Synthesis and structure of 4-O,6-O-glycosylidene glycosides

Article abstract of DOI:10.1021/jo0005868

Interglycosidic spiro ortho esters (9-20) were efficiently prepared from methyl 2,6-di-O-benzylglucoor galactopyranoside and various sugar lactones in the presence of methoxytrimethylsilane and a catalytic amount of trimethylsilyl triflate. All of the prepared sugar ortho esters possess perhydrospiro[2H-pyran-2,2'-pyrano[3;2-d] [1,3]dioxin] ring systems commonly in their molecules and, remarkably, were afforded as single isomers. The configurations of the spiro centers in their molecules were determined or estimated by X-ray single crystallographic analysis and molecular modeling studies. By comparing the conformations of prepared ortho esters, we revealed that the difference in the stability between two possible isomers was principally caused from that between the spiro ring systems in their molecules in each case.

Full text of DOI:10.1021/jo0005868

8164
J . Org. Chem. 2000, 65, 8164-8170
Syn th esis a n d Str u ctu r e of 4-O,6-O-Glycosylid en e Glycosid es
Hiro Ohtake, Naoto Ichiba, Moto Shiro,† and Shiro Ikegami*
School of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-0195, J apan, and
Rigaku Corporation, 3-9-12 Matsubara, Akishima, Tokyo 196-0003, J apan
shi-ike@pharm.teikyo-u.ac.jp
Received April 19, 2000
Interglycosidic spiro ortho esters (9-20) were efficiently prepared from methyl 2,6-di-O-benzylgluco-
or galactopyranoside and various sugar lactones in the presence of methoxytrimethylsilane and a
catalytic amount of trimethylsilyl triflate. All of the prepared sugar ortho esters possess
perhydrospiro[2H-pyran-2,2′-pyrano[3,2-d][1,3]dioxin] ring systems commonly in their molecules
and, remarkably, were afforded as single isomers. The configurations of the spiro centers in their
molecules were determined or estimated by X-ray single crystallographic analysis and molecular
modeling studies. By comparing the conformations of prepared ortho esters, we revealed that the
difference in the stability between two possible isomers was principally caused from that between
the spiro ring systems in their molecules in each case.
In tr od u ction
from D-sugar lactones (1-3) and methyl 2,3-di-O-benzyl-
glucopyranoside (7) and revealed that only one of the two
possible isomers was generated in each case. Yoshimura
and co-workers had extensively studied interglycosidic
ortho esters3 for the purpose of synthesizing orthosomycin
antibiotics and had also synthesized compound 9 as a
single isomer.3e They determined the absolute configu-
ration of the anomeric center of 9 to be R by X-ray
crystallographic analysis after converting it into the
acetylated derivative.3g In a previous paper, we estimated
the configurations of the spiro centers of the other two
ortho esters to be also R by the molecular modeling
studies.6a
In this paper, we report the details of the preparation
and the structure determination of various interglycosidic
spiro ortho esters, including the above three ortho esters,
which possess perhydrospiro[2H-pyran-2,2′-pyrano[3,2-
d][1,3]dioxin] ring systems commonly in their molecules.
Remarkably, all of the prepared ortho esters were af-
forded as single isomers. Considering the structures of
formed ortho esters, we found generality among the
configurations of spiro centers in the predominately
generated isomers, which are also reported in detail in
this report.
P r ep a r a tion of Su ga r Or th o Ester s. Two decades
ago, Yoshimura and co-workers reported the synthesis
of interglycosidic spiro ortho esters from sugar lactones
and silylated diols using TMSOTf as the catalyst3a in a
modification of Noyori’s method.8 As we required a much
more efficient method in the course of the study on our
reductive glycosylation protocol,6 we also modified the
process for ortho ester preparation.7,6a Recently, Kurihara
and Miyata have reported the efficient ketal formation
from diols and ketones in the presence of excess amount
The spiro ortho ester interlinkage between a glycos-
ylidene group and the diol moiety of glycoside has been
found in the orthosomycin family of antibiotics.1,2 Since
this unique ortho ester linkage3,4 restricts conformation
of the saccharide, it created interest also from the point
of designing pseudo-saccharide molecules. For each in-
terglycosidic ortho ester, two stereoisomers are possible
around the spiro center, and X-ray crystallographic
analysis is usually required for the determination of the
absolute configuration of spiro carbon. Although the
configurations of the spiro centers of several such com-
pounds, including orthosomycins, have been determined
by X-ray crystallographic analysis3d,g,4a,5 or estimated by
other spectral methods, the general knowledge about the
predominance in the formation between two possible
isomers of sugar ortho esters have not been reported.
Recently, we were interested in this unique type of
linkage as the intermediate in our novel reductive
glycosidic bond formation6 and modified the process for
the formation of these ortho esters.6a,c As described in a
previous paper,6a we prepared sugar ortho esters (9-11)
* Tel: (+81) 426-85-3728. Fax: (+81) 426-85-1870.
