Synthesis of 4,8-anhydro-d-glycero-d-ido-nonanitol 1,6,7-trisphosphate as a novel IP3 receptor ligand using a stereoselective radical cyclization reaction based on a conformational restriction strategy

Article abstract of DOI:10.1016/j.tet.2005.02.025

4,8-Anhydro-d-glycero-d-ido-nonanitol 1,6,7-trisphosphate (9), designed as a novel IP₃ receptor ligand having an α-C-glycosidic structure, was synthesized via a radical cyclization reaction with a temporary connecting allylsilyl group as the ke

Full text of DOI:10.1016/j.tet.2005.02.025

Tetrahedron 61 (2005) 3697–3707
Synthesis of 4,8-anhydro-D-glycero-D-ido-nonanitol
1,6,7-trisphosphate as a novel IP3 receptor ligand using a
stereoselective radical cyclization reaction based on a
conformational restriction strategy
Masaru Terauchi,a Yumi Yahiro,a Hiroshi Abe,a Satoshi Ichikawa,a Stephen C. Tovey,b
Skarlatos G. Dedos,b Colin W. Taylor,b Barry V. L. Potter,c Akira Matsudaa and Satoshi Shutoa,
*
aGraduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
bDepartment of Pharmacology, Tennis Court Road, University of Cambridge, Cambridge CB 1PD, UK
cWolfson Laboratory for Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK
Received 17 December 2004; accepted 7 February 2005
Abstract—4,8-Anhydro-D-glycero-D-ido-nonanitol 1,6,7-trisphosphate (9), designed as a novel IP3 receptor ligand having an a-C-glycosidic
structure, was synthesized via a radical cyclization reaction with a temporary connecting allylsilyl group as the key-step. Phenyl 2-O-
allyldimethylsilyl-3,4-bis-O-TBS-1-seleno-b-D-glucopyranoside (10a), conformationally restricted in the unusual C4-conformation, was
1
treated with Bu3SnH/AIBN to form the desired a-cyclization product 16a almost quantitatively. On the other hand, when a conformationally
unrestricted O-benzyl-protected 2-O-allyldimethylsilyl -1-selenoglucoside 15 was used as the substrate, the radical reaction was not
stereoselective and gave a mixture of the a-and b-products. From 16a, the target C-glucoside trisphosphate 9 was synthesized via
phosphorylation of the hydroxyls by the phosphoramidite method. During the synthetic study, an efficient procedure for the oxidative C–Si
bond cleavage, via a nucleophilic substitution at the silicon with p-MeOPhLi followed by Fleming oxidation, was developed. The
C-glycoside 9 was found to be a full agonist for Ca2C mobilization, although its activity was weaker than that of the natural ligand IP3. Thus,
the a-C-glucosidic structure was shown to be a useful mimic of the myo-inositol backbone of IP3.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
(4) was originally designed and synthesized as a highly
simplified analogue of adenophostin A, and was demon-
strated to be an agonist of the IP3 receptor.5,7a,b,l These
studies indicated that the a-D-glucopyranoside structure is a
good bioisostere of the myo-inositol backbone of IP3 and
that the three-dimensional positioning of the three phos-
phate moieties and, in particular, the lone ‘auxiliary’
phosphate group, is significant to affect the activity.5,6b It
has also been shown that the adenine moiety of adeno-
phostin A can be replaced by other aromatic rings as a
bioisostere; e.g. the uracil congener 5 inter alia has a strong
Ca2C-mobilizing activity close to that of adenophostin A
(Fig. 1).5,7k
D-Myo-inositol 1,4,5-trisphosphate (IP3, 1, Fig. 1)1 is a
biologically important intracellular Ca2C-mobilizing
second messenger whose analogues have been extensively
synthesized for the development of specific ligands for IP3
receptors. These ligands have been shown to be effective in
investigating the mechanism of IP3-mediated Ca2C signal-
ing pathways. They may also be useful as leads for the
development of potentially beneficial drugs.2,3
Adenophostin A (2), isolated from Penicillium brevicom-
pactum, is a very potent IP3 receptor agonist,4 and several
groups, including ours, have been performing synthetic
studies of novel IP3 receptor ligands based on its structure.5–7
2-Hydroxyethyl a-D-glucopyranoside 3,4,20-trisphosphate
We are interested in C-glycosidic analogues having the
a-D-glucopyranoside structure as potential IP3 receptor
ligands, since C-glycosides are known to be biologically
stable mimics of the corresponding O-glycosides.8 Thus, we
have synthesized the C-glycosidic analogue 3 of adeno-
phostin A and also its uracil congener 6,6d,e which proved to
be very potent IP3-receptor agonists.9 The a-C-glucoside
Keywords: C-Glycosides; Conformation; Fleming oxidation; Inositol
trisphosphate; Radical reactions.
Corresponding author. Tel.: C81 11 706 3229; fax: C81 11 706 4980;
e-mail: shu@pharm.hokudai.ac.jp
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.02.025

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M. Terauchi et al. / Tetrahedron 61 (2005) 3697–3707
that of 4, in order to further clarify the structure–activity
relationship of these C-and O-glucoside trisphosphates.
2. Result and discussion
2.1. Synthetic plan
Due to their unique biological activities, considerable effort
has been devoted to the development of useful methods for
the preparation of C-glycosides.8,11 The use of radical
reactions is one of the most efficient methods for
constructing C-glycosidic bonds; therefore we have been
working on the development of stereoselective intra-
molecular and intermolecular radical C-glycosidation
reactions.6d-f,11c,d
The allylsilyl group was originally used as a very effective
radical acceptor tether for the stereoselective introduction
of a C3 unit by Chattopadohyaya and co-workers.12a
A
branched thymidine derivative having an aminopropyl
group at the 40-posistion, which proved to be an effective
nucleoside unit in antisense studies, was synthesized using
the radical reaction with this tether as the key step.12b We
planned to develop a procedure for introducing a C3 unit
stereoselectively at the anomeric a-position of D-glucose via
the radical cyclization reaction with the allylsilyl group as a
temporary connecting tether13 and apply it to the synthesis
of the target C-glycoside trisphosphate 9.
Scheme 1 shows our synthetic plan. We chose the phenyl
1-seleno-D-glucopyranoside I with an allylsilyl group at the
2-hydroxyl as the substrate for the radical reaction, because
it seemed to be stable and easy to prepare. The radical
cyclization reaction of I under reductive conditions gives
the 7-endo cis-cyclized product II. Subsequent oxidative
cleavage of the C–Si bond would give the desired a-C-
glycoside III, which could then be converted into the target
trisphosphate 9 via introduction of the three phosphate
groups using the phosphoramidite method.
Figure 1. IP3 receptor ligands.
trisphosphate 7, having a C2-chain at the anomeric position,
was also designed and synthesized as a simplified
C-gycosidic IP3 receptor ligand, the binding affinity of
which was only about 2-fold lower than that of IP3 itself.6f
Interestingly, the O-glucoside trisphosphate 4, having a
structure similar to the C-glycoside 7, was 25-fold lower
than IP3 in its affinity for the receptor.5,7a,b,l The
significantly different activity between the C-glycoside 7
and the O-glycoside 4 may be due to the relative properties
of the O- and the C-glycosidic linkage.10 A second
explanation for the difference may be due to the longer
side-chain length of 4 compared with that of 7, since the
three-dimensional location of the phosphate groups of
IP3 receptor ligands seems to be a critical factor for their
biological activity3,5 Another shorter chain, C1-type
a-C-glucoside trisphosphate 8, was also synthesized;
however, its Ca2C-mobilizing activity was about 17-fold
lower than IP3,7h suggesting that the anomeric C1-unit
might be too short for the effective binding of the molecule
to the receptor. On the basis of these findings, we decided
to synthesize another a-C-glucoside trisphosphate, i.e.
4,8-anhydro-D-glycero-D-ido-nonanitol 1,6,7-trisphosphate
(9), whose anomeric C3-side-chain length is similar to
Scheme 1.
