Synthesis of adenophostin analogues lacking the adenine moiety as novel potent IP3 receptor ligands: Some structural requirements for the significant activity of adenophostin a

Article abstract of DOI:10.1021/jo980925l

1-O-Tetrahydrofuranyl-α-D-glucopyranose derivatives 5-8 were designed and synthesized as novel IP₃ receptor ligands. The glycosidation reactions between fluoroglycosyl donor 23 and tetrahydrofuran derivatives 11-14 as glycosyl acceptors selectively gave the corresponding α-glycosides, which were converted into the target compounds 5-8 via the introduction of phosphate groups using the phosphoramidite method. Among these compounds, 1- O-tetrahydrofuranyl-α-D-glucopyranose trisphosphate derivatives 5 and 8 significantly inhibited the binding of [³H] IP³ to IP³ receptor from porcine cerebella, with IC₅₀ values of 25 and 27 nM, respectively, which were comparable to the affinity of IP₃ itself.

Full text of DOI:10.1021/jo980925l

J . Org. Chem. 1998, 63, 8815-8824
8815
Syn th esis of Ad en op h ostin An a logu es La ck in g th e Ad en in e Moiety
a s Novel P oten t IP 3 Recep tor Liga n d s: Som e Str u ctu r a l
Requ ir em en ts for th e Sign ifica n t Activity of Ad en op h ostin A
Satoshi Shuto,* Kazuya Tatani, Yoshihito Ueno, and Akira Matsuda*
Graduate School of Pharmaceutical Sciences, Hokkaido University,
Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, J apan
Received May 15, 1998
1-O-Tetrahydrofuranyl-R-D-glucopyranose derivatives 5-8 were designed and synthesized as novel
IP3 receptor ligands. The glycosidation reactions between fluoroglycosyl donor 23 and tetrahy-
drofuran derivatives 11-14 as glycosyl acceptors selectively gave the corresponding R-glycosides,
which were converted into the target compounds 5-8 via the introduction of phosphate groups
using the phosphoramidite method. Among these compounds, 1-O-tetrahydrofuranyl-R-D-glucopy-
ranose trisphosphate derivatives 5 and 8 significantly inhibited the binding of [3H] IP3 to IP3 receptor
from porcine cerebella, with IC50 values of 25 and 27 nM, respectively, which were comparable to
the affinity of IP3 itself.
In tr od u ction
as a simplified analogue of adenophostins and showed
that it was an agonist at IP3 receptors with ∼10-fold
lower potency than IP3. We hypothesized that the lower
affinity of 4 for the receptor compared to those of
adenophostins may be due to the conformational flex-
ibility of the side-chain moiety of 4. This flexibility of
the side chain may not allow the third phosphate to
achieve efficient positioning for binding to the receptor.
On the basis of these considerations, we designed 1-O-
tetrahydrofuranyl-R-D-glucopyranose derivatives 5, 7,
and 8 (Figure 1) as novel IP3 receptor ligands in which
the location of the third phosphate group in space is
restricted because it is attached to the tetrahydrofuran
ring, as in adenophostins. Compound 6, which is a
derivative of 5 that lacks a third phosphate group, was
also designed to confirm the role of the phosphate group
in binding to the receptor.
While this study was being carried out, the synthesis
and biological activity of methyl 3-O-(R-D-glucopyranos-
yl)-â-D-ribofuranoside 2,3′4′-trisphosphate (9), which was
also designed to restrict the conformation of the side-
chain moiety of 4, were reported.4,10 Biological evalua-
tions of these compounds 5-8, together with previous
results,4,8-11 may help to clarify the structural require-
ments for the significant biological activity of adeno-
phostins. In this paper, we describe the synthesis and
preliminary biological effects of these compounds.12
Considerable attention has been focused on D-myo-
inositol 1,4,5-trisphosphate (IP3), an intracellular Ca2+
-
mobilizing second messenger, because of its significant
biological importance.1,2 Therefore, analogues of IP3 have
been synthesized extensively to develop specific ligands
for IP3 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 IP3 receptor or Ca2+
-
mobilizing activity.3,4 Furthermore, specific antagonists
of the receptor have not yet been developed.3,5
Recently, Takahashi and co-workers isolated adeno-
phostin A and B from Penicillium brevicompactum and
found that they are very strong IP3 receptor ligands; 2
and 3 are 10-100 times more potent than IP3 with regard
to both the affinity for IP3 receptor and Ca2+-mobilizing
ability in cells.6 From synthetic studies of IP3 analogues,
it is now clear that the vicinal 4,5-trans-diphosphate is
essential for this activity and a third phosphate group
at the 1-position enhances binding affinity.3 Therefore,
the R-D-glucopyranose structure of adenophostins may
be a bioisostere of the D-myo-inositol moiety in IP3, and
the three-dimensional locations of the three phosphate
groups of adenophostins may be the same as those of IP3.7
Recently, two groups8,9 designed and synthesized 2-(hy-
droxyethyl)-R-D-glucopyranoside 3,4,2′-trisphosphate (4)
* To whom correspondence should be addresssed. Tel: 81-11-706-
3228. Fax: 81-11-706-4980. E-mail: matuda@pharm.hokudai.ac.jp.
(1) Berridge, M. J . Nature (London) 1993, 361, 315-325.
(2) Sutko, J . L.; Airey, J . A. Pharm. Rev. 1996, 76, 1027-1071.
(3) Potter, B. V. L.; Lampe, D. Angew. Chem., Int. Ed. Engl. 1995,
34, 1933-1972 and references sited therein.
Resu lts a n d Discu ssion
We planned to synthesize these target compounds via
glycosidation reactions with glycosyl donor 10 and tet-
(4) 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.
(8) Wilcox, R. A.; Erneux, C.; Primrose, W. U.; Gigg, R.; Nahorski,
S. R. Mol. Pharmacol. 1995, 47, 1204-1211.
(9) (a) J enkins, D. J .; Marwood, R. D.; Potter, B. V. L. Carbohydr.
Res. 1996, 287, 169-182. (b) 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.
(5) Although heparin and decavanadate have been demonstrated
to inhibit IP3 binding, they did not show specificity for the IP3 receptor,
and therefore their pharmacological uses are limited; see ref 3.
(6) (a) Takahashi, S.; Tanzawa, T.; Miyawaki, A.; Takahashi, M. J .
Antibiot. 1993, 46, 1643-1647. (b) Takahashi, S.; Kinoshita, T.;
Takahashi, M. J . Antibiot. 1993, 46, 95-100. (c) Takahashi, M.;
Tanzawa, K.; Takahashi, S. J . Biol. Chem. 1994, 269, 369-372.
(7) A possibility that the 2′-phosphate group of adenophostin A may
be positioned differently from the 1′-phosphate group of IP3 has also
been suggested by a molecular modeling study; see ref 8.
(10) J enkins, D. J .; Marwood, R. D.; Potter, B. V. L. Chem. Commun.
1997, 449-450.
(11) Compound 9 showed potent IP3 receptor binding and Ca2+
-
mobilizing effects that were comparable to those of IP3; see ref 4.
(12) A part of this study has been published as a communication:
Tatani, K.; Shuto, S.; Ueno, Y.; Matsuda, A. Tetrahedron Lett. 1998,
39, 5065-5068.
10.1021/jo980925l CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/03/1998

8816 J . Org. Chem., Vol. 63, No. 24, 1998
Shuto et al.
F igu r e 1.
Sch em e 2a
F igu r e 2.
Sch em e 1
a
Reagents: (a) (1) Bu2SnO, benzene-MeOH, (2) BnBr, toluene;
(b) NaH, AllBr, DMF; (c) NaBH3CN, HCl, Et2O; (d) NaH, AllBr,
benzene; (e) Ac2O, H2SO4; (f) piperidine, THF; (g) DAST, CH2Cl2.
dibutylstannylidene derivative of 16 with BnBr in DMF.14
We also found that the 2-hydroxyl group was benzylated
with high selectivity when the same stannylidene deriva-
tive was heated with BnBr to give the desired 2′-O-benzyl
product 17 in 95% yield from 16 along with a trace of
the 3′-O-benzyl regioisomer when toluene was used as a
benzylation reaction solvent. After the 3′-hydroxyl of 17
was protected with an allyl group, the benzylidene moiety
of 18 was reductively cleaved with NaBH3CN/HCl15 in
THF to give 6-O-benzyl derivative 19 in 61% yield along
with the corresponding 4-O-benzyl isomer (5%). The
4-hydroxyl of 19 was allylated, and then the resulting
fully protected sugar 20 was acetolysized with Ac2O and
H2SO4. Both the 6-O-Bn and 1-O-Me groups were
replaced by an acetoxy group to give 21 in 79% yield.
After the anomeric acetyl group of 21 was selectively
removed with piperidine in THF, the product 22 was
treated with DAST in CH2Cl2 to give fluoroglycoside 23
(the R/â ratio was 27:73 on the basis of its 1H NMR
spectrum) in 89% yield. Although fluoro sugar 10, the
6-hydroxyl of which was protected by a benzyl group, was
rahydrofuran derivatives 11-14 as glycosyl acceptors
(Figure 2). A typical synthetic route is shown in Scheme
1. We designed a fluoroglycoside 10 as a donor, since
fluoroglycosides are stable and easy to prepare and have
been know to be effective for the selective preparation of
R-glycopyranosides.13
The preparation of the glycosyl donor is shown in
Scheme 2. Ogawa and Kaburagi investigated regiose-
lective benzylation of glucose derivative 16 by various
methods.14 As a result, they obtained 2-O-benzyl ether
17 in the highest yield (70%) by treating the 2,3-O-
(13) (a) Mukaiyama, T.; Murai, Y.; Shoda, S. Chem. Lett. 1981, 431-
432. (b) Hashimoto, S.; Hayashi, M.; Noyori, R. Tetrahedron Lett. 1984,
25, 1379-1382. (c) Kunz, H.; Sager, W. Helv. Chim. Acta 1985, 68,
283-287.
(15) Garegg, P. J .; Hultberg, H. Carbohydr. Res. 1981, 93, C10-
C11.
(14) Ogawa, T.; Kaburagi, T. Carbohydr. Res. 1982, 103, 53-64.

Novel Potent IP3 Receptor Ligands
J . Org. Chem., Vol. 63, No. 24, 1998 8817
Sch em e 3a
Sch em e 4a
a
Reagents: (a) (1) LiAlH4, EtO, (2) TrCl, py; (b) NaH, AllBr,
DMF; (c) TsOH, MeOH; (d) Tf2O, Et3N, DMAP, MeCN.
Sch em e 5
a
Reagents: (a) NaH, AllBr, THF-DMF; (b) NaH, PMBCl,
THF-DMF; (c) (1) HCl, aq THF, (2) NaBH4, MeOH; (d) (1) Ph3P,
DEAD, THF, (2) BzCl, py; (e) NaOMe, MeOH; (f) NaH, BnBr,
DMF; (g) NaH, AllBr, DMF; (h) DDQ, CH2Cl2-H2O.
initially designed as the glycosyl donor at first (Figure
2), we used 23 as a glycosyl donor, since we presumed
that an acetyl group was also suitable for protecting the
6-hydroxy of the fluoroglycosyl donor.
The glycosyl acceptors 11-13 were prepared from a
known D-ribose derivative 2416 as shown in Scheme 3.
The 3-hydroxyl of 24 was protected with an allyl or
4-methoxybenzyl (PMB) group to give the corresponding
3-O-allyl derivative 25 or 3-O-PMB derivative 26, re-
spectively. Although hydride reduction at the anomeric
position of 25 or 26 in the presence of a Lewis acid was
tried under various conditions, it was unsuccessful.
