Synthesis of 3,7-anhydro-D-glycero-D-ido-octitol 1,5,6-trisphosphate as an IP3 receptor ligand using a radical cyclization reaction with a vinylsilyl tether as the key step. Conformational restriction strategy using steric repulsion between adjacent bulky protecting groups on a pyranose ring

Article abstract of DOI:10.1021/jo0002339

3,7-Anhydro-D-glycero-D-ido-octitol 1,5,6-trisphosphate (5) was designed as a novel IP₃-receptor ligand having a C-glycosidic structure and was synthesized via a radical cyclization reaction with a temporary connecting vinylsilyl tether as the key step. The phenyl 2-O-dimethylvinylsilyl-3,4,6-tri-O-benzyl-1-seleno-β-D-glucopyranoside (7), in the usual ⁴C₁-conformation, was successively treated with Bu₃SnH/AIBN and under Tamao oxidation conditions to give a mixture of five C-glycosidic products. On the other hand, similar successive treatment of the corresponding 3,4-di-O-TBS-protected substrates 13 and 24, which were in an unusual ¹C₄-conformation due to the steric repulsion between the bulky silyl protecting groups, gave the desired 1α-C-glycosides 18 and 25, respectively, as the major products. Thus, the course of the radical cyclization was effectively controlled by a change in the conformation of the pyranose ring into a ¹C₄-form due to steric repulsion between the adjacent bulky TBS-protecting groups at the 3- and 4-hydroxyl groups. From 25, the target 5 was synthesized via phosphorylation of the hydroxyls by the phosphoramidite method. The C-glycoside trisphosphate 5 has significant binding affinity for IP₃ receptor of calf cerebella.

Full text of DOI:10.1021/jo0002339

J . Org. Chem. 2000, 65, 5547-5557
5547
Syn th esis of 3,7-An h yd r o-D-glycer o-D-id o-octitol
1,5,6-Tr isp h osp h a te a s a n IP 3 Recep tor Liga n d Usin g a Ra d ica l
Cycliza tion Rea ction w ith a Vin ylsilyl Teth er a s th e Key Step .
Con for m a tion a l Restr iction Str a tegy Usin g Ster ic Rep u lsion
betw een Ad ja cen t Bu lk y P r otectin g Gr ou p s on a P yr a n ose Rin g
Satoshi Shuto,* Yumi Yahiro, Satoshi Ichikawa, and Akira Matsuda
Graduate School of Pharmaceutical Sciences, Hokkaido University,
Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, J apan
shu@pharm.hokudai.ac.jp
Received February 18, 2000
3,7-Anhydro-D-glycero-D-ido-octitol 1,5,6-trisphosphate (5) was designed as a novel IP3-receptor
ligand having a C-glycosidic structure and was synthesized via a radical cyclization reaction with
a temporary connecting vinylsilyl tether as the key step. The phenyl 2-O-dimethylvinylsilyl-3,4,6-
tri-O-benzyl-1-seleno-â-D-glucopyranoside (7), in the usual 4C1-conformation, was successively
treated with Bu3SnH/AIBN and under Tamao oxidation conditions to give a mixture of five
C-glycosidic products. On the other hand, similar successive treatment of the corresponding 3,4-
1
di-O-TBS-protected substrates 13 and 24, which were in an unusual C4-conformaion due to the
steric repulsion between the bulky silyl protecting groups, gave the desired 1R-C-glycosides 18
and 25, respectively, as the major products. Thus, the course of the radical cyclization was effectively
1
controlled by a change in the conformation of the pyranose ring into a C4-form due to steric repulsion
between the adjacent bulky TBS-protecting groups at the 3- and 4-hydroxyl groups. From 25, the
target 5 was synthesized via phosphorylation of the hydroxyls by the phosphoramidite method.
The C-glycoside trisphosphate 5 has significant binding affinity for IP3 receptor of calf cerebella.
In tr od u ction
D-Myo-inositol 1,4,5-trisphosphate (IP3, 1),1 an intra-
cellular Ca2+-mobilizing second messenger, is of great
interest because of its significant biological importance.2
Accordingly, analogues of IP3 have been synthesized
extensively to develop specific ligands for the receptors,
which are very useful for proving the mechanism of IP3-
mediated Ca2+ signaling pathways.3 However, none of
these analogues has surpassed IP3 itself either in binding
affinity for the IP3 receptor or Ca2+-mobilizing activity.3
Recently, Takahashi and co-workers isolated adeno-
phostin A (2) and B (3) from Penicillium brevicompactum
and found them to be very strong IP3 receptor ligands.
Compounds 2 and 3 are 10-100 times more potent than
IP3 with regard to both their affinity for the IP3 receptor
and their Ca2+-mobilizing ability in cells.4 These interest-
ing biological and structural features have prompted
several groups including ours to perform synthetic stud-
ies of novel IP3 receptor ligands based on the structure
of adenophostins.5,6 For instance, two groups6a,b,g inde-
pendently designed and synthesized 2-hydroxyethyl R-D-
* Corresponding author: Tel: 81-11-706-3229; Fax: 81-11-706-4980.
F igu r e 1.
(1) Berridge, M. J . Nature (London) 1993, 361, 315-325.
(2) Wilcox, R. A.; Primrose, W. U.; Nahorski, S. R.; Challiss, R. A.
J . Trends Pharmacol. Sci. 1998, 19, 467-475.
(3) Potter, B. V. L.; Lampe, D. Angew. Chem., Int. Ed. Engl. 1995,
34, 1933-1972, and references sited therein.
(4) (a) Takahashi, M.; Kagasaki, T.; Hosoya, T.; Takahashi, S. J .
Antibiot. 1993, 46, 1643-1647. (b) Takahashi, S.; Kinoshita, T.;
Takahashi, M. J . Antibiot. 1994, 47, 95-100. (c) Takahashi, M.;
Tanzawa, K.; Takahashi, S. J . Biol. Chem. 1994, 269, 369-372. (d)
Hirota, J .; Michikawa, T.; Miyawaki, A.; Takahashi, M.; Tanzawa, K.;
Okura, I.; Furuichi, T.; Mikoshiba, K. FEBS Lett. 1995, 368, 248-
252.
glucopyranoside 3,4,2′-trisphosphate (4) as a simplified
analogue of the adenophostins and showed that it was
an agonist of the IP3 receptor. These studies also indi-
cated that the R-D-glucopyranose structure is a good
bioisostere of the myo-inositol backbone of IP3.
On the basis of these findings, we became interested
in the corresponding C-glycosidic analogues having the
R-D-glucopyranoside structure as potential IP3 receptor
10.1021/jo0002339 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/10/2000

5548 J . Org. Chem., Vol. 65, No. 18, 2000
Shuto et al.
Sch em e 1
ligands. Since C-glycosides can be a biologically stable
mimic of the corresponding O-glycosides,7 we designed
the R-C-glycoside trisphosphates 5 and 6 as novel IP3
receptor ligands.
Sch em e 2
It has been recognized that the three-dimensional
locations of the phosphate groups of IP3 receptor ligands
are critical points for their biological activity.3,5 The
conformation around the glycosidic linkages in carbohy-
drates, such as the adenophostins and their analogues,
which is known to be affected significantly by the
anomeric effect of the sugar-ring oxygen, is an important
determinant in the three-dimensional structure of these
molecules.8 Therefore, we were interested in investigating
the biological activity and the conformation of 6 with the
biological activity and the conformation of the corre-
sponding O-glycoside 4. We thought that the data from
this investigation might indicate the role of the glycosidic
oxygen in the biological activity of these compounds.
Although the O-glycoside trisphosphate 4 is an agonist
of the IP3 receptor, its potency is ∼10-fold lower than IP3.
We hypothesized that the lower affinity of 4 for the
receptor compared to that of IP3 itself may be due to the
length of the side-chain, which may be too long to allow
the third phosphate to achieve an efficient positioning
for binding to the receptor. Therefore, to test this
hypothesis, we designed the one-carbon-reduced analogue
5.9 In this report, we describe the synthesis of the R-C-
glycoside trisphosphate 5 using a radical reaction with
a temporary connecting vinylsilyl tether as the key
C-glycosidation step. During our synthetic study, we
found that the reaction course of the radical cyclization
of the D-glucose substrates was effectively controlled by
a change in the conformation of the pyranose ring to a
1C4-form because of the steric repulsion between the
adjacent bulky TBS-protecting groups at the 3- and
4-hydroxyl groups.10
(5) Studies on analogues of adenophostin A by us: (a) Tatani, K.;
Shuto, S.; Ueno, Y.; Matsuda, A. Tetrahedron Lett. 1998, 39, 5065-
5068. (b) Shuto, S.; Tatani, K.; Ueno, Y.; Matsuda, A. J . Org. Chem.
1998, 63, 8815-8824. (c) Kashiwayanagi, M.; Tatani, K.; Shuto, S.;
Matsuda, A. Eur. J . Neurosci. 2000, 12, 606-612. (d) Abe, H.; Shuto,
S.; Matsuda, A. Tetrahedron Lett. 2000, 41, 2391-2394. (e) Shuto, S.;
Terauchi, M.; Yahiro, Y.; Abe, H.; Ichikawa, S.; Matsuda, A Tetrahe-
dron Lett., 2000, 41, 4151-4155. (f) Abe, H.; Shuto, S.; Matsuda, A. J .
Org. Chem. 2000, 65, 4315-4325.
(6) Studies on the analogues of adenophostin A by others: (a)
J enkins, D. J .; Marwood, R. D.; Potter, B. V. L. Carbohydr. Res. 1996,
287, 169-182. (b) Marchant, J . S.; Beecroft, M. D.; Riley, A. M.;
J enkins, D. J .; Marwood, R. D.; Taylor, C. W.; Potter, B. V. L.
Biochemistry 1997, 36, 12780-12790. (c) Murphy, C. T.; Riley, A. M.;
Lindley, C. J .; J enkins, D. J .; Westwick, J .; Potter, B. V. L. Mol.
Pharmacol. 1997, 52, 741-748. (d) Marwood, R. D.; Riley, A. M.;
Vanessa, C.; Taylor, C. W.; Potter, B. V. L. Bioorg. Med. Chem. Lett.
1999, 9, 453-459. (e) Beecroft, M. D.; Marchant, J . S.; Riley, A. M.;
van Straten, N. C. R.; van der Marel, G. A.; van Boom, J . H; Potter, B.
V. L.; Taylor, C. W. Mol. Pharmacol. 1999, 55, 109-116. (f) Marwood,
R. D.; Shuto, S.; J enkins, D. J .; Potter, B. V. L. Chem. Commun. 2000,
219-220. (g) Wilcox, R. A.; Erneux, C.; Primrose, W. U.; Gigg, R.;
Nahorski, S. R. Mol. Pharmacol. 1995, 47, 1204-1211. (h) van Straten,
N. C. R.; van der Marel, G. A.; van Boom, J . H. Tetrahedron 1997, 53,
6523-6538. (i) van Straten, N. C. R.; Kriek, N. M. A. J .; Cziria, Z. A.
C.; van der Marel, G. A.; van Boom, J . H. Tetrahedron 1997, 53, 6539-
6554. (j) Hotoda, H.; Murayama, K.; Miyamoto, S.; Iwata, Y.; Taka-
hashi, M.; Kawase, Y.; Tanzawa, K.; Kaneko, M. Biochemistry 1999,
38, 9234-9241.
Resu lts a n d Discu ssion
Syn th etic P la n . In the synthesis of the target com-
pound 5, formation of the C-glycosidic linkage with the
desired 1R-configuration is considered the key step.
