Generalizing glycosylation: Synthesis of the blood group antigens Lea, Leb, and Le(x) using a standard set of reaction conditions

Article abstract of DOI:10.1021/ja9608555

Because there are no general reaction conditions for any glycosylation method, biologically interesting oligosaccharides can only be made in a small number of laboratories in the world. To make carbohydrate synthesis accessible to nonspecialists, it is critical to have glycosylation methods that will work in a wide range of cases under a single set of conditions. The Lewis blood group antigens have attracted the attention of numerous synthetic carbohydrate groups because of their structural complexity. Although they have been synthesized many times, they have never been made using a single glycosylation method under one set of reaction conditions. In this paper, we show that the sulfoxide glycosylation method can be used to form all of the glycosidic linkages in the Lewis blood group antigens Le^a (1), Le^b (2), and Le(x) (3) stereoselectively under a uniform set of reaction conditions. This work highlights the flexibility of the sulfoxide method and demonstrates its utility for constructing families of related oligosaccharides.

Full text of DOI:10.1021/ja9608555

J. Am. Chem. Soc. 1996, 118, 9239-9248
9239
Generalizing Glycosylation: Synthesis of the Blood Group
Antigens Lea, Leb, and Lex Using a Standard Set of Reaction
Conditions
Lin Yan and Daniel Kahne*
Contribution from the Department of Chemistry, Princeton UniVersity,
Princeton, New Jersey 08544
ReceiVed March 15, 1996X
Abstract: Because there are no general reaction conditions for any glycosylation method, biologically interesting
oligosaccharides can only be made in a small number of laboratories in the world. To make carbohydrate synthesis
accessible to nonspecialists, it is critical to have glycosylation methods that will work in a wide range of cases under
a single set of conditions. The Lewis blood group antigens have attracted the attention of numerous synthetic
carbohydrate groups because of their structural complexity. Although they have been synthesized many times, they
have never been made using a single glycosylation method under one set of reaction conditions. In this paper, we
show that the sulfoxide glycosylation method can be used to form all of the glycosidic linkages in the Lewis blood
group antigens Lea (1), Leb (2), and Lex (3) stereoselectively under a uniform set of reaction conditions. This work
highlights the flexibility of the sulfoxide method and demonstrates its utility for constructing families of related
oligosaccharides.
Introduction
Synthetic methods to produce oligosaccharides are decades
behind synthetic methods to make other biopolymers. There
are several excellent methods available to form amide and
phosphodiester linkages, and the synthesis of peptides and
oligonucleotides has been automated so that researchers with
little synthetic expertise can make quantities of any natural
peptide or oligonucleotide. In contrast, biologically interesting
oligosaccharides can only be made in a small number of
laboratories in the world. The main reason for this is that there
are no general reaction conditions for any glycosylation method.1
The outcome of a glycosylation reaction is heavily dependent
on the structures of the glycosyl donor and acceptor; changes
in even one protecting group can have unpredictable and often
dramatic effects on the stereochemical outcome and yield of
glycosylation.2 Several different reaction conditions or even
several different glycosylation methods may be necessary to
form the glycosidic bonds in a complicated oligosaccharide, and
the appropriate reactions are typically identified only after
considerable experimentation. Making carbohydrate synthesis
accessible to chemists who do not have special expertise in the
field requires glycosylation methods which will work in a wide
range of cases under a single set of reaction conditions.
Figure 1. Lewis blood antigens.
several times previously. However, the blood group antigens
have never been synthesized using a single glycosylation method
under a single set of reaction conditions. In fact, even for the
most reliable glycosylation methods the conditions used to
synthesize different glycosidic linkages in the family are
The Lewis blood group antigens are a biologically important
family of oligosaccharides (Figure 1) that have attracted the
attention of numerous synthetic carbohydrate groups because
of their structural complexity.3-5 They are branched oligosac-
charides containing both R and â linkages to hindered secondary
alcohols. Each blood group antigen has been synthesized
(4) For syntheses of Leb, see: (a) Rana, S. S.; Barlow, J. J.; Matta, K.
L. Carbohydr. Res. 1981, 96, 231-239. (b) Bovin, N. V.; Khorlin, A. Ya.
Bioorg. Khim. 1985, 10, 476-482. (c) Spohr, U.; Lemieux, R. U.
Carbohydr. Res. 1988, 174, 211-237. (d) Danishefsky, S. J.; Behar, V.;
Randolph, J. T.; Lloyd, K. O. J. Am. Chem. Soc. 1995, 117, 5701-5711.
(5) For syntheses of Lex
, see: (a) Jacquinet, J.-C.; Sinay, P. J. Chem.
Soc., Perkin Trans. 1 1979, 314-318. (b) Hindsgaul, O.; Norberg, T.; Pendu,
J. L.; Lemieux, R. U. Carbohydr. Res. 1982, 109, 109-142. (c) Lonn, H.
Carbohydr. Res. 1985, 139, 115-121. (d) Sato, S.; Ito, Y.; Nukada, T.;
Nakahara, Y.; Ogawa, T. Carbohydr. Res. 1987, 167, 197-210. (e) Nilsson,
M.; Norberg, T. Carbohydr. Res. 1988, 183, 71-82. (f) Sato, S.; Ito, Y.;
Ogawa, T. Tetrahedron Lett. 1988, 29, 5267-5270. (g) Classon, B.; Garegg,
P. J.; Helland, A.-C. J. Carbohydr. Chem. 1989, 8, 543-551. (h) Nilsson,
M.; Norberg, T. J. Carbohydr. Chem. 1989, 8, 613-627. (i) Nicolaou, K.
C.; Caulfield, T. J.; Kataoka, H.; Stylianides, N. A. J. Am. Chem. Soc. 1990,
112, 3693-3695. (j) von dem Bruch, K.; Kunz, H. Angew. Chem., Int. Ed.
Engl. 1994, 33, 101-103. (k) Toepfer, A.; Kinzy, W.; Schmidt, R. R. Liebigs
Ann. Chem. 1994, 449-464.
X Abstract published in AdVance ACS Abstracts, September 1, 1996.
(1) (a) Halcomb, R. L.; Wong, C.-H. Curr. Opin. Struct. Biol. 1993, 3,
694. (b) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503.
(2) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155.
(3) For syntheses of Lea, see: (a) Lemieux, R. U.; Driguez, H. J. Am.
Chem. Soc. 1975, 97, 4063-4068. (b) Jacquinet, J.-C.; Sinay, P. J. Chem.
Soc., Perkin Trans. 1 1979, 319-322. (c) Bovin, N. V.; Zurabyan, S. E.;
Khorlin, A. Ya. Bioorg. Khim. 1980; 6, 121-126. (d) Matta, K. L.; Rana,
S. S. Carbohydr. Res. 1983, 117, 101-111. (e) Bovin, N. V.; Ivanova, I.
A.; Khorlin, A. Ya. Bioorg. Khim. 1986, 11, 362-370. (d) Marz, J.; Kunz,
H. Synlett 1992, 589-590.
S0002-7863(96)00855-4 CCC: $12.00 © 1996 American Chemical Society

9240 J. Am. Chem. Soc., Vol. 118, No. 39, 1996
Yan and Kahne
sufficiently different to suggest that they were arrived at only
after extensive experimentation with different parameters (e.g.,
promoters, temperature, time, and solvent).
Scheme 1a Synthesis of Lea
In 1989 we discovered the sulfoxide glycosylation reaction
and have been exploring its potential for the synthesis of
oligosaccharides both in solution and on the solid phase.6,7 We
wanted to compare the sulfoxide method to the best available
glycosylation methods, which have all been applied to the
synthesis of the blood group antigens. Because we believe that
it is important to have glycosylation methods which can be
applied to new glycosidic linkages without having to experiment
with the reaction conditions, we imposed the constraint that all
the glycosidic linkages be synthesized using a single set of
conditions. Despite this constraint, the solution syntheses of
the Lewis antigens presented below compare favorably with the
best individual syntheses reported to date. Since we have
obviated decisions about how to carry out the individual
glycosylation reactions by defining a “universal” set of condi-
tions that work for all the glycosidic linkages in the Lewis blood
group family, it should be possible to make analogues of the
blood group antigens using the routes outlined. It should be
noted that the availability of methods that permit the synthesis
of a wide range of glycosidic linkages under one set of reaction
conditions may also make possible automated oligosaccharide
synthesis and the construction of carbohydrate libraries.
a (a)Tf2O, DTBMP, CH2Cl2, -78 to -30 °C, 1 h; (b) (1) LiOH,
CH3OH, rt, overnight; (2) Ac2O, DMAP, pyridine, rt, 2 h (78%, two
steps); (3) TFA, CH2Cl2 (v/v ) 1:2), rt, 1 h; (4) PivCl, DMAP, Et3N,
CH2Cl2, rt, 2 h, 93%; (c) Tf2O, DTBMP, CH2Cl2, -78 to 0 °C, 1.5 h;
(d) (1) Hg(OCOCF3)2, wet CH2Cl2, 20 min, 77%; (2) CH3I, NaH, DMF,
rt, 20 min, 84%; (3) Lindlar catalyst, H2, EtOAc, rt, overnight; (4)
Pd/C, H2, EtOAc, rt, 8 h; (5) Ac2O, DMAP, pyridine, rt, 10 min, 66%
(R-anomer 29%, â-anomer 37%) over three steps; (e) NaOCH3, CH3OH,
rt, overnight, 97%.
Results
Schemes 1, 2, and 3 outline our syntheses of the three blood
group antigens using the sulfoxide glycosylation method.
Synthesis of Lea. The synthesis of Lea (Scheme 1) began
with the coupling of phenyl 2-azido-4,6-O-benzylidene-2-deoxy-
1-thio-R-D-glucopyranoside (4)8 with the perpivaloyl galactosyl
sulfoxide 5.9 Compound 4 was treated with sulfoxide 5 (2
equiv) and triflic anhydride (1 equiv) in dichloromethane at -78
°C to produce stereoselectively the â-1,3-linked disaccharide 6
in 83% yield. The stereochemical control was a result of
neighboring group participation from the C-2 pivaloyl ester.10
Scheme 2a Synthesis of Leb
(6) (a) Kahne, D.; Walker, S.; Cheng, Y.; van Engen, D. J. Am. Chem.
Soc. 1989, 111, 6881. (b) Yang, D.; Kim, S.-H.; Kahne, D. J. Am. Chem.
Soc. 1991, 113, 4715. (c) Cheng, Y.; Ho, D. M.; Gottlieb, C. R.; Kahne,
D.; Bruck, M. A. J. Am. Chem. Soc. 1992, 114, 7319. (d) Raghavan, S.;
Kahne, D. J. Am. Chem. Soc. 1993, 115, 1580. (e) Andreotti, A. H.; Kahne,
D. J. Am. Chem. Soc. 1993, 115, 3352. (f) Kim, S.-H.; Augeri, D.; Yang,
D.; Kahne, D. J. Am. Chem. Soc. 1994, 116, 1766. (g) Silva, D. J.; Kahne,
D.; Kraml, C. K. J. Am. Chem. Soc. 1994, 116, 2641. (h) Walker, S.; Gange,
D.; Gupta, V.; Kahne, D. J. Am. Chem. Soc. 1994, 116, 3197. (i) Yan, L.;
Taylor, C. M.; Goodnow, R.; Kahne, D. J. Am. Chem. Soc. 1994, 116,
6953. (j) Yan, L.; Kahne, D. Synlett 1995, 526.
(7) Others have also investigated the sulfoxide method, see: (a) Ikemoto,
N.; Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 9657. (b) Stork, G.;
Kim, G. J. Am. Chem. Soc. 1992, 114, 1087. (c) Chanteloup, L.; Beau,
J.-M. Tetrahedron Lett. 1992, 33, 5347. (d) Sarkar, A. K.; Matta, K. L.
Carbohydr. Res. 1992, 233, 245. (e) Ikemoto, N.; Schreiber, S. L. J. Am.
Chem. Soc. 1992, 114, 2524. (f) Berkowitz, D. B.; Danishefsky, S. J.;
Schulte, G. K. J. Am. Chem. Soc. 1992, 114, 4518. (g) Wang, Y.; Zhang,
H.; Voelter, W. Z. Naturforscher 1993, 48b, 1143. (h) Sliedregt, L. A. J.
M.; van der Marel, G. A.; van Boom, J. H. Tetrahedron Lett. 1994, 35,
4015. (i) Wang, Y.; Zhang, H.; Voelter, W. Chem. Lett. 1995, 273. (j) Wang,
Y.; Zhang, H.; Voelter, W. Z. Naturforscher 1995, 50b, 661. (k) Zhang,
H.; Wang, Y.; Voelter, W. Tetrahedron Lett. 1995, 36, 1243. (l) Crioh,
D.; Sun, S. J. Org. Chem. 1996, 61, 4506.
(8) Compound 4 is synthesized from the readily available 1,3,4,6-tetra-
O-acetyl-2-azido-2-deoxy-D-glucopyranoside (Lemieux, R. U.; Ratcliffe, R.
M. Can. J. Chem. 1979, 57, 1244. Pavliak, V.; Kova´c, P. Carbohydr. Res.
1991, 210, 333): (1) PhSH, BF3‚Et2O, CH2Cl2, 3 days, room temperature
(rt); (2) NaOCH3, CH3OH, 1 h, rt; (3) PhCH(OCH3)2, TsOH‚H2O, DMF,
24 h, rt (54% over three steps).
a (a)Tf2O, DTBMP, CH2Cl2, -78 to -30 °C, 1 h; (b) (1) TFA,
CH2Cl2 (v/v ) 1:2), rt, 1 h, 78%; (2) LiOH, THF, CH3OH, rt, 1 week,
99%; (3) PivCl, DMAP, Et3N, CH2Cl2, rt, 2 h, 74%; (c) Tf2O, DTBMP,
CH2Cl2, -78 to 0 °C, 1.5 h; (d) (1) Hg(OCOCF3)2, wet CH2Cl2, 20
min, 77%; (2) CH3I, NaH, DMF, rt, 30 min, 88%; (3) Na, NH3, -78
°C, 2 h; (4) Ac2O, pyridine, rt, 20 min, 31% (R-anomer 10%, â-anomer
21%) over two steps; (e) NaOCH3, CH3OH, rt, 30 min, 100%.
