Stereoselective synthesis of benzyl-protected β-galactosides by propionitrile-mediated glycosylation

Article abstract of DOI:10.1016/j.tet.2008.01.029

β-Selective galactosylation was studied using a series of 2-O-benzylated phenyl 1-thio-galactosides and glycosyl acceptors in propionitrile with BSP-TTBP-Tf₂O. The glycosylation enabled us to synthesize useful precursors of N-acetyllactosamine

Full text of DOI:10.1016/j.tet.2008.01.029

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2611e2618
www.elsevier.com/locate/tet
Stereoselective synthesis of benzyl-protected b-galactosides
by propionitrile-mediated glycosylation
Akiharu Ueki a,b, Masafumi Hirota a, Yuta Kobayashi c, Keiko Komatsu a,b, Yutaka Takano a,b,
a,b,
Michio Iwaoka c, Yuko Nakahara a,b, Hironobu Hojo a,b, , Yoshiaki Nakahara
*
*
a Department of Applied Biochemistry, Tokai University, 1117 Kitakaname, Hiratsuka-shi, Kanagawa 259-1292, Japan
b Institute of Glycotechnology, Tokai University, 1117 Kitakaname, Hiratsuka-shi, Kanagawa 259-1292, Japan
c Department of Chemistry, Tokai University, 1117 Kitakaname, Hiratsuka-shi, Kanagawa 259-1292, Japan
Received 21 November 2007; received in revised form 7 January 2008; accepted 7 January 2008
Available online 11 January 2008
Abstract
b-Selective galactosylation was studied using a series of 2-O-benzylated phenyl 1-thio-galactosides and glycosyl acceptors in propionitrile
with BSPeTTBPeTf2O. The glycosylation enabled us to synthesize useful precursors of N-acetyllactosamine and core 1 O-glycoserine deriva-
tives in a highly convergent manner.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Glycopeptide; Stereoselective synthesis of b-galactoside; Propionitrile-assisted glycosylation; Thioglycoside
1. Introduction
b-galactoside moieties had to be strategically constructed be-
fore attaching a base-labile Fmoc amino acid moiety. Taking
into consideration the advantages of convergent synthetic pro-
cesses, it is preferable to have an alternative for b-selective
galactosylation without the assistance of 2-O-acetyl group.
In this context, we have previously studied the glycosylation
of a monosaccharyl-amino acid derivative with a benzylated
sialyl galactosyl trichloroacetimidate, and obtained an opti-
mum yield of the desired b-glycoside (53%), which accompa-
nied the generation of an a-isomer (16%).3 This limited
success has prompted us to investigate a more efficient method
of b-galactoside preparation. Till date, only a few papers have
reported useful experiments in this context, using a benzyl-pro-
tected galactosyl donor.4e10 Among them, the recent report
by Crich and Smith,9 who synthesized a b-galactoside by
reaction with phenyl2,3,4,6-tetra-O-benzyl-1-thio-b-D-galacto-
pyranoside (1) in propionitrile, seemed to meet our requirements
for effecting a convergent synthesis of oligosaccharides. Thus,
we have investigated the versatility of this procedure for our
study on the synthesis of benzyl-protected oligosaccharides
and glycoamino acids. The synthesis of Gal-(b1/4)-GlcNAc
and Gal-(b1/3)-GalNAc-Ser derivatives is described here.
Synthetic oligosaccharides and their conjugates are now
recognized as critical tools for chemical glycobiology or as
potential therapeutic agents, because adequate quantities of
homogeneous samples with a defined structure seldom occur
naturally. Extensive efforts have been put into developing use-
ful technologies and concepts for oligosaccharide synthesis.
As part of our study aimed at the synthesis of complex glyco-
peptides of biological importance, we demonstrated that the
benzyl-protected N- and O-glycoamino acids are ideal for
the Fmoc-based solid-phase synthesis of glycopeptides.1 In
these studies, b-galactosides in both N- and O-glycan have
been primarily synthesized by glycosylation with an acetyl-
ated galactosyl donor.2 Transformation of the acetylated galac-
toside into a benzyl-protected glycoamino acid requires
additional processing including deacetylation and benzylation
both performed under the basic conditions. Thus, benzylated
* Corresponding authors. Tel.: þ81 463 50 2075.
E-mail addresses: hojo@keyaki.cc.u-tokai.ac.jp (H. Hojo), yonak@keyaki.
cc.u-tokai.ac.jp (Y. Nakahara).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.029

2612
A. Ueki et al. / Tetrahedron 64 (2008) 2611e2618
R2O
R1O
OBn
O
BnO
BnO
Ph
O
BnO
BnO
OBn
O
BnO
AllO
OBn
O
OBn
O
O
SPh
SPh
SPh
O
BnO
BnO
BnO
BnO
SPh
SPh
BnO
3: R1, R2= -C(CH3)2-
4: R1= R2= MPM
5: R1= R2= H
1
2
7
BnO
6
F
HNR2
HNTCA
BnO
TCANH
BnO
HO
N3
NPhth
BnO
HO
BnO
HO
BnO
R3O
OR1
HO
OTBDPS
OMP
OTBDPS
O
O
O
O
O
OBn
OBn
OBn
OBn
OBn
12: R1 = TBDPS R2 = R3= TCA
13: R1 = H, R2 = R3= TCA
8
9
10
11
F
BnO
BnO
BnO
BnO
TCANH
BnO
OBn
O
OBn
O
OBn
O
N3
NPhth
BnO
O
BnO
O
O
OTBDPS
OTBDPS
OMP
BnO
BnO
O
OBn
O
O
OBn
OBn
BnO
BnO
BnO
14
15
16
Ph
O
O
MPMO
OBn
O
OBn
O
N3
N3
N3
BnO
O
BnO
O
BnO
O
O
O
OTBDPS
MPMO
OTBDPS
OTBDPS
BnO
O
O
O
OBn
O
OBn
BnO
OBn
BnO
BnO
17
18
19
F
MPMO
MPMO
BnO
AllO
BnO
AllO
OBn
O
OBn
O
OBn
TCANH
NHTCA
N3
BnO
O
BnO
BnO
O
O
O
OTBDPS
O
O
O
OBn
OBn
OBn
BnO
BnO
BnO
20
21
22
Figure 1. Glycosyl donors (1e7), glycosyl acceptors (8e11), intermediates (12 and 13), and disaccharides (14e22).
2. Results and discussion
product was obtained as a mixture of 1:3 a/b isomers at
24% yield. However, when Tf2O was added to the mixture
of 1, acceptor 8, and other reagents in EtCN at ꢀ78 ꢁC,
a rapid coupling reaction occurred giving a superior yield
with a similar b-selectivity (entry 2). The same reaction
when performed in CH3CN at ꢀ40 ꢁC afforded more a-gly-
coside (entry 3), whereas the reaction run in dichloromethane
exhibited no b-selectivity as expected9 (entry 4). The
In addition to thioglycoside (1) and its a-isomer (2), phenyl
2,6-di-O-benzyl-3,4-O-isopropylidene-1-thio-b-D-galactopyra-
noside (3)11 and phenyl 2,6-di-O-benzyl-3,4-di-O-(4-methoxy-
phenyl)methyl-1-thio-b-D-galactopyranoside (4) were prepared
as the comparable glycosyl donors. The latter two would en-
able us to elongate the sugar chain at the non-reducing end.
Phenyl 2,3-di-O-benzyl-4,6-O-benzylidene-1-thio-b-D-galac-
topyranoside (6)12 and phenyl 3-O-allyl-2,4,6-tri-O-benzyl-
1-thio-b-D-galactopyranoside (7) were also used as galactosyl
donors in this study (Fig. 1). Compound 4 was easily ob-
tained by 4-methoxybenzylation of the known phenyl 2,6-
di-O-benzyl-1-thio-b-D-galactopyranoside (5)11 in 75% yield.
To synthesize LacNAc equivalents by reaction with 1e7, the
chosen glycosyl acceptors were the 3,6-di-O-benzyl-D-glu-
cosamine derivatives (8,13 9,14 10, and 11) each carrying
a 2-azido, 2-N-phthalimido, or 2-N-trichloroacetamido group.
