A stereoselective approach for the synthesis of α-sialosides

Article abstract of DOI:10.1021/jo010345f

A highly efficient synthesis of the human melanoma associated antigen GD₃ derivative has been described. A key feature of the synthetic approach was the use of sialyl donors that were protected with a C-5 trifiuoroacetamide moiety. These sialyl donors gave high yields and excellent α-anomeric selectivities in direct glycosylations with a wide variety of glycosyl acceptors ranging from C-8 hydroxyls of sialic acids and C-3 hydroxyls of galactosides to reactive primary alcohols.

Full text of DOI:10.1021/jo010345f

5490
J . Org. Chem. 2001, 66, 5490-5497
A Ster eoselective Ap p r oa ch for th e Syn th esis of r-Sia losid es
Cristina De Meo, Alexei V. Demchenko, and Geert-J an Boons*
Complex Carbohydrate Research Center, University of Georgia, 220 Riverbend Road,
Athens, Georgia 30602
Received April 3, 2001
A highly efficient synthesis of the human melanoma associated antigen GD3 derivative has been
described. A key feature of the synthetic approach was the use of sialyl donors that were protected
with a C-5 trifluoroacetamide moiety. These sialyl donors gave high yields and excellent R-anomeric
selectivities in direct glycosylations with a wide variety of glycosyl acceptors ranging from C-8
hydroxyls of sialic acids and C-3 hydroxyls of galactosides to reactive primary alcohols.
In tr od u ction
are needed for the removal of the auxiliary. Alternative
direct glycosylation approaches have been reported, but
these lead to either low yielding glycosylations or forma-
tion of unnatural â-sialosides or mixtures of anomers.12-15
It is obvious that a versatile sialyl donor needs to be
developed that gives excellent yields and high R-anomeric
selectivities in direct glycosylations with a wide range of
acceptors of different reactivities.7 Such a donor would
allow efficient synthesis of oligosaccharides of biological
or medical importance that contain multiple sialic acids
of different linkage type.
Here, we report that the readily available sialyl donor
methyl(methyl 4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-thio-
5-trifluoroacetamido-D-glycero-â-D-galacto-nonulopyra-
nosid)onate (2a ) gives good yields and excellent R-ano-
meric selectivities in direct sialylations with a wide
variety of glycosyl acceptors ranging from sterically
hindered C-8 hydroxyls of a sialic acid and C-3 hydroxyls
of galactosides to reactive primary alcohols. The versatil-
ity of the donor allowed a highly efficient synthesis of
the human melanoma associated antigen GD3 derivative,
which has multiple Neu5Ac residues (Figure 1).
Sialic acids are a diverse family of naturally occurring
2-keto-3-deoxy-nononic acids that are involved in a wide
range of biological processes.1,2 The most abundant sialic
acid derivative is N-acetylneuraminic acid (Neu5Ac);
however, compounds that have a glycolyl moiety at the
C-5 amino group (Neu5Gc) or acetyl esters at one or more
hydroxyls are also frequently encountered in nature.1,3
Sialic acids normally appear at terminal positions of
oligosaccharides of glycoproteins and glycolipids where
they are R(2,3) or R(2,6) linked to galactosides or R(2,6)
linked to 2-acetamido-2-deoxy-galactosides. The disialosyl
structures Neu5AcR(2-8)Neu5Ac and Neu5AcR(2-9)-
Neu5Ac have also been found as constituents of oligosac-
charides of glycoproteins and lipids. These substructures
are receptors for viruses and bacteria and constitute the
immunodominant epitope of tumor-associated antigens.
Neu5Ac or Neu5Gc also occur in linear homopolymers
where they are usually linked internally by R(2,8), R(2,9),
or alternating R(2,8)/R(2,9) glycosidic linkages. These
polysialic acids play important roles as neural cell
adhesion molecules.4
While relatively efficient methods have been developed
for the introduction of Neu5AcR(2-3)Gal and Neu5AcR-
(2-6)Gal glycosidic linkages, the synthesis of oligosac-
charides that contain R(2 f 8)-linked fragments is
complicated by the low reactivity of the C-8 hydroxyl of
Neu5Ac.5-7 The latter glycosides have been successfully
synthesized by indirect chemical approaches whereby
modified sialyl donors are employed that have a partici-
pating auxiliary at C-3.8-11 These highly elaborated
donors require, however, laborious procedures for their
preparation, and after a glycosylation, additional steps
Resu lts a n d Discu ssion
The synthesis of the human melanoma associated
antigen GD3 derivative requires the introduction of
Neu5AcR(2-8)Neu5Ac and Neu5AcR(2-3)Gal glycosidic
linkages. In addition, the anomeric center of a sialyl
acceptor needs temporary protection, which required gly-
cosylation with a primary alcohol. Previous syntheses of
the carbohydrate part of this biologically important gly-
cosphingolipid could only be achieved by indirect sialy-
lation protocols16-18 or a strategy whereby an R(2-8)-
linked fragment was obtained by controlled degradation
of colominic acid.19-21
(1) Sialic Acids: Chemistry, Methabolism and Function; Schauer,
R., Ed.; Springer-Verlag: Wien-New York, 1982; Vol. 10.
(2) Varki, A. Glycobiology 1993, 3, 97-130.
(3) Inoue, Y.; Inoue, S. Pure Appl. Chem. 1999, 71, 789-800.
(4) Reglero, A.; Rodriguez-Aparicio, L. B.; Luengo, J . M. Int. J .
Biochem. 1993, 25, 1517-1527.
(5) Okamoto, K.; Goto, T. Tetrahedron 1990, 46, 5835-5857.
(6) DeNinno, M. P. Synthesis 1991, 583-593.
(7) Boons, G. J .; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-
4565 and references therein.
It was anticipated that sialyl donor 2a (Scheme 1),
which is protected with a 5-trifluoroacetamido (N-TFA)
(12) Tsvetkov, Y. E.; Schmidt, R. R. Tetrahedron Lett. 1994, 35,
8583-8586.
(13) Castro-Palomino, J . C.; Tsvetkov, Y. E.; Schneider, R.; Schmidt,
R. R. Tetrahedron Lett. 1997, 38, 6837-6840.
(8) Ercegovic, T.; Magnusson, G. J . Org. Chem. 1995, 60, 3378-
2284.
(14) Demchenko, A. V.; Boons, G. J . Chem. Eur. J . 1999, 5, 1278-
1283.
(9) Ercegovic, T.; Magnusson, G. J . Org. Chem. 1996, 61, 179-184.
(10) Castro-Palomino, J . C.; Tsvetkov, Y. E.; Schmidt, R. R. J . Am.
Chem. Soc. 1998, 120, 5434-5440.
(11) Hossain, N.; Magnusson, G. Tetrahedron Lett. 1999, 40, 2217-
2220.
(15) Our attempts to synthesize (2-8)-linked dimers by direct
sialylation employing conventional glycosyl donors {2-thiomethyl,
2-thiophenyl, 2-xanthate, and 2-phosphite of methyl 5-acetamido-
4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-â-D-galacto-nonulopyranosid-
(yl)onate} failed, and only traces of the desired products were obtained.
10.1021/jo010345f CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/19/2001

Stereoselective Synthesis of R-Sialosides
J . Org. Chem., Vol. 66, No. 16, 2001 5491
Sch em e 1a
F igu r e 1.
group, would have superior glycosyl donor properties
compared to the traditional donor 2b,22 which has an
acetamido functionality at C-5, therefore allowing an
efficient synthesis of GD3 by a direct sialylation approach.
This expectation was based on our recent finding that
2-thio-sialyl donor 2c, which has an electron-withdrawing
N-acetylacetamido moiety at C-5, gives significantly
higher yields in glycosylations compared to donor 2b.14,23
This new glycosyl donor allowed the synthesis of Neu5AcR-
(2-8)Neu5Ac dimers in good yields albeit as a mixtures
of anomers.14 The improved glycosyl donor properties of
2c were rationalized by the fact that protection of the
C-5 acetamido group with a strong electron-withdrawing
amino protecting group would reduce its nucleophilicity,
thereby minimizing possible site reactions in glycosyla-
tions. In this respect, it has been observed that the C-5
acetamido group can be glycosylated when unreactive
glycosyl acceptors (e.g., C-8 hydroxyl of Neu5Ac) are
used.24
It was also anticipated that the low reactivity of the
C-8 hydroxyl of a neuraminic acid acceptor would be
improved when its amino group would be protected as
an N-TFA derivative. Schmidt and co-worker have pro-
posed that this low reactivity is in part due to unfavorable
hydrogen bonding between the C-5-acetamido and C-8
hydroxyl functions.12,13,25 These unfavorable interactions
should be less pronounced when the C-5 amino group is
protected as an N-TFA function. This predicament is
based on studies with N-acylated 2-hydroxyanilines
wherein it was shown that N-trifluoroacetyl derivatives
display longer and therefore weaker intermolecular
hydrogen bonds (between the C-1 amide and C-2 hydroxyl
functions) than do the analogous N-benzoylated com-
pounds.26 An N-TFA protecting group has the added
advantage that it can be easily introduced and removed
under mild reaction conditions. The latter feature makes
it feasible to functionalize the amino group of sialic acids
as N-acetyl, N-glycolyl, or other derivatives if desired.
a
Reagents and conditions: (i) CF3COOMe/Et3N, MeOH; (ii)
Ac2O/pyridine; (iii) TMS(CH2)2OH, NIS/TfOH/MS3Å, MeCN, -35
°C; (iv) MeONa/MeOH; (v) (MeO)2CHPh/CSA, MeCN; (vi) BH3‚
Me3N/AlCl3/MS4Å , THF.
