 Hz, H-2),
7.30-8.07 (15 H, m, ArH).
2-(Tr im eth ylsilyl)eth yl 2,3-Di-O-ben zoyl-4-C-[(ben zoy-
loxy)m eth yl]-6-O-ben zyl-â-D-ga la ctop yr a n osid e (38). To
a solution of crude 37 (4.60 g) in 25 mL of pyridine was added
at 0 °C benzoyl chloride (2.13 g, 15.2 mmol) and 4-(dimethy-
lamino)pyridine (0.19 g, 1.52 mmol). The mixture was warmed
to 25 °C and stirred for 2 h. Ether (200 mL) was added
followed by extraction with 0.1 M HCl (5 × 100 mL) and 10%
NaHCO3 (3 × 100 mL). The organic layer was washed with
brine (100 mL) and dried over Na2SO4. The solvent was
removed and the residue subjected to flash chromatography
(SiO2, ethyl acetate/hexane 1:2) to yield 38 (3.86 g, 70%) as a
colorless foam.
2-(Tr im eth ylsilyl)eth yl 2,3-Di-O-ben zoyl-6-O-ben zyl-â-
D-xylo-h exop yr a n osid -4-u lose (35). A suspension of 34
(4.49 g, 7.75 mmol), 1.5 g of P2O5, and 3 mL of DMSO in 18
mL of DMF was heated at 50 °C for 2 h. TLC (acetone/hexane
1:3) indicated complete consumption of 34. Phosphate buffer
(pH 7, 600 mL) was added and the mixture extracted with
ether (4 × 250 mL). The combined organic layers were
extracted with water (4 × 250 mL), washed with brine (250
mL), and dried over Na2SO4. The solvent was removed in
vacuo to give 35 (4.50 g) as a yellow oil. Crude 35 was used
without further purification.
38: 1H-NMR (250 MHz, CDCl3) δ -0.02 (9 H, s, -Si(CH3)3),
0.95 (2 H, m, OCH2CH2Si(CH3)3), 3.68 (1 H, td, 10.0/6.5 Hz,
OCHaHbCH2Si(CH3)3), 3.95 (1 H, t (br), 3.0 Hz, H-5), 4.10 (3
H, m, H-6a, H-6b, OCHaHbCH2Si(CH3)3), 4.31 (1 H, s, C4-OH),
4.32 (1 H, d, 12.0 Hz, H-7a), 4.49 (1 H, 12.0 Hz, H-7b), 4.65 (1
H, d, 12.0 Hz, -CH2Ph), 4.75 (1 H, d, 12.0 Hz, -CH2Ph), 4.82
(1 H, d, 7.5 Hz, H-1), 5.81 (1 H, d, 9.5 Hz, H-3), 5.89 (1 H, dd,
9.5/7.5 Hz, H-2), 7.35-8.12 (20 H, m, ArH); 13C-NMR (62.5
MHz, CDCl3) δ -1.5 (3 C, CH3), 18.0 (CH2), 63.2 (CH2), 67.4
(CH2), 69.6 (CH2), 71.0 (CH), 72.3 (CH), 73.4 (CH), 74.2 (CH2),
74.5 (C), 76.1 (CH), 77.3 (C), 101.0 (CH), 118.0 (CH2), 127.8-
136.1 (13 signals, CH, C), 137.4 (C), 165.2 (C), 166.0 (C); MS/
HR calcd for C40H44O10SiLi (M + Li+) 719.2864, found 719.2822.
2,3-Di-O-ben zoyl-4-C-[(ben zoyloxy)m eth yl]-6-O-ben zyl-
r-D-ga la ctop yr a n osyl) tr ich lor oa cetim id a te (32). A solu-
tion of 38 (3.12 g, 4.40 mmol) in 75 mL of CH2Cl2/trifluoroacetic
acid 1:1 was stirred at 0 °C for 2 h. TLC (acetone/hexane 1:1)
indicated complete consumption and the formation of two
products. The mixture was diluted with 150 mL of ethyl
acetate and 250 mL of toluene and evaporated under reduced
pressure (bath temperature 35 °C). The residue was coevapo-
rated with toluene (5 × 200 mL). The remaining yellow foam
was dissolved in CH2Cl2 (100 mL) followed by the addition of
trichloroacetonitrile (0.95 g, 6.60 mmol) and cesium carbonate
(0.29 g, 0.88 mmol). The mixture was stirred for 4 h at 25 °C
and filtered, the solvent removed in vacuo, and the residue
subjected to flash chromatography (SiO2, ethyl acetate/hexane/
CH2Cl2 1:6:1) to yield 32 (2.69 g, 81%) as a colorless foam.
