Synthesis of a versatile neuraminic acid 'C'-disaccharide precursor for the synthesis of C-glycoside analogues of gangliosides

Full text of DOI:10.1021/jo990564p

7254
J . Org. Chem. 1999, 64, 7254-7259
attachment site of pathogens to the cells, and often, the
Syn th esis of a Ver sa tile Neu r a m in ic Acid
removal of this carbohydrate initiates catabolic and
“C”-Disa cch a r id e P r ecu r sor for th e
Syn th esis of C-Glycosid e An a logu es of
Ga n gliosid es
inflammatory processes.16,17
In vivo, sialic acid containing glycoconjugates are
catabolized by the removal of the terminal sialic acid
residue through the action of hydrolase-type enzymes
called neuraminidases that cleave the glycosidic bond of
N-acetylneuraminic acid.18 The design of nonhydrolyzable
analogues of N-acetylneuraminic acid glycosides is an
attractive approach to control, at the molecular level,
events of crucial importance to glycobiology and im-
munology. Thus, the replacement of the interglycosidic
oxygen atom by a hydroxymethylene group generates a
new class of hydrolytically and metabolically inert “C”-
glycosides.
We are interested in the synthesis of the C-glycoside
analogues of GM4 and GM3 (3 and 4, Scheme 1) because
such glycoconjugates are expected to be resistant to
catabolism and to have increased biological half-lives,
leading to derivatives with significant therapeutic po-
tential. For example, the C-glycoside of GM4 is expected
to demonstrate stable cell adhesion over a prolonged
period of time,7 while the C-analogue of GM3 (4, Scheme
1) is expected to inhibit EGF receptor mediated signal
transduction.9 Both analogues 3 and 4 are also potential
candidates as cancer vaccines.
Recently, our laboratory developed a method for the
synthesis of C-glycosides of N-acetyneuraminic acid using
samarium iodide.19 We now report the use of this method
for the synthesis of a common C-glycoside precursor of
GM4 and GM3 (22(S), (Scheme 3), this precursor being
also versatile for the synthesis of C-glycoside analogues
of other related gangliosides such as GM2 or GM1. This
C-glycoside precursor was obtained through samarium-
(II) iodide coupling of the 3-formyl derivative 15 (Scheme
2) with the N-acetyneuraminic acid phenyl sulfone
derivative 17 (Scheme 3).
He´le`ne G. Bazin, Yuguo Du, Tu¨lay Polat, and
Robert J . Linhardt*
Division of Medicinal and Natural Products Chemistry and
Department of Chemical and Biochemical Engineering, The
University of Iowa, PHAR-S328, Iowa City, Iowa 52242
Received March 30, 1999
Gangliosides are cell-surface sialic acid containing
glycolipids. They are found in high concentration on the
surface of central nervous system cells. Gangliosides are
believed to play a role in important biological events
such as cell growth regulation, cell-cell adhesion, and
malignancy.1-3 GM4 (1, Scheme 1) is structurally the
simplest ganglioside and has been isolated as a minor
component from brain, rat kidney, mouse erythrocytes,
and chicken egg yolk.4-6 GM4 is an important cell
adhesion molecule in cell growth and tissue regeneration
and promotes neuron adhesion through its interaction
with myelin-associated glycoprotein.7 GM3 (2, Scheme 1)
was first isolated from equine erythrocytes8 and is known
to modulate the epidermal growth factor (EGF) and the
platelet-derived growth factor (PDGF) receptors.9,10 Tu-
mors, such as those involved in brain cancer, overexpress
EGF receptor. GM4 and GM3 are also found in high
concentration in tumor cells.11
N-Acetylneuraminic acid is often found at the nonre-
ducing end of the oligosaccharide component of these
gangliosides. N-Acetylneuraminic acid is involved in a
number of important biological events, including intra-
cellular interactions such as adhesion, aggregation and
agglutination; masking antigenic oligosaccharides and
suppression of undesired immune reactions; influence on
the cell membrane permeability for ions, amino acids,
and proteins; and protection of glycoproteins against
proteolysis.12-15 Terminal N-acetylneuraminic acid is an
Resu lts a n d Discu ssion
In a previous paper,19 our laboratory described the
synthesis of methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-
2,6-anhydro-3,5-dideoxy-2-C-[(R)-hydroxy[3-(methyl 2,4,6-
tri-O-benzyl-3-deoxy-R-D-galactopyranosidyl)]methyl]-D-
erythro-L-manno-nonate. Attempts to use this C-disaccha-
ride as a building block for the synthesis of 3 and 4, using
previously described chemistry to convert the anomeric
methyl group into thiophenyl20 or acetate, failed. This led
us to design the 3-formyl synthon 15 in which the
anomeric position was protected as a p-methoxyphenyl
* To whom correspondence should be addressed. Fax: 319-335-6634.
E-mail: robert-linhardt @uiowa.edu.
(1) Taki, T.; Hirabayashi, Y.; Ishikawa, H.; Ando, S.; Kon, K.;
Tanaka, Y.; Matsumoto, M. J . Biol. Chem. 1986, 261, 3075-3078.
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Matsumoto, M.; Kon, K.; Ando, S. J . Biol. Chem. 1990, 265, 8144-
8151.
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243-252.
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golipid Biochemistry; Kanfer, J . N., Hakomori S., Eds.; Plenum Press:
New York, 1983; pp 99-101.
(5) Hakomori, S. Annu. Rev. Biochem. 1981, 50, 733-764.
(6) Nores, G. A.; Dohi, T.; Taniguchi, M.; Hakomori, S. J . Immunol.
1987, 139, 3171-3176.
(12) (12)Sialic Acids; Schauer, R., Ed.; Springer-Verlag: New York,
1985.
(13) (13)Biological Roles of Sialic Acid; Rosenberg, V., Shengrund,
C., Eds.; Plenum: New York, 1976.
(14) Sharon, N. Complex carbohydrates; Addison-Wesley: London,
1975.
(15) Varki, A. Glycobiology 1992, 2, 25-40.
(16) Sharon, N.; Lis, H. Science 1989, 246, 227-234.
(17) Lis, H. Lectins; Chapman and Hall: London, 1989.
(18) Air, G. M.; Laver, W. Proteins: Struct., Funct. Genet. 1989, 6,
341-356 and references therein.
(19) Vlahov, I. R.; Vlahova, P. I.; Linhardt, R. J . J . Am. Chem. Soc.
1997, 119, 1480-1481.
(20) Nicolaou, K. C.; Seitz, S. P.; Papahatjis, D. P. J . Am. Chem.
Soc. 1983, 105, 2430-2434.
(7) Yang, L. J .-S.; Zeller, C. B.; Shaper, N. L.; Kiso, M.; Hasegawa,
A.; Shapiro, R. E.; Schnaar, R. L. Proc. Natl. Acad. Sci. U.S.A. 1996,
93, 814-818.
(8) Yamakawa, T.; Suzuki, S. J . Biochem. 1952, 39, 383-402.
(9) Rebbaa, A.; Hurh, J .; Yamamoto, H.; Kersey, D. S.; Bremer, E.
G. Glycobiology 1996, 6, 399-406.
(10) (a) Bremer, E.; Schlessinger, J .; Hakomori, S. J . Biol. Chem.