Compound 10 was prepared from 8 by Zn-reduction, trichloro
acetylation (/12), and then 4-O-deacylation. Glycosyl accep-
tor 11, which would facilitate a more advanced synthesis of
oligosaccharide by the orthogonal strategy,15 was prepared by
desilylation of 12 followed by fluorination and 4-O-deacyl-
ation. We first examined the reaction of 1 and 8, where 1
(2 equiv) was preactivated for 30 min with BSPeTf2Oe
TTBP,9 a combination of reacting agent, in EtCN at ꢀ78 ꢁC
before the addition of 8. As shown in Table 1 (entry 1), the
Table 1
Synthesis of disaccharides
Entry Glycosyl
Glycosyl Solvent Time (h) Products (%) a/b
donor (equiv) acceptor
1
1 (2)
1 (2)
8
EtCN
EtCN
MeCN
16
0.5
0.5
14 (24)
14 (94)
14 (88)
14 (37)
14 (88)
14 (60)
14 (88)
15 (93)
16 (97)
17 (21)
18 (96)
19 (90)
20 (80)
21 (92)
22 (91)
25:75
21:79
39:61
51:49
21:79
23:77
23:77
30:70
19:81
50:50
54:46
15:85
15:85
23:77
23:77
2
8
3
1 (2)
1 (2)
1 (1.5)
1 (1.2)
2 (2)
1 (2)
1 (2)
3 (2)
6 (2)
4 (2)
4 (2)
7 (2)
7 (2)
8
4
8
CH2Cl2 0.5
5
8
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
0.5
22
6
8
7
8
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
8
9
9
11
8
10
11
12
13
14
15
8
8
11
8
10
The reactions were performed at ꢀ78 ꢁC, except for entry 3 (at ꢀ40 ꢁC).

A. Ueki et al. / Tetrahedron 64 (2008) 2611e2618
2613
glycosyl
acceptor
glycosyl donor under identical conditions to selectively pro-
duce b-disaccharides 21 and 22 both at high yield (entries
14 and 15). The effectiveness of this protocol on the synthesis
of glycoamino acid derivatives was demonstrated by glycosyl-
ation of known GalN3-Ser derivative 2318 with glycosyl donor
1 or 4 (Scheme 1). By the addition of Tf2O (2.2 equiv) to
a cold mixture of 1 (2 equiv), 23, BSP (3 equiv), and TTBP
(4 equiv) in EtCN, the glycosylation completed within
30 min to afford the desired b-galactoside 24 (67%) and
a-isomer 25 (15%). Compounds 24 and 25 were identical to
compounds prepared as precursors of core 1 and 8 type O-gly-
coamino acids in our previous studies.19,20 The reaction of gly-
cosyl donor 4 and 23 also succeeded in producing a core 1
O-glycoamino acid analog 26 (79%) and a-isomer 27 (8%).
Compound 26 should be an effective intermediate to synthe-
size the extended O-glycans of cores 1 and 2, because
4-methoxybenzyl groups are selectively removable.
In summary, we have demonstrated an efficient method for
the convergent route to the benzyl-protected b-galactoside.
Using phenyl 1-thio-galactoside derivatives (1, 2, 4, and 7)
as a glycosyl donor, LacNAc-related disaccharides (14e16
and 19e22) were all synthesized in a high yield with b-selec-
tivity. The b-galactoside synthesis was efficient, only when
Tf2O was added to the cooled (ꢀ78 ꢁC) mixture of all the
other reactants in EtCN. However, 3,4-O-isopropylidene 3
and 4,6-benzylidene analog 6 were the inadequate glycosyl
donors and resulted in non-stereoselective reactions in the pro-
pionitrile conditions. The method was also utilized to selec-
tively synthesize core 1 type O-glycoamino acid derivatives
24 and 26. This successful result has enhanced the usefulness
of compound 23 as a crucial intermediate for a series of core
structures of O-glycoamino acid. Further studies on this
nitrile-mediated glycosylation applied to the convergent syn-
thesis of complex oligosaccharides using disaccharyl or trisac-
charyl galactosyl donors are in progress.
RO
RO
OBn
O+
OBn
O
RO
RO
OBn
O
RO
RO
N+ C Et
fast
BnO
iii
BnO
ii
BnO
N+
C
glycosyl
acceptor
i
Et
Figure 2. Plausible intermediates for propionitrile-mediated b-galactosylation.
reaction, with a reduced amount of 1 (1.5 equiv) gave
a slightly lower yield (entry 5). However, a slight excess of
1 (1.2 equiv) resulted in an incomplete conversion of 8,
even after a prolonged reaction period (entry 6). The reaction
with a-thioglycoside donor 2 also showed a similar result
(entry 7). Therefore, b-selective glycosylation may be ex-
plained by the rapid attack of an acceptor on the a-nitrilium
intermediate (ii) preferentially formed from oxacarbenium
ion (i), whereas the absence of the acceptor at the generation
of the intermediate (ii) may induce conversion into the other
non-reactive species, resulting in a lower yield of the disaccha-
ride (Fig. 2). The other glycosyl acceptors 9 and 11 were
equally reactive with the intermediate to produce b-disaccha-
rides 15 and 16,16 respectively, in a high yield (entries 8 and 9).
3,4-O-Isopropylidenated thiogalactoside 3 was a poor gly-
cosyl donor for the b-galactosylation resulting in a low coup-
ling yield with no stereoselectivity under identical conditions
(entry 10). Since donor 3 was definitely consumed and a con-
siderable amount of hemiacetal was generated in the ultimate
products, the intermediates were distorted and/or disarmed by
the isopropylidene group possibly in an unfavorable form to
react with acceptor 8. In contrast, 4,6-O-benzylidene analog
6 gave a high-yielding reaction but with little stereoselectivity
(entry 11). The 4,6-O-benzylidene derivative, relatively less
reactive than 1, might easily permit an equilibrium to exist be-
tween the nitrilium intermediates, resulting in additional for-
mation of a-galactoside via unstable iii. The previous related
discussion has focused on the benzylidene-influenced stereo-
chemical outcome of the glycosylation with 6 in CH2Cl2 me-
dium.12 3,4-Di-O-(4-methoxybenzyl) derivative 4 smoothly
reacted with 8 and 11 to b-selectively produce disaccharides
19 and 20, respectively (entries 12 and 13). Interestingly,
Crich’s promoter system retained an intact allyl group during
glycosylation reactions,17 in contrast to the other thiophilic
and enophilic promoters such as NISeTfOH. Therefore, the
3-O-allyl-protected thioglycoside (7) functioned as a suitable
3. Experimental
3.1. General
Optical rotation values were determined with a Jasco DIP-
370 polarimeter at 20ꢂ2 ꢁC for solutions in CHCl3. Column
chromatography was performed on silica gel PSQ 100B
(Fuji Silysia). TLC and HPTLC were performed on silica
Ph
O
Ph
Ph
O
O
O
O
O
RO
RO
OBn
O
O
O
O
HO
O
O
BnO
O
1 or 3
RO
RO
N3
N3
N3
+
BnO
O
O
O
OBn
FmocNH
CO2All
FmocNH
24: R = Bn
CO2All
FmocNH
25: R = Bn
CO2All
23
26: R = MPM
27: R = MPM
Scheme 1. Synthesis of O-linked glycoamino acid derivatives by b-selective galactosylation.

2614
A. Ueki et al. / Tetrahedron 64 (2008) 2611e2618
1
gel 60 F254 (E. Merck). H and 13C NMR spectra were re-
corded with a Jeol AL400 spectrometer [1H (400 MHz) and
13C (100 MHz)]. For solutions in CDCl3, the parts per million
downfield chemical shifts are expressed from the internal
Me4Si signal. For assignment of the signals of sugar residue
in oligosaccharides, the reducing terminal and the second res-
idues are described as a and b, respectively. High resolution
mass spectra were obtained with a AccuTOF (JMS-T100LC)
spectrometer.
7.42e7.37 (m, 2H, Ar), 7.33e7.17 (m, 14H, Ar), 6.97 (d,
1H, J¼7.8 Hz, eNH), 5.30 (t, 1H, J¼9.3 Hz, H-4), 5.04 (d,
1H, J¼7.8 Hz, H-1), 4.65 (d, 1H, J¼10.2 Hz, eCH2Ph),
4.61 (d, 1H, J¼10.2 Hz, eCH2Ph), 4.39 (d, 1H, J¼12.2 Hz,
eCH2Ph), 4.33 (d, 1H, J¼12.2 Hz, eCH2Ph), 4.26 (br t, 1H,
J¼9.5 Hz, H-3), 3.78 (dt, J¼7.8, 10.2 Hz, H-2), 4.42e3.32
(m, 3H, H-5, H-6ꢃ2). Anal. Calcd for C40H41NO7Cl6Si: C,
54.07; H, 4.65; N, 1.58. Found: C, 54.04; H, 4.72; N, 1.45.