The pivaloyl groups were removed under basic conditions, and
the free alcohols were acetylated. The benzylidene acetal was
then removed using trifluoroacetic acid, and the primary alcohol
was selectively protected to afford the glycosyl acceptor 7 (62%
yield over the four steps). To produce the desired R-fucoside
(9) Compound 5 is synthesized from the readily available phenyl 1-thio-
â-D-galactopyranoside (Ferrier, R. J.; Furneaux, R. H. In Methods in
Carbohydrate Chemistry; BeMiller, J. N., Whilstler, R. L., Eds.; Academic
Press: New York, 1980; Vol. VIII, pp 251): (1) PivCl, DMAP, pyridine,
24 h, reflux; (2) mCPBA, CH2Cl2, 15 min, -78 °C (86% over two steps).
(10) Kunz, H.; Harreus, A. Liebigs Ann. Chem. 1982, 41.

Synthesis of Blood Group Antigens
J. Am. Chem. Soc., Vol. 118, No. 39, 1996 9241
Scheme 3a Synthesis of Lex
4 produced the desired â-linked disaccharide 12 stereoselectively
in 77% yield. This yield is similar to that obtained for the
formation of the â linkage in the synthesis of Lea (Scheme 1,
6). Thus, the differences in the protecting group patterns do
not significantly affect the yield of glycosylation here. In
contrast, the yields obtained with other methods for glycosyl-
ation in the presence of a participating C2 ester are very sensitive
to the protecting groups on the remaining hydroxyls.2 Electron-
withdrawing protecting groups such as esters decrease the
reactivity of glycosyl donors and higher temperatures are
required for the activation with most methods. Yields are often
dramatically reduced.
The protected disaccharide 12 was converted to the diol 13
by hydrolysis of the benzylidene group with trifluoroacetic acid,
saponification of the C2 pivaloyl group with lithium hydroxide,
and selective protection of the C6 alcohol of the glucosamine.
Bisfucosylation to produce 14 was accomplished stereoselec-
tively using 4 equiv of the perbenzylated fucosyl sulfoxide 8.
The desired product was isolated in 82% yield, indicating that
the two fucosylations proceeded in better than 90% yield.
Again, these yields are almost identical to the yield obtained
for fucosylation of Lea. Compound 14 was converted to 15 in
a manner analogous to that used for Lea (Scheme 1, 9 to 10)
and then saponified to produce Leb (2) which correlated with
the reported data.4c
Synthesis of Lex. Lex (Scheme 3) contains the same three
sugars as Lea, but they are linked in a different manner. In
Lea, a â-linked galactose is attached to the C3 position of the
glucosamine and an R-linked fucose is attached to the C4
position. In Lex, the positions of the galactose and fucose sugars
are reversed. Therefore, synthesizing Lea and Lex requires that
one be able to make both an R and a â linkage to both secondary
alcohols at C3 and C4 of glucosamine. Lex was synthesized
from phenyl 2-azido-2-deoxy-3-O-(4′-methoxybenzyl)-6-O-piv-
aloyl-1-thio-R-D-glucopyranoside (16),14 using the same per-
pivaloylated galactosyl sulfoxide 5 used in the synthesis of Lea.
Formation of the â-linkage to the C4 position to produce
protected disaccharide 17 proceeds in slightly lower yield (65%)
than the corresponding glycosylation in the Lea synthesis
(Scheme 1, 6), perhaps because the C4 hydroxyl in 16 is more
hindered than the C3 hydroxyl in 4. After replacing the five
pivaloyl groups in 17 with acetyl groups, the p-methoxybenzyl
ether group was removed with 10% trifluoroacetic acid in
dichloromethane at room temperature to give 18. These acidic
conditions are so mild that they can be used to remove the
p-methoxybenzyl protecting groups even in the presence of
extremely labile glycosidic linkages to tertiary alcohols.6j The
disaccharide nucleophile 18 was fucosylated with the perben-
zylated fucosyl sulfoxide 8 to introduce the R 1,3-linkage in 19
stereoselectively in 83% yield. Compound 19 was converted
to 20 in a manner analogous to that used for Lea (Scheme 1, 9
to 10) and then saponified to produce Lex (3) which correlated
with reported data.5b
a (a) Tf2O, DTBMP, CH2Cl2, -78 to -30 °C, 1 h; (b) (1) LiOH,
CH3OH, rt, overnight; (2) Ac2O, DMAP, pyridine, rt, 2 h (78%, two
steps); (3) 10%TFA in CH2Cl2, rt, 30 min, 97%; (c) Tf2O, DTBMP,
CH2Cl2, -78 to 0 °C, 1.5 h; (d) (1) Hg(OCOCF3)2, wet CH2Cl2, 20
min, 77%; (2) CH3I, NaH, DMF, rt, 1 h, 90%; (3) Lindlar catalyst, H2,
EtOAc, rt, overnight; (4) Pd/C, H2, EtOAc, rt, 8 h; (5) Ac2O, DMAP,
pyridine, rt, 10 min, 55% (R-anomer 22%, â-anomer 33%) over three
steps; (e) NaOCH3, CH3OH, rt, overnight, 100%.
the perbenzylated fucose sulfoxide 811 (2 equiv) was activated
with triflic anhydride (1 equiv) and added to 7 in dichlo-
romethane at -78 °C. The desired R-linked product 9 was
isolated in 95% yield. No â-glycoside was isolated. For
glycosyl donors with C2 ether protecting groups, the sulfoxide
glycosylation method gives good to excellent R selectivity for
glycosylations to secondary alcohols. The R stereoselectivity
is better than those obtained with many other glycosylation
methods (see Discussion section).12
To complete the synthesis of Lea, the anomeric thiophenyl
group of trisaccharide 9 was hydrolyzed with mercury(II)
trifluoroacetate and the resulting lactols were alkylated with
iodomethane in DMF to give a mixture of R and â methyl ethers.
The azido group was then reduced with the Lindlars catalyst,
and the benzyl ethers were hydrogenolyzed using palladium on
charcoal. Treatment with acetic anhydride and DMAP produced
trisaccharide 10 as a mixture of R and â methyl ethers.
Following separation by flash chromatography on silica gel,
treatment of the â methyl glycoside of 10 with sodium
methoxide gave 94% of Lea (1) which was correlated with the
reported data.3a
Synthesis of Leb. Leb (Scheme 2) was constructed following
a route similar to that used to construct Lea except that the
galactosyl sulfoxide used in the first glycosylation reaction was
synthesized with a protecting group pattern which would permit
us to selectively unmask the C2 alcohol of the galactose at a
later stage in the synthesis. The requisite galactosyl sulfoxide
11 was synthesized in three steps from the known 1,2-acetyl-
3,4,6-tri-O-benzyl-D-galactopyranoside.13 Activation of 11 with
triflic anhydride at -78 °C and reaction with glycosyl acceptor
Discussion
The syntheses of the three blood group antigens highlight
the generality of the sulfoxide method for constructing this
family of oligosaccharides. Both the R and â glycosidic
linkages were formed stereoselectively using the same set of
reaction conditions. In general, the sulfoxide reaction is quite
(11) Fucose sulfoxide 8 is synthesized from the readily available phenyl
1-thio-L-fucopyranoside (ref 9): (1) BnCl, NaH, Bn4NI, DMF, 24 h, 60
°C; (2) mCPBA, CH2Cl2, 15 min, -78 °C (96% over two steps).
(12) Thompson, C.; Kahne, D. Unpublished results.
(13) Galactose sulfoxide 11 is synthesized from the readily available 1,2-
di-O-acetyl-3,4,6-tri-O-benzyl-D-galactopyranoside (Kong, F.; Du, J.; Shang,
H. Carbohydr. Res. 1987, 162, 217): (1) PhSH, BF3‚Et2O, CH2Cl2, 5 h, rt;
(2) NaOCH3, CH3OH, 24 h, rt; (3) PivCl, DMAP, Et3N, CH2Cl2, 24 h,
reflux (48% over three steps).
(14) Compound 16 is synthesized from the readily available 1,3,4,6-
tetra-O-acetyl-2-azido-2-deoxy-D-glucopyranoside (see ref 8): (1) PhSH,
BF3‚Et2O, CH2Cl2, 3 days, rt; (2) NaOCH3, CH3OH, 1 h, rt; (3) (CH3)2C-
(OCH3)2, TsOH‚H2O, DMF, 24 h, rt; (4) p-CH3OC6H4CH2Cl, NaH, DMF,
1 h, rt; (5) TsOH‚H2O, CH3OH, 1 h, rt; (6) PivCl, DMAP, Et3N, CH2Cl2,
2 h, rt (36% over six steps).

9242 J. Am. Chem. Soc., Vol. 118, No. 39, 1996
Yan and Kahne
reliable for forming R linkages to secondary alcohols and for
forming â linkages (1,2-trans linkages) whenever neighboring
group participation is used. The high reactivity of anomeric
sulfoxides is the key to the reliable formation of both types of
linkages under the same set of reactions conditions. Like many
other glycosylation reactions, the sulfoxide reaction goes through
an oxonium ion intermediate. We believe that the R selectivity
reflects a kinetic preference for axial attack on a chairlike
transition state. Because glycosyl sulfoxides can be activated
at very low temperatures, the kinetic selectivity for the R isomer
is typically higher than that for other methods. In the formation
of â (1,2-trans) linkages, stereochemical control is typically
achieved using neighboring group participation from an ester
at C2 of the glycosyl donor. While this strategy predictably
produces the desired â configuration, ester groups inductively
disfavor activation and/or ejection of the leaving group at the
anomeric center. Many glycosylation methods are not compat-
ible with neighboring group participation because the glycosyl
donors cannot be activated when there are electron-withdrawing
protecting groups on the ring. (The sensitivity of many
glycosylation reactions to protecting group patterns has been
used to great advantage in “armed/disarmed” strategies for
iterative oligosaccharide synthesis.) However, glycosyl sulfox-
ides with ester protecting groups can be activated under the same
conditions used for electron-donating protecting groups, permit-
ting the use of a standard set of conditions to form very different
glycosidic linkages. The ability to form different glycosidic
linkages with similar efficiency using the same set of reaction
conditions should make the sulfoxide method simpler to use
for newcomers than methods which require different conditions
for different glycosidic linkages. We note that others7 who have
used the sulfoxide glycosylation reaction in a wide range of
substrates have used conditions very similar to those reported
here and in our earlier work.6
Experimental Section
General Methods. NMR spectra were recorded on a JEOL GSX
270 FT or a JEOL GSX 500 FT NMR spectrometer. Proton chemical
shifts are reported in parts per million (ppm) downfield from tetra-
methylsilane (TMS) unless noted otherwise. Coupling constants (J)
are reported in hertz (Hz). Carbon chemical shifts are reported in parts
per million (ppm) with reference to internal solvent CDCl3 (77.00 ppm)
unless noted otherwise. Multiplicities are abbreviated as follows:
singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and
broadened (br). High-resolution mass spectra (HRMS) were obtained
on a Kratos MS50 spectrometer (Princeton University Mass facility),
and high-resolution fast atom bombardment mass spectra (HRFABMS)
were obtained on a VG ZAB or a VG 7070 (University of California,
Riverside, Mass facility).
Analytical thin-layer chromatography (TLC) was performed using
silica gel 60 F254 precoated plates (0.25 mm thick) with a fluorescent
indicator. Flash chromatography was performed using silica gel 60
(200-400 mesh) from EM Science.16
All reactions were carried out under argon atmosphere with dry,
freshly distilled solvents under anhydrous conditions unless otherwise
noted. All reagents were purchased from commercial suppliers and
used without further purification unless otherwise noted.
Phenyl 2,3,4,6-Tetra-O-pivaloyl-1-thio-â-D-galactopyranoside and
Sulfoxide Derivatives (5). To a solution of phenyl 2,3,4,6-tetra-O-
acetyl-1-thio-â-D-galactopyranoside9 (1.28 g, 2.91 mmol) in MeOH (25
mL) at 25 °C was added NaOMe (83 mg, 1.54 mmol). The reaction
mixture was stirred at 25 °C overnight and neutralized with Dowex
50x8-100 acidic resin. The resin was filtered off, and the filtrate was
concentrated to give the crude tetraol as a white residue which was
dried azeotropically by toluene (3 × 5 mL) and taken to the next step
without further purification.
To the crude tetraol (2.91 mmol) and 4-dimethylaminopyridine (178
mg, 1.46 mmol) in pyridine (25 mL) at 25 °C was added pivaloyl
chloride (3.6 mL, 29.1 mmol) dropwise via syringe. The mixture was
refluxed for 24 h and then cooled to room temperature, and the reaction
was quenched with MeOH (5 mL). Solvent was removed in Vacuo,
and the residue was dissolved in CH2Cl2 and washed with 1 N aqueous
HCl (150 mL) and saturated aqueous NaHCO3 (3 × 150 mL). The
organic layers were dried over Na2SO4, concentrated, and purified by
flash chromatography (5% EtOAc in petroleum ether) to afford the
sulfide (1.60 g, 90% 2 steps) as a white solid: Rf ) 0.20 (5% EtOAc
in petroleum ether); 13C NMR (CDCl3, 68 MHz) δ 177.8, 177.2, 176.7,
176.4, 133.5, 131.4, 128.8, 128.3, 85.8, 74.7, 72.1, 66.9, 66.6, 61.5,
38.9, 38.7, 27.1, 27.0; 1H NMR (CDCl3, 270 MHz) δ 7.5-7.2
(5H, m), 5.50 (1H, d, J ) 3.0 Hz), 5.30 (1H, dd, J ) 9.6, 9.9 Hz), 5.21
(1H, dd, J ) 3.0, 9.9Hz), 4.81 (1H, d, J ) 9.6Hz), 4.32-4.06 (3H,
m), 1.30, 1.27, 1.25, 1.17 (4 × 9H, 4s); HRFABMS calcd for C32H47O9S
(M - H-) 607.2941, found 607.2942.
To a solution of the above sulfide (7.50 g, 12.3 mmol) in CH2Cl2
(100 mL) at -78 °C was added 3-chloroperoxybenzoic acid (3.33 g,
12.3 mmol) in CH2Cl2 (10 mL). After 15 min of stirring at -78 °C,
the mixture was poured into saturated aqueous NaHCO3 (500 mL).
