Direct and stereoselective synthesis of β-D-mannosides using 4,6-O-benzylidene-protected mannosyl diethyl phosphite as a donor

Article abstract of DOI:10.1016/j.tet.2005.08.090

A direct and practical method for the construction of β-mannosidic linkages is described. While β-selectivities in the TMSOTf-promoted glycosidation of 2,3,4,6-tetra-O-benzyl-d-mannosyl diethyl phosphite are found to be highly dependent on the reactivity

Full text of DOI:10.1016/j.tet.2005.08.090

Tetrahedron 61 (2005) 10719–10733
Direct and stereoselective synthesis of b-D-mannosides using
4,6-O-benzylidene-protected mannosyl diethyl phosphite
as a donor
Toshifumi Tsuda, Ryoichi Arihara, Shinya Sato, Miyuki Koshiba, Seiichi Nakamura
*
and Shunichi Hashimoto
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Received 22 July 2005; revised 17 August 2005; accepted 18 August 2005
Available online 19 September 2005
Abstract—A direct and practical method for the construction of b-mannosidic linkages is described. While b-selectivities in the TMSOTf-
promoted glycosidation of 2,3,4,6-tetra-O-benzyl-D-mannosyl diethyl phosphite are found to be highly dependent on the reactivity of
acceptor alcohols, 2,3-di-O-benzyl-4,6-O-benzylidene-D-mannosyl diethyl phosphite reacts with a wide range of acceptor alcohols in the
presence of TMSOTf in CH2Cl2 at K45 8C to give b-mannosides in high yields with good to high b-selectivities.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
ether connectors,11 and intramolecular mannosylation via
prearranged glycosides,12 have been reported.
The rapidly growing significance of glycosides and
oligosaccharides as constituents of biologically important
compounds such as antitumor antibiotics and glycoconju-
gates has created an interest in the rational design and
development of stereocontrolled glycosidation reactions.1
Since the b-D-mannosidic linkage is present in virtually all
eukaryotic N-linked glycoproteins as part of the core
pentasaccharide, an enormous amount of creative endeavor
has been devoted to the construction of this linkage.2
Despite these efforts, the stereoselective synthesis of
b-mannosides is recognized as one of the most challenging
problems in carbohydrate chemistry, because both the
anomeric effect and the steric repulsion between a non-
participating group disposed axially at C-2 and an incoming
alcohol uniformly favor the formation of a-mannosidic
linkages. Departing from the seminal work of Paulsen and
Lockhoff on the direct construction of this linkage via an
SN2-type displacement in the presence of insoluble silver
silicate,3 a number of indirect methods involving the
epimerization of accessible b-glucosides at C-2,4 the
hexo-2-ulosyl bromide approach,5 the reductive cleavage
of mannosyl anomeric orthoesters,6 intramolecular aglycon
delivery (IAD)7 using a temporary mixed acetal8–10 or silyl
Although these indirect methods provide reliable access to
pure b-mannosides, additional synthetic steps are required
for the substrate preparation. Therefore, it is clear that a
direct b-mannosylation method would constitute an ideal
procedure in terms of efficiency and practicality. In this
context, good to high b-selectivities have been achieved
using some per-O-benzylated mannosyl donors.13 The use
of sulfonates as non-participating protecting groups at O-2
enhances b-selectivity due to a strong dipole effect.14,15 The
locked anomeric configuration method, wherein 1,2-O-
dibutylstannylene derivatives of mannose are used as
glycosyl donors and the roles of the donor and acceptor
are reversed, results in complete b-selectivity; however, a
significantly long reaction time is required to reach
completion.16 Among the direct methods reported to date,
the protocol recently developed by Crich and Sun is a
notable landmark in this field, in which the activation of
2,3-di-O-benzyl-4,6-O-benzylidene-protected mannosyl
sulfoxide or thioglycoside at K78 8C in dichloromethane
with trifluoromethanesulfonic (triflic) anhydride or benze-
nesulfenyl triflate, respectively, is followed by the addition
of acceptor alcohols to provide b-mannosides in high yields
and with excellent levels of selectivity.17 They claimed that
the success of the two methods hinges critically on the
presence of the 4,6-O-benzylidene group, where the
a-mannosyl triflate as a common intermediate generated
in situ from the donors reacts predominantly via an SN2-like
Keywords: 4,6-O-Benzylidene acetal; Mannosyl diethyl phosphite; b-
Selective glycosidation.
*
Corresponding author. Tel.: C81 11 706 3236; fax: C81 11 706 4981;
e-mail: hsmt@pharm.hokudai.ac.jp
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.090

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T. Tsuda et al. / Tetrahedron 61 (2005) 10719–10733
displacement.18 Very recently, Crich and Chandrasekera,
based on kinetic isotope effects (KIEs) measurements,
proposed that the displacement of the a-mannosyl triflate by
an acceptor alcohol proceeded with the development of a
substantial oxocarbenium ion character.19 The effectiveness
of the intermediate was also recognized by Weingart and
Schmidt20 with the corresponding trichloroacetimidate and
by Kim and co-workers21 with the 2-(hydroxycarbonyl)-
benzyl 4,6-O-benzylidenemannoside.22
a-configuration were predominantly formed in all cases
except for the diethyl phosphites 4a and 4b. The obtained
mannosyl donors were purified by silica gel column
chromatography, and could be stored without decompo-
sition in a freezer (at K30 8C) for several months.
(4)
We have developed glycosyl donors that incorporate
various phosphorus-containing leaving groups. The glyco-
sidations constitute mild and efficient methods for the highly
stereocontrolled construction of 1,2-trans-b- and 1,2-cis-a-
glycosidic linkages with or without a participating group at
C-2.23 The exceptionally high levels of b-selectivity
observed with 2,3,4,6-tetra-O-benzyl-protected glycosyl
diphenyl phosphates,23a N,N,N0,N0-tetramethylphosphoro-
diamidates,23d and diethyl phosphites23e suggest that these
leaving groups would also be promising candidates for the
construction of b-mannosidic linkages. In the following
discussion, the details of our investigations in this area are
presented (Eq. 1).24,25
2.2. Glycosidation of 2,3,4,6-tetra-O-benzyl-D-mannosyl
donors
At the outset of this study, the glycosidation of 2,3,4,6-tetra-
O-benzyl-D-mannosyl donors was explored using O-6- or
O-4-unprotected glycosides 5 or 6 (1.1 equiv each) as highly
reactive and less reactive acceptor alcohols, respectively
(Table 1).29,30 The addition of a 1.0 M solution of TMSOTf
(1.1 equiv) in CH2Cl2 to a cooled solution of the donor and
acceptor in CH2Cl2 afforded a disaccharide and the a:b ratio
was assayed by HPLC (Zorbaxw Sil column). The
TMSOTf-promoted glycosidation of diphenyl phosphate
2a with 5 in CH2Cl2 proceeded at K78 8C within 1 h to give
disaccharide 7 in 86% yield with good b-selectivity (a:bZ
21:79) (Fig. 1). Almost the same results were obtained when
phosphorodiamidate 3a and diethyl phosphite 4a were used
(entries 2 and 3). However, a limitation of the TMSOTf-
promoted glycosidations of 2,3,4,6-tetra-O-benzyl-D-man-
nosyl donors 2a, 3a, and 4a was encountered with the
unreactive O-4-unprotected glycoside 6, the mannosylation
(1)
2. Results and discussion
2.1. Preparation of D-mannosyl donors
2,3,4,6-Tetra-O-benzyl-D-mannosyl and 2,3-di-O-benzyl-4,
6-O-benzylidene-D-mannosyl donors were prepared from
the corresponding mannoses 1a26 and 1b27 according to
standard procedures. Phosphorylation with diphenyl chloro-
phosphate under the Sabesan conditions28 (DMAP, CH2Cl2,
0 8C) provided diphenyl phosphates 2a and 2b in good
yields (Eq. 2). Tetramethylphosphorodiamidates 3a and 3b
were obtained by the condensation of lithium alkoxides
derived from 1a and 1b, respectively, with bis(dimethyla-
mino)phosphorochloridate in THF–HMPA (Eq. 3).23d
Table 1. TMSOTf-promoted glycosidation of 2,3,4,6-tetra-O-benzyl-D-
mannosyl donors 2a, 3a, and 4aa
Entry
Donorb Acceptor Time, h
Disaccharide
Yield,
%
a:bc
(2)
1
2a
3a
4a
2a
3a
4a
5
5
5
6
6
6
1
1
1
1.5
1.5
1.5
7
7
7
8
8
8
86
91
86
75
89
74
21:79
22:78
25:75
77:23
80:20
76:24
2d
3
4
5d
6
a Donor/acceptor/TMSOTf molar ratioZ1.0/1.1/1.1 unless otherwise
noted.
b The anomeric ratio of the donors: 2a, 100:0; 3a, 100:0; 4a, 87:13.
c The ratio was determined by HPLC (column, Zorbaxw Sil, 4.6!250 mm;
eluent, 13% THF in hexane or 20% ethyl acetate in hexane; flow rate 1.5
or 1.0 mL/min).
(3)
Diethyl phosphites 4a and 4b were prepared by the reaction
of mannose derivatives with diethyl chlorophosphite
and triethylamine at 0 8C (Eq. 4). Donors with an
d The reaction was performed using 2.0 equiv of TMSOTf.

T. Tsuda et al. / Tetrahedron 61 (2005) 10719–10733
10721
observations, we selected the phosphite method for the
b-selective mannosylation in terms of reactivity and product
yield.33
Promoters other than TMSOTf were screened for their
ability to activate the mannosyl diethyl phosphite 4b
(Table 3). Although a previous study from this laboratory
demonstrated that the BF3$OEt2-promoted glycosidations
of per-O-benzyl-protected glycosyl diethyl phosphites
exhibited the highest levels of b-selectivities known to
date,23e the coupling of 4b with 5 in the presence of
BF3$OEt2 gave disaccharide 9 in only 54% yield with an
a:b ratio of 40:60 and considerable amounts of mannosyl
fluoride 10 (entry 2). It has been well documented in the
literature that some Brønsted acids such as TfOH are
effective activators of glycosyl phosphites.23g,23j,25,34 While
mannosyl diethyl phosphate 4b could also be activated by
TfOH at K65 8C in CH2Cl2, the reaction with 5 afforded no
discernible benefits (entry 3). Reactions of glycosyl
phosphites have been shown to be promoted by catalytic
amounts of TMSOTf;23f,34a,35 however, the use of 0.2 equiv
of TMSOTf resulted in a diminished b-selectivity (a:bZ
19:81, entry 4). The reason for the attenuated selectivity in
the catalytic reaction is unclear at present.
Figure 1. Products of the mannosylation of alcohols 5 and 6 with 2,3,4,6-
tetra-O-benzyl-D-mannosyl donors.
of which produced disaccharide 8 favoring the a-mannoside
in high yields (entries 4–6).
2.3. Glycosidation of 2,3-di-O-benzyl-4,6-O-benzylidene-
D-mannosyl donors
2.3.1. Reaction optimization. Since the glycosidation of
the fully benzylated mannosyl donors 2a–4a proved to be an
unreliable method for the construction of b-mannosidic
linkages, we were prompted to investigate the glycosidation
of 2,3-di-O-benzyl-4,6-O-benzylidene-D-mannosyl donors.
Consistent with a general trend that 4,6-O-benzylidene-
protected glycosyl donors exhibit reduced reactivities,31
mannosyl donors 2b–4b were activated with TMSOTf in
CH2Cl2 at a higher temperature than that required for the
corresponding per-O-benzylated donors 2a–4a, but the
reaction with 5 gave disaccharide 9 with an enhanced
b-selectivity (Table 2). Although Seeberger and co-workers
reported that the use of 4,6-O-benzylidene-protected
mannosyl phosphate met with failure due to the partial
hydrolysis of the cyclic acetal functionality under acidic
conditions,32 mannosylation with diphenyl phosphate 2b
provided disaccharide 9 in 54% yield with an a:b ratio of
10:90 (entry 1). The use of phosphorodiamidate 3b as a
donor gave virtually the same results as those found with 2b
(entries 1 vs 2), although a protracted reaction time was
required. On the other hand, the TMSOTf-promoted
mannosylation of 5 with diethyl phosphite 4b in CH2Cl2
proceeded to completion at K45 8C within 30 min,
affording disaccharide 9 in 83% yield with a similar high
level of b-selectivity (entry 3). As a result of these
We next explored the optimal solvent for this reaction
(Table 4). Solvents such as toluene and Et2O were found to
be less effective in terms of stereoselectivity (entries 2 and
3). The use of propionitrile gave a complex mixture of
products, most likely due to the low anomeric reactivity of
the nitrilium ion intermediates that causes a nucleophilic
attack by alcohol 5 on a nitrilium carbon (entry 4).23i The
temperature profile of the reaction of 4b with 5 in CH2Cl2
demonstrated that this reaction performed extremely well
over a wide temperature range; only minor erosion (2%) in
b-selectivity was observed (entries 1 vs 5 and 6).
Table 3. Effect of promoter in the glycosidation of 4,6-O-benzylidene-D-
mannosyl diethyl phosphite 4b with 5
Table 2. TMSOTf-promoted glycosidation of 4,6-O-benzylidene-D-
mannosyl donors 2b, 3b, and 4b with 5
Entry
Promoter
Temperature, Time, Yield, a:ba
8C
h
%
Entry
Donora TMSOTf Tempera-
Time
(h)
Yield
(%)
a:bc
equiv
1.1
(equiv)
ture (8C)b
1
TMSOTf
BF3$OEt2 1.1
TfOH
TMSOTf
K45
K45
K65
K45
0.5
6
6
83
54b
79
81
10:90
40:60
9:91
1
2
3
2b
3b
4b
1.5
2.0
1.1
K30
K30
K45
1
2
0.5
54
55
83
10:90
12:88
10:90
2
3c
4
1.1
0.2
1
19:81
a The anomeric ratio of the donors: 2b, 100:0; 3b, 100:0; 4b, 93:7.
b Temperature limit for a smooth reaction.
a The ratio was determined by HPLC (column, Zorbaxw Sil, 4.6!250 mm;
eluent, 20% ethyl acetate in hexane; flow rate, 1.0 mL/min; tR
a-mannoside, 21.1 min; tR b-mannoside, 24.4 min).
c The ratio was determined by HPLC (column, Zorbaxw Sil, 4.6!250 mm;
eluent, 20% ethyl acetate in hexane; flow rate, 1.0 mL/min; tR a-
mannoside, 21.1 min; tR b-mannoside, 24.4 min).
b Mannosyl fluoride 10 was obtained in 31% yield.
c
˚
˚
In the presence of 4 A molecular sieves (4 A MS).

