Divergent syntheses of all possible optically active regioisomers of myo-inositol tris- and tetrakisphosphates

Article abstract of DOI:10.1021/jo0257694

Since the discovery of D-myo-inositol 1,4,5-trisphosphate, which plays a pivotal role as a second messenger in transmembrane signaling, the scope of the phosphoinositide-based signaling processes has been continually expanding. However, the clear understanding of the molecular signal transduction mechanisms including the functions of newly found IP_n is still lacking. As a continuing effort to our previously reported syntheses of all possible 39 optically inactive regioisomers of myoinositol phosphates (IP_n; n = 1-6), we synthesized all possible optically active regioisomers of myo-IP₃ and myo-IP₄ using chiral IBz₃s and IBz₂s, respectively. A series of procedures involving CRL-catalyzed enzymatic resolution of racemic 1,2:5,6-di-O-isopropylidene-myo-inositol and base-catalyzed benzoyl migration in tri- and dibenzoyl-isopropylidene-myo-inositol afforded eight enantiomeric pairs of IBz₃ and six enantiomeric pairs of IBz₂, respectively. Phosphorylation of these intermediates by the phosphitylation and oxidation procedure gave the target products.

Full text of DOI:10.1021/jo0257694

Diver gen t Syn th eses of All P ossible Op tica lly Active Regioisom er s
of m yo-In ositol Tr is- a n d Tetr a k isp h osp h a tes
Sung-Kee Chung,* Yong-Uk Kwon, J ung-Han Shin, Young-Tae Chang, Changgook Lee,
Boo-Gyo Shin, Kyung-Cheol Kim, and Mahn-J oo Kim
Department of Chemistry, Division of Molecular and Life Sciences,
Pohang University of Science & Technology, Pohang 790-784, South Korea
skchung@postech.ac.kr
Received March 28, 2002
Since the discovery of D-myo-inositol 1,4,5-trisphosphate, which plays a pivotal role as a second
messenger in transmembrane signaling, the scope of the phosphoinositide-based signaling processes
has been continually expanding. However, the clear understanding of the molecular signal
transduction mechanisms including the functions of newly found IPn is still lacking. As a continuing
effort to our previously reported syntheses of all possible 39 optically inactive regioisomers of myo-
inositol phosphates (IPn; n ) 1-6), we synthesized all possible optically active regioisomers of myo-
IP3 and myo-IP4 using chiral IBz3s and IBz2s, respectively. A series of procedures involving CRL-
catalyzed enzymatic resolution of racemic 1,2:5,6-di-O-isopropylidene-myo-inositol and base-
catalyzed benzoyl migration in tri- and dibenzoyl-isopropylidene-myo-inositol afforded eight
enantiomeric pairs of IBz3 and six enantiomeric pairs of IBz2, respectively. Phosphorylation of these
intermediates by the phosphitylation and oxidation procedure gave the target products.
In tr od u ction
sibility of a novel I(1,3,4,5)P4 function to connect between
PLC-mediated signaling and the ras signaling pathway.5
The C5-dephosphorylated product I(1,3,4)P3 acts in vivo
as a specific regulator of cellular signaling by I(3,4,5,6)-
P4,6 which inhibits Ca2+-activated Cl- channels.7 I(1,3,4)-
P3 can be rephosphorylated by 6-kinase to I(1,3,4,6)P4,8
which has a weak, but distinct Ca2+ mobilizing activity.9
Both I(1,3,4,5)P4 and I(1,3,4,6)P4 can be phosphorylated
by 5/6-kinase in animal cells to I(1,3,4,5,6)P5, which is
metabolized to three compounds, IP6 (phytic acid) and
the normally inseparable enantiomeric pair I(3,4,5,6)P4
and I(1,4,5,6)P4.10 I(1,3,4,5,6)P5 can also be synthesized
by a 3-kinase from a different precursor, I(1,4,5,6)P4,
which was found in avian erythrocytes11 and Rat-1
fibroblasts.12 Recently, nuclear inositol phosphates were
shown to control mRNA export and transcription.13
Synthesis of I(1,4,5,6)P4 is also required for gene regula-
The phospholipase C catalyzed cleavage of membrane-
bound phosphatidylinositol bisphosphate (PIP2) into two
second messengers, D-myo-inositol 1,4,5-trisphosphate
[I(1,4,5)P3] and diacylglycerol, is a crucially important
means of cellular signaling processes. Since the discovery
that I(1,4,5)P3 mobilizes calcium ions from the intracel-
lular storage, thus activating many calcium-dependent
enzymes in the cell, its interactions with the I(1,4,5)P3
receptor and metabolic enzymes have been extensively
studied.1 One of the major metabolic pathways involves
a specific phosphorylation of I(1,4,5)P3 to I(1,3,4,5)P4, by
I(1,4,5)P3 3-kinase [IP3K].2 It has been suggested that
I(1,3,4,5)P4 also acts as a second messenger that mediates
the entry of extracellular Ca2+ through plasma mem-
brane ion channels3 and mobilizes Ca2+ even from the
intracellular calcium stores, although less potently than
I(1,4,5)P3.4 Putative I(1,3,4,5)P4 binding protein, purified
from pig platelet, was shown to have a GTPase-activating
protein (GAP) activity. This result suggested the pos-
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Shears, S. B. J . Biol. Chem. 1999, 274, 18973-18980.
* Corresponding author. Phone: +82-54-279-2103. Fax: +82-54-
279-3399.
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10.1021/jo0257694 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/29/2002
5626
J . Org. Chem. 2002, 67, 5626-5637