In this synthetic plan, the key would be whether the radical
cyclization occurred stereoselectively to form the desired
a-product. The stereoselectivity of the radical cyclization
is significantly influenced by the conformation of the
substrates.14 Giese and co-workers previously clarified the

M. Terauchi et al. / Tetrahedron 61 (2005) 3697–3707
3699
conformation of the anomeric radical intermediate produced
from tetra-O-acetyl-protected glucose derivative
using ESR spectroscopy:15 the glucosyl radical assuming a
2,5-boat-like conformation is maximally stabilized in the
Based on these considerations, we designed substrate E for
the radical reaction, the conformation of which should be
restricted to an unusual 1C4-chair form. We recently
demonstrated by ab initio calculations that the anomeric
radical intermediate preferentially assumes the substrate-
a
B
conformation due to an effective interaction of the radical
orbital (SOMO) with the s*-orbital of the adjacent C2–O2
bond and also with the p-orbital of a lone pair of the ring
oxygen in their periplanar arrangement. Accordingly, as
shown in Scheme 2, the anomeric radical, derived from the
2-O-allylsilyl substrate A assuming a usual 4C1-chair
conformation, would prefer such a B2,5-boat-like confor-
mation B (B0). Approach of the tether terminal to the
anomeric position from the a-axial direction forming C
might be disfavored because of the significant 1,2- and
1,5-steric repulsion (B) due to the axial orientation of the
2-O-silyl and the 5-H substituents, and consequently
cyclization via the b-equatorial-attack (B0) might preferen-
tially occur to result in the formation of trans-cyclized
product D.
1
like C4-form when the conformation of the precursors of
1
the radical is restricted in an unusual C4-chair form.11d
Hence we expected that the radical cyclization using the
conformationally 1C4-restricted substrate E would give
stereoselectively the desired a-cyclization product G, via
1C4-chair-like anomeric radical intermediate F, where
1,2-trans-cyclization would be sterically impossible
because of the axial orientation of the 20-tether, as shown
in Scheme 2b.16 The conformational restriction of the
substrate to the desired 1C4-form was thought to be possible
by employing the significantly bulky silyl protecting groups
as described bellow.
2.2. Design and preparation of the conformationally
flipped 3,4-O-silyl substrates
Based on the above considerations, the 3,4-bis-O-silyl-
protected substrates 10a, 10b, and 10c, were designed for
the radical reaction (Fig. 2). It is known that introducing a
significantly bulky protecting group at the 3,4-trans-
hydroxyl groups of pyranoses causes a flip of their
1
conformation leading to a C4-form, in which the bulky
substituents are in axial positions due to mutual steric
repulsion.11b–e,17–20 Accordingly, the 3,4-O-silyl substrates
10a–c would assume an unusual C4-conformation due to
1
the significant steric repulsion between the bulky silyl
groups.
Figure 2. Conformationally restricted (a) and unrestricted (b) substrates of
the radical cyclization reaction.
On the other hand, there was concern that the radical
reaction might not be initiated if the silyl group was too
bulky, since attack of the tin radical at the anomeric
selenium might be prevented due to significant steric
hindrance. In fact, we have experienced such decrease in
reactivity at the anomeric position due to the extreme steric
hindrance by bulky silyl groups in 1C4-restricted sub-
strates.11c,d Therefore, we planned to examine three
1C4-restricted substrates 10a, 10b, and 10c, with different
silyl protecting groups as the radical reaction substrates.
Scheme 2.

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M. Terauchi et al. / Tetrahedron 61 (2005) 3697–3707
The substrates 10a–c were prepared from the known glucal
1121 as shown in Scheme 3. TBS, TBDPS, or TIPS groups
were introduced at the 3,4-trans-hydroxyls of 11 by the
usual method to give 12a–c, respectively. The TBS-
protected glucal 12a was successively treated with
dimethyldioxirane and with PhSeH/Et3N in CH2Cl2 to
give 1-b-phenylselenide 13a along with the corresponding
a-anomer. When 2,6-lutidine was used instead of Et3N as a
base in the phenylselenation step, the b-phenylselenide 13a
was obtained as the sole product. Similarly, b-phenyl-
selenides 13b and 13c were stereoselectively prepared.
An allyldimethylsilyl group was then introduced at the
2-hydroxyl of the anomeric phenylselenides 13a–c to
provide the radical reaction substrates 10a–c.
Scheme 5.
2.3. Radical reaction of the conformationally restricted
and unrestricted substrates
1
The radical reactions of the C4-restricted substrates 10a–c
and also the unrestricted substrate 15 were performed by
slow addition of a mixture of Bu3SnH and AIBN to a
refluxing solution of the substrate in benzene (80 8C),
toluene (110 8C), or t-butylbenzene (130 8C) (Schemes 5
and 6). The results are summarized in Table 1. First, the
reaction was examined by slow addition of 2 equiv of
Bu3SnH and 0.67 equiv of AIBN to the 0.005 M solution
of the bis-O-TBS substrate 10a in benzene. However, the
radical reaction was not initiated under the conditions, and
substrate 10a was completely recovered (entry 1). This
suggests that the bulky silyl groups hindered the approach of
the tin radical to the anomeric selenium, as indicated above.
When 10a was treated with 2.0 equiv of Bu3SnH under
higher substrate concentration conditions (0.05 M), the
radical reaction occurred to produce the desired a-C-
glucoside 16a almost quantitatively (entry 2), the structure
of which was confirmed after its conversion into the
corresponding penta-O-benzoate 17, by successive treat-
ment under Tamao oxidation conditions,23 HCl/MeOH, and
BzCl/pyridine (Scheme 5). The corresponding a-cyclized
products 16b and 16c were also exclusively obtained in high
yield by the radical reactions (entries 3 and 4), when the
Scheme 3.
We also prepared a conformationally unrestricted substrate
15, i.e. the 2-O-allyldimethylsilyl ether of phenyl 3,4,6-tri-
O-benzyl-1-seleno-b-D-glucose (Fig. 2b) to clarify whether
the conformational restriction of the substrate in the
1C4-form was in fact essential for the a-selective radical
cyclization. Phenyl 3,4,6-tri-O-benzyl-1-seleno-b-D-glu-
cose (14)22 was treated with allyldimethylchlorosilane,
DMAP, and Et3N in toluene at room temperature to
give quantitatively the corresponding 2-O-silyl ether 15
(Scheme 4).
1
other two C4-restricted substrates, TBDPS-protected 10b
and TIPS-protected 10c, were treated under identical
conditions as for those of entry 2 for 10a.
Scheme 4.
The conformation of the substrates 10a–c and 15 was
investigated by 1H NMR (Fig. 2). The unrestricted substrate
15 has large coupling constants (ca. 10 Hz) between the ring
protons showing its C1-chair-like conformation. On the
other hand, considerably smaller coupling constants (0–
Scheme 6.
4
We next examined the radical cyclization with the
conformationally unrestricted tri-O-benzyl substrate 15 by
a similar procedure with Bu3SnH and AIBN, followed
by the Tamao oxidation (Scheme 6). First, the reaction was
carried out in benzene under reflux under conditions
3.2 Hz) in the 3,4-O-silyl-protected substrates 10a–c
indicate their preference for the flipped C4-conformation,
as expected.
