Synthesis of a thio-analogue of Lewis X by regioselective opening of cyclic sulfamidates

Full text of DOI:10.1021/jo971784a

J . Org. Chem. 1998, 63, 2719-2723
2719
Sch em e 1
Syn th esis of a Th io-An a logu e of Lew is X by
Regioselective Op en in g of Cyclic
Su lfa m id a tes
Begon˜a Aguilera and Alfonso Ferna´ndez-Mayoralas*
Instituto de Quı´mica Orga´nica General, CSIC,
J uan de la Cierva, 3, E-28006 Madrid, Spain
Received September 25, 1997
Lewis X (Lex) trisaccharide 1 present at the termini of
Lex-bearing glycoconjugates plays a major role in biologi-
cally important functions. For instance, Lex-Lex interac-
tion mediates cell-cell adhesion during embryogenesis.1
The tetrasaccharide sialyl Lex is involved in the acute
inflammatory process2 and has been found in tumor cells
and carcinomas.3 Besides, we have reported4 that some
oligosaccharides related to Lex are inhibitors of neural
cell division. Owing to the important biological interest
of this trisaccharide, we planned to prepare the thio-
trisaccharide 2 analogue of Lex containing a sulfur atom
linking the fucosyl and glucosaminyl moieties. Since
thioglycosides have been proven to be resistant to gly-
cosidase enzymes,5 compound 2 will be more stable for
in vivo experiments.
corresponding alcohol. To circumvent this problem, we
have recently described7a the formation of cyclic sulfa-
midate 5 and its use7b in nucleophilic displacements to
get 3-thio and 3-azido glucosamine derivatives. For
instance, the treatment of 5 with fucose thiolate 6
furnished the thiodisaccharide 7 in good yield (Scheme
1). In the present work we report the application of this
method to accomplish an efficient synthesis of 2.
For building the target molecule 2, we first tried to use
diol 8 (Scheme 2), obtained7b by acid hydrolysis of the
benzylidene acetal in 7, containing the thiofucosyl resi-
due. Compound 8 was selectively acetylated at the C-6
hydroxyl to afford 9 (82%). Next, we attempted the
galactosylation of 9 using trichloroacetimidate 11. Both
TMS-triflate and BF3 etherate were used as promotors.8
We observed rapid consumption of 11 but were unable
to detect any glycosylation product. Similar results were
obtained when the galactosylation was tried with bro-
mide 12 and fluoride 13 in the presence of AgOTf9 and
BF3 etherate10 as promotors, respectively. To evaluate
if the reactivity of 4-hydroxyl group of 9 could be
influenced11 by the nature of substituent at vicinal C-6
position, the p-methoxyphenyl derivative 10, prepared
from 8 in a Mitsunobu-type reaction (95%), was subjected
to galactosylation. Again no glycosylation product was
detected. The sulfoxide glycosylation method, which has
been successfully used with unreactive alcohols,12 was
next tried. The reaction of 10 with sulfoxide 14 in the
presence of Tf2O (2 equiv) did not afford the desired
glycoside; instead a new compound was formed which
was identified13 as the oxazine 15. The formation of 15
could be explained by the initial triflation of the aceta-
mido group of 10 followed by intramolecular triflate
displacement by the 4-hydroxyl, as outlined in Scheme
3.14
Several methods have been published6 for the synthesis
of thiooligosaccharides. Most of them involved SN2-type
substitutions of thiolate anions on glycosyl halides, or of
1-thio-donors on acceptors bearing good leaving groups.
Applied to the formation of the 3-S-fucosyl linkage in 2,
both approaches require a nucleophilic displacement of
a leaving group at C-3 of an allosamine derivative with
a sulfur nucleophile (Scheme 1). However, the presence
of the acetamido group at the adjacent C-2 position can
lead to secondary reactions, such as the formation of
oxazoline 4. In fact, 4 was obtained7 when the prepara-
tion of triflate 3 was attempted by triflation of the
(1) (a) Eggens, I.; Fenderson, B. A.; Toyokuni, T.; Dean, B.; Stroud,
M. R.; Hakomori, S. J . Biol. Chem. 1989, 264, 9476-9484. (b) Kojima,
N.; Fenderson, B. A.; Stroud, M. R.; Goldberg, R. I.; Habermann, R.;
Toyokuni, T.; Hakomori, S. Glycoconj. J . 1994, 11, 238-248.
(2) Lasky, L. A. Science 1992, 258, 964-969.
(3) Fukushima, K.; Hirota, M.; Terasaki, P. I.; Wakisaka, A.;
Togashi, H.; Chia, D.; Suyama, N.; Fukushi, Y.; Nudelman, E.;
Hakomori, S. Cancer Res. 1984, 44, 5279-5285.
(4) (a) Santos-Benito, F. F.; Ferna´ndez-Mayoralas, A.; Mart´ın-
Lomas, M.; Nieto-Sampedro, M. J . Exp. Med. 1992, 176, 915-918. (b)
Cotero´n, J . M.; Kamaljit, S.; Asensio, J . L.; Dom´ınguez-Dalda, M.;
Ferna´ndez-Mayoralas, A.; J ime´nez-Barbero, J .; Mart´ın-Lomas, M.;
Abad-Rodr´ıguez, J .; Nieto-Sampedro, M. J . Org. Chem. 1995, 60, 1502-
1519. (c) Nieto-Sampedro, M.; Bailo´n, C.; Ferna´ndez-Mayoralas, A.;
Mart´ın-Lomas, M.; Mellstrom, B.; Naranjo, J . R. J . Neuropath. Exp.
Neur. 1996, 55, 169-177.