The TFA-protected sialyl donor 2a and acceptor 5a
were prepared in a highly convergent manner from the
known precursor 1.27,28 Thus, selective N-trifluoracety-
lation29 of 1 with CF3COOMe in the presence of Et3N in
MeOH followed by O-acetylation with Ac2O/pyridine gave
sialyl donor 2a in overall yield of 73%.30 Compound 1 was
readily converted into glycosyl acceptor 5a . Thus, glyco-
sylation of thioglycoside 2a with 2-(trimethylsilyl)ethyl
alcohol (TEOH) in the presence of NIS/TfOH and molec-
ular sieves in MeCN at -33 °C furnished 3 in a good yield
as mainly the R-anomer (75%, R/â ) 10/1). Separation of
the anomers could be easily accomplished at a later stage
of the synthesis. The glycoside 3 was converted into the
selectively protected derivative 4 by subsequent deacety-
lation with MeONa in MeOH, regioselective protection
of the 8,9-diol as a benzylidene acetal by treatment with
dimethoxytoluene in the presence of camphorsulfonic acid
(CSA) in acetonitrile, and O-acetylation of the remaining
hydroxyls at C-4 and C-7 with Ac2O/pyridine. The ben-
zylidene acetal of 4 was regioselectively opened to a C-8
hydroxyl by the treatment with BH3‚NMe3 complex31 in
the presence of anhydrous AlCl3 and 4 Å molecular sieves
in dry THF to give sialyl acceptor 5a (Scheme 1).
The glycosyl donor properties of 2a were examined in
glycosylations with the C-8 hydroxyl of sialyl acceptors
5a -c bearing a N-TFA, acetamido, or acetylacetamido
moiety at C-5, respectively (Scheme 2). Thus, coupling
of 2a with 5a in the presence of NIS/TfOH/MS3Å in
acetonitrile at -35 °C gave (2-8)-linked sialoside 6a in
an excellent yield of 55%. After Sephadex LH-20 size
exclusion column chromatography, HPLC and NMR
(16) Ito, Y.; Numata, M.; Sugimoto, M.; Ogawa, T. J . Am. Chem.
Soc. 1989, 111, 8508-8510.
(17) Kondo, T.; Tomoo, T.; Abe, H.; Isobe, M.; Goto, T. J . Carbohydr.
Chem. 1996, 15, 857-878.
(18) Kondo, T.; Tomoo, T.; Abe, H.; Isobe, M.; Goto, T. Chem. Lett.
1996, 337-338.
(19) Roy, R.; Pon, R. A. Glycoconjugate J . 1990, 7, 3-12.
(20) Ishida, H.; Ohta, Y.; Tsukada, Y.; Kiso, M.; Hasegawa, A.
Carbohydr. Res. 1993, 246, 75-88.
(27) Sugata, T.; Higuchi, R. Tetrahedron Lett 1996, 37, 2613-2614.
(28) Sugata, T.; Kan, Y.; Nagaregawa, Y.; Miyamoto, T.; Higuchi,
R. J . Carbohydr. Chem. 1997, 16, 917-925.
(29) Byramova, N. E.; Tuzikov, A. B.; Bovin, N. V. Carbohydr. Res.
1992, 237, 161-175.
(30) Kiso and co-workers employed N-TFA-substituted neuraminic
acid derivatives for the preparation of a 6-sulfo-de-N-acetylsialyl Lex
ganglioside. They did not report improved glycosyl donor properties
of this derivative. Komba, S.; Glalustian, C.; Ishida, H.; Feizi, T.;
Kannagi, R.; Kiso, M. Angew. Chem., Int. Ed. Engl. 1999, 38, 1131-
1133.
(21) Diakur, J .; Noujaim, A. A. J . Carbohydr. Chem. 1994, 13, 777-
797.
(22) Hasegawa, A.; Ohki, H.; Nagahama, T.; Ishida, H. Carbohydr.
Res. 1991, 212, 277-281.
(23) Demchenko, A. V.; Boons, G. J . Tetrahedron Lett. 1998, 39,
3065-3068.
(24) Schmidt, R. R., personal communication.
(25) Schmidt, R. R.; Castro-Palomino, J . C.; Retz, O. Pure Appl.
Chem. 1999, 71, 729-744.
(26) Hibbert, F.; Mills, J . F.; Nyburg, S. C.; Parkins, A. W. J . Chem.
Soc., Perkin Trans. 2 1998, 629-634.
(31) Ek, M.; Garegg, P. J .; Hultberg, H.; Oscarson, S. J . Carbohydr.
Chem. 1983, 2, 305-311.

5492 J . Org. Chem., Vol. 66, No. 16, 2001
Meo et al.
Sch em e 2a
Sch em e 3a
a
Reagents and conditions: (i) NIS/TfOH/MS3Å, MeCN, 35 °C;
(ii) 1 M aq NaOH/MeOH; (iii) Ac2O/MeOH.
analysis of the product showed the presence of only one
anomer. Conventional empirical NMR rules for the
assignment of anomeric configurations of sialosides7 may
not be applicable to TFA-protected derivatives. Therefore,
dimer 6a was converted into the known acetamido
derivative 7 by concomitant N,O-deacylation with 1 M
aqueous NaOH/MeOH, followed by selective N-acetyla-
tion with Ac2O in MeOH. The NMR data and optical
rotation of 7 unambiguously confirmed the R-anomeric
configuration of the product. Thus, H-3′eq in the 1H NMR
spectrum of 7 was shifted downfield (δ ) 2.60 ppm)
compared to that of the previously synthesized â-anomer
(δ ) 2.37 ppm),14 whereas H-4′ of 7 appeared at higher
field (δ ) 3.53 ppm) than that of â-anomer (δ ) 4.05
ppm).
a
Reagents and conditions: (i) NIS/TfOH/MS3Å , MeCN, 35 °C;
(ii) 1 M aq NaOH/MeOH; (iii) Ac2O/MeOH; (iv) TFA, DCE; (v)
Ac2O/C6H5N; (vi) PhSH/BF3‚Et2O/MS3Å , DCM; (vii) H2, Pd(OAc)2,
EtOH/EtOAc, 1/1.
a conventional NHAc at C-5, gave anomeric mixtures
with yields ranging from 30% to 60%.33 Furthermore,
these traditional glycosylations require up to 3 equiv of
glycosyl donor 2a , whereas for the preparation of 9 only
2 equiv of 2a were used. The N-TFA protecting group of
9 was converted into the N-acetyl derivative by a two-
step procedure to give 10 in an 85% overall yield. In this
case, the NMR data of 10 also unambiguously confirmed
the presence of R-sialyl linkage (H-4” δ ) 3.79 ppm, ∆δ
{H-9”a - H-9”b} ) 0.12 ppm).
For the synthesis of GD3 derivative 14, dimer 6a was
converted into the second-generation thioglycosyl donor
12 (Scheme 3). Cleavage of the anomeric 2-(trimethyl-
silyl)ethyl glycoside of 6a with TFA/DCM, followed by
acetylation of the resulting lactol with Ac2O/pyridine gave
anomeric acetate 11 as predominantly the â-anomer.
Conversion of the anomeric acetate of 11 into a 2-thiophe-
nyl sialoside 12 was easily accomplished by the treatment
with thiophenol in the presence of BF3‚Et2O. On the other
hand, reaction of 11 with TMSSMe was very sluggish and
gave the corresponding 2-thiomethyl sialoside in a low
yield.22 NIS/TfOH-mediated glycosylation of 12 with
lactosyl acceptor 8b34 afforded tetrasaccharide 13 in an
excellent yield of 42% as only the R-anomer. In this case,
only 1 equiv of sialyl donor 12 was used to achieve this
result. Furthermore, the stereoselective preparation of
Glycosylation of 5b and 5c14 with 2a under similar
reaction conditions (NIS/TfOH/MS3Å/MeCN, -35 °C)
provided stereoselective formation of R-sialosides 6b and
6c, respectively, but yields were significantly lower (34
and 30% yield, respectively). The modest yield of 6c could
be explained by a competing acetyl group migration from
N-5 to N-8 of acceptor 5c, whereas the nucleophilicity
and basicity of the acetamido moiety of 5b probably
caused the low yield of 6b. It is important to note that
glycosylation of 2b22 or 2c23 with acceptor 5a gave
mixtures of anomers in poor or reasonable yield, respec-
tively, demonstrating the superior glycosyl donating
properties of 2a .
Encouraged by these results, attention was focused on
the formation of sialosides of a C-3 hydroxyl of the
galactosyl residue of a partially protected derivative of
D-lactose (Scheme 3). Thus, NIS/TfOH-mediated coupling
of 2a with partially protected lactosyl acceptor 8a 32 gave
trisaccharide 9 in an excellent yield of 84% as only the
R-anomer. This is a remarkable result because similar
glycosylations with monosaccharide donor 2b, which has
(33) Hasegawa, A.; Nagahama, T.; Ohki, H.; Hotta, K.; Ishida, H.;
Kiso, M. J . Carbohydr. Chem. 1991, 10, 493-498.
(34) Nishida, Y.; Thiem, J . Carbohydr. Res. 1994, 263, 295-301.
(32) Demchenko, A. V.; Boons, G. J . J . Org. Chem. 2001, 66, 2547-
2554.