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T. Tsuda et al. / Tetrahedron 61 (2005) 10719–10733
Table 4. Effect of solvent and temperature in the TMSOTf-promoted
glycosidation of 4,6-O-benzylidene-D-mannosyl diethyl phosphite 4b
with 5
Table 5. Effect of mixing sequence of the reactants in the TMSOTf-
promoted glycosidation of 4,6-O-benzylidene-D-mannosyl diethyl phos-
phite 4b with 5
Entry
Solvent
Temperature, Time,
8C
Yield, % a:ba
Entry
Methoda Temperature, Time,
Yield, % a:bb
min
8C
min
1
2
3
4
5
6
CH2Cl2
Toluene
Et2O
EtCN
CH2Cl2
CH2Cl2
K45
K45
K45
K45
K23
0
30
30
30
15
15
15
83
86
77
10:90
20:80
22:78
1
2
3
4
A
B
B
C
K45
K45
K78
K45
30
30
120
30
83
10:90
8:92
5:95
65c
55c
79
Complex mixture
74
75
10:90
11:89
12:88
a Method A. A 1 M solution of TMSOTf in CH2Cl2 was added to a mixture
of donor 4b and alcohol 5 in CH2Cl2 at K45 8C. Method B. After stirring a
solution of donor 4b and TMSOTf in CH2Cl2 at K45 8C for 30 min, a
solution of alcohol 5 in CH2Cl2 was added at the indicated temperature.
Method C (inverse conditions). A solution of donor 4b in CH2Cl2 was
added to a solution of alcohol 5 and TMSOTf in CH2Cl2 at K45 8C.
b The ratio was determined by HPLC (column, Zorbaxw Sil, 4.6!250 mm;
eluent, 20% ethyl acetate in hexane; flow rate, 1.0 mL/min; tR a-
mannoside, 21.1 min; tR b-mannoside, 24.4 min).
a The ratio was determined by HPLC (column, Zorbaxw Sil, 4.6!250 mm;
eluent, 20% ethyl acetate in hexane; flow rate, 1.0 mL/min; tR a-
mannoside, 21.1 min; tR b-mannoside, 24.4 min).
Although it appeared likely that the conditions employed in
the coupling of 4b with 5 could be optimized, the observed
b-selectivity (a:bZ10:90) did not match the selectivity (a:b
ratio with 5 was 4:96 at K78 8C and 6:94 at K45 8C)
obtained by us using the corresponding sulfoxide 11
(Eq. 5).17 It is clear that the difference in selectivity
between the two methods cannot be attributed to the
reaction temperature used. In this context, it is likely that
another factor accounts for the difference in stereoselectiv-
ity. Our procedure involves the dropwise addition of
TMSOTf to a mixture of 4b and 5 in CH2Cl2. On the
other hand, in Crich and Sun’s study, the order of addition of
reactants was critical for the success of the reaction, since
the intermediate triflate should be prepared before the
addition of the alcohol.
c Phosphonate 12 was obtained as a by-product in ca. 15–20% yield.
K45 8C for 30 min followed by the addition of alcohol 5
was found to increase the a:b ratio to 8:92 (method B, entry
2). This protocol enabled the b-selectivity to be enhanced
further by lowering the temperature to K78 8C during the
addition (entry 3). It is noteworthy that the observed
selectivity (a:bZ5:95) is comparable to that obtained by the
sulfoxide method. However, the permuted order of addition
provided much lower yields of mannoside 9 due to the
inevitable formation (ca. 15–20%) of phosphonate 12.36,37
Although Schmidt and Weingart employed the ‘inverse
conditions’38 for the formation of b-mannosides using 4,6-
O-benzylidene-protected mannosyl trichloroacetimidate,20
no difference in stereoselectivity was observed under
inverse conditions, in which 4b was added to a mixture of
5 and TMSOTf at K45 8C (method C, entry 4). These
results strongly suggest that the problem associated with the
phosphite method is that the mannosyl donor 4b cannot be
cleanly converted into the a-mannosyl triflate by treatment
with TMSOTf before the addition of an acceptor alcohol.
This also means that Crich’s optimal protocol is crucial not
only for the preferential formation of b-mannosides using
Kahne’s sulfoxide glycosidation method39 but also for
general use whenever the efficient in situ generation of the
a-mannosyl triflate from 4,6-O-benzylidene-protected
mannosyl donors is possible.
2.3.2. Scope of the TMSOTf-promoted glycosidations of
4,6-O-benzylidene-D-mannosyl diethyl phosphite 4b.
With the reaction conditions optimized, the scope of the
glycosidation reaction of 4b with a range of acceptor
alcohols was then investigated (Fig. 2). The results are
compiled in Table 6.
(5)
Thus, we focused on the possibility of improving the
b-selectivity by changing the mixing sequence (Table 5).
Pretreatment of donor 4b with TMSOTf in CH2Cl2 at

T. Tsuda et al. / Tetrahedron 61 (2005) 10719–10733
10723
Table 6. TMSOTf-promoted glycosidation of 4,6-O-benzylidene-D-
mannosyl diethyl phosphite 4b with acceptor alcoholsa,b
Entry
ROH
Time,
min
Product
Yield, %
a:bc
1
2
3
4
5
6
6
13
14
15
16
17
18
19
20
21
22
60
30
60
30
30
30
30
30
30
15
30
23
24
25
26
27
28
29
30
31
32
33
84
85
72
89
77
96
89
85
89
87
86
11:89
11:89
17:83
24:76
15:85d
5:95
11:89
14:86f
16:84
15:85
17:83
7
8e
9
10
11
a The reaction was carried out on a 0.1 mmol scale.
b Donor 4b/ROH/TMSOTf molar ratioZ1.0/1.1/1.1 unless otherwise
noted.
c The ratio was determined by HPLC (column, Zorbaxw Sil, 4.6!250 mm;
eluent, 5–17% ethyl acetate in hexane or 5–20% THF in hexane; flow rate,
1.0 mL/min), unless otherwise stated.
d Determined by 500 MHz 1H NMR.
e The reaction was performed with 2.0 equiv of TMSOTf.
f
Determined by 126 MHz 13C NMR.
(entries 1 and 3), and the glycosidation of 14 led to the
preferential formation of b-mannoside 25b, which corre-
sponds to a constituent of N-linked glycoproteins (entry 3).
As previously mentioned by Crich, the coupling with
1,2:3,4-di-O-isopropylidenegalactose (15) exhibited a much
lower selectivity (a:bZ24:76, entry 4). Considering that the
reaction reached completion within 30 min, this stereo-
chemical outcome might be attributed to a sterically
mismatched interaction in the transition state leading to
the b-linked disaccharide 26b.41 The best b-selectivity
(a:bZ5:95) was achieved by the mannosylation of the O-2-
unprotected glucoside 17 (entry 6). It is also noteworthy that
chemoselective glycosidation was realized when O-6-
unprotected glucosyl phosphorodiamidate 19 was used as
a disarmed acceptor because 19 was unaffected by such
conditions when kept at temperatures below K5 8C
(entry 8).34b,42 Crich and co-workers demonstrated that
some tert-alcohols such as 1-adamantanol (20) could be
mannosylated upon activation of phenyl thiomannoside
with a variety of thiophilic reagents.17d,f,g In our system,
glycoside 31 with an a:b ratio of 16:84 was obtained from
20 in 89% yield (entry 9). The serine derivative 21 and
cholesterol (22) could be safely glycosylated under these
conditions with good b-selectivities (entries 10 and 11).
Figure 2. Acceptor alcohols and products in Table 6.
As anticipated from the preceding experiments, the
b-selectivities obtained in the reaction of 4b did not surpass
the selectivities observed with the corresponding sulfoxide
11 (entries 2, 4, and 7);17 however, the TMSOTf-promoted
glycosidation in CH2Cl2 at K45 8C offered a facile and
high-yielding route to b-mannosides in all cases, wherein
the a:b ratios ranged from 24:76 to 5:95. The mannosylation
of less reactive O-4-unprotected glycosides 6 and 1440
proceeded to completion within 1 h under these conditions
2.4. Mechanistic considerations
Crich and Sun proposed, based on NMR experiments, that
mannosyl triflate was cleanly generated from 4,6-O-
benzylidene-D-mannosyl sulfoxide upon treatment with

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T. Tsuda et al. / Tetrahedron 61 (2005) 10719–10733
Tf2O in the presence of 2,6-di-tert-butyl-4-methylpyridine
(DTBMP) in CD2Cl2 at K78 8C within 5 min.18 As alluded
to above, Crich and Chandrasekera, based on the KIEs,
proposed that the displacement of the a-mannosyl triflate by
an acceptor alcohol proceeded with the development of a
substantial oxocarbenium ion character, although the
complete set of equilibria between mannosyl triflates, the
transient contact ion pair (CIP) and the solvent-separated
ion pair (SSIP) lie very heavily toward the a-mannosyl
triflate.19 The possibility that the 2,3-di-O-benzyl-4,6-O-
benzylidene-D-mannosyl triflate is also an intermediate in
the phosphite method is suggested by the following: (1) the
effectiveness of the triflate as a counterion of the promoter
and (2) almost the same b-selectivity as that obtained with
the sulfoxide method when premixing the phosphite with
TMSOTf prior to addition of the acceptor alcohol. Based on
these results, the similar reaction mechanism would be
applicable to the phosphite method. While CIP, in which the
triflate anion is necessarily closely associated with the face
of the oxocarbenium ion, would be a possible intermediate
in this reaction, a mechanism involving an ‘exploded’
transition state19 is outlined in Scheme 1.
obtained when the promoter is added to a mixture of donor
4b and the acceptor alcohol. However, a-mannosyl triflate
35a reacts with phosphite 40 in the absence of the acceptor
alcohol, providing b-mannosyl phosphonate 12 as a by-
product.
3. Conclusion
The effectiveness of the diethyl phosphite group as a leaving
group of mannosyl donors has been demonstrated.
b-Selectivities in the TMSOTf-promoted glycosidation of
2,3,4,6-tetra-O-benzyl-D-mannosyl donors were found to be
highly dependent on the reactivity of the acceptor alcohols
used. On the other hand, the TMSOTf-promoted glycosida-
tion of 2,3-di-O-benzyl-4,6-O-benzylidene-D-mannosyl
diethyl phosphite with a broad variety of acceptor alcohols
in CH2Cl2 at K45 8C offered a facile and high-yielding
route to b-mannosides, wherein the a:b ratios ranged from
24:76 to 5:95. Although the b-selectivities did not surpass
those reported by Crich with the sulfoxide or thioglycoside
method, the present method has the following advantages in
terms of practicality: (1) high product yield can be achieved
with approximately equimolar proportions of glycosyl
donors and acceptors; (2) the reaction is very clean,
allowing very easy isolation of the product, in contrast to
the sulfoxide method in which several by-products derived
from the sulfinate moiety are produced; and (3) TMSOTf is
a stable and inexpensive reagent compared to those used for
the activation of thioglycosides. The effectiveness of the
triflate as a counterion of the promoter and almost the same
b-selectivity as that obtained with the sulfoxide method
when the phosphite is premixed with TMSOTf prior to the
addition of the acceptor alcohol suggest that the correspond-
ing mannosyl triflate is an intermediate in the present
mannosidation method.
Diethyl phosphite 4b is activated by silylation of the oxygen
atom34a and the phosphite group is cleaved, to produce an
equilibrium mixture of a- and b-mannosyl triflates 35a and
35b. The displacement by acceptor alcohols at the anomeric
carbon of 35a and 35b affords glycosides 39b and 39a via
triplets 36 and 37, respectively, along with generation of
TfOH. Since the equilibrium between the mannosyl triflates
would heavily lie to 35a on kinetic and thermodynamic
grounds, high b-selectivities are observed in the present
method. The generation of SSIP (38) from 35a and 35b
results in the formation of a-mannoside 39a. Trimethylsilyl
phosphite 40 is converted to diethyl phosphite (41) during
the course of the reaction. Since phosphite 40 is less
nucleophilic than the acceptor alcohols, high yields can be
Scheme 1. Potential pathways for the TMSOTf-promoted glycosidation of 4,6-O-benzylidene-protected mannosyl diethyl phosphite 4b.