† Rigaku Corporation.
(1) (a) Wright, D. E. Tetrahedron 1979, 35, 1207. (b) Ollis, W. D.;
Smith, C.; Wright, D. E. Tetrahedron 1979, 35, 105.
(2) Ganguly, A. K. Oligosaccharide Antibiotics. In Topics in Anti-
biotic Chemistry; Sammes, P. G., Ed.; Ellis Horwood: Chichester, 1978;
Vol. 2, Part B, p 49.
(3) (a) Yoshimura, J .; Tamaru, M. Carbohydr. Res. 1979, 72, C9.
(b) Tamaru, M.; Horito, S.; Yoshimura, J . Bull. Chem. Soc. J pn. 1980,
53, 3687. (c) Yoshimura, J .; Horito, S.; Hashimoto, H. Chem. Lett. 1981,
375. (d) Horito, S.; Ohashi, Y.; Gassner, N.; Yoshimura, J .; Sasada, Y.
Bull. Chem. Soc. J pn. 1981, 54, 2147. (e) Horito, S.; Asano, K.;
Umemura, K.; Hashimoto, H.; Yoshimura, J . Carbohydr. Res. 1983,
121, 175. (f) Yoshimura, J .; Horito, S.; Tamura, J .; Hashimoto, H.
Chem. Lett. 1985, 1335. (g) Asano, K.; Horito, S.; Saito, A.; Yoshimura,
J . Carbohydr. Res. 1985, 136, 1. (h) Tamura, J .; Horito, S.; Hashimoto,
H.; Yoshimura, J . Carbohydr. Res. 1988, 174, 181.
(4) (a) J aurand, G.; Beau, J .-M.; Sinay¨, P. J . Chem. Soc., Chem.
Commun. 1982, 701. (b) Beau, J .-M.; J aurand, G.; Esnault, J .; Sinay¨,
P. Tetrahedron Lett. 1987, 28, 1105. (c) Trumtel, M.; Tavecchia, P.;
Veyrieres, A.; Sinay¨, P. Carbohydr. Res. 1990, 202, 257.
(5) (a) Ganguly, A. K.; Sarre, O. Z.; McPhall, A. T.; Miller, R. W. J .
Chem. Soc., Chem. Commun. 1979, 22. (b) Kupfer, E.; Neupert-Laves,
K.; Dobler, M.; Keller-Schierlein, W. Helv. Chim. Acta 1982, 65, 3.
(6) (a) Ohtake, H.; Iimori, T.; Ikegami, S. Tetrahedron Lett. 1997,
38, 3413. (b) Iimori, T.; Ohtake, H.; Ikegami, S. Tetrahedron Lett. 1997,
38, 3415. (c) Ohtake, H.; Iimori, T.; Shiro, M.; Ikegami, S. Heterocycles
1998, 47, 685. (d) Ohtake, H.; Iimori, T.; Ikegami, S. Synlett 1998, 1420.
(7) DeWolfe, R. H. Carboxylic Ortho Acid Derivatives. In Organic
Chemistry; Blomquist, A. T., Ed.; Academic Press: 1970; Vol. 14.
(8) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21,
1357.
10.1021/jo0005868 CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/31/2000

4-O,6-O-Glycosylidene Glycosides
J . Org. Chem., Vol. 65, No. 24, 2000 8165
Sch em e 1
Sch em e 2
of sec- or tert-alkoxy silane and a catalytic amount of
TMSOTf.9 As the preparation of ortho esters from lac-
tones seemed to be similar to that of ketals from ketones,
we tried to apply their methods to the preparation of
sugar ortho esters. Although a direct application of this
method to the ortho ester formation was not effective,
we revealed that sugar ortho esters were efficiently
formed by using methoxy silane instead of sec- or tert-
alkoxy silane (Scheme 1). To obtain high yields, it was
required that the MeOH and hexamethyldisiloxane pro-
duced were removed from the reaction mixtures under
reduced pressure during the course of the reactions.
By our improved method, we prepared the 12 sugar
ortho esters listed in Table 1 in 71-90% yields. We used
six sugar lactones, 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-
lactone (1),10 2,3,4,6-tetra-O-benzyl-D-galactono-1,5-lac-
tone (2),11 2,3,4,6-tetra-O-benzyl-D-mannono-1,5-lactone
(3),11 2,3,4-tri-O-benzyl-D-fucono-1,5-lactone (4), 2,3,4-tri-
O-benzyl-L-fucono-1,5-lactone (5),12 and 2,3,4-tri-O-benz-
yl-L-rhamnono-1,5-lactone (6), and two â-diol type gly-
cosides, methyl 2,3-di-O-benzyl-R-D-glucopyranoside (7)
and methyl 2,3-di-O-benzyl-R-D-galactopyranoside (8),13
in this preparation. These starting materials are all
known compounds except lactones 4 and 6, which were
prepared by the oxidation of corresponding hemiac-
etals14,15 with DMSO/acetic anhydride. Remarkably, all
the ortho esters in Table 1 were afforded as single
isomers, despite the fact that two stereoisomers were
possible around the spiro centers.