32: 1H-NMR (250 MHz, CDCl3) δ 3.96 (1 H, dd, 11.5/2.5 Hz,
H-6a), 4.19 (1 H, dd, 11.5/2.5 Hz, H-6b), 4.29 (1 H, d, 11.5 Hz,
H-7a), 4.44 (1 H, d, 11.5 Hz, H-7b), 4.45 (1 H, t, 6.0 Hz, H-5),
4.57 (1 H, d, 11.5 Hz, -CH2Ph), 4.72 (1 H, d, 11.5 Hz, -CH2-
Ph), 4.88 (1 H, s, C4-OH), 5.97 (1 H, dd, 10.0/3.5 Hz, H-2), 6.34
(1 H, d (br), 10.0 Hz, H-3), 6.88 (1 H, d, 3.5 Hz, H-1), 7.30-
8.10 (20 H, m, ArH), 8.55 (1 H, s, dNH); 13C-NMR (62.5 MHz,
CDCl3) δ 62.7 (CH2), 68.4 (CH), 69.3 (CH), 69.7 (CH2), 70.8
(CH), 73.4 (CH), 74.6 (CH2), 75.1 (C), 90.8 (C), 94.0 (CH),
127.9-133.4 (nine signals, CH), 128.8 (C), 129.0 (C), 129.2 (C)
136.3 (C), 160.3 (C), 165.5 (2 C, C), 166.1 (C).
1
35: H-NMR (250 MHz, CDCl3) δ 0.00 (9 H, s, -Si(CH3)3),
0.95 (2 H, m, OCH2CH2Si(CH3)3), 3.72 (1 H, m, OCHaHbCH2-
Si(CH3)3), 3.81 (1 H, dd, 11.0/7.0 Hz, H-6a), 4.06 (1 H, dd, 11.0/
3.0 Hz, H-6b), 4.09 (1 H, m, OCHaHbCH2Si(CH3)3), 4.49 (1 H,
dd, 7.0/3.0 Hz, H-5), 4.63 (1 H, d, 12.0 Hz, -CH2Ph), 4.68 (1
H, d, 12.0 Hz, -CH2Ph), 5.17 (1 H, d, 6.0 Hz, H-1), 5.72 (1 H,
dd, 9.0/6.0 Hz, H-2), 5.88 (1 H, d, 9.0 Hz, H-3), 7.30-8.10 (15
H, m, ArH); 13C-NMR (62.5 MHz, CDCl3) δ -1.4 (3 C, CH3),
17.9 (CH2), 67.6 (CH2), 68.3 (CH2), 73.7 (CH2), 74.1 (CH), 75.9
(CH), 77.3 (CH), 99.8 (CH), 127.8-133.6 (7 signals, CH), 128.6
(C), 129.2 (C), 137.7 (C), 164.8 (C), 165.4 (C), 196.1 (C).
2-(Tr im eth ylsilyl)eth yl 2,3-Di-O-ben zoyl-3-C-vin yl-6-O-
ben zyl-â-D-ga la ctop yr a n osid e (36). To a solution of crude
35 (4.50 g) in 60 mL of THF was added at -78 °C vinylmag-
nesium bromide (19.4 mL of a 0.8 M solution in THF, 15.5
mmol) within 2 h. After 1 h of stirring, TLC (ether/hexane
1:1) indicated complete consumption of 35. The reaction was
quenched at -78 °C by addition of 50 mL of saturated NH4Cl
and warmed to 25 °C. The mixture was diluted with 300 mL
of ether and transferred into a separation funnel. The aqueous
layer was exracted with ether (2 × 50 mL), and the combined
organic layers were washed with brine (200 mL) and dried over
Na2SO4. Evaporation of the solvent furnished 36 (4.70 g) as
a yellow/brown oil. Crude 36 was used without further
purification.
36: 1H-NMR (500 MHz, CDCl3) δ -0.05 (9 H, s, -Si(CH3)3),
0.93 (2 H, m, OCH2CH2Si(CH3)3), 3.62 (1 H, s, C4-OH), 3.63 (1
H, m, OCHaHbCH2Si(CH3)3), 3.72 (1 H, t, 3.5 Hz, H-5), 3.85 (2
H, m, H-6a, H-6b), 4.09 (1 H, m, OCHaHbCH2Si(CH3)3), 4.55
(1 H, d, 12.0 Hz, -CH2Ph), 4.63 (1 H, d, 12.0 Hz, -CH2Ph),
4.77 (1 H, d, 8.0 Hz, H-1), 5.23 (1 H, dd, 10.5/1.5 Hz,
-CHdCHaHb), 5.45 (1 H, d, 10.0 Hz, H-3), 5.52 (1 H, dd, 17.0/
1.5 Hz, -CHdCHaHb), 5.76 (1 H, dd, 17.0/10.5 Hz, -CHd
CHaHb), 5.78 (1 H, dd, 10.0/8.0 Hz, H-2), 7.30-7.95 (15 H, m,
Ar-H); 13C-NMR (62.5 MHz, CDCl3) δ -1.4 (3 C, CH3), 18.0
(CH2), 67.4 (CH2), 69.5 (CH2), 70.7 (CH), 74.0 (CH2), 74.8 (CH),
76.1 (CH), 77.3 (C), 101.0 (CH), 118.0 (CH2), 127.8-136.1 (13
signals, CH, C), 137.4 (C), 165.2 (C), 166.0 (C); MS/CI 604 (M-).