T. Tsuda et al. / Tetrahedron 61 (2005) 10719–10733
10725
4. Experimental
extracted with AcOEt (25 mL). The organic extract was
washed with brine (2!15 mL), and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished the
pale yellow oil (1.74 g), which was purified by column
chromatography (silica gel 40 g, 8:1 hexane/AcOEt with
2% Et3N) to give diphenyl phosphate 2a (1.41 g, 86%) as a
colorless oil: [a]2D3 C29.6 (c 1.01, CHCl3); IR (film) 3063,
3030, 2905, 2868, 1952, 1877, 1811, 1726, 1591, 1491,
1454, 1364, 1292, 1188, 1103, 1026, 949, 876, 739,
4.1. General
Melting points were determined on a Bu¨chi 535 digital
melting point apparatus and were uncorrected. Optical
rotations were recorded on a JASCO P-1030 digital
polarimeter. Infrared (IR) spectra were recorded on a
JASCO FT/IR-5300 spectrophotometer and absorbance
bands are reported in wavenumber (cmK1). Proton nuclear
magnetic resonance (1H NMR) spectra were recorded on a
Bruker ARX500 (500 MHz) spectrometer with tetramethyl-
silane (dH 0.00) as an internal standard. Coupling constants
(J) are reported in hertz (Hz). Abbreviations of multiplicity
are as follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br, broad. Data are presented as follows: chemical
shift, multiplicity, coupling constants, integration and
assignment. Carbon nuclear magnetic resonance (13C
NMR) spectra were recorded on JEOL AL400 (100 MHz)
or Bruker ARX500 (126 MHz) spectrometers with CDCl3
(dC 77.0) as an internal standard. Phosphorus nuclear
magnetic resonance (31P NMR) spectra were recorded on
JEOL EX270 (109 MHz) or Bruker ARX500 (202 MHz)
spectrometers with H3PO4 (dP 0.00) as an external standard.
Fast atom bombardment (FAB) mass spectra were obtained
on a JEOL JMS HX110 spectrometer in the Center for
Instrumental Analysis, Hokkaido University.
1
696 cmK1; H NMR (500 MHz, CDCl3) d 3.53 (dd, JZ
1.5, 11.2 Hz, 1H, H-6a), 3.74 (dd, JZ4.1, 11.2 Hz, 1H,
H-6b), 3.76 (dd, JZ1.9, 3.1 Hz, 1H, H-2), 3.82 (dd, JZ3.1,
9.6 Hz, 1H, H-3), 3.85 (ddd, JZ1.5, 4.1, 9.8 Hz, 1H, H-5),
4.10 (dd, JZ9.6, 9.8 Hz, 1H, H-4), 4.43 (d, JZ11.8 Hz, 1H,
OCHPh), 4.46 (d, JZ12.1 Hz, 1H, OCHPh), 4.48 (d, JZ
11.8 Hz, 1H, OCHPh), 4.52 (d, JZ10.7 Hz, 1H, OCHPh),
4.63 (d, JZ12.1 Hz, 1H, OCHPh), 4.69 (s, 2H, OCH2Ph),
4.85 (d, JZ10.7 Hz, 1H, OCHPh), 5.99 (dd, JZ1.9, 4.3
(JH–P) Hz, 1H, H-1), 7.13–7.19 (m, 8H, Ar-H), 7.24–7.35
(m, 22H, Ar-H); 13C NMR (126 MHz, CDCl3) d 68.4, 72.2,
72.7, 73.3, 74.1 (d, JC–PZ9.0 Hz), 74.2, 75.1, 78.8, 97.6 (d,
JC–PZ7.0 Hz), 120.0 (d, JC–PZ5.0 Hz), 125.4 (d, JC–P
Z
6.0 Hz), 127.4, 127.5, 127.60, 127.61, 127.72, 127.75,
127.88, 127.90, 128.21, 128.25, 128.32, 128.34, 129.71,
129.74, 137.5, 138.1, 138.15, 138.20, 150.2, 150.29, 150.34;
31P NMR (202 MHz, CDCl3) d K13.4; FAB-HRMS m/z
calcd for C46H46O9P (MCH)C773.2879, found 773.2870.
Anal. Calcd for C46H45O9P: C, 71.49; H, 5.87, found: C,
71.27; H, 5.88.
Column chromatography was carried out on Kanto silica gel
60 N (40–50 mm or 63–210 mm) or Wakogel C-200 (75–
150 mm). Analytical thin-layer chromatography (TLC) was
carried out on Merck Kieselgel 60 F254 plates. Visualization
was accomplished with ultraviolet light and anisaldehyde or
phosphomolybdic acid stain, followed by heating. HPLC
analyses were performed on a JASCO PU-980 and UV-970
(detector, lZ254 nm). Retention times (tR) and peak ratios
were determined with a Shimadzu Chromatopac C-R6A.
Hexane was HPLC grade, and filtered and degassed prior
to use.
4.2.2. 2,3-Di-O-benzyl-4,6-O-benzylidene-a-D-manno-
pyranosyl diphenyl phosphate (2b). Diphenylphosphoryl
chloride (0.37 mL, 1.8 mmol) was added to a stirred
solution of lactol 1b (673 mg, 1.5 mmol) and DMAP
(367 mg, 3.0 mmol) in CH2Cl2 (7 mL) at 0 8C. After
30 min, the reaction was quenched with crushed ice,
followed by stirring at room temperature for 15 min. The
mixture was poured into a two-layer mixture of Et2O (7 mL)
and saturated aqueous NaHCO3 (10 mL), and the whole was
extracted with AcOEt (20 mL). The organic extract was
washed with brine (2!10 mL), and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished the
pale yellow oil (1.50 g), which was purified by column
chromatography (silica gel 40 g, 4:1 hexane/AcOEt with
2% Et3N) to give diphenyl phosphate 2b (838 mg, 82%) as a
colorless oil: [a]2D5 C30.1 (c 2.00, CHCl3); IR (film) 3065,
2868, 1589, 1489, 1454, 1373, 1288, 1188 cmK1; 1H NMR
(500 MHz, CDCl3) d 3.75 (dd, JZ10.0, 10.2 Hz, 1H,
H-6ax), 3.80 (dd, JZ1.5, 3.2 Hz, 1H, H-2), 3.85 (ddd, JZ
4.7, 9.4, 10.2 Hz, 1H, H-5), 3.90 (dd, JZ3.2, 10.1 Hz, 1H,
H-3), 4.00 (dd, JZ4.7, 10.0 Hz, 1H, H-6eq), 4.25 (dd, JZ
9.4, 10.1 Hz, 1H, H-4), 4.55 (d, JZ12.2 Hz, 1H, OCHPh),
4.67 (d, JZ12.0 Hz, 1H, OCHPh), 4.73 (d, JZ12.2 Hz, 1H,
OCHPh), 4.74 (d, JZ12.0 Hz, 1H, OCHPh), 5.57 (s, 1H,
CHPh), 5.88 (dd, JZ1.5, 6.4 (JH–P) Hz, 1H, H-1), 7.11–7.20
(m, 6H, Ar-H), 7.25–7.37 (m, 17H, Ar-H), 7.46–7.48 (m,
2H, Ar-H); 13C NMR (126 MHz, CDCl3) d 66.0, 68.0, 73.0,
Reagents and solvents were purified by standard means or
used as received unless otherwise noted. Dehydrated
stabilizer free THF was purchased from Kanto Chemical
Co. Inc. Dichloromethane and propionitrile were distilled
from P2O5, and redistilled from calcium hydride prior to
˚
use. 4 A molecular sieves was finely ground in mortar and
heated in vacuo at 220 8C for 12 h.
All reactions were conducted under an argon atmosphere.
Lactols 1a26 and 1b27 were prepared according to literature
procedures.
4.2. Preparation of D-mannosyl donors
4.2.1. 2,3,4,6-Tetra-O-benzyl-a-D-mannopyranosyl
diphenyl phosphate (2a). Diphenylphosphoryl chloride
(0.57 mL, 2.74 mmol) was added to a stirred solution of
lactol 1a (1.14 g, 2.11 mmol) and DMAP (645 mg,
5.28 mmol) in CH2Cl2 (15 mL) at 0 8C. After 30 min, the
reaction was quenched with crushed ice, followed by
stirring at room temperature for 15 min. The mixture was
poured into a two-layer mixture of Et2O (10 mL) and
saturated aqueous NaHCO3 (15 mL), and the whole was
73.7, 75.0, 75.7 (d, JC–PZ9.8 Hz), 78.0, 98.0 (d, JC–P
6.3 Hz), 101.4, 119.85 (d, JC–PZ5.0 Hz), 119.91 (d, JC–P
Z
Z
5.0 Hz), 125.50, 125.53, 125.9, 127.4, 127.5, 127.9, 128.0,
128.1, 128.2, 128.4, 128.8, 129.8, 137.2, 138.1, 150.1 (d,
JC–PZ7.5 Hz), 150.2 (d, JC–PZ7.5 Hz); 31P NMR
(202 MHz, CDCl3) d K13.4; FAB-HRMS m/z calcd for