The role of TMSOMe under these reaction conditions
is still not clear. While the reaction of the diol-type
glycoside 7 with the sugar lactone 1 rapidly attained an
equilibrium to afford the interglycosidic ortho ester 9 in
the presence of TMSOMe and a catalytic amount of
TMSOTf, the reaction of the corresponding trimethyl-
silylated diol 26 with 1 proceeded far more slowly in the
presence of the same amount of catalyst (Scheme 2,
below). Thus, we presume that TMSOMe may activate
the carbonyl groups of sugar lactones instead of diol
groups. It is plausible that the dimethyl or methyl
trimethylsilyl ortho ester 2516 is produced under these
reaction conditions and that the formed ortho ester 25
reacts more efficiently with 7 than the lactone 1 (Scheme
2, above).
Deter m in a tion of th e Absolu te Con figu r a tion s of
th e Sp ir o Cen ter s in th e Su ga r Or th o Ester Mol-
ecu les. All of the ortho esters listed in Table 1 possess
perhydrospiro[2H-pyran-2,2′-pyrano[3,2-d][1,3]dioxin] ring
systems commonly in their molecules and were afforded
as single isomers. To determine the absolute configura-
tion of the spiro centers of ortho esters, X-ray crystal-
(9) Kurihara, M.; Miyata, N. Chem. Lett. 1995, 263.
(10) (a) Kuzuhara, H.; Fletcher, H. G. J r. J . Org. Chem. 1967, 32,
2531. (b) Hanessian, S.; Ugolini, A. Carbohydr. Res. 1984, 130, 261.
(11) Lewis, M. D.; Cha, J . K.; Kishi, Y. J . Am. Chem. Soc. 1982,
104, 4976.
(12) Cai, S.; Stroud, M. R.; Hakomori, S.; Toyokuni, T. J . Org. Chem.
1992, 57, 6693.
(14) Fre´chet, J . M. J .; Baer, H. H. Carbohydr. Res. 1975, 42, 369.
(15) Lai, W.; Martin, O. R. Carbohydr. Res. 1993, 250, 185.
(16) Dimethyl or methyl trimethylsilyl acetals of sugar lactones are
known to be formed from sugar lactones and TMSOMe in the presence
of TMSOTf: Yoshimura, J .; Horito, S.; Asano, K.; Hashimoto, H.
Tennen Yuki Kagobutsu Toronkai Koen Yoshishu, 24th (J apan), 1981;
p 638.
(13) Kiss, J . v.; Burkhardt, F. Helv. Chim. Acta 1970, 53, 1000.

8166 J . Org. Chem., Vol. 65, No. 24, 2000
Ta ble 1. P r ep a r a tion of Su ga r Or th o Ester s fr om Su ga r La cton es a n d Su ga r Diols
Ohtake et al.
a
These reactions were carried out at rt under Ar in toluene (initial concentration [lactone] ) [7 or 8] ) 100-200 mM, [TMSOMe] )
1-2 M (10 equiv), [TMSOTf] ) 5-10 mM (5 mol %)). During the reaction, generated MeOH and TMSOTMS were removed under reduced
pressure (5 mmHg, 1 h × 2). Yield is the isolated yield.
lographic analyses of the four ortho esters (11, 14, 17,
20) were performed. As describe bellow, it was revealed
that the prepared ortho esters could be classified into the
following four groups: the ortho esters formed from
D-sugar lactones (1, 2, 3, 4) and 7, the ones from L-sugar
lactones (5, 6) and 7, the ones from D-sugar lactones and
8, and the ones from L-sugar lactones and 8 from the
point of the configurations of their ring systems. The
analyzed four sugar ortho esters were regarded as the
representatives of these groups.
Among them only ortho ester 11 was a crystalline
compound suitable for X-ray analysis, which was ob-
tained as colorless needles from an ether/hexane solution.
The others were debenzylated by Pd/C-H2 and then
converted into penta- or hexaacetylated compounds (21-
23) with Ac2O/pyridine,3g which were also recrystallized
from ether/hexane to afford colorless prisms. The X-ray
single crystallographic structures of the four ortho esters
are represented in Figure 1 by ball-and-stick models.17
From the spatial relationship of the glycoside and the
glycosylidene moieties, the configuration of the spiro
centers of 11, 14, 17, and 20 were determined as R, R,
S, and S, respectively.
The configuration of the spiro centers of the other ortho
esters were estimated by molecular modeling studies. We
performed LOMD conformational searches18 for two
possible isomers of 12 ortho esters (total 24 molecules)
using MacroModel 6.019 with the MM2* force field. As
summarized in Table 2, it was suggested that one of the
(17) The X-ray analysis revealed that the prisms were formed from
two different conformers in the cases of the ortho esters 14, 17, 20. In
Figure 1, one of the two conformers of each ortho ester was illustrated.