Because of the unique biological activities of C-glycosides,
considerable effort has been devoted to developing practi-
cal methods for their preparation.7 The use of radical
reactions is one of the most efficient methods for con-
structing C-glycosidic bonds and a number of studies
have been reported using these reactions.7
Recently, we developed a regio- and stereoselective
method for introducing three kinds of C2-substituents,
such as 1-hydroxyethyl, 2-hydroxyethyl, and vinyl groups
(7) (a) Postema, M. H. D. Tetrahedron 1992, 48, 8545-8599. (b)
J aramillo, C.; Knapp S. Synthesis 1994, 1-20. (c) Levy, D. E.; Tang,
C. The Chemistry of C-Glycosides; Oxford: Pergamon Press: 1995. (d)
Postema, M. H. D. C-Glycoside Synthesis; CRC Press: Boca Raton,
1995.
(8) (a) J uaristi, E.; Cuevas, G. Tetrahedron 1992, 48, 5019-5087.
(b) Chapleur, Y. Eds.; Carbohydrate Mimics; Wiley-VCH: Weinheim,
1998.
(9) Synthesis of the corresponding O-glycoside of 5 may be difficult,
since the compound would be rather unstable due to the phosporyl-
oxymethyloxy (-OCH2OPO32-) substituent at the anomeric position.
(10) A part of this study has been described in a communication:
Yahiro, Y.; Ichikawa, S.; Shuto, S.; Matsuda, A. Tetrahedron Lett. 1999,
40, 5527-5531.

C-Glycoside Trisphosphate as an IP3 Receptor Ligand
J . Org. Chem., Vol. 65, No. 18, 2000 5549
Sch em e 3
Ta ble 1. Syn th esis of C-glycosid es by th e Ra d ica l Rea ction s w ith 2-O-Vin ylsilyl-Teth er ed Su bstr a tes
entry
substrate (concn, M)
methoda
solvent
temp (°C)
yield
product (ratio)b
1
2
3
4
5
6
7
7 (0.01)
7 (0.002)
7 (0.002)
13a (0.01)
13a (0.002)
13b (0.002)
13c (0.002)
A
B
B
A
B
B
B
benzene
benzene
ClPhH
benzene
ClPhH
ClPhH
ClPhH
80
80
130
80
130
130
130
92
92
45
85
50
63
60
8, 9, 10, 11 (6:35:22:37)
8, 9, 10, 11, 12 (31:20:12:28:9)
8, 12 (20:80)
18, 19, 20 (6:49:45)
18, 19, 20 (74:15:11)
18, 19, 20 (87:6:7)
18, 19, 20 (77:8:15)
a
A: A mixture of the substrate, Bu3SnH (1.3 equiv), and AIBN (0.6 equiv) in benzene was heated under reflux for 20 min. B: To a
refluxing solution of the substrate in benzene or chlorobenzene (ClPhH) was added slowly over 1 h a mixture of Bu3SnH (1.3 equiv) and
b
AIBN (0.6 equiv) in the same solvent. Determined by HPLC.
at the â-position of a hydroxyl group in halohydrins or
in R-phenylselenoalkanols A using an intramolecular
radical cyclization reaction with a dimethyl- or a diphenyl-
vinylsilyl group as a temporary connecting radical-
acceptor tether (Scheme 1).11 Thus, the selective intro-
duction of both 1-hydroxyethyl and 2-hydroxyethyl groups
can be achieved, depending on the concentration of
Bu3SnH in the reaction system, via a 5-exo-cyclization
intermediate G or a 6-endo-cyclization intermediate F ,
respectively, after oxidative ring-cleavage by treating the
cyclization products under Tamao oxidation conditions,12
as shown in Scheme 1.11a,b A vinyl group can also be
introduced by photoirradiation of the vinylsilyl ether A
in the presence of (Bu3Sn)2 followed by treatment of the
resulting atom-transfer 5-exo-cyclization product J with
fluoride ion.11e The results of our investigation of the
radical cyclization mechanism11a,b,f,g suggested that the
kinetically favored 5-exo-cyclized radical C, formed from
radical B, was trapped when the concentration of Bu3SnH
was high enough to give G. At lower concentrations of
Bu3SnH and higher reaction temperatures, the radical
C rearranged into the more stable ring-enlarged 4-oxa-
3-silacyclohexyl radical E via a pentavalent-like silicon
radical transition state D, which was then trapped with
Bu3SnH to give F .11g
We planned to develop a novel procedure for introduc-
ing a C2 unit stereoselectively at the 1R-position of
D-glucose via this radical cyclization reaction with a
vinylsilyl group as a temporary connecting tether and
then to apply this procedure to the synthesis of the target
C-glycoside 5. Scheme 2 shows our synthetic plan. We
chose the phenyl 1-seleno-D-glucopyranosides I with a
vinylsilyl tether at the 2-hydroxyl as the substrates for
the radical reaction because they are stable and easy to
prepare. The radical reaction under thermodynamic
conditions and subsequent Tamao oxidation would give
the desired C-glycosides II, which could then be converted
into the target trisphosphate 5 via introduction of the
three phosphate groups using the phosphoramidite
method.
th e Su bstr a te. First, the radical reaction was investi-
gated with the 2-O-dimethylvinylsilyl ether of 3,4,6-tri-
O-benzyl-protected phenyl l-seleno-â-D-glucose (7) as the
substrate. Phenyl 3,4,6-tri-O-benzyl-1-seleno-â-D-glucose
(6), prepared by the known method,13 was treated with
commercially available dimethylvinylchlorosilane, DMAP,
and Et3N in toluene at room temperature to give the
corresponding 2-O-silyl ether 7, the substrate for the
radical reaction, in high yield (Scheme 3).
The radical reactions were performed with Bu3SnH (1.3
equiv)/AIBN (0.6 equiv) in benzene (80 °C) or chloroben-
zene (130 °C), and the products were obtained after
Tamao oxidation. The results are summarized in Table
1. A mixture of 7, Bu3SnH, and AIBN was heated in
benzene under reflux (kinetic conditions). The reaction
gave a mixture of four R-C-glycosides, i.e., the desired
2-hydroxyethyl derivative 8 via the 6-endo-cyclization
product, the 1-hydroxyethyl derivatives 9 and 10 via the
corresponding 5-exo cyclization products, and 5-epimer-
ized 1-hydroxyethyl derivative 11 in a ratio of 6:35:22:
37 (entry 1). When a mixture of Bu3SnH and AIBN in
benzene was added slowly to a solution of 7 in refluxing
benzene (thermodynamic conditions), the result was a
mixture of 8, 9, 10, 11, and compound 12 in which the
4-benzyloxy group had been eliminated (entry 2). A
similar reaction under thermodynamic conditions at 130
°C with chlorobenzene as a solvent likewise proved
unsuccessful and gave 12 as the major product (entry 3).
(11) (a) Shuto, S.; Kanazaki, M.; Ichikawa, S.; Matsuda, A. J . Org.
Chem. 1997, 62, 5676-5677. (b) Shuto, S.; Kanazaki, M.; Ichikawa,
S.; Minakawa, N.; Matsuda, A. J . Org. Chem. 1998, 63, 746-754. (c)
Ueno, Y.; Nagasawa, Y.; Sugimoto, I.; Kojima, N.; Kanazaki, M.; Shuto,
S.; Matsuda, A. J . Org. Chem. 1998, 63, 1660-1667. (d) Sugimoto, I.;
Shuto, S.; Mori, S.; Shigeta, S.; Matsuda, A. Bioorg. Med. Chem. Lett.
1999, 9, 385-388. (e) Sugimoto, I.; Shuto, S.; Matsuda, A. J . Org.
Chem. 1999, 64, 7153-7157. (f) Sugimoto, I.; Shuto, S.; Matsuda, A.
Synlett 1999, 1766-1768. (g) Shuto, S.; Sugimoto, I.; Abe, H.; Matsuda,
A. J . Am. Chem. Soc. 2000, 122, 1343-1351. (h) Kanazaki, M.; Ueno,
Y.; Shuto, S.; Matsuda, A. J . Am. Chem. Soc. 2000, 122, 2422-2432.
(12) Tamao, K.; Ishida, N.; Kumada, M. J . Org. Chem. 1983, 48,
2120-2122.
(13) Synthesis of C-glycosides via radical cyclizations with a (2-
phenylethynyl)silyl tether has been reported: Stork, G.; Suh, H. S.;
Kim, G. J . Am. Chem. Soc. 1991, 113, 7054-7055.
Ra d ica l Rea ction s w ith 2-O-Vin ylsilyl Eth er s of
P h en yl 3,4,6-Tr i-O-ben zyl-1-selen o-â-D-glu cose a s

5550 J . Org. Chem., Vol. 65, No. 18, 2000
Shuto et al.
Sch em e 4
F igu r e 2.
F igu r e 3.
The stereochemistries of 9, 10, and 11 were confirmed
from their 1H NMR and NOESY spectra and NOE
experiments, after converting the compounds into their
corresponding acetonides 9′, 10′, and 11′ (Figure 2).
A deuterium labeling experiment with Bu3SnD instead
of Bu3SnH under conditions identical to those in entry 1
was performed, and the positions and rates of deuterium
Th e Con for m a tion -F lip Str a tegy: Ra d ica l Rea c-
tion s w ith 2-O-Vin ylsilyl Eth er s of P h en yl 3,4,6-Tr i-
O-TBS-1-selen o-D-glu cosid es a s th e Su bstr a tes. Re-
cently, it was recognized that introducing a significantly
bulky protecting group at the 3- and 4-trans-hydroxyl
groups of pyranoses causes a flip of their conformation
leading to an unusual 1C4-form, in which the bulky
substituents are in axial positions due to mutual steric
repulsion.15-18 Suzuki and co-workers first reported this
type of conformational feature of pyranosides and ef-
ficiently synthesized aryl R-C-glycosides using a confor-
mation-flipped donor (Figure 4a).15 We successfully con-
structed the tricyclic sugar moiety of herbicidin B, a
nucleoside antibiotic, via a facial selective reduction of
the enone system of the substrate, the conformation of
which was effectively restricted by steric repulsion
between the bulky silyl groups on the pyranose ring
(Figure 4b).16 On the basis of these findings, we designed
the 3,4-di-O-TBS-protected D-glucose derivatives 13 as
alternative substrates, which might adopt an unusual
1C4-conformation because of the steric effect of the bulky
TBS groups. We assumed that the exo-cyclized radical
intermediate x, derived from an anomeric radical ix,
would also prefer, due to steric repulsion between the
1
incorporation into the products based on their H NMR
spectra are shown in Figure 3. These results suggested
the reaction pathway shown in Scheme 4, in which the
5-hydrogen abstraction occurs via the 5-exo-cyclized 1′S-
radical ii-S. The anomeric radical i, derived from 7,
cyclized to give a mixture of the 5-exo-products 1′S-radical
ii-S and 1′R-radical ii-R, as we expected, a part of which
was then trapped with Bu3SnD to produce iii-S and iii-
R, deuterium-labeled at the methyl group. The radical
ii-R was ring-enlarged into iv, which was trapped with
Bu3SnD to give v labeled at the position â to the silicon.
In the 1′S-radical ii-S, the primary radical would be
located very close to the 5-position, and accordingly, the
5-hydrogen was abstracted to generate a relatively stable
tertiary radical vi. The reduction of vi by Bu3SnD from
the R- or â-face gave iii-S and its 5-epimer vii, respec-
tively, the 5-positons of which were deuterium-labeled,
and an elimination of benzyloxy radical from vi would
give viii.14 On the basis of this reaction pathway, the 1′-
configuration of the benzyloxy-eliminated product viii
should be S.
(15) Hosoya, T.; Ohashi, Y.; Matsumoto, T.; Suzuki, K. Tetrahedron
Lett. 1996, 37, 663-666.
(16) Ichikawa, S.; Shuto, S.; Matsuda, A. J . Am. Chem. Soc. 1999,
121, 10270-10280.