10726
T. Tsuda et al. / Tetrahedron 61 (2005) 10719–10733
C39H38O9P (MCH)C681.2254, found 681.2252. Anal.
Calcd for C39H37O9P: C, 68.82; H, 5.48, found: C, 68.71;
H, 5.71.
(731 mg, 97%) as a colorless oil: [a]2D2 C31.9 (c 1.00,
CHCl3); IR (film) 3063, 3032, 1454, 1308, 1218, 993 cmK1
;
1H NMR (500 MHz, CDCl3) d 2.45 (d, JH–PZ10.1 Hz, 6H,
N(CH3)2), 2.62 (d, JH–PZ10.0 Hz, 6H, N(CH3)2), 3.82 (dd,
JZ1.5, 3.2 Hz, 1H, H-2), 3.85–3.91 (m, 2H, H-6ax, H-6eq),
3.93 (dd, JZ3.2, 9.9 Hz, 1H, H-3), 4.23 (m, 1H, H-5), 4.29
(dd, JZ9.5, 9.9 Hz, 1H, H-4), 4.66 (d, JZ12.5 Hz, 1H,
OCHPh), 4.77 (d, JZ12.0 Hz, 1H, OCHPh), 4.81 (d, JZ
12.0 Hz, 1H, OCHPh), 4.81 (d, JZ12.5 Hz, 1H, OCHPh),
5.65 (dd, JZ1.5, 5.7 (JH–P) Hz, 1H, H-1), 5.66 (s, 1H,
CHPh), 7.24–7.43 (m, 13H, Ar-H), 7.52 (m, 2H, Ar-H); 13C
NMR (126 MHz, CDCl3) d 36.1 (d, JC–PZ4.2 Hz), 36.3 (d,
4.2.3. 2,3,4,6-Tetra-O-benzyl-a-D-mannopyranosyl N,N,
N0,N0-tetramethylphosphorodiamidate (3a). Butyllithium
in hexane (1.58 M, 1.0 mL, 1.58 mmol) was added to a
stirred solution of lactol 1a (800 mg, 1.48 mmol) in THF
(15 mL) at K78 8C. After 15 min, a solution of bis(di-
methylamino)phosphorochloridate (0.22 mL, 1.48 mmol) in
HMPA (2.0 mL) was added, and the mixture was allowed to
warm to K20 8C over 30 min. After stirring at this
temperature for 2 h, the reaction was quenched with crushed
ice, followed by stirring at 0 8C for 30 min. The mixture was
poured into a two-layer mixture of Et2O (10 mL) and
saturated aqueous NaHCO3 (15 mL), and the whole was
extracted with AcOEt (50 mL). The organic extract was
washed with brine (2!15 mL), and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished the
yellow residue (1.55 g), which was purified by flash column
chromatography (silica gel 40 g, 1:3/1:4 hexane/AcOEt)
to give diamidate 3a (850 mg, 85%) as a colorless oil:
[a]2D4 C24.2 (c 1.00, CHCl3); IR (film) 3030, 2895,
JC–PZ4.2 Hz), 65.7, 68.5, 72.8, 73.3, 74.6, 76.7 (d, JC–P
Z
6.8 Hz), 77.3, 78.5, 94.3 (d, JC–PZ3.9 Hz), 101.3, 125.9,
127.5, 127.6, 127.7, 128.06, 128.13, 128.2, 128.3, 128.7,
137.4, 137.6, 138.2; 31P NMR (202 MHz, CDCl3) d 18.8;
FAB-HRMS m/z calcd for C31H40N2O7P (MCH)C583.2573,
found 583.2568. Anal. Calcd for C31H39N2O7P: C, 63.91; H,
6.75; N, 4.81, found: C, 63.75; H, 6.81; N, 4.82.
4.2.5. 2,3,4,6-Tetra-O-benzyl-D-mannopyranosyl diethyl
phosphite (4a). Diethyl chlorophosphite (0.26 mL,
1.81 mmol) was added to a stirred solution of lactol 1a
(0.85 g, 1.57 mmol) and Et3N (0.44 mL, 3.14 mmol) in
CH2Cl2 (15 mL) at 0 8C. After 30 min, the reaction was
quenched with crushed ice, followed by stirring at room
temperature for 15 min. The mixture was poured into a two-
layer mixture of Et2O (10 mL) and saturated aqueous
NaHCO3 (15 mL), and the whole was extracted with AcOEt
(30 mL). The organic extract was washed with brine (2!
15 mL), and dried over anhydrous Na2SO4. Filtration and
evaporation in vacuo furnished the pale yellow oil (1.18 g),
which was purified by column chromatography (silica gel
25 g, 8:1 hexane/AcOEt with 2% Et3N) to give diethyl
phosphite 4a (755 mg, 73%, a:bZ87:13) as a colorless oil.
The anomeric a:b ratio of the product was determined by
31P NMR: [a]D24 C36.5 (c 1.00, CHCl3); IR (film) 3063,
1
1954, 1454, 1306, 1225, 990 cmK1; H NMR (500 MHz,
CDCl3) d 2.46 (d, JH–PZ10.1 Hz, 6H, N(CH3)2), 2.60 (d,
JH–PZ10.1 Hz, 6H, N(CH3)2), 3.72 (dd, JZ1.5, 10.9 Hz,
1H, H-6a), 3.80 (dd, JZ4.7, 10.9 Hz, 1H, H-6b), 3.81 (dd,
JZ1.8, 3.1 Hz, 1H, H-2), 3.88 (dd, JZ3.1, 9.5 Hz, 1H,
H-3), 3.86 (ddd, JZ1.5, 4.7, 9.7 Hz, 1H, H-5), 4.05 (dd, JZ
9.5, 9.7 Hz, 1H, H-4), 4.52 (d, JZ12.0 Hz, 1H, OCHPh),
4.55 (d, JZ10.6 Hz, 1H, OCHPh), 4.60 (s, 2H, OCH2Ph),
4.66 (d, JZ12.0 Hz, 1H, OCHPh), 4.74 (d, JZ12.1 Hz, 1H,
OCHPh), 4.78 (d, JZ12.1 Hz, 1H, OCHPh), 4.92 (d, JZ
10.6 Hz, 1H, OCHPh), 5.75 (dd, JZ1.8, 8.2 (JH–P) Hz, 1H,
H-1), 7.21 (m, 2H, Ar-H), 7.24–7.34 (m, 16H, Ar-H), 7.42
(m, 2H, Ar-H); 13C NMR (126 MHz, CDCl3) d 36.2 (d,
JC–PZ3.9 Hz), 36.4 (d, JC–PZ4.3 Hz), 69.0, 71.8, 72.4,
73.3, 73.6, 74.4, 75.0 (d, JC–PZ6.5 Hz), 75.3, 78.5, 93.3 (d,
JC–PZ3.8 Hz), 127.3, 127.51, 127.54, 127.6, 127.7, 127.9,
128.0, 128.08, 128.14, 128.19, 128.25, 137.9, 138.1, 138.21,
138.22; 31P NMR (202 MHz, CDCl3) d 19.1; FAB-HRMS
m/z calcd for C38H48N2O7P (MCH)C675.3199, found
675.3189. Anal. Calcd for C38H47N2O7P: C, 67.54; H,
7.16; N, 4.15, found: C, 67.71; H, 7.15; N, 4.29.
1
3030, 1454, 1310, 1207, 1101, 1028, 988 cmK1; H NMR
(500 MHz, CDCl3) (data for a-anomer) d 1.16–1.19 (m, 6H,
2!OCH2CH3), 3.69–3.82 (m, 7H, H-2, H-6a, H-6b, 2!
OCH2CH3), 3.94–3.96 (m, 2H, H-3, H-5), 4.05 (t, JZ
9.6 Hz, 1H, H-4), 4.51 (d, JZ12.0 Hz, 1H, OCHPh), 4.55
(d, JZ10.8 Hz, 1H, OCHPh), 4.61 (d, JZ11.8 Hz, 1H,
OCHPh), 4.65 (d, JZ11.8 Hz, 1H, OCHPh), 4.66 (d, JZ
12.0 Hz, 1H, OCHPh), 4.73 (d, JZ12.5 Hz, 1H, OCHPh),
4.76 (d, JZ12.5 Hz, 1H, OCHPh), 4.90 (d, JZ10.8 Hz, 1H,
OCHPh), 5.56 (dd, JZ1.5, 8.2 (JH–P) Hz, 1H, H-1), 7.17 (m,
2H, Ar-H), 7.23–7.39 (m, 18H, Ar-H); 13C NMR (126 MHz,
CDCl3) d 16.67, 16.71, 58.2 (d, JC–PZ9.8 Hz), 58.4 (d,
JC–PZ11.9 Hz), 69.0, 72.1, 72.4, 72.8, 73.2, 74.7, 75.4
(d, JC–PZ3.2 Hz), 79.2, 91.9 (d, JC–PZ13.3 Hz, C-1a), 94.6
(d, JC–PZ12.9 Hz, C-1b), 127.3, 127.4, 127.5, 127.57,
127.63, 127.7, 127.8, 128.1, 128.15, 128.18, 138.1, 138.27,
138.30, 138.4; 31P NMR (202 MHz, CDCl3) d 139.7 (b),
139.8 (a); FAB-HRMS m/z calcd for C38H46O8P (MC
H)C661.2931, found 661.2921. Anal. Calcd for C38H45O8P:
C, 69.08; H, 6.86, found: C, 68.92; H, 6.83.
4.2.4. 2,3-Di-O-benzyl-4,6-O-benzylidene-a-D-manno-
pyranosyl N,N,N0,N0-tetramethylphosphorodiamidate
(3b). Butyllithium in hexane (1.59 M, 0.89 mL,
1.42 mmol) was added to a stirred solution of lactol 1b
(606 mg, 1.35 mmol) in THF (10 mL) at K78 8C. After
15 min, a solution of bis(dimethylamino)phosphorochlori-
date (0.20 mL, 1.35 mmol) in HMPA (1.5 mL) was added,
and the mixture was allowed to warm to K20 8C over
30 min. After stirring at this temperature for 2 h, the
reaction was quenched with crushed ice, followed by
stirring at 0 8C for 30 min. The mixture was poured into a
two-layer mixture of Et2O (5 mL) and saturated aqueous
NaHCO3 (10 mL), and the whole was extracted with AcOEt
(25 mL). The organic extract was washed with brine (2!
10 mL), and dried over anhydrous Na2SO4. Filtration and
evaporation in vacuo furnished the yellow residue (1.12 g),
which was purified by column chromatography (silica gel
40 g, 1:3/1:4 hexane/AcOEt) to give diamidate 3b
4.2.6. 2,3-Di-O-benzyl-4,6-O-benzylidene-D-mannopyra-
nosyl diethyl phosphite (4b). Diethyl chlorophosphite
(0.21 mL, 1.47 mmol) was added to a stirred solution of
lactol 1b (576 mg, 1.28 mmol) and Et3N (0.36 mL,
2.56 mmol) in CH2Cl2 (6 mL) at 0 8C. After 20 min, the