The organic layer was washed with saturated aqueous NaHCO3 (2 ×
500 mL), dried over Na2SO4, concentrated, and purified by flash
chromatography (20% EtOAc in petroleum ether) to afford sulfoxide
5 (7.4 g, 96%, diastereomeric ratio is 2.1:1 which favors the more polar
product) as a white solid: Rf ) 0.41 (20% EtOAc in petroleum ether);
13C NMR (CDCl3, 68 MHz) δ 177.7, 177.3, 176.7, 176.0, 138.7, 131.5,
128.8, 125.8, 89.4, 75.5, 72.1, 66.4, 64.3, 61.0, 38.9, 38.8, 38.7, 38.6,
27.0, 26.9; 1H NMR (CDCl3, 270 MHz) δ 7.7-7.5 (5H, m), 5.56 (1H,
t, J ) 9.9Hz), 5.38 (1H, d, J ) 3.3Hz), 5.18 (1H, dd, J ) 3.1, 10.1Hz),
4.46 (1H, d, J ) 9.9Hz), 4.44-3.91 (3H, m), 1.24, 1.15, 1.10 (4 ×
9H, 4s); Rf ) 0.25 (20% EtOAc in petroleum ether); 13C NMR (CDCl3,
68 MHz) δ 177.6, 177.0, 176.9, 176.2, 137.0, 132.0, 128.6, 127.1, 92.2,
75.0, 71.7, 66.0, 64.8, 60.2, 38.9, 38.7, 38.6, 27.0, 26.8; 1H NMR
(CDCl3, 270 MHz) δ 7.8-7.5 (5H, m), 5.31 (1H, d, J ) 2.6Hz), 5.16
(1H, dd, J ) 3.0, 9.6Hz), 5.09 (1H, dd, J ) 9.6, 9.9Hz), 4.68 (1H, d,
J ) 9.6Hz), 4.13-4.03 (2H, m), 3.78-3.68 (1H, m), 1.25, 1.16, 1.09,
0.94 (4 × 9H, 4s); HRFABMS calcd for C32H48O10S (M+) 624.2968,
found 624.2968.
Having a uniform set of reaction conditions should ultimately
make solid phase synthesis of oligosaccharides and carbohydrate
libraries possible as well. In fact, some of the choices we made
in the above syntheses were dictated by our interest in
developing solid phase methods for the construction of oli-
gosaccharides. For example, although there are good methods
for the one-step conversion of a 4,6-benzylidene acetal into a
C6 benzyl ether, the conditions are not suitable for resin
synthesis; hence, we used a two-step process to produce a C6
pivaloyl ester. Similarly, hydrogenolytic removal of benzyl
ethers is not reliable in a resin matrix.15 We have developed
mild acidic conditions to remove p-methoxybenzyl groups which
should translate readily to the heterogeneous environment of a
resin. Simply by changing the benzyl groups to p-methoxy-
benzyl groups, the blood group antigens can be synthesized and
deprotected on a solid support using the routes outlined.6j
Conclusions
We have used the sulfoxide glycosylation method to make
all the glycosidic linkages in the Lewis blood group antigens
Lea, Leb, and Lex. Our syntheses are comparable to the best
syntheses of these molecules.3-5 Given the demonstrated
predictability of the sulfoxide glycosylation reaction for this
family of oligosaccharides, it should be possible to make other
members of the Lewis blood group family as well as analogues
without having each synthesis turn into a new problem that must
be solved by experimenting with different reaction conditions
or glycosylation methods.
(15) Schlatter, J. M.; Mazur, R. H. Tetrahedron Lett. 1977, 33, 2851.
(16) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.

Synthesis of Blood Group Antigens
J. Am. Chem. Soc., Vol. 118, No. 39, 1996 9243
Phenyl 2-Azido-4,6-O-benzylidene-2-deoxy-1-thio-r-D-glucopy-
ranoside (4). To a solution of 1,3,4,6-tetra-O-acetyl-2-azido-2-deoxy-
D-glucopyranoside8 (1.33 g, 3.57 mmol) and thiophenol (570 µL, 5.35
mmol) in CH2Cl2 (20 mL) was added BF3‚Et2O (2.2 mL, 17.8 mmol).
The mixture was stirred for 3 days at 25 °C, diluted with CH2Cl2 (20
mL), and poured into 200 mL water. The organic layer was washed
with saturated aqueous NaHCO3 (3 × 100 mL), dried over Na2SO4,
concentrated, and purified by flash chromatography (15% EtOAc in
petroleum ether) to afford the sulfide (1.34 g, 89%, R/â ) 2.1:1) as a
white solid: Rf ) 0.28 (25% EtOAc in petroleum ether); 13C NMR
(CDCl3, 68 MHz) δ 170.4, 169.8, 169.7, 169.6, 134.1, 132.4, 132.2,
130.2, 129.2, 129.1, 128.9, 128.0, 86.5, 85.8, 75.7, 74.4, 72.0, 68.7,
68.5, 68.0, 62.6, 62.0, 61.9, 61.6, 20.6; 1H NMR (CDCl3, 270 MHz) δ
7.6-7.3 (10H, m), 5.65 (1H, d, J ) 5.6Hz), 5.34 (1H, dd, J ) 9.3,
9.9Hz), 5.12-5.01 (2H, m), 4.93 (1H, t, J ) 9.6Hz), 4.59 (1H, m),
4.50 (1H, d, J ) 10.2Hz), 4.30 (1H, dd, J ) 4.8, 12.4Hz), 4.2-4.0
(4H, m), 3.71-3.68 (1H, m), 3.41 (1H, dd, J ) 9.6, 10.2Hz), 2.1-2.0
(18H, m); HRMS calcd for C18H21O7N3S (M+) 423.1100, found
423.1107.
To a solution of the above sulfide (3.5 g, 8.36 mmol) in MeOH/
THF (v/v ) 5:1, 50 mL) was added catalytic amount of NaOMe. After
1 h of stirring at 25 °C, the reaction mixture was neutralized with
Dowex 50x8-100 acidic resin. The resin was filtered off, and the filtrate
was concentrated to give the crude triol as a white residue which was
dried azeotropically by toluene (3 × 20 mL) and taken to next step
without further purification.
To a solution of the above crude triol (8.36 mmol) and benzaldehyde
dimethyl acetal (3.8 mL, 25.08 mmol) in DMF (50 mL) was added
TsOH‚H2O (795 mg, 4.18 mmol). After 24 h of stirring at 25 °C, the
reaction mixture was neutralized with Amberlite IRA-400(OH). The
resin was filtered off, and the filtrate was concentrated in Vacuo. The
residue was dissolved in CH2Cl2 (50 mL) and washed with saturated
aqueous NaHCO3 (2 × 200 mL). The organic layer was dried over
Na2SO4, concentrated, and purified by flash chromatography (15%
EtOAc in petroleum ether) to afford R anomer 4 (1.34 g, 89%) as a
white solid: Rf ) 0.27 (15% EtOAc in petroleum ether); 13C NMR
(CDCl3, 68 MHz) δ 136.8, 133.0, 132.5, 129.5, 129.2, 128.4, 128.0,
126.3, 102.2, 87.8, 81.6, 70.7, 68.5, 63.9, 63.4; 1H NMR (CDCl3, 500
MHz) δ 7.5-7.2 (10H, m), 5.57 (1H, d, J ) 5.9Hz), 5.56 (1H, s), 4.39
(1H, td, J ) 5.1, 9.9Hz), 4.23 (1H, dd, J ) 5.0, 10.5Hz), 4.07 (1H, t,
J ) 9.5Hz), 3.92 (1H, dd, J ) 5.5, 9.9Hz), 3.76 (1H, t, J ) 10.3Hz),
3.58 (1H, dd, J ) 9.2, 9.5Hz), 2.81 (1H, s); HRMS calcd for
C19H19O4N3S (M+) 385.1096, found 385.1106.
stirred overnight at 25 °C, the reaction mixture was neutralized with
Dowex 50x8-100 acidic resin. The resin was filtered off, and the filtrate
was concentrated to produce the crude tetraol as a white residue which
was dried azeotropically by toluene (3 × 5 mL) and taken to next step
without further purification.
To the above crude tetraol (0.303 mmol) and 4-dimethyl-
aminopyridine (19 mg, 0.155 mmol) in pyridine (10 mL) at 25 °C was
added acetic anhydride (230 µL, 2.42 mmol) dropwise via syringe. After
2 h of stirring at 25 °C, the reaction was quenched with MeOH (1 mL)
and concentrated in Vacuo. The residue was dissolved in CH2Cl2 and
washed with 1 N aqueous HCl (50 mL) and saturated aqueous NaHCO3
(3 × 100 mL). The organic layers were dried over Na2SO4,
concentrated, and purified by flash chromatography (14% Et2O in
CHCl3) to afford the tetraacetate (170 mg, 79% two steps) as a white
solid: Rf ) 0.27 (35% EtOAc in petroleum ether); 13C NMR (CDCl3,
68 MHz) δ 170.2, 170.1, 170.0, 169.4, 136.8, 132.6, 132.3, 129.2, 128.3,
128.1, 125.8, 101.3, 87.6, 80.6, 78.1, 71.0, 70.8, 69.5, 68.4, 66.7, 63.6,
63.4, 60.8, 20.7, 20.6, 20.5, 20.4; 1H NMR (CDCl3, 500 MHz) δ 7.5-
7.3 (10H, m), 5.61 (1H, d, J ) 5.5Hz), 5.58 (1H, s), 5.33 (1H, brd, J
) 3.3Hz), 5.27 (1H, dd, J ) 8.1, 10.3Hz), 4.98 (1H, dd, J ) 3.3,
10.3Hz), 4.83 (1H, d, J ) 8.1Hz), 4.42-4.37 (1H, m), 4.20 (1H, dd,
J ) 4.8, 10.3Hz), 4.11-4.02 (2H, m), 3.96 (1H, dd, J ) 5.7, 10.1Hz),
3.90 (1H, dd, J ) 5.9, 11.4Hz), 3.79-3.74 (2H, m), 3.71 (1H, brdd, J
) 6.6, 7.0Hz), 2.14, 2.12, 1.98, 1.94 (4 × 3H, 4s); HRFABMS calcd
for C33H37O13N3S (M+) 715.2047, found 715.2062.
The above tetraacetate (132 mg, 0.185 mmol) was added to a mixture
of trifluoroacetic acid and CH2Cl2 (v/v ) 1:2, 5 mL) at 25 °C. After
1 h of stirring at 25 °C, the mixture was diluted with CH2Cl2 (10 mL)
and poured into saturated aqueous NaHCO3 (100 mL). The organic
layer was washed with saturated aqueous NaHCO3 (2 × 100 mL), dried
over Na2SO4, concentrated, and purified by flash chromatography (55%
EtOAc in petroleum ether) to afford the diol (98 mg, 85%) as a white
solid: Rf ) 0.22 (50% EtOAc in petroleum ether); 13C NMR (CDCl3,
68 MHz) δ 170.3, 169.9, 169.5, 132.6, 132.4, 129.1, 128.1, 101.9, 87.1,
84.5, 72.3, 71.2, 70.7, 69.3, 68.4, 66.8, 62.5, 62.0, 61.6, 20.5, 20.4; 1H
NMR (CDCl3, 500 MHz) δ 7.5-7.3 (5H, m), 5.64 (1H, d, J ) 5.5Hz),
5.41 (1H, brd, J ) 3.3Hz), 5.28 (1H, dd, J ) 8.1, 10.3Hz), 5.06 (1H,
dd, J ) 3.3, 10.6Hz), 4.67 (1H, d, J ) 8.1Hz), 4.20-4.07 (5H, m),
3.87-3.81 (3H, m), 3.64-3.62 (2H, m), 2.14, 2.13, 2.08, 2.00 (4 ×
3H, 4s); HRFABMS calcd for C26H37O13N4S (M + NH4+) 645.2078,
found 645.2068.
To the above diol (98 mg, 0.157 mmol) in pyridine (10 mL) at 25
°C was added pivaloyl chloride (194 µL, 1.56 mmol) dropwise via
syringe. After 2 h of stirring at 25 °C, the reaction was quenched with
MeOH (1 mL) and concentrated in Vacuo. The residue was dissolved
in CH2Cl2 and washed with 1 N aqueous HCl (50 mL) and saturated
aqueous NaHCO3 (3 × 100 mL). The organic layers were dried over
Na2SO4, concentrated, and purified by flash chromatography (35%
EtOAc in petroleum ether) to afford 7 (103 mg, 92%) as a white solid:
Rf ) 0.32 (35% EtOAc in petroleum ether); 13C NMR (CDCl3, 68 MHz)
δ 178.2, 170.4, 170.0, 169.9, 169.6, 132.9, 132.0, 129.2, 127.9, 102.1,
87.3, 84.5, 71.4, 70.7, 69.4, 68.4, 66.8, 63.2, 62.5, 61.7, 38.8, 27.1,
20.6, 20.5, 20.4; 1H NMR (CDCl3, 500 MHz) δ 7.6-7.2 (5H, m), 5.63
(1H, d, J ) 5.5Hz), 5.43 (1H, brd, J ) 2.6Hz), 5.31 (1H, dd, J ) 8.1,
10.6Hz), 5.06 (1H, dd, J ) 3.5, 10.4Hz), 4.67 (1H, d, J ) 8.1Hz),
4.41-4.22 (3H, m), 4.19 (1H, dd, J ) 4.8, 11.4Hz), 4.14 (1H, dd, J )
7.7, 11.4Hz), 4.11 (1H, d, J ) 1.5Hz), 4.07 (1H, dd, J ) 5.5, 7.7Hz),
3.83 (1H, dd, J ) 5.5, 10.3Hz), 3.61 (1H, dd, J ) 8.1, 10.3Hz), 3.56
(1H, dd, J ) 8.4, 9.5Hz), 2.18, 2.13, 2.09, 2.01 (4 × 3H, 4s), 1.18
(9H, s); HRFABMS calcd for C31H42O14N3S (M + H+) 712.2388, found
712.2383.