At this point, we changed our strategy to assemble the
target molecule 2. The galactose and allosamine deriva-
(8) Schmidt, R. R. Adv. Carbohydr. Chem. Biochem. 1994, 50, 21-
153.
(9) J acquinet, J .-C.; Sinay, P. Carbohydr. Res. 1976, 46, 138-142.
(10) Kunz, H.; Sager, W. Helv. Chim. Acta 1985, 68, 283-287.
(11) (a) Sinay, P. Pure Appl. Chem. 1978, 50, 1437-1452. (b)
Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155-173.
(12) Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J . Am. Chem.
Soc. 1989, 111, 6881-6882.
(5) Defaye, J .; Gelas, J . In Studies in Natural Products Chemistry;
Atta-ur-Rahman Ed.; Elsevier: Amsterdam, 1991; Vol. 8, pp 315-357.
(6) Driguez, H. Top. Curr. Chem. 1997, 187, 85-116.
(7) (a) Aguilera, B.; Ferna´ndez-Mayoralas, A. Chem. Commun. 1996,
127-128. (b) Aguilera, B.; Ferna´ndez-Mayoralas, A.; J aramillo, C.
Tetrahedron 1997, 53, 5863-5876.
(13) See Supporting Information for details.
S0022-3263(97)01784-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/19/1998

2720 J . Org. Chem., Vol. 63, No. 8, 1998
Notes
Sch em e 2a
appreciably the reactivity of the hydroxyl at C-4. The
synthesis toward 2 was then continued using disaccha-
ride 22. Deallylation of 22 gave alcohol 23 which was
transformed into the sulfamidate 24 using the two-step
procedure,15 i.e. reaction with thionyl chloride followed
by oxidation. The regioselective opening of 24 with fucose
1-thiolate 6 took place smoothly and furnished thio-
trisaccharide 25 in 77% yield. Two subsequent depro-
tection steps led to target trisaccharide 2, which was
characterized by applying various NMR techniques.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are not corrected. TLC
was performed using TLC plates GF254 with detection by
charring with 5% H2SO4 in EtOH. Column chromatography was
performed on silica gel (230-400 mesh) or sep-pack C18
cartridges. The eluent used is indicated and solvent ratios refer
to volume. Solvents were distilled over drying agents: dime-
thylformamide (DMF), BaO; dichloromethane (DCM), CaH2;
tetrahydrofuran (THF), sodium/benzophenone ketyl; and pyri-
dine (Py), BaO. 1H NMR spectra were registered at 500, 400,
300, or 200 MHz. 13C NMR spectra were obtained at 125, 75,
or 50 MHz.
Ben zyl S-(2,3,4-Tr i-O-a cetyl-r-L-fu cop yr a n osyl)-(1f3)-2-
a ce t a m id o-6-O-a ce t yl-2-d e oxy-3-t h io-â-D -glu cop yr a n o-
sid e (9). To a stirred solution of 87b (155 mg, 0.26 mmol) in
DCM (2 mL) under Ar at -78 °C were added collidine (68.7 µL,
0.52 mmol) and then acetyl chloride dropwise (22.2 µL, 0.31
mmol). After stirring for 3 h at -50 °C, the reaction mixture
was diluted with DCM (25 mL), washed with sat. NaHCO3
solution (25 mL), aq HCl 10% (25 mL), and brine (25 mL), dried
(Na2SO4), and evaporated. The residue was purified by column
chromatography (EtOAc-hexane 2:1) to yield 9 (139 mg, 82%)
as a white solid: mp 102-105 °C; [R]D -156.9° (c 1.5, CHCl3);
1H NMR (CDCl3) δ 7.35-7.27 (m, 5H), 5.74 (d, 1H, J ) 5.0 Hz),
5.50 (d, 1H, J ) 8.0 Hz), 5.28 (dd, 1H, J ) 3.0 Hz, J ) 1.2 Hz),
5.21-5.10 (m, 2H), 4.86 (d, 1H, J ) 11.9 Hz), 4.80 (d, 1H, J )
7.7 Hz), 4.60-4.56 (m, 2H), 4.41-4.39 (m, 2H), 3.57 (m, 1H),
3.54-3.24 (m, 4H), 2.15 (s, 3H), 2.13 (s, 3H), 2.06 (s, 3H), 1.99
(s, 3H), 1.95 (s, 3H), 1.16 (d, 1H, J ) 6.4 Hz); 13C NMR (50 MHz,
CDCl3) δ 171.29, 170.36, 170.26, 169.77, 137.18, 128.46, 128.00,
99.90, 83.22, 78.69, 76.22, 70.76, 70.61, 69.59, 68.19, 68.02, 65.81,
63.64, 56.37, 52.24, 23.42, 20.87, 20.76, 20.59, 20.53, 15.92.
Anal. Calcd for C29H39NO13S: C, 54.28; H, 6.13; N, 2.18; S, 5.0.
Found: C, 54.50; H, 6.10; N, 2.18; S, 4.78.