(17) X-ray crystallographic analysis of a 3,4,6-tri-O-TBS-glucose
derivative in a 1C4-conformation: Walford, C.; J ackson, R. F. W.; Rees,
N. H.; Clegg, W.; Heath, S. L. Chem. Commun. 1997, 1855-1856.
(18) For other examples, see: (a) Roush, W. R.; Sebesta, S. P.;
Bennett, C. E. Tetrahedron 1997, 53, 8825-8836. (b) Roush, W. R.;
Sebesta, D. P.; J ames, R. A. Tetrahedron 1997, 53, 8837-8852. (c)
Nunez, R.; Unwalla, R. J .; Cartledge, F. K.; Cho, S. G.; Riches, B. H.;
Glenn, M. P.; Hungerford, N. L.; Lambert, L. K.; Brecknell, D. J .;
Kitching, W. J . Chem. Soc., Perkin Trans. 2 1997, 1365-1368.
The radical reaction as described above was unsuc-
cessful, and the results suggested that the conformations
of the substrates 7 might be unsuitable for occurring the
desired radical ring-enlargement reaction.
(14) A similar 5-hydrogen abstraction has been found during the
radical cyclization study with a phenyl 1-seleno-â-D-glucoside attaching
an allyl group at the 2-hydroxyl: De Mesmaeker, A.; Waldner, A.;
Hoffmann, P.; Winkler, T. Synlett 1994, 330-332.

C-Glycoside Trisphosphate as an IP3 Receptor Ligand
J . Org. Chem., Vol. 65, No. 18, 2000 5551
Sch em e 5
results are shown in Table 1. These reactions (entries
4-7) gave the three C-glycosidic products, i.e., the 1R-
(2-hydroxyethyl)-C-glycoside 18 via the 6-endo-cycloza-
tion product, and the 1R-(1-hydroxyethyl)-C-glycosides 19
and 20 via the 5-exo-cyclization products, where no
products via the 5-hydrogen abstraction reaction were
detected. Heating the 2-O-dimethylvinylsilyl-â-phenyl-
seleno substrate 13a , having a dimethylvinylsilyl tether,
in the presence of Bn3SnH and AIBN in benzene at 80
°C selectively gave the 1R-(1-hydroxyethyl)-C-glycosides
19 and 20, along with a trace of the 1R-(2-hydroxyethyl)-
C-glycoside 18 (entry 4, 85%, 18:19:20 ) 6:49:45). When
a mixture of Bn3SnH and AIBN was added slowly to a
solution of 13a in chlorobenzene at 130 °C, the ring-
enlargement reaction effectively occurred to give the
desired 1R-(2-hydroxyethyl)-C-glycoside 18 as the major
product (entry 5, 50%, 18:19:20 ) 74:15:11). The yield of
the desired 18 was increased in a similar thermodynamic
reaction with 13b, having a diphenylvinylsily tether, as
a substrate (entry 6, 63%, 18:19:20 ) 87:6:7). Similar
results were obtained with the 2-O-diphenylvinylsilyl-R-
phenylseleno substrate 13c (entry 7, 60%, 18:19:20 ) 77:
8:15). Thus, this conformation-flip strategy successfully
improved the yields of the desired 1R-(2-hydroxyethyl)-
C-glycoside.
F igu r e 4.
TBS groups, a 1C4-conformation, in which the primary
radical would not be close to the 5-hydrogen. Accordingly,
the desired product xii would be obtained as the major
product via the radical ring-enlargement reaction, with-
out the product of 5-hydrogen abstraction, as shown in
Scheme 5.
The substrates were prepared from the known glycal
1419 as shown in Scheme 6. The TBS groups were
introduced at the 3-, 4-, and 6-hydroxyls of 14, and the
resulting compound 15 was successively treated with
dimethyldioxirane and PhSeH/(CF3CO)2O in CH2Cl2 to
give 1-â-phenylselenide 16 and 1-R-phenylselenide 1720
in 53% and 28% yields, respectively. A dimethyl- and/or
diphenylvinylsilyl tether was then introduced at the
2-hydroxyl of the phenylselenides to give 13a , 13b, and
13c, the substrates for the radical reaction. The confor-
mation of the substrate 13a was investigated by 1H NMR
and compared to that of the previous tri-O-benzyl-
protected substrate 7 (Figure 5). While the relatively
large coupling constants in the benzyl substrate 7 suggest
These results demonstrated that the ring-enlargement
reaction of a 3-oxa-2-silacyclopentylmethyl radical into
a 4-oxa-3-silacyclohexyl radical, which was previously
observed in nucleosides and indane derivatives,11 oc-
curred in this hexopyranose system.
Syn th esis of th e P oten t IP 3 Recep tor Liga n d 5.
Based on the above results, the synthesis of the target
compound 5 was next performed, using the radical
reaction based on the conformation-flip strategy, as
summarized in Scheme 7. To introduce the phosphate
units at the desired positions later, selective protection
of the hydroxyls of the radical reaction substrate was
required. Therefore, we chose phenyl 6-O-trityl-3,4-di-
O-TBS-1-seleno-D-glucoside 24, with a diphenylvinylsilyl
tether at the 2-hydroxy, as the substrate. Two TBS
groups were introduced at the free hydroxyls of the
known 6-O-trityl-glycal 2121 by the usual method to give
22. Oxidation of the glycal 22 with dimethyldioxirane
gave the corresponding 1,2-epoxide, which was im-
4
that it has the usual C1-conformation (Figure 5a), the
rather small coupling constants in the TBS-protected 13a
indicate that it prefers a flipped 1C4-conformation, as
expected (Figure 5b).
Radical reactions of 13a , 13b, and 13c were carried
out under kinetic [treatment in the presence of Bn3SnH
(1.3 equiv)/AIBN (0.6 equiv) at 80 °C] or thermodynamic
[slow addition of Bu3SnH (1.3 equiv)/AIBN (0.6 equiv)
over 1 h at 130 °C] conditions. The products were isolated
as the corresponding pentabenzoates (Scheme 6); the
(19) Friesen, R. W.; Danishefsky, S. J . J . Am. Chem. Soc. 1989, 111,
6656-6660.
(20) The anomeric configuration was determined by NOE experi-
ments (400 MHz, pyridine-d5): when the anomeric proton of 17 was
irradiated, an NOE (14.0%) was observed at the 6-protons.
(21) Esswein, A.; Rembold, H.; Schmidt, R. R. Carbohydr. Res. 1990,
200, 287-305.

5552 J . Org. Chem., Vol. 65, No. 18, 2000
Shuto et al.
Sch em e 6
Sch em e 7
F igu r e 5.
mediately treated with PhSeH under basic conditions to
give the 1â-phenylselenide 23 stereoselectively. The
vinylsilyl tether was introduced at the 2-hydroxyl of 23
by the method described above to complete the prepara-
tion of the radical reaction substrate 24. The radical
reaction under conditions identical to those for entry 6
in Table 1, and subsequent oxidative treatment without
fluoride ion to avoid the undesired removal of the TBS
groups, successfully produced the desired 1R-C-glycoside
25 in 55% yield. After protecting the primary hydroxyl
with a TBDPS group, we next investigated various means
of protecting the 2-hydroxyl of compound 26. Although
the protection by a benzyl, THP, or pivaloyl group proved
unsuccessful, the corresponding 2-O-acetate 27 was
obtained quantitatively when 26 was heated with Ac2O
and DMAP at 60 °C in MeCN. The three silyl groups of
27 were removed simultaneously with TBAF to give 28.
Phosphate units were introduced, using the phosphor-
amidite method with o-xylene N,N-diethylphosphoramid-
ite (XEPA) developed by Watanabe and co-workers.22
Thus, 28 was treated with XEPA and tetrazole in CH2Cl2,
followed by oxidation with m-CPBA to give the desired
trisphosphate derivative 29 in 77% yield. Finally, the
o-xylene, trityl, and acetyl protecting groups were suc-
cessively removed with hydrogenation, acidic hydrolysis,
and basic hydrolysis to give the target compound 5 in
84% yield as a sodium salt, after treatment with ion-
exchange resin.
Conditions: (a) TBSCl, imidazole, DMF, 60 °C, 85%; (b) (1)
dimethyldioxirane, CH2Cl2, 0 °C-rt, (2) PhSeH, Et3N, CH2Cl2, 0
°C-rt; (c) diphenylvinylchlorosilane, Et3N, DMAP, toluene, rt, 56%
from 22; (d) (1) Bu3SnH, AIBN, ClPhH, reflux, (2) H2O2, NaHCO3,
aq MeOH/THF, rt, 52%; (e) TBDPSCl, imidazole, DMF, rt, quant,
(f) Ac2O, DMAP, MeCN, 60 °C, quant; (g) TBAF, AcOH, THF, rt,
92%; (h) (1) XEPA, tetrazole, CH2Cl2, rt, (2) m-CPBA, -40 °C, 77%;
(i) (1) H2, Pd-C, MeOH, rt, (2) TFA, MeOH, rt, (3) aq NaOH, rt,
84%.
notable that the binding affinity of the C-glycoside
trisphosphate 5 was only about 2-fold lower than that of
IP3 itself (IC50 ) 16 nM), since the previous study showed
that the O-glycoside trisphosphate 4 was 25-fold lower
than IP3 in the affinity for the receptor.6b The different
activity between the C-glycoside 5 and the O-glycoside 4
may not be due to the property of the glycosidic linkage,
since the side-chain length of 5 is also different from that
of 4. However, these results clearly show that the
C-glycoside trisphosphate 5 can be a good lead for
designing further useful compounds as IP3 receptor
ligands.
The binding affinity of the synthesized 5 for the IP3
receptor of calf cerebella was evaluated in vitro with [3H]
IP3 as a radioligand.23 Compound 5 significantly inhibited
the binding of [3H] IP3 with an IC50 value of 36 nM. It is
(22) Watanabe, Y.; Komoda, Y.; Ebisuya, K.; Ozaki, S. Tetrahedron
Lett. 1990, 31, 255-256.
(23) The binding affinity was evaluated with “Inositol-1,4,5-Tris-
phosphate [3H] Radioreceptor Assay Kit” (NEM Life Science Products),
according to the procedure described in its catalog.

C-Glycoside Trisphosphate as an IP3 Receptor Ligand
J . Org. Chem., Vol. 65, No. 18, 2000 5553
by HPLC (aqueous 60% MeCN, 9.9 mL/min, 260 nm) to give
pure 8 (10 mg), 9 (6 mg), 10 (3 mg), 11 (8 mg), and 12 (2 mg),
respectively.
Con clu sion . We have designed and successfully syn-
thesized 3,7-anhydro-D-glycero-D-ido-octitol 1,5,6-tris-
phosphate (5), as a potential IP3 receptor ligand. During
our synthetic study, we developed a useful method for
constructing the R-C-glycosidic structure using the radi-
cal cyclization reaction with a temporary connecting
vinylsilyl tether, in which conformational restriction due
to steric repulsion between adjacent bulky protecting
groups on a pyranose ring was effectively used. Biological
evaluation of 5 showed that it is a potent IP3 receptor
ligand as we expected.
