Synthesis of all possible regioisomers of scyllo-inositol phosphate

Article abstract of DOI:10.1016/S0968-0896(99)00183-2

scyllo-Inositol is the all equatorial stereoisomer of myo-inositol. All possible 12 regioisomers of scyllo-inositol phosphate were synthesized for the first time via a scyllo-inositol benzoate intermediate, which was derived from a myo-inositol derivative. The stereoinversion of myo-inositol into scyllo-inositol was accomplished by Mitsunobu reaction of the vicinal cis- diol. The requisite intermediates, scyllo-inositol benzoates were obtained by benzoyl migration or random benzoylation, and phosphorylated to give scyllo- IP(n). (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(99)00183-2

Bioorganic & Medicinal Chemistry 7 (1999) 2577±2589
Synthesis of all Possible Regioisomers of scyllo-Inositol
Phosphate
Sung-Kee Chung,* Yong-Uk Kwon, Young-Tae Chang, Kwang-Hoon Sohn,
Jung-Han Shin, Kyu-Hwan Park, Bong-Jin Hong and In-Hee Chung
Department of Chemistry, Pohang University of Science and Technology, Pohang 790-784, South Korea
Received 6 May 1999; accepted 24 June 1999
AbstractÐscyllo-Inositol is the all equatorial stereoisomer of myo-inositol. All possible 12 regioisomers of scyllo-inositol phosphate
were synthesized for the ®rst time via a scyllo-inositol benzoate intermediate, which was derived from a myo-inositol derivative. The
stereoinversion of myo-inositol into scyllo-inositol was accomplished by Mitsunobu reaction of the vicinal cis-diol. The requisite
intermediates, scyllo-inositol benzoates were obtained by benzoyl migration or random benzoylation, and phosphorylated to give
scyllo-IPn. # 1999 Elsevier Science Ltd. All rights reserved.
Introduction
strategy10±14 and tested them on I(1,4,5)P3 receptors,15±17
I(1,3,4,5)P4 binding proteins,18,19 I(1,4,5)P3 3-kinase20,21
and as an iron binding motif.22 Although we could
obtain much useful information on the structure±activ-
ity relationships (SAR) of these biomacromolecules,
availability of IPn molecules of other stereoisomers than
myo- are highly desired in order to obtain more detailed
pictures.
Since the discovery that d-myo-inositol 1,4,5-trispho-
sphate [I(1,4,5)P3] acts as an important intracellular
calcium mobilizing molecule in transmembrane signal-
ling events, a number of related myo-inositol phos-
phates have been found in living systems that are
also distinct bioactive ligands.1 One of the major
metabolites, d-myo-inositol 1,3,4,5-tetrakisphosphate
[I(1,3,4,5)P4], has been suggested to act as a second
messenger mobilizing Ca2+ ions from extra-2 or
intracellular3 sources. One of the binding proteins of
I(1,3,4,5)P4 was also identi®ed as a member of the
GAP1 family.4 d-myo-Inositol 3,4,5,6-tetrakispho-
sphate was identi®ed as a novel mediator which uncou-
ples chloride secretion from intracellular calcium ion
levels in intestinal epithelial cells.5 myo-Inositol hexaki-
sphosphate (IP6, phytic acid), a house-keeping molecule
in plant seeds and one of the oldest known myo-inositol
phosphates, has recently shown to be a promising anti-
cancer agent.6±8 Among all possible 63 regioisomers (15
meso and 24 enantiomeric pairs) of myo-inositol phos-
phates (IP1±IP6), more than half were found in nature
and prepared by various synthetic routes.9 We pre-
viously reported the systematic and divergent syntheses
of all possible optically inactive regioisomers of myo-
inositol phosphates using the acyl migration as the key
In this context, scyllo-inositol with all equatorial hy-
droxyl groups was chosen as our synthetic target, since
it represents the simplest isomer in terms of symmetry.
Although myo-inositol is the most abundant inositol in
nature and its derivatives have been studied extensively,
the occurrence of scyllo-inositol in animals23,24 and in
plants25,26 has also been known. It has been suggested
that a certain human disease is associated with scyllo-
inositol depletion.27 There are 12 regioisomers of scyllo-
inositol phosphate: 3 enantiomeric pairs and 9 meso
forms (Fig. 1). Of these 12 isomers only scyllo-
I(1,2,4)P3, I(1,2,4,5)P4 and I(1,2,3,4)P4 have previously
been synthesized.28±31 We report herein the ®rst com-
plete synthesis of all possible regioisomers of scyllo-ino-
sitol phosphates by employing the benzoyl migration
strategy, which has previously been demonstrated in the
synthesis of all regioisomers of myo-inositol phosphates.
Results and Discussion
Key words: scyllo-Inositol; inositol phosphates; Mitsunobu reaction;
benzoyl migration.
scyllo-Inositol, in which the stereochemistry of 2-OH in
myo-inositol is inverted to the equatorial orientation, is
* Corresponding author. Tel.: +82-562-279-2103; fax: +82-562-279-
3399; e-mail: skchung@postech.ac.kr
0968-0896/99/$ - see front matter # 1999 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(99)00183-2

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S.-K. Chung et al. / Bioorg. Med. Chem. 7 (1999) 2577±2589
Figure 1. All possible regioisomers of scyllo-IPn (P=PO23 ).
highly symmetric. Thus there are only 12 regioisomers
of scyllo-IPn as opposed to 39 optically inactive forms of
myo-IPn regioisomers. The key problems in the scyllo-
IPn synthesis are (i) the preparation of scyllo-inositol
itself and suitably protected derivatives, (ii) ecient
phosphorylation, and (iii) removal of the protecting
groups under mild conditions. The vicinal cis-diol
(10),32,33 obtained in three steps from myo-inositol,34
was successfully converted to scyllo-inositol derivative
11 under Mitsunobu conditions (Scheme 1).35
scyllo-I(1)Bz(2,3,4,5)Bn4 (11) was phosphorylated with
the phosphoramidite reagent and a weak acid, 1H-tet-
razole to give 12, which showed the phosphorous reso-
nance at d 1.44 ppm. The protecting groups of 12 were
removed by hydrogenolysis and treatment with LiOH.
The target compound scyllo-IP1 (1) was obtained after
chromatography on Dowex 50WX8-100 (H+), pH
adjustment to 10 with NaOH, and then lyophilization
(Scheme 2).
Synthesis of scyllo-IP2s requires scyllo-IBz4s as inter-
mediates. Thus, benzoylation of scyllo-I(1)Bz(2,3,4,5)Bn4
(11), followed by hydrogenolysis provided scyllo-
I(1,2)Bz2 (14a). Acetonation of 14a with 2-methoxy-
propene under standard reaction conditions, followed
by benzoylation furnished 15, which was then hydro-
lyzed to give the vicinal diol, 16a (Scheme 3a). Genera-
tion of the 3 possible isomers of scyllo-IBz4 was
attempted by the benzoyl migration method. However,
when 16a was subjected to 60% aq pyridine at 100ꢀC,
only 16a and 16b were produced; the 3,6-diol, scyllo-
I(1,2,4,5)Bz4, was not produced in a signi®cant amount
under these conditions.
Instead, scyllo-Inositol diacetonide was used as the
scyllo-I(1,4)P2 precursor. Acetonation of 18, which was
prepared by hydrogenolysis of 11, gave a mixture of 19
(51%) and 20 (34%). Compound 19 was easily crystal-
lized and separated from 20 which could be recycled by
hydrolysis, and 19 was debenzoylated to give 21
(Scheme 3b). scyllo-Inositol tetrabenzoates (16a and
16b) and diacetonide (21) were phosphorylated by suc-
cessive treatments with diethyl chlorophosphite and
Scheme 1. Reagents and conditions: a. (i) 2,2-dimethoxypropane, p-
TSA, (ii) EtOH/ether (1/5), (iii) TEA, 69%; b. NaH, BnBr, 89%; c.
80% aq AcOH, quant.; d. PPh3, DEAD, BzOH, MS (3 A), 72%.

S.-K. Chung et al. / Bioorg. Med. Chem. 7 (1999) 2577±2589
2579
Scheme 2. Reagents and conditions: a. (i) iPr2NP(OBn)2, 1H-tetrazole, (ii) mCPBA, 94%; b. (i) H2 (50 psi), NaHCO3, Pd/C, (ii) 1 N LiOH, (iii)
Dowex 50WX8-100 (H+), (iv) pH 10 (NaOH), 80%.
Scheme 3. Reagents and conditions: a. BzCl, pyridine, 99.7%; b. H2 (50 psi), Pd(OH)2/C, 95% for 14a, 96% for 18; c. (i) 2-methoxypropene, p-TSA,
(ii) TEA, (iii) BzCl, pyridine, 92%; d. 80% aq AcOH, quant.; e. 60% aq pyridine, 60% for 16a, 25% for 16b; f. (i) (EtO)2PCl, (i-Pr)2NEt, (ii) 30% aq
H2O2, 84% for 17a, 88% for 17b, 72% for 22; g. (i) TMSBr, (ii) 1 N LiOH, (iii) Dowex 50WX8-100 (H+), (iv) pH 10 (NaOH), 90% for 2a, 92% for
2b; h. 2-methoxypropene, p-TSA, 51% for 19, 34% for 20; i. NaOMe, MeOH, quant.; j. (i) TMSBr, (ii) pH 10 (NaOH), 95%.