Sch em e 3
Ben zyl S-(2,3,4-Tr i-O-a cetyl-r-L-fu cop yr a n osyl)-(1f3)-2-
a ceta m id o-2-d eoxy-6-O-(p-m eth oxyp h en yl)-3-th io-â-D-glu -
cop yr a n osid e (10). To a stirred solution of 8 (200 mg, 0.33
mmol), triphenylphosphine (131 mg, 0.5 mmol), and p-methoxy-
phenol (124 mg, 1 mmol) in THF (3 mL) at 70 °C under Ar was
added dropwise diisopropyl azodicarboxylate (98.64 µL, 0.5
mmol), and the mixture was stirred at 70 °C for 3 h. After
cooling, the solvent was evaporated under reduced pressure, and
the residue purified by column chromatography (toluene-
acetone 3:1) to give 10 (223 mg, 95%) as a white solid: mp 89-
93 °C; [R]D -140.3° (c 1.4, CHCl3); 1H NMR (CDCl3) δ 7.35-
7.25 (m, 5H), 7.19-6.81 (m, 4H), 5.75 (d, 1H, J ) 5.2 Hz), 5.68
(d, 1H, J ) 8.3 Hz), 5.28 (dd, 1H, J ) 2.8 Hz, J ) 1.1 Hz), 5.21-
5.10 (m, 2H), 4.84 (d, 1H, J ) 11.9 Hz), 4.75 (d, 1H, J ) 7.9 Hz),
4.62-4.55 (m, 2H), 4.30 (dd, 1H, J ) 2.4 Hz, J ) 10.6 Hz), 4.16
(dd, 1H, J ) 5.5 Hz, J ) 10.6 Hz), 3.76 (s, 3H), 3.69 (m, 1H),
3.59-3.49 (m, 2H), 3.34-3.26 (m, 2H), 2.15 (s, 3H), 2.05 (s, 3H),
1.99 (s, 3H), 1.93 (s, 3H) 1.16 (d, 1H, J ) 6.4 Hz); 13C NMR
(CDCl3) δ 170.40, 170.29, 170.22, 169.80, 152.89, 137.18, 128.39,
128.15, 127.89, 115.95, 114.54, 99.79, 83.40, 77.42, 70.53, 70.47,
70.18, 68.75, 68.14, 67.91, 65.68, 56.06, 55.65, 52.84, 20.71, 20.54,
20.48, 15.84. Anal. Calcd for C34H43NO13S: C, 57.86; H, 6.14;
N, 1.98; S, 4.54. Found: C, 57.58; H, 6.07; N, 2.02; S, 4.28.
Ben zyl 2-Acetam ido-3-O-allyl-4,6-O-ben zyliden e-2-deoxy-
â-D-a llop yr a n osid e (17). Compound 167b (3 g, 7.52 mmol) was
tives should be linked first to give a â(1f4) disaccharide,
which after transformation into a cyclic sulfamidate and
subsequent treatment with a fucose thiolate should
furnish the desired thiotrisaccharide (Scheme 4). Thus,
allylation of 16, followed by acid hydrolysis of the
benzylidene acetal, and selective benzoylation gave 19
through intermediates 17 and 18. Glycosylation of 19
with donor 11 in the presence of TMSOTf for 8 h gave
the desired disaccharide 21 but in low yield (26%),
together with the orthodisaccharide 26 (29%) and recov-
ered acceptor 19 (18%). Longer reaction times gave no
improvement in the yield of 21. A significant increase
in yield, however, was obtained when the glycosylation
was performed on the monosaccharide 20. Disaccharide
22 was isolated in 63% yield together with orthodisac-
charide 27 (8%) and recovered acceptor 20 (7%). In this
case, the change of the substituent benzoyl group at O-6
of the acceptor by a p-methoxyphenyl group influenced
(14) An alternative mechanism could be envisaged through the
initial triflation of the 4-hydroxyl of 10 followed by intramolecular
triflate displacement by the acetamido group, proceeding with retention
of the configuration at C-4 via a 3,4-episulfonium ion. However, the
fact that oxazoline 4 was formed when alcohol 16 was treated with
Tf2O (ref 7) could support the mechanism depicted in Scheme 3.
(15) (a) Alker, D.; Doyle, K. J .; Harwood: L. N.; McGregor, A.
Tetrahedron: Asymmetry 1990, 1, 877-880. (b) Baldwin, J . E.; Spivey,
A. C.; Schofiel, C. J . Tetrahedron: Asymmetry 1990, 1, 881-884.

Notes
J . Org. Chem., Vol. 63, No. 8, 1998 2721
Sch em e 4a
suspended in DMF (40 mL), and NaH (270 mg, 11.27 mmol) was
carefully added at 0 °C. The mixture was stirred at this
temperature under Ar for 5 min, and then dropwise addition of
allyl bromide (0.78 mL, 9.02 mmol) was made. The reaction
mixture was stirred at room temperature for 1 h and cooled at
0 °C, and MeOH (5 mL) was added carefully. Solvents were
evaporated, and the residue was purified by column chroma-
tography (DCM-EtOAc 10:1) to give 17 (3.23 g, 98%) as a white
solid: mp 225-228 °C; [R]D -124.6° (c 1, CHCl3); 1H NMR
(CDCl3) δ 7.50-7.29 (m, 10H), 5.92-5.80 (m, 1H), 5.73 (d, 1H,
J ) 9.3 Hz), 5.51 (s, 1H), 5.31-5.15 (m, 2H), 4.92 (d, 1H, J )
12.4 Hz), 4.67 (d, 1H, J ) 8.6 Hz), 4.58 (d, 1H, J ) 12.4 Hz),
4.49-4.39 (m, 1H), 4.39 (dd, 1H, J ) 4.9 Hz, J ) 9.7 Hz), 4.24
(dt, 1H, J ) 3.1 Hz, J ) 8.9 Hz), 4.11-3.96 (m, 3H), 3.79 (t, 1H,
J ) 10.1 Hz), 3.73 (dd, 1H, J ) 2.2 Hz, J ) 9.4 Hz), 1.98 (s, 3H);
13C NMR (CDCl3) δ 169.87, 138.11, 138.00, 135.22, 129.69,
128.96, 128.89, 128.29, 128.17, 126.71, 117.84, 102.58, 100.0,
80.70, 76.37, 74.08, 71.07, 69.79, 64.27, 52.58, 23.99. Anal.