The galactose configuration at C-4 was proven by NOE
measurements (strong NOE between the axial ring protons
H-3 and H-5 and the internal vinyl proton). The C-4 epimer
of 36 could not be detected.
2-(Tr im eth ylsilyl)eth yl 2,3-Di-O-ben zoyl-4-C-(h ydr oxym -
eth yl)-6-O-ben zyl-â-D-ga la ctop yr a n osid e (37). Ozone was
bubbled through a solution of crude 36 (4.70 g) in 200 mL of
CH2Cl2 at -78 °C until TLC (acetone/hexane 1:2) indicated
complete consumption (∼40 min). Excess ozone was removed
by bubbling argon through the mixture for 1 h. Methanol (15
mL) and NaBH4 (0.88 g, 23.3 mmol) were added, and stirring
was continued at -78 °C for 3 h. The mixture was quenched
with 500 mL of phosphate buffer (pH 7) and warmed to 25 °C.
The organic layer was extracted with phosphate buffer (3 ×
150 mL), washed with brine (150 mL), and dried over Na2-
SO4. The solvent was removed in vacuo to give 37 (4.60 g) as
a yellow oil. Crude 37 was used without further purification.
37: 1H-NMR (250 MHz, CDCl3) δ -0.02 (9 H, s, -Si(CH3)3),
0.96 (2 H, m, OCH2CH2Si(CH3)3), 3.30 (1 H, s (br), C7-OH),
3.55 (2 H, m, C4-OH, H-5), 3.68 (1 H, td, 10.0/6.5 Hz, OCHaHb-
CH2Si(CH3)3), 4.02 (2 H, m, H-7a, H-7b), 4.10 (3 H, m, H-6a,
H-6b,, OCHaHbCH2Si(CH3)3), 4.61 (1 H, d, 12.0 Hz, -CH2Ph),
2-(Tr im eth ylsilyl)eth yl 6-O-Ben zyl-2-deoxy-2-acetam ido-
3-O-(2,3,4-tr i-O-ben zyl-r-L-fu cop yr a n osyl)-4-O-(2,3-d i-O-
ben zoyl-4-C-[(ben zoyloxy)m eth yl]-6-O-ben zyl-â-D-ga la c-
top yr a n osyl)-â-D-glu cop yr a n osid e (42), (3S,4R,6S,7R,8R)-
Ben zoic Acid 7-(Ben zoyloxy)-4-[(ben zyloxy)m eth yl]-1-
p h en yl-2,5,9,10-tetr a oxa tr icyclo[4.3.1.03,8]d ec-3-yl Meth yl
Ester (39), 2,3-Di-O-ben zoyl-4-C-[(ben zoyloxy)m eth yl]-6-
O-ben zyl-1,4-a n h yd r o-D-ga la ctose (40), a n d 2,3-Di-O-ben -
zoyl-4-C-[(ben zoyloxy)m eth yl]-6-O-ben zyl-â-D-ga la ctop y-
r a n osyl) tr ich lor oa ceta m id e (41). To a solution of 2614 (192
mg, 0.231 mmol) in CH2Cl2 (1 mL) was added molecular sieves
(4 Å, powdered, 500 mg) and the mixture stirred at 25 °C for
2 h followed by the addition of BF3 etherate (33.0 mg, 0.23
mmol). A solution of 32 (350 mg, 0.46 mmol) in CH2Cl2 (3 mL)
was added dropwise within 2 h and stirring continued for 30
min. The mixture was filtered and extracted with NaHCO3
(2 × 25 mL). The solvent was removed and the residue
subjected to flash chromatography (SiO2, acetone/hexane 1:4
f 1:2) to yield (in order of elution) 39 and 40 (190 mg of a
inseparable 10:1 mixture, 69% with respect to 32), uncon-
sumed 26 (75.0 mg, 40%), and 42 (180 mg, 55% with respect
to 26).