N,N-diisopropylethylamine in DMF, and then 30%
hydrogen peroxide to yield 17a, 17b and 22, respec-
tively. The protecting groups of 17a and 17b were
removed by successive reactions with TMSBr and
then LiOH. Chromatography on Dowex 50WX8-100
(H+), pH adjustment to 10 with NaOH, and lyophi-
lization gave the two scyllo-IP2 2a and 2b. Treatment
of 22 with TMSBr and the spontaneous acid-cata-
lyzed hydrolysis with addition of water (1 day at rt)
removed all protecting groups, thus giving the Na

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S.-K. Chung et al. / Bioorg. Med. Chem. 7 (1999) 2577±2589
salt of scyllo-I(1,4)P2 (2c) after pH adjustment with
NaOH.
products, 4a±c were obtained after chromatography on
Dowex 50WX8-100 (H+), pH adjustment to 10 with
NaOH, and then lyophilization (Scheme 5).
Random benzoylation of 14a with BzCl (2 eq) provided
the tribenzoates, 23a (20%), 23b (22%), scyllo-IBz4
mixture (22%), and the unreacted starting material
(22%) (Scheme 4a). Tribenzoate (23c) was obtained
from 18 via the orthoformate intermediate (25). Thus,
treatment of 18 with trimethyl orthoformate, p-TSA in
DMF at 100ꢀC resulted in the formation of mono-
benzoyl orthoformate, in which the 2, 4 and 6 hydroxyl
groups were protected, and the normally equatorial hy-
droxyl groups were inverted to the axial orientations.
Complete benzoylation of the remaining hydroxyl
groups required the harsh conditions of excess BzCl and
heating at 100ꢀC presumably because of the steric
hindrance. Hydrolysis of 25 with a catalytic amount of
p-TSA in MeOH at re¯ux removed the orthoformate
group to give crystalline 23c in 87% yield (Scheme 4b).
Tribenzoates, 23a±c were phosphorylated as previously
described to a€ord 24a±c, which were deprotected to
give 3a±c (Scheme 4).
There is only one regioisomer for scyllo-IP5, and it has
been synthesized as follows. The intermediate scyllo-
IBz1 (18) was phosphorylated by the phosphoramidite
method to give 27. However, in this case the phosphor-
ylation yield (35%) was not as high as those for scyllo-
IP2±4, even with a large excess of the phosphorylating
agent over an extended reaction time. This might be due
to the unfavorable steric hindrance or interaction
between the vicinal phosphite groups. In any case,
deprotection of the phosphate and subsequent handling
as previously described provided the Na salt form of
scyllo-IP5, 5 (Scheme 6).
The monobenzoate 18 was hydrolyzed with a catalytic
amount of NaOMe in MeOH at re¯ux to obtain scyllo-
inositol,36 which was phosphorylated by the phosphor-
amidite method to give 29. Hydrogenolysis of 29 over
Pd/C, pH adjustment to 10 with NaOH, and lyophili-
zation a€orded the Na salt of scyllo-IP6, 6 (Scheme 7).
scyllo-IP4s were similarly prepared via scyllo-IBz2 inter-
mediates. scyllo-I(1,2)Bz2 (14a) was subjected to the acyl
migration conditions to generate three scyllo-IBz2
regioisomers (Scheme 5). Each scyllo-IBz2 isomer was
separated by chromatography and phosphorylated as
previously described to yield all 3 regioisomers of scyllo-
We have thus synthesized all possible 12 regioisomers of
scyllo-IPn using variously protected scyllo-inositol
intermediates. These regioisomers were fully character-
1
ized by H, 13C and 31P NMR, and the 31P NMR data
for the fully protected and the Na-salt forms of scyllo-
IPns (n=1±6) are listed in Table 1.
1
IP4 (26a±c), which were fully characterized by H, 13C,
31P NMR and FAB mass spectrometry. In the ®nal
steps, the protecting groups of 26 were removed by
successive treatments with TMSBr and then LiOH. The
scyllo-IPns are the stereoisomers of myo-IPns with the
only di€erence being the inverted 2-OH stereochemistry.
Scheme 4. Reagents and conditions: a. BzCl (2 eq), pyridine, 20% for 23a, 22% for 23b; b. (i) (EtO)2PCl, (i-Pr)2NEt, (ii) 30% aq H2O2, 75% for
24a, 77% for 24b, 85% for 24c; c. (i) TMSBr, (ii) 1 N LiOH, (iii) Dowex 50WX8-100 (H+), (iv) pH 10 (NaOH), 92% for 3a, 90% for 3b, 93% for 3c;
d. (i) trimethyl orthoformate, p-TSA, (ii) TEA, (iii) BzCl, pyridine, 42%; e. p-TSA, MeOH, re¯ux, 87%.

S.-K. Chung et al. / Bioorg. Med. Chem. 7 (1999) 2577±2589
2581
Scheme 5. Reagents and conditions: a. 60% aq pyridine, 48% for 14a, 28% for 14b, 16% for 14c; b. (i) (i-Pr)2NEt, (EtO)2PCl, (ii) 30% aq H2O2,
70% for 26a, 74% for 26b, 75% for 26c; c. (i) TMSBr, (ii) 1 N LiOH, (iii) Dowex 50WX8-100 (H+), (iv) pH 10 (NaOH), 90% for 4a, 87% for 4b,
88% for 4c.
Scheme 6. Reagents and conditions: a. (i) (i-Pr)2NEt, (EtO)2PCl, (ii) 30% aq H2O2, 35%; b. (i) TMSBr, (ii) 1 N LiOH, (iii) Dowex 50WX8-100
(H+), (iv) pH 10 (NaOH), 85%.
Scheme 7. a. NaOMe, MeOH, 88%; b. (i) iPr2NP(OBn)2, tetrazole, (ii) 30% aq H2O2, 44%; c. (i) H2 (50 psi), NaHCO3, Pd/C, (ii) pH 10 (NaOH),
94%.
It is instructive to compare the corresponding geome-
tries of scyllo-IPns and myo-IPns whose biological
activities are known (Fig. 2). For example, d-myo-
I(1,4,5)P3 and d-myo-I(1,3,4,5)P4 are well known
second messengers, and scyllo-I(1,2,4)P3 and scyllo-
I(1,2,3,5)P4 may be viewed as the stereoisomers with
inverted con®guration at C-2. Their binding anities
with relevant biomacromolecules may be compared in
order to gain information on the geometry of the bind-
ing domains (Fig. 2a and b). Similarly, scyllo-I(1,2,3)P3
may be viewed as the C-2 stereoisomer of d-myo-
I(1,2,6)P3 (a-trinositol), which was found to possess an
inhibitory e€ect on neuropeptide Y-evoked vasocon-
striction in many vascular assays, and a potent anti-
in¯ammatory property (Fig. 2c).37 Finally, scyllo-
I(1,2,3,4)P4 may also be compared to d-myo-
I(3,4,5,6)P4, which was shown to be a novel mediator
uncoupling the chloride secretion from intracellular
calcium levels in intestinal epithelial cells (Fig. 2d).5
There are many other such comparisons possible
between scyllo-IPns and myo-IPns for which novel bio-
logical activities have been demonstrated. In this con-
text various binding studies are in progress with the
synthetic set of the scyllo-IPn regioisomers.

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S.-K. Chung et al. / Bioorg. Med. Chem. 7 (1999) 2577±2589
Table 1. 31P NMR chemical shift of scyllo-IPns
spectra were recorded on a Bruker AM 300 or DPX 300
spectrometer. Chemical shifts are reported in ppm, and
tetramethylsilane and phosphoric acid (80%) were used
d (ppm)
scyllo-IPns
(protected form)
(in CDCl3)
scyllo-IPns
(Na salt)
(in D2O, pH 10)
1
as internal and external standard for H NMR and 31P
NMR, respectively. Mass spectra (EI or FAB) were
determined on a micromass PLATFORM II. HRMS
(FAB) were performed by Korea Basic Science Center,
Taejeon, Korea.