(2R,3S,4R,5S,6S)-4,5-Diben zyloxy-6-ben zyloxym eth yl-
3-h yd r oxy-2-(2-h yd r oxyet h yl)t et r a h yd r op yr a n (8): 1H
NMR (500 MHz, CDCl3) 7.46-7.23 (m, 15 H, aromatic), 4.63-
4.53 (m, 6 H, benzyl-CH2), 4.13 (m, 1 H, 2-CH), 4.13 (ddd, 1
H, 6-CH, J ) 4.5, 4.7, 7.6 Hz), 3.89 (dd, 1 H, 6-CH2OBn, J )
7.6, 10.4 Hz), 3.78 (dq, 2 H, 2-CH2CH2OH, J ) 4.7, 4.7 Hz),
3.75 (dd, 1 H, 4-CH, J ) 4.5, 4.5 Hz), 3.61 (br s, 1 H, 3-CH),
3.57 (dd, 1 H, 6-CH2OBn, J ) 4.7, 10.4 Hz), 3.50 (dd, 1 H,
5-CH, J ) 4.5, 4.5 Hz), 3.05, 2.65 (each br s, each 1 H, OH x
2), 2.02, 1.74 (each m, each 1 H, 2-CH2CH2OH); 13C NMR (125
MHz, CDCl3) 137.84, 137.81, 137.27, 128.58, 128.54, 128.45,
128.03, 127.99, 127.90, 127.84, 127.79, 127.63, 77.13, 74.71,
73.56, 73.28, 72.75, 70.13, 69.59, 67.61, 60.67, 31.51; HRMS
(FAB, positive) calcd for C29H35O6 479.2434, found 479.2431
(MH+).
Exp er im en ta l Section
1
Chemical shifts of H and 13C spectra are reported in ppm
1
downfield from TMS. The H NMR assignments reported for
the key compounds were in agreement with COSY spectra.
Thin-layer chromatography was done on Merck coated plate
60F254. Silica gel chromatography was done on Merck silica
gel 5715. HPLC were performed with YMC-Pack (for purifica-
tion, R&D 5-A, 20 × 250 mm; for analysis, ODS-M80, 4.6 ×
250 mm). Reactions were carried out under an argon atmo-
sphere.
(2R,3S,4R,5S,6R)-4,5-Diben zyloxy-6-ben zyloxym eth yl-
3-h yd r oxy-2-[(1R)-1-h yd r oxyeth yl]tetr a h yd r op yr a n (9):
1H NMR (500 MHz, CDCl3) 7.35-7.23 (m, 15 H, aromatic),
4.64-4.48 (m, 6 H, benzyl-CH2), 4.11 [dq, 1 H, 2-CH(OH)CH3,
J ) 6.5, 7.4 Hz], 4.07 (m, 1 H, 6-CH), 3.99 (ddd, 1 H, 3-CH, J
) 2.7, 4.8, 8.0 Hz), 3.79 (t, 1 H, 4-CH, J ) 4.8 Hz), 3.77 (dd, 1
H, 6-CH2OBn, J ) 6.2, 10.0 Hz), 3.67 (dd, 1 H, 6-CH2OBn, J
) 5.1, 10.0 Hz), 3.63 (m, 1 H, 5-CH), 3.57 (dd, 1 H, 2-CH, J )
2.7, 7.4 Hz), 3.42 (d, 1 H, 3-OH, J ) 8.0 Hz), 2.84 [br s, 1 H,
2-CH(OH)CH3], 1.27 [d, 3 H, 2-CH(OH)CH3, J ) 6.5 Hz]; 13C
NMR (125 MHz, CDCl3) 138.07, 137.78, 137.30, 128.56, 128.50,
128.37, 127.99, 127.92, 127.69, 127.66, 127.62, 77.21, 74.57,
74.25, 73.68, 73.30, 73.09, 72.69, 68.39, 68.05, 67.06, 19.71;
HRMS (FAB, positive) calcd for C29H35O6 479.2434, found
479.2422 (MH+).
P h en yl 3,4,6-Tr i-O-ben zyl-2-O-d im eth ylvin ylsilyl-1-se-
len o-â-D-glu cop yr a n osid e (7). A mixture of 6 (1.76 g, 3.00
mmol), Et3N (1.68 mL, 12.0 mmol), DMAP (37 mg, 0.30 mmol),
and dimethylvinylchlorosilane (1.65 mL, 12.0 mmol) in toluene
(30 mL) was stirred at room temperature for 15 min. The
insoluble materials were filtered off with Celite, and the
filtrated was partitioned between EtOAc and saturated aque-
ous NH4Cl. The organic layer was washed with brine, dried
(Na2SO4), and evaporated. The residue was purified by silica
gel column chromatography (EtOAc/hexane; 1:20 then 1:10)
(2R,3S,4R,5S,6R)-4,5-Diben zyloxy-6-ben zyloxym eth yl-
3-h yd r oxy-2-[(1S)-1-h yd r oxyeth yl]tetr a h yd r op yr a n (10):
1H NMR (500 MHz, CDCl3) 7.34-7.18 (m, 15 H, aromatic),
4.62-4.49 (m, 6 H, benzyl-CH2), 4.35 (t, 1 H, 6-CH, J ) 7.0
Hz), 4.04 [ddq, 1 H, 2-CH(OH)CH3, J ) 0.8, 6.3, 6.6 Hz], 3.85
(dd, 1 H, 6-CH2OBn, J ) 7.0, 9.9 Hz), 3.77 (m, 1 H), 3.69 (dd,
1 H, 3-CH, J ) 2.9, 10.8 Hz), 3.69 (dd, 1 H, 6-CH2OBn, J )
6.6, 9.9 Hz), 3.62 (m, 1 H), 3.50 (dd, 1 H, 2-CH, J ) 2.9, 6.6
Hz), 3.46 (d, 1 H, 3-OH, J ) 10.8 Hz), 2.92 [d, 1 H, 2-CH(OH)-
CH3, J ) 0.8 Hz], 1.18 [d, 3 H, 2-CH(OH)CH3, J ) 6.3 Hz];
13C NMR (125 MHz, CDCl3) 137.95, 137.47, 136.93, 130.06,
129.71, 128.96, 128.53, 128.52, 128.38, 128.08, 127.98, 127.92,
127.66, 127.53, 74.60, 74.51, 73.48, 73.25, 72.84, 72.39, 71.86,
67.73, 67.55, 67.45, 17.67; HRMS (FAB, positive) calcd for
to give 7 (1.91 g, 95%) as an oil: [R]22 -40.2 °(c 1.99, CHCl3);
D
1H NMR (500 MHz, CDCl3) 7.65-7.64 (m, 2 H), 7.33-7.19 (m,
16 H), 7.09-7.08 (m, 2 H), 6.20 (dd, 1 H, J ) 14.8, 20.4 Hz),
5.94 (dd, 1 H, J ) 3.7, 14.8 Hz), 5.74 (dd, 1 H, J ) 3.8, 20.4
Hz), 4.90 (d, 1 H, J ) 11.5 Hz), 4.85 (d, 1 H, J ) 11.5 Hz), 4.82
(d, 1 H, J ) 9.8 Hz), 4.70 (d, 1 H, J ) 10.8 Hz), 4.57 (d, 1 H,
J ) 11.9 Hz), 4.54 (d, 1 H, J ) 10.9 Hz), 4.51 (d, 1 H, J ) 11.9
Hz), 3.76 (dd, 1 H, J ) 8.4, 9.8 Hz), 3.74 (dd, 1 H, J ) 2.0,
11.0 Hz), 3.70 (dd, 1 H, J ) 4.4, 11.0 Hz), 3.65 (dd, 1 H, J )
9.4, 9.4 Hz), 3.50 (dd, 1 H, J ) 8.4, 9.4 Hz), 3.46 (ddd, 1 H, J
) 2.0, 4.4, 9.4 Hz), 0.23 (s, 3 H), 0.22 (s, 3 H); 13C NMR (125
MHz, CDCl3) 138.57, 138.09, 137.87, 137.85, 133.65, 133.02,
129.23, 128.74, 128.17, 128.06, 127.68, 127.57, 127.39, 127.28,
127.08, 126.69, 86.90, 35.35, 80.13, 78.07, 75.02, 74.77, 74.73,
73.26, 68.77; HRMS (FAB, positive) calcd for C37H43O5SeSi
675.2045, found 675.2030 (MH+). Anal. Calcd for C37H42O5-
SeSi: C, 65.96; H, 6.28. Found: C, 65.89; H, 6.40.
C
29H35O6 479.2434, found 479.2437 (MH+).
(2R,3S,4R,5S,6S)-4,5-Diben zyloxy-6-ben zyloxym eth yl-
3-h yd r oxy-2-[(1S)-1-h yd r oxyeth yl]tetr a h yd r op yr a n (11):
1H NMR (500 MHz, CDCl3) 7.35-7.21 (m, 15 H, aromatic),
4.57-4.41 (m, 6 H, benzyl-CH2), 4.03 (ddd, 1 H, 6-CH, J )
1.5, 6.1, 7.0 Hz), 4.01 [dq, 1 H, 2-CH(OH)CH3, J ) 6.3, 3.3
Hz], 3.78 (m, 1 H, 4-CH), 3.68 (m, 1 H, 3-CH), 3.65 (dd, 1 H,
6-CH2OBn, J ) 6.1, 9.5 Hz), 3.61 (dd, 1 H, 6-CH2OBn, J )
7.0, 9.5 Hz), 3.58 (dd, 1 H, 5-CH, J ) 1.5, 3.0 Hz), 3.52 (d, 1
H, 3-OH, J ) 11.6 Hz), 3.45 [d, 1 H, 2-CH(OH)CH3, J ) 7.3
Hz], 2.88 [br s, 1 H, 2-CH(OH)CH3], 1.17 [d, 3 H, 2-CH(OH)-
CH3, J ) 6.3 Hz]; 13C NMR (125 MHz, CDCl3) 138.00, 137.66,
136.87, 128.53, 128.40, 128.37, 128.27, 128.01, 127.78, 127.73,
127.62, 80.30, 74.26, 73.61, 73.44, 73.15, 72.35, 72.16, 68.93,
67.66, 67.49, 17.57; HRMS (FAB, positive) calcd for C29H35O6
479.2434. Found 479.2416 (MH+).
(2R,3R,4S)-4-Ben zyloxy-6-ben zyloxym eth yl-3,4-dih ydr o-
3-h ydr oxy-2-[(1S)-1-h ydr oxyeth yl]-2H-pyr an (12): 1H NMR
(500 MHz, CDCl3) 7.40-7.26 (m, 10 H, aromatic), 5.13 (d, 1
H, 5-CH, J ) 5.0 Hz), 4.67-4.54 (m, 4 H, benzyl-CH2), 4.17
[dq, 1 H, 2-CH(OH)CH3, J ) 3.7, 6.4 Hz], 4.04 (d, 1 H,
6-CH2OBn, J ) 13.0 Hz), 4.00 (d, 1 H, 6-CH2OBn, J ) 13.0
Hz), 3.99 (br s, 1 H, 3-CH), 3.71 (d, 1 H, 2-CH, J ) 3.7 Hz),
3.73 (dd, 1 H, 6-CH, J ) 1.9, 5.0 Hz), 3.14 (d, 1 H, 3-OH, J )
4.8 Hz), 2.57 (d, 1 H, 1′-OH, J ) 6.0 Hz), 1.35 [d, 3 H,
2-CH(OH)CH3, J ) 6.4 Hz]; 13C NMR (125 MHz, CDCl3)
153.93, 138.25, 137.88, 128.45, 128.21, 128.05, 127.78, 96.53,
76.17, 72.42, 71.28, 70.17, 69.42, 69.36, 68.52, 19.43.
Ra d ica l Rea ction of 7, 13a , 13b, a n d 13c (Ta ble 1).