However, the 1-position was successfully deoxygenated
via the reductive ring-opening products 27 and 28. Thus,
successive treatment of 25 with HCl under reflux condi-
tions in aqueous THF, followed by NaBH4 in MeOH, gave
the ring-opening product 27 in 74% yield. Treatment of
27 under Mitsunobu reaction conditions17 gave the
desired 1-deoxy derivative 13, which was isolated as the
corresponding 2-O-benzoyl derivative 29 in 71% yield
from 27. The benzoyl group was removed with NaOMe
in MeOH to give the glycosyl acceptor 13. Similarly, 3-O-
PMB-1-deoxy derivative 31 was prepared from 28. After
the 2-hydroxy of 31 was protected with an allyl group,
the 3-O-PMB group was oxidatively removed with DDQ
in CH2Cl2-H2O18 to give glycosyl acceptor 11. In a
similar manner, glycosyl acceptor 12 was readily pre-
pared from 31 via 32.
was protected with an allyl group, the isopropylidene and
trityl groups were simultaneously removed with TsOH
in MeOH to give 37. Intramolecular condensation of 37
was investigated by various methods. Treatment of 37
under Mitsunobu reaction conditions, which are efficient
for preparing tetrahydrofuran derivatives 29 and 30 as
described above, did not give the desired 14. However,
when 37 was treated with Tf2O in MeCN, tetrahydro-
furan derivative 14 was obtained in 41% yield.
Glycosidation reactions with fluoroglycosyl donor 23
were first examined with cyclopentanol as a model
acceptor, and the results are summarized in Table 1.
Reactions were performed with BF3‚Et2O13c or TMSOTf13b
as a promoter, which is known to be effective for glycosi-
dation with fluoroglycosyl donors, in the presence of Et3N
in CH2Cl2 (entries 1 and 2). As a result, TMSOTf proved
to be more effective than BF3‚Et2O in this reaction system
to give the corresponding anomeric mixture of glycosides
in high yield (R:â ) 67:33). The reaction with TMSOTf
as a promoter was investigated with several reaction
solvents, and the R/â ratio was best when Et2O was used
as a solvent (entry 5). The reaction with glycosyl acceptor
11 under the same conditions as those in entry 5 gave
the desired R-glycoside 39 selectively (entry 6; yield 88%,
R:â ) 95:5) (Scheme 5). Similar glycosidation reactions
with glycosyl donor 23 and glycosyl acceptors 12-14 gave
the corresponding glycosides 40-42 in high yields (en-
tries 7-9), and the desired R-glycosides were mainly
produced (R/â ) 93:7, 85:15, and 94:6, respectively).
However, these anomeric mixtures were inseparable at
this stage.
The glycosyl acceptor 14 was synthesized from an
optically active triol derivative 34, which was prepared
from D-isoascorbic acid by a previously reported method,19
as shown in Scheme 4. Successive treatment of 34 with
LiAlH4 in Et2O, followed by TrCl in pyridine, gave tetrol
derivative 35. After the free secondary hydroxyl of 35
(16) Tino, J . A.; Clark, J . M.; Field, A. K.; J acobs, G. A.; Lis, K. A.;
Michalik, T. L.; McGeever-Robin, B.; Slusarchyk, W. A.; Spergel, S.
H.; Sundeen, J . E.; Tuomari, A. V.; Weaver, E. R.; Young, M. G.; Zahler,
R. J . Med. Chem. 1993, 36, 1221-1219.
The 6′-O-acetyl group of 39 was replaced with a benzyl
group by the usual method, and removal of the allyl
groups of the resulting product 15 was examined. The
three allyl groups were found to be deprotected simul-
taneously when 15 was heated with Pd-C and TsOH
(17) Mitsunobu, O. Synthesis 1981, 1-28.
(18) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 889-892.
(19) Abushanab, E.; Vemishetti, P.; Leiby, R. W.; Singh, H. K.;
Mikkilineni, A. B.; Wu, D. C.-J .; Saibaba, R.; Panzica, R. P. J . Org.
Chem. 1988, 53, 2598-2602.

8818 J . Org. Chem., Vol. 63, No. 24, 1998
Shuto et al.
Ta ble 1. Syn th esis of 38-42 by Glycosid a tion Rea ction s w ith F lu or o Su ga r 23 a s a Glycosyl Don or
entry
ROH
Lewis acid
solvent
time (h)
product
yield (%)
R/âa
1
2
3
4
5
6
7
8
9
cyclopentanol
cyclopentanol
cyclopentanol
cyclopentanol
BF3‚Et2O
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
CH2Cl2
CH2Cl2
toluene
EtCN
Et2O
Et2O
Et2O
Et2O
Et2O
11
0.5
1
0.5
7
38
38
38
38
38
39
40
41
42
74
93
62
63
93
88
85
89
78
68:32
67:33
60:40
54:46
77:23
95:5
93:7
85:15
94:6
cyclopentanol
11
12
13
14
1
1.5
0.7
1.5
a
Determined by the 1H NMR spectrum.
Sch em e 6a
a
Reagents: (a) (1) NaOMe, MeOH, (2) NaH, BnBr, DMF; (b) (1) Pd-C, TsOH, aq EtOH, (2) Ac2O, py; (c) (1) NaOMe, MeOH, (2)
(BnO)2PNiPr2, tetrazole, CH2Cl2, then m-CPBA; (d) H2, Pd-C, EtOH.
under reflux conditions in aqueous EtOH,20 and the
product was isolated as triacetate 45 in 98% yield. At
this stage, the desired R-anomer 45 was obtained in a
pure form, after silica gel column chromatography.
Phosphate units were introduced using the phosphora-
midite method. Thus, after the three acetyl groups of
45 were removed, the resulting trihydroxy product was
treated with dibenzyldiisopropylphosphoramidite and
tetrazole in CH2Cl2 followed by oxidation with m-CPBA21
to give the desired triphosphate derivative 48 in 74%
yield from 45. Finally, all of the benzyl groups of 48 were
simultaneously removed by catalytic hydrogenation with
Pd-C in EtOH to give the target compound 5 quantita-
tively as a sodium salt after treatment with ion-exchange
resin.
Similarly, the glycosidation products 40-42 were
converted into the target diphosphate derivatives 6 and
triphosphate derivatives 8 and 7, respectively (Scheme
6).
The binding affinity of the synthesized compounds for
the IP3 receptor of porcine cerebella was evaluated in
vitro with [3H] IP3 as a radioligand,22 and the results are
summarized in Table 2. Compound 5, which corresponds
to the des-adenyl analogue of adenophostin A, signifi-
cantly inhibited the binding of [3H]IP3 with an IC50 value
Ta ble 2. Bin d in g Affin ity of th e Com p ou n d s for IP 3
Recep tor fr om P or cin e Cer ebella a
compd
IC50 (µM)
5
6
0.025
7.8
7
0.54
8
IP3
0.027
0.019
0.0019
adenophostin A
a
Measured with [3H]IP3 (2.3 nM) as a radioligand in Tris-HCl
buffer (50 mM, pH 8.0) containing EDTA (1.0 mM).
of 25 nM, which is comparable to the affinity of IP3 itself
(IC50 ) 19 nM). Compound 6, which lacks the third
phosphate group in 5, was almost inactive (IC50 ) 7.8
µM).23 Compound 7, a regioisomer of 5, showed about
20-fold lower potency (IC50 ) 0.54 µM) than 5, which
suggested that the binding affinity of the compounds
depends on the three-dimensional location of the third
phosphate group. Interestingly, compound 8, which lacks
the hydroxymethyl moiety of 5, had a significant binding
affinity (IC50 ) 27 nM) similar to that of 5. Thus, this
study indicates that the R-D-glucopyranose structure is
a good bioisostere of the myo-inositol backbone of IP3 and
also that adequate conformational restriction of the
phosphate group of the side-chain moiety attached at the
(20) Boss, R.; Scheffold, R. Angew. Chem., Int. Ed. Engl. 1976, 15,
558-559.
(23) Under the voltage-clamp condition (holding potential: -70 mV),
dialysis of 0.1 mM 6 induced inward currents in nine out of 12 isolated
turtle olfactory neurons. The mean magnitude of the response to 6
(53.7 ( 35.8 pA) was nearly 60% of that to IP3. This result suggested
that 6 is an agonist of IP3 receptor: Kashiwayanagi, M. Unpublished
results.
(21) Yu, K.-L.; Fraser-Reed, B. A. Tetrahedron Lett. 1988, 29, 979-
982.
(22) Worley, P. F.; Basadan, J . M.; Supattapone, S.; Wilson, V. S.;
Snyder, S. H. J . Biol. Chem. 1987, 262, 12132-12136.

Novel Potent IP3 Receptor Ligands
J . Org. Chem., Vol. 63, No. 24, 1998 8819
in mineral oil, 278 mg, 6.95 mmol), and allyl bromide (0.120
mL, 1.39 mmol) in benzene (5.8 mL) was heated under reflux
for 22 h. The reaction mixture was poured into saturated
aqueous NH4Cl (30 mL), and the resulting mixture was
extracted with Et2O (50 mL). The organic layer was washed
with brine, dried (Na2SO4), and evaporated under reduced
pressure. The residue was purified by column chromatography
(SiO2, hexane/EtOAc 4:1) to give 20 (427 mg, 81% as an oil):
1R-position improves the binding affinity for IP3 receptor.
Some apparent structure requirements for the binding
affinity of adenophostins to the IP3 receptor suggested
by this study and previous results4,8,-11 are that (1) the
adenine moiety is not essential, but enhances affinity,
(2) the three-dimensional location of the third phosphate
group plays an important role in strong binding to the
receptor, and (3) the hydroxymethyl group of the ribose
moiety does not play a role in binding to the receptor.
Further biological evaluations of the compounds are
now underway.
[R]26 +46.2° (c 1.05, CHCl3); 1H NMR (500 MHz, CDCl3) δ
D
7.37-7.22 (m, 10 H), 6.03-5.93 (m, 1 H), 5.86-5.76 (m, 1 H),
5.32-5.26 (m, 1 H), 5.20-5.13 (m, 2 H), 5.11-5.07 (m, 1 H),
4.77 (d, 1 H, J ) 12.2 Hz), 4.63 (d, 1 H J ) 12.2 Hz), 4.62 (d,
1 H, J ) 12.1 Hz), 4.50 (d, 1 H, J ) 12.1 Hz), 4.59 (d, 1 H, J
) 3.6 Hz), 4.42-4.37 (m, 1 H), 4.30-4.24 (m, 2 H), 4.01-3.95
(m, 1 H), 3.75 (dd, 1 H, J ) 9.2, 9.4 Hz), 3.70-3.61 (m, 3 H),
3.44 (dd, 1 H, J ) 3.6, 9.4 Hz), 3.41 (dd, 1 H, J ) 9.0, 9.2 Hz),
3.35 (s, 3 H); HRMS (FAB) calcd for C27H33O6 (M - 1)+
453.2277, found 453.2266.
Exp er im en ta l Section
Melting points are uncorrected. 1H, 13C, and 31P NMR
spectra were recorded at 270, 400, and 500 MHz (1H) and at
125 MHz (31P). Chemical shifts are reported in ppm downfield
from TMS (1H and 13C) or H3PO4 (31P). Mass spectra were
obtained by electron ionization (EI) or fast atom bombardment
(FAB) methods. Thin-layer chromatography was done on
1,6-Di-O-a cetyl-3,4-d i-O-a llyl-2-O-ben zyl-D-glu cop yr a -
n ose (21). A mixture of 20 (1.58 g, 3.48 mmol) and concen-
trated H2SO4 (35 µL) in Ac2O (17.5 mL) was stirred at 0 °C
for 3 h. The reaction mixture was poured into EtOH (140 mL),
and the resulting solution was stirred at room temperature
for 14 h. The solvent was evaporated under reduced pressure,
and the residue was partitioned between EtOAc and H2O. The
organic layer was washed with brine, dried (Na2SO4), and
evaporated under reduced pressure. The residue was purified
by column chromatography (SiO2, hexane/EtOAc 7:2) to give
21 (1.19 g, 79%, as an oil, the R/â ratio was 81:19 on the basis
Merck coated plate 60F254
. Silica gel chromatography was
done with Merck silica gel 5715. Reactions were carried out
under an argon atmosphere.