Stereoselective Synthesis of R-Sialosides
J . Org. Chem., Vol. 66, No. 16, 2001 5493
the first instance and then for 2-3 h at 390 °C directly prior
to application. Optical rotations were measured with a J asco
P-1020 polarimeter. 1H and 13C NMR spectra were recorded
with a Varian Inova500 spectrometer and a Varian Inova600
spectrometer equipped with Sun workstations. Unless other-
wise noted 1H NMR spectra were recorded in CDCl3 and
referenced to residual CHCl3 at 7.24 ppm, and 13C NMR
spectra to the central peak of CDCl3 at 77.0 ppm. Assignments
were made by standard gCOSY and gHSQC. High-resolution
mass spectra were run in a J MS SX/SX102A tandem mass
spectrometer, equipped with FAB source. The matrix used was
thioglycerol, and the internal standards were ultramark 1621
and PEG.
disaccharides 6a -c, trisaccharide 9, and tetrasaccharide
13 indicates that, regardless of the protecting group
pattern of donor and acceptor, N-TFA-protected sialyl
donors give stereoselective formation of R-sialosides in
good yields. The benzyl ethers of compound 13 were
removed by catalytic hydrogenation over Pd(OAc)2, and
the N-TFA of the resulting intermediate was converted
into the corresponding acetamido moiety by the treat-
ment with sodium hydroxide followed by N-acetylation
with acetic anhydride in methanol to give the requisite
GD3 derivative 14. The NMR data of 14 showed that only
the required R-linked sialosides were formed. On the
basis of the NMR data of 2a , 6a -c, 9, and 11-13 the
anomeric configuration of N-TFA-protected derivatives
can be determined from the chemical shift data of H-4
(δ ) 5.30-5.45 ppm for â-anomers and δ ) 4.92-5.11
ppm for R-anomers).
Meth yl (Meth yl 4,7,8,9-tetr a -O-a cetyl-3,5-d id eoxy-2-
t h io-5-t r iflu or oa cet a m id o-D-glycer o-â-D-ga la cto-n on -2-
u lop yr a n osid )on a te (2a ). Methyl trifluoroacetate (3.5 mL,
34 mmol) was added to a solution of 1 (1.07 g, 3.44 mmol) and
triethylamine (0.96 mL, 6.9 mmol) in methanol (40 mL). After
1.5 h, the reaction mixture was concentrated under reduced
pressure and dried in vacuo. Pyridine (20 mL) and Ac2O (10
mL) were added to the residue. After 16 h, the reaction was
quenched with MeOH (15 mL), concentrated, coevaporated
with toluene (3 × 15 mL), and dried in vacuo. The residue
was purified by silica gel column chromatography (10% gradi-
ent ethyl acetate in hexane) to afford 2a as a white foam (1.44
g, 73%): FAB MS m/z 598.1 [M + Na]+; Rf 0.51 (acetone/
toluene, 3/7, v/v); [R]27D ) -44.4 (c 0.6, CHCl3); 1H NMR δ 6.77
(d, 1H, J NH,5 ) 10.1 Hz, NH), 5.37-5.44 (m, 2H, J 4,5 ) 11.5
Hz, J 7,8 ) 11.2 Hz, H-4, 7), 5.16-5.19 (m, 1H, J 8,9a ) 2.5 Hz,
J 8,9b ) 7.8 Hz, H-8), 4.78 (dd, 1H, J 9a,9b ) 12.5 Hz, H-9a), 4.50
(dd, 1H, J 6,7 ) 2.5 Hz, H-6), 4.18 (dd, 1H, H-9b), 4.03 (dd, 1H,
Con clu sion
It has been shown that modification of the C-5 amino
group of 2-methyl and 2-thiophenyl sialosides into N-TFA
derivatives provides glycosyl donors that give good yields
and high R-anomeric selectivities in direct sialylations
with a wide range of glycosyl acceptors of differing
reactivities. These new donors allowed, for the first time,
the stereoselective synthesis of R-(2-8)-linked dimers in
high yields. The best yields were obtained when the
amino functionality of the sialyl acceptor was also
protected as N-TFA derivative. The favorable properties
of the new donors allowed a highly efficient synthesis of
the human melanoma associated antigen GD3 derivative,
which has two Neu5Ac residues of different linkage type.
A N-TFA-substituted sialyl donor has previously been
employed for the preparation of a 6-sulfo-de-N-acetylsia-
lyl Lex ganglioside; however, no improved glycosyl donor
properties were reported.30 The N-TFA protecting group
could be easily transformed into Neu5Ac derivatives, and
potentially they open an efficient route toward sialic acid
containing oligosaccharides that have modified amino
functionalities. We postulate that the efficiency of the
glycosylations results from a lower nucleophilicity of
TFA-protected amino functionalities and enhanced re-
activity of a C-8 hydroxyl of a sialyl acceptor. The origin
of the high R-selectivity of N-TFA-protected sialyl donors
is still unclear, and further studies are underway to shed
light on this effect.
J 5, 6 ) 10.5 Hz, H-5), 3.83 (s, 3H, OCH3), 2.58 (dd, 1H, J 3e,4
)
5.0 Hz, J 3e,3a ) 13.4 Hz, H-3e), 2.16 (dd, 1H, H-3a), 2.14, 2.09,
2.05, 2.04, (4s, 12H, OCOCH3), 2.03 (s, 3H, SMe); 13C NMR δ
171.4, 171.1, 170.6, 170.0, 167.8, 167.7, 85.0, 72.6, 71.3, 68.9,
68.5, 62.5, 53.2, 50.6, 37.2, 21.3, 21.1, 20.9, 11.73; HR-FAB
MS [M + H]+ calcd for C21H29O12NF3S 576.1363, found
576.1360.
Meth yl [2-(Tr im eth ylsilyl)eth yl 4,7,9-tr i-O-a cetyl-3,5-
d id eoxy-5-t r iflu or oa cet a m id o-D-glycer o-r,â-D-ga la cto-
n on -2-u lop yr a n osid ]on a te (3). A mixture of 2a (1 g, 1.74
mmol), 2-(trimethylsilyl)ethanol (0.5 mL, 3.5 mmol), and
activated molecular sieves (3 Å, 300 mg) in MeCN (35 mL)
was stirred for 16 h under an atmosphere of argon at room
temperature and then cooled to -35 °C, and NIS (783 mg, 3.48
mmol) and TfOH (31 µL, 0.35 mmol) were added. The reaction
mixture was stirred for 15 min until TLC analysis indicated
that the reaction had gone to completion. The reaction mixture
was diluted with DCM (100 mL), the solids were filtered off,
and the residue was washed with DCM (3 × 100 mL). The
combined filtrate (400 mL) was washed with aqueous Na2S2O3
(20%, 150 mL) and H2O (3 × 80 mL). The organic phase was
dried (MgSO4) and filtered, and the filtrate was concentrated
in vacuo. The residue was purified by silica gel column
chromatography (10% gradient ethyl acetate in hexane) to
afford 3 as 10/1 R/â-mixture (848 mg, 75%) as a white foam.
Analytical data for R-3: FAB MS m/z 646.2 [M + H]+; Rf 0.35
Exp er im en ta l Section
Gen er a l. Column chromatography was performed on silica
gel 60 (EM Science, 70-230 mesh), size exclusion column
chromatography was performed on Sephadex LH-20 (MeOH
or MeOH/CH2Cl2, 1/1, v/v elution) or Sephadex G-25 (water
elution). HPLC chromatography was performed on Prodigy 5
µm silica 100 Å column (250 × 10 mm, CH2Cl2/ethyl acetate
elution). Reactions were monitored by TLC on Kieselgel 60 F254
(EM Science), and the compounds were detected by examina-
tion under UV light and by charring with 10% sulfuric acid in
methanol. Solvents were removed under reduced pressure at
<40 °C. CH2Cl2, (ClCH2)2, and MeCN were distilled from CaH2
(twice) and stored over molecular sieves (3 Å). THF was
distilled from sodium directly prior to the application. Metha-
nol was dried by refluxing with magnesium methoxide,
distilled, and stored under argon. Pyridine was dried by
refluxing with CaH2, then distilled ,and stored over molecular
sieves (3 Å). Molecular sieves (3 and 4 Å) used for reactions
were crushed and activated in vacuo at 390 °C during 8 h in
(ethyl acetate/hexane, 2/3, v/v); [R]27 ) -8.3 (c 0.6, CHCl3);
D
1H NMR δ 6.24 (d, 1H, J NH,5 ) 9.8 Hz, NH), 5.35-5.40 (m,
1H, J 8,9a ) 2.4 Hz, J 8,9b ) 4.9 Hz, H-8), 5.26 (dd, 1H, J 7,8 ) 8.3
Hz, H-7), 4.92-4.98 (m, 1H, J 4,5 ) 10.2 Hz, H-4) 4.27 (dd, 1H,
J 9a,9b ) 12.7 Hz, H-9a), 4.23 (dd, 1H, J 6,7 ) 1.9 Hz, H-6), 4.11
(dd, 1H, H-9b), 3.94 (dd, 1H, J 5,6 ) 10.7 Hz, H-5), 3.84-3.90
(m, 1H, J 2) 9.3 Hz, OCH2a) 3.79 (s, 3H, OCH3), 3.28-3.34
(m, 1H, OCH2b), 2.62 (dd, 1H, J 3e,4 ) 4.4 Hz, J 3e,3a ) 12.7 Hz,
H-3e), 2.14, 2.11, 2.01, 1.99, (4s, 12H, OCOCH3), 1.90 (t, 1H,
H-3a), 0.80-0.92 (m, 2H, CH2TMS), 0.00 (s, 9H, TMS); 13C
NMR δ 71.5, 67.0, 62.8, 62.7, 62.0, 52.6, 50.4, 38.3, 20.8, 20.5,
20.4, 17.9, 10.9; HR-FAB MS [M + H]+ calcd for C25H39O13
NF3Si 646.2143, found 646.2148.