T. Tsuda et al. / Tetrahedron 61 (2005) 10719–10733
10727
reaction was quenched with crushed ice, followed by
stirring at room temperature for 15 min. The mixture was
poured into a two-layer mixture of Et2O (7 mL) and
saturated aqueous NaHCO3 (10 mL), and the whole was
extracted with AcOEt (25 mL). The organic extract was
washed with brine (2!10 mL), and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished the
pale yellow oil (741 mg), which was purified by column
chromatography (silica gel 15 g, 8:1 hexane/AcOEt with
2% Et3N) to give diethyl phosphite 4b (644 mg, 88%, a:bZ
93:7) as a colorless oil. The anomeric a:b ratio of the
product was determined by 31P NMR: [a]D23 C45.7 (c 1.01,
CHCl3); IR (film) 3065, 3032, 1454, 1242, 1215, 1026,
The glycosidation was performed according to the typical
procedure (1 mL, CH2Cl2, K78 8C, 1.5 h) employing
diphenyl phosphate 2a (73.6 mg, 0.10 mmol), alcohol 6
(51.1 mg, 0.11 mmol) and TMSOTf (1.0 M in CH2Cl2,
0.11 mL, 0.11 mmol). An anomeric mixture of the known
disaccharide 813i (74.2 mg, 75%, a:bZ77:23) was obtained
as a colorless oil from the crude product (107 mg) after
column chromatography (silica gel 12 g, 20:1/17:1
toluene/AcOEt). The anomeric ratio of the product was
determined by HPLC analysis [eluent, 4:1 hexane/AcOEt;
flow rate, 1.0 mL/min; tR (a-mannoside)Z14.3 min, tR
(b-mannoside)Z26.2 min].
916 cmK1
;
1H NMR (500 MHz, CDCl3) (data for
4.4. Glycosidations of 2,3-di-O-benzyl-4,6-O-benzyl-
idene-D-mannosyl donors 2b–4b
a-anomer) d 1.18–1.27 (m, 6H, 2!OCH2CH3), 3.72–3.89
(m, 6H, H-2, H-6ax, 2!OCH2CH3), 3.97 (ddd, 1H, JZ4.6,
9.6, 10.1 Hz, H-5), 4.01 (dd, JZ3.1, 10.0 Hz, 1H, H-3), 4.13
(dd, JZ4.6, 10.1 Hz, 1H, H-6eq), 4.27 (dd, JZ9.6, 10.0 Hz,
1H, H-4), 4.66 (d, JZ12.2 Hz, 1H, OCHPh), 4.75 (d, JZ
12.2 Hz, 1H, OCHPh), 4.83 (d, JZ12.2 Hz, 1H, OCHPh),
4.85 (d, JZ12.2 Hz, 1H, OCHPh), 5.45 (dd, JZ1.4, 8.2
(JH–P) Hz, 1H, H-1), 5.65 (s, 1H, CHPh), 7.26–7.40 (m,
13H, Ar-H), 7.51 (m, 2H, Ar-H). The b-anomer had an
additional signal at 5.62 (s, 1H, PhCH); 13C NMR
4.4.1. Methyl 2,3,4-tri-O-benzyl-6-O-(2,3-di-O-benzyl-4,
6-O-benzylidene-D-mannopyranosyl)-a-D-glucopyrano-
side (9). The glycosidation was performed according to the
typical procedure (1 mL CH2Cl2, K45 8C, 30 min) employ-
ing diethyl phosphite 4b (56.9 mg, 0.10 mmol), alcohol 5
(51.1 mg, 0.11 mmol) and TMSOTf (1.0 M in CH2Cl2,
0.11 mL, 0.11 mmol). An anomeric mixture of disaccharide
925b (73.9 mg, 83%, a:bZ10:90) was obtained as a white
solid from the crude product (102 mg) after column
chromatography (silica gel 5 g, 4:1 hexane/AcOEt). The
anomeric ratio of 9 was determined by HPLC analysis
[eluent, 4:1 hexane/AcOEt; flow rate, 1.0 mL/min; tR
(a-mannoside)Z21.1 min, tR (b-mannoside)Z24.4 min].
(126 MHz, CDCl3) d 16.70, 16.74, 16.8, 58.2 (d, JC–P
Z
10.0 Hz), 58.5 (d, JC–PZ12.1 Hz), 65.0, 68.6, 73.1, 73.4,
75.5, 77.1 (d, JC–PZ3.3 Hz), 79.0, 93.2 (d, JC–PZ13.4 Hz,
C-1a), 94.9 (d, JC–PZ13.1 Hz, C-1b), 101.4, 126.0, 127.4,
127.5, 127.7, 128.0, 128.1, 128.2, 128.3, 128.7, 137.6,
137.9, 138.5; 31P NMR (202 MHz, CDCl3) d 139.0 (b),
139.5 (a); FAB-HRMS m/z calcd for C31H38O8P (MC
H)C569.2304, found 569.2295.
Data for 2,3-di-O-benzyl-4,6-O-benzylidene-a-D-manno-
pyranosyl fluoride (10): [a]2D3 C13.0 (c 1.06, CHCl3); IR
(CHCl3) 3624, 3026, 3016, 2401, 1226, 1205, 792, 719 cmK1
;
1H NMR (500 MHz, CDCl3) d 3.85 (t, JZ10.0 Hz, 1H,
H-6ax), 3.91–3.98 (m, 3H, H-2, H-3, H-5), 4.26–4.31 (m,
2H, H-4, H-6eq), 4.69 (d, JZ12.0 Hz, 1H, OCHPh), 4.71 (d,
JZ12.0 Hz, 1H, OCHPh), 4.87 (d, JZ12.0 Hz, 2H, 2!
OCHPh), 5.49 (dd, JZ1.4, 49.8 (JH–F) Hz, 1H, H-1), 5.64 (s,
1H, CHPh), 7.29–7.40 (13H, m, Ar-H), 7.50 (2H, m, Ar-H);
13C NMR (126 MHz, CDCl3) d 66.0 (d, JC–FZ1.8 Hz),
68.1, 73.2, 74.0, 74.9 (d, JC–FZ36.0 Hz), 75.5, 78.1, 101.4,
106.8 (d, JC–FZ222.6 Hz), 125.9, 127.4, 127.5, 127.8,
127.9, 128.0, 128.2, 128.3, 128.7, 137.3, 137.5, 138.2; FAB-
HRMS m/z calcd for C27H28O5F (MCH)C451.1921, found
451.1950.
4.3. Glycosidations of 2,3,4,6-tetra-O-benzyl-D-mannosyl
donors 2a–4a
4.3.1. Typical procedure for glycosidation of 2,3,4,6-
tetra-O-benzyl-D-mannosyl donors: methyl 2,3,4-tri-O-
benzyl-6-O-(2,3,4,6-tetra-O-benzyl-D-mannopyranosyl)-
a-D-glucopyranoside (7). TMSOTf in CH2Cl2 (1.0 M,
0.11 mL, 0.11 mmol) was added to a stirred solution of
diphenyl phosphate 2a (73.6 mg, 0.10 mmol) and alcohol 5
(51.1 mg, 0.11 mmol) in CH2Cl2 (1 mL) at K78 8C. After
stirring at this temperature for 1 h, the reaction was
quenched with Et3N (0.15 mL). The reaction mixture was
poured into a two-layer mixture of AcOEt (3 mL) and
NaHCO3 (6 mL), and the whole was extracted with AcOEt
(15 mL). The organic extract was successively washed with
saturated aqueous NaHCO3 (6 mL) and brine (2!6 mL),
and dried over anhydrous Na2SO4. Filtration and evapor-
ation in vacuo furnished the crude product (100.2 mg), from
which an anomeric mixture of the known disaccharide 713i
(84.4 mg, 86%, a:bZ21:79) was obtained as a colorless oil
after column chromatography (silica gel 7 g, 5:1 hexane/
AcOEt). The anomeric ratio of the disaccharide was
determined by HPLC analysis [column, Zorbaxw Sil, 4.6!
250 mm; eluent, 7:1 hexane/THF; flow rate, 1.5 mL/min;
detection, 254 nm; tR (a-mannoside)Z29.4 min, tR (b-man-
noside)Z31.7 min]. The a- and b-mannosides were separated
by flash column chromatography with 5:1 hexane/AcOEt.
Data for diethyl 2,3-di-O-benzyl-4,6-O-benzylidene-b-D-
mannopyranosylphosphonate (12): [a]2D5 K73.0 (c 1.33,
CHCl3); IR (CHCl3) 3013, 1454, 1369, 1249, 1227, 1097,
1
1028 cmK1; H NMR (500 MHz, CDCl3) d 1.16 (t, JZ
7.1 Hz, 3H, OCH2CH3), 1.31 (t, JZ7.0 Hz, 3H, OCH2CH3),
3.41 (ddd, JZ5.0, 9.8, 10.5 Hz, 1H, H-5), 3.72 (dd, JZ3.0,
9.8 Hz, 1H, H-3), 3.85 (t, JZ10.5 Hz, 1H, H-6ax), 3.89 (dd,
JZ1.1, 15.3 (JH–P) Hz, 1H, H-1), 3.98–4.16 (m, 4H,
OCH2CH3), 4.27–4.34 (m, 3H, H-2, H-4, H-6eq), 4.75 (d,
JZ12.5 Hz, 1H, OCHPh), 4.81 (d, JZ10.4 Hz, 1H,
OCHPh), 4.85 (d, JZ12.5 Hz, 1H, OCHPh), 5.11 (d, JZ
10.4 Hz, 1H, OCHPh), 5.65 (s, 1H, CHPh), 7.25–7.38 (m,
11H, Ar-H), 7.47–7.51 (m, 4H, Ar-H); 13C NMR (126 MHz,
CDCl3) d 16.2 (d, JC–PZ5.9 Hz), 16.4 (d, JC–PZ5.8 Hz),
62.3 (d, JC–PZ6.5 Hz), 63.3 (d, JC–PZ6.4 Hz), 68.3, 72.8,
4.3.2. Methyl 2,3,6-tri-O-benzyl-4-O-(2,3,4,6-tetra-O-
benzyl-D-mannopyranosyl)-a-D-glucopyranoside (8).
73.8, 73.9, 75.4, 75.5 (d, JC–PZ2.2 Hz), 77.1 (d, JC–P
173 Hz), 78.85, 79.5 (d, JC–PZ15.8 Hz), 101.5, 126.05,
Z