Phenyl 2,3,4-Tri-O-benzyl-1-thio-â-L-fucopyranoside and Sul-
foxide Derivatives (8). To a solution of phenyl 2,3,4-tri-O-acetyl-1-
thio-â-L-fucopyranoside11 (928 mg, 2.43 mmol) in MeOH (25 mL) at
25 °C was added catalytic amount of K2CO3. The mixture was stirred
overnight at 25 °C and neutralized with Dowex 50x8-100 acidic resin.
The resin was filtered off, and the filtrate was concentrated to afford
the crude triol as a white residue which was dried azeotropically by
toluene (3 × 5 mL) and taken to the next step without further
purification.
Phenyl (2,3,4,6-Tetra-O-pivaloyl-â-D-galactopyranosyl)-(1f3)-2-
azido-4,6-O-benzylidene-2-deoxy-1-thio-r-D-glucopyranoside (6). To
a solution of sulfoxide 5 (109 mg, 0.175 mmol) in CH2Cl2 (5 mL) at
-78 °C was added Tf2O (15 µL, 0.089 mmol), and then the mixture
was warmed up to -60 °C. After 15 min of stirring at -60 °C, to the
mixture were added nucleophile 4 (37 mg, 0.096 mmol) and 2,6-di-
tert-butyl-4-methylpyridine (110 mg, 0.526 mmol) in CH2Cl2 (5 mL)
dropwise via syringe. After 10 min of stirring at -60 °C, the mixture
was slowly warmed up to -30 °C over 30 min, quenched by saturated
aqueous NaHCO3 (5 mL), and washed with saturated aqueous NaHCO3
(2 × 100 mL). The organic layer was dried over Na2SO4, concentrated,
and purified by flash chromatography (13% EtOAc in petroleum ether)
to afford disaccharide 6 (70 mg, 83%) as a white solid: Rf ) 0.32
(15% EtOAc in petroleum ether); 13C NMR (CDCl3, 68 MHz) δ 177.6,
177.3, 176.8, 176.6, 136.8, 132.7, 132.5, 129.3, 129.2, 128.4, 128.1,
126.0, 101.7, 100.5, 87.3, 80.2, 77.1, 71.1, 70.9, 69.3, 68.5, 66.3, 63.6,
1
63.5, 60.6, 39.0, 38.9, 38.7, 38.6, 27.2, 27.1; H NMR (CDCl3, 500
MHz) δ 7.5-7.2 (10H, m), 5.60 (1H, d, J ) 4.4Hz), 5.55 (1H, s), 5.34
(1H, d, J ) 2.6Hz), 5.27 (1H, dd, J ) 8.1, 10.3Hz), 5.08 (1H, dd, J )
3.5, 10.5Hz), 4.87 (1H, d, J ) 8.1Hz), 4.40 (1H, td, J ) 4.8, 9.9Hz),
4.19 (1H, dd, J ) 5.0, 10.5Hz), 4.05-4.04 (2H, m), 4.00 (1H, dd, J )
8.4, 10.6Hz), 3.94 (1H, dd, J ) 6.2, 11.0Hz), 3.79-3.75 (2H, m), 3.72
(1H, dd, J ) 7.0, 8.1Hz), 1.23, 1.22, 1.14, 1.11 (4 × 9H, 4s);
HRFABMS calcd for C45H60O13N3S (M - H-) 882.3847, found
882.3861.
Phenyl (2,3,4,6-Tetra-O-acetyl-â-D-galactopyranosyl)-(1f3)-2-
azido-2-deoxy-6-O-pivaloyl-1-thio-r-D-glucopyranoside (7). To a
solution of disaccharide 6 (267 mg, 0.302 mmol) in MeOH (5 mL)
was added LiOH‚H2O (30 mg, 0.715 mmol). After the solution was
To a solution of the above crude triol (2.43 mmol), benzyl chloride
(1.7 mL, 14.6 mmol), and catalytic amount of tetrabutylammonium

9244 J. Am. Chem. Soc., Vol. 118, No. 39, 1996
Yan and Kahne
iodide in DMF (25 mL) at 25 °C was added NaH (60%, 583 mg, 14.6
mmol). The mixture was heated to 60 °C for 24 h and then cooled
down to 25 °C, and the reaction was quenched with MeOH (2 mL)
and concentrated in Vacuo. The residue was dissolved in CH2Cl2 and
washed with saturated aqueous NaHCO3 (3 × 100 mL). The organic
layers were dried over Na2SO4, concentrated, and purified by flash
chromatography (5% EtOAc in petroleum ether) to afford the sulfide
(1.3 g, 100%, 2 steps) as a white solid: Rf ) 0.34 (10% EtOAc in
petroleum ether); 13C NMR (CDCl3, 68 MHz) δ 138.7, 138.3, 134.3,
131.5, 128.7, 128.4, 128.3, 128.1, 127.9, 127.6, 127.5, 127.4, 126.9,
87.5, 84.5, 77.0, 75.5, 74.6, 72.8, 17.3; 1H NMR (CDCl3, 270 MHz) δ
7.6-7.2 (20H, m), 5.03-4.58 (7H, m), 3.93 (1H, t, J ) 9.2Hz), 3.64-
3.48 (3H, m), 1.26 (3H, d, J ) 6.3Hz); HRMS calcd for C33H34O4S
(M+) 526.2178, found 526.2168.
chromatography (40% EtOAc in petroleum ether) to afford the lactol
(74 mg, 77%) as a white solid: Rf ) 0.34 (40% EtOAc in petroleum
ether); 13C NMR (CDCl3, 68 MHz) δ 178.2, 178.1, 170.1, 170.0, 169.8,
169.6, 169.4, 138.7, 138.6, 138.5, 138.4, 137.7, 128.8, 128.5, 128.4,
128.3, 127.9, 127.7, 127.4, 127.0, 100.8, 98.3, 96.4, 91.4, 80.6, 77.7,
76.4, 75.3, 75.1, 74.9, 74.0, 73.9, 73.8, 72.7, 72.3, 72.1, 71.0, 70.3,
69.7, 68.5, 66.7, 66.5, 65.8, 61.1, 60.9, 60.2, 38.9, 27.3, 20.8, 20.6,
1
20.5, 16.8; H NMR (CDCl3, 500 MHz) δ 7.5-7.2 (25.5H, m), 5.35
(1.7H, d, J ) 3.3Hz), 5.26 (0.7H, dd, J ) 3.3, 3.7Hz), 5.16-5.11 (1.7H,
m), 5.07 (1H, d, J ) 8.1Hz), 5.03-4.93 (4.1H, m), 4.88-4.73 (11.9H,
m), 4.61-4.58 (2.0H, m), 4.55-4.52 (0.7H, m), 4.31-4.28 (0.7H, m),
4.25 (1H, dd, J ) 2.8, 12.3Hz), 4.16-3.87 (10.9H, m), 3.75 (0.7H,
brs), 3.73 (1H, brs), 3.69-3.60 (2.4H, m), 3.55 (1H, dd, J ) 9.5, 9.9Hz),
3.5-3.4 (1H, m), 3.29 (0.7H, dd, J ) 2.9, 10.3Hz), 3.18 (1H, dd, J )
8.1, 9.9Hz), 2.11, 2.10, 2.03, 1.97, 1.96, 1.79, 1.77, 1.75 (20.4H, m),
1.30 (2.1H, d, J ) 6.6Hz), 1.27 (3H, d, J ) 6.6Hz), 1.20 (15.3H, s);
HRFABMS calcd for C52H64O19N3 (M - H-) 1034.4134, found
1034.4172.
To a solution of the above sulfide (7.50 g, 12.3 mmol) in CH2Cl2
(100 mL) at -78 °C was added 3-chloroperoxybenzoic acid (3.33 g,
12.3 mmol) in CH2Cl2 (10 mL). After 15 min of stirring at -78 °C,
the mixture was poured into saturated aqueous NaHCO3 (500 mL).
The organic layer was washed with saturated aqueous NaHCO3 (2 ×
500 mL), dried over Na2SO4, concentrated, and purified by flash
chromatography (20% EtOAc in petroleum ether) to afford sulfoxide
8 (7.4 g, 96%, diastereomeric ratio is 2.1:1 which favors the more polar
product) as a white solid: Rf ) 0.29 (30% EtOAc in petroleum ether);
13C NMR (CDCl3, 68 MHz) δ 140.2, 138.3, 138.0, 137.9, 130.6, 128.4,
128.1, 127.8, 127.7, 127.5, 125.4, 94.0, 84.5, 75.8, 75.7, 75.4, 74.3,
To a solution of the above lactol (82 mg, 0.079 mmol) and
iodomethane (50 µL, 0.803 mmol) in DMF (5 mL) was added NaH
(60%,16 mg, 0.40 mmol). After 20 min of stirring at 25 °C, the mixture
was diluted with CH2Cl2 and poured into saturated aqueous NaHCO3
(50 mL). The organic layer was washed with saturated aqueous
NaHCO3 (2 × 100 mL), dried over Na2SO4, concentrated, and purified
by flash chromatography (30% EtOAc in petroleum ether) to afford
the methyl ether (70 mg, 84%) as a white solid: Rf ) 0.41 (30% EtOAc
in petroleum ether); 13C NMR (CDCl3, 125.8 MHz) δ 177.8, 170.0,
169.7, 169.5, 169.4, 138.6, 138.5, 137.8, 128.9, 128.8, 128.4, 128.3,
128.2, 127.9, 127.7, 127.4, 127.0, 102.8, 100.8, 98.5, 98.3, 97.8, 80.7,
80.6, 77.8, 76.4, 75.5, 75.1, 75.0, 73.9, 73.7, 72.9, 72.5, 72.4, 72.3,
71.0, 70.9, 70.3, 69.5, 68.5, 67.5, 66.8, 66.5, 65.4, 61.5, 61.2, 60.3,
57.0, 55.0, 38.9, 27.3, 27.2, 20.8, 20.7, 20.6, 20.5, 16.8, 16.7; 1H NMR
(CDCl3, 500 MHz) δ 7.5-7.2 (25.5H, m), 5.35 (1.7H, m), 5.16-5.10
(1.7H), 5.11 (1H, d, J ) 8.1Hz), 5.07-4.93 (4.7H, m), 4.87-4.73
(12.6H, m), 4.61-4.53 (1.7H, m), 4.30 (1H, dd, J ) 3.9, 12.3Hz), 4.25
(0.7H, dd, J ) 4.4, 12.1Hz), 4.16-4.12 (2.7H, m), 4.08 (1.7H, dd, J
) 8.4, 10.6Hz), 4.02 (0.7H, dd, J ) 9.5, 9.9Hz), 3.98-3.86 (5.8H,
m), 3.74 (0.7H, brs), 3.72 (1H, brs), 3.66-3.61 (m), 3.55 (1H, t, J )
9.5Hz), 3.52 (3H, s), 3.50-3.44 (1H, m), 3.39 (2.1H, s), 3.34 (0.7H,
dd, J ) 3.5, 10.1Hz), 3.19 (1H, dd, J ) 8.1, 9.9Hz), 2.10, 2.09, 2.03,
1.96, 1.95, 1.79, 1.77 (20.4H, m), 1.30 (2.1H, d, J ) 6.6Hz), 1.26 (3H,
d, J ) 6.6Hz), 1.20 (6.3H, s), 1.19 (9H, s); HRFABMS calcd for
C53H67O19N3Na (M + Na+) 1072.4266, found 1072.4242.
1
73.7, 72.6, 16.5; H NMR (CDCl3, 270 MHz) δ 7.6-7.2 (20H, m),
5.04-4.68 (6H, m), 4.44 (1H, t, J ) 9.6Hz), 3.87 (1H, d, J ) 9.6Hz),
3.64 (1H, dd, J ) 2.8, 9.4Hz), 3.58 (1H, d, J ) 2.0Hz), 3.32 (1H, q,
J ) 6.3Hz), 1.02 (3H, d, J ) 6.3Hz); Rf ) 0.15 (30% EtOAc in
petroleum ether); 13C NMR (CDCl3, 68 MHz) δ 140.2, 138.4, 138.0,
137.8, 130.9, 128.4, 128.2, 128.0, 127.9, 127.6, 127.2, 126.1, 95.3,
1
84.4, 75.7, 75.2, 74.4, 74.2, 73.7, 72.4, 16.7; H NMR (CDCl3, 270
MHz) δ 7.6-7.1 (20H, m), 4.90-4.51 (6H, m), 4.46 (1H, d, J ) 9.2Hz),
3.98 (1H, dd, J ) 8.9, 9.2Hz), 3.68 (1H, dd, J ) 2.5, 9.1Hz), 3.60-
3.57 (2H, m), 1.19 (3H, d, J ) 6.3Hz); HRFABMS calcd for C33H35O5S
(M + H+) 543.2205, found 543.2206.
Phenyl (2,3,4,6-Tetra-O-acetyl-â-D-galactopyranosyl)-(1f3)-
[2,3,4-tri-O-benzyl-r-L-fucopyranosyl-(1f4)]-2-azido-2-deoxy-6-O-
pivaloyl-1-thio-r-D-glucopyranoside (9). To a solution of sulfoxide
8 (142 mg, 0.262 mmol) and 2,6-di-tert-butyl-4-methylpyridine (165
mg, 0.788 mmol) in CH2Cl2 (10 mL) at -78 °C was added Tf2O (22
µL, 0.131 mmol), and then the reaction mixture was warmed to -60
°C. After 15 min of stirring at -60 °C, to the mixture was added
nucleophile 7 (95 mg, 0.134 mmol) in CH2Cl2 (5 mL) dropwise via
syringe. After 10 min of stirring at -60 °C, the reaction was slowly
warmed to -5 °C over 1 h, quenched by saturated aqueous NaHCO3
(5 mL), and washed with saturated aqueous NaHCO3 (2 × 100 mL).