The configurations of anomeric centers and the conformations of ring
systems were the same between the two conformers in each case.
(18) (a) Kolossva´ry, I.; Guida, W. C. J . Am. Chem. Soc. 1996, 118,
5011. (b) Cheng, G.; Guida, W. C.; Still, W. C. J . Am. Chem. Soc. 1989,
111, 4379.

4-O,6-O-Glycosylidene Glycosides
J . Org. Chem., Vol. 65, No. 24, 2000 8167
F igu r e 1. The X-ray single-crystal structure of sugar ortho esters. Hydrogen atoms were omitted. See ref 17.
Ta ble 2. Differ en ce in ∆E betw een F a vor ed Isom er s a n d
20 to be S. The configurations estimated by the calcula-
tions corresponded to the results of the X-ray analysis
in the cases with the ortho esters 11, 14, 17, 20. The
estimated configuration of the ortho ester 9 also cor-
responded to the results of X-ray analysis performed by
Yoshimura and co-workers.
Disfa vor ed Isom er s of Su ga r Or th o Ester s
ortho
ester
anomeric
configuration
dioxane
form
∆∆E
favored
configuration
(kcal)a
9
10
11
12
13
14
15
16
17
18
19
20
R
S
R
S
R
S
R
S
R
S
R
S
R
S
R
S
R
S
R
S
R
S
R
S
chair
skew boat
chair
skew boat
chair
skew boat
chair
skew boat
chair
skew boat
chair
skew boat
skew boat
chair
skew boat
chair
skew boat
chair
skew boat
chair
skew boat
chair
skew boat
chair
4.2
4.9
5.0
3.4
6.4
7.8
9.8
10.0
7.3
8.0
6.1
4.7
R
R
R
R
R
R
Discu ssion
From the above molecular modeling studies, it was
estimated that R-isomers were commonly more stable
than S-ones in the cases of the ortho esters (9-14) formed
from 7, and that S-isomers were energetically more
favorable than R-ones in all the cases of the ortho esters
(15-20) formed from 8. Further, it was indicated by the
calculations that the conformations of the ring systems
of the favored or disfavored isomers were divided into
the four types according to the groups described above.
Namely, it was suggested for each prepared ortho ester
that the conformations of the ring systems proposed for
two possible isomers and the relative stability between
them depended only on whether D- or L-sugar lactone was
located in the glycosylidene moiety and on whether 7 or
8 was located in the diol moiety. In Figures 2 and 3, the
typical four conformations of the ring systems of the
energetically favored isomers (Figure 2) and those of
disfavored ones (Figure 3) are illustrated.20 The benzyl
substituents on the molecules are omitted to show the
shapes of the ring systems more clearly in Figures 2 and
3. The results of our four X-ray crystallographic analyses
and that of Yoshimura and co-workers3g corresponded to
these estimations from the points of the configurations
S
S
S
S
S
S
a
LOMD18 for sugar ortho esters were performed using Macro-
Model ver. 6.019 with the MM2*. ∆∆E ) ∆E(favored isomer) -
∆E(disfavored isomer).
possible isomers of each ortho ester was more stable by
3.4-10.0 kcal/mol than the other in each case. It was well
explained by these differences that the prepared sugar
ortho esters were all afforded as single isomers. From
these results, we estimated the configuration of the spiro
centers of the ortho esters 9-14 to be R, and that of 15-
(20) LOMD for sugar ortho esters were continued until around 3000
conformers for each ortho ester were generated. Even if the steps in
LOMD were not enough for the determination of the conformations of
the whole molecules including benzyl protective groups, the conforma-
tions of the ring systems in the lower energy conformers were the same
in each case.
(19) Mohamadi, F.; Richards, N. G. J .; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendricson, T.; Still, W. C. J .
Comput. Chem. 1990, 11, 440.

8168 J . Org. Chem., Vol. 65, No. 24, 2000
Ohtake et al.
F igu r e 4. Proposed conformations for both isomers of 24a
calculated by LOMD18 using MacroModel ver 6.0.19 All of the
hydrogen atoms were omitted. (a) See ref 23.
Sch em e 3
F igu r e 2. Typical four conformations for favored isomers
calculated by LOMD18 using MacroModel ver 6.0.19 All of the
benzyl groups and the hydrogen atoms on the molecules were
omitted.
favored isomers, which were located in the center of the
molecules, were the chair forms. Contrary, in the cases
of four disfavored isomers, the conformations of dioxane
rings were the skew boat forms (Figure 3). It should be
further noted that 5′-O of the favored isomers were in
the axial positions of the chair formed dioxane rings but
that 5′-O of the disfavored ones could not be in the axial
positions of the central dioxane rings if the rings were
chair formed. The conformational differences between
two possible isomers can be simply explained by consid-
ering the anomeric effects derived from two oxygen atoms
in dioxane rings.21,22 It was expected that each 5′-O atom
prefers to be located in the axial position of dioxane ring
because of the overlapping between the n orbitals of two
oxygen atoms in dioxane ring and the σ* orbital of the
C(1′)-O(5′) bond. By considering the relative stability of
the chair form compared to the skew boat form, it was
easy to explain that one of the two possible isomers was
energetically more favorable than the other in each case.