39: 1H-NMR (250 MHz, CDCl3) δ 3.77 (1 H, dd, 10.0/4.5 Hz,

Synthesis of a Rigid Mimic of Sialyl Lewis x
J . Org. Chem., Vol. 61, No. 2, 1996 523
H-6a), 3.99 (1 H, dd, 10.0/7.0 Hz, H-6b), 4.56 (2 H, m, H-7a,
H-7b), 4.63 (2 H, m, -CH2Ph), 4.72 (1 H, dd, 7.0/4.5 Hz, H-5),
4.97 (1 H, t, 2.0 Hz, H-3), 5.54 (1 H, dd, 3.0/2.0 Hz, H-2), 5.78
(1 H, dd, 3.0/2.0 Hz, H-1), 7.25-8.10 (20 H, m, ArH); 13C-NMR
(62.5 MHz, CDCl3) δ 64.0 (CH2), 67.2 (CH), 69.5 (CH2), 72.0
(CH), 73.5 (CH2), 73.6 (CH), 82.1 (C), 94.3 (CH), 118.0 (C),
126.2-133.3 (11 signals, CH), 129.3 (C), 132.9 (C), 137.4 (C),
164.9 (C), 165.5 (C); MS/CI 594 (M-).
40: 1H-NMR (250 MHz, CDCl3) δ 3.52 (1 H, dd, 10.5/5.0 Hz,
H-6a), 3.63 (1 H, dd, 10.5/7.0 Hz, H-6b), 4.21 (1 H, dd, 7.0/5.0
Hz, H-5), 4.48 (2 H, m, H-7a, H-7b), 4.79 (1 H, d, 11.5 Hz,
-CH2Ph), 4.87 (1 H, d, 11.5 Hz, -CH2Ph), 5.13 (1 H, dd, 2.5/
1.5 Hz, H-2), 5.58 (1 H, d, 1.5 Hz, H-1), 5.98 (1 H, d, 2.5 Hz,
H-3), 7.20-8.12 (20 H, m, Ar-H); 13C-NMR (250 MHz, CDCl3)
δ 58.5 (CH2), 68.4 (CH2), 73.6 (CH2), 76.5 (CH), 76.7 (CH), 82.4
(CH), 87.0 (C), 100.4 (CH), 127.7-133.6 (11 signals, CH), 129.6
(C), 129.8 (C), 129.9 (C), 137.2 (C), 165.3 (C), 165.5 (C), 165.8
(C); MS/CI (FAB) 595 (M + H+).
(11 signals, CH), 137.3 (C), 138.2 (C), 138.6 (C), 138.8 (2 C,
C), 170.8 (C); MS/EI 1132 (M + Na+).
2-(Tr im eth ylsilyl)eth yl 6-O-Ben zyl-2-deoxy-2-acetam ido-
3 -O -( 2 ,3 ,4 -t r i -O -b e n z y l -r-L -f u c o p y r a n o s y l ) -4 -O -
[(2S,5S,6R,8R,9R,10R) 2-(fu r a n -2-yl)-6-[(b en zyloxy)m e-
th yl]-5,9-d ih yd r oxy-1,3,7-tr ioxa bicyclo[4.4.0]d ec-8-yl]-â-
D-glu cop yr a n osid e (44a ) a n d 2-(Tr im eth ylsilyl)eth yl 6-O-
Ben zyl-2-d eoxy-2-a ceta m id o-3-O-(2,3,4-tr i-O-ben zyl-r-L-
fu c o p y r a n o s y l)-4-O -[(2S ,5R ,6R ,8R ,9R ,10R )-6-[(b e n -
zy lo x y )m e t h y l]-2-(fu r a n -2-y l)-9,10-d ih y d r o x y -1,3,7-
tr ioxa sp ir o[4.5]d ec-8-yl]-â-D-glu cop yr a n osid e (44b).
A
solution of 43 (130 mg, 0.12 mmol), furaldehyde diethyl acetal
(60.0 mg, 0.35 mmol), and pyridinium p-toluenesulfonate (30.0
mg, 0.12 mmol) in 4 mL of benzene was heated at 60 °C for 1
h. TLC (acetone/hexane 1:1) indicated complete consumption
and formation of two products. The reaction was quenched
with 5 mL of 10% NaHCO3, the layers were separated, the
aqueous layer was extracted with benzene (5 mL), and the
combined organic layers were washed with brine (5 mL) and
dried over Na2SO4. The solvent was removed and the residue
subjected to flash chromatography (SiO2, acetone/hexane 1:3).
Six-membered ring acetal 44a (46.0 mg, 33%) eluted first
followed by five-membered ring acetal 44b (57.0 mg, 41%).
41:21 1H-NMR (250 MHz, CDCl3) δ 4.04 (2 H, m, H-5, H-6a),
4.15 (1 H, dd, 12.0/2.5 Hz, H-6b), 4.31 (1 H, d, 12.0 Hz, H-7a),
4.41 (1 H, d, 12.0 Hz, H-7b), 4.57 (1 H, d, 11.5 Hz, -CH2Ph),
4.71 (1 H, d, 11.5 Hz, -CH2Ph), 4.75 (1 H, s, C4-OH), 5.35 (1
H, t, 9.0 Hz, H-1), 5.84 (1 H, t, 9.5 Hz, H-2), 5.95 (1 H, d, 10.0
Hz, H-3), 7.30-8.08 (21 H, m, NH, ArH); 13C-NMR (62.5 MHz,
CDCl3) δ 62.9 (CH2), 69.8 (CH2), 70.3 (CH), 71.5 (CH), 74.4
(CH2), 74.8 (CH), 75.0 (C), 80.9 (CH), 91.7 (C), 94.0 (CH),
127.4-136.3 (17 signals, CH, C), 162.3 (C), 165.6 (2 C, C), 167.2
(C); MS/CI 755 (M-).