Meth od A (En tr ies 1 a n d 4). A mixture of a substrate (0.40
mmol), Bu3SnH (130 µL, 0.48 mmol), and AIBN (40 mg, 0.24
mmol) in benzene (40 mL) was heated under reflux for 20 min,
and then the resulting solution was evaporated. A mixture of
the residue, aqueous H2O2 (30%, 480 µL, 4.0 mmol), KF (240
mg, 4.0 mmol), and KHCO3 (128 mg, 1.3 mmol) in MeOH/THF
(1:1, 32 mL) was stirred at room temperature for 15 h. Aqueous
Na2S2O3 (1 M, 20 mL) was added, and the resulting insoluble
materials were filtered off. The filtrate was evaporated under
reduced pressure, and the residue was purified by silica gel
column chromatography (EtOAc/hexane; 1:3, 2:3, then 4:1) to
give a mixture of products as a syrup, which was analyzed by
HPLC (75% MeOH, 1.0 mL/min, 260 nm). Meth od B (En tr ies
2, 3, 5, 6, a n d 7). To a refluxing solution of a substrate (0.40
mmol) in benzene or chlorobenzene (40 mL) was added slowly
over 1 h a mixture of Bu3SnH (130 µL, 0.48 mmol) and AIBN
(40 mg, 0.24 mmol) in the same solvent (40 mL), and then the
resulting mixture was evaporated. The residue was treated
under Tamao oxidation conditions, purified, and analyzed by
the procedure identical to the one described in method A.
P u r ifica tion of th e P r od u cts. The mixture of the products
(50 mg) obtained from the reaction in entry 2 was separated

5554 J . Org. Chem., Vol. 65, No. 18, 2000
Shuto et al.
(1R,5R,6R,8R,9R,10S)-3,3,5-Tr im eth yl-9,10-diben zyloxy-
8-b e n zyloxym e t h yl-b icyclo-[4.4.0]-2,4,7-t r ioxa d e ca n e
(Aceton id e 9′). A mixture of 9 (16 mg, 0.030 mmol),
isopropenyl methyl ether (28 µL, 0.30 mmol), and TsOH‚H2O
(1 mg) in DMF (0.5 mL) was stirred at room temperature for
30 min. EtOAc and aqueous saturated NaHCO3 were added,
and the whole was partitioned. The organic layer was washed
with brine, dried (Na2SO4), and evaporated. The residue was
purified by silica gel column chromatography (EtOAc/hexane;
1:10 then 1:5) to give 9′ (12 mg, 75%) as a syrup: 1H NMR
(500 MHz, CDCl3) 7.38-7.22 (m, 15 H, aromatic), 4.86 (d, 1
H, benzyl-CH2, J ) 11.4 Hz), 4.83 (d, 1 H, benzyl-CH2, J )
11.6 Hz), 4.74 (d, 1 H, benzyl-CH2, J ) 11.6 Hz), 4.48 (d, 1 H,
benzyl-CH2, J ) 11.4 Hz), 4.45 (d, 1 H, benzyl-CH2, J ) 12.2
Hz), 4.39 (d, 1 H, benzyl-CH2, J ) 12.2 Hz), 3.97 (dd, 1 H,
1-CH, J ) 5.2, 5.2 Hz), 3.88 (dd, 1 H, 10-CH, J ) 5.2, 9.5 Hz),
3.80 (dd, 1 H, 6-CH, J ) 5.2, 7.7 Hz), 3.80 (m, 1 H, 8-CH),
3.73 (dd, 1 H, 9-CH, J ) 9.5, 9.5 Hz), 3.67 (dq, 1 H, 5-CH, J )
6.3, 7.7 Hz), 3.52 (d, 2 H, 8-CH2OBn, J ) 3.3 Hz), 1.40 (s, 3 H,
3-CH3), 1.37 (s, 3 H, 3-CH3), 1.25 (d, 3 H, 5-CH3, J ) 6.3 Hz);
HRMS (FAB, positive) calcd for C32H39O6 519.2746, found
519.2773 (MH+).
(1R,5S,6S,8R,9R,10S)-3,3,5-Tr im eth yl-9,10-diben zyloxy-
8-b e n zyloxym e t h yl-b icyclo-[4.4.0]-2,4,7-t r ioxa d e ca n e
(Aceton id e 10′). Compound 10′ (7 mg, 75%) was obtained
from 10 (9 mg, 0.02 mmol) as described for the synthesis of 9′
after purification by silica gel column chromatography (EtOAc/
hexane; 1:10 then 1:5): 1H NMR (500 MHz, CDCl3) 7.34-7.24
(m, 15 H, aromatic), 4.74 (d, 1 H, benzyl-CH2, J ) 11.4 Hz),
4.66 (d, 1 H, benzyl-CH2, J ) 11.7 Hz), 4.62 (d, 1 H, benzyl-
CH2, J ) 11.7 Hz), 4.55 (d, 1 H, benzyl-CH2, J ) 12.1 Hz),
4.54 (d, 1 H, benzyl-CH2, J ) 11.4 Hz), 4.47 (d, 1 H, benzyl-
CH2, J ) 11.4 Hz), 4.10 (dd, 1 H, 1-CH, J ) 1.8, 2.3 Hz), 4.04
(dq, 1 H, 8-CH, J ) 3.1, 8.9 Hz), 3.98 (dq, 1 H, 5-CH, J ) 1.8,
6.3 Hz), 3.92 (dd, 1 H, 9-CH, J ) 6.7, 8.9 Hz), 3.75 (dd, 1 H,
10-CH, J ) 2.3, 6.7 Hz), 3.69 (d, 2 H, 8-CH2Bn, J ) 3.1 Hz),
3.56 (dd, 1 H, 6-CH, J ) 1.8, 1.8 Hz), 1.44 (s, 3 H, 3-CH3),
1.43 (s, 3 H, 3-CH3), 1.27 (s, 3 H, 5-CH3); HRMS (FAB, positive)
calcd for C32H39O6 519.2746, found 519.2745 (MH+).
(1R,5S,6S,8S,9R,10S)-3,3,5-Tr im eth yl-9,10-d iben zyloxy-
8-b e n zyloxym e t h yl-b icyclo-[4.4.0]-2,4,7-t r ioxa d e ca n e
(Aceton id e 11′). Compound 11′ (20 mg, quant) was obtained
from 11 (18 mg, 0.04 mmol) as described for the synthesis of
9′ after purification by silica gel column chromatography
(EtOAc/hexane; 1:10 then 1:5): 1H NMR (500 MHz, CDCl3)
7.36-7.21 (m, 15 H, aromatic), 4.64-4.36 (m, 6 H, benzyl-CH2),
4.02 (dq, 1 H, 5-CH, J ) 1.1, 6.4 Hz), 3.95 (dt, 1 H, 8-CH, J )
0.9, 6.1 Hz), 3.88 (br s, 1 H, 1-CH), 3.76 (br s, 1 H, 10-CH),
3.75 (d, 2 H, 8-CH2OBn, J ) 6.1 Hz), 3.46 (br d, 1 H, 9-CH, J
) 0.9 Hz), 3.33 (br d, 1 H, 6-CH, J ) 1.1 Hz), 1.45 (s, 3 H,
3-CH3), 1.44 (s, 3 H, 3-CH3), 1.28 (d, 3 H, 5-CH3, J ) 6.4 Hz);
FRMS (FAB, positive) calcd for C32H39O6 519.2746, found
519.2744 (MH+).
Deu ter iu m -La bel Exp er im en t of 7 w ith Bu 3Sn D. Com-
pounds 8D (4 mg, 8%), 9D (3 mg, 6%), 10D (8 mg, 17%), and
11D (5 mg, 10%) were obtained from 7 (67 mg, 0.10 mmol) by
the procedure identical to entry 1 in Table 1 described above,
with Bu3SnD instead of Bu3SnH, after HPLC purification
(aqueous 60% MeCN, 9.9 mL/min, 260 nm). 8D: FAB-HRMS
(FAB, positive) calcd for C29H34DO6 480.2496, found 480.2473
(MH+). 9D: HRMS (FAB, positive) calcd for C29H34DO6
480.2496, found 480.2491 (NH+). 10D: FAB-HRMS (FAB,
positive) calcd for C29H34DO6 480.2496, found 480.2482 (MH+).
11D: HRMS (FAB, positive) calcd for C29H34DO6 480.2496,
found 480.2487 (MH+).
H, J ) 7.4, 11.2 Hz), 3.89 (dd, 1 H, J ) 3.6, 3.6 Hz), 3.80 (dd,
1 H, J ) 3.6, 3.6 Hz), 3.76 (dd, 1 H, J ) 3.5, 11.2 Hz), 0.93,
0.90, 0.89 (each s, each 9 H), 0.10, 0.10, 0.08, 0.08, 0.06, 0.05
(each s, each 3 H); 13C NMR (125 MHz, CDCl3) 137.98, 96.37,
75.11, 65.23, 61.74, 56.78, 21.00, 20.87, 20.86, 13.45, 13.09,
13.02, -9.20, -9.31, -9.38, -9.69, -10.19, -10.23; HRMS
(FAB, positive) calcd for C24H53O4Si3 489.3432, found 489.3232
(MH+).
P h en yl 3,4,6-Tr is-(O-ter t-bu tyld im eth ylsilyl)-1-selen o-
â-D-glu cop yr a n osid e (16) a n d P h en yl 3,4,6-Tr is-(O-ter t-
b u t yld im et h ylsilyl)-1-selen o-r-D-glu cop yr a n osid e (17).
To a solution of 15 (885 mg, 1.79 mmol) in CH2Cl2 (20 mL)
was added a solution of dimethyldioxirane (0.05 M in acetone,
80 mL) at 0 °C, and the resulting mixture was stirred at room
temperature for 2 h. After the solvent was evaporated, the
residue was dissolved in CH2Cl2, dried (Na2SO4), and evapo-
rated. To a mixture of the residue and PhSeH (3.8 mL, 36
mmol) in CH2Cl2 (4 mL) was added (CF3CO)2O (22 µL, 0.070
mmol) at -40 °C, and the resulting mixture was stirred at
the same temperature for 10 min and then at room temper-
ature for 10 min. The solvent was evaporated, and the residue
was purified by silica gel column chromatography (benzene/
hexane; 1:2 then 1:1) to give 16 (612 mg, 52%) and 17 (332
mg, 28%) as syrups. 16: [R]23D -88.4° (c 0.56, CHCl3); 1H NMR
(500 MHz, CDCl3) 7.64-7.62 (m, 2 H, aromatic), 7.28-7.23
(m, 3 H, aromatic), 5.48 (d, 1 H, 1-CH, J ) 3.1 Hz), 4.49 (m, 1
H, 5-CH), 3.97 (m, 1H), 3.96 (br s, 1 H, 2-OH), 3.93 (dd, 1 H,
4-CH, J ) 4.4, 11.2 Hz), 3.90-3.85 (m, 2 H, 6-CH2), 3.87 (m,
1H), 0.96-0.90 (m, 27 H, t-Bu x 3), 0.17-0.06 (m, 18 H, Si-
CH3 x 6); 13C NMR (125 MHz, CDCl3) 133.25, 129.18, 127.37,
83.91, 91.52, 73.25, 69.45, 62.99, 26.34, 26.16, 26.01, 18.62,
18.49, 18.11, -4.22, -4.32, -4.45, -5.00, -5.07. Anal. Calcd
for C30H58O5SeSi3: C, 54.43; H, 8.83. Found: C, 54.31; H, 8.71.
1
17: [R]22 +31.1°(c 0.46, CHCl3); H NMR (500 MHz, CDCl3‚
D
D2O) 7.57-7.55 (m, 2 H, aromatic), 7.19-7.16 (m, 3 H,
aromatic), 5.51 (s, 1 H, 1-CH), 3.91 (t, 1 H, 5-CH, J ) 6.8 Hz),
3.82 (br s, 1 H, 3-CH), 3.79 (d, 2 H, 6-CH2, J ) 6.8 Hz), 3.71
(br s, 1 H, 4-CH), 3.66 (br s, 1 H, 2-CH), 0.87, 0.79, 0.78 (each
s, each 9 H, t-Bu), 0.04-0.09 (m, 18 H, Si-CH3 x 6); 13C NMR
(125 MHz, CDCl3) 132.84, 130.76, 128.95, 127.05, 81.42, 80.68,
72.87, 71.36, 68.97, 60.85, 25.89, 25.79, 25.75, 18.24, 17.97,
17.96, -4.74, -4.85, -4.93, -5.39. Anal. Calcd for C30H58O5-
SeSi3: C, 54.43; H, 8.83. Found: C, 54.35; H, 8.74.
