Synthesis of sialyl- and sulfo-Lex/Lea analogs containing N-alkyl-1-deoxynojirimycin as potential selectin blockers

Article abstract of DOI:10.1081/CAR-100108657

A series of novel sialyl- and sulfo-Le^x/Le^a oligosaccharides containing N-alkyl-1-deoxynojirimycin as potential selectin blockers have systematically been synthesized via the suitably protected intermediates containing N-benzyloxycar

Full text of DOI:10.1081/CAR-100108657

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SYNTHESIS OF SIALYL- AND SULFO-Lex/Lea ANALOGS
CONTAINING N-ALKYL-1-DEOXYNOJIRIMYCIN AS
POTENTIAL SELECTIN BLOCKERS
Hiroyasu Furui a , Keiko Ando-Furui a , Haruko Inagaki a , Takayuki Ando a , Hideharu
Ishida a & Makoto Kiso a
a Department of Applied Bioorganic Chemistry , Gifu University , Gifu, 501-1193, Japan
Published online: 19 Aug 2006.
To cite this article: Hiroyasu Furui , Keiko Ando-Furui , Haruko Inagaki , Takayuki Ando , Hideharu Ishida & Makoto Kiso
(2001) SYNTHESIS OF SIALYL- AND SULFO-Lex/Lea ANALOGS CONTAINING N-ALKYL-1-DEOXYNOJIRIMYCIN AS POTENTIAL
SELECTIN BLOCKERS , Journal of Carbohydrate Chemistry, 20:9, 789-812
To link to this article: http://dx.doi.org/10.1081/CAR-100108657
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J. CARBOHYDRATE CHEMISTRY, 20(9), 789–812 (2001)
SYNTHESIS OF SIALYL- AND SULFO-Lex/Lea
ANALOGS CONTAINING N-ALKYL-1-
DEOXYNOJIRIMYCIN AS POTENTIAL
SELECTIN BLOCKERS1
Hiroyasu Furui,2 Keiko Ando-Furui, Haruko Inagaki,
Takayuki Ando, Hideharu Ishida,* and Makoto Kiso*
Department of Applied Bioorganic Chemistry,
Gifu University, Gifu 501-1193, Japan
ABSTRACT
A series of novel sialyl- and sulfo-Lex/Lea oligosaccharides containing N-
alkyl-1-deoxynojirimycin as potential selectin blockers have systematically
been synthesized via the suitably protected intermediates containing N-benzy-
loxycarbonyl-1-deoxynojirimycin. Some of the synthetic oligosaccharides
strongly inhibited the adhesion of HL60 cells to IL-1ꢀ-stimulated HUVECs.
INTRODUCTION
The carbohydrate determinants, sialyl Lewis x (sLex) and sialyl Lewis a
(sLea), which are frequently expressed on cancer cells,3,4 serve as the ligands for
selectin,5 a family of cell adhesion molecules implicated in leukocyte traffic and
recruitment to sites of inflammation. These carbohydrate determinants, therefore,
have been thought to be involved in hematogenous metastasis of some cancer
cells.6,7
In the course of synthetic studies on sialoglycoconjugates,8,9 we have suc-
ceeded not only in the total syntheses10,11 of these carbohydrate determinants but
also in the synthesis of a variety of their analogs12,13 and mimetics.14–16 In this
*Corresponding authors.
789
Copyright © 2002 by Marcel Dekker, Inc.
www.dekker.com

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FURUI ET AL.
course, it has been found17 that the glucosamine residue in these determinants
could be replaced by glucose and 1-deoxynojirimycin without loss of the selectin
binding activity. It has also been strongly suggested that the sialic acid residue may
be substituted by the sulfate group.18,19 This paper describes the systematic syn-
thesis of a series of novel sialyl- and sulfo-Lex/Lea oligosaccharides containing N-
alkyl-1-deoxynojirimycin instead of the N-acetylglucosamine residue.
RESULTS AND DISCUSSION
The sialyl Lewis x (sLex) (11–14) and sialyl Lewis a (sLea) (15–18) analogs
containing 1-deoxynojirimycin or N-alkyl-1-deoxynojirimycin were synthesized
from the corresponding, suitably protected tetrasaccharides14 (1 and 2), respec-
tively (Scheme 1). Hydrogenolytic removal of the benzyloxycarbonyl (Z) and
benzyl (Bn) groups in 1 and 2 were carried out in the presence of palladium chlo-
ride in AcOH, to give 3 and 7, which, upon treatment with formalin,14 bu-
tyraldehyde or decyl aldehyde over palladium hydroxide on carbon in a hydro-
gen atmosphere, gave 4–6 and 8–10 in good yields. Complete O-deacylation of
3–6 and 7–10, followed by saponification of the methyl ester group, afforded a
series of sLex-type (11–14) and sLea-type (15–18) tetrasaccharides in high yields
(Scheme 1).
For the synthesis of the sulfo Lex analogs (27, 37, 38), (2,3,4-tri-O-benzyl-ꢁ-
L-fucopyranosyl)-(1→3)-2-O-acetyl-6-O-benzyl-N-benzyloxycarbonyl-1,5-
dideoxy-1,5-imino-D-glucitol14 (19) was glycosylated with the galactose donor
2020 to give trisaccharide 21 (70%), which was converted stepwise, by hydrolytic
removal of the benzylidene group, benzoylation to 23 and selective removal of the
levulinoyl group, to 24 in high yield (Scheme 2). Treatment of 24 with pyridine
sulfur trioxide complex in N,N-dimethylformamide gave 25 in 96% yield, which
underwent reductive N-methylation as described for 12 and 16, to afford 26 in 83%
yield. Significant signals in the 1H NMR spectrum of 26 were a three proton sin-
glet at ꢂ 2.12 (NMMe) and a one proton doublet of doublets at ꢂ 4.72 (J2,3 ꢃ 10.3,
J
3,4 ꢃ 3.7 Hz, H-3c), showing the desired structure. Compound 27 was prepared by
O-deacylation of 26, quantitatively. In the ion-spray MS of 27, the molecular ion
was clearly detected at m/z 564.0 (MMNaMH)ꢄ and m/z 566.2 (MMNaꢅH)ꢅ in
negative and positive ion modes,21 respectively, indicating the desired structure
unambiguously.
Hydrogenation of 22 over palladium black in AcOH gave 28 (79%), which
was then treated with butyraldehyde or decyl aldehyde in the presence of palladium
hydroxide on carbon in a hydrogen atmosphere, to give 29 (79%) or 30 (80%), re-
spectively (Scheme 3). The remaining hydroxyls were acetylated, and then the le-
vulinoyl group was cleaved by treatment with hydrazine acetate in EtOH to afford
33 and 35. Sulfation of 33 and 35 was performed as described for 25 and the re-
sulting 34 (81%) and 36 (88%) were treated with methanolic sodium methoxide to
1
give 37 and 38, quantitatively. In the H NMR spectra of 34 and 36, H-3c at the
sulfated position appeared at ꢂ 4.68 (dd, J2,3 ꢃ 10.3, J3,4 ꢃ 2.9 Hz) for 34 and ꢂ
4.70 (dd, J2,3 ꢃ 10.3, J3,4 ꢃ 3.3 Hz) for 36, respectively. In the FAB-MS of 37 and

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791
Scheme 1. i) RꢆCHO, H2, Pd(OH)2-C, RꢆCH2OH/AcOH/H2O Rꢆ ꢃ H, C3H7, C9H19.
38, a pair of molecular ions were each clearly detected at m/z 628.3 (MMH)ꢄ and
606.3 (MMNaMH)ꢄ for 37, and m/z 712.32 (MMH)ꢄ and 690.38 (MMNaMH)ꢄ
for 38, accompanied with a significant fragment ion (MMNaMHMFuc)ꢄ at m/z
460.2 for 37 and 544.3 for 38, respectively, providing the distinct evidence for the
desired structures.

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FURUI ET AL.
Scheme 2. i) NIS, TMSOTf, CH2Cl2, 0°C → rt (70%); ii) 80% aq AcOH, 45°C (89%); iii)
NH2NH2ꢇAcOH, EtOH, rt (100%); iv) SO3ꢇpyr, DMF, rt (96%); v) Dowex-Naꢅ, then HCHO, H2/Pd,
MeOH (83%); vi) NaOMe, MeOH.
In the synthetic route to the sulfo Lea analogs (50, 60, 61), 2-O-acetyl-4,6-O-
benzylidene-N-benzyloxycarbonyl-1,5-dideoxy-1,5-imino-D-glucitol (39)14 was
first glycosylated with the galactose donor 40 to give 41 (87%) (Scheme 4). Hy-
drolytic removal of the benzylidene group in 41 and the following regioselective
protection of 6-OH by a tert-butyldimethylsilyl (TBDMS) group gave 43 in high
yield. The remaining 4-OH was then fucosylated with methyl 2,3,4-tri-O-benzyl-
1-thio-ꢀ-L-fucopyranoside14 in the presence of dimethyl(methylthio)sulfonium tri-

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793
flate (DMTST) in benzene to afford 44 (55%). This was converted to 46 by re-
placement of the TBDMS group with the benzoyl group, and then the levulinoyl
group in 46 was selectively cleaved to give 47. Sulfation (99%) of 47 as described
for 25, and reductive N-methylation (92%), followed by the complete O-deacyla-
tion, afforded 50 as the sodium salt (Scheme 4). In the ion-spray MS of 50, the
molecular ion was detected at m/z 564.1 (MMNaMH)ꢄ, from which two major
daughter ions were formed and detected at m/z 417.6 (MMNaMFuc)ꢄ and m/z
96.8 (HSOꢄ4 ), respectively.
Hydrogenolysis of 46 in AcOH and the reductive N-alkylation as described
for 29 and 30, gave 52 (64%) and 53 (75%), respectively, which were then fully
acetylated. Selective removal of the levulinoyl group in 54 and 55, followed by O-
sulfation as described for 34 and 36, afforded 57 and 59, which, upon treatment
with methanolic sodium methoxide, gave the sulfo Lea analogs containing N-butyl-
and N-decyl-1-deoxynojirimycin (60 and 61), respectively. In the FAB-MS, the
Scheme 3. i) H2/Pd, AcOH; ii) C3H7CHO, 1-butanol, H2, Pd(OH)2-C (79%); iii)C9H19CHO,
EtOAc/THF, H2, Pd(OH)2-C (80%); iv) NH2NH2ꢇAcOH, EtOH, rt; v) SO3ꢇpyr, DMF, 33 → 34
(81%), 35 → 36 (88%); VI) NaOMe, MeOH.

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FURUI ET AL.
molecular ions were clearly detected at m/z 606.30 (MMNa)ꢄ for 60, and m/z
712.26 (MMH)ꢄ and 690.31 (MMNa)ꢄ for 61, respectively, showing the structure
assigned.
The preferred conformation of the 1-deoxynojirimycin residue in the pro-
tected oligosaccharide intermediates, such as 1, 2, 19, 21–25 and 42–48, has been
Scheme 4. i) NIS, TMSOTf, CH2Cl2, 0°C → rt (87%); ii) 80% aq AcOH, 45°C (86%); iii) TB-
DMSCl, pyr, CH2Cl2, 0°C → rt (92%); iv) DMTST, benzene, 7°C (55%); v) 80% aq AcOH, rt (88%);
vi) NH2NH2ꢇAcOH, EtOH, rt (93%); vii) SO3ꢇpyr, DMF, rt (99%); viii) Dowex-Naꢅ, then HCHO,
H2/Pd, MeOH (92%); ix) NaOMe, MeOH.