44a : 1H-NMR (500 MHz, CDCl3) δ -0.02 (9 H, s, -Si(CH3)3),
0.90 (2 H, m, OCH2CH2Si(CH3)3), 1.15 (3 H, d, 6.5 Hz, 3 ×
H-6 Fuc), 1.63 (3 H, s, C(O)CH3), 3.09 (1 H, d, 1.5 Hz, C4-OH
Gal), 3.19 (1 H, q (br), 8.5 Hz, H-2 GlcNAc), 3.34 (1 H, ddd,
8.5/4.0/1.5 Hz, H-5 Gal), 3.36 (1 H, s (br), C2-OH Gal), 3.50 (1
H, m, OCHaHbCH2Si(CH3)3), 3.53 (1 H, d, 9.5 Hz, H-3 Gal),
3.58 (1 H, m, H-5 GlcNAc), 3.59 (1 H, dd, 10.0/4.0 Hz, H-6a
Gal), 3.71 (1 H, d, 12.0 Hz, H-7axial Gal), 3.74 (1 H, m, H-4
Fuc), 3.76 (1 H, dd, 9.5/7.5 Hz, H-2 Gal), 3.84 (1 H, dd, 11.5/
1.5 Hz, H-6a GlcNac), 3.89 (1 H, dd, 10.0/8.5 Hz, H-6b Gal),
3.93 (2 H, m, OCHaHbCH2Si(CH3)3, H-6b GlcNAc), 3.98 (1 H,
dd, 10.0/2.5 Hz, H-3 Fuc), 4.00 (1 H, t, 9.0 Hz, H-4 GlcNAc),
4.09 (1 H, dd, 10.0/4.0 Hz, H-2 Fuc), 4.14 (1 H, d, 12.0 Hz,
H-7equatorial Gal), 4.33 (1 H, t, 9.0 Hz, H-3 GlcNAc), 4.39 (2
H, m, -CH2Ph), 4.45 (1 H, q (br), 6.5 Hz, H-5 Fuc), 4.53 (1 H,
d, 12.5 Hz, -CH2Ph), 4.60 (1 H, d, 7.5 Hz, H-1 Gal), 4.61 (1 H,
d, 11.5 Hz, -CH2Ph), 4.65 (1 H, d, 11.5 Hz, -CH2Ph), 4.72 (1
H, d, 12.5 Hz, -CH2Ph), 4.72 (1 H, d, 12.0 Hz, -CH2Ph), 4.76
(1 H, d, 12.0 Hz, -CH2Ph), 4.92 (1 H, d, 11.5 Hz, -CH2Ph),
4.95 (1 H, d, 8.5 Hz, H-1 GlcNAc), 4.95 (1 H, d, 11.5 Hz, -CH2-
Ph), 5.08 (1 H, d, 4.0 Hz, H-1 Fuc), 5.78 (1 H, d, 8.0 Hz, NH
GlcNAc), 5.66 (1 H, s, CH-Fu), 6.39 (1 H, m, Fu(H-4)), 6.54 (1
H, m, Fu(H-3)), 7.21-7.38 (25 H, Ar-H), 7.43 (1 H, m, Fu(H-
5)); 13C-NMR (75 MHz, CDCl3) δ -1.4 (3 C, CH3), 16.9 (CH3),
18.0 (CH2), 23.3 (CH3), 58.7 (CH), 66.9 (CH), 67.0 (CH2), 67.7
(CH2), 67.9 (CH2), 68.7 (C), 69.3 (CH), 72.2 (CH2), 72.8 (CH2),
72.9 (CH), 73.2 (CH2), 73.4 (CH2), 74.3 (CH2), 74.5 (CH), 75.1
(CH2), 75.7 (CH), 77.7 (CH), 79.9 (CH), 82.7 (CH), 96.7 (CH),
97.9 (CH), 99.2 (CH), 101.2 (CH), 108.5 (CH), 110.3 (CH),
127.2-128.7 (14 signals, CH), 137.7 (C), 138.3 (C), 138.7 (2 C,
C), 138.8 (C), 143.0 (CH), 149.5 (C), 170.4 (C), the two missing
tertiary signals might be covered by the chloroform signals;
MS/HR calcd for C66H81NO17SiLi (M + Li+) 1194.5434, found
1194.5433.