1986, 261, 2434-2440. (b) Hanai, N.; Nores, G.; Torres-Mendez, C.-
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10.1021/jo990564p CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/01/1999

Notes
J . Org. Chem., Vol. 64, No. 19, 1999 7255
Sch em e 1
Sch em e 2
Sch em e 3
ether, a protecting group known to be readily converted
into the corresponding hydroxyl,21 halogen, or thio-
phenyl.22
et al.23 and Schmidt et al.24 (Scheme 2). Glycosidation of
â-D-galactose pentaacetate 5 with p-methoxyphenol and
trifluoromethanesulfonate as promoter25 afforded the
The 3-formyl galactoside key intermediate 15 was
synthesized, following the procedure described by Kong
(22) Zhang, Z. Y.; Magnusson, G. Carbohydr. Res. 1996, 295, 41-
55.
(23) Kong, F.; Lu, D. Carbohydr. Res. 1990, 198, 141-148.
(24) Schmidt, R. R.; Beyerbach, A. Liebiegs Ann. Chem. 1992, 983-
986.
(21) Mori, M.; Ito, Y.; Ogawa, T. Carbohydr. Res. 1989, 192, 131-
146.

7256 J . Org. Chem., Vol. 64, No. 19, 1999
Notes
1
corresponding p-methoxyphenyl glycoside 6 in 92% yield.
Deacetylation of 6, followed by regioselective allylation
of the dibutyltin complex of 7, gave the corresponding
3-O-allyl galactopyranoside 8 in 85% yield. Benzylation
of 8 under standard conditions (91%), followed by selec-
tive deallylation using palladium(II) chloride, afforded
the 3-hydroxyl derivative 10 in 94% yield. Oxidation of
10 using DMSO-acetic anhydride26 led to the corre-
sponding 3-ketopyranoside 11 in 84% yield. Methylena-
tion of 11 using Tebbe’s reagent27 afforded the 3-meth-
ylene derivative 12 in 84% yield. Hydroboration of 12
using 9-BBN28 led to a mixture of the corresponding
3-hydroxymethylene galactopyranoside 13 and gulopy-
ranoside 14, which were not separable by chromatogra-
phy on silica gel. These two epimers were obtained in a
ratio galacto-13: gulo-14 of 1.5:1.0, as determined by 1H
NMR spectroscopy. The configuration at C-3 was deduced
from the large J 2,3 vicinal coupling constant (11.1 Hz) for
the galacto epimer 13 and from the smaller J 2,3 vicinal
coupling constant (5.5 Hz) for the gulo epimer 14.
Oxidation of the mixture 13-14 with the system DMSO-
oxalyl chloride-triethylamine29 afforded the 3-formyl
galactopyranoside 15 and the 3-formyl gulopyranoside 16
in 60% and 13% yield, respectively. The two epimers 15
and 16 were easily separable by chromatography on silica
gel, and their configuration at C-3 was determined by
1H NMR spectroscopy. The high J 2,3 vicinal coupling
constant of 11.1 Hz observed for 15 and the smaller J 2,3
vicinal coupling constant of 6.6 Hz observed for 16
allowed the unambiguous assignment of the galacto
configuration in 15 and gulo configuration in 16. The
ratio of the 3-formyl galacto and gulo derivatives 15 and
16 obtained upon oxidation of 13-14 ranged from 4.6:
1.0 to 1.0:1.0. These variations in the ratio could be the
result of a partial in situ epimerization of the 3-formyl
group in the presence of triethylamine.
step, H NMR and 2D NOESY spectroscopy and molec-
ular modeling were carried out to assign the hydroxy-
1
methylene stereochemistry for 20(R) and 20(S). The H
NMR spectrum of the first isomer (20(R)) displayed a
coupling constant between the bridge proton and the
proton H-3′ of the galactose moiety (J Hb,3′) of 2.7 Hz, while
in the second isomer (20(S)), the same coupling was 5.2
Hz. Molecular modeling of the two diastereoisomers 20(R)
and 20(S) used the package SYBYL (ver. 6.3) from Tripos
Inc., St. Louis, MO. All energy calculations were per-
formed with parameters from the Tripos force field.
Charges were assigned according to the Gasteiger-
Huckel protocol. A distance-dependent dielectric (ꢀ ) 4)
was used for chloroform as solvent. After energy mini-
mization of both isomers, the torsion angles between the
bridge carbon (Cb)-bridge hydrogen (Hb) bond and the
carbon 3 (C-3′)-proton 3 (H-3′) bond of the galactose
residue were determined. In the (R) isomer, this torsion
angle was approximately 60°, while in the (S) isomer it
was 180°. These two torsion angles correspond to a
smaller J Hb,3′ coupling constant in the (R) isomer than
in the (S) isomer; the chirality of the bridge carbon was
assigned as (R) in the first isomer and as (S) in the second
isomer. This assignment was further confirmed by the
following observation. The molecular model of the (R)-
isomer indicated that the equatorial proton H-3e of the
neuraminic acid moiety pointed toward the bridge hy-
droxyl, implying that this equatorial proton should be
downfield shifted in the 1H NMR spectrum of the (R)
isomer. In the (S) isomer, molecular modeling indicated
that the axial proton H-3a of the neuraminic acid moiety
pointed toward the bridge hydroxyl, implying a downfield
1
shift of this proton in the H NMR spectrum of the (S)
isomer. The two chemical shifts expected for H-3e and
H-3a of the neuraminic acid residue were in accordance
with the experimental 1H NMR spectra of 20(R) and
20(S). The assigned stereochemistry was also confirmed
by 2D NOESY spectroscopy of 20(R) and 20(S). As
expected, a strong NOE between bridge H/Gal H-3 for
20(R) and bridge H/Gal H-2 for 20(S) were observed.
Differences are observed in the H-4′ (Gal) chemical shifts
of 20(R) and 20(S), 5.26 and 4.60 ppm, respectively. The
signal at 1.78 ppm demonstrates a second shielded
acetate in 20(S). These observations suggest the possible
presence of an orthoacetate involving the bridge hydroxyl
and the 4-hydroxyl group of the neuraminic acid residue.
Removal of the p-methoxyphenyl glycoside in 20(R)
was next attempted by selective oxidation using ceric
ammonium nitrate (CAN) for 50 min at 0 °C.21 FABMS
spectroscopy of the resulting compound indicated the
presence of two different molecular peaks, the first one
at 793 ([M + NH4]+ 811, [M + Na]+ 816, and [M + K]+
832), corresponding to the expecting molecular weight
after p-methoxyphenyl removal, and the second one at
775 ([M + H]+ 776), corresponding to an unsaturated
derivative resulting from an elimination of p-methoxy-
phenol. 1H NMR spectroscopy of the same sample showed
the presence of three anomeric protons between 6.2 and
6.4 ppm. One of these signals was consistent with the
presence of a C1-C2 double bond in the galactose moiety.
The large downfield chemical shifts observed for the two
other anomeric protons indicated a possible acetyl migra-
tion to the anomeric position after p-methoxyphenyl
removal. These two anomeric acetates could not be
separated from the unsaturated derivative. The p-meth-
oxyphenyl glycoside of the peracetylated derivative 21(S)
Reaction of the 3-formyl galactoside 15 with the
neuraminic acid sulfone 17 in the presence of freshly
prepared samarium(II) iodide afforded the corresponding
C-disaccharides 18(R) and 18(S) (Scheme 3) in 85% yield.