To indicate that the differences in energy listed in
Table 2 were principally caused from those of these ring
systems more clearly, the molecular modeling studies on
the isomers of 5,6′-di-tert-butyl-perhydrospiro[2H-pyran-
2,2′-pyrano[3,2-d][1,3]dioxin] (24a -d ) (Scheme 3) were
performed. Figure 4 shows the calculated conformations
of two possible isomers of (5R,4a′R,6′R,8a′S)-5,6′-di-tert-
butyl-perhydrospiro[2H-pyran-2,2′-pyrano[3,2-d][1,3]-
dioxin] (24a ). These molecules could be regarded as the
models for the sugar ortho esters formed from D-sugar
lactones and 7. It was suggested also in this case that
one of the isomers in which the 5′-O atom was in the axial
position of the chair form dioxane ring was more stable
than the other23 and that the dioxane ring in the molecule
of the disfavored isomer formed a skew boat (Table 3,
Figure 4). The conformational searches for the both
F igu r e 3. Typical four conformations for disfavored isomers
calculated by LOMD18 using MacroModel ver 6.0.19 All of the
benzyl groups and the hydrogen atoms on the molecules were
omitted.
of anomeric carbons and the conformations of the ring
systems in the molecules of the favored isomers and thus
strongly supported these estimations. Especially, the
result of the X-ray analysis of the mannosylidene ortho
ester 11 and that of the glucosylidene ortho ester 9 clearly
indicated that even the configurations of the two positions
of the sugar lactones used did not affect the configura-
tions of the adjacent spiro centers and the conformations
of the ring systems in the molecules of the ortho esters
formed.
These results indicate that the difference in stability
of two possible isomers of each ortho ester is principally
caused by that of the ring systems. To reveal the basis
for these results, we compared the difference in the
conformations of the ring systems between the favored
and disfavored isomers of ortho esters estimated by
calculations. As shown in Figure 2, the conformations of
dioxane rings in the molecules of the four representative
(21) (a) Lemieux, R. U. In Molecular Rearrangements; De Mayo, P.,
Ed.; Interscience: New York, 1964. (b) Kirby, A. J . The Anomeric Effect
and Related Stereoelectronic Effects at Oxygen; Springer-Verlag: Ber-
lin, 1983.
(22) Conformational analysis for ortho esters containing 1,3-dioxane
ring systems in their molecules has been reported. (a) Pihlaja, K.;
Heokklia¨, J . Acta Chem. Scand. 1967, 21, 2390. (b) Eliel, E. L.; Nader,
F. W. J . Am. Chem. Soc. 1970, 92, 584. (c) Salzner, U.; Schleyer, P. v.
R. J . Org. Chem. 1994, 59, 2138.

4-O,6-O-Glycosylidene Glycosides
J . Org. Chem., Vol. 65, No. 24, 2000 8169
tri-O-benzyl-L-fucono-1,5-lactone (5),12 methyl 2,3-di-O-benzyl-
R-D-glucopyranoside (7), methyl 2,3-di-O-benzyl-R-D-galacto-
pyranoside (8),13 2,3,4-tri-O-benzyl-D-fucopyranose (27),15 and
2,3,4-tri-O-benzyl-L-rhamnopyranose (28)14 were prepared ac-
cording to the established methods.
2,3,4-Tr i-O-b en zyl-D-fu con o-1,5-la ct on e (4) a n d 2,3,4-
Tr i-O-ben zyl-L-r h a m n on o-1,5-la cton e (6). Compound 27
(1.0 g, 2.2 mmol) was dissolved in dimethyl sulfoxide (24 mL)
and acetic anhydride (12 mL), and the mixture was stirred
under Ar at room temperature overnight. The resulting
mixture was partitioned between EtOAc and water. The
organic layer was washed several times with water to remove
the acetic anhydride, dried over Na2SO4, filtered, and concen-
trated. The residue was chromatographed on silica gel (EtOAc/
Ta ble 3. Differ en ce in ∆E betw een F a vor ed Isom er s a n d
Disfa vor ed Isom er s of Mod el Or th o Ester s
ortho
ester
anomeric
configuration
dioxane
form
∆∆E
favored
configuration
(kcal)a
24a
24b
24c
24d
R
S
R
S
R
S
R
S
skew boat
chair
skew boat
chair
chair
skew boat
chair
4.1
5.2
6.3
4.1
Sb
Sb
Rb
Rb
skew boat
a
LOMD18 for sugar ortho esters were performed using Macro-
Model ver. 6.019 with the MM2*. ∆∆E ) ∆E(favored isomer) -
∆E(disfavored isomer). See ref 23.