The organic layer was dried over Na2SO4, concentrated, and purified
by flash chromatography (27% EtOAc in petroleum ether) to afford
trisaccharide 9 (143 mg, 95%) as a white solid: Rf ) 0.42 (30% EtOAc
in petroleum ether); 13C NMR (CDCl3, 68 MHz) δ 177.8, 170.1, 170.0,
169.7, 169.5, 138.7, 138.6, 137.8, 132.9, 132.1, 129.2, 128.9, 128.5,
128.4, 128.3, 128.2, 127.9, 127.8, 127.7, 127.4, 127.0, 100.8, 98.4,
87.0, 80.6, 77.2, 76.3, 74.9, 74.8, 74.0, 72.9, 72.4, 71.0, 70.8, 70.4,
68.5, 66.8, 66.6, 65.7, 61.7, 60.2, 38.8, 27.3, 20.9, 20.6, 20.5, 16.8; 1H
NMR (CDCl3, 500 MHz) δ 7.5-7.2 (20H, m), 5.60 (1H, d, J ) 4.4Hz),
5.37 (1H, d, J ) 3.3Hz), 5.16 (1H, dd, J ) 8.3, 10.5Hz), 5.04 (1H, d,
J ) 8.1Hz), 5.00 (1H, dd, J ) 3.3, 10.3Hz), 4.98 (1H, d, J ) 12.5Hz),
4.87-4.84 (3H, m), 4.81 (1H, d, J ) 3.3Hz), 4.78 (2H, d, J ) 11.7Hz),
4.75 (1H, q, J ) 7.0Hz), 4.45-4.40 (2H, m), 4.34-4.31 (1H, m), 4.19-
4.13 (2H, m), 4.02-3.94 (3H, m), 3.87-3.80 (2H, m), 3.75 (1H, brs),
3.70 (1H, dd, J ) 8.8, 9.5Hz), 2.11, 2.04, 1.96, 1.78 (4 × 3H, 4s),
1.30 (3H, d, J ) 6.2Hz), 1.16 (9H, s); HRFABMS calcd for
C58H69O20N4S (M + NO2+) 1173.4228, found 1173.4225.
The above methyl ether (17 mg, 0.016 mmol) was dissolved in
EtOAc (5 mL) and stirred vigorously under hydrogen (1 atm) with the
Lindlar catalyst (100 mg). After the reaction was run overnight, the
catalyst was filtered off and the filtrate was concentrated. The residue
was dissolved in EtOAc (5 mL) and stirred vigorously under hydrogen
(1 atm) with Pd/C (100 mg). After 8 h of stirring at 25 °C, the catalyst
was filtered off and the filtrate was concentrated. To the solution of
the residue in CH2Cl2 (5 mL) were added Ac2O, DMAP, and Et3N.
After 10 min of stirring at 25 °C, the reaction was quenched with MeOH
(1 mL) and concentrated in Vacuo. The residue was purified by flash
chromatography (100% EtOAc) to afford 5 mg (34%) of R anomer
10a and 6 mg (41%) of â anomer 10b as white solids. For â-OCH3:
Rf ) 0.15 (100% EtOAc); 13C NMR (CDCl3, 68 MHz) δ 177.8, 170.7,
170.5, 170.3, 170.2, 170.1, 170.0, 169.9, 169.4, 100.5, 100.2, 95.1,
78.0, 76.2, 72.5, 72.2, 71.3, 71.0, 70.8, 68.5, 67.9, 66.8, 65.0, 62.3,
1
60.7, 56.1, 54.0, 38.8, 27.2, 23.5, 20.7, 15.8; H NMR (CDCl3, 500
MHz) δ 5.79 (1H, d, J ) 8.8Hz), 5.41 (1H, d, J ) 2.9Hz), 5.32 (1H,
d, J ) 2.2Hz), 5.26 (1H, dd, J ) 3.3, 11.0Hz), 5.21 (1H, dd, J ) 3.3,
11.0Hz), 5.13 (1H, dd, J ) 8.1, 10.3Hz), 5.04 (1H, d, J ) 3.7Hz),
4.99 (1H, dd, J ) 3.5, 10.4Hz), 4.82 (1H, d, J ) 8.1Hz), 4.74 (1H, q,
J ) 6.5Hz), 4.53 (1H, d, J ) 5.9Hz), 4.46 (1H, dd, J ) 3.5, 11.9Hz),
4.36 (1H, dd, J ) 5.9, 11.4Hz), 4.22 (1H, dd, J ) 8.1, 11.4Hz), 4.06
(1H, dd, J ) 7.0, 7.3Hz), 4.01 (1H, dd, J ) 5.5, 11.7Hz), 3.90 (1H,
dd, J ) 7.0, 7.3Hz), 3.87-3.81 (2H, m), 3.71-3.66 (1H, m), 3.42 (3H,
s), 2.18, 2.17, 2.09, 2.08, 2.07, 2.04, 1.98, 1.97 (8 × 3H, 8s), 1.24
(3H, d, J ) 6.9Hz), 1.22 (9H, s); HRFABMS calcd for C40H60NO23
(M + H+) 922.3556, found 922.3543.
Methyl (2,3,4,6-Tetra-O-acetyl-â-D-galactopyranosyl)-(1f3)-
[2,3,4-tri-O-acetyl-r-L-fucopyranosyl-(1f4)]-2-acetamido-2-deoxy-
6-O-pivaloyl-r,â-D-glucopyranoside (10a,b). To a solution of trisac-
charide 9 (105 mg, 0.093 mmol) in wet CH2Cl2 (10 mL) was added
mercury(II) trifluoroacetate (199 mg, 0.465 mmol). After 20 min of
stirring at 25 °C, the mixture was poured into 1 N aqueous HCl (50
mL). The organic layer was washed with saturated aqueous NaHCO3
(2 × 100 mL), dried over Na2SO4, concentrated, and purified by flash
Methyl â-D-Galactopyranosyl-(1f3)-[r-L-fucopyranosyl-(1f4)]-
2-acetamido-2-deoxy-â-D-glucopyranoside (1). To a solution of

Synthesis of Blood Group Antigens
J. Am. Chem. Soc., Vol. 118, No. 39, 1996 9245
trisaccharide 10b (9 mg, 0.0098 mmol) in MeOH (5 mL) was added
excess LiOH‚H2O. After the solution was stirred overnight at 25 °C,
the reaction mixture was neutralized with Dowex 50x8-100 acidic resin.
The resin was filtered off, and the filtrate was concentrated to give 1
(5 mg, 94%) as a white solid: 13C NMR (D2O, 125.8 MHz, CH3OH as
internal reference) δ 174.8, 103.2, 102.1, 98.4, 76.5, 75.8, 75.1, 72.8,
72.6, 72.2, 70.8, 69.4, 68.6, 68.1, 67.2, 61.9, 60.0, 57.4, 55.8, 22.6,
reaction mixture was warmed to -60 °C. After 15 min of stirring at
-60 °C, nucleophile 4 (98 mg, 0.255 mmol) in CH2Cl2 (7.5 mL) was
added to the mixture dropwise via syringe. After another 10 min of
stirring at -60 °C, the mixture was slowly warmed to 0 °C over 1 h,
and the reaction was quenched by saturated aqueous NaHCO3 (5 mL)
and washed with saturated aqueous NaHCO3 (2 × 100 mL). The
organic layer was dried over Na2SO4, concentrated, and purified by
flash chromatography (15% EtOAc in petroleum ether) to afford
disaccharide 12 (177 mg, 77%) as a white solid: Rf ) 0.33 (20% EtOAc
in petroleum ether); 13C NMR (CDCl3, 68 MHz) δ 176.7, 138.4, 137.8,
137.7, 137.2, 132.7, 132.6, 129.1, 129.0, 128.4, 128.3, 128.2, 128.1,
128.0, 127.8, 127.5, 127.4, 127.0, 126.0, 101.3, 101.0, 87.3, 81.2, 81.0,
77.2, 74.3, 73.5, 73.3, 72.1, 71.7, 68.5, 68.4, 63.5, 38.9, 27.2; 1H NMR
(CDCl3, 500 MHz) δ 7.5-7.2 (25H, m), 5.57 (1H, d, J ) 4.8Hz), 5.51
(1H, s), 5.47 (1H, dd, J ) 8.1, 10.3Hz), 4.89 (1H, d, J ) 11.4Hz),
4.76 (1H, d, J ) 8.1Hz), 4.63-4.48 (3H, m), 4.35 (1H, dt, J ) 4.8,
9.9Hz), 4.30-4.23 (2H, m), 4.14 (1H, dd, J ) 4.8, 10.3Hz), 3.98-
3.97 (2H, m), 3.90 (1H, d, J ) 2.6Hz), 3.81-3.77 (1H, m), 3.69 (1H,
t, J ) 10.3Hz), 3.62 (1H, dd, J ) 9.5, 10.3Hz), 3.50 (1H, dd, J ) 2.6,
10.3Hz), 3.43-3.40 (2H, m), 1.23 (9H, s); HRFABMS calcd for
C51H55O10N3SNa (M + Na+) 924.3506, found 924.3483.
Phenyl (3,4,6-Tri-O-benzyl-â-D-galactopyranosyl)-(1f3)-2-azido-
2-deoxy-6-O-pivaloyl-1-thio-r-D-glucopyranoside (13). Disaccharide
12 (177 mg, 0.196 mmol) was added into a mixture of trifluoroacetic
acid and CH2Cl2 (v/v ) 1:2, 20 mL) at 25 °C. After 1 h of stirring at
25 °C, the mixture was diluted with CH2Cl2 (10 mL) and poured into
saturated aqueous NaHCO3 (150 mL). The organic layer was washed
with saturated aqueous NaHCO3 (2 × 150 mL), dried over Na2SO4,
concentrated, and purified by flash chromatography (35% EtOAc in
petroleum ether) to afford the diol (125 mg, 78%) as a white solid: Rf
) 0.31 (35% EtOAc in petroleum ether); 13C NMR (CDCl3, 68 MHz)
δ 176.9, 137.8, 137.4, 132.8, 132.7, 129.1, 128.4, 128.3, 128.2, 128.0,
127.9, 127.8, 127.7, 127.2, 101.6, 87.1, 82.6, 81.1, 74.3, 73.8, 73.7,
72.5, 72.3, 72.0, 70.8, 69.7, 68.8, 62.4, 62.3, 38.8, 27.1; 1H NMR
(CDCl3, 500 MHz) δ 7.5-7.2 (20H, m), 5.65 (1H, d, J ) 5.5Hz), 5.45
(1H, dd, J ) 7.7, 9.9Hz), 4.9-4.4 (7H, m), 4.18-4.15 (1H, m), 3.85-
3.82 (2H, m), 3.70-3.57 (7H, m), 3.5-3.4 (1H, m), 1.22 (9H, s);
HRFABMS calcd for C44H51O10N3SNa (M + Na+) 836.3193, found
836.3203.
1
15.7; H NMR (D2O, 500 MHz) δ 4.98 (1H, d, J ) 4.0Hz), 4.8-4.7
(1H, m), 4.44 (1H, d, J ) 7.7Hz), 4.41 (1H, d, J ) 8.4Hz), 4.02 (1H,
t, J ) 9.9Hz), 3.95 (1H, brd, J ) 10.3Hz), 3.87-3.67 (4H, m), 3.58
(1H, dd, J ) 3.3, 9.9Hz), 3.53-3.52 (2H, m), 3.46 (3H, s), 3.44 (1H,
t, J ) 9.9Hz), 1.99 (3H, s), 1.14 (3H, d, J ) 6.6Hz); HRFABMS calcd
for C21H37NO15Na (M + Na+) 566.2061, found 566.2082.
Phenyl 3,4,6-Tri-O-benzyl-2-O-pivaloyl-1-thio-â-D-galactopyra-
noside and Sulfoxide Derivatives (11). To a solution of phenyl 2-O-
acetyl-3,4,6-tri-O-benzyl-1-thio-â-D-galactopyranoside13 (2.79 g, 4.78
mmol) in a mixture of MeOH and THF (v/v ) 2:1, 50 mL) at 25 °C
was added NaOMe (136 mg, 2.52 mmol). The mixture was stirred
overnight at 25 °C and neutralized with Dowex 50x8-100 acidic resin.
The resin was filtered off, and the filtrate was concentrated and purified
by flash chromatrography to afford the alcohol (2.32 g, 90%) as a white
solid: Rf ) 0.37 (20% EtOAc in petroleum ether); 13C NMR (CDCl3,
68 MHz) δ 138.5, 137.9, 137.7, 132.5, 132.0, 128.7, 128.4, 128.3, 128.0,
127.8, 127.7, 127.6, 127.5, 127.4, 127.3, 88.3, 83.1, 77.4, 74.2, 73.4,
1
73.1, 72.3, 68.9, 68.6; H NMR (CDCl3, 270 MHz) δ 7.5-7.2 (20H,
m), 4.9-4.4 (7H, m), 4.1-3.9 (2H, m), 3.64 (3H, s), 3.45 (1H, dd, J
) 2.6. 9.4Hz), 2.57 (1H, brs); HRMS calcd for C33H34O5S (M+)
542.2128, found 542.2130.
To a solution of the above alcohol (1.58 g, 2.92 mmol), 4-dimethyl-
aminopyridine (178 mg, 1.43 mmol), and triethylamine (1.2 mL, 8.75
mmol) in CH2Cl2 (50 mL) at 25 °C was added pivaloyl chloride (725
µL, 5.83 mmol). The mixture was refluxed for 24 h and then cooled
to 25 °C, and the reaction was quenched with MeOH (5 mL) and
extracted with saturated aqueous NaHCO3 (3 × 150 mL). The organic
layers were dried over Na2SO4, concentrated, and purified by flash
chromatography (15% EtOAc in petroleum ether) to afford the pivaloate
(1.32 g, 72%) as a white solid: Rf ) 0.29 (10% EtOAc in petroleum
ether); 13C NMR (CDCl3, 68 MHz) δ 176.7, 138.4, 137.8, 137.7, 133.9,
131.7, 128.7, 128.4, 128.3, 128.1, 128.0, 127.8, 127.7, 127.6, 127.4,
127.3, 127.2, 87.1, 81.9, 77.5, 74.2, 73.5, 72.9, 72.3, 69.2, 68.8, 38.7,
27.1; 1H NMR (CDCl3, 270 MHz) δ 7.5-7.2 (20H, m), 5.48 (1H, t, J
) 9.9Hz), 4.92 (1H, d, J ) 11.6Hz), 4.66 (1H, d, J ) 9.9Hz), 4.64-
4.38 (5H, m), 3.97 (1H, d, J ) 2.6Hz), 3.68-3.59 (4H, m), 1.22 (9H,
s); HRFABMS calcd for C38H43O6S (M + H+) 627.2780, found
627.2805.