P h en yl 3,4,6-Tr is-O-(ter t-b u t yld im et h ylsilyl)-2-O-d i-
m eth ylvin ylsilyl-1-selen o-â-D-glu copyr an oside (13a). Com-
pound 13a (213 mg, 48%) was obtained from 16 (400 mg, 0.60
mmol) as described for the synthesis of 7 after purification by
silica gel column chromatography (benzene/hexane; 1:8): [R]22
D
1
-3.8° (c 0.93, CHCl3); H NMR (500 MHz, CDCl3) 7.43-7.41
(m, 2 H, aromatic), 7.08-7.04 (m, 3 H, aromatic), 5.96 (dd, 1
H, vinyl, J ) 14.9, 20.4 Hz), 5.79 (dd, 1 H, vinyl, J ) 3.8, 14.9
Hz), 5.57 (dd, 1 H, vinyl, J ) 3.8, 20.4 Hz), 5.09 (d, 1 H, 1-CH,
J ) 6.7 Hz), 3.76 (br d, 1 H, 2-CH, J ) 6.7 Hz), 3.79-3.61 (m,
5 H), 0.74-0.70 (m, 27 H, t-Bu × 3), 0.06- -0.03 (m, 24 H,
Si-CH3 x 8); 13C NMR (125 MHz, CDCl3) 137.96, 133.48,
133.12, 132.77, 131.24, 128.80, 128.59, 126.72, 83.37, 83.28,
75.97, 74.54, 69.53, 63.85, 26.05, 25.99, 25.74, 18.17, 18.02,
17.86, -1.07, -1.31, -4.41, -4.55, -4.58, -4.67, -5.25; HRMS
(FAB, positive) calcd for C34H67O5SeSi4 746.3153, found 746.3140
(MH+). Anal. Calcd for C34H66O5SeSi4: C, 54.73; H, 8.91.
Found: C, 54.89; H, 9.07.
P h en yl 3,4,6-Tr is-(O-ter t-b u t yld im et h ylsilyl)-2-O-d i-
ph en ylvin ylsilyl-1-selen o-â-D-glu copyr an oside (13b). Com-
pound 13b (198 mg, 78%) was obtained from 16 (198 mg, 0.30
mmol) as described for the synthesis of 7, with diphenylvinyl-
chlorosilane instead of dimethylvinylchlorosilane, after puri-
fication by silica gel column chromatography (benzene/hexane;
1:8 then 1:5): [R]23D -10.5°(c 0.93, CHCl3) 1H NMR (500 MHz,
CDCl3) 7.60-7.59 (m, 4 H, aromatic), 7.42-7.30 (m, 9 H,
aromatic), 7.19-7.17 (m, 2 H, aromatic), 6.47 (dd, 1 H, vinyl,
J ) 14.9, 20.5 Hz), 6.23 (dd, 1 H, vinyl, J ) 3.7, 14.9 Hz), 5.85
(dd, 1 H, vinyl, J ) 3.7, 20.5 Hz), 5.39 (d, 1 H, 1-CH, J ) 5.1
Hz), 4.20 (br d, 1 H, 2-CH, J ) 5.1 Hz), 3.98 (br s, 1 H, 4-CH),
3.97 (m, 1 H, 5-CH), 3.92 (br s, 1 H, 3-CH), 3.91 (dd, 1 H,
6-CH2, J ) 7.2, 12.8 Hz), 3.79 (dd, 1 H, 6-CH2, J ) 8.4, 12.8
(2R,3R,4R)-3,4-Dih ydr o-3,4-bis-(ter t-bu tyldim eth ylsilyl-
oxy)-2-(ter t-bu tyld im eth ylsilyloxym eth yl)-2H-p yr a n (15).
A mixture of 14 (1.00 g, 6.84 mmol), imidazole (4.65 g, 68.3
mmol), and TBSCl (5.15 g, 34.2 mmol) in DMF (50 mL) was
stirred at 60 °C for 12 h. After diluted with EtOAc, the
resulting mixture was washed with water (3×) and brine. The
organic layer was dried (Na2SO4), evaporated, and purified by
silica gel column chromatography (benzene/hexane; 1:4) to give
15 (2.98 g, 90%) as a syrup: 1H NMR (500 MHz, CDCl3) 6.32
(d, 1 H, J ) 6.2 Hz), 4.69 (m, 1 H), 3.99 (m, 1 H), 3.93 (dd, 1

C-Glycoside Trisphosphate as an IP3 Receptor Ligand
J . Org. Chem., Vol. 65, No. 18, 2000 5555
Hz), 0.89, 0.84, 0.84 (each s, each 9 H, t-Bu), 0.09- -0.03 (m,
18 H, Si-CH3 x 6); 13C NMR (125 MHz, CDCl3) 137.55, 135.25,
134.57, 135.42, 134.27, 133.60, 132.93, 131.66, 129.88, 129.84,
128.67, 127.92, 127.70, 127.66, 126.71, 83.76, 82.19, 76.25,
76.05, 69.90, 63.76, 25.96, 25.88, 25.80, 18.34, 17.97, 17.90,
-4.39, -4.61, -4.68, -4.73, -5.14, -5.27; HRMS (FAB,
positive) calcd for C44H71O5SeSi4 871.3544, found 871.3553
(MH+). Anal. Calcd for C44H70O5SeSi4: C, 60.72; H, 8.11.
Found: C, 60.95; H, 7.97.
P h en yl 3,4,6-Tr is-(O-ter t-b u t yld im et h ylsilyl)-2-O-d i-
ph en ylvin ylsilyl-1-selen o-r-D-glu copyr an oside (13c). Com-
pound 13c (65 mg, 76%) was obtained from 17 (65 mg, 0.097
mmol) as described for the synthesis of 7, with diphenylvinyl-
chlorosilane instead of dimethylvinylchlorosilane, after puri-
fication by silica gel column chromatography (benzene/hexane;
1:8 then 1:5): 1H NMR (500 MHz, CDCl3) 7.72-7.59 (m, 6 H,
aromatic), 7.39-7.33 (m, 7 H, aromatic), 7.19-7.17 (m, 2 H,
aromatic), 6.63 (dd, 1 H, vinyl, J ) 15.0, 20.5 Hz), 6.30 (dd, 1
H, vinyl, J ) 3.6, 15.0 Hz), 5.89 (dd, 1 H, vinyl, J ) 3.6, 20.5
Hz), 5.83 (d, 1 H, 1-CH, J ) 4.3 Hz), 4.20 (ddd, 1 H, 5-CH, J
) 1.0, 3.7, 3.8 Hz), 4.17 (m, 1 H, 2-CH), 3.88 (d, 1 H, 3-CH, J
) 8.7 Hz), 3.83 (dd, 1 H, 6-CH2, J ) 1.0, 11.6 Hz), 3.79 (dd, 1
H, 6-CH2, J ) 3.8, 11.6 Hz), 3.76 (d, 1 H, 4-CH, J ) 3.7 Hz),
0.85, 0.79, 0.76 (each s, each 9 H, t-Bu), 0.06 to -0.20 (m, 18
H, Si-CH3 × 6); 13C NMR (125 MHz, CDCl3) 137.84, 135.64,
135.61, 134.75, 133.78, 133.67, 133.40, 133.06, 131.53, 130.14,
130.09, 129.75, 128.55, 127.81, 127.74, 126.58, 86.63, 75.83,
74.61, 73.72, 72.32, 62.56, 25.96, 25.92, 25.76, 18.40, 18.02,
17.80, -3.61, -4.30, -4.59, -5.00, -5.07, -5.41; HRMS (FAB,
positive) calcd for C44H70O5SeSi4Na 893.3364, found 893.3337
(MNa+).
6-CH2OBz, J ) 7.9, 11.8 Hz), 4.60 (dd, 1 H, 2-CH, J ) 3.9, 8.7
Hz), 4.52 (m, 1 H, 6-CH), 4.47 (dd, 1 H, 6-CH2OBz, J ) 3.6,
11.8 Hz), 1.46 [d, 3 H, 2-CH(OBz)CH3, J ) 6.2 Hz]; HRMS
(FAB, positive) calcd for C43H37O11 729.2326, found 729.2364.
(MH+). 20: 1H NMR (500 MHz, CDCl3) 8.20-7.25 (m, 25 H,
aromatic), 6.27 (dd, 1 H, 4-CH, J ) 8.2, 8.2 Hz), 5.69 [m, 1 H,
2-CH(OBz)CH3], 5.68 (m, 1 H, 2-CH), 5.62 (dd, 1 H, 5-CH, J
) 8.2, 8.2 Hz), 4.87 (ddd, 1 H, 6-CH, J ) 3.7, 5.8, 8.2 Hz), 4.62
(dd, 1 H, 6-CH2OBz, J ) 5.8, 12.4 Hz), 4.60 (dd, 1 H,
6-CH2OBz, J ) 3.7, 12.4 Hz), 4.53 (m, 1 H, 3-CH), 1.48 [d, 3
H, 2-CH(OBz)CH3, J ) 6.5 Hz]; 13C NMR (125 MHz, CDCl3)
166.49, 165.70, 165.47, 133.82, 133.68, 133.56, 133.42, 133.30,
130.25, 130.08, 129.94, 129.32, 129.28, 128.89, 128.82, 128.77,
128.63, 128.61, 128.56, 74.32, 72.82, 71.01, 70.33, 70.19, 69.79,
63.78, 16.5; HRMS (FAB, positive) calcd for C43H37O11 729.2326,
found 729.2313.
Syn th esis of 20 fr om 10. A mixture of 10 (21 mg, 0.044
mmol) and Pd-C (10%, 6 mg) in MeOH (2 mL) was shaken
under H2 (3 kg/cm2) at room temperature for 3 h. After the
catalysts were filtered off, the filtrate was evaporated. A
mixture of the residue, BzCl (31 µL, 0.27 mmol), and DMAP
(3 mg, 0.02 mmol) in pyridine (0.5 mL) was stirred at room
temperature for 5 h. The solvent was evaporated, and the
residue was partitioned between EtOAc and water. The
organic layer was washed with aqueous HCl (0.1 M) and brine,
dried (Na2SO4), and evaporated. The residue was purified by
silica gel column chromatography (EtOAc/hexane; 1:6) to give
1
20 (7 mg, 21%), of which H NMR spectrum (500 MHz, CDCl3)
was identical to that of 20 obtained from 13a .