-
Met h yl [2-(Tr im et h ylsilyl)et h yl 4,7-d i-O-a cet yl-9-O-
b en zyl-3,5-d id eoxy-5-t r iflu or oa cet a m id o-D-glycer o-r-D-
ga la cto-n on -2-u lop yr a n osid ]on a te (5a ). Sodium methoxide
(7 mL, 1 M solution in methanol) was added to the solution of
3 (848 mg, 1.31 mmol) in methanol (100 mL). After 2 h, the

5494 J . Org. Chem., Vol. 66, No. 16, 2001
Meo et al.
reaction mixture was neutralized with Dowex-50 H+ resin (pH
) 7), which was removed by filtration. The filtrate was
concentrated under reduced pressure to afford methyl [2-(tri-
methylsilyl)ethyl 3,5-dideoxy-5-trifluoroacetamido-D-glycero-
R-D-galacto-non-2-ulopyranosid]onate (615 mg, 98%). The resi-
due was dissolved in MeCN (15 mL), and benzaldehyde
dimethyl acetal (0.39 mL, 2.57 mmol) and CSA (30 mg, 0.13
mmol) were added. After 1 h, the reaction mixture was
neutralized with triethylamine (pH ) 7), and the solvent was
evaporated under reduced pressure. The residue was dissolved
in DCM (70 mL) and washed with saturated aqueous NaHCO3
(20 mL) and H2O (3 × 25 mL). The organic phase was dried
(MgSO4) and filtered, and the filtrate was concentrated in
vacuo. The residue was purified by silica gel column chroma-
tography (10% gradient ethyl acetate in toluene) to afford
anomerically pure methyl [2-(trimethylsilyl)ethyl 8,9-O-ben-
zylidene-3,5-dideoxy-5-trifluoroacetamido-D-glycero-R-D-galacto-
non-2-ulopyranosid]onate as a white foam (447 mg, 61%, exo/
endo 1/1), which was dissolved in a mixture of Ac2O (8 mL)
and pyridine (16 mL). After 16 h, the reaction was quenched
with MeOH (10 mL) and concentrated in vacuo, and the
residue was coevaporated with toluene (3 × 20 mL) to give 4
as a white foam (492 mg, 96%), which was used without
further purification; Rf 0.42 (acetone/hexane, 2/3 v/v). Com-
parison of the integral intensities of NH 6.31 (d, 1H) and 6.20
(d, 1H), or CHPh 5.87 (s, 1H) and 5.79 (s, 1H) signals in the
1H NMR spectrum showed 1:1 mixture of exo/ endo isomers.
BH3‚NMe3 (307 mg, 4.21 mmol) and AlCl3 (546 mg, 4.10 mmol)
were added to a solution of 4 (441 mg, 0.68 mmol) and
activated molecular sieves (4 Å, 2.65 g) in THF (8 mL) at 0
°C. After stirring for 2 h at 0 °C and another 3 h at room
temperature, the reaction mixture was diluted with Et2O (50
mL), and the solids were filtered off and washed with Et2O (3
× 50 mL). The combined filtrate (200 mL) was washed with
saturated aqueous NaHCO3 (2 × 70 mL) and H2O (3 × 40 mL).
The organic phase was dried (MgSO4) and filtered, and the
filtrate was concentrated in vacuo. The residue was purified
by silica gel column chromatography (10% gradient ethyl
acetate in toluene) to afford 5a as a white foam (319 mg,
72%): FAB MS m/z 652.2 [M + H]+; Rf 0.55 (ethyl acetate/
toluene 2/3, v/v); [R]27D ) -4.7 (c 1.2, CHCl3); 1H NMR δ 7.20-
7.37 (m, 5H, aromatic), 6.54 (d, 1H, J NH,5 )7.8 Hz, NH), 5.12
(d, 1H, J 7,8 ) 8.8 Hz, H-7) 4.92-5.00 (m, 1H, J 4,5 ) 9.8 Hz
H-4), 4.50-4.58 (m, 2H, CH2Ph), 4.11-4.17 (m, 1H, J 8,9a ) 3.4
Hz, J 8,9b ) 6.0 Hz, H-8), 4.05-4.10 (m, 2H, H-5, 6), 3.89 (dd,
1H, J 2 ) 8.5 Hz, OCH2a), 3.86 (s, 3H, OCH3), 3.76 (d, 1H, J OH,8
) 6.0 Hz, OH), 3.53 (dd, 1H, J 9a,9b ) 10.2 Hz, H-9a), 3.46 (dd,
1H, H-9b), 3.42 (dd, 1H, OCH2b), 2.73 (dd, 1H, J 3e,4 ) 4.9 Hz,
J 3e,3a ) 12.7 Hz, H-3e), 2.09, 2.02, (2s, 6H, OCOCH3) 1.98 (t,
1H, H-3a), 0-84-0.95 (m, 2H, CH2TMS), 0.00 (s, 3H, TMS);
13C NMR δ 170.8, 170.2, 169.5, 158.0, 138.0, 128.5, 128.2,
127.8, 98.8, 73.8, 72.2, 70.9, 69.6, 69.2, 62.77, 53.7, 50.3, 37.9,
21.1, 20.9, 18.3, -0.93; HR-FAB MS [M + H]+ calcd for
v/v); [R]27 ) +2.7 (c 1.1, CHCl3); 1H NMR δ 7.67 (d, 1H, J NH,5
D
) 9.8 Hz, NH), 7.25-7.37 (m, 5H, aromatic), 6.24 (d, 1H,
J NH,5′ ) 9.3 Hz, NH), 5.58-5.62 (m, 1H, J 8′,9′b ) 1.9 Hz,
H-8′), 5.32 (dd, 1H, J 7′,8′ ) 9.8 Hz, H-7′), 5.23 (d, 1H, H-7),
5.17 (d, 1H, J 8,9b ) 7.8 Hz, H-8), 4.99-5.06 (m, 1H, J 4′,5′ ) 9.8
Hz, H-4′), 4.89-4.96 (m, 1H, J 4,5 ) 11.7 Hz, H-4), 4.56 (dd,
2H, J 2 ) 11.7 Hz, CH2Ph), 4.42 (dd, 1H, J 6,7 ) 2.4 Hz, H-6),
4.38 (dd, 1H, J 9′a
) 12.7 Hz, H-9′a), 4.21 (dd, 1H, H-9′b),
9′b
4.07-3.95 (m, 3H, J 5,6 ) 10.2 Hz, J 6′,7′ ) 1.5 Hz, J 9a,9b ) 11.2
Hz, H-5, 5′, 6′, 9a), 3.84 (s, 3H, OCH3), 3.83 (s, 3H, OCH3),
3.81 (m, 1H, J 2 ) 8.8 Hz, OCH2a), 3.54 (dd, 1H, H-9b), 3.31-
3.37 (m, 1H, OCH2b), 2.78 (dd,1H, J 3′e,4′ ) 4.4 Hz, J 3′e,3′a
)
12.7 Hz, H-3′e), 2.72 (dd,1H, J 3e,4 ) 4.9 Hz, J 3e,3a ) 12.7 Hz,
H-3e), 2.20, 2.06, 2.05, 2.02, 2.01, 2.00 (6s, 18H, OCOCH3),
2.07-2.18 (m, 1H, H-3′a), 1.93 (dd, 1H, H-3a), 0.75-0.90
(m, 2H, CH2TMS), -0.01 (s, 3H, TMS); 13C NMR δ 172.3,
171.2, 170.8, 170.3, 169.9, 169.8, 168.9, 168.4, 157.6, 138.9,
128.5, 127.6, 127.4, 99.01, 96.9, 73.9, 73.8, 72.5, 71.8, 10.6, 69.9,
69.4, 68.7, 68.6, 66.9, 62.7, 62.5, 53.6, 52.9, 50.8, 50.0, 38.9,
38.2, 31.2, 30.0, 21.5, 20.9, 20.8, 20.7, 18.2, -0.92; HR-FAB
MS [M + Na]+ calcd for C48H64O23N2F6NaSi 1201.3471, found
1201.3472.
Meth yl [2-(Tr im eth ylsilyl)eth yl 5-a ceta m id o-4,7-d i-O-
a cetyl-9-O-ben zyl-3,5-d id eoxy-8-O-(m eth yl 4,7,8,9-tetr a -
O-a cetyl-3,5-d id eoxy-5-tr iflu or oa ceta m id o-D-glycer o-r-D-
ga la cto-n on -2-u lop yr a n osylon a te)-D-glycer o-r-D-ga la cto-
n on -2-u lop yr a n osid ]on a te (6b). A mixture of donor 2a (81
mg, 0.140 mmol), 5b (28 mg, 0.047 mmol), and activated
molecular sieves (3 Å, 300 mg) in MeCN (0.5 mL) was stirred
for 16 h under an atmosphere of argon. The mixture was cooled
to -35 °C, NIS (0.28 mmol) and TfOH (0.03 mmol) were added,
and the reaction mixture was stirred for 20 min until TLC
analysis indicated that reaction had gone to completion. The
reaction mixture was diluted with DCM (10 mL), the solids
were filtered off, and the residue was washed with DCM (3 ×
10 mL). The combined filtrate (40 mL) was washed with
aqueous Na2S2O3 (20%, 15 mL) and H2O (3 × 20 mL). The
organic phase was dried (MgSO4) and filtered, and the filtrate
was concentrated in vacuo. The residue was purified by size
exclusion column chromatography on Sephadex LH-20 (metha-
nol/dichloromethane, 1/1, v/v) to afford 6b as a white foam
(18.0 mg, 34%): FAB MS m/z 1125.4 [M + H]+; Rf 0.51
(acetone/toluene, 5/5, v/v); [R]27D ) +2.4 (c 0.3, CHCl3); 1H NMR
δ 7.31-7.37 (m, 5H, aromatic), 6.37 (d, 1H, J NH,5 ) 9.6 Hz,
NH), 6.17 (d, 1H, J NH,5′ ) 9.9 Hz, NH), 5.51-5.56 (m, 1H, J 8′,9′
) 4.3 Hz, H-8′), 5.29 (dd, 1H, J 7′,8′ ) 9.8 Hz, H-7′), 5.24 (bs,
1H, H-7), 5.00-5.07 (m, 2H, J 4′,5′ ) 10.2 Hz, J 8,9b ) 8.9 Hz,
H-4′, 8), 4.86-4.92 (m, 1H, J 4,5 ) 11.7 Hz, H-4), 4.71 (dd, 2H,
J 2 )11.6 Hz, CH2Ph), 4.25-4.30 (m, 2H, J 9′a,9′b ) 12.7 Hz, H-9′)
4.17 (dd, 1H, J 6,7 )1.9 Hz, H-6), 4.02-4.08 (m, 2H, J 6′,7′ ) 1.4
Hz, J 9a,9b ) 11.9 Hz, H-6′, 9a), 3.93-4.02 (m, 2H, J 5′,6′ ) 9.7
Hz, J 5,6 ) 10.6 Hz, H-5′, 5), 3.86 (s, 3H, OCH3), 3.82 (s, 3H,
OCH3), 3.78-3.84 (m, 1H, J 2 )9.3 Hz, OCH2a), 3.55 (dd, 1H,
H-9b), 3.34-3.40 (m, 1H, OCH2b), 2.76 (dd, 1H, J 3′e,4′ ) 4.7 Hz,
C
28H41O11NF3Si 652.2401, found 652.2410.