3.1.3. tert-Butyldiphenylsilyl 3,6-di-O-benzyl-2-deoxy-2-
trichloroacetamido-b-D-glucopyranoside 10
3.1.1. Phenyl 2,6-di-O-benzyl-3,4-di-O-(4-methoxyphenyl)-
methyl-1-thio-b-D-galactopyranoside 4
A solution of 12 (1.27 g, 1.43 mmol) in 80% aqueous pyr-
idine (70 ml) was heated at 50 ꢁC with stirring for 3 h, before
being concentrated in vacuo. The residue was diluted with
EtOAc, successively washed with water and brine, dried
over MgSO4, and concentrated in vacuo. The crude product
was chromatographed on silica gel with tolueneeEtOAc
(19:1 to 9:1) to give the title compound (1.03 g, 98%). Mp
147e148 ꢁC (recrystallized from hexaneeEtOAc). [a]D ꢀ9.5
To a stirred mixture of phenyl 2,6-di-O-benzyl-1-thio-b-D-
galactopyranoside 5 (728 mg, 1.61 mmol) and 60% NaH
(260 mg, 6.50 mmol) in anhydrous DMF (16 ml) was added
4-methoxybenzyl chloride (0.87 ml, 6.25 mmol) at 0 ꢁC under
Ar. Then the mixture was stirred for 2 h at room temperature,
before adding a few piece of ice to quench the reaction. The
mixture was extracted with EtOAc. The extract was succes-
sively washed with water and brine, dried over Na2SO4, and
concentrated in vacuo. The crude product was chromato-
graphed on silica gel with tolueneeEtOAc (20:1) and then
crystallized from hexaneeEtOAc to give pure 4 (834 mg,
75%). Mp 95.5e96.5 ꢁC. [a]D þ4.9 (c 1.0). Rf 0.43 (2:1
1
(c 1.0). Rf 0.35 (2:1 hexaneeEtOAc). H NMR d: 7.69e7.62
(m, 4H, Ar), 7.40e7.19 (m, 16H, Ar), 6.76 (d, 1H,
J¼8.3 Hz, eNH), 4.80 (d, 1H, J¼7.8 Hz, H-1), 4.74 (d, 1H,
J¼11.2 Hz, eCH2Ph), 4.71 (d, 1H, J¼11.2 Hz, eCH2Ph),
4.44 (d, 1H, J¼12.2 Hz, eCH2Ph), 4.36 (d, 1H, J¼12.2 Hz,
eCH2Ph), 3.82 (dt, J¼8.3, 10.2 Hz, H-2), 3.74 (dt, J¼2.4,
8.8 Hz, H-4), 3.66 (dd, 1H, J¼8.3, 10.2 Hz, H-3), 3.53 (dd,
1H, J¼4.4, 10.2 Hz, H-6), 3.46 (dd, 1H, J¼4.9, 10.2 Hz,
H-6), 3.12 (dt, J¼4.9, 9.3 Hz, H-5), 2.65 (d, 1H, J¼2.4 Hz,
1
hexaneeEtOAc). H NMR d: 7.55 (m, 2H, Ar), 7.39e7.17
(m, 17H, Ar), 6.84 (d, 4H, J¼8.3 Hz, Ar), 4.87 (d, 1H,
J¼11.2 Hz, eCH2Ar), 4.78 (d, 1H, J¼10.2 Hz, eCH2Ar),
4.73 (d, 1H, J¼10.2 Hz, eCH2Ar), 4.66 (d, 1H, J¼11.7 Hz,
eCH2Ar), 4.63 (d, 1H, J¼9.7 Hz, H-1), 4.62 (d, 1H,
J¼11.2 Hz, eCH2Ar), 4.54 (d, 1H, J¼11.2 Hz, eCH2Ar),
4.46 (d, 1H, J¼11.7 Hz, eCH2Ar), 4.40 (d, 1H, J¼11.7 Hz,
eCH2Ar), 3.92e3.87 (m, 2H, H-2, H-6), 3.80 (s, 3H,
eOCH3), 3.79 (s, 3H, eOCH3), 3.63e3.55 (m, 4H, H-3,
H-4, H-5, H-6). Anal. Calcd for C42H44O7S: C, 72.81; H,
6.40. Found: C, 72.80; H, 6.44.
t
eOH), 1.05 (s, 9H, Bu). Anal. Calcd for C38H42NO6Cl3Si:
C, 61.41; H, 5.70; N, 1.88. Found: C, 61.34; H, 5.73; N, 1.78.
3.1.4. 3,6-Di-O-benzyl-2-deoxy-2-trichloroacetamido-a-D-
glucopyranosyl fluoride 11
To an ice-cooled mixture of 12 (107.6 mg, 0.12 mmol) and
AcOH (139 ml, 2.42 mmol) in freshly distilled THF (1.5 ml)
n
was added 1 M Bu4NFeTHF (1.2 ml, 1.21 mmol) under Ar.
3.1.2. tert-Butyldiphenylsilyl 3,6-di-O-benzyl-2-deoxy-2-
trichloroacetamido-4-O-trichloroacetyl-b-D-
glucopyranoside 12
Then the mixture was stirred at 0 ꢁC for 2 days and concen-
trated in vacuo. The residue was diluted with EtOAc, succes-
sively washed with water and brine, dried over MgSO4, and
concentrated in vacuo. To a stirred solution of the crude mix-
ture in freshly distilled THF (2.5 ml) was added Et2NSF3
(32 ml, 0.24 mmol) at 0 ꢁC under Ar and stirred for 30 min.
To the reaction mixture was added 80% aqueous pyridine
(2 ml) and stirred at room temperature for 1 h before being
concentrated in vacuo. The residue was diluted with EtOAc,
successively washed with water and brine, dried over
MgSO4, and concentrated in vacuo. The crude product was
chromatographed on silica gel with tolueneeEtOAc (19:1 to
9:1) to give crystals (35.5 mg, 58% in three steps). Mp
81.0e82.0 ꢁC (recrystallized from hexaneeEtOAc). [a]D
þ51.1 (c 1.0). Rf 0.41 (4:1 tolueneeEtOAc). 1H NMR d:
7.39e7.26 (m, 10H, Ar), 6.69 (d, 1H, J¼8.8 Hz, eNH),
5.69 (dd, 1H, J¼2.4, 53.2 Hz, H-1), 4.82 (d, 1H, J¼12.2 Hz,
eCH2Ph), 4.79 (d, 1H, J¼12.2 Hz, eCH2Ph), 4.63 (d, 1H,
J¼12.2 Hz, eCH2Ph), 4.56 (d, 1H, J¼12.2 Hz, eCH2Ph),
4.18 (dddd, 1H, J¼2.4, 8.8, 10.7, 26.8 Hz, H-2), 3.99e3.89
(m, 2H, H-4, H-5), 3.80 (dd, 1H, J¼3.9, 10.7 Hz, H-6),
A mixture of 8 (88.3 mg, 0.14 mmol), powdered Zn
(354 mg, 5.41 mmol), and AcOH (0.16 ml, 2.83 mmol) in
CH2Cl2 (5 ml) was stirred for 30 min under Ar. The mixture
was diluted with CHCl3 and filtered through Celite. The fil-
trate was concentrated in vacuo. The residue was diluted
with CHCl3, successively washed with water and brine, dried
over Na2SO4, and concentrated in vacuo. The residue was dis-
solved in CH2Cl2 (2 ml), and stirred with trichloroacetyl chlo-
ride (79 ml, 0.71 mmol) and pyridine (0.11 ml, 1.4 mmol) at
0 ꢁC for 30 min under Ar. The reaction was quenched with
satd aq NH4Cl and the mixture was extracted with EtOAc.
The extract was successively washed with satd aq NH4Cl, wa-
ter, and brine, dried over MgSO4, and concentrated in vacuo.
The crude product was chromatographed on silica gel with tol-
ueneeEtOAc (29:1) to afford 12 (87.4 mg, 69% in two steps).
Mp 182.5e183.5 ꢁC (recrystallized from hexaneeEtOAc).
1
[a]D þ3.7 (c 1.0). Rf 0.51 (3:1 hexaneeEtOAc). H NMR d:
7.69 (d, 2H, J¼6.8 Hz, Ar), 7.62 (d, 2H, J¼6.8 Hz, Ar),

A. Ueki et al. / Tetrahedron 64 (2008) 2611e2618
2615
3.72e3.68 (m, 2H, H-3, H-6), 2.81 (br s, 1H, eOH). Anal.
Calcd for C22H23NO5FCl3: C, 52.14; H, 4.57; N, 2.76. Found:
C, 52.20; H, 4.63; N, 2.69.