To a solution of the above diol (125 mg, 0.154 mmol) in MeOH:
THF (v/v ) 3:2, 25 mL) was added LiOH‚H2O (66 mg, 1.53 mmol).
After 1 week of stirring at 25 °C, the mixture was diluted in CH2Cl2
and washed with 1 N aqueous HCl (50 mL) and saturated aqueous
NaHCO3 (3 × 100 mL). The organic layers were dried over Na2SO4,
concentrated, and purified by flash chromatography (45% EtOAc in
petroleum ether) to afford the triol (110 mg, 98%) as a white solid: Rf
) 0.27 (35% EtOAc in petroleum ether); 13C NMR (CDCl3, 68 MHz)
δ 137.9, 137.3, 132.7, 129.1, 128.5, 128.4, 128.3, 128.0, 127.9, 127.8,
127.7, 104.3, 86.7, 85.2, 81.7, 74.5, 74.2, 73.6, 73.0, 72.8, 72.3, 71.4,
To a solution of the above pivaloate (319 mg, 0.51 mmol) in CH2Cl2
(20 mL) at -78 °C was added 3-chloroperoxybenzoic acid (137 mg,
0.51 mmol) in CH2Cl2 (5 mL). After 15 min of stirring at -78 °C,
the mixture was poured into saturated aqueous NaHCO3 (100 mL).
The organic layer was washed with saturated aqueous NaHCO3 (2 ×
100 mL), dried over Na2SO4, concentrated, and purified by flash
chromatography (30% EtOAc in petroleum ether) to afford sulfoxide
11 (290 mg, 89%, diastereomeric ratio is 2.1:1 which favors the more
polar product) as a white solid: Rf ) 0.44 (30% EtOAc in petroleum
ether); 13C NMR (CDCl3, 68 MHz) δ 176.3, 139.6, 138.1, 137.7, 137.5,
131.0, 128.6, 128.4, 128.1, 128.0, 127.8, 127.7, 127.5, 127.2, 125.5,
91.0, 81.8, 78.7, 74.1, 73.4, 72.3, 68.6, 66.8, 38.8, 27.1; 1H NMR
(CDCl3, 270 MHz) δ 7.6-7.1 (20H, m), 5.69 (1H, dd, J ) 9.9, 9.6Hz),
4.85-4.30 (6H, m), 4.22 (1H, d, J ) 9.6Hz), 3.89 (1H, d, J ) 2.6Hz),
3.68 (1H, dd, J ) 2.5, 9.7Hz), 3.58-3.52 (3H, m), 1.23 (9H, s); Rf )
0.33 (30%EtOAc in petroleum ether); 13C NMR (CDCl3, 68 MHz) δ
177.1, 138.3, 137.9, 137.6, 137.4, 131.4, 128.4, 128.2, 128.0, 127.8,
127.7, 127.3, 127.1, 126.8, 92.9, 81.0, 77.3, 73.8, 73.4, 72.4, 72.2, 67.5,
1
70.0, 69.0, 62.5, 62.4; H NMR (CDCl3, 270 MHz) δ 7.5-7.2 (20H,
m), 4.92-4.37 (8H, m), 4.23-4.16 (1H, m), 4.08-4.00 (1H, m), 3.92
(1H, dd, J ) 5.6, 9.9Hz), 3.80-3.57 (8H, m), 3.48 (1H, dd, J ) 2.8,
9.6Hz), 3.40-3.33 (1H, m), 2.75 (1H, d, J ) 2.6Hz), 1.89 (1H, t, J )
6.3Hz); HRFABMS calcd for C39H44O9N3S (M + H+) 730.2798, found
730.2812.
To the above triol (110 mg, 0.151 mmol), triethylamine (63 µL,
0.454 mmol), 4-dimethylaminopyridine (9 mg, 0.074 mmol) in CH2Cl2
(10 mL) at 25 °C was added pivaloyl chloride (28 µL, 0.23 mmol)
dropwise via syringe. After 2 h of stirring at 25 °C, the reaction was
quenched with MeOH (1 mL). The mixture was washed with saturated
aqueous NaHCO3 (3 × 100 mL). The organic layers were dried over
Na2SO4, concentrated, and purified by flash chromatography (25%
EtOAc in petroleum ether) to afford diol 13 (92 mg, 75%) as a white
solid: Rf ) 0.37 (25% EtOAc in petroleum ether); 13C NMR (CDCl3,
68 MHz) δ 178.3, 137.9, 137.2, 133.2, 132.0, 129.1, 128.6, 128.5, 128.4,
128.3, 128.2, 128.0, 127.9, 127.7, 104.6, 86.8, 85.4, 81.7, 74.6, 74.3,
73.8, 73.1, 72.8, 71.5, 70.9, 69.6, 69.0, 63.4, 62.5, 38.8, 27.2; 1H NMR
(CDCl3, 270 MHz) δ 7.5-7.2 (20H, m), 5.58 (1H, d, J ) 5.6Hz), 4.92-
4.35 (9H, m), 4.21 (1H, dd, J ) 5.9, 12.2Hz), 4.07-4.02 (1H, m),
3.92 (1H, dd, J ) 5.6, 10.2Hz), 3.80 (1H, d, J ) 2.6Hz), 3.73-3.54
(4H, m), 3.49 (1H, dd, J ) 2.8, 9.7Hz), 3.34 (1H, dd, J ) 3.3, 8.3Hz),
2.70 (1H, d, J ) 2.3Hz), 1.62 (1H, s), 1.17 (9H, s); HRFABMS calcd
for C44H52O10N3S (M + H+) 814.3373, found 814.3385.
1
67.2, 38.8, 27.1; H NMR (CDCl3, 270 MHz) δ 7.8-6.9 (20H, m),
5.36 (1H, t, J ) 9.6Hz), 4.77-4.30 (7H, m), 3.88 (1H, brs), 3.66-
3.36 (4H, m), 1.24 (9H, s); HRFABMS calcd for C38H42O7SNa (M +
Na+) 665.2549, found 665.2586.
Phenyl (3,4,6-Tri-O-benzyl-2-O-pivaloyl-â-D-galactopyranosyl)-
(1f3)-2-azido-4,6-O-benzylidene-2-deoxy-1-thio-r-D-glucopyrano-
side (12). To a solution of sulfoxide 11 (290 mg, 0.452 mmol) and
2,6-di-tert-butyl-4-methylpyridine (284 mg, 1.36 mmol) in CH2Cl2 (10
mL) at -78 °C was added Tf2O (38 µL, 0.226 mmol), and then the

9246 J. Am. Chem. Soc., Vol. 118, No. 39, 1996
Yan and Kahne
Phenyl (2,3,4-Tri-O-benzyl-r-L-fucopyranosyl)-(1f4)-[(2,3,4-tri-
O-benzyl-r-L-fucopyranosyl)-(1f2)-(3,4,6-tri-O-benzyl-â-D-galac-
topyranosyl)-(1f3)]-2-azido-2-deoxy-6-O-pivaloyl-1-thio-r-D-glu-
copyranoside (14). To a solution of sulfoxide 8 (114 mg, 0.210 mmol)
and 2,6-di-tert-butyl-4-methylpyridine (132 mg, 0.630 mmol) in CH2Cl2
(5 mL) at -78 °C was added Tf2O (18 µL, 0.107 mmol), and then the
reaction mixture was warmed to -60 °C. After 15 min of stirring at
-60 °C, nucleophile 13 (41 mg, 0.050 mmol) in CH2Cl2 (3 mL) was
added to the mixture dropwise via syringe. After 10 min of stirring at
-60 °C, the reaction was slowly warmed to -5 °C over 1 h, quenched
by saturated aqueous NaHCO3 (5 mL), and washed with saturated
aqueous NaHCO3 (2 × 100 mL). The organic layer was dried over
Na2SO4, concentrated, and purified by flash chromatography (20%
EtOAc in petroleum ether) to afford tetrasaccharide 14 (64 mg, 82%)
as a white solid: Rf ) 0.37 (20% EtOAc in petroleum ether); 13C NMR
(CDCl3, 68 MHz) δ 177.7, 139.2, 138.8, 138.7, 138.2, 138.1, 137.8,
137.5, 133.1, 132.2, 129.2, 129.0, 128.7, 128.6, 128.4, 128.2, 128.1,
128.0, 127.9, 127.8, 127.7, 127.5, 127.3, 127.2, 127.1, 126.0, 100.7,
98.7, 98.5, 87.0, 83.6, 80.3, 80.1, 78.0, 75.7, 75.2, 74.9, 74.6, 74.5,
74.3, 73.7, 73.6, 73.5, 73.2, 73.0, 72.9, 72.8, 72.4, 71.9, 71.7, 71.0,
70.9, 67.8, 67.2, 66.6, 65.6, 61.5, 38.8, 27.2, 16.3, 16.1; 1H NMR
(CDCl3, 500 MHz) δ 7.5-6.9 (50H, m), 5.66 (1H, d, J ) 2.9Hz), 5.59
(1H, d, J ) 5.5Hz), 4.98-4.34 (22H, m), 4.13-3.56 (17H, m), 3.19
(1H, brs), 1.21 (3H, d, J ) 6.6Hz), 1.16 (3H, d, J ) 6.6Hz), 1.10 (9H,
s).
After 20 min of stirring at 25 °C, the reaction was quenched with MeOH
(1 mL) and concentrated in Vacuo. The residue was purified using
flash chromatography (100% EtOAc) to give 3 mg (11%) of R anomer
15a and 6 mg (23%) of â anomer as white solids. For â-OCH3: Rf )
0.34 (5% MeOH in EtOAc); 13C NMR (CDCl3, 126 MHz) δ 171.0,
170.7, 170.5, 170.3, 170.2, 169.8, 99.6, 99.3, 96.8, 95.4, 74.0, 73.8,
72.4, 71.6, 71.4, 70.9, 70.6, 68.1, 67.8, 67.7, 67.5, 67.3, 64.8, 61.8,
1
60.6, 56.9, 29.7, 23.3, 20.8, 20.7, 16.1, 15.5; H NMR (CDCl3, 500
MHz) δ 6.14 (1H, d, J ) 7.0Hz), 5.42 (1H, d, J ) 3.7Hz), 5.36 (1H,
dd, J ) 3.3Hz), 5.33-5.27 (6H, m), 5.05-4.95 (5H, m), 4.76 (1H, d,
J ) 5.1Hz), 4.71 (1H, q, J ) 6.6Hz), 4.49-4.44 (2H, m), 4,36 (1H,
dd, J ) 5.7, 11.2Hz), 4.17 (1H, dd, J ) 7.6, 11.4Hz), 3.99 (1H, dd, J
) 3.1, 12.3Hz), 3.96-3.85 (3H, m), 3.72 (1H, brd, J ) 9.9Hz), 3.48
(3H, s), 3.47-3.45 (1H, m), 2.17, 2.12, 2.10, 2.08, 2.05, 2.04, 2.01,
2.00, 1.99, 1.96 (33H, m), 1.23 (3H, d, J ) 6.6Hz), 1.17 (3H, d, J )
6.6Hz); HRFABMS calcd for C47H68NO29 (M + H+): 1110.3877, found
1110.3866.
Methyl r-L-Fucopyranosyl-(1f4)-[r-L-fucopyranosyl-(1f2)-â-
D-galactopyranosyl-(1f3)]-2-acetamido-2-deoxy-â-D-glucopyrano-
side (2). To a solution of tetrasaccharide 15b (5 mg, 0.0045 mmol) in
MeOH (5 mL) was added catalytic NaOMe. After 30 min of stirring
at 25 °C, the reaction mixture was neutralized with Dowex 50x8-100
acidic resin. The resin was filtered off, and the filtrate was concentrated
to give 2 (3 mg, 97%) as a white solid: 13C NMR (D2O, 126 MHz,
CH3OH as internal reference) δ 174.1, 103.0, 100.9, 99.9, 98.1, 76.8,
75.7, 75.1, 75.0, 73.9, 72.5, 72.3, 69.7, 69.4, 69.1, 68.6, 68.1, 67.3,
66.5, 61.9, 59.9, 57.5, 55.9, 22.5, 15.7, 15.6; 1H NMR (D2O, 500 MHz)
δ 5.12 (1H, d, J ) 4.3Hz), 4.99 (1H, d, J ) 3.7Hz), 4.82 (1H, q, J )
7.0Hz), 4.62 (1H, d, J ) 8.7Hz), 4.31 (1H, q, J ) 7.0Hz), 4.30 (1H,
d, J ) 8.4Hz), 4.09 (1H, dd, J ) 10.6, 9.2Hz), 3.96 (1H, brd, J )
10.3Hz), 3.90 (1H, dd, J ) 3.3, 10.3Hz), 3.85-3.65 (15H, m), 3.59-
3.52 (3H, m), 3.45 (3H, s), 2.03 (3H, s), 1.23 (6H, d, J ) 7.0Hz);
HRFABMS calcd for C27H47NO19Na (M + Na+) 712.2640, found
712.2611.