44b: 1H-NMR (500 MHz, CDCl3) δ -0.01 (9 H, s, -Si(CH3)3),
0.90 (2 H, m, OCH2CH2Si(CH3)3), 1.09 (3 H, d, 6.5 Hz, 3 ×
H-6 Fuc), 1.60 (3 H, s, C(O)CH3), 2.55 (1 H, s (br), C3-OH Gal),
3.07 (1 H, q (br), 8.5 Hz, H-2 GlcNAc), 3.36 (1 H, d (br), 9.5
Hz, H-3 Gal), 3.46 (1 H, s (br), H-4 Fuc), 3.49 (1 H, t, 5.0 Hz,
H-5 Gal), 3.51 (1 H, m, OCHaHbCH2Si(CH3)3), 3.51 (2 H, m,
H-5 GlcNAc, H-2 Gal), 3.76 (1 H, dd, 10.5/5.0 Hz, H-6a Gal),
3.79 (1 H, dd, 11.5/2.0 Hz, H-6a GlcNac), 3.93 (3 H, m, OCHaHb-
CH2Si(CH3)3, H-6b GlcNAc, C2-OH Gal), 3.99 (1 H, dd, 10.0/
2.5 Hz, H-3 Fuc), 4.02 (1 H, t, 10.0 Hz, H-4 GlcNAc), 4.05 (1
H, dd, 10.0/3.5 Hz, H-2 Fuc), 4.10 (1 H, dd, 10.5/5.0 Hz, H-6b
Gal), 4.17 (1 H, d, 8.5 Hz, H-7a Gal), 4.20 (1 H, d, 8.5 Hz, H-7b
Gal), 4.34 (1 H, d, 11.5 Hz, -CH2Ph), 4.36 (1 H, t, 9.0 Hz, H-3
GlcNAc), 4.45 (1 H, q (br), 6.5 Hz, H-5 Fuc), 4.51 (1 H, d, 8.0
Hz, H-1 Gal), 4.52 (1 H, d, 12.0 Hz, -CH2Ph), 4.54 (1 H, d,
12.0 Hz, -CH2Ph), 4.56 (1 H, d, 12.0 Hz, -CH2Ph), 4.62 (1 H,
d, 12.0 Hz, -CH2Ph), 4.66 (1 H, d, 11.5 Hz, -CH2Ph), 4.69 (1
H, d, 12.0 Hz, -CH2Ph), 4.71 (1 H, d, 11.5 Hz, -CH2Ph), 4.80
(1 H, d, 11.5 Hz, -CH2Ph), 4.92 (1 H, d, 12.0 Hz, -CH2Ph),
5.01 (1 H, d, 3.5 Hz, H-1 Fuc), 5.07 (1 H, d, 8.0 Hz, H-1
42: 1H-NMR (500 MHz, CDCl3) δ -0.04 (9 H, s, -Si(CH3)3),
0.73 (1 H, ddd, 15.0/10.0/6.0 Hz, OCH2CH2Si(CH3)3), 0.82 (1
H, ddd, 15.0/10.0/6.0 Hz, OCH2CH2Si(CH3)3), 1.20 (3 H, d, 7.0
Hz, 3 × H-6 Fuc), 1.86 (3 H, s, C(O)CH3), 3.16 (1 H, td, 10.0/
6.0 Hz, OCHaHbCH2Si(CH3)3), 3.49 (1 H, q, 5.0 Hz, H-5
GlcNAc), 3.62 (1 H, d (br), 2.5 Hz, H-4 Fuc), 3.66 (1 H, dd,
10.5/5.0 Hz, H-6a GlcNac), 3.67 (1 H, td, 10.5/6.0 Hz, OCHaHb-
CH2Si(CH3)3), 3.71 (1 H, t, 3.0 Hz, H-5 Gal), 3.72 (1 H, dd,
10.5/5.0 Hz, H-6b GlcNAc), 3.75 (1 H, m, H-2 GlcNAc), 3.90 (1
H, dd, 10.5/2.5 Hz, H-3 Fuc), 3.94 (2 H, d, 3.0 Hz, H-6a Gal,
H-6b Gal), 4.08 (1 H, s, C4-OH Gal), 4.09 (2 H, m, H-3 GlcNAc,
H-4 GlcNAc), 4.12 (1 H, dd, 10.5/4.0 Hz, H-2 Fuc), 4.23 (1 H,
q (br), 7.0 Hz, H-5 Fuc), 4.28 (1 H, d, 12.0 Hz, H-7a Gal), 4.43
(1 H, d, 12.0 Hz, H-7b Gal), 4.43 (1 H, d, 7.0 Hz, H-1 GlcNac),
4.44 (1 H, d, 12.0 Hz, -CH2Ph), 4.50 (1 H, d, 11.5 Hz, -CH2-
Ph), 4.52 (1 H, d, 12.0 Hz, -CH2Ph), 4.57 (1 H, d, 11.5 Hz,
-CH2Ph), 4.60 (1 H, d, 11.5 Hz, -CH2Ph), 4.69 (1 H, d, 11.5
Hz, -CH2Ph), 4.77 (1 H, d, 12.0 Hz, -CH2Ph), 4.79 (1 H, d,
11.5 Hz, -CH2Ph), 4.82 (1 H, d, 12.0 Hz, -CH2Ph), 4.88 (1 H,
d, 7.5 Hz, H-1 Gal), 4.93 (1 H, d, 11.5 Hz, -CH2Ph), 5.24 (1 H,
d, 4.0 Hz, H-1 Fuc), 5.72 (1 H, d, 10.0 Hz, H-3 Gal), 5.76 (1 H,