3.2.1. 4-Methoxyphenyl 2,3,4,6-tetra-O-benzyl-b-D-
galactopyranosyl-(1/4)-3,6-di-O-benzyl-2-deoxy-2-
phthalimido-b-D-glucopyranoside 15
[a]D þ30.1 (c 0.9). Rf 0.53 (7:1 tolueneeEtOAc). 1H NMR
d: 7.80e7.67 (m, 4H, Ar), 7.35e7.18 (m, 24H, Ar), 6.98e6.96
(m, 2H, Ar), 6.89e6.80 (m, 6H, Ar), 6.69e6.66 (m, 2H, Ar),
5.61 (d, 1H, J¼8.3 Hz, H-1a), 4.94 (d, 1H, J¼11.7 Hz,
eCH2Ph), 4.91 (d, 1H, J¼12.2 Hz, eCH2Ph), 4.86 (d, 1H,
J¼11.7 Hz, eCH2Ph), 4.83 (d, 1H, J¼11.7 Hz, eCH2Ph),
4.73 (d, 1H, J¼12.2 Hz, eCH2Ph), 4.70 (d, 1H, J¼12.2 Hz,
eCH2Ph), 4.54e4.32 (m, 8H, eCH2Phꢃ5, H-2a, H-3a,
H-1b), 4.27 (d, 1H, J¼11.7 Hz, eCH2Ph), 4.08 (dd, 1H,
J¼8.6, 9.7 Hz, H-4a), 3.90 (d, 1H, J¼3.0 Hz, H-4b), 3.83e
3.77 (m, 3H, H-6aꢃ2, H-2b), 3.69 (s, 3H, eOCH3), 3.68
(m, 1H, H-5a), 3.50e3.42 (m, 4H, H-3b, H-5b, H-6bꢃ2).
Anal. Calcd for C69H67NO13: C, 74.11; H, 6.04; N, 1.25.
Found: C, 74.12; H, 6.25; N, 1.10.
a-Isomer:[a]D þ74.7(c1.1).Rf 0.56(7:1tolueneeEtOAc). 1H
NMR d: 7.64 (m, 4H, Ar), 7.34e7.16 (m, 24H, Ar), 6.85e6.77
(m, 8H, Ar), 6.67e6.65 (m, 2H, Ar), 5.56 (d, 1H, J¼8.3 Hz,
H-1a), 5.53 (d, 1H, J¼3.7 Hz, H-1b), 4.92 (d, 1H, J¼11.5 Hz,
eCH2Ph), 4.78 (d, 1H, J¼11.7 Hz, eCH2Ph), 4.73 (d, 1H,
J¼12.2 Hz, eCH2Ph), 4.72 (d, 1H, J¼11.7 Hz, eCH2Ph), 4.68
(d, 1H, J¼11.7 Hz, eCH2Ph), 4.64(d, 1H, J¼11.5 Hz, eCH2Ph),
4.60e4.39 (m, 6H, eCH2Phꢃ4, H-2a, H-3a), 4.34 (d, 1H,
J¼11.7 Hz, eCH2Ph), 4.31 (d, 1H, J¼12.2 Hz, eCH2Ph), 4.15
(br t, 1H, J¼9.2 Hz, H-4a), 4.08 (dd, 1H, J¼3.9, 10.3 Hz,
H-2b), 4.01e3.98 (m, 2H, H-4b, H-5b), 3.91e3.78 (m, 4H,
H-5a, H-6aꢃ2, H-3b), 3.69 (s, 3H, eOCH3), 3.55e3.47 (m,
2H, H-6bꢃ2). Anal. Calcd for C69H67NO13: C, 74.11; H, 6.04;
N, 1.25. Found: C, 74.23; H, 6.17; N, 1.10.
3.2. Typical glycosylation procedure [synthesis of tert-
butyldiphenylsilyl 2,3,4,6-tetra-O-benzyl-b-D-
galactopyranosyl-(1/4)-2-azido-3,6-di-O-benzyl-2-deoxy-
b-D-glucopyranoside 14]
A mixture of 1 (103 mg, 0.16 mmol), 8 (51 mg, 0.08 mmol),
BSP (51 mg, 0.24 mmol), TTBP (81 mg, 0.33 mmol), and dried
˚
MS (4 A, 300 mg) in anhydrous EtCN (2.5 ml) was cooled at
ꢀ78 ꢁC with stirring under Ar for 10 min. To the cold mix-
ture was added Tf2O (30 ml, 0.18 mmol). The mixture was
stirred at ꢀ78 ꢁC for 30 min before the reaction was
quenched by adding satd aq NaHCO3. The mixture was fil-
tered through Celite. The filtrate was extracted with EtOAc,
washed with water and brine, dried over anhydrous Na2SO4,
and concentrated in vacuo. The crude product was chromato-
graphed on Bio-beads S-X3 with tolueneeEtOAc (3:1) and
then on silica gel with tolueneeEtOAc (99:1 to 49:1) to
give 14 (70 mg, 74%) and a-isomer (18 mg, 20%). Com-
pound14: [a]D ꢀ9.1 (c 1.0). Rf 0.54 (19:1 tolueneeEtOAc).
1H NMR d: 7.72e7.69 (m, 4H, Ar), 7.41e7.10 (m, 36H,
Ar), 5.01 (d, 1H, J¼10.3 Hz, eCH2Ph), 4.96 (d, 1H,
J¼11.2 Hz, eCH2Ph), 4.74 (d, 1H, J¼11.2 Hz, eCH2Ph),
4.69 (br s, 2H, eCH2Phꢃ2), 4.65 (d, 1H, J¼11.0 Hz,
eCH2Ph), 4.61 (d, 1H, J¼10.3 Hz, eCH2Ph), 4.53 (d, 1H,
J¼11.2 Hz, eCH2Ph), 4.42 (d, 1H, J¼7.8 Hz, H-1b), 4.39e
4.33 (m, 2H, eCH2Phꢃ2), 4.30 (d, 1H, J¼7.8 Hz, H-1a), 4.23
(d, 1H, J¼11.7 Hz, eCH2Ph), 4.22 (d, 1H, J¼12.2 Hz,
eCH2Ph), 3.97 (t, 1H, J¼9.5 Hz, H-4a), 3.91 (d, 1H,
J¼2.4 Hz, H-4b), 3.70 (dd, 1H, J¼7.8, 9.5 Hz, H-2b), 3.64
(dd, 1H, J¼3.1, 11.2 Hz, H-6a), 3.52 (br t, 1H, J¼7.6 Hz,
H-6b), 3.44e3.33 (m, 4H, H-2a, H-3b, H-5b, H-6b), 3.24e
3.19 (m, 2H, H-3a, H-6a), 2.82 (br d, 1H, J¼8.6 Hz, H-5a),
3.2.2. 2,3,4,6-Tetra-O-benzyl-b-D-galactopyranosyl-
(1/4)-3,6-di-O-benzyl-2-deoxy-2-trichloroacetamido-a-D-
glucopyranosyl fluoride 16
All physical properties of 16 were identical to those synthe-
sized previously.16
t
1.10 (s, 9H, Bu). Anal. Calcd for C70H75N3O10Si: C, 73.34;
a-Isomer: [a]D þ44.2 (c 1.1). Rf 0.49 (9:1 tolueneeEtOAc).
1H NMR d: 7.35e7.15 (m, 30H, Ar), 6.63 (d, 1H, J¼8.8 Hz,
eNH), 5.71 (dd, 1H, J¼2.9, 54.1 Hz, H-1a), 5.48 (d, 1H,
J¼3.9 Ha, H-1b), 4.89 (d, 1H, J¼11.2 Hz, eCH2Ph), 4.81 (d,
1H, J¼11.2 Hz, eCH2Ph), 4.72 (d, 1H, J¼12.2 Hz, eCH2Ph),
4.70 (d, 1H, J¼11.7 Hz, eCH2Ph), 4.66 (d, 1H, J¼11.7 Hz,
eCH2Ph), 4.61e4.52 (m, 4H, eCH2Phꢃ4), 4.45 (d, 1H,
J¼12.2 Hz, eCH2Ph), 4.35 (d, 1H, J¼11.7 Hz, eCH2Ph),
4.28 (d, 1H, J¼11.2 Hz, eCH2Ph), 4.23 (m, 1H, H-2a), 4.20
(t, 1H, J¼9.3 Hz, H-4a), 4.04e4.01 (m, 2H, H-5a, H-2b),
3.95e3.87 (m, 4H, H-3a, H-6a, H-4b, H-5b), 3.83 (dd, 1H,
J¼2.9, 10.7 Hz, H-3b), 3.67 (dd, 1H, J¼1.5, 11.2 Hz, H-6a),
3.50e3.44 (m, 2H, H-6bꢃ2). Anal. Calcd for C56H57NO10Cl3F:
C, 65.34; H, 5.58; N, 1.36. Found: C, 65.43; H, 5.83; N, 1.30.