Calcd for C25H29NO6: C, 68.32; H, 6.65; N, 3.19. Found: C,
68.64; H, 6.78; N, 3.25.
Ben zyl 2-Acet a m id o-3-O-a llyl-2-d eoxy-â-D-a llop yr a n o-
sid e (18). A mixture of 17 (2.84 g, 6.47 mmol) and camphor-
sulfonic acid (300.5 mg, 1.29 mmol) in MeOH (90 mL) was stirred
at 60 °C for 1 h. After cooling at room temperature, the reaction
mixture was neutralized with triethylamine (1 mL) and evapo-
rated to dryness. Column chromatography (DCM-MeOH 15:
1) of the residue gave 18 (2.07 g, 91%) as a white solid: mp 136-
140 °C; [R]D -87.7° (c 0.8, MeOH). 1H NMR (CD3OD) δ 7.54-
7.42 (m, 5H), 6.24-6.11 (m, 1H), 5.46-5.31(m, 2H), 5.08 (d, 1H,
J ) 11.8 Hz), 4.97 (d, 1H, J ) 8.3 Hz), 4.76 (d, 1H, J ) 11.7 Hz),
4.55-4.48 (m, 1H), 4.34-4.27 (m, 1H), 4.09-3.81 (m, 6H), 2.15
(s, 3H); 13C NMR (CD3OD) δ 172.87, 139.20, 136.66, 129.34,
129.23, 128.96, 128.81, 128.59, 117.39, 99.85, 79.13, 76.17, 75.79,
71.57, 69.57, 63.09, 54.53, 22.60. Anal. Calcd for C18H25NO6:
C, 61.52; H, 7.17; N, 3.99. Found: C, 61.20; H, 7.13; N, 3.97.
Ben zyl 2-Aceta m id o-3-O-a llyl-6-O-ben zoyl-2-d eoxy-â-D-
a llop yr a n osid e (19). To a solution of 18 (800 mg, 2.28 mmol)
in DCM-Py 1:1 (22 mL) at -20 °C under Ar was added dropwise
benzoyl chloride (0.32 mL, 2.73 mmol), and the reaction mixture
was stirred at this temperature for 1 h. Then, the reaction
mixture was quenched with MeOH (1 mL) and evaporated under
reduced pressure. The residue was coevaporated with toluene
(3 × 20 mL) and subjected to flash chromatography (hexane-
acetone 3:2) to yield 19 (940 mg, 91%) as a white solid: mp 167-
169 °C; [R]D -103.2° (c 0.5, CHCl3); 1H NMR (CDCl3) δ 8.10-
7.27 (m, 10H), 5.97-5.83 (m, 2H), 5.30-5.17 (m, 2H), 4.86 (d,
1H, J ) 12.2 Hz), 4.70 (d, 1H, J ) 7.3 Hz), 4.68 (dd, 1H, J ) 4.8
Hz, J ) 11.9 Hz), 4.61 (dd, 1H, J ) 3.5 Hz, J ) 11.9 Hz), 4.58
(d, 1H, J ) 12.2 Hz), 4.31-4.24 (m, 1H), 4.19-4.11 (m, 2H),
4.06-4.00 (m, 2H), 3.78 (dd, 1H, J ) 2.93 Hz, J ) 8.3 Hz), 1.98
(s, 3H); 13C NMR (CDCl3) δ 170.67, 166,84, 137.08, 134.48,
129.60, 129.41, 128.19, 128.08, 127.62, 127.51, 125.67, 117.01,
98.19, 76.91, 73.98, 72.71, 70.07, 67.96, 64.39, 52.13, 22.52.
Anal. Calcd for C25H29NO7: C, 65.92; H, 6.42; N, 3.07. Found:
C, 66.13; H, 6.51; N, 3.09.
Ben zyl 2-Aceta m id o-3-O-a llyl-2-d eoxy-6-O-(p-m eth oxy-
p h en yl)-â-D-a llop yr a n osid e (20). To a mixture of 18 (823 mg,
2.34 mmol), triphenylphosphine (1.22 g, 4.68 mmol), and p-
methoxyphenol (581 mg, 4.68 mmol) in THF (23.4 mL) at 70 °C
under Ar was added dropwise diisopropyl azodicarboxylate (0.92
mL, 4.68 mmol), and the mixture was stirred at this temperature
for 1 h. After cooling, the solvent was evaporated under reduced
pressure and the residue purified by column chromatography
(EtOAc) to give 20 (964 mg, 90%) as a white solid: mp 167-169
°C; [R]D -83.7° (c 0.5, CHCl3); 1H NMR (CDCl3) δ 7.38-7.26 (m,
5H), 6.81 (s, 4H), 6.04 (d, 1H, J ) 8.3 Hz), 5.96-5.83 (m, 1H),
5.29-5.18 (m, 2H), 4.84 (d, 1H, J ) 12.1 Hz), 4.76 (d, 1H, J )
6.3 Hz), 4.59 (d, 1H, J ) 12.1 Hz), 4.29-4.22 (m, 1H), 4.20-
4.09 (m, 5H), 4.03 (t, 1H, J ) 3.3 Hz), 3.95 (dt, 1H, J ) 6.2 Hz,
J ) 3.2 Hz), 2.48 (d, 1H, J ) 6.2 Hz), 1.99 (s, 3H); 13C NMR
(CDCl3) δ 170.70, 153.74, 152.78, 137.18, 134.44, 128.11, 127.64,
127.52, 117.06, 115.59, 114.40, 98.45, 75.91, 73.89, 73.43, 70.11,
68.73, 68.02, 55.48, 51.81, 22.59. Anal. Calcd for C25H31NO7:
C, 65.63; H, 6.83; N, 3.06. Found: C, 65.71; H, 7.02; N, 3.18.