n-hexane 1:6) to afford 4 as a colorless oil (0.90 g, 90%): [R]21
D
b
+ 87.8° (c 1.0, CHCl3); IR (neat, cm-1) 3036, 2938, 2869 1747,
1603, 1496; HRMS(EI) m/z calcd for C27H28O5 432.1937, found
432.1937 (M+). According to the same procedure, 6 was
prepared from corresponding hemiacetal 28 in 88% yield as a
isomers of compounds 24b, 24c, and 24d , which were
regarded as models for the sugar ortho esters formed
from the L-sugar lactones and 7, from the D-sugar
lactones and 8, and from the L-sugar lactones and 8,
respectively, afforded results that were also compatible
to those with the sugar ortho esters (Table 3, Figure 4).
colorless oil: [R]21 -3.2° (c 1.1, CHCl3); IR (neat, cm-1) 3032,
D
2937, 2869, 1772, 1732, 1603, 1496; HRMS(EI) calcd for
C27H28O5 432.1937, found 432.1938.
P r ep a r a tion of Su ga r Or th o Ester s. To a solution of
lactone 1 (400 mg, 0.74 mmol) and diol 8 (277 mg, 0.74 mmol)
in toluene (5 mL) was added TMSOMe (1.0 mL, 7.4 mmol) and
TMSOTf (7 µL, 5 mol %) at room temperature under Ar. After
1 h of stirring, the solvent was removed under reduced
pressure (5 mmHg, 1 h). The reaction vessel was leaked with
Ar, and the remainder was again dissolved in toluene. TM-
SOMe (1.0 mL, 7.4 mmol) and TMSOTf (7 µL, 5 mol %) was
added to the solution, and the mixture was stirred for further
30 min. The solvent was removed under reduced pressure
again. The remainder was dissolved in toluene containing 5%
Et3N, and the mixture was applied to a silica gel column
chromatography (ether/hexane 1:3 then 1:2) to afford 15 as a
colorless syrup (598 mg, 90%). According to the same proce-
dure, other sugar ortho esters were prepared in the yields
listed in Table 1.
Con clu sion
We prepared the 12 sugar ortho esters (9-20), which
possess perhydrospiro[2H-pyran-2,2′-pyrano[3,2-d][1,3]-
dioxin] ring systems commonly in their molecules. Re-
markably, all of the prepared ortho esters were obtain-
able as single structural isomers. The structures of the
formed ortho esters were determined or estimated by the
X-ray single crystallographic analysis and molecular
modeling studies. By comparing the structures of these
ortho esters, we revealed that one of the two possible
isomers that were expected was more stable by the
consideration of anomeric effects derived from the two
oxygen atoms of the central dioxane ring generated
predominately in each case.
Meth yl 2,3-d i-O-ben zyl-4,6-O-(2,3,4,6-tetr a -O-ben zyl-D-
glu cop yr a n o-sylid en e)-r-D-glu cop yr a n osid e (9): colorless
syrup; [R]22D +38.0° (c 0.91, CHCl3); IR (neat, cm-1) 2920, 2857,
1711, 1603, 1456, 1377; MS(FAB) m/z 933 (M + K)+, 917 (M
+ Na)+, 895 (M + H)+, 826 (M - Bn + Na)+; HRMS(FAB) calcd
for C55H58O11Na 917.3877, found 917.3892.
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. 1H and 13C NMR
spectra were recorded with a 400 MHz (1H NMR) pulse Fourier
transform NMR spectrometer in CDCl3 solution with tetra-
methylsilane as an internal standard. Thin-layer chromatog-
raphy (TLC) was performed on precoated plates (Merck TLC
aluminum sheets silica 60 F254) with detection by UV light or
with phosphomolybdic acid in ethanol/H2O followed by heating.
Column chromatography was performed using SiO2 (Wakogel
C-200, Wako).
Meth yl 2,3-d i-O-ben zyl-4,6-O-(2,3,4,6-tetr a -O-ben zyl-D-
ga la ctop yr a n o-sylid en e)-r-D-glu cop yr a n osid e (10): color-
less syrup; [R]22 +31.6° (c 1.0, CHCl3); IR (neat, cm-1) 3063,
D
2920, 1726, 1604, 1587; MS(FAB) m/z 933 (M + K)+, 917 (M
+ Na)+, 895 (M + H)+, 826 (M - Bn + Na)+; HRMS(FAB) calcd
for C55H58O11Na 917.3877, found 917.3866.
Meth yl 2,3-d i-O-ben zyl-4,6-O-(2,3,4,6-tetr a -O-ben zyl-D-
m a n n op yr a n o-sylid en e)-r-D-glu cop yr a n osid e (11): color-
less needle; mp 107.5-108.5 °C; [R]21 -6.9° (c 1.0, CHCl3);
D
Ca lcu la tion s. Low-mode searches (LOMD)18 were per-
formed using MacroModel ver. 6.019 with the MM2* derivative
of the MM2 force field on a Silicon Graphics IRIS-Indigo
workstation. LOMD for the sugar ortho esters (9-20) were
continued until around 3000 conformers for each ortho ester
were generated. In the case of the model compounds (24a -
d ), the total steps in LOMD were 10 000, and 150-700
conformers were generated for each molecule.