scyllo-IP1
1.44
0.70 (2P)
1.08 (2P)
6.98
7.30 (2P)
7.13 (2P)
dl-scyllo-I(1,2)P2
scyllo-I(1,3)P2
scyllo-I(1,4)P2
0.28 (2P)
7.01 (2P)
scyllo-I(1,2,3)P2
dl-scyllo-I(1,2,4)P3
scyllo-I(1,3,5)P3
dl-scyllo-I(1,2,3,4)P4
scyllo-I(1,2,3,5)P4
scyllo-I(1,2,4,5)P4
scyllo-IP5
0.61 (2P), 0.85
0.73, 0.77, 1.01
1.10 (3P)
0.48 (4P)
0.70 (2P), 0.95, 0.98
0.75 (4P)
0.04, 0.29 (2P),
0.53 (2P)
0.66 (6P)
6.38, 7.30 (2P)
7.00, 7.33 (2P)
7.07 (3P)
5.98 (2P), 6.84 (2P)
6.12, 6.75 (2P), 7.08
6.85 (4P)
5.79 (2P), 6.08,
6.55 (2P)
5.99 (6P)
DL-1,4,5,6-Tetra-O-benzyl-2,3-O-isopropylidene-myo-ino-
sitol (9). To a solution of compound 834 (2 g, 9.08 mmol)
and NaH (3.7 g, 146 mmol) in DMF (100 mL) at 0ꢀC
was added BnBr (11 mL, 90.6 mmol). After 30 min, the
mixture was warmed up to rt and stirred for 20 h. The
mixture was diluted with EtOAc and successively
washed with aq NaHSO4, aq NaHCO3 and brine. The
organic layer was separated, dried (anhydrous MgSO4),
®ltered and concentrated. A column chromatography
gave compound 9 (4.67 g, 89%) as an oil. Rf 0.23
scyllo-IP6
Experimental
1
(EtOAc:hexane=1:10); H NMR (CDCl3) d 1.35, 1.51
General
(2s, 6H, CMe2), 3.42 (app. t, J=9.0 Hz, 1H, H-5), 3.70
(dd, J=3.8, 8.8 Hz, 1H, H-1), 3.79 (dd, J=6.9, 9.4 Hz,
1H, H-4), 3.95 (app. t, J=8.6 Hz, 1H, H-6), 4.10 (app. t,
J=6.2 Hz, 1H, H-3), 4.27 (dd, J=3.8, 5.5 Hz, 1H, H-2),
4.72±4.88 (m, 8H, 4CH2Ph), 7.24±7.39 (m, 20H, 4Ph);
13C NMR (CDCl3) d 26.39, 28.33 [CMe2], 73.83, 74.40,
75.79, 75.84 [4CH2Ph], 75.08, 77.70, 79.66, 81.45, 82.71,
83.01 [inositol ring carbons], 110.33 (CMe2), 128.11±
139.19 [4Ph]; MS (FAB) m/z=579 (M++H).
All reactions except hydrolyses were performed in oven-
dried glassware under inert atmosphere of dry argon or
nitrogen. All commercial chemicals were used as
obtained without further puri®cation except for sol-
vents, which were puri®ed and dried by standard meth-
ods prior to use. Melting points were determined on a
Thomas±Hoover apparatus and are uncorrected. Ana-
lytical TLC was carried out on Merck 60 F254 silica gel
plate (0.25 mm thickness) and visualization was done
with UV light, and/or by spraying with a 5% solution of
phosphomolybdic acid followed by charring with a heat
gun. Column chromatography was performed on Merck
60 silica gel (70±230 mesh or 230±400 mesh). NMR
DL-1,4,5,6-Tetra-O-benzyl-myo-inositol (10). A solution
of compound 9 (2.9 g, 5 mmol) in 80% aq acetic acid
(50 mL) was heated at 100ꢀC for 4 h, and then con-
centrated under reduced pressure to give a solid product
Figure 2. Comparison of several myo-IPns with scyllo-IPns.

S.-K. Chung et al. / Bioorg. Med. Chem. 7 (1999) 2577±2589
2583
10. Recrystallization of the crude product from EtOAc:
hexane gave a pure product 10 (2.46 g, 91%). Rf 0.2
(EtOAc:hexane=1:2); mp 126.5±127.5ꢀC (lit. mp 127.5±
128ꢀC32 and 114±115ꢀC33); 1H NMR (CDCl3) d 2.41 (d,
J=4.5 Hz, 1H, OH), 2.48 (s, 1H, OH), 3.44±3.51 (m,
3H, H-1, H-3 and H-5), 3.84 (app. t, J=9.5 Hz, 1H, H-4
or H-6), 3.97 (app. t, J=9.5 Hz, 1H, H-4 or H-6), 4.21
(br. s, 1H, H-2), 4.71±4.97 (m, 8H, 4CH2Ph), 7.25±7.35
(m, 20H, 4Ph); 13C NMR (CDCl3) d 69.74, 72.27, 80.45,
81.89, 82.09, 83.71 [inositol ring carbons], 73.15, 76.08,
76.20, 76.42 [4CH2Ph], 128.11±139.14 [4Ph]; MS (FAB)
m/z=560 (M++Na).
dryness. The residue was redissolved in a small amount
of water (1 mL) and pH was adjusted to 10 with NaOH
and lyophilized again to give the sodium salt of scyllo-
inositol monophosphate (1, 14 mg, 80%). 1H NMR
(D2O, pH 10) d 3.33±3.49 (m, 5H, H-2, H-3, H-4, H-5
and H-6), 3.82 (app. q, J=8.2 Hz, 1H, H-1); 13C NMR
(D2O, pH 10) d 73.71 (2C), 73.75 (2C), 73.88, 77.47
[inositol ring carbons]; 31P NMR (D2O, pH 10) d 6.98.
DL-1,2-Di-O-benzoyl-3,4,5,6-tetra-O-benzyl-scyllo-inositol
(13). To a solution of compound 11 (748 mg, 1.16 mmol)
in pyridine (20 mL) at 0ꢀC was added dropwise benzoyl
chloride (0.4 mL, 3.41 mmol), and the solution was stir-
red at rt for 3 h. The reaction mixture was treated with
water and extracted with EtOAc. The organic layer was
washed with water four times, dried over MgSO4 and
concentrated to give a solid product. The crude solid
was recrystallized from CH2Cl2:hexane to give 13
(860 mg, 99%). Rf 0.38 (EtOAc:hexane=1:3); mp 203±
204ꢀC; 1H NMR (CDCl3) d 3.80±3.84 (m, 4H, H-3, H-4,
H-5 and H-6), 4.66 (d, J=10.9 Hz, 2H, 2CHaCHbPh),
4.80 (d, J=10.9 Hz, 2H, 2CHaCHbPh), 4.91±4.97 (m,
4H, 2CH2Ph), 5.56±5.59 (m, 2H, H-1 and H-2), 7.06±
7.91 (m, 30H, 6Ph); 13C NMR (CDCl3) d 72.83 (2C),
80.64 (2C), 83.24 (2C) [inositol ring carbons], 76.06
(2C), 76.47 (2C) [4CH2Ph], 126.29±137.95 [6Ph], 166.11
(2C) [2COPh]; MS (FAB) m/z=749 (M++H).
DL-1-O-Benzoyl-2,3,4,5-tetra-O-benzyl-scyllo-inositol (11).
A mixture of diol 10 (1 g, 1.85 mmol), PPh3 (0.587 g,
2.01 mmol), benzoic acid (0.25 g, 2.05 mmol) DEAD
(0.352 mL, 2.2 mmol) and 3 A molecular sieve in ben-
zene (20 mL) was stirred at 80ꢀC for 4 h. The reaction
mixture was ®ltered and the ®ltrate was evaporated to
give a crude product, which was chromatographed on
silica gel to a€ord compound 11 (0.86 g, 72%). Rf 0.42
(EtOAc:hexane=1:2); mp 134±135ꢀC; 1H NMR
(CDCl3) d 2.43 (s, 1H, 6-OH), 3.55±3.77 (m, 5H, H-2,
H-3, H-4, H-5 and H-6), 4.65±4.98 (m, 8H, 4CH2Ph),
5.34 (app. t, J=9.7 Hz, 1H, H-1), 7.08±8.05 (m, 25H,
5Ph); 13C NMR (CDCl3) d 73.08, 75.19, 80.85, 82.98,
83.06, 83.46 [inositol ring carbons], 76.05, 76.28 (2C),
76.44 [4CH2Ph], 128.06±138.64 [5Ph], 166.58 [COPh];
MS (FAB) m/z=645 (M++H).
DL-1,2-Di-O-benzoyl-scyllo-inositol (14a). A mixture of
compound 13 (750 mg, 1 mmol) and 20% Pd(OH)2/C
(0.5 g) in a mixed solvent (EtOAc:EtOH=1:5, 24 mL)
was stirred under H2 (50 psi). After 1 day, the catalyst
was ®ltered o€ and the solvent was evaporated under
reduced pressure. A column chromatography gave crys-
talline 14a (388 mg, 95%). Rf 0.13 (EtOAc:hexane=3:
DL-1-Mono-O-benzoyl-2,3,4,5-tetra-O-benzyl-scyllo-ino-
sitol 6-mono(dibenzyl phosphate) (12). To a solution
of compound 11 (130 mg, 0.2 mmol) and 1H-tetra-
zole (72 mg, 1 mmol) in CH2Cl2 (5 mL) at rt was
added dibenzyl diisopropylphosphoramidite (0.25 mL,
0.73 mmol). After 12 h, an excess amount of mCPBA
(640 mg) was added to the mixture. After standing
overnight at rt, the mixture was diluted with CH2Cl2,
and washed with aq Na2SO3, aq NaHCO3 and brine.