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795
Scheme 5. i) H2/Pd, AcOH; ii) C3H7CHO, 1-butanol, H2, Pd(OH)2-C (64%); iii) C8H19CHO, H2,
Pd(OH)2-C, EtOAc (75%); iv) Ac2O, pyr (quant); v) NH2NH2ꢇAcOH, EtOH, (56, 91%; 58, 93%); vi)
SO3ꢇpyr, DMF (ꢀ90%); vii) NaOMe, MeOH (quant).
suggested to be a flexible 1C4 conformation based on 1H NMR data14,22 and X-ray
crystallographic analysis.23 A dramatic conformational change (4C1→1C4) was ob-
served in the reductive ring opening of the 4,6-O-benzylidene group (41→42). On
the contrary, in the N-debenzyloxycarbonylation step (1→3, 2→7, 25→26,
22→28, 48→49, and 46→51), the 1C4 conformation changed to 4C1 as shown in
Scheme 1–5.
The inhibitory effect of the synthetic oligosaccharides on the adhesion of
fixed HL-60 cells to IL-ꢀ-stimulated HUVECs was examined. Among a series of
sialyl Lex/Lea analogs (11–18, Scheme 1), the sLea-type analogs (15–18) ex-
pressed stronger activity than the corresponding sLex-type analogs (11–14). The
hierarchy of inhibition potency due to the N-alkyl group in both sLex and sLea se-
ries were N-butylꢈN-decylꢈN-methyl, and the activity of N-butyl sLea derivative
(17) was most potent. Similarly, a series of sulfo Lea-type analogs (50, 60, 61)
showed stronger inhibitory activity than the corresponding sulfo Lex-type analogs
(27, 37, 38). The details of the biological study will be described elsewhere.

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In conclusion, a series of novel sialyl- and sulfo-Lex/Lea oligosaccharides
containing N-alkyl-1-deoxynojirimycin have systematically been synthesized as
potential selectin blockers.17,24–26
EXPERIMENTAL
General Methods. Optical rotations were determined with a Union PM-
201 polarimeter at 25°C, and IR spectra were recorded with a Jasco IRA-100 spec-
1
trophotometer. H NMR spectra were recorded on a JEOL JNM-GX 270 (270
MHz) or Varian Unity Inova 400 (400 MHz) spectrometer. FAB-MS were
recorded on a JEOL JMS-SX 120A mass spectrometer/JMA-DA 7000 data sys-
tem.9 Ion-spray MS were recorded on an API-III triple quadrupole mass spec-
trometer (Perkin-Elmer Sciex Instruments) fitted with as atmosphere pressure ion-
ization source.21 All reactions were monitored by TLC (Merck silica gel aluminum
plate 60F-254) and preparative column chromatography was performed on silica
gel (Wako Chemical Co., 200 or 300 mesh) with the solvent systems specified.
Concentrations were conducted in vacuo.
(Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-ꢁ-D-
galacto-2-nonulopyranosylonate)-(2→3)-(2,4,6-tri-O-benzoyl-ꢀ-D-galactopy-
ranosyl)-(1→4)-[ꢁ-L-fucopyranosyl-(1→3)]-2-O-acetyl-1,5-dideoxy-1,5-
imino-D-glucitol (3). Compound 1 (113 mg) in acetic acid (10 mL) was
hydrogenolyzed in the presence of palladium chloride (200 mg) for 2 days at rt.
The catalyst was filtered off and washed with MeOH. The combined filtrate and
washings were concentrated. Column chromatography (15:1 CH2Cl2MMeOH) of
1
the residue on silica gel gave 3 (37.6 mg, 75%): [ꢁ]D ꢄ4° (c 0.5, CH2Cl2); H
NMR (CDCl3) ꢂ 1.39 (d, 3H, J5,6 ꢃ 6.6 Hz, H-6b), 1.56 (s, 3H, AcN), 1.65 (t, 1H,
Jgem ꢃ J3ax,4 ꢃ 12.5 Hz, H-3dax), 1.77, 1.90, 1.98, 2.11, 2.25 (5s, 15H, 5AcO),
2.41 (dd, 1H, Jgem ꢃ 12.5, J3eq,4 ꢃ 5.1 Hz, H-3deq), 3.09 (dd, 1H, Jgem ꢃ 12.3,
J
1eq,2 ꢃ 5.1 Hz, H-1aeq), 3.82 (s, 3H, COOMe), 4.91 (d, 1H, J1,2 ꢃ 8.42 Hz, H-1c),
5.12 (d, 1H, J1,2 ꢃ 3.85 Hz, H-1b), 5.14 (dd, 1H, J6,7 ꢃ 2.57 Hz, H-7d), 5.22 (d,
1H, J3,4 ꢃ 3.1 Hz, H-4c), 5.48 (dd, 1H, J2,3 ꢃ 9.9 Hz, H-2c), 5.80 (m, 1H, H-8d),
7.48–8.22 (m, 15H, 3Ph).
Anal. Calcd for C61H74N2O29 (1229.25): C, 56.39; H, 5.74; N, 2.16. Found:
C, 56.12; H, 5.51; N, 2.08.
(Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-ꢁ-D-
galacto-2-nonulopyranosylonate)-(2→3)-(2,4,6-tri-O-benzoyl-ꢀ-D-galactopy-
ranosyl)-(1→4)-[ꢁ-L-fucopyranosyl-(1→3)]-2-O-acetyl-N-butyl-1,5-dideoxy-
1,5-imino-D-glucitol (5). A mixture of 3 (61 mg), butyraldehyde (1 mL),
1-butanol (10 mL), acetic acid (0.5 mL) and water (0.5 mL) was vigorously stirred
with palladium hydroxide on carbon (60 mg) in a hydrogen atmosphere overnight
at rt. The catalyst was filtered off and washed with MeOH. The combined filtrate
and washings were concentrated. Column chromatography (15:1 CH2Cl2MMeOH)

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797
of the residue on silica gel gave 5 (50 mg, 79%): [ꢁ]D ꢄ11° (c 1, CH2Cl2); 1H NMR
(CDCl3) ꢂ 0.87 (t, 3H, J ꢃ 6.4 Hz, Me), 1.24 (m, 4H, MC2H4Me), 1.38 (d, 3H, J5,6
ꢃ 6.6 Hz, H-6b), 1.56 (s, 3H, AcN), 1.65 (t, 1H, Jgem ꢃ J3ax,4 ꢃ 12.5 Hz, H-3dax),
1.76, 1.90, 1.97, 2.11, 2.25 (5s, 15H, 5AcO), 2.40 (dd, 1H, Jgem ꢃ 12.6, J3eq,4 ꢃ 4.4
Hz, H-3deq), 2.51, 2.65 (2m, 2H, NMCH2MC3H7), 3.01 (dd, 1H, Jgem ꢃ 10.8,
J1eq,2 ꢃ 5.1 Hz, H-1aeq), 3.54 (dd, 1H, J2,3 ꢃ 9.9, J3,4 ꢃ 3.7 Hz, H-3c), 3.83 (s, 3H,
COOMe), 5.11 (dd, 1H, H-7d), 5.12 (d, 1H, J1,2 ꢃ 8.8 Hz, H-1c), 5.17 (d, 1H, J1,2
ꢃ 2.8 Hz, H-1b), 5.19 (d, 1H, J3,4 ꢃ 3.7 Hz, H-4c), 5.50 (ꢀt, 1H, J1,2 ꢃ 8.8, J2,3
ꢃ 9.9 Hz, H-2c), 5.80 (m, 1H, H-8d), 7.47–8.24 (m, 15H, 3Ph).
Anal. Calcd for C65H82N2O29 (1355.36): C, 57.60; H, 6.10; N, 2.07. Found:
C, 57.52; H, 6.00; N, 1.83.
(Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-ꢁ-D-
galacto-2-nonulopyranosylonate)-(2→3)-(2,4,6-tri-O-benzoyl-ꢀ-D-galactopy-
ranosyl)-(1→4)-[ꢁ-L-fucopyranosyl-(1→3)]-2-O-acetyl-N-decyl-1,5-dideoxy-
1,5-imino-D-glucitol (6). A mixture of 3 (30 mg), decyl aldehyde (0.5 mL), ethyl
acetate (5 mL), acetic acid (0.1 mL) and water (0.05 mL) was vigorously stirred
with palladium hydroxide on carbon (30 mg) for 10 h at rt. Work-up and column
chromatography (20:1 CH2Cl2MMeOH) on silica gel gave 6 (50 mg, 60%): [ꢁ]D
ꢅ4.3° (c 0.4, CH2Cl2); 1H NMR (CDCl3) ꢂ 0.88 (t, 3H, J ꢃ 6.2 Hz, Me), 1.25 (m,
16H, MC8H16Me), 1.38 (d, 3H, J5,6 ꢃ 6.6 Hz, H-6b), 1.51 (s, 3H, AcN), 1.66 (t,
1H, Jgem ꢃ J3ax,4 ꢃ 12.3 Hz, H-3dax), 1.77, 1.91, 1.97, 2.11, 2.26 (5s, 15H, 5AcO),
2.40 (dd, 1H, Jgem ꢃ 12.3, J3eq,4 ꢃ 4.2 Hz, H-3deq), 3.01 (dd, 1H, Jgem ꢃ 10.8,
J
1eq,2 ꢃ 4.4 Hz, H-1aeq), 3.54 (dd, 1H, J2,3 ꢃ 9.9, J3,4 ꢃ 3.5 Hz, H-3c), 3.81 (s, 3H,
COOMe), 5.12 (d, 1H, J1,2 ꢃ 8.6 Hz, H-1c), 5.17 (dd, 1H, H-7d), 5.19 (d, 1H, J3,4
ꢃ 3.5 Hz, H-4c), 5.50 (ꢀt, 1H, H-2c), 5.81 (m, 1H, H-8d), 7.52–8.35 (m, 15H,
3Ph).
Anal. Calcd for C71H94N2O29 (1439.52): C, 59.24; H, 6.58; N, 1.95. Found:
C, 59.11; H, 6.45; N, 1.85.
(Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-ꢁ-D-
galacto-2-nonulopyranosylonate)-(2→3)-(2,4,6-tri-O-benzoyl-ꢀ-D-galactopy-
ranosyl)-(1→3)-[ꢁ-L-fucopyranosyl-(1→4)]-2-O-acetyl-1,5-dideoxy-1,5-
imino-D-glucitol (7). Compound 2 (179 mg) in acetic acid (10 mL) was
hydrogenolyzed as described for 3. Work-up and column chromatography (10:1
CH2Cl2MMeOH) of the product on silica gel afforded 7 (92 mg, 71%): [ꢁ]D
ꢄ24.1° (c 1.46, CH2Cl2); 1H NMR (CDCl3) ꢂ 1.27 (d, 3H, J5,6 ꢃ 6.6 Hz, H-6b),
1.56 (s, 3H, AcN), 1.65 (t, 1H, Jgem ꢃ J3ax,4 ꢃ 12.6 Hz, H-3dax), 1.78, 1.91, 2.06,
2.16, 2.18 (5s, 15H, 5AcO), 2.42 (dd, 1H, Jgem ꢃ 12.6, J3eq,4 ꢃ 4.4 Hz, H-3deq),
3.09 (dd, 1H, H-1aeq), 3.79 (s, 3H, COOMe), 4.74 (m, 1H, H-2a), 4.81 (m, 1H,
H-4d), 4.95 (d, 1H, H-1b), 5.14 (d, 1H, J1,2 ꢃ 8.3 Hz, H-1c), 5.25 (d, 1H, J3,4 ꢃ 2.8
Hz, H-4c), 5.30 (dd, 1H, H-7d), 5.36 (t, 1H, H-2c), 5.56 (m, 1H, H-8), 7.41–8.09
(m, 15H, 3Ph).
Anal. Calcd for C61H74N2O29 (1299.25): C, 56.39; H, 5.74; N, 2.16. Found:
C, 56.25; H, 5.55; N, 1.96.