(2R,3R,4R)-3,4-Bis(ter t-bu tyld im eth ylsiloxy)-3,4-d ih y-
d r o-2-(t r ip h en ylm et h oxym et h yl)-2H -p yr a n (22). Com-
pound 22 (4.31 g, 85%) was obtained from 21 (3.24 g, 8.34
mmol) as described for the synthesis of 15 after purification
(2R,3S,4S,5R,6R)-3,4,5-Tr iben zoyloxy-2-(2-ben zoyloxy-
eth yl)tetr ah ydr opyr an (18), (2R,3S,4S,5R,6R)-3,4,5-Tr iben -
zoyloxy-2-[(1R)-1-b en zoyloxyet h yl]-6-b en zoyloxym et h -
yltetr a h yd r op yr a n (19), a n d (2R,3S,4S,5R,6R)-3,4,5-Tr i-
benzoyloxy-2-[(1S)-1-benzoyloxyethyl]-6-benzoyloxymethyl-
tetr a h yd r op yr a n (20). The radical reaction and subsequent
Tamao oxidation were carried out by the procedure described
above for 7. To the resulting reaction mixture after the Tamao
oxidation was added saturated aqueous Na2S2O3, and the
resulting insoluble salts were filtered off. After the filtrate was
evaporated, the residue was dissolved in a solution of HCl in
MeOH [prepared from AcCl (600 µL) and MeOH (12 mL) at 0
°C]. The resulting mixture was stirred at room temperature
for 1.5 h, and then the solvent was evaporated. A mixture of
the residue and BzCl (1.8 mL, 15.5 mmol) in pyridine (12 mL)
was stirred at room temperature for 50 h. After MeOH was
added, the resulting mixture was evaporated, and the residue
was partitioned between EtOAc and water. The organic layer
was washed with aqueous HCl (0.1 M) and brine, dried
(Na2SO4), and evaporated. The residue was purified by silica
gel column chromatography (EtOAc/hexane; 1:20, 1:10, then
1:8) to give a mixture of 18, 19, and 20, which was analyzed
by HPLC (75% MeOH, 1.0 mL/min, 260 nm). P u r ifica tion
of th e P r od u cts. The mixture of the pentabenzoyl products
(25 mg) obtained from the reaction in entry 5 was separated
by HPLC (60% MeCN, 9.9 mL/min, 260 nm) to give pure 18
(15 mg), 19 (3 mg), 20 (2 mg), respectively. 18: 1H NMR (500
MHz, CDCl3) 8.05-7.26 (m, 25 H, aromatic), 5.98 (dd, 1 H,
4-CH, J ) 8.3, 8.3 Hz), 5.57 (dd, 1 H, 5-CH, J ) 8.3, 8.3 Hz),
5.54 (dd, 1 H, 3-CH, J ) 5.2, 8.3 Hz), 4.76 (ddd, 1 H, 2-CH, J
) 3.6, 5.2, 11.2 Hz), 4.64 (dd, 1 H, 6-CH2OBz, J ) 6.6, 12.0
Hz), 4.60 (ddd, 1 H, 2-CH2CH2OBz, J ) 4.8, 7.4, 11.2 Hz), 4.55
(dd, 1 H, 6-CH2OBz, J ) 3.1, 12.0 Hz), 4.43 (ddd, 1 H, 6-CH,
J ) 3.1, 6.6, 8.3 Hz), 4.42 (m, 1 H, 2-CH2CH2OBz), 2.51 (m, 1
H, 2-CH2CH2OBz), 2.18 (ddd, 1 H, 2-CH2CH2OBz, J ) 2.8, 7.7,
15.1 Hz); 13C NMR (125 MHz, CDCl3) 166.33, 166.17, 165.55,
165.33, 165.28, 133.52, 133.41, 133.36, 133.10, 132.98, 129.99,
129.89, 129.87, 129.74, 129.56, 128.90, 128.51, 128.39, 128.36,
128.34, 70.66, 70.37, 70.03, 69.38, 69.20, 62.87, 60.97, 25.94;
HRMS (FAB, positive) calcd for C43H37O11 729.2326, found
729.2366 (MH+). 19: 1H NMR (500 MHz, CDCl3) 8.06-7.19
(m, 25 H, aromatic), 5.97 (dd, 1 H, 4-CH, J ) 5.8, 5.9 Hz),
5.71 [m, 1 H, 2-CH(OBz)CH3], 5.54 (dd, 1 H, 3-CH, J ) 3.9,
5.9 Hz), 5.45 (dd, 1 H, 5-CH, J ) 5.8, 5.8 Hz), 4.99 (dd, 1 H,
by silica gel column chromatography (benzene/hexane; 1:4):
1
[R]21 -7.9° (c 1.12, CHCl3); H NMR (500 MHz, CDCl3) 7.48
D
(m, 6 H), 7.31-7.19 (m, 9 H), 6.36 (d, 1 H, J ) 6.2 Hz), 4.65
(ddd, 1 H, J ) 0.8, 3.4, 6.2 Hz), 4.17 (m, 1 H), 3.80 (dd, 1 H, J
) 3.4, 3.4 Hz), 3.62 (dd, J ) 9.1, 10.6 Hz), 3.58 (dd, 1 H, J )
3.4, 3.4 Hz), 3.14 (dd, 1 H, J ) 10.6, 10.6 Hz), 0.8 0-0.05 (m,
21 H); 13C NMR (125 MHz, CDCl3) 144.17, 142.94, 128.79,
127.72, 126.82, 101.42, 86.57, 78.67, 70.84, 66.50, 62.74, 25.82,
25.76, 17.93, -4.33, -4.37, -4.53, -4.67. Anal. Calcd for
C
37H52O4Si2: C, 72.03; H, 8.49. Found: C, 71.89; H, 8.48.
P h en yl 3,4-Bis(O-ter t-bu tyld im eth ylsilyl)-2-O-d ip h en -
ylvin ylsilyl-6-O-tr ityl-1-selen o-â-D-glu cop yr a n osid e (24).
To a solution of 22 (3.0 g, 4.9 mmol) in CH2Cl2 (40 mL) was
added a solution of dimethyldioxirane (0.05 M in acetone, 100
mL) at 0 °C, and the resulting mixture was stirred at room
temperature for 15 min. After the solvent was evaporated, the
residue was dissolved in CH2Cl2, dried (Na2SO4), and evapo-
rated. To a mixture of the residue and PhSeH (10 mL, 97
mmol) in CH2Cl2 (4 mL) was added Et3N (680 µL, 4.9 mmol)
at -20 °C, and the resulting mixture was stirred at the same
temperature for 105 min. The solvent was evaporated, and the
residue was purified by silica gel flash column chromatography
(benzene/hexane; 1:2, 1:1, then 2:1) to give 23 as a syrup. A
mixture of 23 obtained, Et3N (2.68 mL, 19.2 mmol), DMAP
(40 mg, 0.32 mmol), and diphenylvinylchlorosilane (4.24 mL,
19.2 mmol) in toluene (30 mL) was stirred at room temperature
for 2 h. The resulting mixture was partitioned between EtOAc
and saturated aqueous NH4Cl. The organic layer was washed
with brine, dried (Na2SO4), and evaporated. The residue was
purified by silica gel column chromatography (benzene/hexane;
1:4) to give 24 (2.65 g, 56%) as a syrup: [R]23 +1.6° (c 0.66,
D
CHCl3); 1H NMR (500 MHz, CDCl3) 7.61-7.17 (m, 30 H), 6.47
(dd, 1 H, J ) 14.8, 20.3 Hz), 6.23 (dd, 1 H, J ) 3.6, 14.8 Hz),
5.88 (dd, 1 H, J ) 3.6, 20.3 Hz), 5.45 (d, 1 H, J ) 3.6 Hz), 4.27
(br s, 1 H), 4.06 (ddd, 1 H, J ) 4.0, 5.0, 6.5 Hz), 3.85 (br s, 1
H), 3.83 (d, 1 H, J ) 5.0 Hz), 3.38 (dd, 1 H, J ) 6.5, 9.8 Hz),
3.30 (dd, 1 H, J ) 4.0, 9.8 Hz), 0.79, 0.72 (each s, each 9 H),
-0.04, -0.13, -0.14, -0.18 (each s, each 3 H); 13C NMR (125
MHz, CDCl3) 144.22, 137.61, 135.22, 134.22, 133.99, 133.44,
132.86, 132.22, 129.98, 129.94, 128.91, 128.76, 127.77, 127.73,
127.68, 126.79, 126.71, 86.58, 84.29, 80.05, 76.75, 76.05, 75.89,
71.54, 65.02, 25.90, 25.76, 17.93, 17.83, -4.21, -4.34, -4.73,

5556 J . Org. Chem., Vol. 65, No. 18, 2000
Shuto et al.
-4.83. Anal. Calcd for C57H70O5SeSi3: C, 68.57; H, 7.07.
Found: C, 68.53; H, 7.21.
18.20, 17.81, 14.27, -4.55, -4.59, -4.87, -4.90; HRMS (FAB,
positive) calcd for C57H78O7Si3Na 981.4953. Found 981.4970
(MNa+).
(2R,3S,4R,5R,6R)-4,5-Bis(ter t-b u t yld im et h ylsiloxy)-3-
h yd r oxy-2-(2-h yd r oxyeth yl)-6-(tr ip h en ylm eth oxym eth -
yl)tetr a h yd r op yr a n (25). To a refluxing solution of 24 (1.26
g, 1.26 mmol) in chlorobenzene (900 mL) was added slowly
over 4 h a mixture of Bu3SnH (1.02 mL, 3.78 mmol) and AIBN
(248 mg, 1.52 mmol) in the same solvent (40 mL), and then
the resulting mixture was evaporated. The residue was puri-
fied by silica gel column chromatography (EtOAc/hexane; 1:50
then 1:4) to give the crude radical reaction product as a syrup.
A mixture of the syrup obtained, aqueous H2O2 (30%, 1.40 mL,
12.6 mmol), and NaHCO3 (105 mg, 1.25 mmol) in MeOH/THF
(1:1, 13 mL) was stirred at room temperature for 11 days.
Aqueous Na2S2O3 (1 M, 20 mL) was added, and the resulting
insoluble materials were filtered off. The filtrate was evapo-
rated under reduced pressure, and the residue was partitioned
between EtOAc and water. The organic layer was washed with
brine, dried (Na2SO4), and evaporated. The residue was
purified by silica gel column chromatography (EtOAc/hexane;
5:1 then 1:1) to give 25 (471 mg, 55%) as a syrup: 1H NMR
(500 MHz, CDCl3) 7.46-7.44 (m, 6 H, aromatic), 7.30-7.21
(m, 9 H, aromatic), 4.10 (dd, 1 H, 6-CH2OTr, J ) 4.0, 10.4 Hz),
3.90 (dd, 1 H, 2-CH2, J ) 3.5, 9.3 Hz), 3.82 (m, 1 H, 2-CH2CH2-
OH), 3.78 (m, 1 H, 4-CH), 3.77 (m, 1 H, 2-CH), 3.76 (m, 1 H,
6-CH), 3.54 (d, 1 H, 3-OH, J ) 11.6 Hz), 3.40 (d, 1 H, 5-CH, J
) 2.6 Hz), 3.16 (dd, 1 H, 3-CH, J ) 2.9, 11.6 Hz), 3.07 (dd, 1
H, 6-CH2OTr, J ) 3.7, 10.4 Hz), 2.70 (dd, 1 H, 2-CH2CH2OH,
J ) 4.8, 7.2 Hz), 2.10 (m, 1 H, 2-CH2CH2OH), 1.65 (m, 1 H,
2-CH2CH2OH), 0.91, 0.69 (each s, each 9 H, t-Bu), 0.09, 0.08,
-0.06, -0.09 (each s, each 3 H, Si-CH3); 13C NMR (125 MHz,
CDCl3) 143.99, 128.56, 127.86, 127.02, 86.81, 79.29, 71.34,
70.62, 69.78, 66.53, 60.75, 60.66, 60.37, 25.75, 25.64, 17.97,
17.76, -5.06, -5.07, -5.11, -5.13; HRMS (FAB, positive) calcd
for C39H59O6Si2 679.3850, found 679.3854 (MH+).
(2R,3R,4S,5S,6R)-3-Acetoxy-4,5-dih ydr oxy-2-(2-h ydr oxy-
eth yl)-6-(tr iph en ylm eth oxym eth yl)tetr ah ydr opyr an (28).