The organic layer was dried over MgSO4, concentrated
and chromatographed to give 12 (171 mg, 94%). Rf 0.5
(EtOAc:hexane=1:2); mp 132±134ꢀC; 1H NMR
(CDCl3) d 3.65±3.77 (m, 4H, H-2, H-3, H-4 and H-5),
4.44 (dd, J=8.4, 11.9 Hz, 1H, H-6), 4.53±4.90 (m, 12H,
6 CH2Ph), 5.50 (app. t, J=9.5 Hz, 1H, H-1), 6.83±8.06
(m, 35H, 7Ph); 13C NMR (CDCl3) d 69.42 (2C), 75.60,
76.06, 76.34, 76.41 [6CH2Ph], 73.23, 78.55, 80.28, 81.14,
82.70, 83.04 [inositol ring carbons], 127.62±138.56 [7Ph],
166.07 [COPh]; 31P NMR (CDCl3) d 1.44; HRMS
(FAB): calcd for C55H54O10P m/z 905.3455, found,
905.3459 (M++H).
ꢀ
1
1); mp 114±116 C; H NMR (CD3OD) d 3.44±3.48 (m,
2H), 3.67±3.72 (m, 2H), 5.34±5.38 (m, 2H, H-1 and H-
2), 7.32±7.89 (m, 10H, 2Ph); 13C NMR (CD3OD) d
72.58 (2C), 74.29 (2C), 74.57 (2C) [inositol ring car-
bons], 128.35±133.20 [2Ph], 166.52 (2C) [2COPh]; MS
(FAB) m/z=389 (M++H), 411 (M++Na).
DL-1,2,3,4-Tetra-O-benzoyl-5,6-O-isopropylidene-scyllo-
inositol (15). To a solution of compound 14a (690 mg,
1.78 mmol) and p-TSA (110 mg) in DMF (8 mL) at rt
was added 2-methoxypropene (1 mL, 10 mmol). After 1
day, the reaction mixture was treated with triethylamine
(5 mL), and then the low-boiling substance evaporated.
To the resulting mixture in pyridine (12 mL) at 0ꢀC were
added dropwise DMAP (55 mg) and BzCl (1 mL,
8.6 mmol). After 15 h at rt, the reaction mixture was
stirred with H2O (3 mL) for 30 min and diluted with
EtOAc, and washed with aq NaHSO4, aq NaHCO3 and
then brine. The organic layer was dried (MgSO4), con-
centrated, and chromatographed on silica gel to give 15
(1.044 g, 92%). Rf 0.62 (EtOAc:hexane=1:1); mp 321±
Sodium salt of scyllo-inositol 1-monophosphate (1). To a
solution of compound 12 (58 mg, 0.064 mmol) and
NaHCO3 (5 mg) in a mixed solvent (H2O:MeOH=1:10,
11 mL) was added 10% Pd/C (50 mg). The mixture was
stirred under H2 (50 psi). After 1 day, the catalyst was
®ltered o€ and the solution was concentrated under
reduced pressure. The reaction mixture was treated with
1 N LiOH (5 mL) at 80ꢀC for 3 h. The basic solution was
cooled and loaded on Dowex 50WX8-100 (H+ form)
and eluted with water. The acidic e‚uent was collected,
washed with CH2Cl2 three times and lyophilized to
324ꢀC; H NMR (CDCl3) d 1.51 (s, 6H, CMe2), 4.16
1
(dd, J=2.6, 6.9 Hz, 2H, H-5 and H-6), 5.84±5.93 (m,
4H, H-1, H-2, H-3 and H-4), 7.26±7.98 (m, 20H, 4Ph);
13C NMR (CDCl3) d 27.17 (2C) [CMe2], 71.58 (2C),
73.56 (2C), 76.75 (2C) [inositol ring carbons], 114.41
[CMe2], 128.70±133.68 [4Ph], 165.76(2C), 165.83 (2C)
[4COPh]; MS (FAB) m/z=637 (M++H).

2584
S.-K. Chung et al. / Bioorg. Med. Chem. 7 (1999) 2577±2589
DL-1,2,3,4-Tetra-O-benzoyl-scyllo-inositol (16a). A solu-
tion of 15 (790 mg) in 80% aq AcOH (50 ml) was
re¯uxed for 4 h, and evaporated to dryness to give 16a
quantitatively. Rf 0.15 (EtOAc:hexane=1:1); mp 257±
242ꢀC; 1H NMR (CDCl3) d 0.74±0.79 (m, 12H,
4CH2CH3), 3.47±3.72 (m, 8H, 4CH2CH3), 5.09 (app. q,
J=9.5 Hz, 2H, H-4 and H-6), 5.74±5.79 (m, 4H, H-1,
H-2, H-3 and H-5), 7.25±8.22 (m, 20H, 4Ph); 13C NMR
(CDCl3) d 15.68 (2C), 15.77 (2C) [4CH2CH3], 64.29
(2C), 64.35 (2C) [4CH2CH3], 70.56, 71.14 (2C), 71.78,
75.63 (2C) [inositol ring carbons], 128.65±133.82 (4Ph),
165.62, 165.72 (2C), 165.77 [4COPh]; 31P NMR
(CDCl3) d 1.08 (2P); MS (FAB) m/z=869 (M++H).
260ꢀC; H NMR (DMSO-d6) d 4.05±4.08 (m, 2H, H-5
1
and H-6), 5.67±5.74 (m, 2H, H-1 and H-4), 5.81 (d,
J=4.1 Hz, 2H, 2OH), 5.98 (dd, J=2.8, 7.1 Hz, 2H, H-2
and H-3), 7.44±7.98 (m, 20H, 4Ph); 13C NMR (DMSO-
d6) d 72.00 (2C), 72.52 (2C), 74.31 (2C) [inositol ring
carbons], 126.29±134.41 [4Ph], 165.84(2C), 166.06 (2C)
[4COPh]; MS (FAB) m/z=597 (M++H).
Preparation of sodium salts of scyllo-inositol bisphos-
phate (2a and b). To compound 17a (40 mg, 0.046 mmol)
in CH2Cl2 (2 mL) at rt was added TMS-Br (1 mL), and
the solution was stirred overnight. The solvent and
excess reagent were evaporated, and the residue was
dissolved in MeOH (5 mL), then treated with drops of
water at 0ꢀC. The reaction mixture was slowly warmed
up to rt, concentrated to dryness, and treated with 1 N
LiOH (5 mL) at 80ꢀC for 3 h. The basic solution was
cooled and loaded on Dowex 50WX8-100 (H+ form)
and eluted with water. The acidic e‚uent was collected,
washed with CH2Cl2 three times and lyophilized to
dryness. The residue was redissolved in a small amount
of water (1 mL) and pH was adjusted to 10 with NaOH
and lyophilized again to give the sodium salt of scyllo-
inositol 1,2-bisphosphate (2a, 17.7 mg, 90%) in quanti-
tative yield. Compound 2b (22.5 mg, 92%) was similarly
prepared from 17b (50 mg).
1,2,3,5-Tetra-O-benzoyl-scyllo-inositol (16b). Compound
16a (400 mg) in pyridine:water (6:4, 75 ml) was stirred at
100ꢀC for 1.5 h. The solution was cooled, and con-
centrated under reduced pressure. Addition of acetone
and evaporation of the solvents were repeated twice.
The crude mixture was chromatographed on silica gel.
The ®rst eluted compound was 1,2,3,5-tetra-O-benzoyl-
scyllo-inositol (16b) (100 mg), and the second eluted
material was 16a (240 mg). 16b: Rf 0.4 (EtOAc:hex-
ane=1:1); mp 246±248ꢀC; H NMR (DMSO-d6) d 4.18
1
(app. dt, J=5.9, 9.5 Hz, 2H, H-4 and H-6), 5.34 (t,
J=9.6 Hz, 1H, H-5), 5.59 (app. t, J=9.8 Hz, 2H, H-1
and H-3), 5.74 (d, J=5.7 Hz, 2H, 2OH), 5.77 (t,
J=9.9 Hz, 1H, H-2), 7.35±8.03 (m, 20H, 4Ph); 13C
NMR (DMSO-d6) d 69.94 (2C), 72.63, 74.34 (2C), 76.54
[inositol ring carbons], 129.47±134.38 [4Ph], 165.90
(2C), 165.94 (2C) [4COPh]; MS (FAB) m/z=597
(M++H).
Sodium salt of DL-scyllo-inositol 1,2-bisphosphate (2a).
1H NMR (D2O, pH 10) d 3.39 (dd, J=2.7, 6.7 Hz, 2H,
H-4 and H-5), 3.49±3.56 (m, 2H, H-3 and H-6), 3.82±
3.92 (m, 2H, H-1 and H-2); 13C NMR (D2O, pH 10) d
73.85 (2C), 74.43 (2C), 76.41 (2C) [inositol ring car-
bons]; 31P NMR (D2O, pH 10) d 7.30 (2P).
Phosphorylation of scyllo-IBz4 regioisomers (16a and b).