Ben zyl O-(2,3,4,6-Tetr a-O-ben zoyl-â-D-galactopyr an osyl)-
(1f4)-2-a cet a m id o-3-O-a llyl-6-O-b en zoyl-2-d eoxy-â-D-a l-
lop yr a n osid e (21). A mixture of 19 (30 mg, 0.066 mmol) and
2,3,4,6-tetra-O-benzoyl-R/â-D-galactopyranosyl trichloroacetimi-
date (73 mg, 0.099 mmol) and 4 Å molecular sieves (ca. 30 mg)
in DCM (1.5 mL) under Ar was stirred at room temperature for
30 min. Then, a solution of trimethylsilyl triflate in DCM (0.1
M, 99 µL, 0.0099 mmol) was added dropwise at room tempera-
ture, and the reaction mixture was stirred under Ar. After 1 h,
more trimethylsilyl triflate (0.1 M in DCM, 66 µL, 0.066 mmol)
was added and the reaction was stirred for 9 h. Triethylamine
was added, and the mixture was filtered through Celite and

2722 J . Org. Chem., Vol. 63, No. 8, 1998
Notes
concentrated. The residue was purified by column chromatog-
raphy (hexane-EtOAc 2:1fEtOAc) to give 26 (19 mg, 29%), 21
(17 mg, 26%) and recovered 19 (5 mg, 18%).
Ar, and the reaction was stirred for 2 h at room temperature.
Water (2.8 mL) and I2 (174.5 mg, 0.68 mmol) were added, and
the mixture was stirred for 3 h. DCM (30 mL) was added, and
the crude was washed with Na2S2O3 10% (2 × 30 mL) and then
with water (30 mL), dried (Na2SO4), and concentrated. Column
chromatography (hexane-EtOAc 1:1) of the residue gave 23 (529
mg, 82%). Mp 103-106 °C; [R]D +42.2° (c 2.4, CHCl3); 1H NMR
(CDCl3) δ 7.99-7.12 (m, 25H), 6.57-6.40 (m, 4H), 5.92 (d, 1H,
J ) 3.4 Hz), 5.84 (d, 1H, J ) 9.5 Hz), 5.72 (dd, 1H, J ) 7.9 Hz,
J ) 10.5 Hz), 5.50 (dd, 1H, J ) 3.5 Hz, J ) 10.5 Hz), 4.88 (d,
1H, J ) 7.9 Hz), 4.73 (d, 1H, J ) 12.3 Hz), 4.57 (d, 1H, J ) 7.8
Hz), 4.51 (dd, 1H, J ) 4.6 Hz, J ) 11.6 Hz), 4.46 (d, 1H, J )
12.4 Hz), 4.39 (dd, 1H, J ) 5.4 Hz, J ) 11.5 Hz), 4.30 (m, 2H),
4.19 (m, 1H), 3.95-3.85 (m, 3H), 3.74 (dd, 1H, J ) 3.9 Hz, J )
10.4 Hz), 3.67 (s, 3H), 1.80 (s, 3H); 13C NMR (CDCl3) δ 169.45,
166.04, 165.44, 165.36, 165.28, 153.85, 152.76, 137.58, 133.67,
133.41, 133.32, 129.94, 129.68, 129.62, 129.18, 128.91, 128.64,
128.44, 128.27, 127,68, 127.57, 115.61, 114.48, 101.66, 98.34,
77.48, 72.13, 71.25, 69.97, 69.49, 68.87, 68.08, 67.63, 62.34, 55.65,
51.05, 23.34. Anal. Calcd for C56H53NO16: C, 67.53; H, 5.36;
N, 1.41. Found: C, 67.84; H, 5.33; N, 1.46.
26: 1H NMR (CDCl3) δ 8.00-7.17 (m, 30H), 6.04 (d, 1H, J )
5.0 Hz), 5.81-5.67 (m, 2H), 5.79 (dd, 1H, J ) 1.7 Hz, J ) 3.6
Hz), 5.08 (m, 1H), 5.04-4.97 (m, 2H), 4.77 (d, 1H, J ) 12.3 Hz),
4.73 (dd, 1H, J ) 6.8 Hz, J ) 5.0 Hz),4.59 (d, 1H, J ) 7.3 Hz),
4.49 (m, 3H), 4.33 (dd, 1H, J ) 8.5 Hz, J ) 13.5 Hz), 4.22 (m,
1H), 4.14-4.07 (m, 3H), 4.05-3.98 (m, 2H), 3.95-3.89 (m, 2H),
1.97 (s, 3H); 13C NMR (CDCl3) δ 169.52, 166.28, 165.87, 165.12,
164.93, 138.03, 137.45, 134.59, 133.58, 133.34, 133.14, 132.93,
130.18, 129.85, 129.78, 128.73, 129.66, 129.37, 129.02, 128.87,
128.59, 128.34, 127.7, 125.53, 117.16, 98.85, 98.55, 77.32, 74.26,
73.40, 71.55, 70.22, 70.15, 69.09, 66.59, 63.58, 51.62, 23.45.