1

M. Terauchi et al. / Tetrahedron 61 (2005) 3697–3707
3701
Table 1. Synthesis of C-glycosides by the radical reactions with 2-O-allylsilyl-tethered substratesa
Entry
Substrate (concn, M)
Solvent
Temp (8C)
Product
Yield (%)
a/b ratio
1
2
3
4
5
6
7
10a (0.005)
10a (0.05)
10b (0.05)
10c (0.05)
15 (0.005)
15 (0.005)
15 (0.005)
Benzene
Benzene
Benzene
Benzene
Benzene
Toluene
t-BuPhH
80
80
80
80
80
110
130
No reaction
16a
16b
—
97b
85
84
73
80
62
—
Only a
Only a
Only a
1:2.9c
1:4.1c
1:3.1c
16c
18, 19
18, 19
18, 19
a To a heating solution of the substrate in benzene, toluene, or t-BuPhH, a mixture of Bu3SnH (entries 1, 5–7, 1.3 equiv; entries 2–4, 2 equiv;) and AIBN
(0.67 equiv) in the same solvent was added slowly (entries 1, 5–7, over 4 h; entries 2–4, over 2 h).
b Mean value of three experiments.
c After treatment of a mixture of the radical reaction products under Tamao oxidation conditions, the a/b ration was determined by HPLC.
identical to those of entry 1 for 10a. The radical reaction
took place in spite of the lower concentration of the
substrate (0.005 M) to give, after the Tamao oxidation, a
mixture of the a-C-glucoside 18 and the b-C-glucoside 19
(entry 5: yield 73%). After isolation of the both anomers,
1H NMR analyses proved that the major product was not
the a-anomer 18 but the b-anomer 19 (a/bZ1:2.9). When
the reaction was performed at 110 8C in toluene, the
b-selectivity was further increased (entry 6: yield 80%,
a:bZ1:4.1). At further higher temperature, the yield and
the b-stereoselectivity decreased (entry 7). Therefore, the
desired a-C-glycoside 18 was not obtained as the major
product via the radical reaction of the unrestricted tri-O-
benzyl substrate 15. However, it should be noted that the
reaction with the substrate 15 gave the trans-cyclized b-C-
glycoside as the major product, since intermolecular
anomeric radical reactions of glucose derivatives have
been demonstrated to produce the corresponding a-product
selectively probably because of the anomeric effect.
These results clearly indicate that the conformational
restriction strategy is highly effective for realizing stereo-
selective radical cyclization at the anomeric position.
2.4. Synthesis of the target C-glucoside trisphosphate via
the novel C–Si bond fission
The 3,4-O-TBS-protected radical reaction product 16a, the
overall yield of which was the highest among the series, was
used for further derivatization, as shown in Scheme 7. To
convert 16a into the target C-glucoside trisphosphate 9,
oxidative C–Si bond fission in 16a was required without
cleaving the 3,4-O-TBS groups. The usual Tamao oxidation
conditions, including use of the fluoride ion, would likely
remove the silyl protecting groups, at least to some extent.
Consequently, 16a was exposed to conditions with H2O2/
KHCO3/KBr in aqueous MeOH/THF at room temperature.
Although, the desired C–Si bond fission occurred selec-
tively under these conditions, the reaction was extremely
slow to require one month of stirring. Furthermore, the
reaction was not reproducible. Thus, an alternative method
was sought.
It is known that aromatic carbon–Si bonds are much more
readily cleaved via an electrophilic substitution at the
silicon center than aliphatic ones;24 therefore, the arylsilyl
groups could be a useful latent hydroxy group. Thus, 16a
was treated with PhLi in Et2O at K78 8C followed by
acetylation of the 2-hydroxyl to produce, in 86% yield, the
ring-opened derivative 20 having a Ph–Si bond (Scheme 7).
Although Fleming oxidation of 20 was examined under
various conditions, detritylation was unavoidable under
these conditions and resulted in a lower yield of the desired
primary alcohol 22.
Considerable acidic conditions are required for the Fleming
oxidation, because ipso-protonation is essential to proceed
the oxidation.24 We speculated that if an electron-donating
substituent were attached at the ortho- or para-position of
the phenyl moiety, the ipso-protonation could effectively
took place even under mild acidic conditions so that the
oxidation would progress without removal of the trityl
group. Thus, another ring-opening intermediate 21 having
a p-MeOPhSi group was prepared by treating 16a with
p-MeOPhLi in THF followed by acetylation. When 21 was
treated under Fleming oxidation conditions with AcOOH/
AcOH/AcONa/H2SO4/KBr,25 the desired primary alcohol
22 was successfully obtained in 61% yield, as expected.
Scheme 7.

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M. Terauchi et al. / Tetrahedron 61 (2005) 3697–3707
The two O-silyl groups of 22 were simultaneously removed
with TBAF in the presence of AcOH to give 23. Using the
phosphoramidite method with o-xylene N,N-diethyl-
phosphoramidite (XEPA) developed by Watanabe and
co-workers,26 the phosphate units were next introduced.
Thus, 23 was treated with XEPA and tetrazole in CH2Cl2,
followed by oxidation with m-CPBA to give the desired
trisphosphate derivative 24 in 84% yield. Finally, the
o-xylene, trityl, and acetyl protecting groups were success-
ively removed by hydrogenation, acidic hydrolysis, and
basic hydrolysis to furnish the target 9 in 69% yield as the
sodium salt, after treatment with ion-exchange resin.
Figure 3. Putatively unstable a-O-glucoside trisphosphates.
phosphate moieties and, in particular, that of the lone
‘auxiliary’ phosphate group, was effectively investigated,
and the myo-inositol backbone of IP3 was shown to be
replaced by the a-D-C-glucosidic structure. It should be
noted that this strategy, employing a series of C-glycosides
as stable mimics of the O-glycoside, is essential because the
corresponding O-glycoside trisphosphates, e.g. 25 and 26
(Fig. 3), could not be provided due to their predictable
instability due to the O–C–O–O–P (25) or O–C–O–C–O–P
(26) structure. Full details of C-glycoside based IP3
analogue structure–activity relationships will appear
elsewhere.
As described above, we have synthesized the C-glucosidic
trisphosphate 9 via the radical cyclization reaction using the
conformationally restricted substrate as the key step. During
the study, we also developed an efficient procedure for
oxidative C–Si bond cleavage via nucleophilic substitution
at the silicon atom with p-MeOPhLi. There has been
growing interest in the use of silicon-containing tethers for
intramolecular radical cyclization reactions, which are very
useful for the regio- and stereoselective introduction of a
carbon substituent based on a temporary silicon connec-
tion.27 One drawback of this kind of temporary silicon-
connecting radical reaction methods is that silyl protecting
groups, which may be the most versatile protecting groups
in recent organic chemistry, do not survive the subsequent
oxidative Si–C bond cleavage step under normal Tamao
oxidation conditions. As a result, the two-step method
described here, i.e. the nucleophilic ring-opening with
p-MeOPhLi followed by Fleming oxidation, could be of
significant utility.
3. Experimental
3.1. General methods
Chemical shifts are reported in ppm downfield from
tetramethylsilane (1H and 13C) or H3PO4 (31P), and J values
are given in hertz. The 1H NMR assignments described were
in agreement with COSY spectra. Thin-layer chromato-
graphy was done on Merck coated plate 60F254. Silica gel
chromatography was done on Merck silica gel 7734 or 9385.
Reactions were carried out under an argon atmosphere.
2.5. Biological effects
The ability of synthesized 9 to stimulate opening of the pore
of recombinant rat type 1 IP3 receptors expressed in chicken
B cells that otherwise lack IP3 receptors was measured using
a fluorescent Ca2C indicator trapped within the lumen of the
intracellular Ca2C store.28–31 The results are shown in Table
2 and are presented as relative potency to those obtained
using both IP3 (1) and adenophostin A (2). The C-glycoside
9 having a C3-chain was found to be a full agonist for Ca2C
mobilization with a potency about 8-fold lower than that of
IP3. The activity of 9 seems to be somewhat stronger than 8
having a C1-chain, which was about 16-fold less potent
than IP3.5,7i By contrast, the binding affinity of 7, having a
C2-chain, for IP3 receptors was shown to be only about
2-fold lower than that of IP3 itself.6f These results clearly
show that C-glycoside chain length can have a marked effect
upon biological activity with an optimum chain length of C2
in this series. All of the compounds studied were clearly
significantly weaker than adenophostin A.