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FURUI ET AL.
(Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-ꢁ-D-
galacto-2-nonulopyranosylonate)-(2→3)-(2,4,6-tri-O-benzoyl-ꢀ-D-galactopy-
ranosyl)-(1→3)-[ꢁ-L-fucopyranosyl-(1→4)]-2-O-acetyl-N-butyl-1,5-dideoxy-
1,5-imino-D-glucitol (9). A mixture of 7 (50 mg), butyraldehyde (1 mL),
1-butanol (10 mL), acetic acid (0.5 mL) and water (0.5 mL) was hydrogenated as
described for 5. Work-up and column chromatography (15:1 CH2Cl2MMeOH) of
1
the product on silica gel gave 9 (34 mg, 65%): [ꢁ]D ꢄ12° (c 0.74, CH2Cl2); H
NMR (CDCl3) ꢂ 0.86 (t, 3H, J ꢃ 6.6 Hz, Me), 1.24 (m, 4H, MC2H4Me), 1.25 (d,
3H, J5,6 ꢃ 6.1 Hz, H-6b), 1.53 (s, 3H, AcN), 1.65 (t, 1H, Jgem ꢃ J3ax,4 ꢃ 12.8 Hz,
H-3dax), 1.77, 1.91, 2.07, 2.12, 2.18 (5s, 15H, 5AcO), 2.43 (dd, 1H, Jgem ꢃ 13.4,
J
3eq,4 ꢃ 4.9 Hz, H-3deq), 2.45 (m, 2H, NMCH2MC3H7), 2.91 (dd, 1H, H-1aeq),
3.81 (s, 3H, COOMe), 4.68 (m, 1H, H-2a), 4.82 (m, 1H, H-4d), 5.03 (d, 1H, J1,2 ꢃ
3.3 Hz, H-1b), 5.16 (d, 1H, J1,2 ꢃ 8.1 Hz, H-1c), 5.26 (dd, 1H, J7,8 ꢃ 9.5 Hz, H-7),
5.33 (dd, 1H, J3,4 ꢃ 3.5 Hz, H-4c), 5.36 (t, 1H, H-2c), 5.56 (m, 1H, H-8d),
7.41–8.09 (m, 15H, 3Ph).
Anal. Calcd for C65H82N2O29 (1355.36): C, 57.60; H, 6.01; N, 2.07. Found:
C, 57.47; H, 6.02; N, 1.92.
(Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-ꢁ-D-
galacto-2-nonulopyranosylonate)-(2→3)-(2,4,6-tri-O-benzoyl-ꢀ-D-galactopy-
ranosyl)-(1→3)-[ꢁ-L-fucopyranosyl-(1→4)]-2-O-acetyl-N-decyl-1,5-dideoxy-
1,5-imino-D-glucitol (10). A mixture of compound 7 (20 mg), decyl aldehyde
(0.5 mL), ethyl acetate (5 mL), acetic acid (0.5 mL) and water (0.1 mL) was hy-
drogenated as described for 6. Work-up and column chromatography (20:1
CH2Cl2MMeOH) on silica gel gave 10 (11 mg, 56%): [ꢁ]D ꢅ2.5° (c 0.24,
1
CH2Cl2); H NMR (CDCl3) ꢂ 0.88 (t, 3H, J ꢃ 6.2 Hz, Me), 1.25 (m, 16H,
MC8H16Me), 1.25 (d, 3H, H-6b), 1.52 (s, 3H, AcN),1.67 (t, 1H, Jgem ꢃ J3ax,4
ꢃ 12.6 Hz, H-3dax), 1.78, 1.91, 2.07, 2.13, 2.20 (5s, 15H, 5AcO), 2.44 (dd, 1H,
J
gem ꢃ 12.5, J3eq,4 ꢃ 4.2 Hz, H-3deq), 2.45 (m, 2H, NCH2), 2.95 (dd, 1H, Jgem ꢃ
11.7, J1eq,2 ꢃ 4 Hz, H-1aeq), 3.82 (s, 3H, COOMe), 4.72 (m, 1H, H-2a), 4.83 (m,
1H, H-4d), 5.03 (d, 1H, J1,2 ꢃ 3.5 Hz, H-1b), 5.16 (d, 1H, H-1c), 5.26 (dd, 1H, J6,7
ꢃ 2.6, J7,8 ꢃ 9.5 Hz, H-7d), 5.31 (d, 1H, J3,4 ꢃ 4.2 Hz, H-4c), 5.36 (dd, 1H, J1,2 ꢃ
8.24, J2,3 ꢃ 10.3 Hz, H-2c), 5.56 (m, 1H, H-8d), 7.42–8.10 (m, 15H, 3Ph).
Anal. Calcd for C71H94N2O29 (1439.52): C, 59.24; H, 6.58; N, 1.95. Found:
C, 59.18; H, 6.44; N, 1.93.
(5-Acetamido-3,5-dideoxy-D-glycero-ꢁ-D-galacto-2-nonulopyranosylonic
acid)-(2→3)-(ꢀ-D-galactopyranosyl)-(1→4)-[ꢁ-L-fucopyranosyl-(1→3)]-1,5-
dideoxy-1,5-imino-D-glucitol (11). Compound 3 (30.3 mg) was treated with a
catalytic amount of NaOMe in dry MeOH overnight. One mL of 0.2 M KOH was
added and the mixture was stirred overnight at rt. The solution was neutralized with
Amberlite IR-120 (Hꢅ), then filtered and concentrated. The product was purified
by column chromatography (1:1 MeOHMH2O) on Sephadex LH-20 to give 11
1
(17.8 mg) in quantitative yield: [ꢁ]D ꢄ19° (c 0.5, 1:1 MeOHMH2O); H NMR
(D2O) ꢂ 1.18 (d, 3H, H-6b), 1.78 (t, 3H, J ꢃ 12 Hz, H-3dax), 2.03 (s, 3H, AcN),

ORDER
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SIALYL- AND SULFO-Lex/Lea ANALOGS
799
2.76 (dd, 1H, Jgem ꢃ 12, J3eq,4 ꢃ 4.4 Hz, H-3deq), 3.03 (dd, 1H, Jgem ꢃ 12.5 Hz,
H-1aeq), 5.39 (d, 1H, J1,2 ꢃ 4 Hz, H-1b), 5.54 (d, 1H, J1,2 ꢃ 7.7 Hz, H-1c): FAB-
MS (negative ion mode): m/z 761.35 (MMH)ꢄ for C29H49N2O21 (Exact mass:
761.2828).
Anal. Calcd for C29H50N2O21 (762.71): C, 45.67; H, 6.61; N, 3.67. Found:
C, 45.38; H, 6.42; N, 3.49.
(5-Acetamido-3,5-dideoxy-D-glycero-ꢁ-D-galacto-2-nonulopyranosylonic
acid)-(2→3)-(ꢀ-D-galactopyranosyl)-(1→4)-[ꢁ-L-fucopyranosyl-(1→3)]-N-
butyl-1,5-dideoxy-1,5-imino-D-glucitol (13). Compound 5 (50 mg) was treated
with a catalytic amount of NaOMe, and then 0.2 M KOH as described for 11. Work-
up and column chromatography (1:1 MeOHMH2O) on Sephadex LH-20 gave 13
1
(30 mg, quant): [ꢁ]D ꢄ46° (c 0.5, 1:1 MeOHMH2O); H NMR (D2O) ꢂ 0.95 (t,
3H, J ꢃ 7.3 Hz, Me), 1.19 (d, 3H, J5,6 ꢃ 6.6 Hz, H-6b), 1.40, 1.74 (m, 4H,
C2H4Me), 1.79 (t, 3H, J ꢃ 12 Hz, H-3dax), 2.03 (s, 3H, AcN), 2.77 (dd, 1H, Jgem
ꢃ 12.5, J3eq,4 ꢃ 4.4 Hz, H-3deq), 3.29 (m, 2H, NMCH2M), 5.36 (d, 1H, H-1b).
Anal. Calcd for C33H58N2O21 (818.82): C, 48.41; H, 7.14; N, 3.42. Found:
C, 48.26; H, 6.88; N, 3.18.
(5-Acetamido-3,5-dideoxy-D-glycero-ꢁ-D-galacto-2-nonulopyranosylonic
acid)-(2→3)-(ꢀ-D-galactopyranosyl)-(1→4)-[ꢁ-L-fucopyranosyl-(1→3)]-N-de-
cyl-1,5-dideoxy-1,5-imino-D-glucitol (14). The title compound was prepared
from 6 (65 mg) as described for 13 and purified by column chromatography (2:1
MeOHMH2O) on Sephadex LH-20 to afford 14 (41 mg, quant): [ꢁ]D ꢄ43° (c 0.8,
2:1 MeOHMH2O); 1H NMR (D2O) ꢂ 0.87 (t, 3H, Me), 1.18 (d, 3H, J5,6 ꢃ 6 Hz,
H-6b), 1.28, 1.59 (m, 16H, C8H16Me), 1.80 (t, 3H, H-3dax), 1.90 (s, 3H, AcN),
5.41 (d, 1H, H-1b).
Anal. Calcd for C39H70N2O21 (902.98): C, 51.88; H, 7.81; N, 3.10. Found:
C, 51.74; H, 7.67; N, 3.00.
(5-Acetamido-3,5-dideoxy-D-glycero-ꢁ-D-galacto-2-nonulopyranosylonic
acid)-(2→3)-(ꢀ-D-galactopyranosyl)-(1→3)-[ꢁ-L-fucopyranosyl-(1→4)]-1,5-
dideoxy-1,5-imino-D-glucitol (15). The title compound was prepared from 7 (62
mg) as described for 11 to give 15 (36.4 mg, quant): [ꢁ]D ꢄ30° (c 0.74, 1:1
1
MeOHMH2O); H NMR (D2O) ꢂ 1.19 (d, 3H, H-6b), 1.80 (t, 1H, J ꢃ 12 Hz,
H-3dax), 2.03 (s, 3H, AcN), 2.77 (dd, 1H, Jgem ꢃ 12, J3eq,4 ꢃ 4.4 Hz, H-3deq), 2.99
(dd, 1H, H-1aeq), 4.83 (d, 1H, J1,2 ꢃ 8.1 Hz, H-1c), 5.02 (d, 1H, J1,2 ꢃ 3.5 Hz,
H-1b): FAB-MS (negative ion mode): m/z 761.32 (MMH)ꢄ for C29H49N2O21 (Ex-
act mass: 761.2828).
Anal. Calcd for C29H50N2O21 (762.71): C, 45.67; H, 6.61; N, 3.67. Found:
C, 45.42; H, 6.60; N, 3.60.
(5-Acetamido-3,5-dideoxy-D-glycero-ꢁ-D-galacto-2-nonulopyranosylonic
acid)-(2→3)-(ꢀ-D-galactopyranosyl)-(1→3)-[ꢁ-L-fucopyranosyl-(1→4)]-N-
butyl-1,5-dideoxy-1,5-imino-D-glucitol (17). Deprotection of 9 (34 mg) and