Meth yl 2-O-Ben zyl-4,6-O-ben zylid en e-R-D-glu cop yr a -
n osid e (17). A mixture of 16 (10.0 g, 35.5 mmol) and Bu2-
SnO (8.84 g, 35.5 mmol) in benzene-MeOH (10:1, 120 mL)
was heated under reflux under azeotropic conditions for 3 h,
and then the resulting mixture was evaporated under reduced
pressure. A mixture of the residue and BnBr (42.2 mL, 355
mmol) was heated in toluene (75 mL) under reflux for 12 h,
and the resulting solution was evaporated under reduced
pressure. To a solution of the residue in EtOAc (360 mL) was
added an aqueous KF solution (6.2 g of KF in 6.5 mL of H2O),
and the mixture was stirred at room temperature for 3.5 h.
After filtration of the resulting insoluble materials, the filtrate
was dried (Na2SO4) and evaporated under reduced pressure.
The residue was purified by column chromatography (SiO2,
hexane/EtOAc 3:1) to give 17 (12.5 g, 95% as a white solid):
[R]26 +35.2° (c 1.00, CHCl3) [lit.14 [R]25 +34.7° (c 0.95,
of its 1H NMR spectrum): [R]27 +60.5 ° (c 1.20, CHCl3); 1H
D
NMR (500 MHz, CDCl3) δ 7.38-7.24 (m, 5 H), 6.26 (d, 0.81 H,
J ) 3.7 Hz), 6.02-5.84 (m, 2 H), 5.56 (d, 0.19 H, J ) 8.1 Hz),
5.33-5.15 (m, 4 H), 4.77 (d, 0.19 H, J ) 11.4 Hz), 4.71 (d, 0.19
H, J ) 11.4 Hz), 4.67 (d, 0.81 H, J ) 11.6 Hz), 4.63 (d, 0.81 H,
J ) 11.6 Hz), 4.43-4.05 (m, 6 H), 3.86 (ddd, 0.81 H, J ) 2.5,
3.9, 9.9 Hz), 3.74 (t, 0.81 H, J ) 9.4 Hz), 3.60-3.51 (m, 0.38
H), 3.55 (dd, 0.81 H, J ) 3.7, 9.4 Hz), 3.46 (dd, 0.19 H, J )
8.1, 9.2 Hz), 3.37 (dd, 0.19 H, J ) 8.8, 9.8 Hz), 3.36 (dd, 0.81
H, J ) 9.4, 9.9 Hz), 2.14 (s, 2.43 H), 2.07 (s, 2.43 H), 2.08 (s,
0.57 H), 2.05 (s, 0.57 H); HRMS (FAB) calcd for C23H29O8 (M
- 1)+ 433.1861, found 433.1892. Anal. Calcd for C23H30O8:
C, 63.58; H, 6.96. Found: C, 63.35; H, 6.94.
D
D
CHCl3)].
Met h yl 3-O-Allyl-2-O-b en zyl-4,6-O-b en zylid en e-R-D-
glu cop yr a n osid e (18). A solution of 17 (15.5 g, 41.7 mmol)
in DMF (160 mL) was added dropwise to a suspension of NaH
(60% in mineral oil, 5.00 g, 125 mmol) in DMF (50 mL) at 0
°C, and the mixture was stirred at the same temperature for
1.5 h. Allyl bromide (4.33 mL, 50.0 mmol) was added, and
the resulting mixture was stirred at room temperature for 13
h. The reaction mixture was poured into saturated aqueous
NH4Cl (500 mL), and the resulting mixture was extracted with
EtOAc (350 mL × 2). The organic layer was washed with
brine, dried (Na2SO4), and evaporated under reduced pressure.
The residue was treated with EtOAc-hexane to give a crystal-
6-O-Acet yl-3,4-d i-O-a llyl-2-O-b en zyl-D-glu cop yr a n ose
(22). A mixture of 21 (1.15 g, 2.65 mmol) and piperidine (13.1
mL, 132 mmol) in THF (26.5 mL) was stirred at room
temperature for 36 h. The reaction mixture was diluted with
CHCl3 (60 mL), and the resulting solution was washed with
aqueous HCl (0.5 M) and saturated aqueous NaHCO3, dried
(Na2SO4), and evaporated under reduced pressure. The resi-
due was purified by column chromatography (SiO2, hexane/
EtOAc 2:1) to give 22 (962 mg, 93% as an oil, the R/â ratio
1
was 55:45 on the basis of its H NMR spectrum): [R]22 +36.2
D
° (c 1.07, CHCl3): 1H NMR (500 MHz, CDCl3) δ 7.40-7.27 (m,
5 H), 6.02-5.84 (m, 2 H), 5.33-5.14 (m, 4.55 H), 4.90 and 4.76
(each d, each 0.45 H, J ) 11.1 Hz), 4.77 and 4.67 (each d, each
0.55 H, J ) 11.8 Hz), 4.69 (dd, 0.45 H, J ) 5.4, 7.7 Hz), 4.41-
4.23 (m, 4.65 H), 4.20 (dd, 0.45 H, J ) 5.4, 11.9 Hz), 4.11-
4.05 (m, 0.90 H), 4.04-4.00 (m, 0.55 H), 3.77 (t, 0.55 H, J )
9.3 Hz), 3.52-3.43 (m, 1.45 H), 3.36-3.26 (m, 1.45 H), 3.11
(d, 0.45 H, J ) 5.3 Hz), 2.88 (d, 0.55 H, J ) 2.4 Hz), 2.09 (s,
1.35 H, Ac), 2.08 (s, 1.65 H); HRMS (FAB) calcd for C21H29O7
line 18 (15.2 g, 89% as a needle): [R]28 +1.1° (c 0.91, CHCl3)
D
[lit.24[R]23D +1.3° (c 0.96, CHCl3)]; mp 98-99 °C [lit.24 mp 96-
98 °C].
Meth yl 3-O-Allyl-2,6-d i-O-ben zyl-R-D-glu cop yr a n osid e
(19). To a mixture of 18 (1.24 g, 3.01 mmol), NaBH3CN (1.89
g, 30.1 mmol), and molecular sieves 3 A powder (7.0 g) in THF
(50 mL) was added a saturated HCl solution in Et2O at 0 °C
to adjust the pH of the mixture at ca. 3. The mixture was
stirred at 0 °C for 1 h and filtered through Celite. The filtrate
was washed with saturated aqueous NaHCO3 and brine, dried
(Na2SO4), and evaporated under reduced pressure. The resi-
due was purified by column chromatography (SiO2, hexane/
EtOAc 3:1) to give 19 (757 mg, 61% as an oil): [R]28D +28.1° (c
(M + 1)+ 393.1913, found 393.1890. Anal. Calcd for C21H28
O7: C, 64.27; H, 7.19. Found: C, 63.98; H, 7.18.
-
6-O-Acet yl-3,4-d i-O-a llyl-2-O-b en zyl-D-glu cop yr a n os-
yl F lu or id e (23). A mixture of 22 (950 mg, 2.24 mmol) and
DAST (0.64 mL, 4.8 mmol) in CH2Cl2 (12 mL) was stirred at
0 °C for 2 h. The reaction mixture was diluted with CH2Cl2
(30 mL), and the resulting solution was washed with saturated
aqueous NaHCO3 and brine, dried (Na2SO4), and evaporated
under reduced pressure. The residue was purified by column
chromatography (SiO2, hexane/EtOAc 4:1) to give 23 (890 mg,
1.05, CHCl3) [lit.24 [R]23 +28.7° (c 1.81, CHCl3)] and the
D
corresponding 4-O-benzyl regioisomer (63 mg, 5% as a solid)
[[R]32 +44.8° (c 1.03, CHCl3) [lit.24 [R]23 +48.4° (c 1.09,
D
D
CHCl3)].
93% as an oil, the R/â ratio was 27:73 on the basis of its 1H
Meth yl 3,4-Di-O-a llyl-2,6-d i-O-ben zyl-R-D-glu cop yr a -
n osid e (20). A mixture of 19 (481 mg, 1.16 mmol), NaH (60%
1
NMR spectrum): [R]21 +37.4° (c 1.60, CHCl3); H NMR (500
D
MHz, CDCl3) δ 7.38-7.28 (m, 5 H), 6.02-5.83 (m, 2 H), 5.48
(dd, 0.27 H, H-1, J ) 2.6, 52.9 Hz), 5.33-5.15 (m, 4.73 H),
(24) Kuster, J . M.; Dyong, I. Liebigs Ann. Chem. 1975, 2179-2189.

8820 J . Org. Chem., Vol. 63, No. 24, 1998
Shuto et al.
4.81 and 4.69 (each d, 0.73 H, J ) 11.2 Hz), 4.79 and 4.69
(each d, each 0.27 H, J ) 12.0 Hz), 4.42-4.06 (m, 5 H), 3.94
(ddd, 0.27 H, J ) 2.4, 4.2, 10.2 Hz), 3.79 (t, 0.27 H, J ) 9.3
Hz), 3.60 (ddd, 0.73 H, J ) 2.2, 5.2, 9.7 Hz), 3.51-3.39 (m,
2.46 H), 3.35 (dd, 0.27 H, J ) 9.3, 10.2 Hz), 2.10 (s, 2.19 H,
Ac), 2.08 (s, 0.81 H, Ac); HRMS (FAB) calcd for C21H26FO6
393.1713, found 393.1687.
H, J ) 5.4, 9.7 Hz), 3.46 (dd, 1 H, J ) 6.2, 7.3 Hz), 3.35 (br s,
1 H), 3.09-2.22 (br m, 2 H).
3-O-(4-Meth oxyben zyl)-5-O-ben zyl-D-r ibitol (28). 5-O-
Benzyl-3-O-(4-methoxybenzyl)-D-ribofuranose (solids, 5.50 g,
81%) was obtained from 26 (5.50 g, 13.8 mmol) as described
above for the synthesis of 3-O-allyl-5-O-benzyl-D-ribofura-
nose: 1H NMR (270 MHz, CDCl3) δ 7.40-7.19 (m, 7 H), 6.92-
6.84 (m, 2 H), 5.30-5.20 (m, 1 H), 4.62-4.41 (m, 4 H), 4.29-
3.93 (m, 3 H), 3.81 (s, 3 H), 3.65 (d, 0.15 H, J ) 9.8 Hz), 3.63
(dd, 0.85 H, J ) 3.0, 10.3 Hz), 3.55-3.40 (m, 1.15 H), 3.37 (d,
0.85 H, J ) 7.1 Hz), 2.88 (d, 0.15 H, J ) 7.5 Hz), 2.68 (d, 0.85
H, J ) 3.1 Hz); HRMS (EI) calcd for C20H24O6 360.1573, found
360.1553. Anal. Calcd for C20H24O6: C, 66.65; H, 6.71.
Found: C, 66.44; H, 6.57.
3-O-Allyl-5-O-ben zyl-1,2-O-isopr opyliden e-R-D-r ibofu r a-
n ose (25). A solution of 24 (876 mg, 3.13 mmol) in THF (10
mL) was added dropwise to a suspension of NaH (60% in
mineral oil, 250 mg, 6.25 mmol) in DMF (5 mL) at 0 °C, and
the mixture was stirred at the same temperature for 19 h. Allyl
bromide (4.33 mL, 50.0 mmol) was added at 0 °C, and the
resulting mixture was stirred at room temperature for 3 h.