To a solution of compound 16a (60 mg, 0.1 mmol) in
DMF (5 mL) at 42ꢀC were added dropwise excess di-
isopropylethylamine (1.5 mL, 8.5 mmol) and then diethyl
chlorophosphite (0.25 mL, 1.7 mmol) with vigorous
stirring. After 30 min, the reaction mixture was allowed
to slowly warm up to rt and stirred for additional 8 h.
The mixture was cooled in an ice bath, and sodium
phosphate bu€er (1 N, pH 7, 5 mL) and excess 30%
H2O2 (5 mL) were added. After standing overnight at rt,
the mixture was diluted with water, and extracted
extensively with EtOAc. The organic layer was washed
with brine, dried over MgSO4, concentrated and chro-
matographed to give 17a (73 mg, 84%). Compound 16b
(60 mg, 0.1 mmol) was similarly phosphorylated to give
17b (76.5 mg, 88%).
1
Sodium salt of scyllo-inositol 1,3-bisphosphate (2b). H
NMR (D2O, pH 10) d 3.33±3.42 (m, 4H, H-2, H-4, H-5
and H-6), 3.73 (app. t, J=8.1 Hz, 2H, H-1 and H-3);
13C NMR (D2O, pH 10) d 73.15, 73.75, 73.88 (2C),
77.28 (2C) [inositol ring carbons]; 31P NMR (D2O, pH
10) d 7.13 (2P).
1-O-Benzoyl-scyllo-inositol (18). A mixture of com-
pound 11 (645 mg, 1 mmol) and 20% Pd(OH)2/C
(0.35 g) in a mixed solvent (CH2Cl2:EtOH=1:2, 21 mL)
was stirred under H2 (50 psi). After 1 day, the catalyst
was ®ltered o€ and the solvent was evaporated under
reduced pressure. A column chromatography gave
crystalline compound 18 (273 mg, 96%). Mp 244±
DL-1,2,3,4-Tetra-O-benzoyl-scyllo-inositol 5,6-bis(diethyl
phosphate) (17a). Rf 0.31 (EtOAc:hexane=2:1); mp 227±
228.5ꢀC; H NMR (CDCl3) d 0.84 (t, J=6.9 Hz, 6H,
246ꢀC; H NMR (CD3OD) d 3.29±3.39 (m, 3H), 3.52
1
1
2CH2CH3), 1.25 (t, J=7.1 Hz, 6H, 2CH2CH3), 3.58±
4.19 (m, 8H, 4CH2CH3), 4.98±5.05 (m, 2H, H-5 and H-
6), 5.83 (m, 4H, H-1, H-2, H-3 and H-4), 7.25±8.01 (m,
20H, 4Ph); 13C NMR (CDCl3) d 15.79 (2C), 16.23 (2C)
[4CH2CH3], 64.39 (2C), 64.92 (2C) [4CH2CH3], 70.63
(2C), 71.09 (2C), 76.50 (2C) [inositol ring carbons],
128.66±133.69 (4Ph), 165.67(4C) [4COPh]; 31P NMR
(CDCl3) d 0.70 (2P); HRMS (FAB): calcd for C42H47
O16P2 m/z 869.2339, found, 869.2355 (M++H).
(app. t, J=9.2 Hz, 2H), 5.06 (t, J=9.7 Hz, 1H, H-1),
7.45±8.09 (m, 5H, Ph); 13C NMR (CD3OD) d 72.86
(2C), 74.48, 74.67 (2C), 76.59 (inositol ring carbons),
128.41±133.11 (Ph), 166.96 (COPh); MS (EI) m/z=284
(M+).
DL-1-Mono-O-benzoyl-(2,3;5,6)-di-O-isopropylidene-scyllo-
inositol (19) and DL-1-mono-O-benzoyl-(2,3;4,5)-di-O-
isopropylidene-scyllo-inositol (20). To a solution of
compound 18 (285 mg, 1 mmol) and p-TSA (100 mg) in
DMF (5 mL) at rt was added 2-methoxypropene (1 mL,
10 mmol). After 1 day, the reaction mixture was poured
1,2,3,5-Tetra-O-benzoyl-scyllo-inositol 4,6-bis(diethyl phos-
phate) (17b). Rf 0.24 (EtOAc:hexane=2:1); mp 240±

S.-K. Chung et al. / Bioorg. Med. Chem. 7 (1999) 2577±2589
2585
into aq NaHCO3 with vigorous stirring, and extracted
with EtOAc. The organic layer was dried (MgSO4),
concentrated, and chromatographed on silica gel to give
19 (184 mg, 51%) and 20 (122 mg, 34%). 19: Rf 0.25
(EtOAc:hexane=1:2); mp 284±285ꢀC; 1H NMR
(CDCl3) d 1.44, 1.47 (each s, each 6H, 2CMe2), 2.46 (d,
J=2.7 Hz, 1H, OH), 3.76 (app. t, J=9.3 Hz, 2H, H-3
and H-5), 3.85 (app. t, J=9.3 Hz, 2H, H-2 and H-6),
4.13 (dt, J=2.7, 8.9 Hz, 1H, H-4), 5.60 (t, J=9.2 Hz,
1H, H-1), 7.26±8.10 (m, 5H, Ph); 13C NMR (CDCl3) d
27.06 (4C) [2CMe2], 69.37, 70.07, 78.70 (2C), 80.73 (2C)
[inositol ring carbons], 113.99 (2C) [2CMe2], 128.71
(2C), 130.02, 130.46 (2C), 133.65 [Ph], 165.72 [COPh];
MS (FAB) m/z=365 (M++H). 20: Rf 0.40 (EtOAc:
(CDCl3) d 0.28 (2P); HRMS (FAB): calcd for C20H39
O12P2 m/z 533.1917, found, 533.1907 (M++H).
Sodium salt of scyllo-inositol 1,4-bisphosphate (2c). To
compound 22 (25 mg, 0.047 mmol) in CH2Cl2 (2 mL) at
rt was added TMS-Br (1 mL), and the mixture was stir-
red overnight. The mixture was concentrated and redis-
solved in MeOH (3 mL), and then treated with drops of
water at 0ꢀC. After slowly being warmed up to rt and
standing for 1 day, the reaction mixture was con-
centrated and pH adjusted to 10 with NaOH and lyo-
1
philized to give the sodium salt of 2c (19 mg, 95%). H
NMR (D2O, pH 10) d 3.50 (dd, J=2.6, 6.4 Hz, 4H, H-2,
H-3, H-5 and H-6), 3.78±3.84 (m, 2H, H-1 and H-4);
13C NMR (D2O, pH 10) d 73.53 (4C), 77.38 (2C) [ino-
sitol ring carbons]; 31P NMR (D2O, pH 10) d 7.01 (2P).
hexane=1:2); mp 206±207ꢀC; H NMR (CDCl3) d 1.46
1
(s, 6H), 1.49 (s, 3H), 1.51 (s, 3H) [2CMe2], 2.87 (d,
J=4.1 Hz, 1H, OH), 3.67±3.95 (m, 4H, H-2, H-3, H-4
and H-5), 4.13 (ddd, J=4.1, 7.9, 10.2 Hz, 1H, H-6), 5.43
(dd, J=7.9, 10.4 Hz, 1H, H-1), 7.44±8.11 (m, 5H, Ph);
13C NMR (CDCl3) d 26.99, 27.02, 27.10 (2C) [2CMe2],
73.03, 75.62, 75.84, 76.30, 79.26, 81.75 [inositol ring
carbons], 114.36, 114.44 [2CMe2], 128.87 (2C), 129.66,
130.49 (2C), 133.99 [Ph], 167.11 [COPh]; MS (FAB) m/
z=365 (M++H).
1,2,3-Tri-O-benzoyl-scyllo-inositol (23a) and DL-1,2,4-
tri-O-benzoyl-scyllo-inositol (23b). To a solution of
compound 14a (389 mg, 1 mmol) in pyridine (6 mL) at
0ꢀC was added benzoyl chloride (0.24 mL, 2 mmol) with
vigorous stirring, and slowly warmed up to rt. After
14 h, the reaction mixture was stirred with water (1 mL)
for 30 min, diluted with EtOAc, and then successively
washed with aq NaHSO4, aq NaHCO3 and brine. The
organic layer was separated, dried (MgSO4), ®ltered and
concentrated. A column chromatography gave 1,2,3-tri-
O-benzoyl-scyllo-inositol (23a) (100 mg, 20%), dl-1,2,4-
tri-O-benzoyl-scyllo-inositol (23b) (110 mg, 22%), and
scyllo-IBz4 mixture (130 mg, 22%) together with the
starting material 7a (85 mg, 22%). 23a: Rf 0.35 (EtOAc);
(1,2;4,5)-Di-O-isopropylidene-scyllo-inositol (21). A solu-
tion of 19 (114 mg, 0.31 mmol) and NaOMe (cat.) in
MeOH (10 mL) was heated at re¯ux for 4 h. After cool-
ing, the solution was concentrated under reduced pres-
sure. After addition of CH2Cl2, the reaction mixture
was ®ltered through silica gel. The ®ltrate was evapo-
rated to give a solid product 21 in quantitative yield. Rf
0.15 (EtOAc:hexane=1:1); mp 261±263ꢀC; 1H NMR
(CDCl3, with a few drops of DMSO-d6) d 1.44 (s, 12H,
2CMe2), 3.56 (dd, J=2.6, 6.5 Hz, 4H, H-1, H-2, H-4
and H-5), 3.90±3.94 (m, 2H, H-3 and H-6), 5.43 (d,
J=4.7 Hz, 2H, 2OH); 13C NMR (CDCl3, with a few
drops of DMSO-d6) d 32.02 (4C) [2CMe2], 73.44 (2C),
85.82 (4C) [inositol ring carbons], 117.34 (2C) [2CMe2];
MS (FAB) m/z=261 (M++H).