21: [R]D +23.3° (c 0.63, CHCl3); 1H NMR (CDCl3) δ 7.94-
7.14 (m, 30H), 5.93 (m, 1H), 5.90 (dd, 1H, J ) 3.3 Hz, J ) 0.9
Hz), 5.75 (dd, 1H, J ) 7.9 Hz, J ) 10.4 Hz), 5.70 (bs, 1H, NH),
5.46 (dd, 1H, J ) 3.3 Hz, J ) 10.4 Hz), 5.26-5.14 (m, 2H), 4.89
(d, 1H, J ) 7.7 Hz), 4.72 (d, 1H, J ) 12.3 Hz), 4.55-4.43 (m,
3H), 4.41-4.34 (m, 3H), 4.22-4.11 (m, 5H), 4.00 (m, 1H), 3.93
(dd, 1H, J ) 2.3 Hz, J ) 9.1 Hz), 1.90 (s, 3H); 13C NMR (CDCl3)
δ 169.33, 165.81, 156.66, 165.51, 165.43, 165.32, 165.21, 137.48,
135.05, 133.42, 133.16, 128.77, 129.70, 129.56, 129.04, 128.63,
128.47, 128.31, 127.68, 117.22, 102.43, 98.79, 77.48, 74.02, 71.54,
71.44, 70.77, 70.04, 69.81, 68.99, 67.87, 65.03, 63.23, 54.85, 23.40.
Ben zyl O-(2,3,4,6-Tetr a-O-ben zoyl-â-D-galactopyr an osyl)-
(1f4)-2-a cet a m id o-2-d eoxy-6-O-p -m et h oxyp h en yl-â-D-a l-
lop yr a n osyl 2,3-Su lfa m id a te (24). Compound 23 (200 mg, 0.2
mmol) was dissolved in THF (2 mL) under Ar at 10 °C. Pyridine
(40 µL, 0.48 mmol) and thionyl chloride (18 µL, 0.24 mmol) were
added dropwise, and the reaction mixture was stirred under Ar
at 10 °C for 1 h. Then, more pyridine (20 µL, 0.24 mmol) and
thionyl chloride (18 µL, 0.24 mmol) were added, and the reaction
was continued for 30 min. After this time, the mixture was
diluted with DCM (30 mL) and washed with ice-water (30 mL),
and the aqueous phase was extracted with DCM (3 × 20 mL).
The combined organics were dried (Na2SO4) and concentrated.
The residue was dissolved in a mixture of CCl4 (0.4 mL),
acetonitrile (0.4 mL), and water (0.4 mL), sodium periodate (92.8
mg, 0.4 mmol) and RuCl3‚H2O (1 mg) were added, and the
reaction was stirred at 0 °C for 1 h. The mixture was filtered
through a pad of Celite; the filtrate was diluted with DCM (30
mL), washed with water (30 mL), dried (Na2SO4), and evapo-
rated. The residue was purified by column chromatography
(hexane-EtOAc 2:1) to give 24 (130 mg, 61%). mp 105-108 °C;
Anal. Calcd for C59H55NO16
: C, 68.53; H, 5.36; N, 1.35.
Found: C, 68.81; H, 5.40; N, 1.41.
Ben zyl O-(2,3,4,6-Tetr a-O-ben zoyl-â-D-galactopyr an osyl)-
(1f4)-2-a cet a m id o-3-O-a llyl-2-d eoxy-6-O-(p -m et h oxyp h e-
n yl)-â-D-a llop yr a n osid e (22). A mixture of 20 (720 mg, 1.57
mmol) and 2,3,4,6-tetra-O-benzoyl-R/â-D-galactopyranosyl trichlo-
roacetimidate (1.74 g, 2.36 mmol) and 4 Å molecular sieves (ca.
300 mg) in DCM (40 mL) under Ar was stirred at room
temperature for 30 min. Then, a solution of trimethylsilyl
triflate in DCM (0.1 M, 2.36 mL, 0.236 mmol) was added
dropwise at room temperature, and the reaction mixture was
stirred under Ar. After 1 h, more trimethylsilyl triflate (0.1 M
in DCM, 1.57 mL, 0.157 mmol) was added, and the reaction was
stirred for 9 h. Triethylamine was added, and the mixture was
filtered through Celite and concentrated. The residue was
purified by column chromatography (hexane-EtOAc 2:1fEtOAc)
to give 27 (130.4 mg, 8%), 22 (1.03 g, 63%), and recovered 20
(50.4 mg, 7%).
1
[R]D +39.5° (c 0.9, CHCl3); IR (KBr) 1380, 1180 cm-1; H NMR
(CDCl3) δ 8.09-7.17 (m, 25H), 6.73-6.58 (m, 4H), 5.93 (d, 1H,
J ) 2.7 Hz), 5.78 (dd, 1H, J ) 10.3 Hz, J ) 7.9 Hz), 5.48 (m,
2H), 4.95 (d, 1H, J ) 7.8 Hz), 4.84 (d, 1H, J ) 5.4 Hz), 4.82 (d,
1H, J ) 12.1 Hz), 4.66 (dd, 1H, J ) 11.3 Hz, J ) 7.2 Hz), 4.53-
4.42 (m, 4H), 4.34 (t, 1H, J ) 6.8 Hz), 4.08 (m, 1H), 3.98 (d, 1H,
J ) 10.5 Hz), 3.84 (dd, 1H, J ) 10.7 Hz, J ) 3.7 Hz), 3.77 (s,
3H), 2.33 (s, 3H); 13C NMR (CDCl3) δ 166.0, 165.89, 165.62,
165.42, 164.74, 154.28, 152.16, 136.30, 133.72, 133.52, 133.33,
129.69, 129.62, 129.59, 128.71, 128.57, 128.46, 128.41, 128.25,
128.06, 127.76, 115.48, 114.69, 102.89, 98.27, 79.93, 72.07, 71.77,
71.42, 70.99, 70.31, 69.30, 67.73, 66.78, 62.03, 58.93, 55.68, 22.30.