J 3′e,3′a ) 12.9 Hz, H-3′e), 2.65 (dd, 1H, J 3e,4 ) 4.8 Hz, J 3e,3a
)
Met h yl [2-(Tr im et h ylsilyl)et h yl 4,7-d i-O-a cet yl-9-O-
12.8 Hz, H-3e), 2.22 (s, 3H, NHCOCH3), 2.06, 2.05, 2.04, 2.02,
2.01, 1.90 (6s, 18H, OCOCH3), 2.03 (m, 1H, H-3′a), 1.91 (dd,
1H, H-3a), 0.76-0.90 (m, 2H, CH2TMS), 0.00 (s, 3H, TMS);
13C NMR δ 171.3, 171.1, 170.8, 170.6, 170.2, 170.0, 168.7,
168.5, 138.9, 128.5, 127.6, 127.4, 99.0, 97.4, 74.4, 74.0, 72.7,
71.7, 70.5, 70.0, 68.6, 67.1, 62.6, 62.4, 53.5, 52.8, 50.9, 49.3,
38.7, 38.1, 30.0, 23.4, 21.8, 21.3, 21.1, 21.0, 18.3, -0.89; HR-
FAB MS [M + H]+ calcd for C48H68O23N2F3NaSi 1125.3934,
found 1125.3900.
Meth yl [2-(Tr im eth ylsilyl)eth yl 5-(N-a cetyla ceta m id o)-
4,7-di-O-acetyl-9-O-ben zyl-3,5-dideoxy-8-O-(m eth yl 4,7,8,9-
tetr a-O-acetyl-3,5-dideoxy-5-tr iflu or oacetam ido-D-glycer o-
r-D -ga la ct o-n on -2-u lop yr a n osylon a t e )-D -glycer o-r-D -
ga la cto-n on -2-u lop yr a n osid ]on a te (6c). A mixture of donor
2a (97 mg, 0.169 mmol), 5c (36 mg, 0.056 mmol), and activated
molecular sieves (3 Å, 340 mg) in MeCN (2.0 mL) was stirred
for 16 h under an atmosphere of argon. The mixture was cooled
to -35 °C, NIS (0.34 mmol) and TfOH (0.03 mmol) were added,
and the reaction mixture was stirred for 5 min until TLC
analysis indicated that reaction had gone to completion. The
ben zyl-3,5-d id eoxy-8-O-(m eth yl 4,7,8,9-tetr a -O-a cetyl-3,5-
d id eoxy-5-tr iflu or oa ceta m id o-D-glycer o-r-D-ga la cto-n on -
2-u lop yr a n osylon a te)-5-tr iflu or oa ceta m id o-D-glycer o-r-
D-ga la cto-n on -2-u lop yr a n osid ]on a te (6a ). A mixture of
donor 2a (85 mg, 0.147 mmol), 5a (32 mg, 0.049 mmol), and
activated molecular sieves (3 Å, 250 mg) in MeCN (1.5 mL)
was stirred for 16 h under an atmosphere of argon at room
temperature. The mixture was cooled to -35 °C, NIS (0.294
mmol) and TfOH (0.03 mmol) were added, and the reaction
mixture was stirred for 5 min until TLC analysis indicated
that reaction had gone to completion. The reaction mixture
was diluted with DCM (10 mL), the solids were filtered off,
and the residue was washed with DCM (3 × 10 mL). The
combined filtrate (40 mL) was washed with aqueous Na2S2O3
(20%, 15 mL) and H2O (3 × 20 mL). The organic phase was
dried (MgSO4) and filtered, and the filtrate was concentrated
in vacuo. The residue was purified by size exclusion column
chromatography on Sephadex LH-20 (methanol/dichlorometh-
ane, 1/1, v/v) to afford 6a as a white foam (32.0 mg, 55%): FAB
MS m/z 1201.3 [M + Na]+; Rf 0.51 (ethyl acetate/hexane, 5/5,

Stereoselective Synthesis of R-Sialosides
J . Org. Chem., Vol. 66, No. 16, 2001 5495
reaction mixture was diluted with DCM (10 mL), the solids
were filtered off, and the residue was washed with DCM (3 ×
10 mL). The combined filtrate (40 mL) was washed with
aqueous Na2S2O3 (20%, 15 mL) and H2O (3 × 20 mL). The
organic phase was dried (MgSO4) and filtered, and the filtrate
was concentrated in vacuo. The residue was purified by size
exclusion column chromatography on Sephadex LH-20 (metha-
nol/dichloromethane, 1/1, v/v) to afford 6c as a white foam (19.5
mg, 30%): FAB MS m/z 1189.4 [M + Na]+; Rf 0.53 (ethyl
acetate/ hexane, 5/5, v/v); [R]27D ) -6.2 (c 0.7, CHCl3); 1H NMR
mL). The combined filtrate (40 mL) was washed with aqueous
Na2S2O3 (20%, 15 mL) and H2O (3 × 20 mL). The organic phase
was dried (MgSO4) and filtered, and the filtrate was concen-
trated in vacuo. The residue was purified by size exclusion
column chromatography on Sephadex LH-20 (methanol/dichlo-
romethane, 1/1, v/v) to afford 9 as a white foam (71 mg, 84%):
FAB MS m/z 1425.5 [M + Na]+; Rf 0.51 (acetone/toluene, 3/7,
v/v); [R]27 ) +3.7 (c 0.7, CHCl3); 1H NMR δ 7.20-7.42 (m,
D
25H, aromatic), 6.28 (d, 1H, J NH
,
) 9.8 Hz, NH), 5.44-5.50
5′′
(m, 1H, J 8′′,9′′a ) 2.4 Hz, J 8′′,9′′b ) 5.4 Hz, H-8′′), 5.28 (dd, 1H,
J 7′′,8′′ ) 8.3 Hz, H-7′′), 4.95-5.01 (m, 1H, J 4′′,5′′ ) 10.2 Hz, H-4′′),
4.86 (dd, 2H, J 2 ) 10.7 Hz, CH2Ph), 4.77 (dd, 2H, J 2 ) 11.2
Hz, CH2Ph), 4.73 (dd, 2H, J 2 ) 11.7 Hz, CH2Ph), 4.59 (d, 1H,
J 1′,2′ ) 7.3 Hz, H-1′), 4.49 (dd, 2H, J 2 ) 12.2 Hz, CH2Ph), 4.40
(dd, 2H, J 2 ) 11.7 Hz, CH2Ph), 4.34 (d, 1H, J 1,2 ) 7.8, H-1),
δ 7.23-7.39 (m, 5H, aromatic), 6.21 (d, 1H, J NH
, ) 9.6 Hz,
5′
NH), 5.49-5.56 (m, 1H, J 4,5 ) 10.4 Hz, H-4), 5.29-5.33 (m,
1H, J 8′,9′a ) 2.4 Hz, J 8′,9′b ) 3.7 Hz, H-8′), 5.26 (dd, 1H, J 7′, 8′
)
9.2 Hz, H-7′), 5.04-5.11 (m, 2H, J 4′,5′) 10.4 Hz, J 7, 8 ) 9.2 Hz,
H-4′, 7), 4.96 (dd, 1H, J 6,7 ) 1.4 Hz, H-6), 4.59 (dd, 2H, J 2
)
)
12.0 Hz, CH2Ph.), 4.41-4.45 (m, 1H, J 8, ) 4.3 Hz, J 8,9b
4.27 (dd, 1H, J 9′′a,9′′b ) 12.2 Hz, H-9′′a), 4.17 (dd, 1H, J 6′′,7′′ )
2.0 Hz, H-6′′, 4.05 (dd, 1H, J 3′,4′ ) 3.4 Hz, H-3′), 3.90-4.03 (m,
4H, H-4, 5′′, 9′′b, OCH2a), 3.81 (bt, 1H, H-4′), 3.77 (s, 3H,
9a
6.4 Hz, H-8), 4.24 (dd, 1H, J 9′a,9′b ) 12.6 Hz, H-9′a), 4.03-4.12
(m, 4H, J 5,6 ) 9.9 Hz, J 6′,7′ ) 1.8 Hz, J 9a,9b ) 11.2 Hz H-5, 6′,
9a, 9′b), 3.89 (m, 1H, J 5′,6′ ) 9.9 Hz, H-5′), 3.87 (m, 1H, J 2
)
OCH3), 3.73, (d, 2H, H-6), 3.67 (dd, 1H, J 6′a,
) 11.2 Hz,
6′b
8.8 Hz, OCH2a), 3.86 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.68
(dd, 1H, H-9b), 3.34 (m, 1H, OCH2b), 2.75 (dd,1H, J 3e,4
H-6′a), 3.58-3.62 (m, 2H, H-3, OCH2b), 3.46-3.57 (m, 3H, J 2′,3′
) 9.3 Hz, J 5′,6′a ) 8.8 Hz, H-2′, 5′, 6′b), 3.34-3.41 (m, 4H, J 5,6
) 2.9 Hz, H-2, 5, CH2N), 2.70 (d, 1H, J OH,4′ ) 3.4 Hz, OH),
2.56 (dd, 1H, J 3′′e,3′′a ) 13.1 Hz, J 3′′e,4′′ ) 4.8 Hz, H-3′′e), 2.01
(m, 1H, 3′′a), 2.10, 2.01, 1.98, 1.89 (4s, 12H, OCOCH3), 1.87
(m, 2H, CCH2C); 13C NMR δ 170.8, 170.7, 170.3, 169.8, 168.2,
158.0, 157.5, 139.2, 139.0, 138.7, 138.6, 138.5, 128.6, 128.5,
128.4, 128.3, 128.2, 128.1, 128.0, 127.8, 127.7, 127.6, 127.5,
127.4, 127.3, 103.1, 102.5 83.2, 82.1, 78.7, 76.7, 75.6, 75.4, 75.3,
73.6, 73.4, 72.7, 72.2, 69.3, 68.8, 68.7, 68.2, 67.3, 66.7, 62.4,
53.4, 50.3, 48.7, 36.7, 29.6, 21.4, 21.3, 21.0, 20.7; HR-FAB MS
[M + Na]+ calcd for C70H81O23N4F3Na 1425.5141, found
1425.5109.