10728
T. Tsuda et al. / Tetrahedron 61 (2005) 10719–10733
127.48, 127.51, 127.6, 128.0, 128.2, 128.4, 128.5, 128.9,
137.5, 138.3, 138.4; 31P NMR (109 MHz, CDCl3) d 17.6;
FAB-HRMS m/z calcd for C31H38O8P (MCH)C569.2304,
found 569.2257.
4.79 (d, JZ11.9 Hz, 1H, OCHPh), 4.87 (d, JZ11.9 Hz, 1H,
OCHPh), 5.09 (d, JZ10.4 Hz, 1H, OCHPh), 5.51 (s, 1H,
CHPh), 7.20–7.41 (m, 23H, Ar-H), 7.47 (m, 2H, Ar-H); 13C
NMR (126 MHz, CDCl3) d 57.1, 65.7, 67.3, 68.3, 68.5,
72.6, 73.6, 74.8, 75.11, 75.13, 77.1, 78.4, 78.7, 81.6, 101.3
(C-10), 101.4, 102.8 (C-1), 126.1, 127.4, 127.49, 127.54,
127.8, 127.96, 128.01, 128.10, 128.14, 128.30, 128.31,
128.5, 128.8, 137.6, 138.48, 138.53, 138.6; FAB-HRMS m/z
calcd for C48H52N3O10 (MCH)C830.3653, found
830.3660. Data for a-anomer (25a): [a]2D4 K16.0 (c 0.30,
CHCl3); IR (film) 3032, 2922, 2858, 2110, 1496, 1454,
1363, 1275, 1116, 1064 cmK1; 1H NMR (500 MHz, CDCl3)
d 3.32 (dd, JZ9.4, 9.8 Hz, 1H, H-3), 3.38–3.42 (m, 2H, H-2,
H-5), 3.57 (s, 3H, OCH3), 3.72 (dd, JZ4.5, 11.0 Hz, 1H,
H-6a), 3.76–3.81 (m, 4H, H-4, H-6b, H-20, H-60ax), 3.83 (dt,
JZ3.9, 10.3 Hz, 1H, H-50), 3.90 (dd, JZ3.1, 10.3 Hz, 1H,
H-30), 4.12 (m, 1H, H-60eq), 4.19 (d, JZ7.9 Hz, 1H, H-1),
4.24 (t, JZ10.3 Hz, 1H, H-40), 4.25 (d, JZ11.8 Hz, 1H,
OCHPh), 4.47 (d, JZ11.8 Hz, 1H, OCHPh), 4.54 (d, JZ
11.4 Hz, 1H, OCHPh), 4.56 (d, JZ12.1 Hz, 1H, OCHPh),
4.59 (d, JZ12.2 Hz, 1H, OCHPh), 4.63 (d, JZ12.1 Hz, 1H,
OCHPh), 4.82 (d, JZ12.2 Hz, 1H, OCHPh), 4.94 (d, JZ
11.4 Hz, 1H, OCHPh), 5.26 (d, JZ1.2 Hz, 1H, H-10), 5.61
(s, 1H, CHPh), 7.15 (m, 2H, Ar-H), 7.21–7.37 (m, 21H, Ar-
H), 7.50 (m, 2H, Ar-H); 13C NMR (126 MHz, CDCl3) d
57.1, 65.3, 66.2, 68.6, 69.0, 73.1, 73.4, 73.6, 74.6, 74.7,
76.2, 76.3, 77.7, 79.0, 83.0, 101.2 (C-10), 101.4, 103.0 (C-1),
126.1, 127.0, 127.46, 127.48, 127.6, 127.7, 127.8, 128.2,
128.3, 128.4, 128.6, 128.8, 137.7, 138.1, 138.2, 138.7; FAB-
HRMS m/z calcd for C48H52N3O10 (MCH)C830.3653,
found 830.3669.
4.4.2. Methyl 2,3,6-tri-O-benzyl-4-O-(2,3-di-O-benzyl-4,
6-O-benzylidene-D-mannopyranosyl)-a-D-glucopyrano-
side (23). The glycosidation was performed according to the
typical procedure (1 mL CH2Cl2, K45 8C, 60 min) employ-
ing diethyl phosphite 4b (56.9 mg, 0.10 mmol), alcohol 6
(51.1 mg, 0.11 mmol) and TMSOTf (1.0 M in CH2Cl2,
0.11 mL, 0.11 mmol). An anomeric mixture of the known
disaccharide 2325b (75.0 mg, 84%, a:bZ11:89) was
obtained as a colorless oil from the crude product
(106.8 mg) after column chromatography (silica gel 10 g,
4:1 hexane/AcOEt). The anomeric ratio of 23 was
determined by HPLC analysis [eluent, 5:1 hexane/AcOEt;
flow rate, 1.0 mL/min; tR (a-mannoside)Z16.2 min, tR
(b-mannoside)Z30.6 min].
4.4.3. Methyl 2,3,4-tri-O-acetyl-6-O-(2,3-di-O-benzyl-4,
6-O-benzylidene-D-mannopyranosyl)-a-D-glucopyrano-
side (24). The glycosidation was performed according to the
typical procedure (1 mL CH2Cl2, K45 8C, 30 min) employ-
ing diethyl phosphite 4b (56.9 mg, 0.10 mmol), alcohol 13
(35.2 mg, 0.11 mmol) and TMSOTf (1.0 M in CH2Cl2,
0.11 mL, 0.11 mmol). An anomeric mixture of the known
disaccharide 2417d (63.7 mg, 85%, a:bZ11:89) was
obtained from the crude product (88.7 mg) after column
chromatography (silica gel 5 g, 2:1 hexane/AcOEt). The
anomeric ratio of 24 was determined by HPLC analysis
[eluent, 4:1 hexane/THF; flow rate, 1.0 mL/min; tR
(a-mannoside)Z21.1 min, tR (b-mannoside)Z26.1 min].
4.4.5. 6-O-(2,3-Di-O-benzyl-4,6-O-benzylidene-D-manno-
pyranosyl)-1,2:3,4-di-O-isopropylidene-a-D-galactopyr-
anose (26). The glycosidation was performed according to
the typical procedure (1 mL CH2Cl2, K45 8C, 30 min)
employing diethyl phosphite 4b (56.9 mg, 0.10 mmol),
alcohol 15 (28.6 mg, 0.11 mmol) and TMSOTf (1.0 M in
CH2Cl2, 0.11 mL, 0.11 mmol). An anomeric mixture of the
known disaccharide 2617d (61.5 mg, 89%, a:bZ24:76) was
obtained as a colorless oil from the crude product (83.0 mg)
after column chromatography (silica gel 6 g, 5:1 hexane/
AcOEt). The anomeric ratio of 26 was determined by HPLC
analysis [eluent, 7:2 hexane/AcOEt; flow rate, 1.0 mL/min;
tR (a-mannoside)Z8.2 min, tR (b-mannoside)Z11.4 min].
4.4.4. Methyl 2-azido-3,4-di-O-benzyl-2-deoxy-4-O-(2,3-
di-O-benzyl-4,6-O-benzylidene-D-mannopyranosyl)-b-D-
glucopyranoside (25). The glycosidation was performed
according to the typical procedure (1 mL CH2Cl2, K45 8C,
60 min) employing diethyl phosphite 4b (56.9 mg,
0.10 mmol), alcohol 14 (43.9 mg, 0.11 mmol) and TMSOTf
(1.0 M in CH2Cl2, 0.11 mL, 0.11 mmol). An anomeric
mixture of disaccharide 25 (59.8 mg, 72%, a:bZ17:83) was
obtained as a colorless oil from the crude product
(100.5 mg) after flash column chromatography (silica gel
7 g, 30:1 toluene/AcOEt). The anomeric ratio of 25 was
determined by HPLC analysis [eluent, 5:1 hexane/AcOEt;
flow rate, 1.0 mL/min; tR (a-mannoside)Z10.3 min, tR
(b-mannoside)Z18.9 min]. The a- and b-mannosides were
separated by flash column chromatography with 30:1
toluene/AcOEt. Data for b-anomer (25b): [a]2D4 K58.2
(c 1.00, CHCl3); IR (film) 3030, 2922, 2857, 2110, 1497,
4.4.6. Benzyl 2,4,6-tri-O-benzyl-3-O-(2,3-di-O-benzyl-4,
6-O-benzylidene-D-mannopyranosyl)-a-D-glucopyrano-
side (27). The glycosidation was performed according to the
typical procedure (1 mL CH2Cl2, K45 8C, 30 min) employ-
ing diethyl phosphite 4b (56.9 mg, 0.10 mmol), alcohol 16
(60.0 mg, 0.11 mmol) and TMSOTf (1.0 M in CH2Cl2,
0.11 mL, 0.11 mmol). An anomeric mixture of disaccharide
27 (75.4 mg, 77%, a:bZ15:85) was obtained as a colorless
syrup from the crude product (105.9 mg) after column
chromatography (silica gel 6 g, 5:1 hexane/AcOEt). The
1454, 1366, 1279, 1213, 1092, 1055 cmK1 1H NMR
;
(500 MHz, CDCl3) d 3.07 (ddd, JZ4.8, 9.6, 10.4 Hz, 1H,
H-50), 3.29 (ddd, JZ2.0, 3.4, 9.4 Hz, 1H, H-5), 3.34–3.41
(m, 3H, H-2, H-3, H-30), 3.49 (t, JZ10.4 Hz, 1H, H-60ax),
3.54 (dd, JZ3.4, 11.1 Hz, 1H, H-6a), 3.56 (s, 3H, OCH3),
3.64 (dd, JZ2.0, 11.1 Hz, 1H, H-6b), 3.72 (d, JZ3.0 Hz,
1H, H-20), 3.96 (dd, JZ9.0, 9.4 Hz, 1H, H-4), 4.05 (dd, JZ
4.8, 10.4 Hz, 1H, H-60eq), 4.09 (t, JZ9.6 Hz, 1H, H-40),
4.13 (d, JZ7.5 Hz, 1H, H-1), 4.38 (d, JZ12.1 Hz, 1H,
OCHPh), 4.48 (s, 1H, H-10), 4.58 (d, JZ12.4 Hz, 1H,
OCHPh), 4.63 (d, JZ12.1 Hz, 1H, OCHPh), 4.64 (d, JZ
10.4 Hz, 1H, OCHPh), 4.74 (d, JZ12.4 Hz, 1H, OCHPh),
1
anomeric ratio of the product was determined by H NMR
[integration of benzylidene proton, b-anomer (5.57 ppm),
a-anomer (5.60 ppm)]. The a- and b-mannosides were
separated by flash column chromatography with 5:1 hexane/
AcOEt. Data for b-anomer (27b): [a]2D3 C32.5 (c 1.01,
CHCl3); IR (CHCl3) 3067, 3025, 3015, 2872, 1497, 1454,
1
1366, 1209, 1090, 791, 671 cmK1; H NMR (500 MHz,

T. Tsuda et al. / Tetrahedron 61 (2005) 10719–10733
10729
CDCl3) d 3.27 (ddd, JZ4.9, 9.5, 10.4 Hz, 1H, H-50), 3.41
(dd,0JZ3.6, 9.7 Hz, 1H, H-2), 3.45 (dd, JZ3.0, 9.9 Hz, 1H,
H-3 ), 30.56–3.59 (m, 2H, H-4, H-6a), 3.68–3.75 (m, 2H, H-
6b, H-6 ax), 3.77 (m, 1H, H-5), 3.81 (d, JZ3.0 Hz, 1H, H-
20), 4.14 (dd, JZ9.5, 9.9 Hz, 1H, H-40), 4.17 (dd, JZ9.2,
9.7 Hz, 1H, H-3), 4.21 (dd, JZ4.9, 10.4 Hz, 1H, H-60eq),
4.26 (d, JZ11.6 Hz, 1H, OCHPh), 4.33 (d, JZ10.1 Hz, 1H,
OCHPh), 4.37 (d, JZ11.6 Hz, 1H, OCHPh), 4.48–4.52 (m,
3H, 3!OCHPh), 4.62–4.67 (m, 3H, 3!OCHPh), 4.84–
4.90 (m, 4H, H-1, H-10, 2!OCHPh), 5.13 (d, JZ10.1 Hz,
1H, OCHPh), 5.57 (s, 1H, CHPh), 7.15 (m, 2H, Ar-H), 7.21–
7.36 (m, 29H, Ar-H), 7.45–7.49 (m, 4H, Ar-H); 13C NMR
(126 MHz, CDCl3) d 67.3, 68.4, 68.7, 69.2, 70.1, 72.5, 72.6,
73.6, 74.7, 74.9, 75.9, 78.6, 78.8, 80.3, 81.1, 94.9 (C-10),
101.3, 102.8 (C-1), 126.1, 127.4, 127.47, 127.51, 127.7,
127.9, 127.97, 128.02, 128.05, 128.06, 128.11, 128.25,
128.31, 128.37, 128.39, 128.5, 128.7, 136.9, 137.7, 137.8,
138.0, 138.6, 138.9; FAB-HRMS m/z calcd for
C61H62O11Na (MCNa)C993.4190, found 993.4234. Anal.
Calcd for C61H62O11: C, 75.44; H, 6.43, found C, 75.13; H,
6.55. Data for a-anomer (27a): [a]2D4 C38.2 (c 0.33,
CHCl3); IR (CHCl3) 3029, 3007, 2928, 1497, 1454, 1366,
3.92 (t, JZ10.3 Hz, 1H, H-60ax), 4.18 (t, JZ9.6 Hz, 1H,
H-40), 4.30 (dd, JZ4.8, 10.3 Hz, 1H, H-60eq), 4.36 (d, JZ
7.1 Hz, 1H, H-1), 4.45 (d, JZ12.1 Hz, 1H, OCHPh), 4.51
(d, JZ11.7 Hz, 1H, OCHPh), 4.55–4.60 (m, 3H, 3!
OCHPh), 4.64 (d, JZ12.1 Hz, 1H, OCHPh), 4.72–4.74
(m, 2H, H-10, OCHPh), 4.78 (d, JZ12.1 Hz, 1H, OCHPh),
4.84 (d, JZ12.1 Hz, 1H, OCHPh), 4.85 (d, JZ11.7 Hz, 1H,
OCHPh), 5.59 (s, 1H, CHPh), 7.14–7.38 (m, 28H, Ar-H),
7.48 (m, 2H, Ar-H); 13C NMR (126 MHz, CDCl3) d 56.7,
67.4, 68.6, 68.7, 72.5, 73.5, 74.5, 74.78, 74.81, 75.1, 76.4,
78.2, 78.6, 78.7, 80.9, 85.0, 101.3, 102.0 (C-10), 102.6 (C-1),
126.0, 126.9, 127.3, 127.4, 127.5, 127.6, 127.7, 127.8,
127.9, 128.1, 128.2, 128.3, 128.37, 128.42, 128.7, 137.6,
137.8, 138.1, 138.4, 138.5; FAB-HRMS m/z calcd for
C55H59O11 (MCH)C895.4057, found 895.4059. Anal.
Calcd for C55H58O11: C, 73.81; H, 6.53, found: C, 73.62;
H, 6.54. Data for a-anomer (28a): [a]2D4 C51.1 (c 1.00,
CHCl3); IR (film) 3030, 2926, 2865, 1497, 1454, 1368,
1215, 1092, 914, 750, 698 cmK1 1H NMR (500 MHz,
;
CDCl3) d 3.40 (s, 3H, OCH3), 3.42 (ddd, JZ1.5, 4.5, 9.4 Hz,
1H, H-5), 3.48 (dd, JZ9.1, 9.2 Hz, 1H, H-3), 3.59 (dd, JZ
7.8, 9.1 Hz, 1H, H-2), 3.60 (dd, JZ9.2, 9.4 Hz, 1H, H-4),
3.67 (dd, JZ4.5, 9.8 Hz, 1H, H-6a), 3.72 (dd, JZ1.5,
9.8 Hz, 1H, H-6b), 3.77 (t, JZ10.0 Hz, 1H, H-60ax), 3.84
(dd, JZ01.0, 3.1 Hz, 1H, H-20), 3.92 (dd, JZ3.1, 10.0 Hz,
1H, H-3 ), 4.03 (ddd, JZ4.8, 9.6, 10.0 Hz, 1H, H-50), 4.09
(dd, JZ4.8, 10.0 Hz, 1H, H-60eq), 4.13 (d,0JZ7.8 Hz, 1H,
H-1), 4.24 (dd, JZ9.6, 10.0 Hz, 1H, H-4 ), 4.50 (d, JZ
10.8 Hz, 1H, OCHPh), 4.53 (d, JZ12.3 Hz, 1H, OCHPh),
4.60 (d, JZ12.3 Hz, 1H, OCHPh), 4.64 (d, JZ12.3 Hz, 1H,
OCHPh), 4.70 (d, JZ10.7 Hz, 1H, OCHPh), 04.74–4.81 (m,
5H, 5!OCHPh), 5.38 (d, JZ1.0 Hz, 1H, H-1 ), 5.60 (s, 1H,
CHPh), 7.11–7.16 (m, 5H, Ar-H), 7.22–7.43 (m, 25H,
Ar-H); 13C NMR (126 MHz, CDCl3) d 56.7, 64.4, 68.66,
68.70, 72.9, 73.0, 73.5, 74.9, 75.1, 75.7, 75.9, 76.1, 76.9,
78.2, 79.1, 83.2, 98.7 (C-10), 101.3, 104.3 (C-1), 126.2,
127.4, 127.56, 127.60, 127.62, 127.7, 127.8, 127.9, 128.0,
128.2, 128.3, 128.35, 128.38, 128.6, 137.7, 137.90, 137.94,
138.0, 138.2, 138.6; FAB-HRMS m/z calcd for C55H59O11
(MCH)C895.4057, found 895.4064. Anal. Calcd for
C55H58O11: C, 73.81; H, 6.53, found: C, 73.48; H, 6.60.
1229, 1071, 1026, 756, 737, 716, 669 cmK1 1H NMR
;
(500 MHz, CDCl3) d 3.38 (dd, JZ3.7, 9.7 Hz, 1H, H-2),
3.50 (dd, JZ1.8, 10.8 Hz, 1H, H-6a), 03.58–3.63 (m, 2H,
H-4, H-6b), 3.74–3.81 (m, 3H, H-5, H-2 , H-60ax), 3.960(dd,
JZ3.1, 9.6 Hz, 1H, H-30), 4.14–4.19 (m, 2H, H-3, H-6 eq),
4.22 (t, JZ9.6 Hz, 1H, H-40), 4.29 (ddd, JZ4.7, 9.6, 9.9 Hz,
1H, H-50), 4.36 (d, JZ12.0 Hz, 1H, OCHPh), 4.41–4.49 (m,
5H, 5!OCHPh), 4.53–4.61 (m, 4H, 4!OCHPh), 4.63 (d,
JZ12.2 Hz, 1H, OCHPh), 4.80 (d, JZ12.5 Hz, 1H,
OCHPh), 4.82 (d, JZ3.7 Hz, 1H, H-1), 5.34 (d, JZ
1.0 Hz, 1H, H-10), 5.60 (s, 1H, CHPh), 7.14–7.36 (m,
33H, Ar-H), 7.47 (m, 2H, Ar-H); 13C NMR (126 MHz,
CDCl3) d 64.2, 68.3, 68.8, 69.3, 70.0, 72.6, 73.0, 73.2, 73.6,
74.0, 76.5, 77.5, 77.8, 78.8, 79.2, 95.6 (C-10), 99.9 (C-1),
101.4, 126.2, 126.8, 127.4, 127.5, 127.6, 127.7, 127.77,
127.83, 127.96, 128.04, 128.1, 128.2, 128.3, 128.36, 128.39,
128.44, 128.5, 128.6, 137.2, 137.7, 137.8, 138.0, 138.1,
138.2, 138.9; FAB-HRMS m/z calcd for C61H63O11 (MC
H)C971.4371, found 971.4413.
4.4.8. Methyl 4-O-(2,3-di-O-benzyl-4,6-O-benzylidene-D-
mannopyranosyl)-2,3-O-isopropylidene-a-L-rhamno-
pyranoside (29). The glycosidation was performed accord-
ing to the typical procedure (1 mL CH2Cl2, K45 8C,
30 min) employing diethyl phosphite 4b (56.9 mg,
0.10 mmol), alcohol 18 (25.6 mg, 0.11 mmol) and TMSOTf
(1.0 M in CH2Cl2, 0.11 mL, 0.11 mmol). An anomeric
mixture of the known disaccharide 2917d (59.1 mg, 89%,
a:bZ11:89) was obtained as a colorless oil from the crude
product (79 mg) after column chromatography (silica gel
7 g, 10:1 hexane/AcOEt). The anomeric ratio of 29 was
determined by HPLC analysis [eluent, 13:1 hexane/AcOEt;
flow rate, 1.0 mL/min; tR (b-mannoside)Z47.7 min, tR
(a-mannoside)Z51.9 min].
4.4.7. Methyl 3,4,6-tri-O-benzyl-2-O-(2,3-di-O-benzyl-4,
6-O-benzylidene-D-mannopyranosyl)-b-D-glucopyrano-
side (28). The glycosidation was performed according to the
typical procedure (1 mL CH2Cl2, K45 8C, 30 min) employ-
ing diethyl phosphite 4b (56.9 mg, 0.10 mmol), alcohol 17
(51.2 mg, 0.11 mmol) and TMSOTf (1.0 M in CH2Cl2,
0.11 mL, 0.11 mmol). An anomeric mixture of disaccharide
28 (85.6 mg, 96%, a:bZ5:95) was obtained as a colorless
syrup from the crude product (105.4 mg) after column
chromatography (silica gel 15 g, 20:1/15:1 toluene/
AcOEt). The anomeric ratio of 28 was determined by
HPLC analysis [eluent, 4:1 hexane/AcOEt; flow rate,
1.0 mL/min; tR (a-mannoside)Z4.9 min, tR (b-mannosi-
de)Z26.7 min]. The a- and b-mannosides were separated
by column chromatography with 5:1 hexane/AcOEt. Data
for b-anomer (28b): [a]D24 K27.5 (c 1.02, CHCl3); IR (film)
3021, 2976, 2895, 1522, 1424, 1215, 1047, 928, 775,
4.4.9. 2,3-Di-O-benzyl-4,6-O-benzylidene-D-mannopyra-
nosyl-(1/6)-2,3,4-tri-O-benzoyl-a-D-glucopyranosyl N,
N,N0,N0-tetramethylphosphorodiamidate (30). The gly-
cosidation was performed according to the typical pro-
cedure (1 mL CH2Cl2, K45 8C, 30 min) employing diethyl
phosphite 4b (56.9 mg, 0.10 mmol), alcohol 19 (68.9 mg,
1
673 cmK1; H NMR (500 MHz, CDCl3) d 3.25 (ddd, JZ
4.8,09.6, 10.3 Hz, 1H, H-50), 3.37 (dd, JZ2.9, 9.6 Hz, 1H,
H-3 ), 3.48 (m, 1H, H-5), 3.54 (s, 3H, OCH3), 3.56–3.67 (m,
3H, H-2, H-3, H-4), 3.70–3.77 (m, 3H, H-6a, H-6b, H-20),