Anal. Calcd for C56H51NO18S: C, 63.57; H, 4.86; N, 1.32; S, 3.03.
Found: C, 63.87; H, 4.90; N, 1.37; S, 3.30.
27: 1H NMR (CDCl3) δ 7.97-7.25 (m, 25H), 6.83-6.76 (m,
4H), 6.31 (d, 1H, J ) 5.0 Hz), 6.03 (bs, 1H, NH), 5.99-5.75 (m,
1H), 5.72 (dd, 1H, J ) 3.7 Hz, J ) 1.6 Hz), 5.25 (m, 1H), 5.17-
4.93 (m, 2H), 4.87 (dd, 1H, J ) 5.0 Hz, J ) 6.7 Hz), 4.81 (d, 1H,
J ) 12.1 Hz), 4.72 (d, 1H, J ) 6.6 Hz), 4.64-4.51 (m, 2H), 4.45-
4.18 (m, 6H), 4.12-4.00 (m, 4H), 3.75 (s, 3H), 1.92 (s, 3H); 13C
NMR (CDCl3) δ 169.61, 165.88, 165.16, 164.96, 153.97, 152.92,
138.19, 137.50, 134.56, 133.58, 133.35, 133.14, 129.83, 129.73,
129.39, 129.01, 128.87, 128.60, 128.51, 128.35, 127.70, 125.49,
121.14, 117.02, 115.71, 114.57, 99.05, 98.50, 74.33, 72.94, 72.71,
71.57, 70.88, 70.14, 70.03, 69.07, 68.34, 66.58, 66.35, 62.06, 55.67,
51.26, 23.4.
22: mp 89-92 °C; [R]D +33.1° (c 1, CHCl3); 1H NMR (CDCl3)
δ 8.03-7.21 (m, 25H), 6.76-6.59 (m, 4H), 6.10-5.92 (m, 1H),
5.98 (d, 1H, J ) 2.7 Hz), 5.81 (dd, 1H, J ) 10.4 Hz, J ) 7.8 Hz),
5.54 (dd, 1H, J ) 10.4 Hz, J ) 3.2 Hz), 5.37-5.23 (m, 2H), 4.98
(d, 1H, J ) 7.9 Hz), 4.80 (d, 1H, J ) 12.3 Hz), 4.66-4.58 (m,
1H), 4.63 (d, 1H, J ) 7.4 Hz), 4.52 (d, 1H, J ) 12.3 Hz), 4.50
(dd, 1H, J ) 6.4 Hz, J ) 11.3 Hz), 4.34 (t, 1H, J ) 6.4 Hz), 4.30-
4.22 (m, 4H), 4.17 (dd, 1H, J ) 2.3 Hz, J ) 8.5 Hz), 4.11-4.03
(m, 1H), 3.96 (dd, 1H, J ) 2.7 Hz, J ) 10.4 Hz), 3.84 (dd, 1H, J
) 10.4 Hz, J ) 3.9 Hz), 3.79 (s, 3H), 2.01 (s, 3H); 13C NMR
(CDCl3) δ 169.33, 165.94, 165.37, 165.19, 165.10, 153.95, 152.63,
137.59, 135.05, 133.55, 133.29, 129.79, 129.66, 129.16, 129.01,
128.81, 128.60, 128.43, 128.26, 127.77, 127.59, 117.16, 115.65,
114.55, 102.2, 99.05, 73.64, 71.83, 71.46, 69.95, 67.48, 61.88,
55.68, 51.26, 23.38. Anal. Calcd for C59H59NO16: C, 68.4; H,
5.55; N, 1.35. Found: 68.78; H, 5.47; N, 1.40.
Ben zyl S-(2,3,4-Tr i-O-a cetyl-r-L-fu cop yr a n osyl)-(1f3)-
[O-(2,3,4,6-tetr a -O-ben zoyl-â-D-ga la ctop yr a n osyl)-(1f4)]-2-
a ceta m id o-2-d eoxy-6-O-(p-m eth oxyp h en yl)-3-th io-â-D-glu -
cop yr a n osid e (25). To a solution of 2,3,4-tri-O-acetyl-1-thio-
R-L-fucopyranose16 (41 mg, 0.133 mmol) in DMF (0.4 mL) was
added NaH (3.5 mg, 0.146 mmol) at 0 °C under Ar, and the
mixture was stirred for 5 min at this temperature. Then, a
solution of 24 (70 mg, 0.066 mmol) in dry DMF (0.4 mL) was
added slowly at 0 °C. After stirring for 30 min at room
temperature, the solvent was evaporated under reduced pres-
sure. The residue was treated with a mixture of THF-H2SO4-
H2O (300:3:1, 0.4 mL) at room temperature for 30 min. The
reaction mixture was diluted with DCM (30 mL), washed with
sat. NaHCO3 solution (20 mL) and water (20 mL), dried
(Na2SO4), and concentrated. The residue was purified by column
chromatography (hexane-EtOAc 1:1) to yield 25 (65 mg, 77%).