dd, 10.0/7.5 Hz, H-2 Gal), 6.12 (1 H, d, 8.0 Hz, N-H GlcNAc),
7.18-7.98 (40 H, m, Ar-H); 13C-NMR (62.5 MHz, CDCl3) δ -1.4
(3 C, CH3), 16.8 (CH3), 17.8 (CH2), 23.2 (CH3), 54.5 (CH), 63.3
(CH2), 66.4 (CH2), 66.9 (CH), 69.2 (CH2), 69.5 (CH2), 71.2 (CH),
72.0 (CH), 72.7 (CH2), 73.0 (CH2), 73.2 (CH), 73.3 (CH2), 73.6
(CH), 74.1 (CH2), 74.3 (C), 74.7 (CH), 74.8 (CH2), 75.4 (CH),
76.7 (CH), 78.0 (CH), 79.2 (CH), 97.1 (CH), 99.1 (CH), 99.9
(CH), 127.2-133.2 (16 signals, CH), 128.9 (C), 129.2 (C), 129.3
(C), 136.6 (C), 138.0 (C), 138.7 (C), 138.8 (C), 138.9 (C), 165.6
(C), 165.7 (C), 166.8 (C), 169.9 (C), MS/HR calcd for C82H91
-
NO19SiLi (M + Li+) 1428.6115, found 1428.6131.
2-(Tr im eth ylsilyl)eth yl 6-O-Ben zyl-2-deoxy-2-acetam ido-
3-O-(2,3,4-t r i-O-b en zyl-r-L-fu cop yr a n osyl)-4-O-[4-C-(h y-
d r oxym eth yl)-6-O-ben zyl-â-D-ga la ctop yr a n osyl]-â-D-glu -
cop yr a n osid e (43). A solution of 42 (130.0 mg, 0.091 mmol)
in absolute methanol (1.5 mL) was treated with NaOMe (0.01
mmol) at 25 °C for 3 h. Dowex W X 8 ion exchange resin (100
mg) was added and the resulting mixture stirred for 5 min.
The solution was filtered, the resin washed with methanol,
and the solvent removed in vacuo. The residue was subjected
to flash chromatography (SiO2, acetone/hexane 1:2 f 2:1) to
yield 43 (85.0 mg, 84%) as a colorless foam.
43: 13C-NMR (62.5 MHz, CDCl3) δ -1.4 (3 C, CH3), 16.8
(CH3), 17.9 (CH2), 23.2 (CH3), 58.4 (CH), 63.3 (CH2), 66.9 (CH2),
67.0 (CH), 68.8 (CH2), 68.9 (CH2), 72.2 (CH2), 72.4 (CH), 73.2
(CH2), 73.3 (CH), 73.5 (CH2), 73.6 (C), 73.9 (CH), 74.2 (CH2),
74.5 (CH), 74.8 (CH2), 75.1 (CH), 76.1 (CH), 76.8 (CH), 77.8
(CH), 79.8 (CH), 98.1 (CH), 99.0 (CH), 100.8 (CH), 127.2-128.6

524 J . Org. Chem., Vol. 61, No. 2, 1996
Thoma et al.
GlcNAc), 5.77 (1 H, d, 2.0 Hz, N-H GlcNAc), 6.03 (1 H, s, CH-
Fu), 6.33 (1 H, m, Fu(H-4)), 6.49 (1 H, m, Fu(H-3)), 7.21-7.38
(26 H, ArH, Fu(H-5)); 13C-NMR (75 MHz, CDCl3) δ -1.4 (3 C,
CH3), 16.7 (CH3), 17.9 (CH2), 23.2 (CH3), 59.3 (CH), 66.8 (CH),
66.9 (CH2), 67.1 (CH2), 68.7 (CH2), 69.2 (CH2), 72.1 (CH2), 73.2
(CH), 73.3 (CH2), 73.4 (CH2), 74.1 (CH2), 74.2 (CH), 74.3 (CH),
74.4 (CH), 75.3 (CH2), 75.6 (CH), 75.9 (CH), 76.4 (CH), 78.3
(CH), 79.7 (CH), 81.7 (C), 97.9 (CH), 98.7 (CH), 99.8 (CH),
100.1 (CH), 110.3 (CH), 110.4 (CH), 127.1-128.6 (12 signals,
CH), 138.2 (2 C, C), 138.7 (2 C, C), 138.9 (C), 143.4 (CH), 149.4
(C), 170.5 (C); MS/HR calcd for C66H81NO17SiLi (M + Li+)
1194.5434, found 1194.5441.