A mixture of 27 (191 mg, 0.119 mmol), TBAF (1 M in THF,
1.39 mL, 1.39 mmol), and AcOH (40 µL, 0.70 mmol) in THF
(2 mL) was stirred at room temperature for 24 h. The solvent
was evaporated, and the residue was partitioned between
EtOAc and water. The organic layer was washed with aqueous
saturated NH4Cl and brine, dried (Na2SO4), and evaporated.
The residue was purified by silica gel column chromatography
(MeOH/CHCl3; 1:50 then 1:15) to give 28 (44 mg, quant) as a
syrup: 1H NMR (500 MHz, CDCl3) 7.44-7.22 (m, 15 H), 4.85
(dd, 1 H, J ) 5.9, 9.5 Hz), 4.18 (ddd, 1 H, J ) 2.7, 5.9, 11.8
Hz), 3.78 (br s, 2 H), 3.76 (m, 1 H), 3.69 (m, 1 H), 3.46 (dd, 1
H, J ) 2.9, 9.3 Hz), 3.40 (dd, 1 H, J ) 4.2, 10.0 Hz), 3.33 (dd,
1 H, J ) 5.9, 10.0 Hz), 2.83 (d, 1 H, J ) 2.9 Hz), 2.74 (d, 1 H,
J ) 2.9 Hz), 2.18 (br s, 1 H), 2.10 (s, 3 H), 2.00, 1.64 (each m,
each 1 H); 13C NMR (125 MHz, CDCl3) 170.59, 143.37, 128.54,
127.89, 127.16, 87.43, 73.19, 72.66, 72.27, 71.86, 71.32, 64.63,
60.55, 27.90, 21.04; HRMS (FAB, positive) calcd for C29H33O7
493.2226. Found 493.2253 (MH+).
(2R,3S,4R,5R,6R)-3-Acetoxy-4,5-dih ydr oxy-6-(tr iph en yl-
m eth oxym eth yl)-4,5-bis(o-xyloxyp h osp h or yl)-2-(2-o-xyl-
oxyp h osp h or yleth yl)tetr a h yd r op yr a n (29). XEPA (126 µL,
0.59 mmol) was added to a mixture of 28 (76 mg, 0.15 mmol)
and 1H-tetrazole (41 mg, 0.59 mmol) in CH2Cl2 (4.5 mL) at 0
°C, and the mixture was stirred at room temperature for 30
min. After addition of H2O (40 µL), the mixture was stirred at
room temperature for 10 min. The resulting mixture was
cooled to -40 °C, and then m-CPBA (130 mg, 0.75 mmol) was
added. The mixture was warmed to room temperature over
20 min. The reaction mixture was partitioned between EtOAc
(40 mL) and aqueous saturated Na2SO3, and the organic layer
was washed with water, aqueous saturated NaHCO3, and
brine, dried (Na2SO4), and evaporated. The residue was
purified by silica gel column chromatography (EtOAc/CHCl3;
1:4) to give 29 (120 mg, 77%) as a foam: 1H NMR (500 MHz,
CDCl3) 7.48-7.13 (m, 27 H, aromatic), 5.46-4.94 (m, 12 H,
benzyl-CH2), 4.77 (t, 1 H, 4-CH, J ) 13.7 Hz), 4.62-4.52 (m,
2 H, 3-CH and 5-CH), 4.47-4.41 (m, 3 H, 2-CH and 2-CH2CH2-
OP), 3.84 (m, 1 H, 6-CH), 3.52 (dd, 1 H, 6-CH2OP, J ) 1.0,
10.3 Hz), 3.43 (dd, 1 H, 6-CH2OP, J ) 7.5, 10.3 Hz), 2.22 (s, 3
H, CH3CO), 2.14 (m, 1 H, 2-CH2CH2OP), 1.13 (m, 1 H, 2-CH2-
CH2OP); 31P NMR (125 MHz, D2O, H-decoupled) 0.21, -1.49,
-3.12 (each s); HRMS (FAB, positive) calcd for C53H54O16P3
1039.2625. Found 1039.2630 (MH+).
(2R,3S,4R,5R,6R)-3-Hyd r oxyl-6-h yd r oxym eth yl-4,5-d i-
ph osph or yl-2-(2-ph osph or yleth yl)tetr ah ydr opyr an Hexa-
sod iu m Sa lt (3,7-An h yd r o-D-glycer o-D-id o-oct it ol 1,5,6-
Tr isp h osp h a te Hexa sod iu m Sa lt, 5). A mixture of 29 (53
mg, 0.051 mmol) and Pd-C (10%, 60 mg) in MeOH (5 mL)
was stirred under atmospheric pressure of H2 at room tem-
perature for 2 h. After the catalysts were filtrated off with
Celite, and the filtrate was evaporated. To a solution of the
residue in MeOH (1 mL) was added TFA (2 µL, 0.026 mmol)
and then evaporated. The residue was dissolved in water and
washed with EtOAc (three times), and evaporated. The residue
was dissolved in aqueous NaOH (1 M, 4 mL), and the solution
was stirred at room temperature for 12 h. The resulting
solution was applied to Diaion PK-212 column (H+ form,
developed with H2O), and the fractions containing 5 (acidic
fractions) were evaporated. The residue was dissolved in
water-EtOH and evaporated (three times) to remove AcOH.
A solution of the residue in water (1 mL) was applied to Diaion
WK-20 column (Na+ form, developed with H2O), and the
fractions containing 5 were evaporated and dried in vacuo to
give 5 (sodium salt, 25 mg, 84%) as a white solid: [R]23D -40.3°
(c 0.88, H2O); 1H NMR (400 MHz, D2O) 4.30 (ddd, 1 H, 4-CH,
J ) 8.8, 8.8, 8.8 Hz), 4.24 (ddd, 1 H, 2-CH, J ) 4.4, 4.4, 5.4
Hz), 3.96 (ddd, 1 H, 5-CH, J ) 8.8, 8.8, 8.8 Hz), 3.93-3.89 (m,
3 H, 6-CH2OP and 2′-CH2), 3.83 (dd, 1 H, 3-CH, J ) 5.4, 8.8
Hz), 3.75-3.72 (m, 2 H, 6-CH2OP and 6-CH), 2.00 (m, 2 H,
1′-CH2); 13C NMR (100 MHz, D2O) 76.71 (d, J C-P ) 2.77 Hz),
(2R,3S,4R,5R,6R)-4,5-Bis(ter t-bu tyld im eth ylsilyloxy)-
2-(2-ter t-bu tyldiph en ylsiloxyeth yl)-3-h ydr oxy-6-(tr iph en -
ylm eth oxym eth yl)tetr a h yd r op yr a n (26). Compound 26
(521 mg, quant) was obtained from 25 (394 mg, 0.58 mmol)
by the reaction at room temperature as described for the
synthesis of 15 with TBDPSCl (181 µL, 0.70 mmol) instead of
TBSCl, after purification by silica gel column chromatography
(EtOAc/hexane; 1:50): 1H NMR (500 MHz, CDCl3) 7.62-7.18
(m, 25 H), 3.97 (m, 1 H), 3.97 (m, 1 H), 3.84 (s, 1 H), 3.78 (t, 2
H, J ) 6.0 Hz), 3.67 (dd, 1 H, J ) 8.0, 10.0 Hz), 3.66 (s, 1 H),
3.47 (d, 1 H, J ) 11.6 Hz), 3.36 (dd, 1 H, J ) 5.9, 10.0 Hz),
3.21 (d, 1 H, J ) 11.6 Hz), 1.97 (m, 1 H), 1.76 (m, 1 H), 0.98,
0.91, 0.71 (each s, each 9 H), 0.11, 0.09, -0.04, -0.06 (each s,
each 3 H, Si-CH3); 13C NMR (125 MHz, CDCl3) 144.20, 135.51,
135.49, 134.79, 134.01, 133.97, 129.45, 129.41, 128.67, 127.76,
127.58, 127.56, 126.92, 86.75, 79.19, 71.24, 70.46, 70.11, 64.67,
61.77, 60.62, 26.91, 26.56, 25.79, 25.75, 19.12, 17.96, 17.84,
-4.89, -4.93, -5.04, -5.12; LRMS (FAB, positive) m/z 917
(MH+). Anal. Calcd for C55H76O6Si3: C, 72.00; H, 8.35. Found:
C, 71.80; H, 8.44.
(2R,3S,4R,5R6R)-3-Acet oxy-4,5-b is-(ter t-b u t yld im et h -
ylsilyloxy)-2-(2-ter t-bu tyldiph en ylsiloxyeth yl)-6-(tr iph en -
ylm eth oxym eth yl)tetr a h yd r op yr a n (27). A mixture of 26
(43 mg, 0.047 mmol), Ac2O (8.9 µL, 0.094 mmol), and DMAP
(12 mg, 0.10 mmol) in MeCN (0.5 mL) was stirred at 60 °C for
15 h. The solvent was evaporated, and the residue was
partitioned between EtOAc and water. The organic layer was
washed with brine, dried (Na2SO4), and evaporated. The
residue was purified by silica gel column chromatography
(EtOAc/hexane; 1:50) to give 27 (44 mg, quant) as a syrup:
1H NMR (500 MHz, CDCl3) 7.60-7.18 (m, 25 H), 4.38 (s, 1 H),
4.09 (m, 1 H), 3.96 (dd, 1 H, J ) 6.2, 7.6 Hz), 3.88 (s, 1 H),
3.75 (m, 2 H), 3.61 (s, 1 H), 3.53 (dd, 1 H, J ) 7.6, 10.0 Hz),
3.43 (dd, 1 H, J ) 6.2, 10.0 Hz), 2.05 (s, 3 H), 1.90, 1.55 (each
m, each 1 H), 0.97, 0.87, 0.76 (each s, each 9 H), 0.07, 0.03
(each s, each 3 H), 0.02 (s, 6 H); 13C NMR (125 MHz, CDCl3)
170.86, 144.11, 135.40, 133.69, 129.43, 129.37, 128.55, 127.67,
127.50, 126.80, 86.69, 78.62, 72.06, 69.39, 68.95, 62.96, 62.01,
60.40, 60.33, 34.38, 26.88, 25.96, 25.80, 21.15, 21.12, 19.13,

C-Glycoside Trisphosphate as an IP3 Receptor Ligand
J . Org. Chem., Vol. 65, No. 18, 2000 5557
73.47 (d, J C-P ) 3.69 Hz), 72.44 (d, J C-P ) 2.77 Hz), 71.38 (s),
70.88 (d, J C-P ) 1.84 Hz), 61.34 (d, J C-P ) 5.53 Hz), 60.64 (s),
26.29 (d, J C-P ) 7.38 Hz); 31P NMR (125 MHz, D2O, H-
decoupled) 2.68, 2.56, -0.33 (each s); HRMS (FAB, positive)
calcd for C8H14O15Na6P3 580.8932, found 580.8914 (MH+).
Anal. Calcd for C8H13Na6O15P3‚2H2O: C, 15.60; H, 2.78.
Found: C, 15.45; H, 2.92.
T. Iizawa and Drs. M. Takahashi and H. Hotoda,
Sankyo Co. Ltd, for the biological evaluation. We are
also grateful to Ms. H. Matsumoto, A. Maeda, S. Oka,
and N. Hazama, Center for Instrumental Analysis,
Hokkaido University, for technical assistance with
NMR, MS, and elemental analysis.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectral
charts of 8, 9, 10, 11, 12, 8D, 9D, 10D, 11D, 9′, 10′, 11′, 13c,
15, 18, 19, 20, and 25. This material is available free of charge
via the Internet at http://pubs.acs.org.
Ack n ow led gm en t . This investigation was sup-
ported in part by a Grant from the Ministry of Educa-
tion, Science, Sports, and Culture of J apan. We ac-
knowledge Dr. A. M. Riley and Prof. B. V. L. Potter,
University of Bath, for useful discussions and also Miss
J O0002339