1
Mp 111-114 °C; [R]D -52.5° (c 0.83, CHCl3); H NMR (CDCl3)
Ben zyl O-(2,3,4,6-Tetr a-O-ben zoyl-â-D-galactopyr an osyl)-
(1f4)-2-a ceta m id o-2-d eoxy-6-O-(p-m eth oxyp h en yl)-â-D-a l-
lop yr a n osid e (23). A solution of 22 (671 mg, 0.65 mmol) and
[Ir(COD)(PMePh2)2]PF6 (3 mg) in dry THF (8 mL) was degassed
and placed under H2 atmosphere until the color of the solution
turned from pale red to pale green. Then, H2 was replaced by
δ 8.05-7.20 (m, 25H), 6.84-6.66 (m, 4H), 6.37 (d, 1H, J ) 9.0
Hz), 5.96 (d, 1H, J ) 3.5 Hz), 5.75 (d, 1H, J ) 5.6 Hz), 5.69 (dd,
(16) Hashimoto, H.; Shimada, K.; Horito, S. Tetrahedron: Asym-
metry 1994, 5, 2351-2366.

Notes
J . Org. Chem., Vol. 63, No. 8, 1998 2723
1H, J ) 7.9 Hz, J ) 10.5 Hz), 5.56 (dd, 1H, J ) 10.5 Hz, J ) 3.5
Hz), 5.23 (dd, 1H, J ) 5.6 Hz, J ) 10.7 Hz), 5.09 (d, 1H, J ) 3.2
Hz), 5.04 (dd, 1H, J ) 10.6 Hz, J ) 3.2 Hz), 4.85 (d, 1H, J ) 7.9
Hz), 4.77 (dd 1H, J ) 6.3 Hz, J ) 11.2 Hz), 4.64 (d, 1H, J ) 12.1
Hz), 4.51-4.34 (m, 4H), 4.28-4.24 (m, 3H), 4.14 (t, 1H, J ) 5.1
Hz), 4.03 (dd, 1H, J ) 4.0 Hz, J ) 9.8 Hz), 3.79 (m, 1H), 3.77 (s,
3H), 3.30 (t, 1H, J ) 5.1 Hz), 2.13 (s, 3H), 2.10 (s, 3H), 2.04 (s,
3H), 1.94 (s, 3H), 1.05 (d, 1H, J ) 6.4 Hz); 13C NMR (CDCl3) δ
170.46, 170.25, 169.95, 169.66, 165.87, 165.75, 165.61, 165.33,
154.33, 151.94, 137.21, 133.70, 133.36, 129.78, 129.73, 129.25,
129.04, 128.83, 128.75, 128.65, 128.49, 128.35, 128.28, 127.67,
127.39, 115.23, 114.91, 100.35, 99.97, 84.41, 77.20, 75.72, 75.58,
71.73, 71.01, 70.92, 70.52, 69.94, 68.42, 67.83, 67.61, 65.25, 61.38,
55.73, 54.27, 44.67, 23.27, 20.87, 20.64, 15.94. Anal. Calcd for
C68H69NO22S: C, 63.59; H, 5.42; N, 1.09; S, 2.50. Found C, 63.31;
H, 5.48; N, 1.12; S, 2.76.
Ben zyl S-(r-L-F u cop yr a n osyl)-(1f3)-[O-(â-D-ga la ctop y-
r a n osyl)-(1f4)]-2-a ceta m id o-2-d eoxy-3-th io-â-D-glu cop yr a -
n osid e (2). To an ice cold solution of 25 (38 mg, 0.029 mmol)
in CH3CN-H2O 4:1 (0.4 mL) was added ceric ammonium nitrate
(38.1 mg, 0.069 mmol), and the reaction mixture was stirred for
30 min at 0 °C. After this time, the mixture was diluted with
DCM (10 mL) and partitioned between brine (10 mL) and DCM,
and the aqueous phase was extracted with DCM (3 × 10 mL).
The combined organics were washed with water (10 mL), dried
(Na2SO4), and concentrated. The residue was suspended in
MeOH (1 mL) and treated with NaOMe (0.1 M, 1 mL) for 3 h at
room temperature. Then, the mixture was neutralized with
Amberlite IR-120 (H+), filtered, and concentrated. The residue
was purified by reverse-phase column chromatography, using
CH3CN-H2O 5% as eluent to give 2 (16 mg, 86%): mp 167-
170 °C; [R]D -123.6° (c 0.48, MeOH); 1H NMR (D2O) δ 7.27-
7.16 (m, 5H, Ar), 5.30 (d, 1H, J ) 5.6 Hz), 4.69 (d, 1H, J ) 9.8
Hz), 4.48 (d, 1H, J ) 12.2 Hz), 4.43 (m, 1H), 4.31 (d, 2H, J ) 7.9
Hz), 3.83 (dd, 1H, J ) 2.3 Hz, J ) 12.3 Hz), 3.79 (dd, 1H, J )
5.6 Hz, J ) 10.4 Hz), 3.73-3.41 (m, 14H), 3.33 (dd, 1H, J ) 7.7
Hz, J ) 9.9 Hz), 2.69 (t, 1H, J ) 10.8 Hz), 1.72 (s, 3H), 0.98 (d,
1H, J ) 6.4 Hz); 13C NMR (CD3OD) δ 173.22, 139.16, 129.32,
128.85, 128.67, 103.56, 102.75, 86.81, 80.19, 76.38, 74.99, 73.53,
72.92, 72.28, 71.44, 70.13, 69.81, 68.64, 62.55, 62.34, 57.87, 23.01,
16.82. Anal. Calcd for C27H41NO14S: C, 51.02; H, 6.50; N, 2.20;
S, 5.04. Found: C, 51.31; H, 6.28; N, 2.27; S, 5.28.
Ack n ow led gm en t. Financial support by Ministerio
de Educacio´n y Cultura (to B. A.), DGICYT (grant PB93-
0127-C02-01) and Comunidad de Madrid (grant 07/115/
96), is greatly appreciated.
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra for compound 15 (6 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page ordering information.
J O971784A