The reaction was quenched with aqueous NH4Cl (1 M, 25 mL),
and the resulting mixture was extracted with EtOAc (50 mL
× 2). The organic layer was washed with brine, dried (Na2-
SO4), and evaporated under reduced pressure. The residue
purified by column chromatography (SiO2, hexane/EtOAc 7:2)
to give 25 (928 mg, 93% as an oil): [R]25D +79.9° (c 1.35, CHCl3);
1H NMR (500 MHz, CDCl3) δ 7.36-7.24 (m, 5 H), 5.95-5.86
(m, 1 H), 5.78 (d, 1 H, J ) 3.7 Hz), 5.31-5.25 (m, 1 H), 5.23-
5.19 (m, 1 H), 4.64 and 4.55 (each d, each 1 H, J ) 12.2 Hz),
4.60 (dd, 1 H J ) 3.7, 4.4 Hz), 4.17-4.12 (m, 2 H), 4.08-4.03
(m, 1 H), 3.84 (dd, 1 H, J ) 4.4, 9.2 Hz), 3.79 (dd, 1 H, J ) 2.0,
11.3 Hz), 3.61 (dd, 1 H, J ) 3.9, 11.3 Hz), 1.58 and 1.36 (each
s, each 3 H); HRMS (EI) calcd for C18H24O5 320.1624, found
320.1622. Anal. Calcd for C18H24O5: C, 67.48; H, 7.55.
Found: C, 67.33; H 7.47.
Compound 28 (3.22 g, 91% as an oil) was obtained from 5-O-
benzyl-3-O-(4-methoxybenzyl)-D-ribofuranose (3.50 g, 9.72 mmol)
as described above for the synthesis of 27: [R]27D +13.6° (c 1.24,
MeOH); 1H NMR (500 MHz, CDCl3) δ 7.38-7.28 (m, 5 H),
7.18-7.15 (m, 2 H), 6.87-6.83 (m, 2 H), 4.58 and 4.53 (each
d, each 1 H, J ) 11.8 Hz), 4.57 and 4.47 (each d, each 1 H, J
) 10.9 Hz), 3.97 (ddd, 1 H, J ) 3.4, 5.5. 7.3 Hz), 3.91-3.87
(m, 1 H), 3.81-3.74 (m, 2 H), 3.80 (s, 3 H), 3.68 (dd, 1 H, J )
3.4, 9.6 Hz), 3.60 (dd, 1 H, J ) 5.5, 9.6 Hz), 3.56 (dd, 1 H, J )
6.5, 7.3 Hz), 3.45-2.60 (br, 3 H); HRMS (EI) calcd for C20H26
-
O6 362.1729, found 362.1719. Anal. Calcd for C20H26O6‚1/
3H2O: C, 65.20; H, 7.30. Found: C, 64.93; H, 7.23.
1,4-An h yd r o-3-O-a llyl-2-O-b en zoyl-5-O-b en zyl-D-r ib i-
tol (29). A mixture of 27 (3.26 g, 11.6 mmol), Ph3P (4.56 g,
17.4 mmol), and diethyl azodicarboxylate (2.74 mL, 17.4 mmol)
in THF (110 mL) was heated at 60 °C for 42 h. The resulting
mixture was evaporated under reduced pressure, and the
residue was purified by column chromatography (SiO2, hexane/
EtOAc 2:1) to give crude 13 as an oil, which was contaminated
5-O-Ben zyl-1,2-O-isop r op ylid en e-3-O-(4-m eth oxyben z-
yl)-R-D-r ibofu r a n ose (26). Compound 26 (10.8 g, 95% as an
oil) was obtained from 24 (412 mg, 0.90 mmol) as described
for the synthesis of 25, with 4-methoxybenzyl chloride (4.64
with compounds derived from diethyl azodicarboxylate.
A
mL, 115 mmol) instead using allyl bromide: [R]30 +85.4° (c
D
mixture of the obtained oil and BzCl (2.02 mL, 17.4 mmol) in
CH2Cl2 (20 mL) and pyridine (20 mL) was stirred at room
temperature for 2 h. After the reaction was quenched with
ice-water, EtOAc (40 mL) and saturated aqueous NaHCO3
(15 mL) were added, and the whole was partitioned. The
organic layer was washed with saturated aqueous NaHCO3
and brine, dried (Na2SO4), and evaporated under reduced
pressure. The residue was purified by column chromatography
1
1.02, CHCl3); H NMR (500 MHz, CDCl3) δ 7.35-7.24 (m, 7
H), 6.88-6.83 (m, 2 H), 5.75 (d, 1 H, J ) 3.7 Hz), 4.66 and
4.48 (each d, each 1 H, J ) 11.7 Hz), 4.56 and 4.49 (each d,
each 1 H, J ) 12.3 Hz), 4.53 (dd, 1 H, J ) 3.7, 4.4 Hz), 4.16
(ddd, 1 H, J ) 2.0, 3.8, 9.1 Hz), 3.84 (dd, 1 H, J ) 4.4, 9.1 Hz),
3.79 (s, 3 H), 3.75 (dd, 1 H, J ) 2.1, 11.3 Hz), 3.55 (dd, 1 H, J
) 3.8, 11.3 Hz), 1.59 and 1.35 (each s, each 3 H); HRMS (EI)
calcd for C23H28O6 400.1886, found 400.1868. Anal. Calcd for
(SiO2, hexane/EtOAc 7:2) to give 29 (3.04 g, 71% as an oil):
C
23H28O6: C, 68.98; H, 7.05. Found: C, 68.83; H, 7.13.
1
[R]25 +109.3° (c 1.14, CHCl3); H NMR (500 MHz, CDCl3) δ
D
3-O-Allyl-5-O-ben zyl-D-r ibitol (27). A solution of 25 in a
8.10-8.05 (m, 2 H), 7.59-7.54 (m, 1 H), 7.47-7.41 (m, 2 H),
7.38-7.25 (m, 5 H), 5.82-5.73 (m, 1 H), 5.59 (dt, 1 H, J ) 2.5,
4.6 Hz), 5.22-5.16 (m, 1 H), 5.12-5.08 (m, 1 H), 4.65 and 4.58
(each d, each 1 H, J ) 12.1 Hz), 4.29 (dd, 1 H, J ) 4.6, 10.6
Hz), 4.14-4.05 (m, 3 H), 4.05 (dd, 1 H, J ) 2.5, 10.6 Hz), 3.99-
3.94 (m, 1 H), 3.76 (dd, 1 H, J ) 2.5, 10.7 Hz), 3.62 (dd, 1 H,
J ) 4.2, 10.7 Hz); HRMS (EI) calcd for C22H24O5 368.1624,
found 368.1635. Anal. Calcd for C22H24O5: C, 71.72; H, 6.57.
Found: C, 71.54, H, 6.66.
mixed solution of 1 M HCl and THF (1:1, 140 mL) was heated
under reflux for 5.5 h. After being neutralized with NaHCO3
at 0 °C, the mixture was concentrated under reduced pressure
(for removing THF), and the resulting solution was extracted
with CHCl3 (100 mL × 2). The organic layer was washed with
brine, dried (Na2SO4), and evaporated under reduced pressure.
The residue was purified by column chromatography (SiO2,
hexane/EtOAc 1:1) to give 3-O-allyl-5-O-benzyl-D-ribofuranose
1
(3.85 g, quant as an oil): H NMR (500 MHz, CDCl3) δ 7.39-
1,4-An h yd r o-2-O-ben zoyl-5-O-ben zyl-3-O-(4-m eth oxy-
ben zyl)-D-r ibitol (30). Compound 30 (4.07 g, 78% as an oil)
was obtained from 28 (4.19 g, 11.6 mmol) as described above
for the synthesis of 29: [R]20D +112.7° (c 1.06, CHCl3); 1H NMR
(270 MHz, CDCl3) δ 8.12-8.06 (m, 2 H), 7.61-7.54 (m, 1 H),
7.48-7.41 (m, 2 H), 7.39-7.28 (m, 5 H), 7.16-7.10 (m, 2 H),
6.78-6.72 (m, 2 H), 5.63-5.57 (m, 1 H), 4.58 and 4.50 (each
d, each 1 H, J ) 12.1 Hz), 4.58 and 4.38 (each d, each 1 H, J
) 11.2 Hz), 4.28 (dd, 1 H, J ) 4.6, 10.6 Hz), 4.14-4.08 (m, 2
H), 4.06 (dd, 1 H, J ) 2.5, 10.6 Hz), 3.75 (s, 3 H), 3.74-3.66
(m, 1 H), 3.56-3.49 (m, 1 H); MS (EI) m/z 448 (M+).
7.24 (m, 5 H), 5.92-5.83 (m, 1 H), 5.30-5.20 (m, 3 H), 4.66
and 4.58 (each d, each 0.58 H, J ) 11.9 Hz), 4.59 and 4.52
(each d, each 0.42 H, J ) 12.0 Hz), 4.25-3.91 (m, 5 H, allylic),
3.69 (dd, 0.58 H, J ) 3.0, 10.2 Hz), 3.63 (d, 0.42 H, J ) 9.8
Hz), 3.59 (dd, 0.58 H, J ) 3.0, 10.2 Hz), 3.56 (d, 0.84 H, J )
4.1 Hz), 3.40 (d, 0.58 H, J ) 7.4 Hz), 2.87 (d, 0.42 H, J ) 7.8
Hz), 2.69 (d, 0.58 H, J ) 3.2 Hz); HRMS (FAB) calcd for C15
-
H
19O5 (M - 1)+ 279.1232, found 279.1238. Anal. Calcd for
C15H20O5‚0.75H2O: C, 61.32; H, 7.38. Found: C, 61.70; H,
7.20. A mixture of 3-O-allyl-5-O-benzyl-D-ribofuranose (3.43
g, 12.3 mmol) and NaBH4 (931 mg, 24.6 mmol) in MeOH (40
mL) was stirred at room temperature for 20 h. After being
neutralized with AcOH, the mixture was evaporated under
reduced pressure. The residue was purified by column chro-
matography (SiO2, CHCl3/MeOH, 20:1, 15:1, and 10:1) to give
27 (3.27 g, 95% as an oil): 1H NMR (500 MHz, CDCl3) δ 7.39-
7.27 (m, 5 H), 5.90-5.80 (m, 1 H), 5.26-5.14 (m, 2 H), 4.60
and 4.56 (each d, each 1 H, J ) 11.7 Hz), 4.15-4.10 (m, 1 H),
4.06-4.01 (m, 1 H), 3.96 (ddd, 1 H, J ) 3.5, 5.4, 7.3 Hz), 3.91-
3.86 (m, 1 H), 3.80 (dd, 1 H, J ) 4.0, 11.5 Hz), 3.76 (dd, 1 H,
J ) 4.4, 11.5 Hz), 3.70 (dd, 1 H, J ) 3.5, 9.7 Hz), 3.64 (dd, 1
3-O-Allyl-1,4-a n h yd r o-5-O-ben zyl-D-r ibitol (13). A mix-
ture of 29 (3.03 g, 8.23 mmol) and NaOMe (28% in MeOH,
0.48 mL, 2.5 mmol) in MeOH (30 mL) was stirred at room
temperature for 4 h. After the mixture was neutralized with
Dowex 50W resin (×2, H+ form), the resin was filtered off. The
filtrate was evaporated under reduced pressure, and the
residue was purified by column chromatography (SiO2, hexane/
EtOAc 2:1) to give 13 (1.77 g, 81% as an oil): [R]24 +41.7° (c
D
1
1.15, CHCl3); H NMR (500 MHz, CDCl3) δ 7.38-7.24 (m, 5
H), 5.93-5.84 (m, 1 H), 5.31-5.19 (m, 2 H), 4.62 and 4.55 (each
d, each 1 H, J ) 12.1 Hz), 4.28-4.23 (m, 1 H), 4.08-4.03 (m,

Novel Potent IP3 Receptor Ligands
J . Org. Chem., Vol. 63, No. 24, 1998 8821
3 H), 4.00 (ddd, 1 H, J ) 3.8, 4.3, 5.9 Hz), 3.91 (dd, 1 H, J )
5.7, 5.9 Hz), 3.79 (dd, 1 H, J ) 4.0, 9.7 Hz), 3.64 (dd, 1 H, J )
3.8, 10.5 Hz), 3.57 (dd, 1 H, J ) 4.3, 10.5 Hz), 2.66 (d, 1 H, J
) 4.9 Hz); HRMS (EI) calcd for C15H20O4 264.1361, found
264.1385. Anal. Calcd for C15H20O4‚0.2H2O: C, 67.24; H, 7.67.
Found: C, 67.09; H, 7.31.