Ma ter ia ls. Solvents were freshly distilled prior to use.
TMSOMe was a commercial product and was used as received.
TMSOTf was distilled under an inert atmosphere of argon.
All of the starting substrates for the preparation of sugar
lactones and percially protected sugar compounds were com-
mercially available and were used as received or were purified
by distillation, if necessary. 2,3,4,6-Tetra-O-benzyl-D-glucono-
1,5-lactone (1),10 2,3,4,6-tetra-O-benzyl-D-galactono-1,5-lactone
(2),11 2,3,4,6-tetra-O-benzyl-D-mannono-1,5-lactone (3),11 2,3,4-
IR (KBr, cm-1) 3374, 2930, 2857, 2361, 2339, 1711, 1460, 1377;
MS(FAB) m/z 933 (M + K)+, 917 (M + Na)+, 895 (M + H)+,
826 (M - Bn + Na)+; HRMS(FAB) calcd for C55H58O11Na
917.3877, found 917.3894. Anal. Calcd for C55H58O11: C, 73.81;
H, 6.53. Found: C, 73.84; H, 6.53.
Meth yl 2,3-d i-O-ben zyl-4,6-O-(2,3,4-tr i-O-ben zyl-D-fu -
cop yr a n osyl-id en e)-r-D-glu cop yr a n osid e (12): colorless
syrup; [R]20D +26.7° (c 1.1, CHCl3); IR (neat, cm-1) 3373, 2926,
1711, 1460, 1377; MS(FAB) m/z 827 (M + K)+, 811 (M + Na)+,
789 (M + H)+; HRMS(FAB) calcd for C48H52O10Na 811.3458,
found 811.3472.
Meth yl 2,3-d i-O-ben zyl-4,6-O-(2,3,4-tr i-O-ben zyl-L-fu -
cop yr a n osyl-id en e)-r-D-glu cop yr a n osid e (13): colorless
syrup; [R]20D -32.9° (c 1.1, CHCl3); IR (neat, cm-1) 3347, 2855,
2359, 1462, 1377; MS(FAB) m/z 827 (M + K)+, 811 (M + Na)+,
789 (M + H)+; HRMS(FAB) calcd for C48H52O10Na 811.3458,
found 811.3474.
Meth yl 2,3-di-O-ben zyl-4,6-O-(2,3,4-tr i-O-ben zyl-L-r h am -
n op yr a n osyl-id en e)-r-D-glu cop yr a n osid e (14): colorless
(23) In the case of compound 24a , the configuration of the spiro
carbon in the favored isomer should be indicated as S, because the
substituents on the ring system are different from that of sugar ortho
esters.
syrup; [R]21 +9.5° (c 1.1, CHCl3); IR (neat, cm-1) 3378, 2924,
D
2361, 1462, 1377; MS(FAB) m/z 827 (M + K)+, 811 (M + Na)+,

8170 J . Org. Chem., Vol. 65, No. 24, 2000
Ohtake et al.
789 (M + H)+; HRMS(FAB) calcd for C48H52O10Na 811.3458,
found 811.3442.
calcd for C48H52O10Na 811.3458, found 811.3448. Anal. Calcd
for C48H52O10: C, 73.08; H, 6.64. Found: C, 72.88; H, 6.71.
P r ep a r a tion of Acetyla ted Su ga r Or th o Ester s. Benzyl-
protected sugar ortho esters (14, 17, 20) were debenzylated
by Pd/C under H2 atmosphere according to the method
reported by Yoshimura and co-workers.3g The resulting com-
pounds were treated with acetic anhydride/pyridine (1:1) to
afford acetylated ortho esters in 85-95% yields.
Meth yl 2,3-d i-O-a cetyl-4,6-O-(2,3,4-tr i-O-a cetyl-D-r h a m -
n op yr a n osyl-id en e)-r-D-glu cop yr a n osid e (21): colorless
prisms; mp 165-166 °C; [R]24D +39.2° (c 1.0, CHCl3); IR (KBr,
cm-1) 1757, 1372, 1213; MS(EI) m/z 548 (M)+, 517( M - OMe)+,
488 (M - AcOH)+. Anal. Calcd for C23H32O15: C, 50.36; H, 5.88.
Found: C, 50.35; H, 5.90.
Meth yl 2,3-d i-O-ben zyl-4,6-O-(2,3,4,6-tetr a -O-ben zyl-D-
glu cop yr a n o-sylid en e)-r-D-ga la ctop yr a n osid e (15): color-
less syrup; [R]20 +76.5° (c 1.1, CHCl3); IR (neat, cm-1) 3063,
D
2361, 2340, 1736, 1604, 1497; MS(FAB) m/z 933 (M + K)+,
917 (M + Na)+, 895 (M + H)+, 826 (M - Bn + Na)+; HRMS-
(FAB) calcd for C55H58O11Na 917.3877, found 917.3865.