10730
T. Tsuda et al. / Tetrahedron 61 (2005) 10719–10733
0.11 mmol) and TMSOTf (1.0 M in CH2Cl2, 0.20 mL,
0.20 mmol). An anomeric mixture of disaccharide 30
(90.0 mg, 85%, a:bZ14:86) was obtained as a colorless
syrup from the crude product (101 mg) after column
chromatography (silica gel 4 g, 3:4 hexane/AcOEt). The
anomeric ratio of the product was determined by 13C NMR
[peak height of C-10, b-anomer (102.7 ppm), a-anomer
(99.9 ppm)]. The a- and b-mannosides were separated by
flash column chromatography with 10:1 CH2Cl2/acetone.
Data for b-anomer (30b): [a]2D3 K5.20 (c 1.07, CHCl3); IR
4.4.10. 1-Adamantyl 2,3-di-O-benzyl-4,6-O-benzylidene-
D-mannopyranoside (31). The glycosidation was per-
formed according to the typical procedure (1 mL CH2Cl2,
K45 8C, 30 min) employing diethyl phosphite 4b (56.9 mg,
0.10 mmol), 1-adamantanol (20, 16.7 mg, 0.11 mmol) and
TMSOTf (1.0 M in CH2Cl2, 0.11 mL, 0.11 mmol). An
anomeric mixture of the known mannoside 3117d (52.0 mg,
89%, a:bZ16:84) was obtained as a colorless oil from the
crude product (69.8 mg) after column chromatography
(silica gel 10 g, 9:1 hexane/AcOEt). The anomeric ratio of
31 was determined by HPLC analysis [eluent, 20:1 hexane/
AcOEt; flow rate, 1.0 mL/min; tR (a-mannoside)Z
27.4 min, tR (b-mannoside)Z40.1 min].
1
(CHCl3) 3016, 1730, 1452, 1278, 1093 cmK1; H NMR
(500 MHz, CDCl3) d 2.59 (d, JH–PZ10.1 Hz, 6H, N(CH3)2),
2.65 (d, JH–PZ10.0 Hz, 6H, N(CH3)2), 3.27 (ddd, JZ4.8,
9.6, 10.2 Hz, 1H, H-50), 3.60 (dd, JZ3.0, 9.9 Hz, 1H, H-30),
3.68 (dd, JZ5.0, 11.6 Hz, 1H, H-6a), 3.86 (dd, JZ10.2,
10.4 Hz, 1H, H-60ax), 4.10 (d, JZ3.0 Hz, 1H, H-20), 4.17
(dd, JZ0.9, 11.6 Hz, 1H, H-6b), 4.18 (dd, JZ9.6, 9.9 Hz,
1H, H-400), 4.23 (dd, JZ4.8, 10.4 Hz, 1H, H-60eq), 4.448 (s,
1H, H-1 ), 4.453 (ddd, JZ0.9, 5.0, 10.0 Hz, 1H, H-5), 4.62
(d, JZ12.5 Hz, 1H, OCHPh), 4.71 (d, JZ12.5 Hz, 1H,
OCHPh), 4.93 (d, JZ12.0 Hz, 1H, OCHPh), 4.99 (d, JZ
12.0 Hz, 1H, OCHPh), 5.35 (ddd, JZ3.2, 10.0, 1.6
(JH–P) Hz, 1H, H-2), 5.58 (s, 1H, CHPh), 5.63 (t, JZ
10.0 Hz, 1H, H-4), 6.13 (dd, JZ3.2, 8.1 (JH–P) Hz, 1H,
H-1), 6.17 (t, JZ10.0 Hz, 1H, H-3), 7.26–7.55 (m, 24H,
Ar-H), 7.87 (m, 2H, Ar-H), 7.92–7.96 (m, 4H, Ar-H); 13C
NMR (126 MHz, CDCl3) d 36.4 (d, JC–PZ3.9 Hz), 36.5 (d,
JC–PZ3.9 Hz), 67.6, 68.1, 68.3, 68.4, 68.6, 70.0, 70.8, 71.5
(d, JC–PZ6.3 Hz), 72.2, 75.1, 76.2, 77.2, 77.9, 78.4, 92.0 (d,
JC–PZ3.3 Hz, C-1), 101.3, 102.7 (C-10), 126.0, 127.4,
127.5, 128.07, 128.13, 128.2, 128.27, 128.33, 128.34, 128.4,
128.68, 128.74, 128.9, 129.6, 129.7, 129.8, 133.2, 133.3,
133.5, 137.5, 138.3, 138.5, 165.2, 165.4, 165.9; 31P NMR
(109 MHz, CDCl3) d 19.9; FAB-HRMS m/z calcd for
C58H62N2O15P (MCH)C1057.3888, found 1057.3900.
Anal. Calcd for C58H61N2O15P: C, 65.90; H, 5.82; N,
2.65, found: C, 65.66; H, 5.88; N, 2.72. Data for a-anomer
(30a): [a]2D4 C43.3 (c 0.86, CHCl3); IR (CHCl3) 3016,
1730, 1452, 1278, 1093 cmK1; 1H NMR (500 MHz, CDCl3)
4.4.11. Allyl N-(benzyloxycarbonyl)-O-(2,3-di-O-benzyl-
4,6-O-benzylidene-D-mannopyranosyl)-L-serinate (32).
The glycosidation was performed according to the typical
procedure (1 mL CH2Cl2, K45 8C, 15 min) employing
diethyl phosphite 4b (56.9 mg, 0.10 mmol), alcohol 21
(30.7 mg, 0.11 mmol) and TMSOTf (1.0 M in CH2Cl2,
0.11 mL, 0.11 mmol). An anomeric mixture of mannoside
32 (61.7 mg, 87%, a:bZ15:85) was obtained from the
crude product (95.9 mg) after column chromatography
(silica gel 7 g, 3:1 hexane/AcOEt). The anomeric ratio of
32 was determined by HPLC analysis [eluent, 5:1 hexane/
AcOEt; flow rate, 1.0 mL/min; tR (a-mannoside)Z
24.9 min, tR (b-mannoside)Z30.0 min]. The a- and
b-mannosides were separated by flash column chromato-
graphy with 5:1 hexane/AcOEt. Data for b-anomer (32b):
[a]2D4 K35.4 (c 1.74, CHCl3); IR (CHCl3) 3020, 2878, 1720,
1
1508, 1217, 1093 cmK1; H NMR (500 MHz, CDCl3) d
3.28 (ddd, JZ4.7, 9.5, 10.3 Hz, 1H, H-5), 3.55 (dd, JZ2.9,
9.8 Hz, 1H, H-3), 3.78 (dd, JZ2.9, 10.1 Hz, 1H, Ser-b-CH),
3.87–3.91 (m, 2H, H-2, H-6ax), 4.18 (dd, JZ9.5, 9.8 Hz,
1H, H-4), 4.28 (dd, JZ4.7, 10.4 Hz, 1H, H-6eq), 4.34 (dd,
JZ3.0, 10.1 Hz, 1H, Ser-b-CH), 4.40 (s, 1H, H-1), 4.57 (m,
1H, Ser-a-CH), 4.60 (d, JZ12.4 Hz, 1H, OCHPh), 4.62–
4.73 (m, 2H, CH2CH]CH2), 4.70 (d, JZ12.4 Hz, 1H,
OCHPh), 4.75 (d, JZ12.3 Hz, 1H, OCHPh), 4.87 (d, JZ
12.3 Hz, 1H, OCHPh), 5.11 (d, JZ12.4 Hz, 1H, CO2-
CHPh), 5.14 (d, JZ12.4 Hz, 1H, CO2CHPh), 5.23 (d, JZ
10.4 Hz, 1H, CH2CH]CH), 5.33 (d, JZ17.2 Hz, 1H,
CH2CH]CH), 5.57 (d, JZ8.2 Hz, 1H, NH), 5.60 (s, 1H,
CHPh), 5.88 (m, 1H, CH2CH]CH2), 7.22–7.42 (m, 18H,
Ar-H), 7.49 (m, 2H, Ar-H); 13C NMR (126 MHz, CDCl3) d
54.2, 66.4, 67.2, 67.7, 68.4, 69.8, 72.5, 74.5, 75.2, 77.8,
78.5, 101.4, 102.4 (C-1), 118.9, 126.0, 127.5, 127.59,
127.63, 128.16, 128.20, 128.29, 128.32, 128.5, 128.6, 128.9,
131.4, 136.1, 137.5, 138.2, 155.9, 169.5; FAB-HRMS m/z
calcd for C41H44NO10 (MCH)C710.2965, found 710.2920.
Data for a-anomer (32a): [a]2D3 C36.0 (c 0.61, CHCl3); IR
(CHCl3) 3020, 2935, 1722, 1504, 1454, 1238, 1199,
d 2.59 (d, JH–PZ10.5 Hz, 6H, N(CH3)2), 2.66 (d, JH–P
Z
10.0 Hz, 6H, N(CH3)2), 3.62 (dd, JZ3.5, 11.4 Hz, 1H,
H-6a), 3.65 (ddd, JZ4.8, 9.5, 10.2 Hz, 1H, H-50), 3.73–3.78
(m, 2H, H-20, H-60ax), 3.88 (dd, JZ3.8, 11.4 Hz, 1H, H-6b),
3.96 (dd, JZ3.30, 9.9 Hz, 1H, H-30), 4.00 (dd, JZ4.08,
10.1 Hz, 1H, H-6 eq), 4.18 (dd, JZ9.5, 9.9 Hz, 1H, H-4 ),
4.37 (ddd, JZ3.5, 3.8, 9.8 Hz, 1H, H-5), 4.56 (d, JZ
11.9 Hz, 1H, OCHPh), 4.69 (d, JZ12.1 Hz, 1H, OCHPh),
4.76 (d, JZ11.9 Hz, 1H, OCHPh), 4.78 (d, JZ12.1 Hz, 1H,
OCHPh), 4.82 (d, JZ1.0 Hz, 1H, H-10), 5.38 (ddd, JZ3.2,
10.0, 1.6 (JH–P) Hz, 1H, H-2), 5.58 (s, 1H, CHPh), 5.67 (dd,
JZ9.8, 10.0 Hz, 1H, H-4), 6.08 (dd, JZ3.2, 7.8 (JH–P) Hz,
1H, H-1), 6.14 (t, JZ10.0 Hz, 1H, H-3), 7.26–7.53 (m, 24H,
Ar-H), 7.88 (m, 2H, Ar-H), 7.92–7.96 (m, 4H, Ar-H); 13C
NMR (126 MHz, CDCl3) d 36.4 (d, JC–PZ4.0 Hz), 36.5 (d,
JC–PZ4.0 Hz), 64.4, 66.1, 68.6, 68.9, 70.0, 70.1, 71.5 (d,
1
1062 cmK1; H NMR (500 MHz, CDCl3) d 3.70–3.75 (m,
2H, H-2, H-5), 3.84 (t, JZ10.1 Hz, 1H, H-6ax), 3.87 (dd,
JZ3.2, 9.9 Hz, 1H, H-3), 3.88 (dd, JZ3.2, 10.2 Hz, 1H,
Ser-b-CH), 3.93 (dd, JZ2.8, 10.2 Hz, 1H, Ser-b-CH), 4.21–
4.25 (m, 2H, H-4, H-6eq), 4.54 (m, 1H, Ser-a-CH), 4.59 (br
d, JZ4.7 Hz, 2H, CH2CH]CH2), 4.63 (d, JZ12.0 Hz, 1H,
OCHPh), 4.68 (d, JZ12.3 Hz, 1H, OCHPh), 4.74 (s, 1H,
H-1), 4.79 (d, JZ12.3 Hz, 1H, OCHPh), 4.84 (d, JZ12.0 Hz,
1H, OCHPh), 5.10 (d, JZ12.1 Hz, 1H, CO2CHPh), 5.15
(d, JZ12.1 Hz, 1H, CO2CHPh), 5.19 (d, JZ10.6 Hz, 1H,
CH2CH]CH), 5.28 (d, JZ17.2 Hz, 1H, CH2CH]CH),
JC–PZ6.3 Hz), 73.2, 73.6, 76.3, 76.4, 78.9, 92.1 (d, JC–P
Z
3.5 Hz, C-1), 99.9 (C-10), 101.3, 126.2, 127.6, 127.7,
128.00, 128.03, 128.3, 128.35, 128.38, 128.5, 128.7,
129.0, 129.7, 129.8, 129.9, 133.3, 133.36, 133.42, 137.8,
138.1, 138.8; 31P NMR (109 MHz, CDCl3) d 19.9; FAB-
HRMS m/z calcd for C58H61N2O15PNa (MC
Na)C1079.3703, found 1079.3750.