3.1.1. (2R,3R,4R)-3,4-Bis-(tert-butyldiphenylsilyloxy)-
3,4-dihydro-2-(triphenylmethoxymethyl)-2H-pyran
(12b). A mixture of 1121 (1.94 g, 5 mmol), TBDPSCl
(3.90 mL, 15 mmol) and imidazole (20.0 g, 30 mmol) in
DMF (40 mL) was stirred at 60 8C for 20 h. The resulting
mixture was partitioned between AcOEt and H2O, and the
organic layer was washed with brine, dried (Na2SO4), and
evaporated. The residue was purified by column chroma-
tography (SiO2, 20–33% benzene in hexane) to give 12b
(3.90 g, 89%) as a white solid: 1H NMR (400 MHz, CDCl3)
d 7.53–7.13 (m, 35H), 6.39 (d, 1H, JZ6.2 Hz), 4.45 (m,
1H), 4.24 (m, 1H), 3.84 (dd, 1H, JZ8.7, 10.8 Hz), 3.81 (s,
1H), 3.18 (d, 1H, JZ5.0 Hz), 2.97 (dd, 1H, JZ2.6,
10.8 Hz), 0.89 (s, 9H), 0.71 (s, 9H); 13C NMR (100 MHz,
CDCl3) d 143.9, 142.7, 135.5, 135.5, 135.4, 135.4, 133.7,
133.4, 133.2, 129.5, 129.5, 129.4, 129.4, 129.3, 128.6,
127.5, 127.5, 127.4, 127.2, 126.6, 100.3, 86.4, 78.1, 70.8,
64.7, 62.3, 26.9, 26.8, 19.3, 19.0; LRMS (FAB, positive)
m/z 887 (MNaC). Anal. Calcd for C57H60O4Si2: C, 79.12;
H, 6.99. Found: C, 79.16; H, 7.17.
Thus, the three-dimensional positioning of the three
Table 2. Ca2C release by rat type 1 IP3 receptors expressed in DT40 cells
Compound
EC50, nM
Hill slope
Ca2C release, %
n
Relative potency
Adenophostin A
IP3
IP3 (1)
Adenophostin A (2)
9
24.8G2.1
2.1G0.2
213G37
1.21G0.06
1.54G0.13
1.39G0.27
78G2
76G1
69G2
11
12
5
1
0.087G0.009
1
0.009G0.001
12.77G4.46
0.12G0.01

M. Terauchi et al. / Tetrahedron 61 (2005) 3697–3707
3703
3.1.2. (2R,3R,4R)-3,4-Bis-(triisopropylsilyloxy)-3,4-dihy-
dro-2-(triphenylmethoxymethyl)-2H-pyran (12c). Com-
pound 12c (2.30 g, 65%) was obtained as a colorless oil
from 11 (1.94 g, 5.0 mmol) as described above for the
synthesis of 12b, after purification by column chroma-
tography (SiO2, 20–33% benzene in hexane): 1H NMR
(400 MHz, CDCl3) d 7.46 (d, 6H, JZ7.1 Hz), 7.44–7.15 (m,
9H), 6.36 (d, 1H, JZ6.3 Hz), 4.72 (m, 1H), 4.30 (m, 1H),
3.81–3.74 (m, 3H), 3.07 (dd, 1H, JZ2.4, 11.1 Hz), 1.01 (m,
21H), 0.87 (m, 21H); 13C NMR (100 MHz, CDCl3) d 144.0,
142.5, 128.6, 127.5, 126.6, 100.4, 86.5, 78.7, 70.6, 64.8,
62.4, 18.2, 18.6, 18.1, 12.6, 12.4; LRMS (FAB, positive)
m/z 723 (MNaC). Anal. Calcd for C43H64O4Si2: C, 73.66;
H, 9.20. Found: C, 73.45; H, 9.25.
allyl-CH), 5.29 (d, 1H, 1-CH, JZ5.7 Hz), 5.25–4.79 (m,
2H, allyl-CH2), 3.97 (dd, 1H, 2-CH, JZ2.9, 5.7 Hz), 3.95
(ddd, 1H, 5-CH, JZ1.2, 5.2, 6.7 Hz), 3.80 (dd, 1H, 3-CH,
JZ2.0, 2.9 Hz), 3.76 (dd, 1H, 4-CH, JZ1.2, 2.0 Hz), 3.48
(dd, 1H, 6-CH, JZ6.7, 9.6 Hz), 3.24 (dd, 1H, 6-CH, JZ5.2,
9.6 Hz), 1.67–1.60 (m, 2H, allyl-CH2), 0.82 (s, 9H, –tBu),
0.81 (s, 9H, –tBu), 0.18 (s, 3H, –SiCH3), 0.17 (s, 3H,
–SiCH3), 0.13 (s, 3H, –SiCH3), 0.00 (s, 6H, –SiCH3 x 2),
K0.06 (s, 3H, –SiCH3); 13C NMR (100 MHz, CDCl3) d
144.0, 133.9, 133.1, 132.5, 131.4, 128.8, 128.7, 128.7,
127.6, 127.5, 126.7, 126.6, 113.6, 86.7, 83.5, 81.5, 75.9,
71.0, 65.3, 60.4, 26.0, 26.0, 25.3, 21.2, 18.1, 18.0, 14.8,
K1.4, K4.2, K4.3, K4.6; LRMS (FAB, positive) m/z 911
(MNaC). Anal. Calcd for C48H68O5SeSi3: C, 64.90; H, 7.72.
Found: C, 64.85; H, 7.88.
3.1.3. Phenyl 3,4-Bis-O-tert-butyldiphenylsilyl-6-O-tri-
phenylmethyl-1-seleno-b-D-glucopyranoside (13b). A
mixture of 12b (864 mg, 1.0 mmol) and dimethyldioxilane
(ca. 0.1 M in acetone, 14 mL, ca. 1.4 mmol) in CH2Cl2
(10 mL) was stirred at room temperature for 1 h and then
dried (Na2SO4) and evaporated. A mixture of the residue,
PhSeH (128 mL, 1.2 mmol) and 2,6-lutidine (800 mL,
6.9 mmol) in CH2Cl2 (5 mL) was stirred at 0 8C for 12 h
and then evaporated. The residue was partitioned between
AcOEt and H2O, and the organic layer was washed with
brine, dried (Na2SO4) and evaporated. The residue was
purified by column chromatography (SiO2, 0–1% AcOEt
in hexane) to give 13b (467 mg, 45%) as a white foam:
1H NMR (400 MHz, CDCl3) d 7.69–6.99 (m, 40H), 5.47
(d, 1H, JZ5.0 Hz), 4.09 (dd, 1H, JZ4.8, 7.2 Hz), 3.94
(brs, 1H), 3.78 (m, 1H), 3.75 (dd, 1H, JZ7.2, 9.9 Hz),
3.65 (d, 1H, JZ2.9 Hz), 3.04 (d, 1H, JZ9.1 Hz), 2.89
(dd, 1H, JZ4.7, 9.9 Hz), 0.87 (s, 9H), 0.72 (s, 9H); HRMS
calcd C63H66NaO5SeSi2: 1061.3521 (MNaC), found
1061.3510.
3.1.6. Phenyl 2-O-allyldimethylsilyl-3,4-bis-O-tert-butyl-
diphenylsilyl-6-O-triphenylmethyl-1-seleno-b-D-gluco-
pyranoside (10b). Compound 10b (1.2 g, 57%) was
obtained as a white foam from 13b (1.9 g, 1.8 mmol) as
described above for the synthesis of 10a, after purification
by column chromatography (SiO2, 2–5% AcOEt in hexane):