3.68 (dd, 1 H, J ) 3.1, 10.6 Hz), 3.57 (dd, 1 H, J ) 5.1, 10.6
Hz), 2.69 (d, 1 H, J ) 6.9 Hz); HRMS (EI) calcd for C19H22O4
314.1518, found 314.1534. Anal. Calcd for C19H22O4: C, 72.59;
H, 7.05. Found: C, 72.57; H, 7.20.
3,4-O-Isop r op ylid en e-1-O-tr ityl-D-er yth r itol (35). A so-
lution of 34 (16.7 g, 98.3 mmol) in Et2O (100 mL) was added
dropwise to a suspension of LiAlH4 (4.46 g, 118 mmol) in Et2O
(96 mL) at 0 °C. The mixture was stirred at room temperature
for 4 h and then heated under reflux for 1 h. Water (4.9 mL)
and aqueous NaOH (15%) were added, and the resulting
mixture was stirred at room temperature for 24 h. The
resulting precipitates were filtered off with Celite and washed
with hot EtOAc. The filtrate and washings were combined
and evaporated under reduced pressure, and the residue was
coevaporated with toluene (×3) and pyridine (×3). A mixture
of the resulting residue and TrCl (30.1 g, 108 mmol) in pyridine
(200 mL) was heated at 70 °C for 23 h. The resulting mixture
was evaporated under reduced pressure, and the residue was
partitioned between Et2O (300 mL) and H2O (150 mL). The
aqueous layer was extracted with Et2O (300 mL). The organic
layer was combined, washed with brine, dried (Na2SO4), and
evaporated under reduced pressure. The residue was purified
1,4-An h yd r o-5-O-ben zyl-3-O-(4-m eth oxyben zyl)-D-r ibi-
tol (31). Compound 31 (855 mg, 91% as an oil) was obtained
from 30 (1.23 g, 2.75 mmol) as described above for the
1
synthesis of 13: [R]25 +40.8 ° (c 1.08, CHCl3); H NMR (270
D
MHz, DMSO-d6) δ 7.40-7.14 (m, 7 H), 6.94-6.80 (m, 2 H),
4.80 (d, 1 H, J ) 5.3 Hz), 4.60 and 4.37 (each d, each 1 H, J )
11.4 Hz), 4.49 and 4.43 (each d, each 1 H, J ) 12.2 Hz), 4.23-
4.12 (m, 1 H), 3.92-3.80 (m, 1 H), 3.86 (dd, 1 H, J ) 4.6, 9.2
Hz), 3.73 (s, 3 H), 3.70 (dd, 1 H, J ) 4.6, 6.9 Hz), 3.58 (dd, 1
H, J ) 3.3, 9.2 Hz), 3.52 (dd, 1 H, J ) 3.1, 10.7 Hz), 3.41 (dd,
1 H, J ) 5.1, 10.7 Hz); HRMS (EI) calcd for C20H24O5 344.1624,
found 344.1616. Anal. Calcd for C20H24O5‚0.2H2O: C, 69.03;
H, 7.07. Found: C, 69.08; H, 7.05.
1,4-An h yd r o-2,5-d i-O-ben zyl-3-O-(4-m eth oxyben zyl)-D-
r ibitol (32). A mixture of 31 (812 mg, 2.36 mmol) and NaH
(60% in mineral oil, 283 mg, 7.08 mmol) in DMF (12 mL) was
stirred at room temperature for 2 h. BnBr (0.337 mL, 2.83
mmol) was added, and the resulting mixture was stirred at
room temperature for 2 h. After the reaction was quenched
with aqueous NH4Cl (1 M, 20 mL), EtOAc (40 mL) and H2O
(10 mL) were added to the mixture, and then the whole was
partitioned. The organic layer was washed with brine, dried
(Na2SO4), and evaporated under reduced pressure. The resi-
due was purified by column chromatography (SiO2, hexane/
EtOAc 3:1) to give 32 (900 mg, 88% as an oil): [R]31D +49.8° (c
by column chromatography (SiO2, hexane/EtOAc 5:1) to give
1
35 (25.9 g, 65% as a syrup): [R]25 -2.2° (c 1.52, MeOH); H
D
NMR (500 MHz, CDCl3) δ 7.45-7.41 (m, 6 H), 7.32-7.27 (m,
6 H), 7.26-7.22 (m, 3 H), 4.09 (dt, 1 H, J ) 6.2, 6.3 Hz), 4.00
(dd, 1 H, J ) 6.3, 8.4 Hz), 3.94 (dd, 1 H, J ) 6.2, 8.4 Hz), 3.78
(ddt, 1 H, J ) 4.0, 6.0, 6.2 Hz), 3.32 (dd, 1 H, J ) 4.0, 9.8 Hz),
3.26 (dd, 1 H, J ) 6.0, 9.8 Hz), 2.33 (d, 1 H, J ) 4.0 Hz), 1.35
and 1.33 (each s, each 3 H); HRMS (EI) calcd for C26H28O4
404.1986, found 404.2000.
1
1.08, CHCl3); H NMR (500 MHz, CDCl3) δ 7.37-7.24 (m, 10
2-O-Allyl-3,4-O-isop r op ylid en e-1-O-t r it yl-D-er yt h r it ol
(36). Compound 36 (5.07 g, 57% as a syrup) was obtained from
35 (8.08 g, 20.0 mmol) as described above for the synthesis of
H), 7.23-7.19 (m, 2 H), 6.85-6.80 (m, 2 H), 4.60 and 4.58 (each
d, each 1 H, J ) 12.8 Hz), 4.57 and 4.45 (each d, each 1 H, J
) 11.6 Hz), 4.56 and 4.49 (each d, each 1 H, J ) 12.1 Hz),
4.15-4.11 (m, 1 H), 4.02-3.96 (m, 2 H), 3.93 (dd, 1 H, J )
3.7, 8.8 Hz), 3.91 (dd, 1 H, J ) 5.0, 6.1 Hz), 3.79 (s, 3 H), 3.61
(dd, 1 H, J ) 3.3, 10.7 Hz), 3.50 (dd, 1 H, J ) 4.4, 10.7 Hz);
HRMS calcd for C27H30O5 434.2093, found 434.2122.
25: [R]23 +10.7 ° (c 1.12, CHCl3); 1H NMR (500 MHz, CDCl3)
D
δ 7.49-7.41 (m, 6 H), 7.33-7.20 (m, 9 H), 5.95-5.86 (m, 1 H),
5.29-5.22 (m, 1 H), 5.18-5.13 (m, 1 H), 4.24-4.18 (m, 1 H),
4.14 (ddd, 1 H, J ) 5.7, 6.4, 6.6 Hz), 4.12-4.07 (m, 1 H), 4.01
(dd, 1 H, J ) 6.4, 8.2 Hz), 3.97 (dd, 1 H, J ) 6.6, 8.2 Hz), 3.59
(ddd, 1 H, J ) 3.5, 5.3, 5.7 Hz), 3.30 (dd, 1 H, J ) 3.5, 10.2
Hz), 3.16 (dd, 1 H, J ) 5.3, 10.2 Hz), 1.36 and 1.32 (each s,
each 3 H); HRMS (EI) calcd for C28H29O4 429.2064 (M - CH3)+,
found 429.2054.
2-O-Allyl-1,4-a n h yd r o-5-O-ben zyl-3-O-(4-m eth oxyben z-
yl)-D-r ibitol (33). Compound 33 (1.33 g, 90% as an oil) was
obtained from 31 (1.32 g, 3.84 mmol) as described above for
the synthesis of 32, with allyl bromide (0.399 mL, 4.61
mmol): [R]21 +53.0° (c 1.02, CHCl3); 1H NMR (270 MHz,
2-O-Allyl-D-er yth r itol (37). A mixture of 36 (898 mg, 2.02
mmol) and p-TsOH‚H2O (115 mg, 0.605 mmol) in MeOH (10
mL) was stirred at room temperature for 4 days. The mixture
was evaporated under reduced pressure, and the residue was
purified by column chromatography (SiO2, CHCl3/EtOH 9:1)
to give 37 (164 mg, 50% as an oil): 1H NMR (270 MHz, DMSO-
d6) δ 6.04-5.89 (m, 1 H), 5.36-5.13 (m, 2 H), 4.66 (d, 1 H, J
) 5.1 Hz), 4.51 (t, 1 H, J ) 5.7 Hz), 4.47 (t, 1 H, J ) 5.7 Hz),
4.24-4.03 (m, 2 H), 3.74-3.30 (m, 6 H); HRMS (EI) calcd for
C7H14O4 162.0891, found 162.0879.
2-O-Allyl-1,4-an h ydr o-D-er yth r itol (14). Trifluoromethane-
sulfonyl anhydride (2.03 mL, 12.1 mmol) was added to a
solution of 37 (1.95 g, 12.0 mmol), Et3N (3.36 mL, 24.1 mmol),
and DMAP (147 mg, 1.20 mmol) in MeCN (40 mL) at room
temperature, and the mixture was stirred at the same tem-
perature for 3 days. The reaction was quenched with H2O,
and the resulting mixture was evaporated under reduced
pressure. The residue was partitioned between CHCl3 and
saturated aqueous NaHCO3, and the organic layer was washed
with brine, dried (Na2SO4), and evaporated under reduced
pressure. The residue was purified by column chromatography
(SiO2, hexane/EtOAc 1:1) to give 14 (792 mg, 41% as an oil):
1H NMR (500 MHz, CDCl3) δ 5.97-5.88 (m, 1 H), 5.35-5.22
(m, 2 H), 4.29-4.25 (m, 1 H), 4.11-4.08 (m, 2 H), 4.02 (ddd, 1
H, J ) 5.2, 5.6, 6.2 Hz), 3.93 (dd, 1 H, J ) 6.2, 9.5 Hz), 3.90
(dd, 1 H, J ) 5.0, 9.7 Hz), 3.77 (dd, 1 H, J ) 5.2, 9.5 Hz), 3.75
(dd, 1 H, J ) 3.9, 9.7 Hz), 2.73 (br, 1 H); HRMS (EI) calcd for
C7H12O3 144.0786, found 144.0778.
D
CDCl3) δ 7.39-7.19 (m, 7 H), 6.89-6.79 (m, 2 H), 6.01-5.84
(m, 1 H), 5.33-5.14 (m, 2 H), 4.59 and 4.48 (each d, each 1 H,
J ) 11.5 Hz), 4.57 and 4.49 (each d, each 1 H, J ) 12.2 Hz),
4.14-3.85 (m, 7 H), 3.80 (s, 3 H), 3.61 (dd, 1 H, J ) 3.3, 10.6
Hz), 3.49 (dd, 1 H, J ) 4.3, 10.6 Hz); HRMS (EI) calcd for C23
28O5 384.1937, found 384.1921. Anal. Calcd for C23H28O5:
C, 71.85; H, 7.34. Found: C, 71.74; H, 7.41.
-
H
2-O-Allyl-1,4-a n h yd r o-5-O-ben zyl-D-r ibitol (11). A mix-
ture of 33 (1.02 g, 2.26 mmol), DDQ (725 mg, 3.19 mmol), and
H2O (0.5 mL) in CH2Cl2 (9 mL) was stirred at room temper-
ature for 34 h. After addition of saturated aqueous NaHCO3
(20 mL), the mixture was extracted with CH2Cl2 (15 mL × 2).
The organic layer was washed with brine, dried (Na2SO4), and
evaporated under reduced pressure. The residue was purified
by column chromatography (SiO2, hexane/EtOAc 3:1) to give
11 (596 mg, 85% as an oil): [R]26 +56.7 ° (c 1.04, CHCl3); 1H
D
NMR (500 MHz, CDCl3) δ 7.36-7.24 (m, 5 H), 5.96-5.87 (m,
1 H), 5.33-5.27 (m, 1 H), 5.25-5.21 (m, 1 H), 4.59 and 4.56
(each d, each 1 H, J ) 12.2 Hz), 4.14-3.99 (m, 5 H), 3.91 (dt-
like ddd, 1 H, J ) 3.1, 5.0, 5.3 Hz), 3.82 (dd, 1 H, J ) 4.2, 9.7
Hz), 3.69 (dd, 1 H, J ) 3.1, 10.6 Hz), 3.58 (dd, 1 H, J ) 5.0,
10.6 Hz), 2.68 (d, 1 H, J ) 7.1 Hz); HRMS (EI) calcd for C15
20O4 264.1361, found 264.1356. Anal. Calcd for C15H20O4:
C, 68.16; H, 7.63. Found: C, 67.93; H, 7.55.