2-(Tr im eth ylsilyl)eth yl 6-O-Ben zyl-2-deoxy-2-acetam ido-
3 -O -( 2 ,3 ,4 -t r i -O -b e n z y l -r-L -f u c o p y r a n o s y l ) -4 -O -
[(2S,5S,6R,8R,9R,10R)-2-ca r boxy-6-[(ben zyloxy)m eth yl]-
5,9-d ih yd r oxy-1,3,7-t r ioxa b icyclo[4.4.0]d e c-8-yl]-â-D -
glu copyr an oside (45). Ozone was bubbled through a solution
of 44a (34.0 mg, 0.029 mmol) in 2 mL of CH2Cl2 at -78 °C for
approximately 2 min. TLC (ether/hexane 4:1) indicated com-
plete consumption. Excess ozone was removed by bubbling
argon through the mixture for 30 min. Then, hydrogen
peroxide (100 µL of a 30% solution) and THF (2 mL) were
added at -78 °C, and the mixture was warmed to rt and
stirred for 16 h. The mixture was diluted with CH2Cl2 (5 mL),
washed with brine (3 mL), and dried over Na2SO4. The solvent
was removed and the residue subjected to flash chromatog-
raphy (SiO2, ethyl acetate/ methanol/acetic acid 80:19:1) to
yield 45 (22.0 mg, 66%) as a colorless solid.
(C), 141.6 (C), 174.1 (2 C, C); MS/MALDI-TOF calcd for C63H78-
NO18SiNa (sodium salt of 42) 1188.3, found 1188.7.
2-(Tr im eth ylsilyl)eth yl 2-Deoxy-2-a ceta m id o-3-O-(r-L-
fu cop yr a n osyl)-4-O-[(2S,5S,6R,8R,9R,10R)-2-ca r boxy-5,9-
d ih yd r oxy-6-(h yd r oxym eth yl)-1,3,7-tr ioxa bicyclo[4.4.0]-
d ec-8-yl]-â-D-glu cop yr a n osid e (2). A solution of 45 (21.0
mg, 0.02 mmol) in 3 mL of dioxane/water 2:1 was hydrogenated
in the presence of 50 mg of Pd/C (10%) at 25 °C for 24 h.
Additional catalyst (20 mg) was added and the hydrogenation
continued for 24 h. The catalyst was filtered off and washed
with methanol and the solvent removed in vacuo to give 2 (12.2
mg, 94%) as a colorless solid. The crude material was passed
through a RP 18 column (methanol/water 1:4 f 1.1). Product-
containing fractions were combined, the solvent was removed,
and the residue was dissolved in water and lyophilized: MS/
HR calcd for C28H49NO18SiNa (sodium salt of 2) 738.2616,
found 738.2619. NMR data are shown in Table 1.
Ack n ow led gm en t. We wish to thank Dr. T. Winkler
for NMR measurements and discussions, Dr. A. A.
Sta¨mpfli for performing HR/MS, and Dr. J . L. Magnani
for biological assaying.22 We also thank Mr. Oliver
Dosenbach and Mr. Simon Marti for technical as-
sistance.
Su p p or tin g In for m a tion Ava ila ble: 1H-NMR spectra of
compounds 11-14, 16, C-4 epimer of 16, 17, 19a ,b, 22-25,
32-34, 36-38, 41, 42, 44a ,b, and 2; 13C-NMR spectra of
compounds 10, 15, 18, 35, 39, 40, 43, and 45 (32 pages). This
material is contained in libraries on microfiche, immediately
follows this article in microfilm version of the journal, and can
be ordered from the ACS; see any current masthead page for
ordering information.
45: 13C-NMR (62.5 MHz, CD3OD) δ -0.3 (3 C, CH3), 18.0
(CH3), 20.0 (CH2), 22.1 (CH3), 58.7 (CH), 68.6 (CH), 68.9 (CH2),
69.9 (C), 70.2 (CH2), 70.5 (CH2), 71.1 (CH), 74.2 (CH2), 74.5
(CH2), 75.1 (CH2), 75.2 (CH2), 75.3 (CH2), 75.6 (CH), 76.6 (CH),
77.4 (CH), 77.5 (CH2), 78.0 (CH), 80.9 (CH), 81.1 (CH), 85.1
(CH), 98.7 (CH), 101.0 (CH), 103.3 (CH), 104.1 (CH), 129.3-
130.5 (12 signals, CH), 140.5 (C), 140.8 (C), 140.9 (C), 141.3
J O951067L