TLC of the reaction mixture indicated a diastereoisomeric
ratio of approximately 4:1. However, the first minor
isomer (R) was difficult to resolve from the second major
isomer (S), decreasing its isolated yield and leading to
an R/S ratio of 1.0:1.5. Standard debenzylation of the
diastereoisomeric mixture 18(R)-18(S) afforded the cor-
responding disaccharides 19(R) and 19(S) in 90% yield,
separable by chromatography on silica gel. Although both
(R) and (S) isomers could be isolated pure at this stage,
the chirality of the hydroxymethylene bridge in each
1
isomer could not be assigned from their H NMR spectra
because of overlapping signals. Acetylation of the first
isomer (19(R)) quantitatively afforded the corresponding
acetylated derivative 20(R) having the free bridge hy-
droxyl, while acetylation of the second isomer (19(S))
under the same conditions quantitatively afforded the
corresponding acetylated derivative 20(S) having the free
bridge hydroxyl, together with some peracetylated de-
rivative 21(S), the ratio 20(S)/21(S) being 1.6:1.0. At this
(25) Murakata, C.; Ogawa, T. Carbohydr. Res. 1992, 235, 95-114.
(26) Albright, J . D.; Goldman, L. J . Am. Chem. Soc., 1965, 87, 4214-
4216.
(27) Cannizzo, L. F.; Grubbs, R. H. J . Org. Chem. 1985, 50, 2386-
2387.
(28) Molino, B. F.; Cusmano, J .; Mootoo, D. R.; Faghih, R.; Fraser-
Reid, B. J . Carbohydr. Chem. 1987, 6, 479-493.
(29) Tidwell, T. T. Synthesis 1990, 857-870.

Notes
J . Org. Chem., Vol. 64, No. 19, 1999 7257
nium iodide (4.17 g, 11.34 mmol). The suspension was stirred
under nitrogen at 60 °C for 18 h. TLC of the resulting brownish
solution showed the presence of 50% of unreacted starting
material. This solution was reacted with additional allyl bromide
(0.58 mL, 6.80 mmol). After 18 h at 60 °C, the solvent was
evaporated, and the residue was purified by chromatography
on silica gel (ethyl acetate) to afford 8 in 85% yield (3.16 g),
isolated as yellowish crystals. Recrystallization of 8 in ethyl
acetate afforded white crystals: mp ) 140-141 °C; [R]23D ) -8°
was converted directly to the corresponding thiophenyl
glycoside 22(S) in 73% yield by reaction of 21(S) with
thiophenol and trifluoroboron etherate.22 C-Disaccharide
22(S) is the common key intermediate for the full
elaboration of the C-glycoside analogues of GM4 and
GM3 or other related gangliosides.
Con clu sion
1
(c 1, CHCl3); H NMR (500 MHz, CD3OD) δ 3.32 (m, 1 H, H-5),
3.39 (dd, 1H, J 2,3 9.5 Hz, J 3,4 3.2 Hz, H-3), 3.58 (t, 1 H, J 5,6b 6.1
Hz, J 6a,6b 6.0 Hz, H-6b), 3.75 (s, 3 H, OMe), 3.78 (dd, 1 H, J 5,6a
A common versatile N-acetylneuraminic acid C-disac-
charide precursor of the C-glycoside analogues of gan-
gliosides GM4 and GM3 has been synthesized. Samarium-
(II) iodide coupling of N-acetylneuraminic acid sulfone
with a 3-formyl galactopyranoside derivative afforded the
corresponding C-disaccharide as a mixture of (R) and (S)
isomers at the newly formed hydroxymethylene bridge.
This diastereoisomeric mixture was resolved after de-
benzylation of the galactoside residue, and the chirality
of each isomer assigned after acetylation. After 48 h
acetylation, the bridge hydroxyl in the (R) isomer could
not be acetylated, while this hydroxyl was partially
acetylated in the (S) isomer. Conversion of the p-meth-
oxyphenyl group in the peracetylated (S) isomer into the
corresponding thiophenyl glycoside was accomplished,
affording the key intermediate for the synthesis of
C-glycoside analogues of GM4, GM3, and other related
gangliosides.
4.8 Hz, H-6a), 3.86 (dd, 1H, J 1,2 7.9 Hz, H-2), 4.07 (d, 1 H, J 4,5
<
1.5 Hz, H-4), 4.17 and 4.26 (2 dd, 1 H each, OCH2), 4.74 (d, 1H,
H-1), 5.18 and 5.34 (2 dd, 1 H each, CHdCH2), 6.00 (m, 1 H,
CH)CH2), 6.80 and 7.08 (2 d, 2 H each, Ph). Anal. Calcd for
C
16H22O7 (326.3): C, 58.89; H, 6.79. Found: C, 59.18; H, 6.91.
p-Meth oxyp h en yl 3-O-Allyl-2,4,6-tr i-O-ben zyl-â-D-ga la c-
top yr a n osid e (9). To a solution of 8 (1.21 g, 3.71 mmol) in
anhydrous DMF (15 mL), under nitrogen and cooled at 0 °C,
was added NaH (116 mg, 4.83 mmol). The reaction mixture was
stirred for 15 min at 0 °C and treated with benzyl bromide (0.66
mL, 5.57 mmol). After 12 h at room temperature, the reaction
mixture was cooled at 0 °C, quenched by slow addition of water,
and extracted with chloroform. The combined organic layers
were washed with H2O, dried over anhydrous Na2SO4, and
filtered, and the solvents were evaporated. Purification by
chromatography on silica gel (ethyl acetate-petroleum ether,
v/v 1:3) afforded 9 as white crystals in 91% yield (2.01 g): mp )
59-61 °C; [R]24 ) -23°(c 1, CHCl3); 1H NMR (500 MHz,
D
CDCl3): δ 3.48 (dd, 1H, J 2,3 9.6 Hz, J 3,4 2.8 Hz, H-3), 3.63 (bs, 3
H, H-5, H-6a and H-6b), 3.75 (s, 3 H, OMe), 3.90 (d, 1 H, J 4,5
<
1.5 Hz, H-4), 4.01 (dd, 1H, J 1,2 7.8 Hz, H-2), 4.22 (m, 2 H, OCH2),
4.40, 4.45, 4.64, 4.84, 4.96 and 4.97 (6 d, 1 H each, J A,B 11.7 Hz,
CH2Ph), 4.83 (d, 1H, H-1), 5.19 and 5.33 (2 dd, 1 H each, CHd
CH2), 5.95 (m, 1 H, CH)CH2), 6.78 and 7.02 (2 d, 2 H each,
C6H4), 7.22-7.40 (m, 15 H, 3 C6H5). Anal. Calcd for C37H40O7
(596.7): C, 74.48; H, 6.76. Found: C, 74.32; H, 6.75.