ORDER
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800
FURUI ET AL.
column chromatography as described for gave the title compound 17 (20 mg,
quant): [ꢁ]D ꢄ52° (c 0.45, 1:1 MeOHMH2O); 1H NMR (D2O) ꢂ 0.96 (t, 3H, J ꢃ
7.3 Hz, Me), 1.22 (d, 3H, J5,6 ꢃ 6.6 Hz, H-6b), 1.40, 1.72 (m, 4H, C2H4Me), 1.81
(t, 1H, J ꢃ 12.5 Hz, H-3dax), 2.05 (s, 3H, AcN), 2.78 (dd, 1H, Jgem ꢃ 12.5, J3eq,4
ꢃ 4.6 Hz, H-3deq), 5.11 (d, 1H, H-1b).
Anal. Calcd for C33H58N2O21 (818.82): C, 48.41; H, 7.14; N, 3.42. Found:
C, 48.11; H, 7.04; N, 3.27.
(5-Acetamido-3,5-dideoxy-D-glycero-ꢁ-D-galacto-2-nonulopyranosylonic
acid)-(2→3)-(ꢀ-D-galactopyranosyl)-(1→3)-[ꢁ-L-fucopyranosyl-(1→4)]-N-de-
cyl-1,5-dideoxy-1,5-imino-D-glucitol (18). The title compound was prepared
from 10 (52 mg) as described for 14 to afford 18 (33 mg, quant): [ꢁ]D ꢄ35° (c 0.62,
2:1 MeOHMH2O); 1H NMR (D2O) ꢂ 0.87 (t, 3H, Me), 1.18 (d, 3H, J ꢃ 6 Hz, H-
6b), 1.28, 1.55 (m, 16H, C8H16Me), 1.80 (t, 3H, H-3dax), 1.90 (s, 3H, AcN), 5.15
(d, 1H, H-1b).
Anal. Calcd for C39H70N2O21 (902.98): C, 51.88; H, 7.81; N, 3.10. Found:
C, 51.69; H, 7.68; N, 2.93.
(2-O-Benzoyl-4,6-O-benzylidene-3-O-levulinoyl-ꢀ-D-galactopyranosyl)-
(1→4)-[2,3,4-tri-O-benzyl-ꢁ-L-fucopyranosyl-(1→3)]-2-O-acetyl-6-O-benzyl-
N-benzyloxycarbonyl-1,5-dideoxy-1,5-imino-D-glucitol (21). To a stirred
mixture of 19 (154 mg, 1 equiv), methyl 2-O-benzoyl-4,6-O-benzylidene-3-O-le-
vulinoyl-1-thio-ꢀ-D-galactopyranoside20 (20, 182 mg, 2 equiv), molecular sieves
4Å (300 mg) and CH2Cl2 (5 mL), were added N-iodosuccinimide (NIS, 164 mg, 4
equiv) and trimethylsilyl trifluoromethanesulfonate (TMSOTf, 14 ꢉL, 0.4 equiv)
at 0°C, and stirring was continued overnight at 0°Cꢀrt. The solids were filtered
off and the filtrate was successively washed with M Na2CO3, Na2S2O3 and water,
dried (Na2SO4), and concentrated. The residue was chromatographed (1:2 EtOAc-
hexane) on a column of silica gel to give 21 (164 mg, 70%): [ꢁ]D ꢄ30° (c 1.33,
CH2Cl2); 1H NMR (CDCl3) ꢂ 1.10 (d, 3H, J5,6 ꢃ 6.6 Hz, H-6b), 1.63 (s, 3H, AcO),
1.92 (s, 3H, LevMMe), 2.43–2.61 (m, 4H, LevMC2H4), 3.28 (dd, 1H, Jgem ꢃ 11.9
Hz, H-1a), 4.44 (d, 1H, J1,2 ꢃ 8.2 Hz, H-1c), 4.56–4.70 (4d, 4H, 2PhCH2O), 4.89
(d, 1H, H-1b), 4.90 (dd, 1H, H-3c), 4.89, 4.97 (2d, 2H, Jgem ꢃ 12.5 Hz,
PhCH2OCO), 5.52 (t, 1H, J1,2 ꢃ J2,3 ꢃ 8.24 Hz, H-2c), 5.53 (s, 1H, benzylidene
CH), 7.17–7.94 (m, 35H, 7Ph).
Anal. Calcd for C75H79NO19 (1298.44): C, 69.38; H, 6.13; N, 1.08. Found:
C, 69.13; H, 6.06; N, 1.03.
(2-O-Benzoyl-3-O-levulinoyl-ꢀ-D-galactopyranosyl)-(1→4)-[(2,3,4-tri-O-
benzyl-ꢁ-L-fucopyranosyl)-(1→3)]-2-O-acetyl-6-O-benzyl-N-benzyloxycar-
bonyl-1,5-dideoxy-1,5-imino-D-glucitol (22). A solution of 21 (164 mg) in 80%
aq AcOH (10 mL) was stirred overnight at 45°C and concentrated. The residue
was chromatographed (3:1 EtOAc-hexane) on a column of silica gel to give 22
1
(136 mg, 89%): [ꢁ]D ꢄ39° (c 1, CH2Cl2); H NMR (CDCl3) ꢂ 1.01 (d, 3H, J5,6
ꢃ 6 Hz, H-6b), 1.92 (s, 3H, AcO), 2.10 (s, 3H, LevMMe), 2.37–2.69 (m, 4H,

ORDER
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SIALYL- AND SULFO-Lex/Lea ANALOGS
801
LevMC2H4), 3.30 (dd, 1H, H-1a), 4.92 (br s, 1H, H-1b), 5.50 (t, 1H, J1,2 ꢃ J2,3
ꢃ 9.9 Hz, H-2c), 7.19–7.93 (m, 30H, 4Ph).
Anal. Calcd for C68H75NO19 (1210.34): C, 67.48; H, 6.25; N, 1.16. Found:
C, 67.42; H, 6.18; N, 0.98.
(2,4,6-Tri-O-benzoyl-3-O-levulinoyl-ꢀ-D-galactopyranosyl)-(1→4)-
[(2,3,4-tri-O-benzyl-ꢁ-L-fucopyranosyl)-(1→3)]-2-O-acetyl-6-O-benzyl-N-
benzyloxycarbonyl-1,5-dideoxy-1,5-imino-D-glucitol (23) and (2,4,6-Tri-O-
benzoyl-ꢀ-D-galactopyranosyl)-(1→4)-[(2,3,4-tri-O-benzyl-ꢁ-L-fucopyranosy
l)-(1→3)]-2-O-acetyl-6-O-benzyl-N-benzyloxycarbonyl-1,5-dideoxy-1,5-
imino-D-glucitol (24). To a solution of 22 (48 mg) in pyridine (5 mL) was added
benzoyl chloride (18 ꢉL, 4 equiv) and the mixture was stirred overnight at rt.
Work-up and column chromatography (2:3 EtOAc-hexane) gave 23 (48 mg, 86%):
1
[ꢁ]D ꢄ37° (c 1, CH2Cl2); H NMR (CDCl3) ꢂ 0.99 (d, 3H, H-6b), 1.64 (s, 3H,
AcO), 1.88 (s, 3H, LevMMe), 2.32–2.59 (m, 4H, LevMC2H4), 3.23 (near d, 1H,
J
gem ꢃ 14.7 Hz, H-1a), 3.62 (dd, 1H, J2,3 ꢃ 10.3, J3,4 ꢃ 2.2 Hz, H-3b), 4.53 (d, 1H,
J1,2 ꢃ 8.8 Hz, H-1c), 4.58, 4.69 (2d, 2H, Jgem ꢃ 12.3 Hz, PhCH2OCO), 4.94 (d,
1H, J1,2 ꢃ 3.7 Hz, H-1b), 5.28 (dd, 1H, J2,3 ꢃ 10.3 Hz, H-3c), 5.52 (dd, 1H, H-2c),
5.76 (d, 1H, J3,4 ꢃ 3.3 Hz, H-4c), 7.21–8.12 (m, 40H, 8Ph).
To a solution of 23 (131 mg) in EtOH (20 mL) was added hydrazine acetate
(10 mg, 1.2 equiv) and the mixture was stirred for 1 h at rt, and then concentrated.
The residue was chromatographed (125:1 CH2Cl2MMeOH) on a column of silica
gel to afford 24 (122 mg, quant): [ꢁ]D ꢄ50° (c 2.4, CH2Cl2); 1H NMR (CDCl3) ꢂ
0.98 (d, 3H, J5,6 ꢃ 6 Hz, H-6b), 1.81 (s, 3H, AcO), 3.62 (near d, 1H, Jgem ꢃ 14.7
Hz, H-1a), 3.95 (dd, 1H, J2,3 ꢃ 10 Hz, H-3c), 4.94 (s, 1H, J1,2 ꢃ 3.7 Hz, H-1b),
5.72 (d, 1H, J3,4 ꢃ 3.5 Hz, H-4c), 7.13–8.14 (m, 40H, 8Ph).
Anal. Calcd for C77H77NO19 (1320.45): C, 70.04; H, 5.88; N, 1.06. Found:
C, 69.88; H, 5.75; N, 1.01.
(2,4,6-Tri-O-benzoyl-3-O-sulfo-ꢀ-D-galactopyranosyl)-(1→4)-[(2,3,4-tri-
O-benzyl-ꢁ-L-fucopyranosyl)-(1→3)]-2-O-acetyl-6-O-benzyl-N-benzyloxy-
carbonyl-1,5-dideoxy-1,5-imino-D-glucitol (25) and (2,4,6-Tri-O-benzoyl-3-O-
sulfo-ꢀ-D-galactopyranosyl)-(1→4)-[ꢁ-L-fucopyranosyl)-(1→3)]-2-O-acetyl-1
,5-dideoxy-1,5-imino-N-methyl-D-glucitol sodium salt (26). To a solution of
24 (119 mg) in N,N-dimethylformamide (0.5 mL) was added pyridine sulfur triox-
ide complex (115 mg, 8 equiv) and the mixture was stirred for 1 h at rt, then cooled
to 0°C. MeOH (1 mL) was added and the mixture was stirred for 30 min at 0°C and
concentrated. Column chromatography (15:1 CH2Cl2MMeOH) of the residue on
silica gel gave 25 (121 mg, 96%): [ꢁ]D ꢄ16.6° (c 2.4, CH2Cl2). Compound 25 (114
mg) in MeOH was treated with cation-exchange resin Dowex-Naꢅ, and then hy-
drogenolyzed in the presence of formalin (0.5 mL) and HCl-free palladium black
(300 mg). Work-up and column chromatography (10:1 CH2Cl2MMeOH) afforded
26 (62 mg, 83%): [ꢁ]D ꢄ30.5° (c 0.89, MeOH); 1H NMR (DMSO-d6, 50°C) ꢂ 1.18
(d, 3H, J5,6 ꢃ 6.6 Hz, H-6b), 1.99 (s, 3H, AcO), 2.04 (t, 1H, J1ax,2 ꢃ 10.4 Hz, H-
1aax), 2.12 (s, 3H, NMMe), 2.79 (dd, 1H, Jgem ꢃ 10.8, J1eq,2 ꢃ 4.8 Hz, H-1aeq),