mp 216±218ꢀC; H NMR (CDCl3, with a few drops of
1
CD3OD) d 3.67 (t, J=9.3 Hz, 1H, H-5), 3.78 (app. t,
J=9.3 Hz, 2H, H-4 and H-6), 5.52 (app. t, J=9.9 Hz,
2H, H-1 and H-3), 5.69 (t, J=10.0 Hz, 1H, H-2), 7.19±
7.90 (m, 15H, 3Ph); 13C NMR (CDCl3, with a few drops
of CD3OD) d 71.46, 72.72 (2C), 73.61 (2C), 74.64 [ino-
sitol ring carbons], 128.62±133.62 [3Ph], 166.29, 166.67
(2C) [3COPh]; MS (FAB) m/z=493 (M++H). 23b: Rf
0.4 (EtOAc:CH2Cl2=1:2); mp 169±171ꢀC; 1H NMR
(CDCl3, with a few drops of CD3OD) d 3.82 (app. t,
J=9.4 Hz, 1H), 3.91 (app. t, J=9.1 Hz, 1H,), 4.03 (app.
t, J=9.6 Hz, 1H), 5.38 (app. t, J=9.5 Hz, 1H), 5.50
(app. t, J=9.6 Hz, 1H), 5.59 (app. t, J=9.7 Hz, 1H),
7.31±8.12 (m, 15H, 3Ph); 13C NMR (CDCl3, with a few
drops of CD3OD) d 71.59, 72.84, 72.94, 73.37, 73.99,
76.02 [inositol ring carbons], 128.67±133.67 [3Ph],
166.79, 166.84, 167.39 [3COPh]; MS (FAB) m/z=493
(M++H).
(1,2;4,5)-Di-O-isopropylidene-scyllo-inositol 3,6-bis(di-
ethyl phosphate) (22). To a solution of compound 21
(26 mg, 0.1 mmol) in DMF (5 mL) at 42ꢀC were added
dropwise excess diisopropylethylamine (1.5 mL,
8.5 mmol) and then diethyl chlorophosphite (0.25 mL,
1.7 mmol) with vigorous stirring. After 30 min, the
reaction mixture was allowed to slowly warm up to rt,
and stirred for additional 8 h. The mixture was cooled in
an ice bath, and sodium phosphate bu€er (1 N, pH 7,
5 mL) and excess 30% H2O2 (5 mL) were added. After
standing overnight at rt, the mixture was diluted with
water, and extracted extensively with EtOAc. The
organic layer was washed with brine, dried over MgSO4,
concentrated and chromatographed to give 22 (38 mg,
71%). Rf 0.32 (MeOH:CH2Cl2=1:20); mp 185±186ꢀC;
1H NMR (CDCl3) d 1.32 (t, J=7.1 Hz, 12H, 4CH2
CH3), 1.41 (s, 12H, 2CMe2), 3.71 (dd, J=2.6, 6.6 Hz,
4H, H-1, H-2, H-4 and H-5), 4.15 (app. quin, J=7.1 Hz,
8H, 4CH2CH3), 4.63±4.70 (m, 2H, H-3 and H-6); 13C
NMR (CDCl3) d 16.37 (4C) [4CH2CH3], 27.05 (4C)
[2CMe2], 64.41 (4C) [4CH2CH3], 73.74 (2C), 78.99 (4C)
[inositol ring carbons], 113.81 (2C) [2CMe2]; 31P NMR
1,3,5-Tri-O-benzoyl-scyllo-inositol orthoformate (25). A
solution of compound 18 (250 mg, 0.88 mmol) and tri-
methyl orthoformate (2.5 mL, 22.6 mmol) in DMF
(5 mL) containing TSA (20 mg) was heated at 100ꢀC.
After 12 h, triethylamine (2.5 mL) was added, and the
solution was concentrated at 50ꢀC over 2 h. To the
reaction residue in pyridine (5 mL) at rt, was added
dropwise benzoyl chloride (2.3 mL, 19.6 mmol) with
vigorous stirring, and the solution was stirred at 100ꢀC
for 1 day. The reaction mixture was cooled and stirred
with water (10 mL) for 30 min, diluted with EtOAc, and
successively washed with aq NaHSO4, aq NaHCO3 and
brine. The organic layer was separated, dried (MgSO4),

2586
S.-K. Chung et al. / Bioorg. Med. Chem. 7 (1999) 2577±2589
®ltered, concentrated and chromatographed to give
compound 25 (186 mg, 42%). Rf 0.3 (EtOAc:hexane=
1:5); mp 248±250ꢀC; 1H NMR (CDCl3) d 4.97 (dd,
J=2.9, 4.6 Hz, 3H, H-2, H-4 and H-6), 5.76 (s, 1H,
HCO3), 5.78 (dd, J=2.9, 4.6 Hz, 3H, H-1, H-3 and H-
5), 6.91±7.72 (m, 15H, 3Ph); 13C NMR (CDCl3) d 67.45
(3C), 67.71 (3C) [inositol ring carbons], 103.67 [HCO3],
128.63±133.73 [3Ph], 166.03 (3C) [3COPh]; MS (FAB)
m/z=503 (M++H).
31P NMR (CDCl3) d 0.73, 0.77, 1.01; MS (FAB) m/z
=901 (M++H).
1,3,5-Tri-O-benzoyl-scyllo-inositol 2,4,6-tris(diethyl phos-
phate) (24c). Rf 0.37 (MeOH:CH2Cl2=1:10); mp 212±
213 C; 1H NMR (CDCl3) d 0.73 (t, J=7.1 Hz, 18H,
6CH2CH3), 3.42±3.67 (m, 12H, 6CH2CH3), 4.93 (app.
q, J=9.7 Hz, 3H, H-2, H-4 and H-6), 5.74 (t,
J=10.0 Hz, 3H, H-1, H-3 and H-5), 7.40±8.18 (m, 15H,
3Ph); 13C NMR (CDCl3) d 15.70 [6CH2CH3], 64.29
[6CH2CH3], 71.40 (3C), 75.31 (3C) [inositol ring car-
bons], 128.83±133.80 [3Ph], 165.75 (3C) [3COPh]; 31P
NMR (CDCl3) d 1.10 (3P); HRMS (FAB): calcd for
C39H52O18P3 m/z 901.2367, found, 901.2377 (M++H).
1,3,5-Tri-O-benzoyl-scyllo-inositol (23c). A solution of
compound 25 (152 mg, 0.3 mmol) and TSA (50 mg) in
MeOH (10 mL) was stirred at re¯ux overnight. After the
low boiling solvents were evaporated o€, the mixture
was diluted with EtOAc, and successively washed with
aq NaHCO3, aq NaHSO4 and brine. The organic layer
was separated, dried (MgSO4), ®ltered, concentrated
and chromatographed to give compound 23c (130 mg,
87%). Rf 0.55 (EtOAc:CH2Cl2=1:2); mp 226±228ꢀC 1H
NMR (CDCl3) d 2.84 (d, J=6.4 Hz, 3H, 3OH), 4.06 (dt,
J=6.1, 9.7 Hz, 3H, H-2, H-4 and H-6), 5.47 (t,
J=9.7 Hz, 3H, H-1, H-3 and H-5), 7.41±8.08 (m, 15H,
3Ph); 13C NMR (CDCl3) d 70.91 (3C), 75.91 (3C) [ino-
sitol ring carbons], 128.22±133.17 [3Ph], 166.84 (3C)
[3COPh]; HRMS (FAB): calcd for C27H25O9 m/z
493.1499, found, 493.1487 (M++H).
Preparation of sodium salts of scyllo-inositol trisphos-
phate (3a±c). To compound 24a (45 mg, 0.05 mmol) in
CH2Cl2 (2 mL) at rt was added TMS-Br (1 mL), and the
solution was stirred overnight. The solvent and excess
reagent were evaporated, and the residue was dissolved
in MeOH (5 mL), then treated with drops of water at
0ꢀC. The reaction mixture was slowly warmed up to rt,
evaporated to dryness, and treated with 1 N LiOH
(5 mL) at 80ꢀC for 3 h. The basic solution was cooled
and loaded on Dowex 50WX8-100 (H+ form) and
eluted with water. The acidic e‚uent was collected,
washed with CH2Cl2 three times and lyophilized to
dryness. The residue was redissolved in a small amount
of water (1 mL) and pH was adjusted to 10 with NaOH
and lyophilized to give the sodium salt of scyllo-inositol
1,2,3-trisphosphate (3a, 46 mg, 92%). Similarly, 3b and c
were prepared in 90 and 93% yields, respectively.