Exp er im en ta l Section
Nuclear magnetic resonance (1H NMR) spectra were recorded
at 25 °C, in deuterated chloroform or methanol. Chemical shifts
were recorded in ppm (δ) and coupling constants in Hz, relative
to tetramethylsilane as the internal standard. The 1H NMR
spectra were fully assigned using single frequency decoupling,
2D COSY, and 2D NOESY NMR spectroscopy. Melting points
are uncorrected. Thin-layer chromatography (TLC) was per-
formed using E. Merck plates of silica gel 60 with fluorescent
indicator. Visualization was effected by spraying plates with
Von’s reagent (1.0 g of ceric ammonium sulfate and 24.1 g of
ammonium molybdate in 31 mL of sulfuric acid and 470 mL of
water) followed by heating at 140 °C. Flash chromatography was
conducted with silica gel (230-430 mesh, E. Merck).
p-Meth oxyp h en yl 2,4,6-Tr i-O-ben zyl-â-D-ga la ctop yr a n o-
sid e (10). Compound 9 (2.67 g, 4.49 mmol) was dissolved in a
mixture of anhydrous methanol and toluene (21 mL, v/v 3:1) and
reacted with PdCl2 (∼100 mg) under nitrogen and at room
temperature. After 4 h of reaction, the reaction mixture was
filtrated over a pad of Celite, and the solvents were evaporated.
Purification of the residue by chromatography on silica gel (ethyl
acetate-petroleum ether, v/v 1:4) afforded 10 as white crystals
in 94% yield (2.35 g): mp ) 84-86 °C; [R]24D ) -11° (c 1, CHCl3);
1H NMR (500 MHz, CDCl3) δ 3.66-3.73 (m, 3 H, H-5, H-6a and
H-6b), 3.74 (t, 1H, J 2,3 9.5 Hz, J 3,4 2.9 Hz, H-3), 3.76 (s, 3 H,
OMe), 3.83 (dd, 1H, J 1,2 7.7 Hz, H-2), 3.90 (d, 1 H, J 4,5 < 1.5 Hz,
H-4), 4.44, 4.49, 4.66, 4.78, 4.81 and 5.05 (6 d, 1 H each, J A,B
11.8 Hz, CH2Ph), 4.84 (d, 1H, H-1), 6.78 and 7.02 (2 d, 2 H each,
C6H4), 7.22-7.40 (m, 15 H, 3 C6H5). Anal. Calcd for C34H36O7
(556.7): C, 73.36; H, 6.52. Found: C, 72.96; H, 6.63.
p-Meth oxyp h en yl 2,3,4,6-Tetr a -O-a cetyl-â-D-ga la ctop y-
r a n osid e (6). p-Methoxyphenol (20.5 mmol, 2.5 g) and trim-
ethylsilyl trifluoromethanesulfonate (0.25 mL) were added to a
solution of â-D-galactose pentaacetate (5.0 g, 12.8 mmol) in
anhydrous CH2Cl2 at 0 °C under nitrogen. After 4 h at 0 °C, the
reaction mixture was neutralized by addition of triethylamine
(1 mL) and concentrated under reduced pressure. Purification
by chromatography on silica gel (ethyl acetate-petroleum ether,
v/v 1:3 f 1.5:1) afforded 6 as an amorphous white solid in 92%
p-Meth oxyp h en yl 2,4,6-Tr i-O-ben zyl-â-D-xylo-h ex-3-u lo-
p yr a n osid e (11). Compound 10 (2.93 g, 5.27 mmol) in solution
in anhydrous DMSO (18 mL) was reacted with Ac2O (15 mL)
under nitrogen and at room temperature. After 12 h, Ac2O was
evaporated and the remaining solution diluted with H2O and
extracted with CHCl3. The combined organic layers were washed
with H2O, dried over anhydrous Na2SO4, and filtered, and the
solvent was evaporated. The residue was purified by chroma-
tography on silica gel (ethyl acetate-petroleum ether, v/v 1:3)
to give 11 as a light yellow solid in 84% yield (2.45 g): mp )
yield (5.35 g): [R]23 ) +3° (c 1, CHCl3) [lit.22 [R]D ) +9.6° (c
D
0.54, CHCl3)]; 1H NMR (500 MHz, CDCl3) δ 2.01, 2.06, 2.08 and
2.19 (4 s, 3 H each, 4 OAc), 3.78 (s, 3 H, OMe), 4.01 (m, 1 H,
H-5), 4.16 (dd, 1 H, J 5,6b 6.5 Hz, J 6a,6b 11.3 Hz, H-6b), 4.23 (dd,
1 H, J 5,6a 6.9 Hz, H-6a), 4.92 (d, 1H, J 1,2 8.0 Hz, H-1), 5.09 (dd,
1H, J 2,3 10.4 Hz, J 3,4 3.3 Hz, H-3), 5.5.44-5.48 (m, 2 H, H-2 and
H-4), 6.80 and 6.96 (2 d, 2 H each, Ph).
p-Meth oxyp h en yl 3-O-a llyl-â-D-ga la ctop yr a n osid e (8). To
a solution of 6 (5.25 g, 11.57 mmol) in anhydrous methanol (50
mL) and under nitrogen was added a catalytic amount of sodium
methoxide. After 5 h at room temperature, the reaction mixture
was neutralized with resin IR 120 (H+) and filtered, and the
solvent was evaporated. The resulting p-methoxyphenyl â-D-
galactopyranoside 7 was used without any further purification
and characterization. Compound 7 (3.24 g, 11.34 mmol) in
solution in anhydrous methanol (50 mL) and under nitrogen was
reacted with dibutyltin oxide (3.11 g, 12.48 mmol). After 4 h at
reflux, the reaction mixture was concentrated under vacuum.
The dried residue was suspended in toluene (80 mL) and treated
with allyl bromide (1.17 mL, 13.61 mmol) and tetrabutylammo-
85-87 °C; [R]23 ) -52° (c 1, CHCl3); 1H NMR (500 MHz,
D
CDCl3): δ 3.76 (s, 3 H, OMe), 3.66-3.73 (bs, 3 H, H-5, H-6a
and H-6b), 3.92 (s, 1 H, J 4,5 < 1.5 Hz, H-4), 4.34, 4.42, 4.45, 4.51,
4.59 and 4.94 (6 d, 1 H each, J A,B 11.8 Hz, CH2Ph), 4.76 (bd, 2
H, H-1 and H-2), 6.78 and 7.08 (2 d, 2 H each, C6H4), 7.22-7.40
(m, 15 H, 3 C6H5). Anal. Calcd for C34H34O7 (554.6): C, 73.63;
H, 6.18. Found: C, 73.76; H, 6.35.