)
5.5 Hz, J 3e,3a ) 13 Hz, H-3e), 2.67 (dd,1H, J 3′e, ) 4.8 Hz,
4′
J 3′e,3′a ) 13 Hz, H-3′e), 2.30, 2.28 (2s, 6H, N(COCH3)2), 2.16,
2.03, 2.01, 1.99, 1.98, (5s, 18H, OCOCH3), 2.01 (m, 1H, H-3′a),
1.84 (dd, 1H, H-3a), 0.84-0.88 (m, 2H, CH2TMS), 0.00 (s,
3H, TMS); 13C NMR δ 174.2, 174.0, 170.7, 170.2, 170.1,
169.7, 169.6, 168.2, 168.1, 157.4, 139.0, 128.3, 127.6, 127.4,
99.4, 98.9, 75.3, 73.6, 71.7, 71.1, 70.8, 70.3, 68.7, 68.4, 67.1,
66.9, 62.4, 62.1, 60.7, 57.9, 53.4, 52.9, 50.7, 39.1, 38.5, 30.0,
28.2, 26.1, 21.4, 21.3, 21.1, 21.0, 20.9, 18.4, 14.6, -0.88; HR-
FAB MS [M + Na]+ calcd for C50H69O24N2F3NaSi 1189.3859,
found 1189.3880.
2-(Tr im eth ylsilyl)eth yl 5-Aceta m id o-8-O-(5-a ceta m id o-
3,5-d id eoxy-D-glycer o-r-D-ga la cto-n on -2-u lop yr a n osyl-
on ic a cid )-9-O-ben zyl-3,5-d id eoxy-D-glycer o-r-D-ga la cto-
n on -2-u lop yr a n oson ic Acid Disod iu m Sa lt (7). F r om 6a .
Aqueous NaOH (1 M, 0.5 mL) was added dropwise to a solution
of 6a (20 mg, 16.9 µmol) in MeOH (1 mL). After 72 h (control
TLC, methanol/n-buthanol/water/triethylamine, 20/60/15/5,
v/v/v/v) the reaction mixture was concentrated in vacuo, and
the residue was subjected to freeze-drying for 16 h. MeOH (0.8
mL) and Ac2O (0.2 mL) were added, and the reaction mixture
was kept for 16 h and then concentrated under the reduced
pressure. The residue was purified by size exclusion column
chromatography on Sephadex G25 (35 cm3, water elution) to
3-Azid op r op yl O-(5-Aceta m id o-3,5-d id eoxy-D-glycer o-
r-D-ga la cto-n on -2-u lop yr a n osylon ic a cid )-(2 f 3)-O-(2,6-
d i-O-b en zyl-â-D-ga la ct op yr a n osyl)-(1 f 4)-2,3,6-t r i-O-
ben zyl-â-D-glu cop yr a n osid e Sod iu m Sa lt (10). Aqueous
NaOH (1 M,0.4 mL) was added dropwise to a solution of 9 (6
mg, 4.27 µmol) in MeOH (1 mL). After 5 h (control TLC,
methanol/n-buthanol/water/triethylamine, 20/60/15/5, v/v/v/v)
the reaction mixture was concentrated in vacuo, and the
residue was subjected to freeze-drying for 16 h. MeOH (0.6
mL) and Ac2O (0.2 mL) were added, and the reaction mixture
was kept for 16 h and then concentrated under the reduced
pressure. After purification by size exclusion column chroma-
tography on Sephadex LH-20 (35 cm3, MeOH elution) com-
pound 10 was isolated as a white foam (4.3 mg, 85%): FAB
MS m/z 1211.6 [M + Na]+; Rf 0.70; 1H NMR (CD3OD) δ 7.60-
7.20 (m, 25H, aromatic), 4.86 (dd, 2H, J 2 ) 10.7 Hz, CH2Ph),
4.79 (dd, 2H, J 2 ) 11.2 Hz, CH2Ph), 4.72 (dd, 2H, J 2 ) 11.7
afford 7 (11 mg, 78%) as a white film: FAB MS m/z 857.3 [M
1
+ H]+; Rf 0.42; [R]27 ) +7.8 (c 0.375, H2O); H NMR (D2O) δ
D
7.21-7.30 (m, 5H, arom), 4.51 (dd, 2H, J 2 )11.8 Hz, CH2Ph),
4.35-4.38 (m, 1H, J 8′,9′a ) 2.4 Hz, H-8′), 4.11 (dd, 1H, J 9′a,9′b
)
11.7 Hz, H-9′a), 3.64-3.80 (m, 8H, J 7′,8′ ) 7.8 Hz, H-5, 6, 5′,
6′, 7′, 9a, 9′b, OCH2a), 3.50-3.58 (m, 2H, H-4′, 8), 3.35-3.47
(m, 4H, H-4, 7, 9b, OCH2b), 2.60 (dd, 1H, J 3′e,3′a ) 12.6 Hz,
J 3′e,4′ ) 4.7, H-3′e), 2.49 (dd, 1H, J 3e,3a ) 12.6 Hz, J 3e,4 ) 4.1,
H-3e), 1.92, 1.88 (2s, 6H, NHCOCH3) 1.60 (t, 1H, H-3′a), 1.41
(dd, 1H, H-3a), 0.67-0.77 (m, 2H, CH2TMS), -0.18 (s, 3H,
TMS); 13C NMR (D2O) δ 175.2, 173.9, 173.5, 137.8, 128.8, 128.3,
101.3, 100.4, 76.1, 74.4, 73.4, 72.7, 72.2, 71.8, 71.0, 70.2, 68.8,
68.4, 68.2, 63.2, 62.7, 52.7, 51.9, 41.2, 40.6, 22.5, 22.2, 18.0,
-3.0. The compound 7 obtained from 6b, 6c, and isolated in a
similar way was completely identical (comparison of the NMR
data, HPLC retention times, and [R]D values) to the sample
obtained from 6a .
3-Azid op r op yl O-[Met h yl 4,7,8,9-t et r a -O-a cet yl-3,5-
d id eoxy-5-tr iflu or oa ceta m id o-D-glycer o-r-D-ga la cto-n on -
2-u lop yr a n osylon a te]-(2 f 3)-O-(2,6-d i-O-ben zyl-â-D-ga -
la ct op yr a n osyl)-(1 f 4)-2,3,6-t r i-O-b en zyl-â-D-glu cop y-
r a n osid e (9). A mixture of donor 2a (70 mg, 0.122 mmol), 8a
(53 mg, 0.060 mmol), and activated molecular sieves (3 Å, 320
mg) in MeCN (1.0 mL) was stirred for 16 h under an
atmosphere of argon. The mixture was cooled to -35 °C, NIS
(0.24 mmol) and TfOH (0.02 mmol) were added, and the
reaction mixture was stirred for 5 min until TLC analysis
indicated that reaction had gone to completion. The reaction
mixture was diluted with DCM (10 mL), the solids were
filtered off, and the residue was washed with DCM (3 × 10
Hz, CH2Ph), 4.48 (d, 1H, J 1′,2′ ) 7.8, H-1′), 4.42 (dd, 2H, J 2
)
11.7 Hz, CH2Ph), 4.38 (dd, 2H, J 2 ) 11.7 Hz, CH2Ph), 4.37 (d,
1H, J 1,2 ) 7.8, H-1), 4.15 (dd, 1H, J 3′,4′ ) 3.3 Hz, H-3′), 4.01 (d,
1H, H-4′), 3.93-3.98 (m, 1H, J 8′′, ) 2.8 Hz, J 8′′,9′′b ) 5.0 Hz,
9′′
H-8′′), 3.88-3.92 (m, 2H, J 4,5 ) 1.9 Hz, H-4, OCH2a), 3.83 (dd,
1H, J 6a,6b ) 11.2 Hz, H-6a), 3.79-3.81 (m, 2H, H-4′′, 5′′), 3.74
(dd, 1H, J 9′′a,9′′b ) 11.2 Hz, H-9′′a), 3.46-3.68 (m, 10H, J 7′′,8′′
)
8.7 Hz, H-6′a, 9′′b, 6b, 6′b, 2′, 3, 7′′, 5′, 6′′,OCH2 b), 3.38 (t,
2H, CH2N), 3.34 (dd, 1H, J 5,6a ) 4.2 Hz, H-5), 3.25 (dd, 1H,
J 2,3 ) 9.3 Hz, H-2), 2.86 (dd, 1H, J 3′′e,3′′a ) 12.6, J 3′′e,4′′ ) 4.4
Hz, H-3′′e), 2.02 (s,3H, NHCOCH3), 1.84 (dd, 1H, J 3′′a,4′′ ) 4.1
Hz, H-3′′a), 1.83 (m, 2H, CCH2C); 13C NMR (CD3OD) δ 191.4,
178.5, 174.2, 139.3, 138.8, 138.5, 138.3, 128.4, 128.2, 128.0,
127.9, 127.7, 127.5, 127.0, 103.4, 102.8, 82.8, 81.8, 78.6, 76.7,
76.0, 75.3, 75.1, 74.9, 74.8, 74.0, 73.8, 73.2, 73.0, 71.8, 69.8,
68.8, 68.7, 68.1, 66.5, 63.4, 53.0, 48.5, 40.3, 29.7, 21.5; HR-
FAB MS [M + Na]+ calcd for C61H73O19N4Na2 1211.4664, found
1211.4636.