1H NMR (400 MHz, CDCl3) d 8.05–8.02 (m, 2H, aromatic),
7.93–7.24 (m, 38H, aromatic), 5.91–5.80 (m, 1H, allyl-CH),
5.55 (d, 1H, 1-CH, JZ7.6 Hz), 5.00–4.95 (m, 2H, allyl-
CH2), 4.36 (d, 1H, 2-CH, JZ7.6 Hz), 4.23–4.17 (m, 2H,
3-CH, 5-CH), 3.72 (d, 1H, 4-CH, JZ3.2 Hz), 3.71 (t, 1H,
6-CH2, JZ9.5 Hz), 2.68 (dd, 1H, 6-CH2, JZ2.5, 9.5 Hz),
1.50–1.46 (m, 2H, allyl-CH2), 1.11 (s, 9H, –tBu), 0.93 (s,
9H, –tBu), 0.10 (s, 3H, –SiCH3), 0.09 (s, 3H, –SiCH3); 13
C
NMR (100 MHz, CDCl3) d 144.1, 135.8, 135.7, 135.5,
134.2, 132.9, 132.9, 132.8, 132.8, 131.0, 129.4, 129.4,
128.8, 128.7, 127.5, 127.4, 127.4, 127.3, 127.3, 126.8,
126.5, 113.2, 86.3, 84.1, 84.0, 76.2, 75.8, 71.1, 66.9, 26.9,
25.4, 19.2, 19.1, K1.6, K1.7; LRMS (FAB, positive) m/z
1159 (MNaC). Anal. Calcd for C68H76O5SeSi3: C, 71.86; H,
6.74. Found: C, 71.62; H, 6.72.
3.1.4. Phenyl 3,4-bis-O-triisopropylsilyl-6-O-triphenyl-
methyl-1-seleno-b-D-glucopyranoside (13c). Compound
13c (1.7 g, 65%) was obtained as a colorless oil from 12c
(2.2 g, 3.0 mmol) as described above for the synthesis
of 13b, after purification by column chromatography (SiO2,
3.1.7. Phenyl 2-O-allyldimethylsilyl-3,4-bis-O-triisopro-
pylsilyl-6-O-triphenylmethyl-1-seleno-b-D-glucopyrano-
side (10c). Compound 10c (1.4 g, 73%) was obtained as a
colorless oil from 13c (1.7 g, 1.9 mmol) as described above
for the synthesis of 10a, after purification by column
1
0–1% AcOEt in hexane): H NMR (400 MHz, CDCl3) d
7.72–7.23 (m, 20H), 5.53 (d, 1H, JZ5.1 Hz), 4.07–3.51 (m,
7H), 1.39 (m, 21H), 0.99 (m, 21H); 13C NMR (100 MHz,
CDCl3) d 143.9, 143.9, 143.7, 133.4, 132.3, 130.7, 128.7,
128.7, 128.6, 128.4, 127.6, 127.5, 127.0, 126.8, 126.7, 87.1,
80.7, 77.6, 77.2, 71.2, 71.0, 38.8, 30.5, 29.0, 23.9, 23.1,
18.4, 18.3, 18.3, 18.2, 18.1, 18.1, 18.0, 17.9, 14.2, 12.5,
12.4, 12.4, 12.3, 12.2, 11.1; LRMS (FAB, positive) m/z 897
(MNaC). Anal. Calcd for C49H70O5SeSi2: C, 67.32; H, 8.07.
Found: C, 67.68; H, 8.37.
1
chromatography (SiO2, 2–5% AcOEt in hexane): H NMR
(400 MHz, CDCl3) d 7.76–7.18 (m, 20H, aromatic), 5.81–
5.70 (m, 1H, allyl-CH), 5.23 (d, 1H, 1-CH, JZ7.6 Hz),
4.86–4.79 (m, 2H, allyl-CH2), 4.12 (dd, 1H, 2-CH, JZ4.5,
7.6 Hz), 3.98–3.94 (m, 2H, 3-CH, 5-CH), 3.86 (brs, 1H,
4-CH), 3.56 (dd, 1H, 6-CH, JZ7.9, 9.4 Hz), 3.05 (dd, 1H,
6-CH, JZ4.7, 9.4 Hz), 1.65 (m, 2H, allyl-CH2), 1.03–0.84
(m, 42H, –CH(CH3)2), 0.15 (s, 3H, –SiCH3), 0.11 (s, 3H,
–SiCH3); 13C NMR (100 MHz, CDCl3) d 144.0, 134.3,
132.9, 130.6, 128.7, 128.7, 127.5, 127.4, 126.8, 126.6,
126.5, 113.3, 86.6, 83.7, 83.3, 77.1, 71.4, 66.4, 25.9, 18.5,
18.5, 18.3, 18.3, 12.8, 12.7, 12.3, K1.1, K1.3; HRMS calcd
C54H80NaO5SeSi3: 995.4376 (MNaC), found 995.4352.
3.1.5. Phenyl 2-O-allyldimethylsilyl-3,4-bis-O-tert-butyl-
dimethylsilyl-6-O-triphenylmethyl-1-seleno-b-D-gluco-
pyranoside (10a). A mixture of 13a6f (1.2 g, 1.5 mmol),
allyldimethylchlorosilane (438 mL, 3.0 mmol) and MS 3A
(20 mg) in pyridine (10 mL) was stirred at room tempera-
ture for 1 h. The mixture was partitioned between AcOEt
and H2O, and the organic layer was washed with brine, dried
(Na2SO4) and evaporated. The residue was purified by
column chromatography (SiO2, 2–5% AcOEt in hexane) to
give 10a (1.3 g, 97%) as a colorless oil: 1H NMR (400 MHz,
CDCl3) d 7.78–7.17 (m, 20H, aromatic), 5.84–5.69 (m, 1H,
3.1.8. Phenyl 2-O-allyldimethyl-3,4,6-tri-O-benzyl-1-
seleno-b-D-glucopyranoside (15). A mixture of 14
(800 mg, 1.37 mmol), Et3N (190 mL, 2.06 mmol), DMAP
(17 mg, 0.137 mmol) and allyldimethylchlorosilane
(300 mL, 2.06 mmol) was stirred at room temperature
for 3 h. The mixture was partitioned between AcOEt and

3704
M. Terauchi et al. / Tetrahedron 61 (2005) 3697–3707
H2O, and the organic layer was washed with brine, dried
(Na2SO4) and evaporated. The residue was purified by
column chromatography (SiO2, 2–5% AcOEt in hexane) to
give 15 (923 mg, 98%) as a colorless oil: 1H NMR
(270 MHz, CDCl3) d 7.66–7.07 (m, 20H, aromatic), 5.75
(m, 1H, allyl-H), 4.95 (d, 1H, benzyl-CH2, JZ11.5 Hz),
4.83 (d, 2H, allyl-CH2, JZ12.3 Hz) 4.83 (d, 2H, benzyl-
CH2, JZ12.5 Hz), 4.78 (d, 1H, 1-CH, JZ10.9 Hz), 4.59
(d, 1H, benzyl-CH2, JZ11.9 Hz), 4.55 (d, 1H, benzyl-CH2,
JZ11.5 Hz), 4.51 (d, 1H, benzyl-CH2, JZ11.9 Hz), 3.74
(dd, 1H, 5-CH, JZ9.7, 3.6 Hz), 3.74 (dd, 1H, 3-CH, JZ
10.9, 9.5 Hz), 3.73 (dd, 1H, 2-CH, JZ10.9, 10.9 Hz), 3.73
(dd, 1H, 4-CH, JZ9.5, 9.7 Hz), 3.49 (dd, 2H, 6-CH2, JZ
3.6, 8.9 Hz), 1.67 (dd, 2H, Si–CH2–, JZ1.3, 7.6 Hz), 0.15
(s, 3H, Si–CH3), 0.11 (s, 3H, Si–CH3); 13C NMR (125 MHz,
CDCl3) d 138.6, 138.2, 137.9, 134.2, 133.7, 129.3, 128.9,
128.4, 128.3, 128.2, 127.9, 127.7, 127.6, 127.5, 127.2,
126.8, 113.7, 87.0, 85.47, 80.3, 78.3, 75.2, 74.9, 74.8, 73.5,
68.9, 25.4, K1.3, K1.4; LRMS (FAB, positive) m/z 711
(MNaC).
12.6, 12.6, 12.5, 12.4, 12.4, K0.1, K0.4; LRMS (FAB,
positive) m/z 839 (MNaC). Anal. Calcd for C48H76O5Si3: C,
70.53; H, 9.37. Found: C, 70.61; H, 9.45.