-
H
1,4-An h yd r o-2,5-d i-O-ben zyl-D-r ibitol (12). Compound
12 (541 mg, 90% as a solid) was obtained from 32 (835 mg,
1.92 mmol) as described above for the synthesis of 11: [R]27
D
+50.5° (c 1.00, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.38-
7.24 (m, 10 H), 4.64 and 4.58 (each d, each 1 H, J ) 11.7 Hz),
4.59 and 4.55 (each d, each 1 H, J ) 12.1 Hz), 4.11-4.04 (m,
3 H), 3.93 (ddd, 1 H, J ) 3.1, 5.1, 5.2 Hz), 3.88-3.83 (m, 1 H),
Gen er a l P r oced u r e for Glycosid a tion Rea ction s w ith
Glycosyl Don or 23. TMSOTf (86 µL, 0.445 mmol) was added
to a solution of 23 (96 mg, 0.244 mmol), Et3N (31 µL, 0.222
mmol), and a glycosyl acceptor (0.222 mmol) in a solvent (4

8822 J . Org. Chem., Vol. 63, No. 24, 1998
Shuto et al.
mL) at room temperature, and the mixture was stirred at the
same temperature for several hours (indicated in Table 1). The
reaction mixture was diluted with EtOAc (20 mL) and then
washed with H2O, saturated aqueous NaHCO3, and brine. The
organic layer was dried (Na2SO4) and evaporated under
reduced pressure. The residue was purified by column chro-
matography (SiO2, hexane/EtOAc 4:1 or 2:1) to give the
corresponding glycosidation product in the yield shown in
Table 1.
the resin was filtered off. The filtrate was evaporated under
reduced pressure, and the residue was coevaporated with
toluene (×3). A mixture of the resulting residue and NaH
(60% in mineral oil, 278 mg, 6.95 mmol) in DMF (12 mL) was
stirred at room temperature for 1 h. BnBr (0.331 mL, 2.78
mmol) was added, and the resulting mixture was stirred at
room temperature for 12 h. After the reaction was quenched
with aqueous NH4Cl (1 M, 20 mL), the resulting mixture was
extracted with Et2O (60 mL). The organic layer was washed
with brine (20 mL), dried (Na2SO4), and evaporated under
reduced pressure. The residue was purified by column chro-
matography (SiO2, hexane/EtOAc 3:1) to give 15 (1.53 mg, 96%
as an oil, containing a trace amount of the â-anomer): 1H NMR
(500 MHz, CDCl3) δ 7.39-7.22 (m, 15 H), 6.01-5.75 (m, 3 H),
5.29-5.06 (m, 7 H, H-1), 4.75 and 4.62 (each d, each 1 H, J )
11.9 Hz), 4.56 and 4.40 (each d, each 1 H, J ) 12.0 Hz), 4.53
and 4.47 (each d, each 1 H, J ) 12.0 Hz), 4.42-4.36 (m, 1 H),
4.28-4.19 (m, 3 H), 4.17-4.13 (m, 1 H), 4.13-3.99 (m, 4 H),
3.98-3.93 (m, 1 H), 3.89 (dd, 1 H, J ) 4.9, 8.7 Hz), 3.76 (t, 1
H, J ) 9.3 Hz), 3.64-3.58 (m, 2 H), 3.56 (dd, 1 H, J ) 3.5,
10.6 Hz), 3.55 (dd, 1 H, J ) 4.3, 10.6 Hz), 3.49-3.43 (m, 2 H),
Cyclop en tyl 6-O-a cetyl-3,4-d i-O-a llyl-2-O-ben zyl-D-glu -
cop yr a n osid e (38): entry 5 in Table 1, the R/â ratio was 77:
1
23 based on its H NMR spectrum; 1H NMR (500 MHz, CDCl3)
δ 7.37-7.28 (m, 5 H), 6.05-5.82 (m, 2 H), 5.33-5.14 (m, 4 H),
4.87 and 4.66 (each d, each 0.23 H, J ) 10.9 Hz), 4.78 (d, 0.77
H, J ) 3.6 Hz), 4.72 and 4.60 (each d, each 0.77 H, J ) 11.9
Hz), 4.57-4.19 (m, 5.23 H), 4.13-4.03 (m, 2 H), 3.85-3.72 (m,
1.77 H), 3.46-3.24 (m, 2.23 H), 2.08 (s, 0.69 H), 2.07 (s, 2.31
H), 1.83-1.52 (m, 8 H); HRMS (FAB) calcd for C26H37O7
461.2539 (M + 1)+, found 461.2514.
(2R,3S,4S)-4-(Allyloxy)-2-(b en zyloxym et h yl)t et r a h y-
d r ofu r a n -3-yl 6-O-a cet yl-3,4-d i-O-a llyl-2-O-b en zyl-R-D-
glu cop yr a n osid e (39): containing 5% of the â-anomer; 1H
NMR (500 MHz, CDCl3) δ 7.37-7.24 (m, 10 H), 6.01-5.81 (m,
3 H), 5.31-5.20 (m, 3 H), 5.19-5.11 (m, 3 H), 5.16 (d, 1 H, J
) 3.5 Hz), 4.76 and 4.61 (each d, each 1 H, J ) 11.9 Hz), 4.58
and 4.52 (each d, each 1 H, J ) 12.1 Hz), 4.44-4.38 (m, 1 H),
4.33-4.28 (m, 1 H), 4.27-4.01 (m, 10 H), 3.91-3.86 (m, 1 H),
3.79 (dd, 1 H, J ) 9.3, 9.6 Hz), 3.72 (ddd, 1 H, J ) 2.2, 4.5, 9.8
Hz), 3.62 (dd, 1 H, J ) 3.3, 10.7 Hz), 3.57 (dd, 1 H, J ) 4.0,
10.7 Hz), 3.45 (dd, 1 H, J ) 3.5, 9.6 Hz), 3.28 (dd, 1 H, J )
9.3, 9.8 Hz), 2.02 (s, 3 H); HRMS (FAB) calcd for C36H45O10
637.3012 (M - 1)+, found 637.3057.
3.42 (dd, 1 H, J ) 9.3, 9.7 Hz); HRMS (FAB) calcd for C41H49
-
O9 685.3376 (M - 1)+, found 685.3386.
(2R,3S,4S)-4-(Ben zyloxy)-2-(ben zyloxym eth yl)tetr a h y-
d r ofu r a n -3-yl 3,4-Di-O-a llyl-2,6-d i-O-ben zyl-R-D-glu cop y-
r a n osid e (43). Compound 43 (488 mg, 92% as an oil,
containing a trace amount of the â-anomer) was obtained from
40 (494 mg, 0.718 mmol) as described above for the synthesis
of 15: 1H NMR (500 MHz, CDCl3) δ 7.36-7.16 (m, 20 H), 5.99-
5.89 (m, 1 H), 5.85-5.75 (m, 1 H), 5.27-5.06 (m, 5 H), 4.67
and 4.56 (each d, each 1 H, J ) 11.8 Hz), 4.61 and 4.50 (each
d, each 1 H, J ) 11.8 Hz), 4.57 and 4.40 (each d, each 1 H, J
) 12.1 Hz), 4.52 and 4.47 (each d, each 1 H, J ) 12.0 Hz),
4.38-4.32 (m, 1 H), 4.27-4.16 (m, 4 H), 4.12-4.08 (m, 1 H),
4.00 (dd, 1 H, J ) 5.2, 9.1 Hz), 3.97-3.92 (m, 1 H), 3.90 (dd,
1 H, J ) 5.5, 9.1 Hz), 3.76 (m, 1 H), 3.67-3.53 (m, 4 H), 3.49-
3.39 (m, 3 H); HRMS (FAB) calcd for C45H53O9 737.3689 (M +
1)+, found 737.3726.
(2R,3S,4S)-4-(Ben zyloxy)-2-(ben zyloxym eth yl)tetr a h y-
d r ofu r a n -3-yl 6-O-a cet yl-3,4-d i-O-a llyl-2-O-b en zyl-R-D-
glu cop yr a n osid e (40): containing 7% of the â-anomer; 1H
NMR (500 MHz, CDCl3) δ 7.38-7.16 (m, 15 H), 5.99-5.83 (m,
2 H), 5.29-5.09 (m, 5 H), 5.66 and 4.56 (each d, each 1 H, J )
11.7 Hz), 4.62 and 4.49 (each d, each 1 H, J ) 11.9 Hz), 4.58
and 4.52 (each d, each 1 H, J ) 12.1 Hz), 4.39-4.33 (m, 1 H),
4.32-4.27 (m, 1 H, allylic), 4.24-4.02 (m, 7 H), 4.02 (dd, 1 H
J ) 5.4, 9.1 Hz), 3.90 (dd, 1 H, J ) 5.8, 9.1 Hz), 3.78 (dd, 1 H,
J ) 9.2, 9.5 Hz), 3.74 (ddd, 1 H, J ) 2.0, 4.5, 10.0 Hz), 3.62
(dd, 1 H, J ) 3.4, 10.7 Hz), 3.58 (dd, 1 H, J ) 4.2, 10.7 Hz),
3.42 (dd, 1 H, J ) 3.6, 9.5 Hz), 3.27 (dd, 1 H, J ) 9.2, 10.0
Hz), 2.02 (s, 3 H); HRMS (FAB) calcd for C40H49O10 689.3325
(M + 1)+, found 689.3290.
(3S,4R)-3-(Allyloxy)tetr a h yd r ofu r a n -4-yl 3,4-Di-O-a llyl-
2,6-d i-O-ben zyl-R-D-glu cop yr a n osid e (44). Compound 44
(1.76 g, 94% as an oil) was obtained from 42 (1.72 g, 3.32 mmol)
as described above for the synthesis of 15: [R]27 +58.0 ° (c
D
1
1.06, CHCl3); H NMR (500 MHz, CDCl3) δ 7.38-7.23 (m, 10
H), 6.00-5.77 (m, 3 H), 5.30-5.06 (m, 6 H), 5.10 (d, 1 H, J )
3.6 Hz), 4.71 and 4.67 (each d, each 1 H, J ) 12.0 Hz), 4.62
and 4.49 (each d, each 1 H, J ) 12.1 Hz), 4.41-4.13 (m, 6 H),
4.08-3.92 (m, 5 H), 3.83-3.76 (m, 3 H), 3.71-3.66 (m, 1 H),
3.64-3.59 (m, 1 H), 3.46 (dd, 1 H, J ) 3.6, 9.6 Hz), 3.41 (t, 1
H, J ) 9.2 Hz); HRMS (FAB) calcd for C33H43O8 567.2958 (M
+ 1)+, found 567.2985.
(2R,3R,4S)-3-(Allyloxy)-2-(b en zyloxym et h yl)t et r a h y-
d r ofu r a n -4-yl 6-O-a cet yl-3,4-d i-O-a llyl-2-O-b en zyl-R-D-
1
glu cop yr a n osid e (41): containing 15% of the â-anomer; H
NMR (500 MHz, CDCl3) δ 7.38-7.23 (m, 10 H), 6.01-5.82 (m,
3 H), 5.32-5.08 (m, 6 H), 4.74 and 4.59 (each d, each 1 H, J )
11.9 Hz), 4.74 (d, 1 H, J ) 3.6 Hz), 4.61 and 4.54 (each d, each
1 H, J ) 12.0 Hz), 4.41-4.36 (m, 1 H), 4.34-4.23 (m, 3 H),
4.20-4.02 (m, 6 H), 4.02-3.95 (m, 2 H), 3.92-3.86 (m, 2 H),
3.81 (dd, 1 H, J ) 9.3, 9.4 Hz), 3.65 (dd, 1 H, J ) 3.2, 10.6
Hz), 3.55 (dd, 1 H, J ) 4.2, 10.6 Hz), 3.41 (dd, 1 H, J ) 3.6,
9.4 Hz), 3.29 (dd, 1 H, J ) 9.3, 9.6 Hz), 2.05 (s, 3 H); HRMS
(FAB) calcd for C36H45O10 637.3012 (M - 1)+, found 637.3008.