Meth yl [2,4,7-Tr i-O-a cetyl-9-O-ben zyl-3,5-d id eoxy-8-O-
(m eth yl 4,7,8,9-tetr a -O-a cetyl-3,5-d id eoxy-5-tr iflu or oa c-
etam ido-D-glycer o-r-D-ga la cto-n on -2-u lopyr an osylon ate)-
5-tr iflu or oa ceta m id o-D-glycer o-r-D-ga la cto-n on -2-u lop y-
r a n osid ]on a te (11). Trifluoroacetic acid (3 mL) was added
dropwise to a solution of 6a (210 mg, 0.18 mmol) in 1,2-
dichloroethane (6 mL). After 2 h, the reaction mixture was
concentrated under reduced pressure and dried in vacuo.

5496 J . Org. Chem., Vol. 66, No. 16, 2001
Meo et al.
Pyridine (6 mL), Ac2O (3 mL), and DMAP (catalytic amount)
were added to the residue. The reaction mixture was kept for
3 days at room temperature, then quenched with MeOH (6
mL), and concentrated in vacuo. The residue was coevaporated
with toluene (3 × 6 mL) and dried in vacuo to give 11 as 1/3.5
R/â-mixture (186 mg, 93%) as a white foam, which was
separated by silica gel column chromatography (10% gradient
ethyl acetate in hexane). Selected analytical data for R-11:
FAB MS m/z 1143.3 [M + Na]+; Rf 0.35 (ethyl acetate/hexane
8b (25.5 mg, 0.03 mmol), and activated molecular sieves (3 Å,
200 mg) in MeCN (1.5 mL) was stirred for 16 h under an
atmosphere of argon. The mixture was cooled to -35 °C, NIS
(0.06 mmol) and TfOH (6.3 µmol) were added, and the reaction
mixture was stirred for 30 min until TLC analysis indicated
that reaction had gone to completion. The reaction mixture
was diluted with DCM (5 mL), the solids were filtered off, and
the residue was washed with DCM (3 × 5 mL). The combined
filtrate (20 mL) was washed with aqueous Na2S2O3 (20%, 7
mL) and H2O (3 × 10 mL). The organic phase was dried
(MgSO4) and filtered, and the filtrate was concentrated in
vacuo. The residue was purified by size exclusion column
chromatography on Sephadex LH-20 (methanol/dichlorometh-
ane, 1/1, v/v) to 13 as a white foam (23.5 mg, 42%): FAB MS
3/2, v/v); [R]25 ) +3.0 (c 0.6, CHCl3);1H NMR δ 7.95 (d, 1H,
D
J NH
1H, J NH
, ) 10.2 Hz, NH), 7.25-7.42 (m, 5H, aromatic), 6.23 (d,
5
, ) 9.8 Hz, NH), 5.67-5.71 (m, 1H,, J 8′,9′a ) 2.5 Hz
5′
H-8′), 5.31 (dd, 1H, J 7′,8′ ) 9.1 Hz, H-7′), 5.24 (bs, 1H, H-7),
5.00-5.12 (m, 3H, J 8,9b ) 8.9 Hz, J 4′,5′ ) 9.7 Hz, H-4, 4′, 8),
4.51 (dd, 2H, J 2 ) 11.7 Hz, CH2Ph), 3.83 (s, 3H, OCH3), 3.78
(s, 3H, OCH3), 3.54 (dd, 1H, J 9a,9b ) 11.6 Hz, H-9b), 2.78
(dd,1H, J 3′e,4′ ) 4.8 Hz, J 3′e,3a′ ) 12.9 Hz, H-3′e), 2.65 (dd,1H,
J 3e, ) 5.0 Hz, J 3e, ) 13.6 Hz, H-3e), 2.20, 2.10, 2.06, 2.05,
m/z 1889.6 [M + Na]+; Rf 0.69 (ethyl acetate/hexane, 3/2, v/v);
1
[R]27 ) +4.6 (c 0.6, CHCl3); H NMR δ 7.61 (d, 1H, J NH
,
)
5′′′
D
5′′
9.8 Hz, NH), 7.14-7.37 (m, 30H, aromatic), 6.16 (d, 1H, J NH
) 9.2 Hz, NH), 5.50-5.56 (m, 1H, J 8′′′,9′′′a ) 2.4 Hz, J 8′′′,9′′′b
,
4
3a
)
2.02, 2.01, 1.94 (7s, 21H, OCOCH3), 2.11-2.21 (m, 1H, H-3′a),
1.98-2.04 (dd, 1H, H-3a).
4.9 Hz, H-8′′′), 5.27 (dd, 1H, J 7′′′,8′′′ ) 9.8 Hz, H-7′′′), 5.20 (s,
1H, H-7′′), 5.06 (d, 1H, H-8′′), 4.92-5.03 (m, 2H, J 4′′,5′′ ) 10.7
Hz, J 4′′′,5′′′ ) 10.3 Hz, H-4′′, 4′′′), 4.81 (dd, 2H, J 2 ) 10.7 Hz,
CH2Ph), 4.75 (dd, 2H, J 2 ) 10.7 Hz, CH2Ph), 4.70 (dd, 2H, J 2
) 11.7 Hz, CH2Ph), 4.30-4.56 (m, 6H, CH2Ph) 4.39 (d, 1H,
J 1′,2′ ) 7.8 Hz, H-1′), 4.34 (dd, 1H, J 6′′′,7′′′ ) 1.9 Hz, H-6′′′), 4.28
(dd, 1H, J 9′′′a,9′′′b ) 12.7 Hz, H-9′′′a), 4.26 (d, 1H, J 1,2 ) 7.3 Hz,
H-1), 4.22 (dd, 1H, J 9′′a,9′′b ) 11.7 Hz, H-9′′a), 4.20 (dd, 1H,
H-9′′′b), 4.04 (dd, 1H, J 5′′,6′′ ) 10.7 Hz, H-5′′), 4.00 (dd, 1H,
J 6′′′,7′′′ ) 1.5 Hz, H-6′′′), 3.97 (dd, 1H, J 3′,4′ ) 3.4 Hz, H-3′), 3.92
(t, 1H, J 5′′′,6′′′ ) 10.3 Hz, H-5′′′), 3.65-3.86 (m, 4H, H-4, 4′, 6),
3.81 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 3.54 (s, 3H, OCH3),
3.42-3.60 (m, 4H, J 2′,3′ ) 9.3 Hz, H-2′, 3, 6′a, 9′′b), 3.30-3.40
(m, 3H, H-2, 5, 6′b), 3.12 (t, J 5′,6′a ) 6.3 Hz, H-5′), 2.75 (dd,
1H, J 3′′′e,3′′′a ) 13.2 Hz, J 3′′′e,4′′′ ) 4.9 Hz, H-3′′′e), 2.60 (dd, 1H,
J 3′′e,3′′a ) 13.2 Hz, J 3′′e,4′′ ) 4.8 Hz, H-3′′e), 2.41(s, 1H, OH), 2.01
(m, 1H, 3′′a), 1.98 (m, 1H, 3′′′a), 2.17, 2.03, 1.98, 1.97, 1.90,
1.86 (6s, 18H, OCOCH3); 13C NMR δ 170.0, 168.8, 168.3, 138.9,
138.7, 138.5, 138.3, 128.6, 128.4, 128.3, 128.1, 127.9, 127.6,
127.4, 104.8, 102.5, 98.9, 96.8, 83.0, 82.1, 76.7, 7.4, 75.6, 75.1,
74.8, 74.2, 73.6, 73.5, 73.3, 72.5, 71.6, 70.6, 69.4, 69.2, 68.7,
68.5, 68.4, 67.9, 66.8, 62.4, 57.3, 53.7, 53.4, 50.1, 50.0, 39.1,
36.7, 21.6, 20.9, 20.8, 20.6.