Phosphorylation of scyllo-IBz3 regioisomers (23a±c). To
a solution of compound 23a (50 mg, 0.1 mmol) in DMF
(5 mL) at 42ꢀC were added dropwise excess diisopro-
pylethylamine (1.5 mL, 8.5 mmol) and then diethyl
chlorophosphite (0.2 mL, 1.35 mmol) with vigorous
stirring. After 30 min, the reaction mixture was allowed
to slowly warm up to rt, and stirred for additional 8 h.
The mixture was cooled in an ice bath, and sodium
phosphate bu€er (1 N, pH 7, 5 mL) and excess 30%
H2O2 (5 mL) were added. After standing overnight at rt,
the mixture was diluted with water, and extracted
extensively with EtOAc. The organic layer was washed
with brine, dried over MgSO4, concentrated and chro-
matographed to give 24a (67.5 mg, 75%). Similarly, 24b
and c were prepared in 77 and 85% yields, respectively.
Sodium salt of scyllo-inositol 1,2,3-trisphosphate (3a).
1H NMR (D2O, pH 10) d 3.45±3.58 (m, 3H, H-4, H-5
and H-6), 3.87±4.04 (m, 3H, H-1, H-2 and H-3); 13C
NMR (D2O, pH 10) d 74.33, 74.61 (2C), 75.70, 77.25
(2C) [inositol ring carbons]; 31P NMR (D2O, pH 10) d
6.38, 7.30 (2P).
Sodium salt of DL-scyllo-inositol 1,2,4-trisphosphate (3b).
1H NMR (D2O, pH 10) d 3.54±3.60 (m, 3H, H-3, H-5
and H-6), 3.84±3.91 (m, 3H, H-1, H-2 and H-4); 13C
NMR (D2O, pH 10) d 73.81, 74.20, 74.35, 76.16, 76.28,
77.28 [inositol ring carbons]; 31P NMR (D2O, pH 10) d
7.00, 7.33 (2P).
1,2,3-Tri-O-benzoyl-scyllo-inositol 4,5,6-tris(diethyl phos-
phate) (24a). Rf 0.2 (EtOAc); mp 129±131ꢀC; H NMR
1
(CDCl3) d 0.87±1.40 (m, 18H, 6CH2CH3), 3.62±4.29 (m,
12H, 6CH2CH3), 4.76±4.95 (m, 3H, H-4, H-5 and H-6),
5.70±5.79 (m, 3H, H-1, H-2 and H-3), 7.23±8.00 (m,
15H, 3Ph); 13C NMR (CDCl3) d 15.81±16.54 [6CH2
CH3], 64.35±64.90 [6CH2CH3], 70.84, 71.13 (2C), 76.04
(2C), 76.63 [inositol ring carbons], 128.64±133.66 [3Ph],
165.61 (3C) [3COPh]; 31P NMR (CDCl3) d 0.61 (2P),
0.85; MS (FAB) m/z=901 (M++H).
Sodium salt of scyllo-inositol 1,3,5-trisphosphate (3c). 1H
NMR (D2O, pH 10) d 3.54 (t, J=9.2 Hz, 3H, H-2, H-4
and H-6), 3.89 (app. q, J=8.6 Hz, 3H, H-1, H-3 and H-5);
13C NMR (D2O, pH 10) d 73.49 (3C), 77.28 (3C) [ino-
sitol ring carbons]; 31P NMR (D2O, pH 10) d 7.07 (3P).
Preparation of 14b±c by acyl migration of 14a. Com-
pound 14a (250 mg) in the solvent mixture of pyridine:
water (6:4, 30 mL) was heated at 100ꢀC for 1.5 h. The
solution was cooled, and concentrated under reduced
pressure. Addition of acetone and evaporation of the sol-
vents were repeated twice. The crude mixture was chro-
matographed on silica gel to give 3 regioisomers. The ®rst
eluted was 1,4-di-O-benzoyl-scyllo-inositol (14c) (40 mg).
The second and third eluted were 1,3-di-O-benzoyl-scyllo-
inositol (14b) (70 mg) and 14a (120 mg), respectively.
DL-1,2,4-Tri-O-benzoyl-scyllo-inositol 3,5,6-tris(diethyl
phosphate) (24b). Rf 0.32 (EtOAc); mp 172±173ꢀC; H
1
NMR (CDCl3) d 0.72±1.26 (m, 18H, 6CH2CH3), 3.47±
4.16 (m, 12H, 6CH2CH3), 4.85±5.04 (m, 3H, H-3, H-5
and H-6), 5.66±5.77 (m, 3H, H-1, H-2 and H-4), 7.29±
8.23 (m, 15H, 3Ph); 13C NMR (CDCl3) d 15.88±16.58
[6CH2CH3], 64.52±65.16 [6CH2CH3], 70.94, 71.17,
71.54, 75.60, 76.32, 76.39 [inositol ring carbons],
128.91±133.96 [3Ph], 165.82, 165.89, 165.93 [3COPh];

S.-K. Chung et al. / Bioorg. Med. Chem. 7 (1999) 2577±2589
2587
1,3-Di-O-benzoyl-scyllo-inositol (14b). Rf 0.27 (EtOAc:
hexane=3:1); mp 242±243ꢀC; 1H NMR (CD3OD) d
3.47 (t, J=9.9 Hz, 1H, H-5), 3.62 (app. t, J=9.5 Hz,
2H, H-4 and H-6), 3.87 (t, J=9.8 Hz, 1H, H-2), 5.21
(app. t, J=9.6 Hz, 2H, H-1 and H-3), 7.44±8.10 (m,
10H, 2Ph); 13C NMR (CD3OD) d 71.02, 72.72 (2C),
74.62, 76.41 (2C) [inositol ring carbons], 128.40±133.11
[2Ph], 166.73 (2C) [2COPh]; HRMS (FAB): calcd for
C20H21O8 m/z 389.1236, found, 389.1234 (M++H).
12H, 4CH2CH3), 1.20 (t, J=7.1 Hz, 12H, 4CH2CH3),
3.47±4.15 (m, 16H, 8CH2CH3), 4.74±4.82 (m, 4H, H-2,
H-3, H-5 and H-6), 5.53±5.60 (m, 2H, H-1 and H-4),
7.43±8.21 (m, 10H, 2Ph); 13C NMR (CDCl3) d 16.02
(4C), 16.55 (4C) [8CH2CH3], 64.61 (4C), 65.15 (4C)
[8CH2CH3], 71.27 (2C), 76.19 (4C) [inositol ring car-
bons], 128.97±133.86 [2Ph], 165.93 (2C) [2COPh]; 31P
NMR (CDCl3) d 0.75 (4P); MS (FAB) m/z=933
(M++H).
1,4-Di-O-benzoyl-scyllo-inositol (14c). Rf 0.41 (EtOAc:
Preparation of sodium salts of scyllo-inositol tetrakisphos-
phate (4a±c). To compound 26a (47 mg, 0.05 mmol) in
CH2Cl2 (2 mL) at rt was added TMS-Br (1 mL), and the
solution was stirred overnight. The solvent and excess
reagent were evaporated, and the residue was dissolved
in MeOH (5 mL), then treated with drops of water at
0ꢀC. The reaction mixture was slowly warmed up to rt,
evaporated to dryness, and treated with 1 N LiOH
(5 mL) at 80ꢀC for 3 h. The basic solution was cooled
and loaded on Dowex 50WX8-100 (H+ form) and
eluted with water. The acidic e‚uent was collected,
washed with CH2Cl2 three times and lyophilized to
dryness. The residue was redissolved in a small amount
of water (1 mL) and pH was adjusted to 10 with NaOH
and lyophilized to give the sodium salt of scyllo-inositol
tetrakisphosphate (4a, 30 mg, 90%). Similarly, com-
pounds 26b and 26c were converted to 4b (29 mg, 87%)
and 4c (29.5 mg, 88%), respectively.
hexane=3:1); mp 253±254ꢀC; H NMR (DMSO-d6) d
1
3.47 (m, 4H, 4-OH), 4.93 (m, 2H, H-1 and H-4), 5.25
(m, 4H, H-2, H-3, H-5 and H-6), 7.49±8.00 (m, 10H,
2Ph); 13C NMR (DMSO-d6) d 72.74 (4C), 77.20 (2C)
[inositol ring carbons], 129.34±133.80 [2Ph], 166.16 (2C)
[2COPh]; MS (FAB) m/z=389 (M++H).
Phosphorylation of scyllo-IBz2 regioisomers (14a±c). To
a solution of compound 14a (39 mg, 0.1 mmol) in DMF
(5 mL) at 42ꢀC were added dropwise excess diisopro-
pylethylamine (1.5 mL, 8.5 mmol) and then diethyl
chlorophosphite (0.2 mL, 1.35 mmol) with vigorous
stirring. After 30 min, the reaction mixture was allowed
to slowly warm up to rt, and stirred for additional 8 h.