Meth yl 2,3-d i-O-ben zyl-4,6-O-(2,3,4,6-tetr a -O-ben zyl-D-
ga la ctop yr a n o-sylid en e)-r-D-ga la ctop yr a n osid e (16): col-
orless powder; mp 108.5-109.5 °C; [R]21D +73.6° (c 1.0, CHCl3);
IR (neat, cm-1) 3348, 2924, 2855, 1711, 1462, 1377; MS(FAB)
m/z 933 (M + K)+, 917 (M + Na)+, 895 (M + H)+, 826 (M - Bn
+ Na)+; HRMS(FAB) calcd for C55H58O11Na 917.3877, found
917.3866. Anal. Calcd for C55H58O11
Found: C, 73.89; H, 6.56.
:
C, 73.81; H, 6.53.
Met h yl 2,3-d i-O-a cet yl-4,6-O-(2,3,4,6-t et r a -O-a cet yl-D-
m a n n op yr a n o-sylid en e)-r-D-ga la ctop yr a n osid e (22): col-
Meth yl 2,3-d i-O-ben zyl-4,6-O-(2,3,4,6-tetr a -O-ben zyl-D-
m a n n op yr a n o-sylid en e)-r-D-ga la ctop yr a n osid e (17): col-
orless syrup; [R]20D +18.2° (c 1.1, CHCl3); IR (neat, cm-1) 3373,
2926, 1711, 1460, 1377; MS(FAB) m/z 933 (M + K)+, 917 (M
+ Na)+, 895 (M + H)+, 826 (M - Bn + Na)+; HRMS(FAB) calcd
for C55H58O11Na 917.3877, found 917.3884.
Meth yl 2,3-d i-O-ben zyl-4,6-O-(2,3,4-tr i-O-ben zyl-D-fu -
cop yr a n osyl-id en e)-r-D-ga la ctop yr a n osid e (18): colorless
syrup; [R]20D +86.4° (c 1.1, CHCl3); IR (neat, cm-1) 3347, 2855,
2359, 1462, 1377; MS(FAB) m/z 827 (M + K)+, 811 (M + Na)+,
789 (M + H)+; HRMS(FAB) calcd for C48H52O10Na 811.3458,
found 811.3474.
orless prisms; mp 147-148 °C; [R]24 +144.1° (c 1.0, CHCl3);
D
IR (KBr, cm-1) 1754, 1373, 1221; MS(EI) m/z 606 (M)+, 575
(M - OMe)+, 546 (M - AcOH)+. Anal. Calcd for C25H34O17: C,
49.51; H, 5.65. Found: C, 49.02; H, 5.59.
Meth yl 2,3-d i-O-a cetyl-4,6-O-(2,3,4-tr i-O-a cetyl-D-r h a m -
n op yr a n osyl-id en e)-r-D-ga la ctop yr a n osid e (23): colorless
prisms; mp 198-200 °C; [R]27D +111.5° (c 1.0, CHCl3); IR (KBr,
cm-1) 1750, 1373, 1227; MS(EI) m/z 548 (M)+, 517 (M - OMe)+,
488 (M - AcOH)+. Anal. Calcd for C23H32O15: C, 50.36; H, 5.88.
Found: C, 50.32; H, 5.90.
Ack n ow led gm en t. We are grateful to Misses J .
Shimode, J . Nonobe, and M. Kitsukawa for spectroscopic
measurements. Partial financial support for this re-
search from the Ministry of Education, Science, Sports
and Culture of J apan is gratefully acknowledged.
Meth yl 2,3-d i-O-ben zyl-4,6-O-(2,3,4-tr i-O-ben zyl-L-fu -
cop yr a n osyl-id en e)-r-D-ga la ctop yr a n osid e (19): colorless
syrup; [R]21 +6.1° (c 0.7, CHCl3); IR (neat, cm-1) 3380, 2926,
D
1725, 1462, 1377; MS(FAB) m/z 827 (M + K)+, 811 (M + Na)+,
789 (M + H)+; HRMS(FAB) calcd for C48H52O10Na 811.3458,
found 811.3456.
Su p p or tin g In for m a tion Ava ila ble: X-ray data for 11,
21-23 and the peak assignments in 1H and 13C NMR spectra
for 4, 6, and 9-23. This material is available free of charge
via the Internet at http://pubs.acs.org.
Meth yl 2,3-di-O-ben zyl-4,6-O-(2,3,4-tr i-O-ben zyl-L-r h am -
n op yr a n osyl-id en e)-r-D-ga la ctop yr a n osid e (20): colorless
powder; mp 93.5-95.0 °C; [R]19 +52.1° (c 1.1, CHCl3); IR
D
(neat, cm-1) 3409, 2926, 2359, 1711, 1458, 1377; MS(FAB) m/z
827 (M + K)+, 811 (M + Na)+, 789 (M + H)+; HRMS(FAB)
J O0005868