Methyl (2,3,4-Tri-O-acetyl-r-L-fucopyranosyl)-(1f4)-[(2,3,4-tri-
O-acetyl-r-L-fucopyranosyl)-(1f2)-(3,4,6-tri-O-acetyl-â-D-galacto-
pyranosyl)-(1f3)]-6-O-acetyl-2-acetamido-2-deoxy-r,â-D-glucopy-
ranoside (15a,b). To a solution of tetrasaccharide 14 (73 mg, 0.044
mmol) in wet CH2Cl2 (10 mL) was added mercury(II) trifluoroacetate
(57 mg, 0.131 mmol). After 20 min of stirring at 25 °C, the reaction
mixture was poured into 1 N aqueous HCl (50 mL). The organic layer
was washed with saturated aqueous NaHCO3 (2 × 100 mL), dried over
Na2SO4, concentrated, and purified by flash chromatography (40%
EtOAc in petroleum ether) to afford the lactol (48 mg, 70%) as a white
solid: Rf ) 0.49 (30% EtOAc in petroleum ether); 13C NMR (CDCl3,
126 MHz) δ 177.9, 139.2, 138.8, 138.7, 138.3, 138.1, 137.8, 137.6,
129.0, 128.7, 128.6, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8,
127.7, 127.5, 127.4, 127.3, 127.2, 127.1, 126.1, 100.7, 98.7, 98.6, 96.4,
91.8, 83.6, 80.3, 80.2, 79.9, 78.0, 77.5, 75.6, 75.3, 75.1, 75.0, 74.7,
74.5, 74.4, 74.3, 74.1, 73.7, 73.1, 73.0, 72.8, 72.6, 72.5, 72.4, 72.2,
71.7, 71.0, 70.1, 68.6, 68.0, 67.8, 67.2, 66.6, 65.4, 60.6, 38.9, 29.7,
Phenyl 2-Azido-2-deoxy-3-O-(4′-methoxybenzyl)-6-O-pivaloyl-1-
thio-r-D-glucopyranoside (16). To a solution of the phenyl 3,4,6-
tri-O-acetyl-2-azido-2-deoxy-1-thio-R-D-glucopyranoside8 (2.4 g, 5.67
mmol) in MeOH (25 mL) was added catalytic amount of NaOMe. After
1 h of stirring, the reaction mixture was neutralized with Dowex 50x8-
100 acidic resin. The resin was filtered off, and the filtrate was
concentrated to give the crude triol as a white residue which was dried
azeotropically by toluene (3 × 10 mL) and taken to next step without
further purification.
1
29.4, 27.2, 16.2; H NMR (CDCl3, 500 MHz) δ 7.4-6.9 (m), 5.64
(1H, d, J ) 3.3 Hz), 5.0-2.7 (m), 1.21 (3H d, J ) 6.2Hz), 1.17 (3H,
d, J ) 6.6Hz), 1.14 (s), 1.12 (s), 1.07 (3H, d, J ) 6.2Hz).
To a solution of the above crude triol (5.67 mmol) and 2,2-
dimethoxypropane (1.4 mL, 11.35 mmol) in DMF (25 mL) was added
catalytic amount of TsOH‚H2O. After 24 h of stirring at 25 °C, the
reaction mixture was neutralized with Amberlite IRA-400(OH). The
resin was filtered off, and the filtrate was concentrated in Vacuo. The
residue was dissolved in CH2Cl2 (50 mL) and washed with saturated
aqueous NaHCO3 (2 × 200 mL). The organic layer was dried over
Na2SO4, concentrated, and purified by flash chromatography (20%
EtOAc in petroleum ether) to afford the ketal (1.3 g, 69%, R/â ) 2.3:
1) as a colorless syrup: Rf ) 0.36 (25% EtOAc in petroleum ether);
13C NMR (CDCl3, 68 MHz) δ 133.4, 133.0, 132.4, 131.0, 129.1, 128.5,
127.9, 100.2, 100.0, 87.7, 86.9, 74.4, 73.0, 71.2, 70.9, 65.3, 64.3,
64.0, 61.8, 61.7, 28.9, 28.8, 19.1, 19.0; 1H NMR (CDCl3, 270 MHz) δ
7.6-7.2 (10H, m), 5.55 (1H, d, J ) 4.9Hz), 4.50 (1H, d, J ) 10.2Hz),
4.25-4.16 (1H, m), 3.99-3.20 (11H, m), 1.53, 1.50, 1.48, 1.43 (4 ×
3H, 4s); HRMS calcd for C15H19O4N3S (M+) 337.1098, found 337.1106.
To a solution of the ketal (462 mg, 1.37 mmol) and p-methoxybenzyl
chloride (380 µL, 2.74 mmol) in DMF (20 mL) at 25 °C was added
NaH (60%, 110 mg, 2.75 mmol). After 1 h of stirring at 25 °C, the
reaction was quenched with MeOH (5 mL) and concentrated in Vacuo.
The residue was dissolved with CH2Cl2 and washed with saturated
aqueous NaHCO3 (2 × 150 mL). The organic layer was dried over
Na2SO4, concentrated, and purified by flash chromatography (10%
EtOAc in petroleum ether) to afford the p-methoxybenzyl ether (459
mg, 73%) as a colorless syrup: Rf ) 0.22 (10% EtOAc in petroleum
ether); 13C NMR (CDCl3, 68 MHz) δ 159.4, 133.1, 132.4, 130.0, 129.9,
129.1, 127.8, 113.8, 99.6, 87.9, 77.7, 75.5, 74.6, 64.7, 63.3, 62.1, 55.2,
29.2, 19.2; 1H NMR (CDCl3, 270 MHz) δ 7.5-6.9 (9H, m), 5.50 (1H,
d, J ) 5.3Hz), 4.78 (2H, dd, J ) 10.6, 34.0Hz), 4.23 (1H, dt, J ) 5.3,
To a solution of the above lactol (48 mg, 0.031 mmol) and
iodomethane (20 µL, 0.321 mmol) in DMF (5 mL) was added NaH
(60%, 6 mg, 0.150 mmol). After 30 min of stirring at 25 °C, the
mixture was diluted with CH2Cl2 and poured into saturated aqueous
NaHCO3 (50 mL). The organic layer was washed with saturated
aqueous NaHCO3 (2 × 100 mL), dried over Na2SO4, concentrated,
and purified by flash chromatography (20% EtOAc in petroleum ether)
to afford the methyl ether (43 mg, 88%) as a white solid: 13C NMR
(CDCl3, 126 MHz) δ 177.7, 139.2, 138.8, 138.6, 138.2, 138.1, 137.8,
137.6, 137.5, 129.0, 128.8, 128.7, 128.6, 128.4, 128.2, 128.1, 128.0,
127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 127.3, 127.2, 127.1, 126.1,
102.9, 100.7, 98.7, 98.6, 98.0, 83.6, 80.3, 79.9, 78.0, 77.2, 75.6, 75.2,
75.0, 74.9, 74.7, 74.5, 74.3, 73.9, 73.6, 73.2, 73.0, 72.9, 72.7, 72.5,
72.3, 71.6, 71.0, 69.6, 68.0, 67.5, 67.1, 66.6, 65.0, 61.0, 57.0, 54.9,
1
38.8, 27.2, 16.2; H NMR (CDCl3, 270 MHz) δ 7.3-6.9 (45H, m),
5.64 (1H, d, J ) 2.6Hz), 5.1-3.1 (26H, m), 1.2-1.0 (15H, m).
To condensed ammonia at -78 °C was added sodium beads until
the dark blue color was sustained. A solution of the above methyl
ether (38 mg, 0.024 mmol) in THF (1 mL) was added to the sodium-
ammonia solution dropwise via syringe over 5 min. After 2 h of stirring
at -78 °C, the reaction was quenched by addition of MeOH (1 mL),
slowly warmed up to room temperature, and dried with stream of argon.
The white residue was dissolved in MeOH (3 mL), cooled to 0 °C,
and neutralized with Dowex 50x8-100 acidic resin. The resin was
filtered, and the filtrate was concentrated, dried azeotropically with
pyridine (3 × 5 mL), and dissolved in pyridine (3 mL). To the mixture
were added Ac2O (57 µL, 0.603 mmol) and DMAP (2 mg, 0.016 mmol).

Synthesis of Blood Group Antigens
J. Am. Chem. Soc., Vol. 118, No. 39, 1996 9247
9.6Hz), 3.9-3.7 (8H, m), 1.52, 1.48 (2 × 3H, 2s); HRMS calcd for
C23H27O5N3S (M+) 457.1673, found 457.1677.
concentrated, and purified by flash chromatography (13% Et2O in
CH2Cl2) to afford the pentaacetate (319 mg, 78% 2 steps) as a white
solid: Rf ) 0.32 (13% Et2O in CH2Cl2); 13C NMR (CDCl3, 68 MHz)
δ 170.3, 170.1, 170.0, 169.4, 159.3, 133.1, 131.7, 129.9, 129.4, 129.1,
127.7, 113.7, 101.0, 86.7, 79.0, 77.9, 75.1, 71.0, 70.8, 69.8, 69.4, 66.6,
63.4, 62.1, 60.4, 55.2, 20.7, 20.6, 20.5; 1H NMR (CDCl3, 500 MHz) δ
7.5-6.8 (9H, m), 5.56 (1H, d, J ) 5.5Hz), 5.36 (1H, d, J ) 3.3Hz),
5.25 (1H, dd, J ) 8.1, 10.3Hz), 5.01-4.97 (2H, m), 4.74 (1H, d, J )
9.9Hz), 4.58 (1H, d, J ) 8.1Hz), 4.40-4.30 (2H, m), 4.24 (1H, dd, J
) 4.6, 11.9H), 4.16 (1H, dd, J ) 7.0, 11.4Hz), 4.20-4.15 (1H, m),
4.07-4.03 (1H, m), 3.93-3.87 (2H, m), 3.83-3.72 (6H, m), 2.17, 2.10,
2.04, 1.99, 1.98 (5 × 3H, 5s); HRFABMS calcd for C36H43O15N3SNa
(M + Na+) 812.2313, found 812.2296.
To a solution of the above p-methoxybenzyl ether (314 mg, 0.69
mmol) in MeOH (10 mL) at 25 °C was added a catalytic amount of
TsOH‚H2O. After 1 h of stirring, the reaction mixture was neutralized
with Amberlite IRA-400(OH). The resin was filtered off, and the
filtrate was concentrated in Vacuo. The residue was purified by flash
chromatography (45% EtOAc in petroleum ether) to afford the diol
(270 mg, 94%) as a colorless syrup: Rf ) 0.43 (50% EtOAc in
petroleum ether); 13C NMR (CDCl3, 68 MHz) δ 159.4, 133.0, 132.3,
129.8, 129.1, 127.8, 114.0, 87.1, 81.0, 75.0, 72.4, 70.4, 63.5, 61.5, 55.1;
1H NMR (CDCl3, 270 MHz) δ 7.5-6.8 (9H, m), 5.45 (1H, d, J )
5.3Hz), 4.85 (1H, d, J ) 10.9Hz), 4.71 (1H, d, J ) 10.9Hz), 4.10 (1H,
m), 3.8-3.6 (8H, m), 3.32 (1H, d, J ) 3.3Hz), 2.52 (1H, m); HRMS
calcd for C20H23O5N3S (M+) 417.1358, found 417.1366.
The above pentaacetate (33 mg, 0.042 mmol) was added into a
solution (5 mL) of 10% trifluoroacetic acid in CH2Cl2 at 25 °C. The
mixture gradually turned dark pink. After 30 min of stirring at 25 °C,
the mixture was diluted with CH2Cl2 (5 mL) and poured into saturated
aqueous NaHCO3 (50 mL). The organic layer was washed with
saturated aqueous NaHCO3 (2 × 50 mL), dried over Na2SO4,
concentrated, and purified by flash chromatography (45% EtOAc in
petroleum ether) to afford 18 (28 mg, 96%) as a white solid: Rf )
0.36 (45% EtOAc in petroleum ether); 13C NMR (CDCl3, 68 MHz) δ
170.5, 170.0, 169.9, 169.5, 132.9, 132.2, 129.1, 127.9, 102.0, 86.4,
83.3, 72.6, 71.5, 70.8, 68.7, 68.2, 66.8, 62.9, 62.6, 62.1, 20.7, 20.6,
To a solution of the above diol (0.688 mmol), 4-dimethylaminopy-
ridine (40 mg, 0.327 mmol), and triethylamine (270 µL, 1.94 mmol)
in CH2Cl2 (5 mL) at 25 °C was added pivaloyl chloride (121 µL, 0.97
mmol) dropwise via syringe. After 2 h of stirring, the reaction was
quenched by MeOH (2 mL) and washed with saturated aqueous
NaHCO3 (3 × 150 mL). The organic layer was dried over Na2SO4,
concentrated, and purified by flash chromatography (20% EtOAc in
petroleum ether) to afford 16 (280 mg, 81%) as a white solid: Rf )
0.44 (25% EtOAc in petroleum ether); 13C NMR (CDCl3, 68 MHz) δ
179.3, 159.6, 133.3, 131.8, 130.0, 129.8, 129.1, 127.7, 114.1, 87.2,
1
20.4; H NMR (CDCl3, 270 MHz) δ 7.5-7.2 (5H, m), 5.51 (1H, d, J
1
) 5.3Hz), 5.41 (1H, d, J ) 3.9Hz), 5.29 (1H, dd, J ) 7.9, 10.6Hz),
5.03 (1H, dd, J ) 3.3, 10.6Hz), 4.64 (1H, d, J ) 1.6Hz), 4.58 (1H, d,
J ) 7.9Hz), 4.50-4.45 (1H, m), 4.23-4.00 (6H, m), 3.83 (1H, dd, J
) 5.3, 10.2Hz), 3.50 (1H, dd, J ) 7.9, 9.9Hz), 2.19, 2.13, 2.09, 2.06,
1.99 (5 × 3H, 5s); HRFABMS calcd for C28H35O14N3S (M+) 669.1839,
found 669.1849.
80.5, 75.2, 71.3, 70.9, 63.5, 63.1, 55.2, 38.9, 27.1; H NMR (CDCl3,
270 MHz) δ 7.5-6.8 (9H, m), 5.56 (1H, d, J ) 5.6Hz), 4.83 (2H, dd,
J ) 10.9, 24.1Hz), 4.44 (1H, dd, J ) 4.6, 11.9Hz), 4.35-4.30 (1H,
m), 4.19 (1H, dd, J ) 2.0, 12.2Hz), 3.86-3.80 (4H, m), 3.65 (1H, dd,
J ) 8.6, 10.2Hz), 3.47-3.39 (1H, m), 2.88 (1H, d, J ) 3.6Hz), 1.18
(9H, s); HRMS calcd for C25H31O6N3S (M+) 501.1935, found 501.1932.