ORDER
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802
FURUI ET AL.
4.10, 4.51 (2dd, 2H, Jgem ꢃ 10.8, J5,6 ꢃ 8.3, 4.8 Hz, H-6c,6ꢆc), 4.72 (dd, 1H, J2,3
ꢃ 10.3, J3,4 ꢃ 3.7 Hz, H-3c), 4.94 (d, 1H, J1,2 ꢃ 3.7 Hz, H-1b), 5.05 (d, 1H, J1,2
ꢃ 8.2 Hz, H-1c), 5.41 (dd, 1H, J2,3 ꢃ 10.3 Hz, H-2c), 5.82 (d, 1H, J3,4 ꢃ 3.7 Hz,
H-4c), 7.49–8.12 (m, 15H, 3Ph).
Anal. Calcd for C42H48NO20SNa (941.89): C, 53.56; H, 5.14; N, 1.49. Found:
C, 53.46; H, 4.97; N, 1.44.
(3-O-Sulfo-ꢀ-D-galactopyranosyl)-(1→4)-[ꢁ-L-fucopyranosyl-(1→3)]-
1,5-dideoxy-1,5-imino-N-methyl-D-glucitol sodium salt (27). A mixture of 26
(49 mg) and a small amount of NaOMe in MeOH was stirred overnight at rt and
concentrated. The residue was chromatographed (1:1 MeOHMH2O) on a column
1
of Sephadex LH-20 to give 27 (30 mg, quant) as an amorphous mass: H NMR
(DMSO-d6, 55°C) ꢂ 1.01 (d, 3H, J5,6 ꢃ 6.4 Hz, H-6b), 2.00 (t, 1H, Jgem ꢃ J1ax,2
ꢃ 10.7 Hz, H-1aax), 2.23 (s, 3H, NMMe), 2.77 (dd, 1H, Jgem ꢃ 11, J1eq,2 ꢃ 5.1 Hz,
H-1aeq), 4.49 (d, 1H, J1,2 ꢃ 8.3 Hz, H-1c), 4.60 (q, 1H, J5,6 ꢃ 6.4 Hz, H-5b), 5.11
(d, 1H, J1,2 ꢃ 3.6 Hz, H-1b). LRMS (ion-spray MS, negative ion mode) m/z 564.0
(MMNaMH)ꢄ, (ion-spray MS, positive ion mode) m/z 566.2 (MMNaꢅH)ꢅ.
HRMS Calcd for C19H35NO16S: 565.1677. Found: 565.1675.
(2-O-Benzoyl-3-O-levulinoyl-ꢀ-D-galactopyranosyl)-(1→4)-[ꢁ-L-fu-
copyranosyl-(1→3)]-2-O-acetyl-1,5-dideoxy-1,5-imino-D-glucitol (28). Com-
pound 22 (457 mg) in AcOH (15 mL) was hydrogenolyzed with palladium black
(500 mg). Work-up and column chromatography (5:1 CH2Cl2MMeOH) gave 28
1
(213 mg, 79%): [ꢁ]D ꢄ50° (c 1.1, MeOH); H NMR (CD3OD) ꢂ 1.34 (d, 3H,
H-6b), 2.10 (s, 3H, LevMMe), 2.43–2.64 (m, 4H, LevMC2H4), 3.42 (dd, 1H,
H-1aeq), 5.05 (d, 1H, H-1c), 5.13 (d, 1H, H-1b), 5.55 (d, 1H, J1,2 ꢃ J2,3 ꢃ 9.7 Hz,
H-2c).
Anal. Calcd for C32H45NO17 (715.70): C, 53.70; H, 6.34; N, 1.96. Found:
C, 53.64; H, 6.06; N, 1.66.
(2-O-Benzoyl-3-O-levulinoyl-ꢀ-D-galactopyranosyl)-(1→4)-[ꢁ-L-fucopy-
ranosyl-(1→3)]-2-O-acetyl-N-butyl-1,5-dideoxy-1,5-imino-D-glucitol (29).
A
mixture of 28 (51.3 mg), 1-butanol (2 mL) and butyraldehyde (98 ꢉL, 20 equiv)
was hydrogenated in the presence of palladium hydroxide on carbon (50 mg).
Work-up and column chromatography (10:1 CH2Cl2MMeOH) on silica gel af-
1
forded 29 (43.7 mg, 79%): [ꢁ]D ꢄ53.6° (c 0.88, CH2Cl2); H NMR (CD3OD) ꢂ
0.85 (t, 3H, Me), 1.15–1.35 (m, 4H, C2H4), 1.35 (d, 3H, H-6b), 1.97 (s, 3H, AcO),
2.05 (s, 3H, LevMMe), 2.19 (t, 1H, J ꢃ 10.6 Hz, H-1aax), 2.35–2.70 (m, 6H,
LevMC2H4, NMCH2), 3.02 (dd, 1H, Jgem ꢃ 10.8, J1eq,2 ꢃ 4.8 Hz, H-1aeq), 4.09
(d, 1H, J3,4 ꢃ 3.0 Hz, H-4c), 4.90 (m, 1H, H-2a), 4.99 (d, 1H, J1,2 ꢃ 7.9 Hz, H-1c),
5.05 (dd, 1H, J2,3 ꢃ 10, J3,4 ꢃ 3.0 Hz, H-3c), 5.14 (d, 1H, J1,2 ꢃ 3.8 Hz, H-1b),
5.54 (dd, 1H, J1,2 ꢃ 8, J2,3 ꢃ 10 Hz, H-2c), 7.47–8.10 (m, 5H, Ph).
Anal. Calcd for C36H53NO17 (771.81): C, 56.02; H, 6.92; N, 1.81. Found:
C, 55.90; H, 6.84; N, 1.79.

ORDER
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SIALYL- AND SULFO-Lex/Lea ANALOGS
803
(2-O-Benzoyl-3-O-levulinoyl-ꢀ-D-galactopyranosyl)-(1→4)-[ꢁ-L-fucopy-
ranosyl-(1→3)]-2-O-acetyl-N-decyl-1,5-dideoxy-1,5-imino-D-glucitol (30).
A
mixture of 28 (73 mg), decyl aldehyde (296 ꢉL, 20 equiv) and 1:1 EtOAc-THF (2
mL) was hydrogenated in the presence of palladium hydroxide on carbon (55 mg).
Work-up and column chromatography as described for 29 gave 30 (70 mg, 80%):
[ꢁ]D ꢄ47.6° (c 1.4, CH2Cl2); 1H NMR (CD3OD) ꢂ 0.89 (t, 3H, Me), 1.15–1.35 (m,
16H, C8H16), 1.36 (d, 3H, H-6b), 1.98 (s, 3H, AcO), 2.05 (s, 3H, LevMMe), 2.19
(t, 1H, J ꢃ 10.6 Hz, H-1aax), 2.35–2.70 (m, 6H, LevMC2H4, NMCH2), 3.02 (dd,
1H, Jgem ꢃ 10.8, J1eq,2 ꢃ 4.8 Hz, H-1aeq), others are same as those of 29.
Anal. Calcd for C42H65NO17 (855.97): C, 58.93; H, 7.65; N, 1.64 Found:
C, 58.93; H, 7.53; N, 1.60.
(4,6-Di-O-acetyl-2-O-benzoyl-3-O-levulinoyl-ꢀ-D-galactopyranosyl)-
(1→4)-[(2,3,4-tri-O-acetyl-ꢁ-L-fucopyranosyl)-(1→3)]-2,6-di-O-acetyl-N-
butyl-1,5-dideoxy-1,5-imino-D-glucitol (31) and (4,6-Di-O-acetyl-2-O-benzoyl-
ꢀ-D-galactopyranosyl)-(1→4)-[(2,3,4-tri-O-acetyl-ꢁ-L-fucopyranosyl)-(1→3)]
-2,6-di-O-acetyl-N-butyl-1,5-dideoxy-1,5-imino-D-glucitol (33). Compound
29 (45 mg) in pyridine (1 mL) was treated with Ac2O (66 ꢉL) overnight at rt.
Work-up and column chromatography (50:1 CH2Cl2MMeOH) on silica gel gave
31 (60 mg, quant): [ꢁ]D ꢄ62° (c 1.12, CH2Cl2); 1H NMR (CD3OD) ꢂ 0.83 (t, 3H,
Me), 1.10–1.30 (m, 4H, C2H4), 1.34 (d, 3H, H-6b), 1.98–2.24 (8s, 24H, 7AcO,
LevMMe), 2.30–2.70 (m, 6H, LevMC2H4, NMCH2), 3.02 (dd, 1H, Jgem ꢃ 11.2,
J
1eq,2 ꢃ 5.3 Hz, H-1aeq), 3.74, 3.85 (2t, 2H, J ꢃ 9 Hz, H-3a,4a), 3.90 (t, 1H, J ꢃ 7
Hz, H-5c), 4.19, 4.28 (2dd, 2H, H-6a,6ꢆa), 4.34, 4.57 (2dd, 2H, Jgem ꢃ 11.4, J5,6 ꢃ
7.7, J5,6ꢆ ꢃ 6.6 Hz, H-6c,6ꢆc), 4.61 (d, 1H, J1,2 ꢃ 8.2 Hz, H-1c), 4.90 (m, 1H, H-
2a), 5.03 (q, 1H, J ꢃ 6 Hz, H-5b), 5.07 (dd, J1,2 ꢃ 4, J2,3 ꢃ 10.8 Hz, H-2b), 5.11
(dd, 1H, J2,3 ꢃ 10.3, J3,4 ꢃ 3.5 Hz, H-3c), 5.22 (dd, 1H, J2,3 ꢃ 10.8, J3,4 ꢃ 3.3 Hz,
H-3b), 5.39 (dd, 1H, J1,2 ꢃ 8.2, J2,3 ꢃ 10.3 Hz, H-2c), 5.45–5.50 (m, 3H, H-1b, H-
4b, H-4c), 7.45–8.10 (m, 5H, Ph).
A mixture of 31 (55.2 mg) and hydrazine acetate (6.1 mg, 1.2 equiv) in
ethanol was stirred for 1.5 h at rt. Work-up and column chromatography (100:1
CH2Cl2MMeOH) afforded 33 (46.5 mg, 93%): [ꢁ]D ꢄ74.4° (c 0.93, CH2Cl2); 1H
NMR (CD3OD) ꢂ 1.98–2.24 (7s, 21H, 7AcO), 2.87 (br s, 1H, 3-OH of Gal), 3.95
(br dd, 1H, J2,3 ꢃ 10.4, J3,4 ꢃ 4 Hz, H-3c), 5.20 (dd, 1H, J1,2 ꢃ 8.2, J2,3 ꢃ 10.4 Hz,
H-2c), 5.38 (dd, 1H, J3,4 ꢃ 3.7 Hz, H-4c), 5.44 (d, 1H, J3,4 ꢃ 2.9 Hz, H-4b), 5.47
(d, 1H, J1,2 ꢃ 4 Hz, H-1b), other peaks are similar to those of 31.
Anal. Calcd for C43H59NO21 (925.93): C, 55.78; H, 6.42; N, 1.51. Found:
C, 55.53; H, 6.37; N, 1.25.
(4,6-Di-O-acetyl-2-O-benzoyl-3-O-levulinoyl-ꢀ-D-galactopyranosyl)-
(1→4)-[(2,3,4-tri-O-acetyl-ꢁ-L-fucopyranosyl)-(1→3)]-2,6-di-O-acetyl-N-de-
cyl-1,5-dideoxy-1,5-imino-D-glucitol (32) and (4,6-Di-O-acetyl-2-O-benzoyl-ꢀ-
D-galactopyranosyl)-(1→4)-[(2,3,4-tri-O-acetyl-ꢁ-L-fucopyranosyl)-(1→3)]-2,
6-di-O-acetyl-N-decyl-1,5-dideoxy-1,5-imino-D-glucitol (35). Acetylation of
30 (70 mg) was performed as described for 31. Column chromatography (100:1