H, 6.59; N, 3.67. Found: C, 73.31; H, 6.57; N, 3.62.
a-Isomer: [a]D þ18.5 (c 1.5). Rf 0.63 (19:1 toluenee
1
EtOAc). H NMR d: 7.72e7.67 (m, 4H, Ar), 7.41e7.12 (m,
36H, Ar), 5.60 (d, 1H, J¼3.9 Hz, H-1b), 4.85 (d, 1H,
J¼11.7 Hz, eCH2Ph), 4.78 (d, 1H, J¼11.2 Hz, eCH2Ph),
4.73 (d, 1H, J¼11.2 Hz, eCH2Ph), 4.70 (d, 1H, J¼11.7 Hz,
eCH2Ph), 4.63 (d, 1H, J¼11.7 Hz, eCH2Ph), 4.60 (d, 1H,
J¼11.7 Hz, eCH2Ph), 4.54 (d, 1H, J¼11.7 Hz, eCH2Ph),
4.51 (d, 1H, J¼11.7 Hz, eCH2Ph), 4.35 (d, 1H, J¼7.8 Hz,
H-1a), 4.32e4.29 (m, 3H, eCH2Phꢃ3), 4.23 (d, 1H,
J¼11.7 Hz, eCH2Ph), 4.04 (dd, 1H, J¼8.3, 9.7 Hz, H-4a),
3.97 (dd, 1H, J¼3.9, 10.3 Hz, H-2b), 3.95 (br s, 1H, H-4b),
3.89 (br t, 1H, J¼7.3 Hz, H-5b), 3.79 (dd, 1H, J¼2.9,
10.3 Hz, H-3b), 3.81 (dd, 1H, J¼3.9, 11.2 Hz, H-6a), 3.52e
3.48 (m, 2H, H-2a, H-6b), 3.42e3.37 (m, 2H, H-3a, H-6b),
3.31 (dd, 1H, J¼1.9, 11.2 Hz, H-6a), 3.03 (br d, 1H,
J¼9.7 Hz, H-5a), 1.11 (s, 9H, tBu). Anal. Calcd for
C70H75N3O10Si: C, 73.34; H, 6.59; N, 3.67. Found: C,
73.34; H, 6.70; N, 3.66.
3.2.3. tert-Butyldiphenylsilyl 2,6-di-O-benzyl-3,4-O-
isopropylidene-b-D-galactopyranosyl-(1/4)-2-azido-3,6-
di-O-benzyl-2-deoxy-b-D-glucopyranoside 17
[a]D þ2.4 (c 1.0). Rf 0.31 (3:1 hexaneeEtOAc). 1H NMR d:
7.73e7.69 (m, 4H, Ar), 7.44e7.14 (m, 26H, Ar), 4.92 (d, 1H,

2616
A. Ueki et al. / Tetrahedron 64 (2008) 2611e2618
J¼10.0 Hz, eCH2Ph), 4.73 (d, 1H, J¼11.7 Hz, eCH2Ph),
4.65 (d, 1H, J¼10.3 Hz, eCH2Ph), 4.61 (d, 1H, J¼11.7 Hz,
eCH2Ph), 4.51 (d, 1H, J¼12.2 Hz, eCH2Ph), 4.42 (d, 1H,
J¼12.0 Hz, eCH2Ph), 4.40 (d, 1H, J¼8.1 Hz, H-1b), 4.31
(d, 1H, J¼7.6 Hz, H-1a), 4.29 (d, 1H, J¼11.2 Hz, eCH2Ph),
4.25 (d, 1H, J¼12.2 Hz, eCH2Ph), 4.11 (br d, 1H,
J¼3.4 Hz, H-4b), 4.05e3.97 (m, 2H, H-4a, H-3b), 3.74e
3.62 (m, 3H, H-6a, H-5b, H-6b), 3.53 (dd, 1H, J¼5.9,
9.3 Hz, H-6b), 3.38e3.20 (m, 4H, H-2a, H-3a, H-6a, H-2b),
2.87 (br d, 1H, J¼9.8 Hz, H-5a), 1.38 (s, 3H, eCH3), 1.34
(s, 3H, eCH3), 1.11 (s, 9H, tBu). Anal. Calcd for
C59H67N3O10Si: C, 70.42; H, 6.71; N, 4.18. Found: C,
70.22; H, 6.79; N, 4.08.
eCH2Arꢃ3), 4.48 (d, 1H, J¼10.7 Hz, eCH2Ar), 4.41 (d,
1H, J¼7.8 Hz, H-1b), 4.37 (d, 1H, J¼12.2 Hz, eCH2Ar),
4.35 (d, 1H, J¼11.7 Hz, eCH2Ar), 4.29 (d, 1H, J¼7.8 Hz,
H-1a), 4.23 (d, 1H, J¼11.7 Hz, eCH2Ar), 4.22 (d, 1H,
J¼11.7 Hz, eCH2Ar), 3.96 (t, 1H, J¼9.3 Hz, H-4a), 3.86 (d,
1H, J¼2.9 Hz, H-4b), 3.79 (s, 3H, eOCH3), 3.75 (s, 3H,
eOCH3), 3.69e3.62 (m, 2H, H-6a, H-2b), 3.50 (br t, 1H, J¼
7.3 Hz, H-6b), 3.43e3.32 (m, 4H, H-2a, H-3b, H-5b, H-6b),
3.24e3.18 (m, 2H, H-3a, H-6a), 2.83 (br d, 1H, J¼8.3 Hz,
t
H-5a), 1.10 (s, 9H, Bu). Anal. Calcd for C72H79N3O12Si: C,
71.68; H, 6.60; N, 3.48. Found: C, 71.66; H, 6.70; N, 3.40.
a-Isomer: [a]D þ12.9 (c 0.6). Rf 0.29 (3:1 hexaneeEtOAc).
1H NMR d: 7.70e7.68 (m, 4H, Ar), 7.40e7.12 (m, 30H, Ar),
6.81e6.76 (m, 4H, Ar), 5.59 (d, 1H, J¼3.9 Hz, H-1b), 4.78e
4.69 (m, 4H, eCH2Arꢃ4), 4.54 (br s, 2H, eCH2Arꢃ2), 4.53
(d, 1H, J¼11.7 Hz, eCH2Ar), 4.45 (d, 1H, J¼11.2 Hz,
eCH2Ar), 4.34 (d, 1H, J¼7.8 Hz, H-1a), 4.32e4.27 (m, 3H,
eCH2Arꢃ3), 4.22 (d, 1H, J¼11.7 Hz, eCH2Ar), 4.03 (dd,
1H, J¼8.7, 9.7 Hz, H-4a), 3.95 (dd, 1H, J¼3.9, 10.2 Hz,
H-2b), 3.91 (br s, 1H, H-4b), 3.86 (br t, 1H, J¼7.3 Hz,
H-5b), 3.78e3.75 (1H, H-3b), 3.77 (s, 3H, eOCH3), 3.75 (s,
3H, eOCH3), 3.55 (dd, 1H, J¼3.9, 11.2 Hz, H-6a), 3.50 (dd,
1H, J¼7.8, 9.8 Hz, H-2a), 3.47 (br t, 1H, J¼8.3 Hz, H-6b),
3.41e3.35 (m, 2H, H-3a, H-6b), 3.31 (dd, 1H, J¼2.0,
11.2 Hz, H-6a), 3.03 (br d, 1H, J¼9.3 Hz, H-5a), 1.11 (s,
a-Isomer: [a]D þ29.7 (c 1.5). Rf 0.37 (3:1 hexaneeEtOAc).
1H NMR d: 7.73e7.69 (m, 4H, Ar), 7.40e7.12 (m, 26H, Ar),
5.41 (d, 1H, J¼3.4 Hz, H-1b), 4.78 (d, 1H, J¼11.2 Hz,
eCH2Ph), 4.72 (d, 1H, J¼10.7 Hz, eCH2Ph), 4.60 (d, 1H,
J¼12.2 Hz, eCH2Ph), 4.56 (d, 1H, J¼11.7 Hz, eCH2Ph),
4.49 (d, 1H, J¼12.2 Hz, eCH2Ph), 4.43 (d, 1H, J¼10.7 Hz,
eCH2Ph), 4.37 (d, 1H, J¼8.3 Hz, H-1a), 4.31e4.24 (m, 4H,
eCH2Phꢃ2, H-3b, H-5b), 4.14 (dd, 1H, J¼2.4, 5.9 Hz,
H-4b), 3.92 (br t, J¼9.7 Hz, H-4a), 3.64e3.55 (m, 3H, H-6a,
H-6bꢃ2), 3.53e3.47 (m, 3H, H-2a, H-6a, H-2b), 3.31 (dd,
1H, J¼8.8, 9.8 Hz, H-3a), 3.05 (m, 1H, H-5a), 1.30 (s, 3H,
t
eCH3), 1.28 (s, 3H, eCH3), 1.12 (s, 9H, Bu). Anal. Calcd
t
for C59H67N3O10Si: C, 70.42; H, 6.71; N, 4.18. Found: C,
70.29; H, 6.83; N, 4.08.