Analytical data for â-11: Rf 0.31 (ethyl acetate/hexane 3/2,
v/v); [R]25 ) -5.0 (c 1.3, CHCl3); 1H NMR δ 7.29-7.40 (m,
D
6H, NH, aromatic), 6.30 (d, 1H, J NH
, ) 9.2 Hz, NH), 5.34-
5′
5.40 (m, 2H,, J 8′,9′a ) 2.5 Hz H-8′, 4), 5.22 (dd, 1H, J 7′,8′ ) 9.1
Hz, H-7′), 5.20 (bs, 1H, H-7), 4.96-5.02 (m, 1H, J 4′,5′ ) 9.7 Hz,
H-4′), 4.59-4.64 (m, 1H, J 8,9b ) 7.9 Hz, H-8), 4.53 (dd, 2H, J 2
) 12.1 Hz, CH2Ph), 4.33 (dd, 1H, J 6,7 ) 2.2 Hz, H-6), 4.25 (dd,
1H, J 9′a
) 12.4 Hz, H-9′a), 3.89-4.07 (m, 5H, J 5,6 ) 10.9
9′b
Hz, J 6′,7′ ) 1.6 Hz, J 9a,9b ) 11.5 Hz, H-5, 5′, 6′, 9a,9′b), 3.79 (s,
3H, OCH3), 3.74 (s, 3H, OCH3), 3.56 (dd, 1H, H-9b), 2.69
(dd,1H, J 3′e,4′ ) 4.4 Hz, J 3′e,3a′ ) 13.0 Hz, H-3′e), 2.57 (dd,1H,
J 3e, ) 5.1 Hz, J 3e, ) 13.5 Hz, H-3e), 2.18, 2.16, 2.03, 2.02,
4
3a
1.98, 1.97, 1.96 (7s, 21H, OCOCH3), 1.94-2.00 (m, 2H, H-3′a,
3a); 13C NMR δ 172.3, 171.2, 170.8, 170.3, 169.9, 169.8, 168.9,
168.4, 157.4, 138.9, 128.5, 127.6, 127.4, 99.01, 96.9, 73.9, 73.8,
72.5, 71.8, 70.6, 69.9, 69.4, 68.7, 68.6, 66.9, 62.7, 62.5, 53.6,
52.9, 50.8, 50.0, 38.9, 38.2, 31.2, 30.0, 21.5, 20.9, 20.8, 20.7,
18.2, -0.92
Meth yl [P h en yl 4,7-tr i-O-acetyl-9-O-ben zyl-3,5-dideoxy-
8-O-(m eth yl 4,7,8,9-tetr a -O-a cetyl-3,5-d id eoxy-5-tr iflu o-
r oa cet a m id o-D-glycer o-r-D-ga la cto-n on -2-u lop yr a n osy-
lon ate)-2-th io-5-tr iflu or oacetam ido-D-glycer o-r-D-ga la cto-
n on -2-u lop yr a n osid ]on a te (12). To a solution of 11 (82.5 mg,
0.07 mmol) in 1,2-dichloroethane (1 mL) were added ben-
zenethiol (30 µL, 0.3 mmol) and BF3‚Et2O (37 mL, 0.3
mmol). After 30 min, the reaction mixture was diluted with
DCM (6 mL) and then washed with aqueous NaHCO3 (15%,
2 mL) and H2O (3 × 6 mL). The organic phase was dried
(MgSO4) and filtered, and the filtrate was concentrated in
vacuo. The residue was purified by silica gel column chroma-
tography (10% gradient acetone in toluene) to afford anomeri-
cally pure 12 as white foam (72 mg, 84%): FAB MS m/z 1172.0
Meth yl O-(5-Aceta m id o-3,5-d id eoxy-D-glycer o-r-D-ga -
la cto-n on -2-u lop yr a n osylon ic a cid )-(2 f 8)-O-(5-a ceta -
m id o-3,5-d id eoxy-D-glycer o-r-D-ga la cto-n on -2-u lop yr a -
n osylon ic a cid )-(1 f 3)-O-â-D-ga la ctop yr a n osyl)-(1 f 4)-
â-D-glu cop yr a n osid e Disod iu m Sa lt (14). Compound 13 (13
mg, 7 µmol) was dissolved in ethanol/ethyl acetate (2 mL, 1/1,
v/v), and Pd(OAc)2 (13 mg) was added. The mixture was stirred
under an atmosphere of H2 for 18 h. The catalyst was removed
by filtration, and the filtrate was concentrated to dryness in
vacuo. The residue was dissolved in MeOH (1 mL), and 1 M
aqueous NaOH (0.3 mL) was added dropwise. After 72 h
(control TLC, methanol/n-buthanol/water/triethylamine, 20/
60/15/5, v/v/v/v) the reaction mixture was concentrated in
vacuo ,and the residue was subjected to freeze-drying for 16
h. MeOH (0.5 mL) and Ac2O (0.1 mL) were added, and the
reaction mixture was kept for 6 h and then concentrated under
the reduced pressure. The residue was purified by size
exclusion column chromatography on Sephadex G25 (35 cm3,
water elution) to afford 14 as white foam (4.4 mg, 71%): FAB
MS m/z 983.3 [M + H]+; Rf 0.40; [R]27D ) +3.4 (c 0.5, H2O); 1H
NMR (D2O) δ 4.40 (d, 1H, J 1′,2′ ) 8.3 Hz, H-1′), 4.20 (d, 1H,
J 1,2 ) 8.3 Hz, H-1), 4.06 (dd, 1H, J 9′′a,9′′b ) 12.2 Hz, H-9′′a),
4.00-4.03 (m, 1H, J 8′′′,9′′′a ) 2.4 Hz, J 8′′′,9′′′b ) 5.4 Hz, H-8′′′),
3.97 (dd, 1H, J 3′,4′ ) 3.4 Hz, H-3′), 3.91 (dd, 1H, J 9′′′a,9′′′b ) 12.2
Hz, H-9′′′a), 3.84 (d, 1H, H-4′), 3.42-3.82 (m, 20 H, H-2′, 3, 4,
4′′, 4′′′, 5, 5′, 5′′, 5′′′, 6, 6′, 6′′, 6′′′, 7′′, 7′′′, 8′′, 9′′b, 9′′′b), 3.45 (s,
3H, OCH3), 3.19 (t, 1H, J 2,3 ) 8.8 Hz, H-2), 2.66 (dd, 1H, J 3′′′e,3′′′a
[M + H]+; Rf 0.60 (acetone/toluene 3/7, v/v); [R]25 ) +5.7 (c
D
0.1, CHCl3); 1H NMR δ 8.03 (d, 1H, J NH
, ) 10.5 Hz, NH),
5
7.18-7.54 (m, 10H, aromatic), 6.16 (d, 1H, J NH
, ) 9.4 Hz,
5′
NH), 5.60-5.66 (m, 1H, J 8′,9′a ) 2.3 Hz, J 8′,9′b ) 4.9 Hz, H-8′),
5.33-5.40 (m, 2H, H-4, 7), 5.27 (d, 1H, J 7′,8′ ) 10.0 Hz, H-7′),
5.09 (dd, 1H, J 6,7 ) 1.8 Hz, H-6), 4.99-5.06 (m, 1H, H-4′,8),
4.49 (dd, 2H, J 2 ) 12.2 Hz, CH2Ph), 4.15 (dd, 1H, J 9′a
)
9′b
12.6 Hz, H-9′a), 4.12 (dd, 1H, J 9a ) 12.3 Hz, H-9a), 3.98-
9b
4.10 (m, 3H, J 5,6 ) 10.4 Hz, J 6′,7′ ) 1.2 Hz, H-5, 5′, 6′), 3.95
(dd, 1H, H-9′b), 3.87 (s, 3H, OCH3), 3.44 (dd, 1H, H-9b), 3.41
(s, 3H, OCH3), 2.86 (dd,1H, J 3e,4 ) 4.9 Hz, J 3e,3a ) 13.6 Hz,
H-3e), 2.82 (dd, 1H, J 3′e, ) 8.5 Hz, J 3′e, ) 12.9 Hz, H-3′e),
4′
3′a
2.24, 2.05, 2.03, 2.02, 2.00 (6s, 18H, OCOCH3), 2.17 (dd, 1H,
H-3a), 2.05 (dd, 1H, H-3′a); 13C NMR (1H) δ 75.0, 72.9, 72.7,
71.6, 69.9, 69.0, 68.5, 68.1, 66.3, 61.8, 53.5, 52.2, 49.9, 50.5,
38.9, 38.3
Meth yl O-(Meth yl 4,7,8,9-tetr a -O-a cetyl-3,5-d id eoxy-5-
tr iflu or oa ceta m id o-D-glycer o-r-D-ga la cto-n on -2-u lop yr a -
n osylon a te)-(2 f 8)-O-(m eth yl 4,7-d i-O-a cetyl-9-O-ben zyl-
3,5-d id eoxy-5-tr iflu or oa ceta m id o-D-glycer o-r-D-ga la cto-
n on -2-u lop yr a n osylon a t e)-(2 f 3)-O-(2,6-d i-O-b en zyl-â-
D-ga la ctop yr a n osyl)-(1 f 4)-2,3,6-tr i-O-ben zyl-â-D-glu co-
p yr a n osid e (13). A mixture of donor 12 (37 mg, 0.03 mmol),
) 12.2 Hz, J 3′′′e,4′′′ ) 4.4 Hz, H-3′′′e), 2.56 (dd, 1H, J 3′′e,3′′a
)
12.2 Hz, J 3′′e,4′′ ) 4.4 Hz, H-3′′e), 1.95, 1.91 (2s, 6H, NHCOCH3),
1.58-1.66 (m, 2H, H-3′′a,3′′′a); 13C NMR (D2O) δ 181.5, 175.1,
162.8, 103.3, 102.9, 100.7, 100.4, 78.4, 75.7, 75.4, 75.0, 74.2,
73.1, 72.9, 71.9, 69.6, 68.7, 68.4, 62.8, 61.8, 61.3, 60.2, 57.5,
52.5, 52.0, 40.7, 40.0, 22.6, 22.3.

Stereoselective Synthesis of R-Sialosides
J . Org. Chem., Vol. 66, No. 16, 2001 5497
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra for compounds 2a , 3, 5a , 6a -c, 7, 9, 10, and 12-14.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Ackn owledgm en t. The authors thank Drs. J. Glush-
ka and K. Kolli for technical assistance with NMR and
MS spectroscopy, respectively. The Office of the Vice
President of Research is acknowledged for financial
support.
J O010345F