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FURUI ET AL.
CH2Cl2MMeOH) on silica gel gave 32 (91 mg, quant): [ꢁ]D ꢄ58.4° (c 1.64,
1
CH2Cl2); H NMR (CD3OD) ꢂ 0.88 (t, 3H, Me), 1.10–1.30 (m, 16H, C8H16),
1.98–2.24 (8s, 24H, 7AcO, LevMMe), 5.11 (dd, 1H, J2,3 ꢃ 10, J3,4 ꢃ 3.5 Hz, H-
3c), other peaks are similar to those of 31.
The levulinoyl group of 32 (81.7 mg) was selectively removed by treatment
with hydrazine acetate (8.4 mg, 1.2 equiv) as described for 33 to afforded 35 (71
1
mg, 95%): [ꢁ]D ꢄ67.4° (c 1.42, CH2Cl2); H NMR (CD3OD) ꢂ 1.98–2.24 (7s,
21H, 7AcO), 2.86 (br s, 1H, 3-OH of Gal), 3.01 (dd, 1H, Jgem ꢃ 11.2, J1eq,2 ꢃ 5.3
Hz, H-1aeq), 3.73, 3.82 (2t, 2H, J3,4 ꢃ J4,5 ꢃ 9.2 Hz, H-3a, H-4a), 3.85 (t, 1H, H-
5c), 3.95 (dd, 1H, J2,3 ꢃ 10.4, J3,4 ꢃ 3.7 Hz, H-3c), 4.25, 4.37 (2dd, 2H, H-6a, H-
6ꢆa), 4.34, 4.54 (2dd, 2H, H-6c, H-6ꢆc), 4.50 (d, 1H, J1,2 ꢃ 8 Hz, H-1c), 4.89 (m,
1H, J1ax,2 ꢃ J2,3 ꢃ 10, J1eq,2 ꢃ 5 Hz, H-2a), 5.03 (q, 1H, J5,6 ꢃ 6 Hz, H-5b), 5.07
(dd, 1H, J1,2 ꢃ 4, J2,3 ꢃ 10.8 Hz, H-2b), 5.20 (dd, 1H, J1,2 ꢃ 8, J2,3 ꢃ 10.4 Hz, H-
2c), 5.21 (dd, 1H, J2,3 ꢃ 10.8, J3,4 ꢃ 3 Hz, H-3b), 5.38 (d, 1H, H-4c), 5.44 (d, 1H,
H-4b), 5.47 (d, 1H, H-1b), 7.45–8.15 (m, 5H, Ph).
Anal. Calcd for C49H71NO21 (1010.09): C, 58.27; H, 7.09; N, 1.39. Found:
C, 58.25; H, 6.92; N, 1.29.
(4,6-Di-O-acetyl-2-O-benzoyl-3-O-sulfo-ꢀ-D-galactopyranosyl)-(1→4)-
[(2,3,4-tri-O-acetyl-ꢁ-L-fucopyranosyl)-(1→3)]-2,6-di-O-acetyl-N-butyl-1,5-
dideoxy-1,5-imino-D-glucitol (34) and (3-O-Sulfo-ꢀ-D-galactopyranosyl)-
(1→4)-[ꢁ-L-fucopyranosyl-(1→3)]-N-butyl-1,5-dideoxy-1,5-imino-D-glucitol
sodium salt (37). To a solution of 33 (38.4 mg) in N,N-dimethylformamide (2
mL) was added pyridine sulfur trioxide complex (33.7 mg, 5 equiv) and the mix-
ture was stirred for 2 h at rt, then cooled to 0°C. MeOH (1 mL) was added and the
mixture was stirred for 30 min at 0°C and concentrated. Column chromatography
(10:1 CH2Cl2MMeOH) of the residue on silica gel gave 34 (36.4 mg, 81%): [ꢁ]D
1
ꢄ42° (c 0.75, CH2Cl2); H NMR (DMSO-d6) ꢂ 4.68 (dd, 1H, J2,3 ꢃ 10.3, J3,4
ꢃ 2.9 Hz, H-3c), 4.75 (d, 1H, J1,2 ꢃ 8 Hz, H-1c).
A mixture of 34 (40 mg) and methanolic sodium methoxide (3 mL) was
stirred overnight at rt, and then concentrated. Column chromatography (1:1
MeOHMH2O) of the residue on Sephadex LH-20 afforded 37 (41 mg, quant): [ꢁ]D
ꢄ40° (c 0.92, 1:1 MeOHMH2O); 1H NMR (DMSO-d6) ꢂ 0.86 (t, 3H, Me), 1.00
(d, 3H, J5,6 ꢃ 6.4 Hz, H-6b), 1.10–1.40 (m, 4H, C2H4), 2.08 (t, 1H, Jgem ꢃ J1ax,2
ꢃ 11 Hz, H-1aax), 2.79 (dd, 1H, J1eq,2 ꢃ 5 Hz, H-1aeq), 4.42 (d, 1H, J1,2 ꢃ 7.7 Hz,
H-1c), 4.52 (q, 1H, H-5b), 5.04 (d, 1H, J1,2 ꢃ 3.7 Hz, H-1b). LRMS (FAB-MS,
negative ion mode) m/z 628.27 (MMH)ꢄ, 606.27 (MMNaMH)ꢄ. HRMS Calcd
for C22H39NO16SNa: 628.1887. Found: 628.1886.
(4,6-Di-O-acetyl-2-O-benzoyl-3-O-sulfo-ꢀ-D-galactopyranosyl)-(1→4)-
[(2,3,4-tri-O-acetyl-ꢁ-L-fucopyranosyl)-(1→3)]-2,6-di-O-acetyl-N-decyl-1,5-
dideoxy-1,5-imino-D-glucitol (36) and (3-O-Sulfo-ꢀ-D-galactopyranosyl)-
(1→4)-[ꢁ-L-fucopyranosyl-(1→3)]-N-decyl-1,5-dideoxy-1,5-imino-D-glucitol
sodium salt (38). To a solution of 35 (46.4 mg) in DMF (2 mL) was added pyri-
dine sulfur trioxide complex (74.6 mg, 10 equiv) and the mixture was stirred for

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805
1.5 h at rt. Work-up and column chromatography (20:1 CH2Cl2MMeOH) as de-
scribed for 34 gave 36 (47.5 mg, 88%): [ꢁ]D ꢄ35.7° (c 0.85, CH2Cl2); 1H NMR
(DMSO-d6) ꢂ 4.70 (dd, 1H, J2,3 ꢃ 10.3, J3,4 ꢃ 3.3 Hz, H-3c), 4.76 (d, 1H, J1,2
ꢃ 8.6 Hz, H-1c).
A mixture of 36 (45 mg) in methanolic sodium methoxide (3 mL) was treated
as described for 37 to afford 38 (46 mg, quant): [ꢁ]D ꢄ51° (c 1, 1:1 MeOHMH2O);
1H NMR (DMSO-d6) ꢂ 0.86 (t, 3H, Me), 1.00 (d, 3H, J5,6 ꢃ 6.4 Hz, H-6b),
1.10–1.40 (m, 16H, C8H16), 2.08 (t, 1H, J ꢃ 10 Hz, H-1aax), 2.79 (dd, 1H, Jgem
ꢃ 11, J1eq,2 ꢃ 5 Hz, H-1aeq), 4.43 (d, 1H, J1,2 ꢃ 7.5 Hz, H-1c), 4.53 (q, 1H, H-5b),
5.06 (d, 1H, J1,2 ꢃ 3.7 Hz, H-1b). LRMS (FAB-MS, negative ion mode) m/z
712.32 (MMH)ꢄ, 690.38 (MMNaMH)ꢄ. HRMS Calcd for C28H51NO16SNa:
712.2826. Found: 712.2824.
Methyl 2,4,6-Tri-O-benzoyl-3-O-levulinoyl-1-thio-ꢀ-D-galactopyra-
noside (40). To a stirred solution of methyl 2,6-di-O-benzoyl-1-thio-ꢀ-D-galac-
topyranoside27 (740 mg) in 1:1 CH2Cl2-pyridine (40 mL) was added dropwise a so-
lution of levulinic anhydride (570 mg, 1.5 equiv) in CH2Cl2 (10 mL) at ꢄ50°C.
The mixture was stirred for 20 min at ꢄ50°C and washed successively with 2 M
HCl and water, dried (Na2SO4), and concentrated. The residue was chro-
matographed (1:2 EtOAc-hexane) on silica gel to give methyl 2,6-di-O-benzoyl-3-
O-levulinoyl-1-thio-ꢀ-D-galactopyranoside (760 mg, 84%): [ꢁ]D ꢅ29° (c 1,
CH2Cl2); 1H NMR (CDCl3) ꢂ 2.11 (s, 3H, LevMMe), 2.23 (s, 3H, SMe), 2.43–2.73
(m, 4H, LevMC2H4), 3.08 (d, 1H, J ꢃ 4.2 Hz, 4-OH), 4.03 (t, 1H, J5,6 ꢃ J5,6ꢆ ꢃ 6.3
Hz, H-5), 4.30 (br t, 1H, H-4), 4.55 (d, 1H, J1,2 ꢃ 9.9 Hz, H-1), 4.62, 4.67 (2dd,
2H, J5,6 ꢃ 6.0, J5,6ꢆ ꢃ 6.6 Hz, H-6,6ꢆ), 5.13 (dd, 1H, J2,3 ꢃ 10, J3,4 ꢃ 3.1 Hz, H-3),
5.68 (t, 1H, J1,2 ꢃ J2,3 ꢃ 10 Hz, H-2), 7.40–8.10 (m, 10H, 2Ph). This compound
was benzoylated with benzoyl chloride in pyridine to afford the title compound 40:
1
[ꢁ]D ꢅ50° (c 0.74, CH2Cl2); H NMR (CDCl3) ꢂ 5.88 (dd, 1H, J3,4 ꢃ 3.3, J4,5
ꢃ 0.73 Hz, H-4).
Anal. Calcd for C33H32O10S (620.68): C, 63.86; H, 5.20. Found: C, 63.85; H,
5.04.
(2,4,6-Tri-O-benzoyl-3-O-levulinoyl-ꢀ-D-galactopyranosyl)-(1→3)-2-O-
acetyl-4,6-O-benzylidene-N-benzyloxycarbonyl-1,5-dideoxy-1,5-imino-D-glu-
citol (41). A mixture of 39 (53 mg), 40 (92 mg, 1.2 equiv), molecular sieves 4Å
(200 mg) and CH2Cl2 (4 mL) was stirred overnight at rt, then cooled to 0°C. NIS
(67 mg, 2.4 equiv) and TMSOTf (6 ꢉL, 0.24 equiv) were added, and the mixture
was stirred overnight at 0°Cꢀrt as described for 21. Work-up and column chro-
matography (500:1 CH2Cl2MMeOH) gave 41 (108 mg, 87%): [ꢁ]D ꢄ14.4° (c
1
2.17, CH2Cl2); H NMR (CDCl3) ꢂ 1.69 (s, 3H, AcO), 1.91 (s, 3H, LevMMe),
2.27–2.62 (m, 4H, LevMC2H4), 3.33 (dd, 1H, Jgem ꢃ 14, J1ax,2 ꢃ 6.4 Hz, H-1aax),
3.42 (m, 1H, J4,5 ꢃ J5,6 ꢃ 10, J5,6ꢆ ꢃ 4.3 Hz, H-5a), 3.78 (dd, 1H, Jgem ꢃ 14, J1eq,2
ꢃ 2.4 Hz, H-1aeq), 4.32, 4.46 (2dd, 2H, Jgem ꢃ 11.3, J5,6 ꢃ 7.6, J5,6ꢆ ꢃ 5.8 Hz, H-
6b,6ꢆb), 4.77 (m, 1H, J2,3 ꢃ 6.7 Hz, H-2a), 4.85 (dd, 1H, Jgem ꢃ 11, J5,6ꢆ ꢃ 4.3 Hz,
H-6ꢆa), 5.05 (d, 1H, J1,2 ꢃ 7.9 Hz, H-1b), 5.10 (2d, 2H, ZMCH2), 5.33 (dd, 1H,