p-Meth oxyp h en yl 2,4,6-Tr i-O-ben zyl-3-d eoxy-3-C-(m eth -
ylen e)-â-D-xylo-h ex-3-u lop yr a n osid e (12). To a solution of 11
(2.36 g, 4.26 mmol) in anhydrous THF (60 mL) under nitrogen
and cooled at -40 °C was added dropwise within 20 min Tebbe’s
reagent (17 mL). After 1 h at - 40 °C, the reaction mixture was
allowed to warm at 0 °C. After 50 min at 0 °C was added very

7258 J . Org. Chem., Vol. 64, No. 19, 1999
Notes
slowly a 10% aqueous NaOH solution (10 mL), and the reaction
mixture was stirred for 30 min at 0 °C. The reaction mixture
was filtered through a pad of Celite and the solid washed several
times with ethyl acetate. The combined organic extracts were
evaporated, and the residue was purified by chromatography
on silica gel (ethyl acetate-petroleum ether, v/v 1:5) to afford
er yth r o-L-m a n n o-n on a te (18(R)) a n d Meth yl 5-Aceta m id o-
4,7,8,9-t e t r a -O-a ce t yl-2,6-a n h yd r o-3,5-d id e oxy-2-C-[(R)-
h yd r oxy-[3-(p-m eth oxyp h en yl 2,4,6-tr i-O-ben zyl-3-d eoxy-
â-D -g a la c t o p y r a n o s id y l)]m e t h y l]-D -er yt h r o-L -m a n n o-
n on a te (18(S)). A solution of compounds 15 (111 mg, 0.19 mmol)
and 17 (100 mg, 0.16 mmol) in CHCl3 (2 mL) was evaporated to
dryness and the resulting residue dried for 1 h under high
vacuum. To the dried residue placed under nitrogen was added
a solution of freshly prepared SmI2 (∼0.1 M, 15 mL), and the
reaction mixture was stirred at room temperature for 15 min.
The reaction mixture was then diluted with ether, washed
successively with 1 N HCl, saturated aqueous Na2S2O3 and H2O,
dried over anhydrous Na2SO4, and filtered, and the solvents were
evaporated. The residue was purified by chromatography on
silica gel (CHCl3-CH3OH, v/v 40:1) to give 18(R) and 18(S) as
a white solid in 85% yield (142 mg). 18(R): 1H NMR (500 MHz,
CDCl3) δ 1.77 (t, 1 H, J 3a,4, J 3a,3e 12.4 Hz, H-3a), 1.89, 1.96, 2.00,
2.02 and 2.17 (5 s, 3 H each, 5 OAc), 2.15 (ovl with OAc, 1 H,
H-3′), 2.54 (dd, 1 H, J 3e,4 4.4 Hz, H-3e), 3.68 (dd, 1 H, J 5′,6′b 6.7
Hz, J 6′a,6′b 9.3 Hz, H-6′b), 3.73 (s, 3 H, CO2CH3), 3.77 (s, 3 H,
PhOCH3), 3.79 (dd, 1 H, J 5′,6′a < 1.5 Hz, H-6′a), 3.90 (t, 1 H,
H-5′), 3.97 (dd, 1 H, J 4,5, J 5,6 10.4 Hz, J 5,NH 10.2 Hz, H-5), 4.00
(m ovl with H-9b, 1 H, J 1′,2′ 7.5 Hz, H-2′), 4.01 (dd ovl with H-2′,
1 H, J ′9a,9b 12.5 Hz, H-9b), 4.11 (m, 2 H, H-6 and Hb), 4.23 (dd,
1 H, J 8,9a 2.2 Hz, H-9a), 4.35 (bs, 1 H, H-4′), 4.52, 4.58, 4.61,
4.67, 4.76 and 5.06 (6 d, 1 H each, 3 CH2Ph), 4.80 (m, 1 H, H-4),
5.01 (d, 1 H, H-1′), 5.14 (d, 1 H, NH), 5.28 (dd, 1 H, J 6,7 < 1.5
Hz, J 7,8 9.4 Hz, H-7), 5.44 (m, 1 H, H-8), 6.60 and 7.10 (2d, 2 H
each, PhOCH3), 7.20-7.40 (m, 15 H, 3 CH2Ph). 18(S): 1H NMR
(500 MHz, CDCl3) δ 1.82, 1.84, 1.94, 2.00 and 2.16 (5 s, 3 H each,
5 OAc), 2.21 (dd, 1 H, J 3e,4 5.1 Hz, H-3e), 2.27 (t, 1 H, J 3a,4, J 3a,3e
13.0 Hz, H-3a), 2.38 (m, 1 H, J 2′,3′ 11.2 Hz, H-3′), 3.17 (d, 1 H,
J Hb,OH 1.5 Hz, OH), 3.64 (m, 2 H, Hb and H-5′), 3.73 (m, 1 H,
12 as white crystals in 84% yield (1.98 g): mp ) 74-76 oC; [R]23
D
) -9° (c 1, CHCl3); 1H NMR (500 MHz, CDCl3) δ 3.74-3.81 (m,
3 H, H-5, H-6a and H-6b), 3.76 (s, 3 H, OMe), 3.98 (s, 1 H, J 4,5
< 1.5 Hz, H-4), 4.30 (dt, 1H, J 1,2 7.6 Hz, H-2), 4.24, 4.48, 4.52,
4.54, 4.79 and 4.99 (6 d, 1 H each, J A,B 11.7 Hz, CH2Ph), 4.81
(d, 1H, H-1), 5.17 and 5.56 (2 t, 1 H each, CdCH2), 6.79 and
7.03 (2 d, 2 H each, C6H4), 7.22-7.42 (m, 15 H, 3 C6H5). Anal.
Calcd for C35H36O6 (552.6): C, 76.06; H, 6.57. Found: C, 76.16;
H, 6.70.
p -Met h oxyp h en yl 2,4,6-t r i-O-b en zyl-3-d eoxy-3-C-(h y-
dr oxym eth yl)-â-D-ga la cto-h exopyr an oside (13) an d p-Meth -
oxyph en yl 2,4,6-Tr i-O-ben zyl-3-deoxy-3-C-(h ydr oxym eth yl)-
â-D-gu lo-h exop yr a n osid e (14). Compound 12 (1.89 g, 3.42
mmol) in solution in anhydrous THF (80 mL) was reacted with
9-BBN (0.5 M in THF, 43 mL, 21.6 mmol) at reflux and under
nitrogen. After 5 h of reaction, the reaction mixture was cooled
at 0 °C, and a 10% aqueous solution of NaOH (34 mL) was slowly
added followed by a 30% aqueous solution of H2O2 (34 mL). The
reaction mixture was stirred for 30 min and extracted with
CHCl3. The combined organic extracts were washed with a 20%
aqueous solution of sodium hydrogen sulfite and with H2O, dried
over anhydrous Na2SO4, and filtered, and the solvent was
evaporated. The residue was purified by chromatography on
silica gel (ethyl acetate-petroleum ether, v/v 1:5) to give 13 and
14 as a colorless oil in 91% yield (2.452 g), in a ratio of 13:14 )
1.5:1.0. 13: 1H NMR (500 MHz, CDCl3) δ 1.90 (m, 1 H, J 2,3 11.1
Hz, J 3,4 < 1.5 Hz, H-3), 3.65-3.87 (m, 5 H, H-5, H-6a, H-6b,
CH2), 3.77 (s, 3 H, OMe), 3.85 (dd, 1 H, J 1,2 7.7 Hz, H-2), 3.95
(d, 1 H, H-4), 4.35-5.03 (m, 3 CH2Ph), 4.92 (d, 1 H, H-1), 6.80
and 7.04 (2 d, 2 H each, C6H4), 7.20-7.40 (m, 15 H, 3 C6H5). 14:
1H NMR (500 MHz, CDCl3): δ 2.61 (bq, 1 H, J 2,3 5.5 Hz, J 3,4
<1.5 Hz, H-3), 3.65-3.87 (m, 4 H, H-6a, H-6b, CH2), 3.76 (s, 3
H, OMe), 3.95 (d, 1 H, H-4), 4.02 (bt, 2 H, H-2, H-5) 4.35-5.03
(m, 3 CH2Ph), 5.27 (d, 1 H, J 1,2 6.2 Hz, H-1), 6.80 and 7.04 (2 d,
2 H each, C6H4), 7.20-7.40 (m, 15 H, 3 C6H5).
J
5′,6′b 2.9 Hz, H-6′b), 3.76 (s, 3 H, CO2CH3), 3.77 (s, 3 H, PhOCH3),
3.82 (m, 2 H, J 8,9b 5.0 Hz, H-9b and H-6′a), 3.90 (m, 2 H, H-5
and H-4′), 3.93 (dd, 1 H, J 5,6 10.4 Hz, J 6,7 2.0 Hz, H-6), 4.07 (dd,
1 H, J 1′,2′ 7.4 Hz, H-2′), 4.14 (dd, 1 H, J 8,9a 1.5 Hz, J 9a,9b 12.0 Hz,
H-9a), 4.47, 4.48, 4.54, 4.62, 4.66 and 5.18 (6 d, 1 H each, 3 CH2-
Ph), 4.76 (m, 1 H, H-4), 5.02 (d, 1 H, J 5,NH 9.7 Hz, NH), 5.20 (dd,
1 H, J 7,8 8.9 Hz, H-7), 5.29 (d, 1 H, H-1′), 5.43 (m, 1 H, H-8),
6.80 and 7.00 (2d, 2 H each, PhOCH3), 7.20-7.40 (m, 15 H, 3
CH2Ph).
p-Meth oxyph en yl 2,4,6-Tr i-O-ben zyl-3-deoxy-3-C-(for m yl)-
â-D-ga la cto-h exop yr a n osid e (15) a n d p-Meth oxyp h en yl
2,4,6-Tr i-O-ben zyl-3-d eoxy-3-C-(for m yl)-â-D-gu lo-h exop yr a -
n osid e (16). Anhydrous DMSO (1.30 µL) was carefully added
to a 2.0 M solution of oxalyl chloride in CH2Cl2 (3.86 mL, 7.71
mmol) under nitrogen and cooled at -78 °C. After 10 min, a
solution of 12-13 (1.76 g, 3.08 mmol) in anhydrous CH2Cl2 (10
mL) was added dropwise and the reaction mixture stirred 1 h
at -78 °C. The reaction mixture was treated with triethylamine
(4.3 mL, 30.9 mmol) for 45 min at -78 °C, allowed to warm at
0 °C, quenched by addition of H2O, and extracted with CHCl3.
The combined organic layers were washed with saturated
aqueous NaHCO3 and H2O, dried over anhydrous Na2SO4, and
filtered, and the solvents were evaporated. The residue was
purified by chromatography on silica gel (ethyl acetate-
petroleum ether, v/v 1:5) to give 16 as a colorless oil in 13% yield
Meth yl 5-Aceta m id o-4,7,8,9-tetr a -O-a cetyl-2,6-a n h yd r o-
3,5-dideoxy-2-C-[(R)-h ydr oxy-[3-(p-m eth oxyph en yl 3-deoxy-
â-D-ga la ctop yr a n osid yl)]-m eth yl]-D-er yth r o-L-m a n n o-n on -
a te (19(R)) a n d Meth yl 5-Aceta m id o-4,7,8,9-tetr a -O-a cetyl-
2 ,6 -a n h y d r o -3 ,5 -d i d e o x y -2 -C -[ ( R ) -h y d r o x y -[ 3 -( p -
m eth oxyp h en yl 3-d eoxy-â-D-ga la ctop yr a n osid yl)]m eth yl]-
D-er yth r o-L-m a n n o-n on a te (19(S)). A solution of compounds
18(R)-18(S) (558 mg, 0.53 mmol) in EtOAc/CH3OH/H2O/80%
aqueous AcOH (20 mL/20 mL/10 mL/1 drop) was stirred at room
temperature under an atmosphere of H2. After 15 h, the reaction
mixture was filtered over a pad of Celite and the filtrate
evaporated under vacuum. The residue was purified by chro-
matography on silica gel (CHCl3-CH3OH, v/v 35:1) to give 19(R)
and 19(S) as white solids in 54% (223 mg) and 36% (149 mg)
yields, respectively. 19(R): mp ) 146-149 °C; [R]23D ) +4° (c 1,
CHCl3); HRFABMS (+ve) calcd for C34H47NO19 [M + Na]+
796.2640, found 796.2628; 1H NMR (500 MHz, CDCl3) δ 1.88,
2.01, 2.02, 2.15 and 2.17 (5 s, 3 H each, 5 OAc), 1.86 (t, 1 H,
J 3a,4, J 3a,3e 13.0 Hz, H-3a), 1.99 (ovl with OAc, 1 H, H-3′), 2.54
(dd, 1 H, J 3e,4 4.4 Hz, H-3e), 3.63 (t, 1 H, J 5′,6′b 5.5 Hz, J 6′a,6′b
10.7 Hz, H-6′b), 3.77 (s, 6 H, PhOCH3 and CO2CH3), 3.83 (dd, 1
H, J 5′,6′a < 1.5 Hz, H-6′a), 3.89 (m, 1 H, H-5′), 3.94 (dd, 1 H, J 8,9b
8.1 Hz, J 9a,9b 12.3 Hz, H-9b), 4.08 (dd, 1 H, J 4,5, J 5,6 10.2 Hz,
J 5,NH 9.5 Hz, H-5), 4.22 (bt, 1 H, J 1′,2′ 7.6 Hz, J 2′,3′ 9.4 Hz, H-2′),
4.30 (bd ovl with H-9a, 1 H, J 6,7 2.0 Hz, H-6), 4.33 (dd, 1 H, J 8,9a
< 1.5 Hz, H-9a), 4.37 and 4.75 (2 bs, 1 H each, Hb and H-4′),
4.79 (m, 1 H, H-4), 4.85 (d, 1 H, H-1′), 5.22 (dd, 1 H, J 7,8 9.2 Hz,
H-7), 5.28 (bd, 1 H, NH), 5.56 (bt, 1 H, H-8), 6.80 and 7.10 (2 d,
(0.22 g) and 15 as white needles in 60% yield (1.05 g): 16 [R]23
D
) -32° (c 0.5, CHCl3); 1H NMR (500 MHz, CDCl3) δ 2.56 (bd, 1
H, J 1,2 7.2 Hz, J 2,3 6.6 Hz, H-3), 3.67 (m, 2 H, H-6a and H-6b),
4.05 (m, 1 H, H-5), 3.76 (s, 3 H, OMe), 4.07 (m, 1 H, H-4), 5.16
(dd, 1H, H-2), 4.41, 4.45, 4.47, 4.48, 4.71 and 4.95 (6 d, 1 H each,
J A,B 11.7 Hz, CH2Ph), 5.10 (d, 1H, H-1), 6.78 and 7.00 (2 d, 2 H
each, C6H4), 7.20-7.38 (m, 15 H, 3 C6H5), 9.89 (s, 1 H, CHO).