The mixture was cooled in an ice bath, and sodium
phosphate bu€er (1 N, pH 7, 5 mL) and excess 30%
H2O2 (5 mL) were added. After standing overnight at rt,
the mixture was diluted with water, and extracted
extensively with EtOAc. The organic layer was washed
with brine, dried with MgSO4, concentrated and chro-
matographed to give 26a (65 mg, 70%). Similarly, com-
pounds 14b and c were phosphorylated to give 26b
(69 mg, 74%) and 26c (70 mg, 75%), respectively.
Sodium salt of DL-scyllo-inositol 1,2,3,4-tetrakisphos-
1
phate (4a). H NMR (D2O, pH 10) d 3.94 (br. s, 2H,
H-5 and H-6), 4.17±4.24 (m, 4H, H-1, H-2, H-3 and H-
4); 13C NMR (D2O, pH 10) d 74.04 (2C), 76.09 (2C),
80.37 (2C) [inositol ring carbons]; 31P NMR (D2O, pH
10) d 5.98 (2P), 6.84 (2P).
DL-1,2-Di-O-benzoyl-scyllo-inositol 3,4,5,6-tetrakis(di-
ethyl phosphate) (26a). Rf 0.4 (MeOH:CH2Cl2=1:10);
Sodium salt of scyllo-inositol 1,2,3,5-tetrakisphosphate
1
mp 74±75.5ꢀC; H NMR (CDCl3) d 0.93±1.37 (m, 24H,
(4b). H NMR (D2O, pH 10) d 3.78±3.83 (m, 2H, H-4
1
8CH2CH3), 3.70±4.26 (m, 16H, 8CH2CH3), 4.77±4.84
(m, 2H), 4.88±4.95 (m, 2H), 5.68 (dd, J=2.4, 5. Hz, 2H,
H-1 and H-2), 7.33±7.98 (m, 10H, 2Ph); 13C NMR
and H-6), 4.05±4.13 (m, 4H, H-1, H-2, H-3 and H-5);
13C NMR (D2O, pH 10) d 73.49, 75.89 (2C), 76.96,
78.35 (2C) [inositol ring carbons]; 31P NMR (D2O, pH
10) d 6.12, 6.75 (2P), 7.08.
(CDCl3)
d
15.83±16.68 [8CH2CH3], 64.43±65.14
[8CH2CH3], 71.98 (2C), 76.37 (2C), 76.57 (2C) [inositol
ring carbons], 128.85±133.85 [2Ph], 165.75 (2C)
[2COPh]; 31P NMR (CDCl3) d 0.48 (4P); MS (FAB)
m/z=933 (M++H).
Sodium salt of scyllo-inositol 1,2,4,5-tetrakisphosphate
1
(4c). H NMR (D2O, pH 10) d 3.92 (br. s, 2H, H-3 and
H-6), 4.05-4.13 (m, 4H, H-1, H-2, H-4 and H-5); 13C
NMR (D2O, pH 10) d 75.95 (4C), 78.30 (2C) [inositol
ring carbons]; 31P NMR (D2O, pH 10) d 6.85 (4P).
1,3-Di-O-benzoyl-scyllo-inositol 2,4,5,6-tetrakis(diethyl
phosphate) (26b). Rf 0.45 (MeOH:CH2Cl2=1:10); mp
129±130ꢀC; 1H NMR (CDCl3) d 0.73±1.36 (m, 24H,
8CH2CH3), 3.41±4.27 (m, 16H, 8CH2CH3), 4.65±4.80
(m, 3H, H-4, H-5 and H-6), 4.92 (app. q, J=9.5 Hz, 1H,
H-2), 5.64 (app. t, J=9.1 Hz, 2H, H-1 and H-3), 7.43±
8.19 (m, 10H, 2Ph); 13C NMR (CDCl3) d 15.79±16.66
[8CH2CH3], 64.35±65.04 [8CH2CH3], 71.57 (2C), 75.57,
75.78 (2C), 76.04 [inositol ring carbons], 128.89-133.82
[2Ph], 165.82 (2C) [2COPh]; 31P NMR (CDCl3) d 0.70
(2P), 0.95, 0.98; HRMS (FAB): calcd for C36H57O20P4
m/z 933.2394, found, 933.2392 (M++H).
1-Mono-O-benzoyl-scyllo-inositol 2,3,4,5,6-pentakis(di-
ethyl phosphate) (27). To a solution of compound 18
(43 mg, 0.15 mmol) in DMF (5 mL) at 42ꢀC were
added dropwise excess diisopropylethylamine (2 mL,
11.4 mmol) and then diethyl chlorophosphite (0.6 mL,
4.1 mmol) with vigorous stirring. After 30 min, the
reaction mixture was allowed to slowly warm up to rt,
and stirred for additional 12 h. The mixture was cooled
in an ice bath, and sodium phosphate bu€er (1 N, pH 7,
5 mL) and excess 30% H2O2 (5 mL) were added. After
standing overnight at rt, the mixture was diluted with
water, and extracted extensively with EtOAc. The
organic layer was washed with brine, dried with MgSO4,
concentrated and chromatographed to give oily 27
1,4-Di-O-benzoyl-scyllo-inositol 2,3,5,6-tetrakis(diethyl
phosphate) (26c). Rf 0.5 (MeOH:CH2Cl2=1:10); mp
143±144ꢀC; 1H NMR (CDCl3) d 0.79 (t, J=7.1 Hz,

2588
S.-K. Chung et al. / Bioorg. Med. Chem. 7 (1999) 2577±2589
(51 mg, 35%). Rf 0.35 (MeOH:CH2Cl2=1:10); 1H
NMR (CDCl3) d 0.96±1.38 (m, 30H, 10CH2CH3), 3.71±
4.26 (m, 20H, 10CH2CH3), 4.83±4.93 (m, 5H, H-2, H-3,
H-4, H-5 and H-6), 5.67 (t, J=7.7 Hz, 1H, H-1),
7.34.8.14 (m, 5H, Ph); 13C NMR (CDCl3) d 15.91±16.49
[10CH2CH3], 64.50±65.17 [10CH2CH3], 72.71, 76.42,
77.14 (2C), 77.30 (2C) [inositol ring carbons], 128.74
(2C), 129.95, 130.52 (2C), 133.70 [Ph], 165.70 [COPh];
31P NMR (CDCl3) d 0.04, 0.29 (2P), 0.53 (2P); HRMS
(FAB): calcd for C33H62O22P5 m/z 965.2421, found,
965.2435 (M++H).
Pd/C (30 mg) and NaHCO3 (5 mg) in a mixed solvent
(H2O:MeOH=1:2, 9 mL) was stirred under H2 (50 psi).
After 1 day, the catalyst was ®ltered o€ and the solvent
was evaporated under reduced pressure. The reaction
mixture was redissolved in a small amount of water
(1 mL), pH adjusted to 10 with NaOH, and lyophilized
to give the sodium salt of scyllo-inositol hexakispho-
sphate (6, 15.5 mg, 94%). 1H NMR (D2O, pH 10) d 4.57
(d, J=10.3 Hz, 6H, H-1, H-2, H-3, H-4, H-5 and H-6);
13C NMR (D2O, pH 10) d 71.14 [inositol ring carbons];
31P NMR (D2O, pH 10) d 5.99 (6P).
Sodium salt of scyllo-inositol 1,2,3,4,5-pentakisphosphate
(5). To compound 27 (45 mg, 0.047 mmol) in CH2Cl2
(2 mL) at rt was added TMS-Br (1 mL), and the solution
was stirred for 1 day. The solvent and excess reagent
were evaporated, and the residue was dissolved in
MeOH (5 mL), then treated with drops of water at 0ꢀC.
The reaction mixture was slowly warmed up to rt, eva-
porated to dryness, and treated with 1 N LiOH (5 mL)
at 80ꢀC for 3 h. The basic solution was cooled and loaded
on Dowex 50WX8-100 (H+ form) and eluted with
water. The acidic e‚uent was collected, washed with
CH2Cl2 three times and lyophilized to dryness. The
residue was redissolved in a small amount of water
(1 mL) and pH was adjusted to 10 with NaOH and lyo-
philized to give the sodium salt of scyllo-inositol penta-
kisphosphate (5, 32 mg, 85%). 1H NMR (D2O, pH 10) d
4.25 (br. s, 1H, H-6), 4.47 (m, 5H, H-1, H-2, H-3, H-4
and H-5); 13C NMR (D2O, pH 10) d 71.03, 72.41±72.73
[inositol ring carbons]; 31P NMR (D2O, pH 10) d 5.79
(2P), 6.08, 6.55 (2P).
Acknowledgements
This work was supported by the Korea Science and
Engineering Foundation/Center for Biofunctional
Molecules and the Ministry of Education/Basic Science
Research Institute Fund (98-3437).
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