9H, Bu). Anal. Calcd for C72H79N3O12Si: C, 71.68; H, 6.60;
N, 3.48. Found: C, 71.68; H, 6.76; N, 3.40.
3.2.4. tert-Butyldiphenylsilyl 2,3-di-O-benzyl-4,6-O-
benzylidene-b-D-galactopyranosyl-(1/4)-2-azido-3,6-di-
O-benzyl-2-deoxy-b-D-glucopyranoside 18
Spectral data of 18 were identical with those previously
reported.2b
3.2.6. 2,6-Di-O-benzyl-3,4-di-O-(4-methoxyphenyl)methyl-
b-D-galactopyranosyl-(1/4)-3,6-di-O-benzyl-2-deoxy-2-
trichloroacetamido-a-D-glucopyranosyl fluoride 20
[a]D þ29.1 (c 1.2). Rf 0.50 (19:1 CHCl3eEtOAc). 1H NMR
d: 7.33e7.16 (m, 24H, Ar), 6.85 (d, 2H, J¼8.3 Hz, Ar), 6.76
(d, 2H, J¼8.3 Hz, Ar), 6.64 (d, 1H, J¼7.8 Hz, eNH), 5.75
(dd, 1H, J¼2.4, 54.2 Hz, H-1a), 5.02 (d, 1H, J¼11.2 Hz,
eCH2Ar), 4.86 (d, 1H, J¼10.7 Hz, eCH2Ar), 4.83 (d, 1H,
J¼10.2 Hz, eCH2Ar), 4.74 (d, 1H, J¼10.7 Hz, eCH2Ar),
4.65e4.58 (m, 3H, eCH2Arꢃ3), 4.55 (d, 1H, J¼12.2 Hz,
eCH2Ar), 4.47 (d, 1H, J¼11.2 Hz, eCH2Ar), 4.39e4.32
(m, 3H, eCH2Arꢃ2, H-1b), 4.24 (d, 1H, J¼12.2 Hz,
eCH2Ar), 4.16e4.05 (m, 2H, H-2a, H-4a), 3.91e3.69 (m,
5H, H-3a, H-5a, H-6a, H-2b, H-4b), 3.79 (s, 3H, eOCH3),
3.74 (s, 3H, eOCH3), 3.56 (br d, J¼9.8 Hz, H-6a), 3.44 (dd,
1H, J¼10.2, 10.7 Hz, H-6b), 3.37e3.29 (m, 3H, H-3b, H-5b,
H-6b). Anal. Calcd for C58H61NO12Cl3F: C, 63.94; H, 5.64;
N, 1.29. Found: C, 64.03; H, 5.75; N, 1.19.
a-Isomer: [a]D þ32.0 (c 1.0). Rf 0.51 (19:1 toluenee
1
EtOAc). H NMR d: 7.73e7.70 (m, 4H, Ar), 7.48e7.15 (m,
31H, Ar), 5.70 (d, 1H, J¼3.4 Hz, H-1b), 5.37 [s, 1H,
PhCH(O)2e], 4.79e4.72 (m, 3H, eCH2Phꢃ3), 4.67 (d, 1H,
J¼12.2 Hz, eCH2Ph), 4.63 (d, 1H, J¼12.2 Hz, eCH2Ph),
4.54 (d, 1H, J¼11.7 Hz, eCH2Ph), 4.37 (d, 1H, J¼10.7 Hz,
eCH2Ph), 4.36 (d, 1H, J¼8.3 Hz, H-1a), 4.18 (d, 1H,
J¼11.7 Hz, eCH2Ph), 4.13e4.04 (m, 2H, H-4a, H-4b), 4.02
(dd, 1H, J¼3.4, 10.2 Hz, H-2b), 3.89 (br d, 1H, J¼12.2 Hz,
H-6b), 3.85 (dd, 1H, J¼3.4, 10.3 Hz, H-3b), 3.66 (br d, 1H,
J¼12.2 Hz, H-6b), 3.54e3.50 (m, 3H, H-2a, H-6a, H-5b),
3.40 (dd, 1H, J¼8.8, 9.3 Hz, H-3a), 3.23 (br d, 1H,
J¼10.7 Hz, H-6a), 3.01 (br d, J¼9.3 Hz, H-5a), 1.11 (s, 9H,
tBu). Anal. Calcd for C63H67N3O11Si: C, 71.77; H, 6.41; N,
3.99. Found: C, 71.84; H, 6.50; N, 3.84.
a-Isomer: [a]D þ40.0 (c 0.9). Rf 0.55 (19:1 CHCl3e
EtOAc). 1H NMR d: 7.34e7.13 (m, 24H, Ar), 6.82e6.79
(m, 4H, Ar), 6.64 (d, 1H, J¼8.8 Hz, eNH), 5.70 (dd, 1H,
J¼2.4, 53.7 Hz, H-1a), 5.47 (d, 1H, J¼3.9 Hz, H-1b), 4.81
(d, 1H, J¼11.2 Hz, eCH2Ar), 4.80 (d, 1H, J¼11.2 Hz,
eCH2Ar), 4.72 (d, 1H, J¼11.7 Hz, eCH2Ar), 4.63e4.56
(m, 5H, eCH2Arꢃ5), 4.49 (d, 1H, J¼11.2 Hz, eCH2Ar),
4.44 (d, 1H, J¼12.2 Hz, eCH2Ar), 4.35 (d, 1H, J¼11.7 Hz,
eCH2Ar), 4.29 (d, 1H, J¼11.7 Hz, eCH2Ar), 4.21 (m, 1H,
H-2a), 4.19 (t, 1H, J¼9.3 Hz, H-4a), 4.02 (m, 1H, H-5a),
3.99 (dd, 1H, J¼3.9, 10.3 Hz, H-2b), 3.94e3.87 (m, 4H,
3.2.5. tert-Butyldiphenylsilyl 2,6-di-O-benzyl-3,4-di-O-
(4-methoxyphenyl)methyl-b-D-galactopyranosyl-(1/4)-2-
azido-3,6-di-O-benzyl-2-deoxy-b-D-glucopyranoside 19
[a]D ꢀ4.7 (c 1.0). Rf 0.25 (3:1 hexaneeEtOAc). 1H NMR d:
7.72e7.69 (m, 4H, Ar), 7.42e7.10 (m, 30H, Ar), 6.84e6.77
(m, 4H, Ar), 5.00 (d, 1H, J¼10.7 Hz, eCH2Ar), 4.86 (d,
1H, J¼11.2 Hz, eCH2Ar), 4.73 (d, 1H, J¼11.2 Hz, eCH2Ar),
4.64 (d, 1H, J¼11.2 Hz, eCH2Ar), 4.63e4.57 (m, 3H,

A. Ueki et al. / Tetrahedron 64 (2008) 2611e2618
2617
H-3a, H-6a, H-4b, H-5b), 3.81 (dd, 1H, J¼2.4, 10.3 Hz, H-3b),
3.77 (s, 3H, eOCH3), 3.76 (s, 3H, eOCH3), 3.66 (dd, 1H,
J¼1.5, 10.7 Hz, H-6a), 3.44 (br d, 2H, J¼6.3 Hz, H-6bꢃ2).
Anal. Calcd for C58H61NO12Cl3F: C, 63.94; H, 5.64; N, 1.29.
Found: C, 63.84; H, 5.87; N, 1.23.