Anal. Calcd for C35H36O7 (568.7): C, 73.92; H, 6.38. Found: C,
72.98; H, 7.08. 15: mp ) 114-116 °C; [R]23D ) +1° (c 1, CHCl3);
1H NMR (500 MHz, CDCl3) δ 2.56 (bd, 1 H, J 1,2 7.7 Hz, J 2,3 11.1
Hz. H-3), 3.64 (dd, 1 H, J 5,6b 9.3 Hz, J 6a,6b 9.3 Hz, H-6b), 3.69 (t,
1 H, H-6a), 3.76 (m, 1 H, H-5), 3.76 (s, 3 H, OMe), 4.22 (d, 1 H,
J 4,5 < 1.5 Hz, H-4), 4.34 (dd, 1H, H-2), 4.47, 4.48, 4.49, 4.52,
4.82 and 5.05 (6 d, 1 H each, J A,B 11.7 Hz, CH2Ph), 4.94 (d, 1H,
H-1), 6.80 and 7.08 (2 d, 2 H each, C6H4), 7.20-7.38 (m, 15 H,
3 C6H5), 9.55 (s, 1 H, CHO). Anal. Calcd for C35H36O7 (568.7):
C, 73.92; H, 6.38. Found: C, 73.39; H, 6.36.
2 H each, PhOCH3). 19(S): mp ) 138-141 °C; [R]23 ) -12.5°
D
(c 1, CHCl3); HRFABMS (+ve) calcd for C34H47NO19 [M + Na]+
796.2640, found 796.2629; 1H NMR (500 MHz, CDCl3) δ 1.86,
1.88, 2.04, 2.12 and 2.15 (5 s, 3 H each, 5 OAc), 2.16 (bd ovl
with OAc, 1 H, H-3′), 2.31 (t, 1 H, J 3a,4 12.6 Hz, J 3a,3e 13.1 Hz,
H-3a), 2.46 (dd, 1 H, J 3e,4 4.6 Hz, H-3e), 3.66 (bt, 1 H, H-6′b),
3.85 (bs, 2 H, H-5′ and H-6′a), 3.94 (dd, 1 H, J 8,9b 7.1 Hz, J 9a,9b
Meth yl 5-Aceta m id o-4,7,8,9-tetr a -O-a cetyl-2,6-a n h yd r o-
3,5-d id eoxy-2-C-[(R)-h yd r oxy-[3-(p-m eth oxyp h en yl 2,4,6-
tr i-O-ben zyl-3-d eoxy-â-D-ga la ctop yr a n osid yl)]-m eth yl]-D-

Notes
J . Org. Chem., Vol. 64, No. 19, 1999 7259
12.0 Hz, H-9b), 3.95 (dd, 1 H, J 5,6 10.5 Hz, J 6,7 1.9 Hz, H-6),
4.03 (dd, 1 H, J 4,5 10.5 Hz, J 5,NH 10.0 Hz, H-5), 4.14 (bt, 1 H,
J 1′,2′ 7.7 Hz, H-2′), 4.28 (bs, 2 H, Hb and H-4′), 4.29 (dd, 1 H,
J 8,9a 2.5 Hz, H-9a), 4.92 (m, 1 H, H-4), 5.03 (d, 1 H, H-1′), 5.21
(dd, 1 H, J 7,8 8.8 Hz, H-7), 5.02 (b, 1 H, NH), 5.51 (m, 1 H, H-8),
6.80 and 7.00 (2d, 2 H each, PhOCH3).
H-4), 5.08-5.13 (m, 3 H, H-2′, Hb and NH), 5.25 (d, 1 H, J 1′,2′
7.6 Hz, H-1′), 5.31 (dd, 1 H, J 7,8 10.2 Hz, H-7), 5.78 (m, 1 H,
H-8), 6.80 and 7.00 (2 d, 2 H each, PhOCH3). Anal. Calcd for
C
42H55NO23 (941.9): C, 53.56; H, 5.89. Found: C, 53.54; H, 5.81.
20(S). The purity of 20(S) was confirmed on TLC using both
silica and aluminum oxide developed with CHCl3/CH3OH, 9:1:
mp ) 132-134 °C; [R]22D ) -9° (c 1, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 1.80, 1.88, 2.03, 2.04, 2.10, 2.15, 2.18 and 2.20 (8 s, 3
H each, 8 OAc), 2.30 (t, 1 H, J 3a,4 12.5 Hz, J 3a,3e 13.2 Hz, H-3a),
2.40 (dd, 1 H, J 3e,4 4.7 Hz, H-3e), 2.49 (bd, 1 H, J OH,Hb 5.2 Hz,
OH), 2.82 (bd, 1 H, J 2′,3′ 11.4 Hz, J 3′,Hb 5.2 Hz, J 3′,4′ 2.7 Hz, H-3′),
3.61 (m, 1 H, H-5′), 3.76 (s, 3 H, CO2CH3), 3.82 (s, 3 H, PhOCH3),
3.89 (dd, 1 H, J 8,9b 6.9 Hz, J 9a,9b 12.4 Hz, H-9b), 3.97-4.08 (m,
5 H, H-5, H-6, Hb, H-6′a and H-6′b), 4.30 (dd, 1 H, J 8,9a 2.6 Hz,
H-9a), 4.60 (d, 1 H, H-4′), 4.83 (m, 1 H, H-4), 5.11 (bd, 1 H, J 5,NH
9.6 Hz, NH), 5.18 (d, 1 H, J 1′,2′ 7.7 Hz, H-1′), 5.27 (bd, 1 H, J 6,7
< 1.9 Hz, J 7,8 10.2 Hz, H-7), 5.44 (dd, 1 H, H-2′), 5.68 (m, 1 H,
H-8), 6.80 and 7.00 (2 d, 2 H each, PhOCH3); HRMS calcd for
Meth yl 5-Aceta m id o-4,7,8,9-tetr a -O-a cetyl-2,6-a n h yd r o-
3,5-d id eoxy-2-C-[(R)-h yd r oxy-[3-(p-m eth oxyp h en yl 2,4,6-
t r i-O-a cet yl-3-d eoxy-â-D-ga la ct op yr a n osid yl)]m et h yl]-D-
er yth r o-L-m a n n o-n on a te (20(R)). A solution of 19(R) (52 mg,
0.067 mmol) in anhydrous pyridine (5 mL) was reacted with
Ac2O (0.1 mL) under nitrogen. After 48 h at room temperature,
the reaction mixture was quenched with CH3OH and evaporated
under vacuum. The residue was dried by coevaporation with
toluene and purified by chromatography on silica gel (CHCl3-
CH3OH, v/v 45:1) to afford 20(R) as a white solid in quantitative
yield (60 mg): mp ) 120-122 °C; [R]23D ) +12° (c 1, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 1.83 (t, 1 H, J 3a,4 12.2 Hz, J 3a,3e 12.7
Hz, H-3a), 1.90, 2.02, 2.04, 2.06, 2.10, 2.11, 2.15 and 2.16 (8 s, 3
H each, 8 OAc), 2.35 (bd, 1 H, J 2′,3′ 11.4 Hz, J 3′,4′, J 3′,Hb 2.7 Hz
H-3′), 2.60 (dd, 1 H, J 3e,4 4.4 Hz, H-3e), 2.92 (d, 1 H, J OH,Hb 2.9
Hz, OH), 3.74 (s, 3 H, CO2CH3), 3.77 (s, 3 H, PhOCH3), 3.88 (m,
1 H, H-5′), 4.05 (m, 2 H, J 6,7 < 1.5 Hz, H-5 and H-6), 4.10 (dd,
1 H, J 8,9b 5.4 Hz, J 9a,9b 12.5 Hz, H-9b), 4.30 (dd, 1 H, J 8,9a 2.9
Hz, H-9a), 4.37-4.40 (m, 2 H, H-6′a and H-6′b), 4.41 (bs, 1 H,
Hb), 4.83 (m, 1 H, H-4), 4.88 (d, 1 H, J 1′,2′ 7.8 Hz, H-1′), 5.16
(bd, 1 H, J 5,NH 9.4 Hz, NH), 5.26 (d, 1 H, H-4′), 5.33 (bd, 1 H,
J 7,8 10.0 Hz, H-7), 5.39 (m, 1 H, H-8), 5.43 (dd, 1 H, H-2′), 6.80
and 7.10 (2 d, 2 H each, PhOCH3). Anal. Calcd for C40H53NO22
(899.9): C, 53.39; H, 5.94. Found: C, 53.13; H, 6.11.