Phenyl (2,3,4,6-Tetra-O-pivaloyl-â-D-galactopyranosyl)-(1f4)-2-
azido-2-deoxy-3-O-(4′-methoxybenzyl)-6-O-pivaloyl-1-thio-r-D-glu-
copyranoside (17). To a solution of sulfoxide 5 (300 mg, 0.481 mmol)
in CH2Cl2 (10 mL) at -78 °C was added Tf2O (40 µL, 0.243 mmol),
and then the reaction mixture was warmed to -60 °C. After 15 min
of stirring at -60 °C, nucleophile 16 (96 mg, 0.192 mmol) and 2,6-
di-tert-butyl-4-methylpyridine (302 mg, 1.44 mmol) in CH2Cl2 (5 mL)
were added to the mixture dropwise via syringe. After 10 min of
stirring at -60 °C, the reaction was slowly warmed to 0 °C over 1 h,
quenched by saturated aqueous NaHCO3 (5 mL), and washed with
saturated aqueous NaHCO3 (2 × 100 mL). The organic layer was dried
over Na2SO4, concentrated, and purified by flash chromatography (15%
EtOAc in petroleum ether) to afford disaccharide 17 (123 mg, 64%)
as a white solid: Rf ) 0.31 (15% EtOAc in petroleum ether); 13C NMR
(CDCl3, 68 MHz) δ 177.8, 177.6, 177.3, 176.8, 176.6, 159.2, 133.4,
131.6, 130.1, 129.5, 129.1, 127.7, 113.7, 100.3, 86.9, 78.5, 77.2, 76.8,
75.1, 71.3, 70.1, 69.2, 66.6, 63.3, 62.2, 61.0, 55.2, 39.0, 38.9, 38.8,
Phenyl (2,3,4,6-Tetra-O-acetyl-â-D-galactopyranosyl)-(1f4)-
[(2,3,4-tri-O-benzyl-r-L-fucopyranosyl)-(1f3)]-6-O-acetyl-2-azido-
2-deoxy-1-thio-r-D-glucopyranoside (19). To a solution of sulfoxide
8 (128 mg, 0.236 mmol) and 2,6-di-tert-butyl-4-methylpyridine (149
mg, 0.711 mmol) in CH2Cl2 (5 mL) at -78 °C was added Tf2O (20
µL, 0.119 mmol), and then the reaction mixture was warmed to -60
°C. After 15 min of stirring at -60 °C, nucleophile 18 (27 mg, 0.040
mmol) in CH2Cl2 (5 mL) was added to the mixture dropwise via syringe.
After 10 min of stirring at -60 °C, the reaction was slowly warmed to
0 °C over 1 h, quenched by saturated aqueous NaHCO3 (5 mL), and
washed with saturated aqueous NaHCO3 (2 × 50 mL). The organic
layer was dried over Na2SO4, concentrated, and purified by flash
chromatography (45% EtOAc in petroleum ether) to afford trisaccharide
19 (36 mg, 83%) as a white solid: Rf ) 0.29 (40% EtOAc in petroleum
ether); 13C NMR (CDCl3, 68 MHz) δ 170.1, 170.0, 169.7, 168.8, 138.9,
138.6, 138.3, 133.3, 131.7, 129.2, 128.3, 128.2, 127.8, 127.6, 127.3,
127.0, 100.7, 98.0, 86.6, 80.0, 76.8, 75.4, 74.0, 73.7, 73.0, 72.6, 70.8,
70.7, 70.1, 68.6, 66.5, 66.3, 64.3, 61.8, 60.4, 60.0, 20.8, 20.6, 20.5,
1
38.7, 27.2, 27.1, 27.04; H NMR (CDCl3, 500 MHz) δ 7.5-6.9 (9H,
1
m), 5.51 (1H, d, J ) 4.8Hz), 5.41 (1H, brd, J ) 2.9Hz), 5.34 (1H, dd,
J ) 8.1, 10.6Hz), 5.10 (1H, d, J ) 10.3Hz), 5.05 (1H, dd, J ) 3.3,
10.6Hz), 4.68 (1H, d, J ) 10.6Hz), 4.62 (1H, d, J ) 8.1Hz), 4.33-
4.30 (2H, m), 4.24 (1H, dd, J ) 4.6, 11.9Hz), 4.16 (1H, dd, J ) 7.0,
11.4Hz), 4.03 (1H, dd, J ) 7.0, 11.0Hz), 3.95-3.89 (2H, m), 3.82-
3.73 (5H, m), 1.21, 1.20, 1.17, 1.16, 1.12 (5 × 9H, 5s); HRFABMS
calcd for C51H72O15N3S (M + Na+) 1022.4660, found 1022.4670.
Phenyl (2,3,4,6-Tetra-O-acetyl-â-D-galactopyranosyl)-(1f4)-6-O-
acetyl-2-azido-2-deoxy-1-thio-r-D-glucopyranoside (18). To a solu-
tion of disaccharide 17 (518 mg, 0.519 mmol) in MeOH (5 mL) was
added excess LiOH‚H2O. After the solution was stirred overnight at
25 °C, the reaction mixture was neutralized with Dowex 50x8-100
acidic resin. The resin was filtered off, and the filtrate was concentrated
to produce the crude pentaol as a white residue which was dried
azeotropically by toluene (3 × 5 mL) and taken to next step without
further purification.
16.8; H NMR (CDCl3, 500 MHz) δ 7.5-7.2 (20H, m), 5.65 (1H, d,
J ) 5.5Hz), 5.42 (1H, d, J ) 3.7Hz), 5.35 (1H, d, J ) 2.6Hz), 5.11
(1H, dd, J ) 8.2, 10.4Hz), 4.97 (1H, d, J ) 12.1Hz), 4.93 (1H, dd, J
) 3.3, 10.6Hz), 4.91-4.68 (5H, m), 4.66 (1H, d, J ) 6.6Hz), 4.48
(1H, d, J ) 8.1Hz), 4.47 (1H, m), 4.33 (1H, m), 4.21-4.03 (5H, m),
3.93 (1H, dd, J ) 2.6, 10.3Hz), 3.86-3.81 (3H, m), 3.73 (1H, brs),
2.06, 2.05, 2.02, 1.95, 1.82 (5 × 3H, 5s), 1.27 (3H, d, J ) 6.6Hz);
HRFABMS calcd for C55H63O18N3SNa (M + Na+) 1108.3725, found
1108.3783.
Methyl (2,3,4,6-Tetra-O-acetyl-â-D-galactopyranosyl)-(1f4)-
[(2,3,4-tri-O-acetyl-r-L-fucopyranosyl)-(1f3)]-2-acetamido-6-O-
acetyl-2-deoxy-r,â-D-glucopyranoside (20a,b). To a solution of
trisaccharide 19 (105 mg, 0.097 mmol) in wet CH2Cl2 (10 mL) was
added mercury(II) trifluoroacetate (199 mg, 0.457 mmol). After 20
min of stirring at 25 °C, the mixture was poured into 1 N aqueous HCl
(50 mL). The organic layer was washed with saturated aqueous
NaHCO3 (2 × 100 mL), dried over Na2SO4, concentrated, and purified
by flash chromatography (40% EtOAc in petroleum ether) to afford
the lactol (74 mg, 77%) as a white solid: Rf ) 0.39 (55% EtOAc in
petroleum ether); 13C NMR (CDCl3, 68 MHz) δ 170.3, 170.0, 169.8,
169.7, 168.8, 139.0, 138.9, 138.5, 138.2, 128.5, 128.4, 128.3, 128.2,
128.1, 127.6, 127.5, 127.3, 127.0, 100.6, 97.4, 96.6, 91.9, 80.0, 79.9,
75.5, 74.9, 74.1, 73.4, 73.3, 72.8, 71.5, 70.8, 70.7, 70.6, 69.1, 68.6,
To the above crude pentaol (0.067 mmol) and 4-dimethylaminopy-
ridine (32 mg, 0.262 mmol) in pyridine (10 mL) at 25 °C was added
acetic anhydride (493 µL, 5.19 mmol) dropwise via syringe. After 2
h of stirring at 25 °C, the reaction mixture was quenched with MeOH
(1 mL) and concentrated in Vacuo. The residue was dissolved in
CH2Cl2, washed with 1 N aqueous HCl (50 mL), and saturated aqueous
NaHCO3 (3 × 50 mL). The organic layers were dried over Na2SO4,

9248 J. Am. Chem. Soc., Vol. 118, No. 39, 1996
Yan and Kahne
67.2, 66.43, 66.3, 66.2, 64.1, 61.6, 61.5, 59.9, 20.8, 20.6, 20.5, 16.7;
1H NMR (CDCl3, 500 MHz) δ 7.5-7.2 (15H, m), 5.54 (0.5H, d, J )
4.0Hz), 5.36-5.33 (1.5H, m), 5.11-4.57 (11H, m), 4.52 (0.5H, d, J )
8.1Hz), 4.49 (0.5H, d, J ) 8.1Hz), 4.18-3.82 (7.5H, m), 3.72 (1H, s),
3.65 (1H, t, J ) 9.4Hz), 3.51 (1H, dd, J ) 8.1, 9.9Hz), 3.46-3.41
(1.5H, m), 2.10, 2.04, 2.02, 2.01, 2.00, 1.95, 1.94, 1.81 (15H, s), 1.25
(1H, d, J ) 6.2Hz); HRFABMS calcd for C49H59N3O19 (M+) 993.3743,
found 993.3749.
To a solution of the above lactol (27 mg, 0.027 mmol) and
iodomethane (17 µL, 0.272 mmol) in DMF (5 mL) was added NaH
(60%, 5 mg, 0.125 mmol). After 1 h of stirring at 25 °C, the mixture
was diluted with CH2Cl2 and poured into saturated aqueous NaHCO3
(50 mL). The organic layer was washed with saturated aqueous
NaHCO3 (2 × 100 mL), dried over Na2SO4, concentrated, and purified
by flash chromatography (55% EtOAc in petroleum ether) to afford
the methyl ether (25 mg, 92%) as a white solid.
11.0Hz), 5.11 (1H, dd, J ) 8.1, 10.3Hz), 5.04-4.99 (2H, m), 4.73
(1H, q, J ) 6.6Hz), 4.60 (1H, dd, J ) 3.3, 12.1Hz), 4.55 (1H, d, J )
6.6Hz), 4.47 (1H, d, J ) 8.1Hz), 4.45 (1H, dd, J ) 6.2, 11.7Hz), 4.28
(1H, dd, J ) 7.7, 11.4Hz), 4.21 (1H, dd, J ) 5.0, 11.9Hz), 4.09 (1H,
dd, J ) 7.7, 8.1Hz), 3.88 (1H, dd, J ) 7.0, 7.3Hz), 3.85 (1H, t, J )
7.7Hz), 3.82-3.75 (1H, m), 3.63-3.60 (1H, m), 3.43 (3H, s), 2.20,
2.15, 2.14, 2.11, 2.08, 2.07, 2.00, 1.99, 1.97 (9 × 3H, 9s), 1.21 (3H, d,
J ) 6.6Hz); HRFABMS calcd for C37H54NO23 (M + H+) 880.3087,
found 880.3115.
Methyl â-D-Galactopyranosyl-(1f4)-[r-L-fucopyranosyl-(1f3)]-
2-acetamido-2-deoxy-â-D-glucopyranoside (3). To a solution of
trisaccharide 20b (5 mg, 0.0057 mmol) in MeOH (5 mL) was added
NaOMe (1 mg, 0.019 mmol). After 30 min of stirring at 25 °C, the
reaction mixture was neutralized with Dowex 50x8-100 acidic resin.
The resin was filtered off, and the filtrate was concentrated to give 3
(3 mg, 97%) as a white solid: 13C NMR (D2O, 126 MHz, CH3OH as
internal reference) δ 174.8, 102.2, 102.1, 99.0, 75.7, 75.3, 75.2, 73.7,
72.7, 72.2, 71.3, 69.5, 68.6, 68.0, 67.0, 61.8, 60.0, 57.5, 55.9, 22.5,
15.6; 1H NMR (D2O, 500 MHz) δ 5.08 (1H, d, J ) 4.0Hz), 4.82-4.78
(1H, m), 4.45 (1H, d, J ) 8.4Hz), 4.43 (1H, d, J ) 8.1Hz), 3.99 (1H,
brd, J ) 10.3Hz), 3.93-3.82 (6H, m), 3.77 (1H, d, J ) 2.9Hz), 3.72-
3.65 (3H, m), 3.64 (1H, dd, J ) 3.7, 9.9Hz), 3.59-3.54 (2H, m), 3.49-
3.46 (4H, m), 2.01 (3H, s), 1.16 (3H, d, J ) 6.6Hz); HRFABMS calcd
for C21H37NO15Na (M + Na+) 566.2061, found 566.2080.
The above methyl ether (28 mg, 0.028 mmol) was dissolved in
EtOAc (5 mL) and stirred vigorously under hydrogen (1 atm) with the
Lindlar catalyst (100 mg). After the reaction was conducted overnight,
the catalyst was filtered off and the filtrate was concentrated. Then,
the residue was dissolved in EtOAc (5 mL) and stirred vigorously under
hydrogen (1 atm) with palladium on charcoal (100 mg). After 8 h of
stirring at 25 °C, the catalyst was filtered off and the filtrate was
concentrated. To a solution of the residue in CH2Cl2 (5 mL) were
added Ac2O (27 µL, 0.28 mmol), DMAP (2 mg, 0.016 mmol), and
Et3N (58 µL, 0.42 mmol). After 10 min of stirring at 25 °C, the reaction
was quenched with MeOH (1 mL) and concentrated in Vacuo. The
residue was purified by flash chromatography (100% EtOAc) to afford
8 mg (33%) of â anomer 20b and 5 mg (20%) of R anomer 20a as
white solids. For â anomer: Rf ) 0.30 (100% EtOAc); 13C NMR
(CDCl3, 126 MHz) δ 171.0, 170.7, 170.6, 170.5, 170.4, 170.0, 169.9,
169.4, 100.9, 100.3, 94.8, 74.2, 72.7, 72.4, 71.2, 71.1, 70.7, 68.8, 68.1,
68.0, 66.6, 64.4, 62.3, 60.7, 56.6, 54.2, 29.7, 23.4, 20.9, 20.8, 20.7,
Acknowledgment. This work was supported by the Office
of Naval Research.
Supporting Information Available: 1H and 13C NMR
spectra for 1-9, 10b, 11-14, 15b, 16-19, and 20b (46 pages).
See any current masthead for ordering and Internet access
instructions.
1
20.6, 15.9; H NMR (CDCl3, 500 MHz) δ 5.63 (1H, d, J ) 8.8Hz),
5.43-5.42 (2H, m), 5.36 (1H, d, J ) 2.6Hz), 5.20 (1H, dd, J ) 3.3,
JA9608555