eCH2Ph), 4.43 (d, 1H, J¼7.8 Hz, H-1b), 4.37 (d, 1H,
J¼12.2 Hz, eCH2Ph), 4.33 (d, 1H, J¼11.7 Hz, eCH2Ph),
4.23 (d, 1H, J¼11.7 Hz, eCH2Ph), 4.22 (d, 1H, J¼12,2 Hz,
eCH2Ph), 4.15 (dt, 2H, J¼1.5, 5.3 Hz, eCH2CH]CH2), 4.03
(br t, 1H, J¼8.5 Hz, H-4a), 3.85 (br d, 1H, J¼3.4 Hz, H-4b),
3.81 (br t, 1H, J¼7.8 Hz, H-3a), 3.75 (dd, 1H, J¼7.8, 9.8 Hz,
H-2a), 3.67e3.63 (m, 2H, H-6a, H-2b), 3.47 (dd, 1H, J¼7.8,
8.3 Hz, H-6b), 3.40 (dd, 1H, J¼4.9, 7.8 Hz, H-5b), 3.34e3.29
(m, 3H, H-6a, H-3b, H-6b), 3.07 (m, 1H, H-5a), 1.05 (s, 9H,
tBu). Anal. Calcd for C68H74NO11Cl3Si: C, 67.18; H, 6.14; N,
1.15. Found: C, 67.08; H, 6.26; N, 1.13.
3.2.7. tert-Butyldiphenylsilyl 3-O-allyl-2,4,6-tri-O-benzyl-
b-D-galactopyranosyl-(1/4)-2-azido-3,6-di-O-benzyl-2-
deoxy-b-D-glucopyranoside 21
[a]D ꢀ13.7 (c 1.1). Rf 0.54 (19:1 tolueneeEtOAc). 1H NMR
d: 7.72e7.70 (m, 4H, Ar), 7.42e7.11 (m, 31H, Ar), 5.91 (m, 1H,
eCH]CH2), 5.31 (dd, 1H, J¼1.5, 17.1 Hz, eCH]CH2), 5.16
(dd, 1H, J¼1.5, 10.7 Hz, eCH]CH2), 5.01 (d, 1H, J¼10.2 Hz,
eCH2Ph), 4.95 (d, 1H, J¼11.7 Hz, eCH2Ph), 4.73 (d, 1H,
J¼11.7 Hz, eCH2Ph), 4.62 (d, 1H, J¼11.2 Hz, eCH2Ph),
4.61 (d, 1H, J¼10.2 Hz, eCH2Ph), 4.53 (d, 1H, J¼11.2 Hz,
eCH2Ph), 4.41 (d, 1H, J¼7.8 Hz, H-1b), 4.37 (d, 1H,
J¼11.7 Hz, eCH2Ph), 4.35 (d, 1H, J¼11.7 Hz, eCH2Ph),
4.30 (d, 1H, J¼7.8 Hz, H-1a), 4.23 (d, 1H, J¼11.7 Hz,
eCH2Ph), 4.22 (d, 1H, J¼11.7 Hz, eCH2Ph), 4.15 (br d, 2H,
J¼5.4 Hz, eCH2CH]CH2), 3.96 (t, 1H, J¼9.8 Hz, H-4a),
3.86 (d, 1H, J¼2.9 Hz, H-4b), 3.67e3.62 (m, 2H, H-6a,
H-2b), 3.53 (t, 1H, J¼7.8 Hz, H-6b), 3.44e3.34 (m, 3H, H-2a,
H-6b, H-5b), 3.31 (dd, 1H, J¼2.9, 9.8 Hz, H-3b), 3.25e3.19
(m, 2H, H-3a, H-6a), 2.83 (br d, J¼9.8 Hz, H-5a), 1.11 (s, 9H,
tBu). Anal. Calcd for C66H73N3O10: C, 72.30; H, 6.71; N,
3.83. Found: C, 72.34; H, 6.71; N, 3.74.
a-Isomer: [a]D þ14.0 (c 1.1). Rf 0.46 (19:1 toluenee
1
EtOAc). H NMR d: 7.70e7.63 (m, 4H, Ar), 7.38e7.14 (m,
31H, Ar), 6.85 (d, 1H, J¼6.9 Hz, eNH), 5.88 (m, 1H,
eCH]CH2), 5.32 (d, 1H, J¼3.9 Hz, H-1b), 5.26 (dd, 1H,
J¼1.5, 17.1 Hz, eCH]CH2), 5.12 (dd, 1H, J¼1.5, 10.7 Hz,
eCH]CH2), 4.84 (d, 1H, J¼11.2 Hz, eCH2Ph), 4.79 (d,
1H, J¼6.8 Hz, H-1a), 4.71 (d, 1H, J¼10.7 Hz, eCH2Ph),
4.65 (d, 1H, J¼12.2 Hz, eCH2Ph), 4.57 (d, 1H, J¼11.2 Hz,
eCH2Ph), 4.51 (d, 1H, J¼12.2 Hz, eCH2Ph), 4.50 (d, 1H,
J¼11.2 Hz, eCH2Ph), 4.34 (d, 1H, J¼11.7 Hz, eCH2Ph),
4.31 (br s, 2H, eCH2Phꢃ2), 4.26 (d, 1H, J¼11.7 Hz,
eCH2Ph), 4.14e4.07 (m, 4H, H-2a, H-4a, eCH2CH]CH2),
3.90e3.81 (m, 4H, H-3a, H-2b, H-4b, H-5b), 3.62e3.57 (m,
2H, H-6a, H-3b), 3.50e3.43 (m, 2H, H-6bꢃ2), 3.40 (dd, 1H,
J¼5.8, 8.8 Hz, H-6a), 3.30 (m, 1H, H-5a). Anal. Calcd for
C68H74NO11Cl3Si: C, 67.18; H, 6.14; N, 1.15. Found: C,
67.00; H, 6.23; N, 1.16.
a-Isomer: [a]D þ17.7 (c 0.6). Rf 0.62 (19:1 tolueneeEtOAc).
1H NMR d: 7.71e7.68 (m, 4H, Ar), 7.40e7.13 (m, 31H, Ar),
5.87 (m, 1H, eCH]CH2), 5.59 (d, 1H J¼3.9 Hz, H-1b), 5.25
(dd, 1H, J¼1.5, 17.5 Hz, eCH]CH2), 5.11 (dd, 1H, J¼1.5,
10.2 Hz, eCH]CH2), 4.84 (d, 1H, J¼11.2 Hz, eCH2Ph),
4.76 (d, 1H, J¼11.7 Hz, eCH2Ph), 4.73 (d, 1H, J¼11.7 Hz,
eCH2Ph), 4.72 (d, 1H, J¼11.7 Hz, eCH2Ph), 4.53 (d, 1H,
J¼11.7 Hz, eCH2Ph), 4.50 (d, 1H, J¼11.2 Hz, eCH2Ph),
4.34 (d, 1H, J¼7.8 Hz, H-1a), 4.32e4.26 (m, 3H, eCH2Phꢃ3),
4.23 (d, 1H, J¼11.7 Hz, eCH2Ph), 4.08 (br d, 2H, J¼5.4 Hz,
eCH2CH]CH2), 4.02 (t, 1H, J¼9.8 Hz, H-4a), 3.93 (dd, 1H,
J¼3.9, 10.2 Hz, H-2b), 3.90e3.85 (m, 2H, H-4b, H-5b), 3.66
(dd, 1H, J¼2.4, 10.2 Hz, H-3b), 3.56e3.47 (m, 3H, H-2a,
H-6a, H-6b), 3.40e3.36 (m, 2H, H-3a, H-6b), 3.31 (dd, 1H,
J¼1.9, 11.2 Hz, H-6a), 3.02 (br d, 1H, J¼8.8 Hz, H-5a), 1.11
(s, 9H, tBu). Anal. Calcd for C66H73N3O10: C, 72.30; H, 6.71;
N, 3.83. Found: C, 72.42; H, 6.72; N, 3.74.
3.2.9. N-(9-Fluorenylmethoxycarbonyl)-O-[2,3,4,6-tetra-O-
benzyl-b-D-galactopyranosyl-(1/3)-2-azido-4,6-O-
benzylidene-2-deoxy-a-D-galactopyranosyl]-L-serine allyl
ester 24 and N-(9-fluorenylmethoxycarbonyl)-O-[2,3,4,6-
tetra-O-benzyl-a-D-galactopyranosyl-(1/3)-2-azido-4,6-
O-benzylidene-2-deoxy-a-D-galactopyranosyl]-L-serine allyl
ester 25
According to the typical procedure, to a stirred mixture of 1
(66 mg, 0.10 mmol), 23 (34 mg, 0.05 mmol), BSP (33 mg,
˚
0.16 mmol), TTBP (52 mg, 0.21 mmol), and dried MS (4 A,
100 mg) in anhydrous EtCN (1.5 ml) was added Tf2O (19 ml,
0.11 mmol) at ꢀ78 ꢁC. The reaction mixture was stirred for
30 min and quenched with satd aq NaHCO3. After work-up,
the crude product was chromatographed on silica gel with tol-
ueneeEtOAc (7:1) to give known 2419 (41 mg, 67%) and then
2520 (16 mg, 15%).
3.2.8. tert-Butyldiphenylsilyl 3-O-allyl-2,4,6-tri-O-benzyl-b-
D-galactopyranosyl-(1/4)-3,6-di-O-benzyl-2-deoxy-2-
trichloroacetamido-b-D-glucopyranoside 22
3.2.10. N-(9-Fluorenylmethoxycarbonyl)-O-[2,6-di-O-
benzyl-3,4-di-O-(4-methoxyphenyl)methyl-b-D-
Mp 115.5e116.5 ꢁC (recrystallized from hexaneeEtOAc).