C
40H53NO22 [M + Na+]+ 922.2942, found 922.2954. Anal. Calcd
for C40H53NO22 (899.9): C, 53.39; H, 6.11. Found: C, 52.91; H,
6.11.
Meth yl 5-Aceta m id o-4,7,8,9-tetr a -O-a cetyl-2,6-a n h yd r o-
3,5-d id eoxy-2-C-[(R)-O-a cetyl-[3-(p h en yl 2,4,6-tr i-O-a cetyl-
3-d eoxyth io-â-D-ga la cto-p yr a n osid yl)]m eth yl]-D-er yth r o-L-
m a n n o-n on a te (22(S)). To a solution of 22(S) (27 mg, 0.029
mmol) in anhydrous toluene (3 mL) and under nitrogen were
added thiophenol (15 µL, 0.143 mmol) and BF3‚OEt2 (3.6 µL,
0.029 mmol). After 48 h at 60 °C, the reaction mixture was
successively washed with saturated aqueous NaHCO3 and H2O,
dried over anhydrous Na2SO4, and filtered, and the solvents were
evaporated. The residue was purified by chromatography on
silica gel (CHCl3-CH3OH, v/v 40:1) to afford 22(S) as a yellowish
solid in 73% yield (19 mg): FABMS (+ve) [M + Na]+ 950, [M +
Meth yl 5-Aceta m id o-4,7,8,9-tetr a -O-a cetyl-2,6-a n h yd r o-
3,5-d id eoxy-2-C-[(R)-O-a cetyl-[3-(p-m eth oxyp h en yl 2,4,6-
t r i-O-a cet yl-3-d eoxy-â-D-ga la ct op yr a n osid yl)]m et h yl]-D-
er yth r o-L-m a n n o-n on a te (21(S)) a n d Meth yl 5-Aceta m id o-
4,7,8,9-t e t r a -O-a ce t yl-2,6-a n h yd r o-3,5-d id e oxy-2-C-[(R)-
h yd r oxy-[3-(p -m et h oxyp h en yl 2,4,6-t r i-O-a cet yl-3-d eoxy-
â-D -g a la c t o p y r a n o s id y l)]m e t h y l]-D -er yt h r o-L -m a n n o-
n on a te (20(S)). A solution of 19(S) (50 mg, 0.065 mmol) in
anhydrous pyridine (5 mL) was reacted with Ac2O (0.1 mL)
under nitrogen. After 48 h at room temperature, the reaction
mixture was quenched with CH3OH and evaporated under
vacuum. The residue was dried by coevaporation with toluene
and purified by chromatography on silica gel (CHCl3-CH3OH,
v/v 45:1) to afford 21(S) and 20(S) as white solids in 38% (23
mg) and 61% (35 mg) yields, respectively. 21(S); mp ) 127-130
1
NH4]+ 945; H NMR (500 MHz, CDCl3) δ ∼1.70 (ovl with OAc,
H-3a), 1.79, 1.88, 2.01, 2.02, 2.07, 2.09, 2.10, 2.18 and 2.20 (9 s,
3 H each, 9 OAc), 2.28 (dd, 1 H, J 3e,4 4.4 Hz, J 3a,3e 12.8 Hz, H-3e),
3.05 (m, 1 H, J 2′,3′ 10.5 Hz, J 3′,Hb 4.7 Hz, J 3′,4′ 2.9 Hz, H-3′), 3.76
(s, 4 H, H-5′ and CO2CH3), 3.93 (dd, 1 H, J 8,9b 6.1 Hz, J 9a,9b 12.3
Hz, H-9b), 3.97 (dd, 1 H, J 5,6 10.2 Hz, J 6,7 2.3 Hz, H-6), 4.03-
4.06 (m, 2 H, H-6′a and H-6′b), 4.07 (dd, 1 H, J 4,5 10.8 Hz, J 5,NH
10.3 Hz, H-5), 4.29 (dd, 1 H, J 8,9a 2.6 Hz, H-9a), 4.66 (d, 1 H,
H-4′), 4.77 (m, 1 H, H-4), 4.96 (dd, 1 H, J 1′,2′ 9.7 Hz, H-2′), 5.12
(bd, 1 H, NH), 5.17 (d, 1 H, H-1′), 5.32 (dd, 1 H, J 7,8 10.0 Hz,
H-7), 5.75 (m, 1 H, H-8), 7.40-7.50 (m, 5 H, SPh).
°C; [R]22 ) -1° (c 1, CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.74
Ack n ow led gm en t. The authors thank Dr. J esu´s
J ime´nez-Barbero for his helpful suggestions in inter-
preting the NMR spectra of these compounds.
D
(t, 1 H, J 3a,4 12.3 J 3a,3e 12.7 Hz, H-3a), 1.78, 1.88, 2.01, 2.04, 2.07,
2.11, 2.14, 2.18 and 2.21 (9 s, 3 H each, 9 OAc), 2.30 (dd, 1 H,
J 3e,4 4.4 Hz, H-3e), 3.05 (m, 1 H, J 2′,3′ 11.4 Hz, J 3′,Hb 4.5 Hz, J 3′,4′
3.2 Hz, H-3′), 3.75 (s, 4 H, H-5′ and CO2CH3), 3.87 (s, 3 H,
PhOCH3), 3.98 (dd, 1 H, J 8,9b 6.7 Hz, J 9a,9b 12.3 Hz, H-9b), 3.89
(dd, 1 H, J 5,6 10.8 Hz, J 6,7 2.4 Hz, H-6), 4.03-4.06 (m, 2 H, H-6′a
and H-6′b), 4.09 (dd, 1 H, J 4,5 10.5 Hz, J 5,NH 10.0 Hz, H-5), 4.29
(dd, 1 H, J 8,9a 2.6 Hz, H-9a), 4.64 (d, 1 H, H-4′), 4.78 (m, 1 H,
Su p p or tin g In for m a tion Ava ila ble: NMR spectra for
compounds 20(S) and 20(R). This material is available free of
charge via the Internet at http://pubs.acs.org.
J O990564P