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806
FURUI ET AL.
J
2,3 ꢃ 10, J3,4 ꢃ 3.4 Hz, H-3b), 5.55 (dd, 1H, H-2b), 5.60 (s, 1H, benzylidene CH),
5.78 (d, 1H, J3,4 ꢃ 3.4 Hz, H-4b), 7.20–8.20 (m, 25H, 5Ph).
Anal. Calcd for C55H53NO17 (1000.02): C, 66.06; H, 5.34; N, 1.40. Found:
C, 65.93; H, 5.11; N, 1.37.
(2,4,6-Tri-O-benzoyl-3-O-levulinoyl-ꢀ-D-galactopyranosyl)-(1→3)-2-O-
acetyl-N-benzyloxycarbonyl-1,5-dideoxy-1,5-imino-D-glucitol (42) and (2,4,6-
Tri-O-benzoyl-3-O-levulinoyl-ꢀ-D-galactopyranosyl)-(1→3)-2-O-acetyl-N-
benzyloxycarbonyl-6-O-tert-butyldimethylsilyl-1,5-dideoxy-1,5-imino-D-gluci
tol (43). A mixture of 41 (323 mg) and 80% aq AcOH (20 mL) was stirred
overnight at 45°C, then concentrated. Column chromatography (125:1 CH2Cl2M
MeOH) of the residue on silica gel gave 42 (252 mg, 86%): [ꢁ]D ꢄ39° (c 0.66,
CH2Cl2); 1H NMR (CDCl3) ꢂ 1.43 (s, 3H, AcO), 1.89 (s, 3H, LevMMe), 4.67 (m,
1H, J ꢃ 4ꢀ5 Hz, H-2a), 4.88 (d, 1H, J1,2 ꢃ 7.9 Hz, H-1b), 5.02, 5.15 (2d, 2H, Jgem
ꢃ 12.5 Hz, ZMCH2), 5.42 (dd, 1H, J2,3 ꢃ 10.6, J3,4 ꢃ 3.1 Hz, H-3b), 5.61 (dd, 1H,
H-2b), 5.83 (d, 1H, H-4b).
To a cooled solution of 42 (213 mg) in CH2Cl2 (10 mL) and pyridine (5 mL)
was added tert-butyldimethylsilyl chloride (176 mg, 3 equiv), and the mixture
was stirred overnight at rt. Work-up and column chromatography (250:1
CH2Cl2MMeOH) on silica gel afforded 43 (221 mg, 92%): [ꢁ]D ꢅ34.6° (c 1.66,
CH2Cl2); 1H NMR (CDCl3) ꢂ 0.86 (s, 9H, t-butyl), 1.27 (s, 3H, AcO), 1.92 (s, 3H,
LevMMe), 2.30–2.60 (m, 4H, LevMC2H4), 3.30 (dd, 1H, Jgem ꢃ 12.8 Hz, H-1a),
4.69 (narrow m, 1H, H-2a), 4.85 (d, 1H, J1,2 ꢃ 7.9 Hz, H-1b), 5.03, 5.16 (2d, 2H,
J
gem ꢃ 12.3 Hz, ZMCH2), 5.40 (dd, 1H, J2,3 ꢃ 10.4, J3,4 ꢃ 3 Hz, H-3b), 5.63 (dd,
1H, H-2), 5.84 (d, 1H, J3,4 ꢃ 3 Hz, H-4b), 7.20–8.20 (m, 20H, 4Ph).
Anal. Calcd for C54H63NO17Si (1026.17): C, 63.21; H, 6.19; N, 1.36. Found:
C, 63.17; H, 6.00; N, 1.21.
(2,4,6-Tri-O-benzoyl-3-O-levulinoyl-ꢀ-D-galactopyranosyl)-(1→3)-
[(2,3,4-tri-O-benzyl-ꢁ-L-fucopyranosyl)-(1→4)]-2-O-acetyl-N-benzyloxycar-
bonyl-6-O-tert-butyldimethylsilyl-1,5-dideoxy-1,5-imino-D-glucitol (44). To
a stirred mixture of 43 (47 mg), methyl 2,3,4-tri-O-benzyl-1-thio-ꢀ-L-fucopyra-
noside14 (26 mg, 1.2 equiv) and molecular sieves 4Å (100 mg) in benzene was
added dimethyl(methylthio)sulfonium triflate (DMTST, 63 mg, 4 equiv) at 7°C,
and stirring was continued for 1.5 h at 7°C. Work-up and column chromatography
(1:2 EtOAc-hexane) gave 44 (36 mg, 55%): [ꢁ]D ꢄ43° (c 0.5, CH2Cl2); 1H NMR
(CDCl3) ꢂ 0.87 (s, 9H, t-butyl), 1.07 (d, 3H, J5,6 ꢃ 6.4 Hz, H-6c), 1.81 (s, 3H,
AcO), 1.91 (s, 3H, LevMMe), 5.09 (d, 1H, J1,2 ꢃ 3.7 Hz, H-1c), 7.10–8.15 (m,
35H, 7Ph).
Anal. Calcd for C81H91NO21Si (1442.69): C, 67.44; H, 6.36; N, 0.97. Found:
C, 67.25; H, 6.19; N, 0.72.
(2,4,6-Tri-O-benzoyl-3-O-levulinoyl-ꢀ-D-galactopyranosyl)-(1→3)-
[(2,3,4-tri-O-benzyl-ꢁ-L-fucopyranosyl)-(1→4)]-2-O-acetyl-N-benzyloxycar-
bonyl-1,5-dideoxy-1,5-imino-D-glucitol (45) and (2,4,6-Tri-O-benzoyl-3-O-lev-

ORDER
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SIALYL- AND SULFO-Lex/Lea ANALOGS
807
ulinoyl-ꢀ-D-galactopyranosyl)-(1→3)-[(2,3,4-tri-O-benzyl-ꢁ-L-fucopyra-
nosyl)-(1→4)]-2-O-acetyl-6-O-benzoyl-N-benzyloxycarbonyl-1,5-dideoxy-1,5-
imino-D-glucitol (46). A mixture of 44 (36 mg) and 80% aq AcOH (10 mL) was
stirred for 3 h at rt, then concentrated. Column chromatography (125:1 CH2Cl2M
MeOH) of the residue on silica gel gave 45 (29 mg, 88%): [ꢁ]D ꢄ43° (c 1,
CH2Cl2); 1H NMR (CDCl3) ꢂ 1.12 (d, 3H, J5,6 ꢃ 6.2 Hz, H-6c), 1.79 (s, 3H, AcO),
1.93 (s, 3H, LevMMe), 4.90 (d, 1H, Jgem ꢃ 11.5 Hz, ZMCH2), 4.93 (d, 1H, J1,2
ꢃ 7.9 Hz, H-1b), 5.38 (dd, 1H, J2,3 ꢃ 10.4, J3,4 3 Hz, H-3b), 5.55 (d, 1H, H-2b),
5.83 (d, 1H, H-4b), 7.2–8.2 (m, 35H, 7Ph).
To a solution of 45 (29 mg) in pyridine (10 mL) was added benzoyl chloride
(3 ꢉL, 1.2 equiv) and the mixture was stirred overnight at rt. Work-up and column
chromatography (250:1 CH2Cl2MMeOH) afforded 46 (31 mg, quant): [ꢁ]D ꢄ60°
(c 2.37, CH2Cl2); 1H NMR (CDCl3) ꢂ 1.10 (d, 3H, J5,6 ꢃ 6.2 Hz, H-6c), 1.79 (s,
3H, AcO), 1.89 (s, 3H, LevMMe), 4.93 (d, 1H, J1,2 ꢃ 7.9 Hz, H-1b), 5.40 (d, 1H,
H-3b), 5.60 (dd, 1H, J2,3 ꢃ 10.4 Hz, H-2b), 5.82 (d, 1H, J3,4 ꢃ 3.3 Hz, H-4b).
Anal. Calcd for C82H81NO22 (1432.54): C, 68.75; H, 5.70; N, 0.98. Found:
C, 68.48; H, 5.42; N, 0.70.
(2,4,6-Tri-O-benzoyl-3-O-sulfo-ꢀ-D-galactopyranosyl)-(1→3)-[(ꢁ-L-fu-
copyranosyl)-(1→4)]-2-O-acetyl-6-O-benzyl-1,5-dideoxy-1,5-imino-N-
methyl-D-glucitol sodium salt (49) and (3-O-sulfo-ꢀ-D-galactopyranosyl)-
(1→3)-[(ꢁ-L-fucopyranosyl)-(1→4)]-1,5-dideoxy-1,5-imino-N-methyl-D-glucit
ol sodium salt (50). Treatment of 46 (155 mg) with hydrazine acetate (10 mg) in
EtOH, as described for 24, gave 47 (135 mg, 93%): [ꢁ]D ꢄ76° (c 2, CH2Cl2); 1H
NMR (CDCl3) ꢂ 1.08 (d, 3H, J5,6 ꢃ 6.4 Hz, H-6c), 1.82 (s, 3H, AcO), 3.23 (bs, 1H,
H-1a), 4.87 (d, 1H, Jgem ꢃ 12.1 Hz, CH2 of Z), 4.92 (d, 1H, J1,2 ꢃ 8.1 Hz, H-1b),
5.08 (bs, 1H, H-1c), 5.40 (dd, 1H, J2,3 ꢃ 10.1 Hz, H-2b), 5.77 (d, 1H, J3,4 ꢃ 3.3
Hz, H-4b). A mixture of 47 (101 mg) and pyridine sulfur trioxide complex (96 mg,
8 equiv) in N,N-dimethylformamide (0.5 mL) was stirred for 2 h at rt. Work-up and
column chromatography on silica gel, as described for 25, afforded 48 (109 mg,
quant): [ꢁ]D ꢄ56° (c 2, CH2Cl2). Compound 48 (99 mg) in MeOH was treated with
cation-exchange resin Dowex-Naꢅ, and then hydrogenolyzed in MeOH (5 mL) in
the presence of formalin (0.5 mL) and HCl-free palladium black (200 mg) for 4
days at rt. Work-up and column chromatography (10:1 CH2Cl2MMeOH) on silica
1
gel gave 49 (66 mg, 92%): [ꢁ]D ꢄ30.5° (c 0.9, MeOH); H NMR (DMSO-d6,
50°C) ꢂ 1.20 (d, 3H, J5,6 ꢃ 6.4 Hz, H-6c), 1.99 (s, 3H, AcO), 2.05 (t, 1H, J ꢃ 10.1
Hz, H-1aax), 2.20 (s, 3H, NMMe), 2.81 (dd, Jgem ꢃ 11, J1eq,2 ꢃ 5.1 Hz, H-1aeq),
4.75 (d, 1H, J1,2 ꢃ 3.7 Hz, H-1c), 4.79 (dd, 1H, H-3b), 5.16 (d, 1H, J1,2 ꢃ 8.2 Hz,
H-1b), 5.36 (dd, 1H, J2,3 ꢃ 10.4 Hz, H-2b), 5.86 (d, 1H, J3,4 ꢃ 3.1 Hz, H-4b),
7.44–8.05 (m, 20H, 4Ph).
To a solution of 49 (56 mg) in MeOH (5 mL) was added a small amount of
NaOMe (pH ꢃ 12), and the mixture was stirred for 2 days at rt. and concentrated.
The residue was chromatographed (1:1 MeOHMH2O) on a column of Sephadex
LH-20 to give 50 (31 mg, quant) as an amorphous mass: [ꢁ]D ꢄ56° (c 0.114, 1:1
1
MeOHMH2O); H NMR (DMSO-d6, 50°C) ꢂ 0.99 (d, 3H, H-6c), 2.01 (t, 1H, J