(3S,4R)-3-(Allyloxy)t et r a h yd r ofu r a n -4-yl 6-O-a cet yl-
3,4-d i-O-a llyl-2-O-ben zyl-R-D-glu cop yr a n osid e (42): con-
taining 6% of the â-anomer; 1H NMR (500 MHz, CDCl3) δ
7.38-7.24 (m, 5 H), 6.01-5.83 (m, 3 H), 5.31-5.22 (m, 3 H),
5.19-5.12 (m, 3 H), 5.08 (d, 1 H, H-1), 4.72 and 4.68 (each d,
each 1 H, J ) 11.9 Hz), 4.43-4.38 (m, 1 H), 4.35-4.30 (m, 1
H), 4.28-4.18 (m, 4 H, allylic), 4.14 (m, 1 H), 4.09-4.02 (m, 3
H), 3.98 (dd, 1 H, J ) 5.8, 9.2 Hz), 3.96 (dd, 1 H, J ) 5.8, 9.2
Hz), 3.84-3.75 (m, 4 H), 3.45 (dd, 1 H, J ) 3.6, 9.7 Hz), 3.29-
3.24 (dd, 1 H), 2.08 (s, 3 H); HRMS (FAB) calcd for C28H37O9
517.2437 (M - 1)+, found 517.2463.
(2R,3R,4S)-3-(Allyloxy)-2-(b en zyloxym et h yl)t et r a h y-
d r ofu r a n -4-yl 3,4-Di-O-a llyl-2,6-d i-O-ben zyl-R-D-glu cop y-
r a n osid e (51). Compound 51 (477 mg, 65% as an oil) was
obtained from 41 (678 mg, 1.06 mmol) as described above for
the synthesis of 15: 1H NMR (500 MHz, CDCl3) δ 7.40-7.22
(m, 15 H), 6.02-5.76 (m, 3 H), 5.31-5.04 (m, 6 H), 4.77 (d, 1
H, J ) 3.5 Hz), 4.75 (d, 1 H, J ) 12.2 Hz), 4.65-4.57 (m, 3 H),
4.54 (d, 1 H, J ) 12.1 Hz), 4.49 (d, 1 H, J ) 12.0 Hz), 4.40-
4.34 (m, 1 H), 4.30-4.23 (m, 2 H), 4.21-4.17 (m, 1 H), 4.13-
4.07 (m, 2 H), 4.02-3.84 (m, 6 H), 3.79 (t, 1 H, J ) 9.3 Hz),
3.68-3.62 (m, 2 H), 3.61-3.57 (m, 1 H), 3.54 (dd, 1 H, J )
4.4, 10.6 Hz), 3.46-3.40 (m, 2 H); HRMS (FAB) calcd for C41
51O9 687.3533 (M + 1)+, found 687.3503.
(2R,3R,4S)-4-Acetoxy-2-(ben zyloxym eth yl)tetr a h yd r o-
-
H
fu r a n -3-yl 3,4-Di-O-a cetyl-2,6-d i-O-ben zyl-R-D-glu cop yr a -
n osid e (45). A mixture of 15 (1.51 g, 2.20 mmol), Pd-C (10%,
211 mg), and p-TsOH‚H2O (206 mg, 1.08 mmol) in EtOH (15
mL) and H2O (3 mL) was heated under reflux for 4 h. The
insoluble materials were filtered off, and the filtrate was
evaporated under reduced pressure. After the residue was
coevaporated with pyridine (×3), a mixture of the resulting
residue and Ac2O (0.747 mL, 7.92 mmol) in pyridine (11 mL)
was stirred at room temperature for 15 h. After the reaction
was quenched with ice-water, the resulting mixture was
evaporated under reduced pressure, and the residue was
(2R,3S,4S)-4-(Allyloxy)-2-(b en zyloxym et h yl)t et r a h y-
d r ofu r a n -3-yl 3,4-Di-O-a llyl-2,6-d i-O-ben zyl-R-D-glu cop y-
r a n osid e (15). A mixture of 39 (1.48 g, 2.32 mmol) and
NaOMe (28% in MeOH, 0.695 mL, 3.60 mmol) in MeOH (12
mL) was stirred at room temperature for 6 h. After the
mixture was neutralized with Dowex 50W resin (×2, H+ form),

Novel Potent IP3 Receptor Ligands
J . Org. Chem., Vol. 63, No. 24, 1998 8823
partitioned between EtOAc (35 mL) and H2O (10 mL). The
organic layer was washed with brine, dried (Na2SO4), and
evaporated under reduced pressure. The residue was purified
by column chromatography (SiO2, hexane/EtOAc 3:1) to give
45 (1.49 g, 98% as an oil): 1H NMR (500 MHz, CDCl3) δ 7.38-
7.18 (m, 15 H), 5.40 (dd, 1 H, J ) 9.8, 9.9 Hz), 5.37-5.33 (m,
1 H), 5.04 (dd, 1 H, H-4, J ) 9.8, 10.0 Hz), 5.03 (d, 1 H, J )
3.5 Hz), 4.66 and 4.49 (each d, each 1 H, J ) 12.2 Hz), 4.54
and 4.49 (each d, each 1 H, J ) 12.1 Hz), 4.51 and 4.31 (each
d, each 1 H, J ) 12.1 Hz), 4.37 (dd, 1 H, J ) 5.5, 6.5 Hz),
4.18-4.15 (m, 1 H), 4.16 (dd, 1 H, J ) 4.9, 10.1 Hz), 3.90 (dd,
1 H, J ) 3.6, 10.1 Hz), 3.89-3.84 (m, 1 H), 3.69 (dd, 1 H, J )
2.8, 11.0 Hz), 3.61 (dd, 1 H, J ) 3.9, 11.0 Hz), 3.55 (dd, 1 H, J
) 3.5, 9.9 Hz), 3.33 (dd, 1 H, J ) 2.5, 10.8 Hz), 3.29 (dd, 1 H,
J ) 4.0, 10.8 Hz), 1.94, 1.89, and 1.88 (each s, each 3 H); HRMS
(EI) calcd for C38H44O12 692.2830, found 692.2841.
(2R,3S,4S)-4-(Ben zyloxy)-2-(ben zyloxym eth yl)tetr a h y-
d r ofu r a n -3-yl 3,4-Di-O-a cetyl-2,6-d i-O-ben zyl-D-glu cop y-
r a n osid e (46). Compound 46 (261 mg, 55% as an oil) was
obtained from 43 (470 mg, 0.685 mmol) as described above for
the synthesis of 45: 1H NMR (500 MHz, CDCl3) δ 7.34-7.18
(m, 18 H), 7.12-7.07 (m, 2 H), 5.43 (dd, 1 H, J ) 9.7, 9.8 Hz),
5.29 (d, 1 H, J ) 3.6 Hz), 5.05 (dd, 1 H, J ) 9.7, 10.0 Hz), 4.65
and 4.57 (each d, each 1 H, J ) 11.8 Hz), 4.56 and 4.37 (each
d, each 1 H, J ) 12.4 Hz), 4.53 and 4.47 (each d, each 1 H, J
) 12.1 Hz), 4.52 and 4.33 (each d, each 1 H, J ) 12.2 Hz),
4.29 (t, 1 H, J ) 5.0 Hz), 4.21 (dt, 1 H, J ) 4.0, 5.0 Hz), 4.11
(ddd, 1 H, J ) 5.0, 5.4, 6.1 Hz), 4.01 (dd, 1 H, J ) 5.4, 8.9 Hz),
3.90 (dd, 1 H, J ) 6.1, 8.9 Hz), 3.86 (ddd, 1 H, J ) 2.5, 4.0,
10.0 Hz), 3.59 (d, 2 H, J ) 4.0 Hz), 3.56 (dd, 1 H, J ) 3.6, 9.8
Hz), 3.34 (dd, 1 H, J ) 2.5, 10.8 Hz), 3.28 (dd, 1 H, J ) 4.0,
10.8 Hz), 1.98 and 1.88 (each s, each 3 H); HRMS (FAB) calcd
for C43H49O11 (M + 1)+, 741.3274, found 741.3247.
stirred at room temperature for 7 h. After the reaction was
quenched with H2O (0.3 mL), m-CPBA (3.00 g, 13.9 mmol) was
added at -40 °C. The resulting mixture was stirred at room
temperature for 2 h, aqueous Na2SO3 (10%, 50 mL) and EtOAc
(50 mL) were added, and then the whole was partitioned. The
organic layer was washed with aqueous saturated NaHCO3,
H2O, and brine, dried (Na2SO4), and evaporated under reduced
pressure. The residue was purified by column chromatography
(SiO2, CHCl3/Et2O 3:1) to give 48 (1.98 g, 74% as an oil): 1H
NMR (500 MHz, CDCl3) δ 7.38-7.02 (m, 45 H), 5.26 (d, 1 H,
J ) 3.6 Hz), 5.02-4.82 (m, 13 H, H-2′ benzylic), 4.75-4.69
(m, 1 H), 4.73 and 4.45 (each d, each 1 H, J ) 11.6 Hz), 4.58
(m, 1 H), 4.46 and 4.39 (each d, each 1 H, J ) 11.9 Hz), 4.41
and 4.30 (each d, each 1 H, J ) 11.9 Hz), 4.24-4.20 (m, 1 H),
4.14-4.10 (m, 1 H), 3.99-3.93 (m, 2 H), 3.80-3.75 (m, 1 H),
3.64 (dd, 1 H, J ) 4.4, 11.0 Hz), 3.60-3.55 (m, 2 H), 3.52 (dd,
1 H, J ) 3.6, 10.9 Hz), 3.50 (dd, 1 H, J ) 3.8, 10.9 Hz); 31P
NMR (125 MHz, CDCl3) δ -0.57, -1.70, -1.87; HRMS (FAB)
calcd for C74H78O18P3 1347.4401 (M - 1)+, found 1347.4480.
(2R,3S,4S)-4-(Ben zyloxy)-2-(ben zyloxym eth yl)tetr a h y-
d r ofu r a n -3-yl 2,6-Di-O-ben zyl-R-D-glu cop yr a n osid e 3,4-
Bis(d iben zyl p h osp h a te) (49). Compound 49 (371 mg, 68%
as an oil) was obtained from 46 (349 mg, 0.472 mmol) as
described above for the synthesis of 48: 1H NMR (500 MHz,
CDCl3) δ 7.29-7.15 (m, 40 H), 5.33 (d, 1 H, J ) 3.5 Hz), 5.11-
4.76 (m, 9 H), 4.65-4.55 (m, 3 H), 4.50-4.38 (m, 5 H), 4.31 (d,
1 H, J ) 11.8 Hz), 4.24 (t, 1 H, J ) 4.6 Hz), 4.19-4.15 (m, 1
H), 4.11-4.05 (m, 1 H), 3.97 (dd, 1 H, J ) 5.4, 8.8 Hz), 3.87
(dd, 1 H, J ) 6.6, 8.8 Hz), 3.85-3.80 (m, 1 H), 3.67 (dd, 1 H,
J ) 4.4, 10.8 Hz), 3.62-3.49 (m, 5 H); 31P NMR (125 MHz,
CDCl3) δ -1.73, -1.93; HRMS (FAB) calcd for C67H71O15P2
1177.4268, found 1177.4220.