[a]D ꢀ7.8 (c 1.0). Rf 0.37 (19:1 tolueneeEtOAc). 1H NMR d:
7.70e7.63 (m, 4H, Ar), 7.40e7.11 (m, 31H, Ar), 6.89 (d, 1H,
J¼7.8 Hz, eNH), 5.91 (m, 1H, eCH]CH2), 5.31 (m, 1H,
eCH]CH2), 5.16 (dd, 1H, J¼1.5, 10.3 Hz, eCH]CH2),
4.94 (d, 1H, J¼10.7 Hz, eCH2Ph), 4.93 (d, 1H, J¼11.7 Hz,
eCH2Ph), 4.99 (d, 1H, J¼7.3 Hz, H-1a), 4.72 (d, 1H,
J¼11.2 Hz, eCH2Ph), 4.64 (d, 1H, J¼11.2 Hz, eCH2Ph),
4.53 (d, 1H, J¼10.7 Hz, eCH2Ph), 4.51 (d, 1H, J¼11.7 Hz,
galactopyranosyl-(1/3)-2-azido-4,6-O-benzylidene-2-
deoxy-a-D-galactopyranosyl]-L-serine allyl ester 26 and
N-(9-fluorenylmethoxycarbonyl)-O-[2,6-di-O-benzyl-3,4-di-
O-(4-methoxyphenyl)methyl-a-D-galactopyranosyl-(1/3)-
2-azido-4,6-O-benzylidene-2-deoxy-a-D-galactopyranosyl]-
L-serine allyl ester 27
According to the typical procedure, to a stirred mixture of 4
(216 mg, 0.31 mmol), 23 (100 mg, 0.16 mmol), BSP (98 mg,
0.47 mmol), TTBP (155 mg, 0.62 mmol), and dried MS

2618
A. Ueki et al. / Tetrahedron 64 (2008) 2611e2618
˚
(4 A, 300 mg) in anhydrous EtCN (4.5 ml) was added Tf2O
(58 ml, 0.34 mmol) at ꢀ78 ꢁC. The reaction mixture was
stirred for 30 min and quenched with satd aq NaHCO3. After
work-up, the crude product was chromatographed on silica
gel with tolueneeEtOAc (10:1 to 7:1) to give 26 (152 mg,
79%) and 27 (6 mg, 8%). Compound 26: [a]D þ91.1 (c 1.1).
Rf 0.58 (3:1 tolueneeEtOAc). 1H NMR d: 7.76 (d, 2H,
J¼7.3 Hz, Ar), 7.59 (d, 2H, J¼7.3 Hz, Ar), 7.52e7.49 (m,
2H, Ar), 7.41e7.18 (m, 21H, Ar), 6.86e6.79 (m, 4H, Ar),
5.96e5.86 (m, 2H, eNH, eCH]CH2), 5.46 [s, 1H,
PhCH(Oe)2], 5.34 (br d, 1H, J¼17.6 Hz, eCH]CH2), 5.26
(br d, 1H, J¼10.2 Hz, eCH¼CH2), 5.03 (d, 1H, J¼3.4 Hz,
H-1a), 4.99 (d, 1H, J¼10.7 Hz, eCH2Ar), 4.86 (d, 1H,
J¼11.2 Hz, eCH2Ar), 4.75 (d, 1H, J¼11.2 Hz, eCH2Ar),
4.71e4.56 (m, 5H, eCH2CH]CH2, eCH2Ar, H-1b, Sere
aH), 4.51 (d, 1H, J¼11.2 Hz, eCH2Ar), 4.46e4.29 (m, 5H,
eCH2Arꢃ3, eOCH2CHAr2), 4.24e4.00 (m, 4H, Sere
bHꢃ2, H-3a, eOCH2CHAr2), 3.87e3.50 (m, 11H, H-2a,
H-4a, H-5a, H-6aꢃ2, H-2b, H-3b, H-4b, H-5b, H-6bꢃ2),
3.80 (s, 3H, eOCH3), 3.77 (s, 3H, eOCH3). Anal. Calcd for
C70H72N4O16: C, 68.61; H, 5.92; N, 4.57. Found: C, 68.74;
H, 6.04; N, 3.98. (Because of unstable 26 by drying at
80 ꢁC, a lower value was obtained for N analysis.) HRMS
Acknowledgements
The authors acknowledge Ms. Akie Tohyama and Mr. Shota
Nagasaki for their contribution to the preliminary experiments
on this project. This work was supported by grant-in-aid for
creative scientific research (17GS0420) from Japan Society
for the Promotion of Science. We are indebted to Tokyo Chem-
ical Industry Co., Ltd. for the generous gifting of compound 7.
Thanks are due to Dr. T. Chihara and his staff at Riken for the
combustion analyses. We also thank Tokai University for their
support by grant-in-aid for high technology research.
References and notes
1. Nakahara, Y. Trends Glycosci. Glycotechnol. 2003, 15, 257e273.
2. For example: (a) Nakahara, Y.; Iijima, H.; Ogawa, T. Carbohydr. Lett.
1994, 1, 99e106; (b) Takano, Y.; Kojima, N.; Nakahara, Y.; Hojo, H.;
Nakahara, Y. Tetrahedron 2003, 59, 8415e8427.
3. Nakahara, Y.; Nakahara, Y.; Ito, Y.; Ogawa, T. Carbohydr. Res. 1998, 308,
287e296.
4. Hashimoto, S.; Honda, T.; Ikegami, S. J. Chem. Soc., Chem. Commun.
1989, 685e687.
5. Hashimoto, S.; Honda, T.; Ikegami, S. Chem. Pharm. Bull. 1990, 38,
2323e2325.
6. Hashimoto, S.; Yanagiya, Y.; Honda, T.; Harada, H.; Ikegami, S. Tetra-
hedron Lett. 1992, 33, 3523e3526.
12
16
calcd for
1247.46996.
C
70
1H7214N423Na1
O
m/z 1247.48410. Found
16
7. Hashimoto, S.; Umeo, K.; Sano, A.; Watanabe, N.; Nakajima, M.;
Ikegami, S. Tetrahedron Lett. 1995, 36, 2251e2254.
8. Watanabe, Y.; Nakamoto, C.; Yamamoto, T.; Ozaki, S. Tetrahedron 1994,
50, 6523e6536.
Compound 27: [a]D þ92.3 (c 1.0). Rf 0.53 (3:1 toluenee
1
EtOAc). H NMR d: 7.76 (d, 2H, J¼7.3 Hz, Ar), 7.57 (d, 2H,
J¼7.3 Hz, Ar), 7.48e7.09 (m, 23H, Ar), 6.85e6.77 (m, 4H,
Ar), 5.94e5.84 (m, 2H, eCH]CH2, eNH), 5.38 [s, 1H,
PhCH(Oe)2], 5.32 (br d, 1H, J¼17.6 Hz, eCH]CH2), 5.25e
5.23 (m, 2H, eCH]CH2, H-1b), 4.99 (d, 1H, J¼2.9 Hz,
H-1a), 4.84 (d, 1H, J¼10.7 Hz, eCH2Ar), 4.73 (d, 1H,
J¼11.2 Hz, eCH2Ar), 4.66e4.28 (m, 12H, eCH2CH]CH2,
eCH2Arꢃ6, SereaH, eOCH2CHAr2), 4.21e4.03 (m, 7H,
SerebH, H-3a, H-4a, H-6a, H-2b, H-3b, H-5b), 3.97e3.93
(m, 3H, H-2a, H-4b, SerebH), 3.86 (br d, 1H, J¼12.7 Hz,
H-6a), 3.79 (s, 3H, eOCH3), 3.75 (s, 3H, eOCH3), 3.59 (br s,
1H, H-5a), 3.57e3.47 (m, 2H, H-6bꢃ2). Anal. Calcd for
C70H72N4O16: C, 68.61; H, 5.92; N, 4.57. Found: C, 68.89; H,
6.15;N, 3.64.(Becauseofunstable27bydryingat80 ꢁC, alower
value was obtained for N analysis.) HRMS calcd for
9. Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015e9020.
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Carbohydr. Res. 2002, 337, 1247e1259.
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13. Murakata, C.; Ogawa, T. Carbohydr. Res. 1992, 234, 75e91.
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15. Kanie, O.; Ito, Y.; Ogawa, T. J. Am. Chem. Soc. 1994, 116, 12073e12074.
16. Ueki, A.; Nakahara, Y.; Hojo, H.; Nakahara, Y. Tetrahedron 2007, 63,
2170e2181.
17. Crich, D.; Jayalath, P. Org. Lett. 2005, 7, 2277e2280.
18. Macindoe, W. M.; Iijima, H.; Nakahara, Y.; Ogawa, T. Carbohydr. Res.
1995, 269, 227e257.
19. Nakahara, Y.; Nakahara, Y.; Ogawa, T. Carbohydr. Res. 1996, 292, 71e81.
20. Maemura, M.; Ohgaki, A.; Nakahara, Y.; Hojo, H.; Nakahara, Y. Biosci.
Biotechnol. Biochem. 2005, 69, 1575e1583.
1H7214N423Na1
O m/z 1247.48410. Found 1247.47154.
16
12
16
C
70