3.2.1. 4,8-Anhydro-6,7,9-tri-O-benzyl-2,3-dideoxy-D-gly-
cero-D-ido-nonitol (18) and 4,8-anhydro-6,7,9-tri-O-ben-
zyl-2,3-dideoxy-D-glycero-D-gulo-nonitol (19). To a
refluxing solution of 15 (206 mg, 0.3 mmol) in a solvent
(60 mL), a solution of Bu3SnH (97 mL, 0.36 mmol) and
AIBN (30 mg, 0.18 mmol) in the same solvent (8.4 mL) was
added dropwise by a syringe pump over 4 h. The mixture
was evaporated, and a mixture of the resulting residue,
KF (349 mg, 6.0 mmol), KHCO3 (180 mg, 1.8 mmol) and
aqueous H2O2 (30%, 2.2 mL) in MeOH (1.7 mL) and THF
(1.7 mL) was stirred at room temperature for 12 h. Aqueous
saturated Na2S2O3 was added, and the resulting mixture was
filtrated through Celite. The filtrate was partitioned between
AcOEt and H2O, and the organic layer was washed with
brine, dried (Na2SO4) and evaporated. The residue was
purified by column chromatography (SiO2, 20–35% AcOEt
in CHCl3) to give a mixture of 18 and 19 (yield, see Table 1)
as a white solid. The a/b ratio was determined by HPLC
analysis [YMC Pack R-ODS-5A; 85% aqueous MeOH,
1.0 mL/min, room temperature, 260 nm; retention time,
11 min (18), 13.5 min (19)]. From a mixture of 18 and
19 (78 mg, 18:19Z1:2.9), 18 (12 mg, white solid) and 19
(35 mg, white solid) were obtained in a pure form by
preparative HPLC (YMC Pack D-ODS-5A, 20!250 mm;
95% aqueous MeOH, 10 mL/min, room temperature,
260 nm). 18: 1H NMR (400 MHz, CDCl3) d 7.37–7.21
(m, 15H, aromatic), 4.68–4.52 (m, 6H, benzyl-CH2), 4.03
(q, 1H, 8-CH2, JZ5.0 Hz), 3.91 (ddd, 1H, 4-CH, JZ3.3,
3.6, 5.0 Hz), 3.78–3.58 (m, 7H, 1-, 9-CH2, 5-, 6-, 7-CH),
1.68 (m, 4H, 2-, 3-CH2); 13C NMR (100 MHz, CDCl3) d
137.6, 137.5, 137.0, 128.2, 128.2, 128.0, 127.6, 127.6,
127.6, 127.5, 127.4, 127.3, 77.7, 74.9, 73.3, 73.1, 73.1, 72.8,
71.7, 69.8, 67.9, 62.5, 29.2, 24.8; LRMS (FAB, positive)
m/z 493 (MHC). Anal. Calcd for C30H36O6$1/2H2O: C,
3.2. General procedure for the radical reactions of 10a–c
To a refluxing solution of 10a–c (0.30 mmol) in benzene
(6 mL), a solution of Bu3SnH (161 ml, 0.6 mmol) and AIBN
(33 mg, 0.2 mmol) in benzene (1.5 mL) was added dropwise
by a syringe pump over 2 h. The mixture was partitioned
between AcOEt and H2O, and the organic layer was washed
with brine, dried (Na2SO4) and evaporated. The residue was
purified by column chromatography (SiO2, 2–5% AcOEt in
hexane) to give 16a–c as colorless oil. 16a: 1H NMR
(400 MHz, CDCl3) d 7.47–7.15 (m, 15H), 3.98 (ddd, 1H,
JZ3.2, 3.7, 9.9 Hz), 3.85 (d, 1H, JZ3.7 Hz), 3.63 (d, 1H,
JZ3.7 Hz), 3.52 (dd, 1H, JZ3.2, 9.9 Hz), 3.39 (d, 1H, JZ
9.9 Hz), 3.35 (d, 1H, JZ3.7 Hz), 3.02 (d, 6H, JZ3.7 Hz),
2.03 (m, 2H), 0.76 (s, 9H), 0.74 (s, 9H), 0.15 (s, 3H), 0.05 (s,
3H), K0.02 (s, 3H), K0.05 (s, 6H), K0.12 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 144.1, 128.6, 127.5, 126.6, 86.1,
77.5, 77.3, 74.4, 72.2, 71.2, 70.4, 63.3, 33.6, 26.1, 26.0,
25.9, 18.5, 18.1, 18.1, 18.0, 0.0, K1.0, K3.7, K3.9, K4.2,
K4.3; LRMS (FAB, positive) m/z 755 (MNaC). Anal.
Calcd for C42H64O5Si3: C, 68.80; H, 8.80. Found: C, 68.52;
H, 8.98. 16b: 1H NMR (400 MHz, CDCl3) d 7.56–7.08 (m,
35H), 4.08 (ddd, 1H, JZ1.3, 2.9, 9.5 Hz), 3.97 (t, 1H, JZ
4.6 Hz), 3.89 (d, 1H, JZ1.3 Hz), 3.69 (t, 1H, JZ9.5 Hz),
3.41 (t, 1H, JZ1.3 Hz), 3.39 (t, 1H, JZ1.3 Hz), 2.43 (dd,
1H, JZ2.9, 9.5 Hz), 2.16–2.08 (m, 1H), 2.02–1.96 (m, 1H),
1.76–1.69 (m, 1H), 1.38–1.26 (m, 1H), 0.91 (s, 9H), 0.84–
0.78 (m, 1H), 0.73 (s, 9H), 0.58–0.52 (m, 1H), 0.07 (s, 3H),
K0.22 (s, 3H); 13C NMR (100 MHz, CDCl3) d 144.1,
135.7, 135.5, 135.4, 133.7, 133.6, 133.1, 133.0, 129.5,
129.4, 129.2, 129.1, 128.6, 127.4, 127.3, 127.3, 127.1,
126.5, 85.9, 79.1, 72.2, 70.3, 70.1, 66.8, 62.1, 34.7, 27.0,
26.8, 19.3, 19.2, 17.7, 16.9, K0.1, K1.0; LRMS (FAB,
positive) m/z 1003 (MNaC). Anal. Calcd for C62H72O5Si3:
C, 75.87; H, 7.39. Found: C, 75.58; H, 7.58. 16c: 1H NMR
(400 MHz, CDCl3) d 7.52–7.43 (m, 2H), 7.27–7.18 (m, 9H),
4.24 (m, 1H), 3.86 (brs, 2H), 3.68 (t, 1H, JZ9.9 Hz), 3.53
(brs, 2H), 2.86 (dd, 1H, JZ3.2, 9.9 Hz), 2.06–2.03 (m, 1H),
1.98–1.95 (m, 1H), 1.73–1.69 (m, 1H), 1.03–0.87 (m, 44H),
0.11 (s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz, CDCl3) d
144.2, 128.8, 128.6, 127.5, 127.4, 126.5, 86.1, 79.7, 72.7,
71.4, 70.2, 66.9, 62.2, 34.7, 18.3, 18.2, 18.1, 17.8, 16.9,
1
71.83; H, 7.43. Found: C, 71.84; H, 7.44. 19: H NMR
(400 MHz, CDCl3) d 7.52–7.17 (m, 15H, aromatic), 4.97–
4.52 (m, 6H, benzyl-CH2), 3.69 (dd, 1H, 9-CH2, JZ2.0,
10.8 Hz), 3.68–3.62 (m, 3H, 1-CH2, 9-CH2), 3.58 (dd, 1H,
7-CH, JZ9.4, 9.4 Hz), 3.46 (dd, 1H, 6-CH, JZ8.8, 9.4 Hz),
3.43 (ddd, 1H, 8-CH, JZ2.0, 4.5, 9.4 Hz), 3.32 (dd, 1H,
5-CH, JZ8.8, 9.1 Hz), 3.22 (ddd, 1H, 4-CH, JZ2.1,2.1,
9.1 Hz), 1.98 (m, 1H, 3-CH2), 1.72 (m, 2H, 2-CH2), 1.55 (m,
1H, 3-CH2); 13C NMR (100 MHz, CDCl3) d 138.2, 137.6,
137.5, 128.3, 128.1, 128.0, 127.6, 127.6, 127.5, 127.3, 86.5,
79.2, 78.5, 78.1, 76.5, 75.0, 74.6, 73.4, 73.3, 68.7, 62.5,
28.7, 28.5; LRMS (FAB, positive) m/z 493 (MHC). Anal.