(3S,4R)-3-Hyd r oxytetr a h yd r ofu r a n -4-yl 2,6-Di-O-ben z-
yl-R-D-glu cop yr a n osid e 3,4,3′-Bis(d ib en zyl p h osp h a t e)
(50). Compound 50 (1.13 g, 74% as an oil) was obtained from
47 (1.22 g, 1.99 mmol) as described above for the synthesis of
48: 1H NMR (500 MHz, CDCl3) δ 7.38-7.02 (m, 40 H), 5.06
(d, 1 H, J ) 3.6 Hz), 5.06-4.34 (m, 19 H), 4.11-4.06 (m, 1 H),
3.97-3.84 (m, 3 H), 3.84-3.66 (m, 4 H), 3.56 (dd, 1 H, J )
3.6, 9.8 Hz); 31P NMR (125 MHz, CDCl3) δ -0.71, -1.58, -1.86;
HRMS (FAB) calcd for C66H70O17P3 1227.3826 (M + 1)+, found
1227.3800.
[(2R,3R,4S)-2-(Ben zyloxym et h yl)-3-h yd r oxyt et r a h y-
d r ofu r a n -4-yl 2,6-Di-O-ben zyl-R-D-glu cop yr a n osid e 3,4,3′-
Tr is(d iben zyl p h osp h a te) (53). Compound 53 (88 mg, 23%
as an oil) was obtained from 52 (200 mg, 0.289 mmol) as
described above for the synthesis of 48: 1H NMR (500 MHz,
CDCl3) δ 7.37-7.10 (m, 45 H), 5.12-4.69 (m, 14 H), 4.67 and
4.41 (each d, each 1 H, J ) 12.1 Hz), 4.47 and 4.44 (each d,
each 1 H, J ) 12.3 Hz), 4.43 and 4.31 (each d, each 1 H, J )
11.9 Hz), 4.34-4.17 (m, 3 H), 3.89 (dd, 1 H, J ) 5.1, 9.4 Hz),
3.82 (dd, 1 H, J ) 3.2, 11.2 Hz), 3.77-3.70 (m, 2 H), 3.66-
3.43 (m, 5 H); 31P NMR (125 MHz, CDCl3) δ -0.86, -1.53,
-1.81; HRMS (FAB) calcd for C74H78O18P3 1347.4401 (M + 1)+,
found 1347.4330.
(3S,4R)-3-Acetoxytetr a h yd r ofu r a n -4-yl 3,4-Di-O-a cetyl-
2,6-d i-O-ben zyl-R-D-glu cop yr a n osid e (47). Compound 47
(350 mg, 77% as an oil) was obtained from 44 (451 mg, 0.613
mmol) as described above for the synthesis of 45: [R]23D +58.1°
1
(c 1.23, CHCl3); H NMR (500 MHz, CDCl3) δ 7.35-7.24 (m,
10 H), 5.41 (t-like dd, 1 H, J ) 9.8, 9.9 Hz), 5.28-5.24 (m, 1
H), 5.10 (t-like dd, 1 H, J ) 9.8, 9.9 Hz), 4.98 (d, 1 H, J ) 3.6
Hz), 4.65 and 4.50 (each d, each 1 H, J ) 12.2 Hz), 4.57 and
4.45 (each d, each 1 H, J ) 12.1 Hz), 4.35-4.31 (m, 1 H), 4.05
(dd, 1 H, J ) 5.9, 10.1 Hz), 3.95 (dd, 1 H, J ) 6.0, 9.4 Hz),
3.93-3.84 (m, 3 H), 3.54 (dd, 1 H, J ) 3.6, 9.9 Hz), 3.48 (dd,
1 H, J ) 2.9, 10.7 Hz), 3.45 (dd, 1 H, J ) 4.5, 10.7 Hz), 1.96,
1.92, and 1.90 (each s, each 3 H); HRMS (FAB) calcd for C30
37O11 573.2335 (M + 1)+, found 573.2357.
(2R,3R,4S)-3-Acetoxy-2-(ben zyloxym eth yl)tetr a h yd r o-
-
H
fu r a n -4-yl 3,4-Di-O-a cetyl-2,6-d i-O-ben zyl-R-D-glu cop yr a -
n osid e (52). Compound 52 (1.35 g, 77% as an oil) was
obtained from 51 (1.73 g, 3.06 mmol) as described above for
1
the synthesis of 45: [R]30 +114.8° (c 1.01, CHCl3); H NMR
D
(500 MHz, CDCl3) δ 7.36-7.22 (m, 15 H), 5.37 (dd, 1 H, J )
9.9, 9.7 Hz), 5.09 (t, 1 H, J ) 5.7 Hz), 5.08 (dd, 1 H, J ) 9.7,
9.8 Hz), 4.74 (d, 1 H, J ) 3.5 Hz), 4.63 and 4.51 (each d, each
1 H, J ) 12.3 Hz), 4.58 and 4.53 (each d, each 1 H, J ) 12.1
Hz), 4.57 and 4.40 (each d, each 1 H, J ) 12.1 Hz), 4.43-4.38
(m, 1 H), 4.17-4.15 (m, 1 H), 4.09 (dd, 1 H, J ) 5.6, 9.4 Hz),
3.91 (ddd, 1 H, J ) 2.7, 3.7, 9.8 Hz), 3.80 (dd, 1 H, J ) 5.5, 9.4
Hz), 3.64 (dd, 1 H, J ) 3.0, 10.7 Hz), 3.56 (dd, 1 H, J ) 4.1,
10.7 Hz), 3.56 (dd, 1 H, J ) 3.5, 9.9 Hz), 3.45 (dd, 1 H, J )
2.7, 10.8 Hz), 3.41 (dd, 1 H, J ) 3.7, 10.8 Hz), 2.12, 2.00, and
1.88 (each s, each 3 H); HRMS (FAB) calcd for C38H43O12
691.2754 (M - 1)+, found 691.2745.
(2R,3R,4S)-4-Hyd r oxy-2-(h yd r oxym et h yl)t et r a h yd r o-
fu r a n -3-yl R-D-Glu cop yr a n osid e 3,4,4′-Tr isp h osp h a t e
Hexa sod iu m Sa lt (5). A mixture of 48 (686 mg, 0.510 mmol)
and Pd-C (10%, 170 mg) in EtOH (35 mL) was stirred under
atmospheric pressure of H2 at room temperature for 24 h. The
catalyst was filtered off with Celite, and the filtrate was
evaporated under reduced pressure. The residue was dissolved
in H2O (3 mL) and applied to a Diaion WK-20 resin column
(Na+ form), which was developed by H2O. The eluent was
evaporated under reduced pressure to give 5 (341 mg, quant
as a solid) as a sodium salt: 1H NMR (500 MHz, D2O) δ 5.28
(d, 1 H, J ) 3.3 Hz), 4.80-4.70 (m, 1 H), 4.46-4.39 (m, 1 H),
4.29-4.25 (m, 1 H), 4.15-4.08 (m, 2 H), 4.06-3.92 (m, 3 H),
3.84-3.66 (m, 5 H); 31P NMR (125 MHz, D2O) δ 2.02, 1.66,
0.72; HRMS (FAB) calcd for C11H19Na5O18P3 646.9273 (M +
2H - Na)+, found 646.9303.
(2R,3R,4S)-2-(Ben zyloxym eth yl)-4-h yd r oxytetr a h yd r o-
fu r a n -3-yl 2,6-Di-O-b en zyl-R-D-glu cop yr a n osid e 3,4,4′-
Tr is(d iben zyl p h osp h a te) (48). A mixture of 45 (1.38 g, 2.32
mmol) and NaOMe (28% in MeOH, 0.115 mL, 0.597 mmol) in
MeOH (10 mL) was stirred at room temperature for 4 h. After
the mixture was neutralized with Dowex 50W resin (×2, H+
form), the resin was filtered off. The filtrate was evaporated
under reduced pressure, and the residue was coevaporated
with benzene (×3). A mixture of the resulting residue,
tetrazole (976 mg, 13.9 mmol), and dibenzyl(diisopropyl)-
phosphoroamidite (3.01 mL, 8.96 mmol) in CH2Cl2 (35 mL) was
(2R,3S,4S)-4-H yd r oxy-2-(h yd r oxym et h yl)t et r a h yd r o-
fu r a n -3-yl R-D-Glu cop yr a n osid e 3,4-Bisp h osp h a te Tet-
r a sod iu m Sa lt (6). Compound 6 (166 mg, quant as a solid)
was obtained as a sodium salt from 49 (360 mg, 0.306 mmol)

8824 J . Org. Chem., Vol. 63, No. 24, 1998
Shuto et al.
as described above for the synthesis of 5: 1H NMR (500 MHz,
D2O) δ 4.84 (d, 1 H, J ) 3.9 Hz), 4.25-4.17 (m, 1 H), 4.12-
4.04 (m, 1 H), 3.98 (dd, 1 H, J ) 4.7, 7.3 Hz), 3.83-3.70 (m, 4
H), 3.62 (dd, 1 H, J ) 2.3, 10.3 Hz), 3.59 (dd, 1 H, J ) 2.9,
12.5 Hz), 3.55-3.48 (m, 2 H), 3.48-3.40 (m, 2 H); 31P NMR
IP 3 Recep tor Bin d in g Assa y. [3H]IP3 binding assay was
performed as described previously. The compounds were
incubated with porcine cerebella homogenate in Tris-HCl
buffer (50 mM, pH 8.0, 500 µL) containing EDTA (1 mM) and
[3H]IP3 (2.5 nM) at 4 °C. After 5 min, the samples were
centrifuged for 5 min at 4 °C. The supernatant was removed,
and the radioactivity in the pellet was then determined.
Nonspecific binding was measured in the presence of 1 mM of
cold IP3.
(125 MHz, D2O) δ 3.91, 3.66; HRMS (FAB) calcd for C11H19
-
Na4O15P2 544.9790 (M + H)+, found 544.9805.
(2R,3R,4S)-3-Hyd r oxy-2-(h yd r oxym et h yl)t et r a h yd r o-
fu r a n -4-yl R-D-Glu cop yr a n osid e 3,4,3′-Tr isp h osp h a t e
Hexa sod iu m Sa lt (7). Compound 7 (34 mg, 91% as a solid)
was obtained as a sodium salt from 53 (75 mg, 0.056 mmol)
as described above for the synthesis of 5: 1H NMR (500 MHz,
D2O) δ 5.00 (d, 1 H, H-1, J ) 3.9 Hz), 4.48-4.32 (m, 3 H),
4.06-3.85 (m, 5 H), 3.82-3.72 (m, 3 H), 3.66-3.57 (m, 2 H);
31P NMR (125 MHz, D2O) δ 2.55, 1.98, 1.04; HRMS (FAB) calcd
for C11H19Na5O18P3 646.9273 (M + 2H - Na)+, found 646.9243.
Ack n ow led gm en t. We thank to Miss Yumi Kawase,
Biomedical Research Labs, Sankyo Co. Ltd., and Dr.
Makoto Kashiwayanagi, Graduate School of Pharma-
ceutical Sciences, Hokkaido University, for evaluating
of the biological effects of the compounds.
(3S,4R)-3-H yd r oxyt et r a h yd r ofu r a n -4-yl
R-D-Glu co-
p yr a n osid e 3,4,3′-Tr isp h osp h a te Hexa sod iu m Sa lt (8).
Compound 8 (40 mg, 89% as a solid) was obtained as a sodium
salt from 50 (86 mg, 0.070 mmol) as described above for the
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H
NMR spectra of all new compounds not accompanied by
elemental analyses (30 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
1
synthesis of 5: H NMR (500 MHz, D2O) δ 5.19 (d, 1 H, J )
3.7 Hz), 4.75-4.67 (m, 1 H), 4.41-4.31 (m, 2 H), 4.00-3.89
(m, 4 H), 3.87-3.78 (m, 3 H), 3.72-3.61 (m, 2 H); 31P NMR
(125 MHz, D2O) δ 2.42, 1.72, 1.15; HRMS (FAB) calcd for C10
-
H
16Na6O17P3 638.8987 (M + H)+, found 638.8979.
J O980925L