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FURUI ET AL.
ꢃ 10.4 Hz, H-1aax), 2.23 (s, 3H, NMMe), 2.82 (dd, 1H, Jgem ꢃ 10.8, J1eq,2 ꢃ 4.8
Hz, H-1aeq), 4.62 (d, 1H, J1,2 ꢃ 7.7 Hz, H-1b), 4.77 (q, 1H, J5,6 ꢃ 6.6 Hz, H-5c),
4.93 (d, 1H, J1,2 ꢃ 3.7 Hz, H-1c). Ion-spray MS (negative-ion mode) m/z 564.1
(MMNaMH)ꢄ; MS/MS (P ꢃ m/z 563.9) m/z 417.6 (MMNaMFuc)ꢄ. 96.8
(HSO4)ꢄ.
(2,4,6-Tri-O-benzoyl-3-O-levulinoyl-ꢀ-D-galactopyranosyl)-(1→3)-[(ꢁ-
L-fucopyranosyl)-(1→4)]-2-O-acetyl-1,5-dideoxy-1,5-imino-D-glucitol (51).
Compound 46 (1.34 g) in AcOH (25 mL) was hydrogenolyzed with palladium
black (1.30 g) as described for 28 to give 51 (660 mg, 71%): [ꢁ]D ꢄ45° (c 1.63,
MeOH); 1H NMR (CD3OD) ꢂ 1.41 (d, 3H, H-6c), 1.82 (s, 3H, AcO), 2.10 (s, 3H,
LevMMe), 2.26–2.54 (m, 4H, LevMC2H4), 3.11 (dd, 1H, Jgem ꢃ 12.5 Hz, H-
1aeq), 3.64 (t, 1H, J3,4 ꢃ 9.7 Hz, H-3a), 4.56 (m, 1H, J1ax,2 ꢃ J2,3 ꢃ 10.3, J1eq,2
ꢃ 5.3 Hz, H-2a), 5.05 (d, 1H, J1,2 ꢃ 3.9 Hz, H-1c), 5.28 (d, 1H, J1,2 ꢃ 7.7 Hz,
H-1b),7.43–8.12 (m, 15H, 3Ph).
Anal. Calcd for C46H53NO19 (923.92): C, 59.80; H, 5.78; N, 1.52. Found:
C, 59.63; H, 5.71; N, 1.41.
(2,4,6-Tri-O-benzoyl-3-O-levulinoyl-ꢀ-D-galactopyranosyl)-(1→3)-[(ꢁ-
L-fucopyranosyl)-(1→4)]-2-O-acetyl-1,5-imino-N-butyl-D-glucitol (52) and
(2,4,6-Tri-O-benzoyl-3-O-levulinoyl-ꢀ-D-galactopyranosyl)-(1→3)-[(2,3,4-tri-
O-acetyl-ꢁ-L-fucopyranosyl)-(1→4)]-2,6-di-O-acetyl-1,5-dideoxy-1,5-imino-
N-butyl-D-glucitol (54). A mixture of 51 (67.5 mg), 1-butanol (3 mL) and bu-
tyraldehyde (129 ꢉL, 20 equiv) was hydrogenated with palladium hydroxide on
carbon (68 mg) overnight at rt. Work-up and column chromatography (25:1
CH2Cl2-MeOH) on silica gel gave 52 (46 mg, 64%): [ꢁ]D ꢄ32.3° (c 1.0, CH2Cl2);
1H NMR (CDCl3) ꢂ 0.85 (t, 3H, Me), 1.15–1.35 (m, 4H, C2H4), 1.37 (d, 3H, H-6c),
1.91 (s, 3H, AcO), 2.02 (s, 3H, LevMMe), 2.34–2.60 (m, 4H, LevMC2H4), 2.95
(dd, 1H, Jgem ꢃ 11.9, ꢃ J1eq,2 ꢃ 4.2 Hz, H-1aeq), 5.51 (dd, 1H, J1,2 ꢃ 8.1, J2,3
ꢃ 10.4 Hz, H-2b), 7.30–8.13 (m, 15H, 3Ph). Treatment of 52 (46.7 mg) with Ac2O
(36 ꢉL, 8 equiv) in pyridine (1 mL) afforded 54: [ꢁ]D ꢄ53° (c 1.0, CH2Cl2); ꢂ 0.85
(t, 3H, Me), 1.23–1.30 (m, 4H, C2H4), 1.30 (s, 3H, H-6c), 1.93–2.20 (5s, 15H,
5AcO), 2.06 (s, 3H, LevMMe), 2.14 (t, 1H, Jgem ꢃ J1ax,2 ꢃ 11.7 Hz, H-1aax),
2.35–2.63 (m, 4H, LevMC2H4), 3.02 (dd, 1H, Jgem ꢃ 11.7, ꢃ J1eq,2 ꢃ 4.8 Hz,
H-1aeq), 5.06 (d, 1H, J1,2 ꢃ 3.5 Hz, H-1c), 5.49 (dd, 1H, J1,2 ꢃ 8.1, J2,3 ꢃ 10.4 Hz,
H-2b), 7.40–8.11 (m, 15H, 3Ph).
Anal. Calcd for C58H69NO23 (1148.17): C, 60.67; H, 6.06; N, 1.22. Found:
C, 60.66; H, 5.83; N, 0.99.
(2,4,6-Tri-O-benzoyl-3-O-levulinoyl-ꢀ-D-galactopyranosyl)-(1→3)-O-
[(ꢁ-L-fucopyranosyl)-(1→4)]-2-O-acetyl-1,5-dideoxy-1,5-imino-N-decyl-D-
glucitol (53) and (2,4,6-Tri-O-benzoyl-3-O-levulinoyl-ꢀ-D-galactopyranosyl)-
(1→3)-O-[(2,3,4-tri-O-acetyl-ꢁ-L-fucopyranosyl)-(1→4)]-2,6-di-O-acetyl-1,5-
dideoxy-1,5-imino-N-decyl-D-glucitol (55). A mixture of 51 (79 mg), EtOAc (1
mL) and decyl aldehyde (320 ꢉL, 20 equiv) was hydrogenated with palladium hy-

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SIALYL- AND SULFO-Lex/Lea ANALOGS
809
droxide on carbon (79 mg) for 2 days at rt., and worked up as described for 52 to
afford 53 (67.3 mg, 75%): [ꢁ]D ꢄ30.3° (c 1.36, CH2Cl2); 1H NMR (CDCl3) ꢂ 0.87
(t, 3H, Me), 1.23 (m, 16H, C8H16), 1.37 (d, 3H, H-6c), 1.91 (s, 3H, AcO), 2.02 (s,
3H, LevMMe), 2.34–2.60 (m, 4H, LevMC2H4). Treatment of 53 (66.6 mg) with
Ac2O (47 ꢉL) and pyridine (1 mL) gave 55 (77 mg): [ꢁ]D ꢄ51° (c 1.43, CH2Cl2);
1H NMR (CDCl3) ꢂ 0.88 (t, 3H, Me), 1.24 (m, 16H, C8H16), 1.31 (s, 3H, H-6c),
1.93–2.21 (5s, 15H, 5AcO), 2.07 (s, 3H, LevMMe), 2.31–2.63 (m, 4H,
LevMC2H4), 3.03 (dd, 1H, Jgem ꢃ 11.7, J1eq,2 ꢃ 5.1 Hz, H-1aeq), 5.05 (d, 1H, J1,2
ꢃ 3.1 Hz, H-1c), 5.50 (dd, 1H, J1,2 ꢃ 8.2, J2,3 ꢃ 10.4 Hz, H-2b), 7.40–8.11 (m,
15H, 3Ph).
Anal. Calcd for C64H81NO23 (1232.34): C, 62.38; H, 6.63; N, 1.14. Found:
C, 62.31; H, 6.62; N, 0.92.
(3-O-Sulfo-ꢀ-D-galactopyranosyl)-(1→3)-[(ꢁ-L-fucopyranosyl)-(1→4)]-
1,5-dideoxy-1,5-imino-N-butyl-D-glucitol sodium salt (60). Compound 54
(50.3 mg) was treated with hydrazine acetate (5 mg, 1.2 equiv) in EtOH (1 mL) as
described for 24 to give 56 (42 mg, 91%): [ꢁ]D ꢄ64° (c 0.84, CH2Cl2); 1H NMR
(CDCl3) ꢂ 0.85 (d, 3H, Me), 1.19 (d, 3H, H-6c), 1.18–1.26 (m, 4H, C2H4),
1.92–2.18 (5s, 15H, 5AcO), 2.43–2.56 (m, 2H, NMCH2), 3.05 (dd, 1H, Jgem
ꢃ 11.7 Hz, H-1aeq), 4.12 (dd, 1H, H-3b), 4.53, 4.83 (2dd, 2H, Jgem ꢃ 11.4, J5,6 ꢃ
6.8, J5,6ꢆ ꢃ 5.9 Hz, H-6b,6ꢆb), 5.08 (d, 1H, J1,2 ꢃ 8.4 Hz, H-1b), 5.77 (d, 1H, J3,4
ꢃ 3.7 Hz, H-4b), 7.41–8.12 (m, 15H, 3Ph), and complete loss of the Lev group. A
mixture of 56 (55 mg) and pyridine sulfur trioxide complex (74.6 mg, 10 equiv) in
N,N-dimethylformamide (2 mL) was stirred for 1.5 h at rt, worked up as described
for 48, and purified on a column of silica gel (20:1 CH2Cl2MMeOH) to give 57 (56
mg): [ꢁ]D ꢄ41.3° (c 0.4, CH2Cl2); 1H NMR (DMSO-d6) ꢂ 0.86 (t, 3H, Me), 1.24
(m, 4H, C2H4), 1.99–2.11 (5s, 15H, 5AcO), 5.12 (d, 1H, J1,2 ꢃ 9.3 Hz, H-1b), 5.25
(d, 1H, J1,2 ꢃ 3.1 Hz, H-1c), 5.90 (d, 1H, J3,4 ꢃ 3.1 Hz, H-4b), 7.46–8.13 (m, 15H,
3Ph). O-Deacylation of 57 (56 mg) and chromatography on a column of Sephadex
LH-20, as described for 50, afforded 60 (quant) as an amorphous mass: [ꢁ]D ꢄ67°
(c 0.33, 1:1 MeOHMH2O); 1H NMR (DMSO-d6) ꢂ 0.86 (t, 3H, Me), 0.99 (d, 3H,
H-6c), 1.10–1.40 (m, 4H, C2H4), 2.80 (dd, 1H, H-1aeq), 4.60 (d, 1H, J1,2 ꢃ 7.7 Hz,
H-1b), 4.90 (d, 1H, J1,2 ꢃ 3.5 Hz, H-1c). FAB-MS (negative ion mode) m/z 606.30
(MMNa)ꢄ, (C22H40NO16S: Exact 606.2068).
(3-O-Sulfo-ꢀ-D-galactopyranosyl)-(1→3)-[(ꢁ-L-fucopyranosyl)-(1→4)]-
1,5-dideoxy-1,5-imino-N-decyl-D-glucitol sodium salt (61). Treatment of 55
with hydrazine acetate in EtOH, as described for 56, gave 58: [ꢁ]D ꢄ58° (c 1.32,
1
CH2Cl2); H NMR (CDCl3) ꢂ 0.88 (t, 3H, Me), 1.91–1.21 (m, 16H, C8H16),
1.92–2.18 (5s, 15H, 5AcO), 2.20–2.55 (m, 2H, NMCH2), 3.06 (dd, 1H, H-1aeq),
4.14 (dd, 1H, H-3b), 4.54, 4.84 (2dd, 2H, Jgem ꢃ 11.5, J5,6 ꢃ J5,6ꢆ ꢃ 7.0 Hz,
H-6b,6ꢆb), 5.31 (dd, 1H, J1,2 ꢃ 8.3, J2,3 ꢃ 3.7 Hz, H-2b), 5.32 (dd, 1H, J1,2 ꢃ 3.5,
J
2,3 ꢃ 9.0 Hz, H-2c), 5.76 (d, 1H, J3,4 ꢃ 3.7 Hz, H-4b), and complete loss of the
Lev group. Sulfation of 58 (60 mg) was carried out as described for 57 to give 59
(61 mg), which was treated with NaOMe in MeOH to afford 61 (quant) as an amor-

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FURUI ET AL.
phous mass: 1H NMR (DMSO-d6) ꢂ 0.86 (t, 3H, Me), 0.98 (d, 3H, H-6c), 1.25 (m,
16H, C8H16), 2.15–2.19 (m, 2H, NMCH2), 2.81 (dd, 1H, Jgem ꢃ 11.4 Hz, H-1aeq),
4.59 (d, 1H, J1,2 ꢃ 7.7 Hz, H-1b), 4.89 (d, 1H, J1,2 ꢃ 3.5 Hz, H-1c). FAB-MS (neg-
ative ion mode) m/z 712.26 (MMH)ꢄ, (C28H51NO16SNa: Exact 712.2826), 690.31
(MMNa)ꢄ (C28H52NO16S: Exact 690.3007).
ACKNOWLEDGMENTS
This work was supported in part by Grants-in-Aid for Scientific Research
from the Ministry of Education, Science, and Culture of Japan. The authors thank
Dr. Takao Ikami of Sanwa Kagaku Kenkyusho for FAB-MS measurements, Dr.
Akihiro Kondo of Biotechnology Research Laboratories, Takara Shuzo Co., Ltd.
for the ion-spray MS analysis, and Drs. Yohji Ezure, Yoshiaki Yoshikuni, and
Tadaaki Ohgi of Nippon Shinyaku Co., Ltd. for multiform support including se-
lectin binding assay.
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Received May 28, 2001
Accepted August 23, 2001

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