Calcd for C30H36O6$1/2H2O: C, 71.83; H, 7.43. Found: C,
71.84; H, 7.44.
3.2.2. (2R,3S,4R,5R,6R)-3-acetoxy-6-(triphenylmethoxy)-
methyl-4,5-di-tert-butyldimethylsilyloxy-2-[(3-dimethyl-
phenylsilyl)propyl)tetrahydropyran (20). A mixture of
16a (655 mg, 0.73 mmol) and PhLi (0.72 M in Et2O, 5 mL,
3.6 mmol) in THF (14 mL) was stirred at K20 8C for 5 min,
and then aqueous saturated NH4Cl was added. The resulting
mixture was partitioned between AcOEt and H2O, and the
organic layer was washed with brine, dried (Na2SO4) and
evaporated. A mixture of the residue and AcCl (142 mL,
2.0 mmol) in pyridine (10 mL) was stirred at room

M. Terauchi et al. / Tetrahedron 61 (2005) 3697–3707
3705
temperature for 12 h. The mixture was partitioned between
AcOEt and H2O, and the organic layer was washed with
brine, dried (Na2SO4) and evaporated. The residue was
purified by column chromatography (SiO2, 0–1% AcOEt in
3.2.5. 4,8-Anhydro-4-O-acetyl-9-O-triphenylmethyl-2,3-
dideoxy-D-glycero-D-ido-nonitol (23). A solution of 22
(32 mg, 44 mmol), TBAF (1 M in THF, 100 mL, 100 mmol)
and AcOH (29 mL, 50 mmol) in THF (1 mL) was stirred at
room temperature for 12 h. The mixture was partitioned
between AcOEt and H2O, and the organic layer was washed
with brine, dried (Na2SO4) and evaporated. The residue was
purified by column chromatography (SiO2, 0–1% AcOEt in
hexane) to give 23 (22 mg, 99%) as a colorless oil: 1H NMR
(400 MHz, CDCl3) d 7.45–7.43 (m, 6H), 7.33–7.23 (m, 9H),
4.88 (dd, 1H, JZ5.9, 9.7 Hz), 4.15 (ddd, 1H, 2.6, 3.5, 5.9),
3.78 (m, 1H), 3.68 (d, 2H, JZ2.7 Hz), 3.56–3.52 (m, 2H),
3.39 (dd, 2H, JZ4.4, 11.4 Hz), 2.72 (brs, 1H), 2.44 (brs,
1H), 2.11 (s, 3H), 1.72 (m, 2H), 1.56 (m, 2H); HRMS (FAB)
calcd C30H34O6Na: 529.2202 (MNaC), found 529.2224.
1
hexane) to give 20 (524 mg, 86%) as yellow oil: H NMR
(400 MHz, CDCl3) d 7.65–7.08 (m, 20H), 4.21 (s, 1H), 4.04
(dd, 1H, JZ3.5, 8.7 Hz), 3.70 (s, 1H), 3.65 (s, 1H), 3.48 (dd,
1H, JZ8.7, 10.1 Hz), 3.28 (s, 1H), 2.98 (dd, 1H, JZ3.5,
10.1 Hz), 1.97 (s, 3H), 1.70–1.40 (m, 2H), 1.36–1.18
(m, 2H), 0.89–0.79 (m, 2H), 0.78 (s, 9H), 0.62 (s, 9H),
0.13 (s, 3H), 0.12 (s, 3H), K0.05 (s, 3H), K0.06 (s, 3H),
K0.07 (s, 3H), K0.11 (s, 3H); 13C NMR (100MHz, CDCl3)
d 144.3, 128.8, 128.7, 127.6, 126.7, 86.2, 77.6, 74.4, 72.2,
71.2, 70.2, 63.3, 33.6, 29.1, 27.4, 26.7, 26.2, 25.9, 18.3,
18.0, 18.0, 17.9, 13.7, 9.4, K0.1, K1.1, K3.9, K4.0, K4.4,
K4.4; HRMS (FAB) calcd C50H72O6Si3Na 875.4534
(MNaC), found 875.4549.
3.2.6. 4,8-Anhydro-2,3-dideoxy-D-glycero-D-ido-nonitol
1,6,7-trisphosphate derivative 24. A mixture of 23
(15 mg, 30 mmol), XEPA (29 mg, 120 mmol) and 1H-
tetrazole (10 mg, 135 mmol) in CH2Cl2 was stirred at 0 8C
for 30 min. After addition of H2O (10 mL), the mixture was
stirred at room temperature for further 10 min. The resulting
mixture was cooled to K40 8C, and then m-CPBA (35 mg,
200 mmol) was added. The mixture was warmed to room
temperature over 30 min and partitioned between AcOEt
and aquerous saturated Na2SO3, and the organic layer was
washed with H2O, aqueous saturated NaHCO3 and brine,
dried (Na2SO4) and evaporated. The residue was purified by
preparative thin layer chromatography (SiO2, 75% AcOEt
3.2.3. (2R,3S,4R,5R,6R)-3-acetoxy-6-(triphenylmethoxy)-
methyl-4,5-di-tert-butyldimethylsilyl-2-[3-(dimetyl-p-
methoxyphenylsilyl)propyl]tetrahydropyrane (21).
Compound 21 (328 mg, 77%) was obtained as yellow oil
from 16a (366 mg) as described above for the synthesis of
20 using p-MeOPhLi (prepared from p-lithioanisole and
BuLi) instead of PhLi, after purification by column
1
chromatography (SiO2, 0–1% AcOEt in hexane): H NMR
(400 MHz, CDCl3) d 7.43–7.41 (m, 6H), 7.32–7.14 (m,
11H), 6.87 (t, 1H, JZ7.2 Hz), 6.77 (d, 1H, JZ8.2 Hz), 4.28
(s, 1H), 4.07 (dd, 1H, JZ4.3, 9.5 Hz), 3.76 (s, 1H), 3.72
(brs, 4H), 3.55 (t, 1H, JZ9.5 Hz), 3.34 (s, 1H), 3.02 (dd, 1H,
JZ4.3, 9.5 Hz), 2.03 (s, 3H), 1.68–1.66 (m, 1H), 1.43–1.41
(m, 1H), 1.27–1.23 (m, 2H), 0.84 (s, 9H), 0.77–0.73
(m, 2H), 0.67 (s, 9H), 0.18 (s, 3H), 0.17 (s, 3H), 0.00
(s, 3H), K0.01 (s, 3H), K0.03 (s, 3H), K0.06 (s, 3H); 13C
NMR (100MHz, CDCl3) d 170.8, 164.1, 144.0, 135.0,
130.5, 128.5, 127.6, 126.8, 126.7, 120.3, 109.3, 86.3,
79.1, 77.2, 71.2, 69.8, 68.6, 65.4, 61.5, 55.0, 34.8, 26.0,
25.8, 21.2, 20.3, 18.3, 17.8, 15.8, K2.5, K2.6, K4.5, K4.6,
K4.8, K4.9; LRMS (FAB, positive) m/z 905 (MNaC).
Anal. Calcd for C51H74O7Si3: C, 69.34; H, 8.44. Found: C,
69.52, H, 8.52.
1
in hexane) to give 24 (22 mg, 99%) as a colorless oil: H
NMR (400 MHz, CDCl3) d 7.41–7.35 (m, 6H), 7.28–7.13
(m, 20H), 7.07–7.05 (m, 1H), 5.39 (dd, 1H, JZ8.9,
13.8 Hz), 5.23–4.80 (m, 11H), 4.69 (t, 1H, JZ13.8 Hz),
4.54–4.38 (m, 2H), 4.24–4.15 (m, 3H), 3.78–3.75 (m, 1H),
3.42 (dd, 1H, JZ1.2, 10.3 Hz), 3.34 (dd, 1H, JZ7.3,
10.3 Hz), 2.12 (s, 3H), 1.94–1.77 (m, 2H), 1.70–1.65
(m, 2H); 31P NMR (202 MHz, D2O, H-decoupled) d 0.32
(s), K2.19 (s), K3.82 (s); HRMS (FAB) calcd
C54H55O16P3Na: 1075.2601 (MNaC), found 1075.2530.