T. Tsuda et al. / Tetrahedron 61 (2005) 10719–10733
10731
5.59 (d, JZ8.1 Hz, 1H, NH), 5.63 (s, 1H, CHPh), 5.83 (m,
1H, CH2CH]CH2), 7.25–7.39 (m, 18H, Ar-H), 7.49 (m,
2H, Ar-H); 13C NMR (126 MHz, CDCl3) d 54.3, 64.7, 66.3,
67.3, 68.3, 68.6, 73.4, 73.7, 76.3, 78.9, 100.1 (C-1), 101.5,
119.1, 126.1, 127.5, 127.6, 127.8, 128.0, 128.1, 128.2,
128.3, 128.4, 128.6, 128.8, 131.3, 136.0, 137.6, 138.0,
138.6, 155.8, 169.5; FAB-HRMS m/z calcd for C41H44NO10
(MCH)C710.2965, found 710.2974.
128.8, 137.8, 138.3, 138.9, 140.5; FAB-HRMS m/z calcd for
C54H71O6 (MKH)C815.5250, found 815.5275.
Acknowledgements
This research was supported in part by a Grant-in-Aid for
Scientific Research on Priority Areas (A) ‘Exploitation of
Multi-Element Cyclic Molecules’ from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
T. T. is grateful to JSPS for a graduate fellowship. We thank
Ms. H. Matsumoto, A. Maeda, S. Oka, and M. Kiuchi of the
Center for Instrumental Analysis, Hokkaido University, for
technical assistance in MS and elemental analysis.
4.4.12. Cholesteryl 2,3-di-O-benzyl-4,6-O-benzylidene-D-
mannopyranoside (33). The glycosidation was performed
according to the typical procedure (1 mL CH2Cl2, K45 8C,
30 min) employing diethyl phosphite 4b (56.9 mg,
0.10 mmol), cholesterol (22, 42.6 mg, 0.11 mmol) and
TMSOTf (1.0 M in CH2Cl2, 0.11 mL, 0.11 mmol). An
anomeric mixture of mannoside 33 (70.5 mg, 86%, a:bZ
17:83) was obtained from the crude product (110.6 mg)
after column chromatography (silica gel 8 g, 10:1 hexane/
AcOEt). The anomeric ratio of 33 was determined by HPLC
analysis [eluent, 20:1 hexane/THF; flow rate, 1.0 mL/min;
tR (a-mannoside)Z8.1 min, tR (b-mannoside)Z9.1 min].
The a- and b-mannosides were separated by flash column
chromatography with 15:1 hexane/AcOEt. Data for
b-anomer (33b): mp 108.0–109.0 8C (colorless fine needles
from MeOH): [a]2D5 C49.6 (c 1.62, CHCl3); IR (CHCl3)
References and notes
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3018, 2943, 1454, 1381, 1217, 1095 cmK1 1H NMR
;
(500 MHz, CDCl3) d 0.68 (s, 3H, H-18), 0.86–1.67 (m,
33H), 1.81–1.87 (m, 2H), 1.96–2.03 (m, 3H), 2.21 (m, 1H,
H-4a), 20.29 (m, 1H, H-4b), 3.31 (ddd, JZ4.8, 9.4, 10.2 Hz,
1H, 0H-5 ), 3.56 (m, 1H, H-3), 3.58 (dd, JZ3.0, 9.7 Hz, 1H,
H-3 ), 3.87 (d, JZ3.0 Hz, 1H, H-20), 3.92 (dd, JZ10.02,
10.4 Hz, 1H, H-60ax), 4.21 (dd, JZ9.4, 9.7 Hz, 1H, H-40),
4.28 (dd, JZ4.8, 10.4 Hz, 1H, H-60eq), 4.58 (s, 1H, H-1 ),
4.59 (d, JZ12.5 Hz, 1H, OCHPh), 4.68 (d, JZ12.5 Hz, 1H,
OCHPh), 4.90 (d, JZ12.4 Hz, 1H, OCHPh), 4.99 (d, JZ
12.4 Hz, 1H, OCHPh), 5.35 (m, 1H, H-6), 5.61 (s, 1H,
CHPh), 7.25–7.37 (m, 11H, Ar-H), 7.48–7.50 (m, 4H, Ar-
H); 13C NMR (126 MHz, CDCl3) d 11.8, 18.7, 19.4, 21.0,
22.5, 22.8, 23.8, 24.3, 28.0, 28.2, 29.6, 31.88, 31.94, 35.8,
36.2, 36.8, 37.2, 38.8, 39.5, 39.8, 42.3, 50.2, 56.1, 56.07,
67.5, 68.7, 72.3, 74.7, 76.3, 77.2, 78.1, 78.6, 100.0 (C-1 ),
101.4, 122.0, 126.0, 127.4, 127.48, 127.49, 128.0, 128.1,
128.3, 128.7, 128.8, 137.7, 138.4, 138.5, 140.5; FAB-
HRMS m/z calcd for C54H72O6Na (MCNa)C839.5226,
found 839.5244. Anal. Calcd for C54H72O6: C, 79.37; H,
8.88, found: C, 79.12; H, 8.86. Data for a-anomer (33a):
[a]2D3 C37.5 (c 0.99, CHCl3); IR (CHCl3) 3009, 2939, 1454,
1375, 1099 cmK1; 1H NMR (500 MHz, CDCl3) d 0.67 (3H,
s, H-18), 0.86–1.58 (m, 33H), 1.74–1.84 (m, 3H), 1.95–2.02
(m, 2H), 2.28 (br d, JZ7.5 Hz, 2H, H-4a, 0H-4b), 3.43 (m,
1H, H-3), 3.80 (dd, JZ1.3, 3.1 Hz, 1H, H-2 ), 3.84–3.91 (m,
2H, H-50, H-60ax), 4.00 (dd, JZ3.1, 9.9 Hz, 1H, H-30),
4.22–4.28 (m, 2H, H-40, H-60eq), 4.67 (d, JZ12.2 Hz, 1H,
OCHPh), 4.72 (d, JZ12.2 Hz, 1H, OCHPh), 4.84 (d, JZ
12.2 Hz, 1H, OCHPh), 4.85 (d, JZ12.2 Hz, 1H, OCHPh),
4.93 (d, JZ1.3 Hz, 1H, H-10), 5.33 (br d, JZ4.1 Hz, 1H, H-
6), 5.65 (s, 1H, CHPh), 7.26–7.39 (m, 13H, Ar-H), 7.52 (m,
2H, Ar-H); 13C NMR (126 MHz, CDCl3) d 11.9, 18.7, 19.3,
21.1, 22.6, 22.8, 23.8, 24.3, 27.5, 28.0, 28.2, 31.87, 31.91,
35.8, 36.2, 36.7, 37.0, 39.5, 39.8, 39.9, 42.3, 50.1, 56.2,
56.8, 64.3, 68.9, 73.2, 73.6, 79.4, 97.3 (C-10), 101.4, 122.0,
126.0, 127.40, 127.43, 127.7, 128.1, 128.2, 128.3, 128.4,
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1
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1
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