3.2.7. 4,8-Anhydro-2,3-dideoxy-D-glycero-D-ido-nonitol
1,6,7-trisphosphate hexasodium salt (9). A mixture of 24
(18 mg, 17 mmol) and Pd–C (10%, 20 mg) in MeOH (2 mL)
was stirred at room temperature under atmospheric pressure
of H2 for 40 min. 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 (1 mL, 13 mmol) and then
the mixture was evaporated. A solution of the residue in
H2O was washed with AcOEt (three times) and evaporated.
A solution of the residue in aqueous NaOH (1 M, 2 mL) was
stirred at room temperature for 12 h. The resulting mixture
was applied to Diaion PK-212 (HC-form) column, and the
column was developed with H2O. The fractions containing 9
(acidic fractions) were evaporated. A solution of the residue
in H2O (1 mL) was applied to Daiaion WK-100 (NaC-form)
column, and the column was developed with H2O. The
fractions containing 9 were evaporated and dried in vacuo to
3.2.4. 4,8-Anhydro-4-O-acetyl-6,7-di-O-tert-butyldi-
methylsilyl-9-O-triphenylmethyl-2,3-dideoxy-D-glycero-
D-ido-nonitol (22). To a mixture of 21 (54 mg,
0.060 mmol), KBr (15 mg, 0.12 mmol) and AcONa
(50 mg, 0.61 mmol) in AcOH (12 mL) was added dropwise
a mixture of AcOOH (32% in AcOH, 165 mL, 0.61 mmol)
and H2SO4 (1.5 mL, 0.03 mmol) in AcOH at 0 8C, and the
resulting mixture was stirred at room temperature for 14 h.
After addition of aqueous saturated Na2S2O3, the mixture
was partitioned between AcOEt and H2O, and the organic
layer was washed with brine, dried (Na2SO4) and evapor-
ated. The residue was purified by column chromatography
(SiO2, 0–2% AcOEt in hexane) to give 22 (23 mg, 61%) as
1
colorless oil: H NMR (400 MHz, CDCl3) d 7.45–7.18 (m,
1
15H), 4.32 (s, 1H), 4.10 (dd, 1H, JZ4.4, 9.1 Hz), 3.77 (brs,
2H), 3.62 (t, 2H, JZ5.7 Hz) 3.56, (t, 1H, JZ9.1 Hz), 3.34
(s, 1H), 3.10 (dd, 1H, JZ4.4, 9.1 Hz), 2.05 (s, 3H), 1.73–
1.68 (m, 2H), 1.45–1.43 (m, 2H), 0.88 (s, 9H), 0.84 (s, 9H),
0.01 (s, 3H), 0.00 (s, 3H), K0.01 (s, 3H), K0.05 (s, 3H);
LRMS (FAB, positive) m/z 753 (MNaC).
give 9 (sodium salt, 12 mg, quant.) as a white solid. H
NMR (400 MHz, D2O) d 4.17 (dd, 1H, JZ8.5, 17.3 Hz),
3.90 (dd, 1H, JZ5.4, 10.6 Hz), 3.83–3.63 (m, 5H), 3.59–
3.49 (m, 2H), 1.70–1.44 (m, 4H); 13C NMR (100 MHz,
D2O) d 77.46 (dd, Jc,pZ3.3, 4.9 Hz), 75.18 (s), 73.26 (d,
Jc,pZ2.5 Hz), 73.03 (d, Jc,pZ2.5 Hz), 71.72 (s), 65.53 (d,

3706
M. Terauchi et al. / Tetrahedron 61 (2005) 3697–3707
Jc,pZ5.8 Hz), 26.78 (d, Jc,pZ6.6 Hz), 21.63 (s); 31P NMR
(202 MHz, D2O, H-decoupled) d 2.54 (s), 2.45 (s), 2.13 (s);
HRMS (FAB) calcd C9H17O15Na3P3: 526.9473 (MK),
found 526.9444.
Mg2C-free CLM (140 mM KCl, 20 mM NaCl, 1 mM
EGTA, 375 mM CaCl2 (w200 nM free [Ca2C]), 20 mM
Pipes, pH 7.0). The permeabilized cells (with Mag-fluo-4
trapped within the lumen of the endoplasmic reticulum, ER)
were then attached to 96-well plates (w8!105 cells/well)
coated with poly-L-lysine (0.01%) and centrifuged onto the
plate (300!g; 2 min). Immediately before an experiment,
the cells were washed twice in Mg2C-free CLM to remove
cytosolic Mag-fluo-4 and the plates were then mounted in a
FlexStation fluorescence plate reader (Molecular Devices,
Sunnyvale, CA), which allows automated additions to the
sample wells while recording fluorescence. Mag-fluo-4
fluorescence was monitored by excitation at 485 nm with
emission detected at 520 nm. Active Ca2C uptake into the
ER was initiated by addition of Mg2C-ATP (1.5 mM) and
after 150 s, when the stores had loaded to a steady-state
Ca2C content, IP3 was added. The amount of Ca2C released
by IP3 was expressed as a fraction of the total Ca2C content
of the ER as assessed by addition of 1 mM ionomycin. Data
are presented as means Gs.e. means from at least three
independent experiments, each performed in triplicate.
Concentration–effect relationships were fitted to four-
parameter logistic equations using non-linear curve-fitting
procedures (GraphPad Prism, San Diego, CA).
3.3. Materials for the bioassay
RPMI 1640 medium, L-glutamine, 2-mercaptoethanol and
G-418 were from Invitrogen (Paisley, UK), sera were from
Sigma (Poole, UK) and Mag-fluo-4AM was from Molecular
Probes (Leiden, The Netherlands).
3.3.1. Stable transfection of DT40 cells with rat type 1
IP3R. The open reading frame of rat type 1 IP3R (IP3R1)
was amplified by polymerase chain reaction (PCR) from
the expression vector pCMVI-9-IP3R128 using the follow-
ing primers: 500-AGGAATTCGCCACCATGTCTGACAAA
ATG-30 and 5 -CCGGTACCGAATTCTTAGGCTGGCTG
CTGT-30 and cloned as an EcoRI fragment into pcDNA3
(Invitrogen). The chicken b-actin hybrid promoter29 was
excised from the vector pAneo31 and cloned in place of the
CMV promoter upstream of the InsP3R1 open reading frame
to create the construct pcDNA3-IP3R1. DT40 cells in which
the genes for all three endogenous IP3R subtypes have been
deleted (DT40/IP3R-KO)30 were stably transfected by
electroporation with linearized pcDNA3-IP3R1 using a
Gene Pulser apparatus (Bio-Rad Laboratories) at 330 V,
500 mFwith5 mg DNA/106 cells. Clonalisolationwas carried
out in the presence of 2 mg/ml G-418 and positive clones
were amplified and screened for the presence of rat InsP3R1
by western blotting using an anti-peptide antiserum31
corresponding to the C-terminal 15-residues of rat IP3R1.
Acknowledgements
We acknowledge financial support from the Japan Society
for Promotion of Science for Creative Scientific Research
(13NP0401), the Wellcome Trust for Programme Grants
039662 (to CWT) and 060554 (to BVLP). We thank Dr. A.
M. Riley (University of Bath) for useful discussions and
Ms. H. Matsumoto, A. Maeda, and S. Oka (Center for
Instrumental Analysis, Hokkaido University) for technical
assistance with NMR, MS, and elemental analyses.
3.4. Cell culture
DT40/IP3R-KO cells stably expressing recombinant rat
IP3R1 (DT40/IP3R1 cells) were cultured in suspension in
RPMI 1640 medium supplemented with foetal bovine serum
(10%), L-glutamine (2 mM), 2-mercaptoethanol (50 mM)
and heat-inactivated chicken serum (1%). Cells were
incubated in a humidified atmosphere (95% O2; 5% CO2
at 37 8C) and passaged every 2–3 days when they had
reached a density of w2!106 cells/ml.
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