Syntheses of myo-Inositol Tris- and Tetrakisphosphates
tion. Thus, the phospholipase C pathway produces mul-
tiple IPn messengers that modulate distinct cellular and
nuclear processes. These observations suggest that ac-
tivation of IPn signaling may control gene expression.
Because of the biological importance as second mes-
sengers in the intracellular signal transduction, IP3, IP4,
and related molecules have been targets of many chemi-
cal syntheses.1 Studies to elucidate the functions of newly
found IPn, including binding affinity to specific proteins,
are also in progress in many laboratories. There are 20
(four meso and eight enantiomeric pairs) IP3 regioisomers
and 15 (three meso and six enantiomeric pairs) IP4
regioisomers. Some of the IP3s14and IP4s14k,m,w,15 have
been synthesized in the enantiomerically pure forms by
optical resolution of racemic myo-inositol derivatives with
chemical resolving agents and enzymes, or from chiral
starting materials.
proteins,19 and I(1,4,5)P3 3-kinase,20 and as an iron
binding motif.21 Although we could obtain much useful
information on the structure-activity relationships (SAR)
of these biomacromolecules using optically inactive IPn
isomers, the availability of optically active regioisomers
of IP3 and IP4 would facilitate obtaining more precise
pictures. We report herein the first complete syntheses
of all possible optically active regioisomers of IP3 and IP4
by employing the CRL-catalyzed enzymatic resolution
and the benzoyl migration strategy.
Resu lts a n d Discu ssion
Syn th esis of Eigh t En a n tiom er ic P a ir s of m yo-
In ositol Tr isp h osp h a tes. The key issues in the syn-
thesis of optically active regioisomers of IP3 and IP4 are
how (1) to obtain enantiomerically pure inositol deriva-
tives and (2) to efficiently prepare IBz3s and IBz2s, the
key intermediates. Our synthetic approaches to homo-
chiral regioisomers of IP3 and IP4 are based on the
enzyme-catalyzed asymmetric acetylation of (()-1,2:5,6-
di-O-isopropylidene-myo-inositol22 with acetic anhydride
in the presence of lipase from Candida rugosa (CRL,
Sigma), which we previously utilized in the synthesis of
two enantiomeric pairs of myo-IP5.23 The conversions of
the enantiomeric diols, 1D and 1L, to two enantiomeric
pairs of all possible IP3 and IP4 regioisomers involve the
identical series of reactions except that the corresponding
substrates and products along the synthetic route have
opposite configurations. Therefore, the procedure starting
from 1D only is described as the representative proce-
dure.
Chiral IBz3s, the key intermediates for the synthesis
of eight enantiomeric pairs of myo-IP3, were prepared as
follows. First, benzoylation of the chiral diol 1D23 under
the conventional conditions with BzCl in pyridine, fol-
lowed by acid-catalyzed partial solvolysis with a catalytic
amount of AcCl in MeOH-CH2Cl2 gave the diol 3Da
(59%) and the tetrol 4Da (32%) (Scheme 1). The tetrol
4Da was also prepared by direct hydrolysis of 2D in 80%
aq AcOH. To cause the limited benzoyl migration, a series
of IBz3s protected with the acetonide group was prepared.
The dibenzoate 3Da was further benzoylated with BzCl
We previously reported the systematic and divergent
syntheses of all possible 39 optically inactive regioisomers
of myo-inositol phosphates16 using the acyl migration as
the key strategy17 and utilized them to probe the binding
domains of I(1,4,5)P3 receptors,18 I(1,3,4,5)P4 binding
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J . Org. Chem, Vol. 67, No. 16, 2002 5627

Chung et al.
SCHEME 1a
SCHEME 2a
a
Reagents and conditions: (a) 80% aq AcOH, 100 °C, quant.;
(b) (i) (EtO)2PCl, N,N-diisopropylethylamine, (ii) H2O2, 65-77%;
(c) (i) TMSBr, (ii) 1 N LiOH, (iii) Dowex 50WX8-100 (H+), (iv) pH
10 (NaOH), ca. 90%.
TABLE 1. Op tica l Rota tion s of IBz3s
[R]2D5
IBz3
D-form
L-form
6a [I(1,2,6)Bz3] -151.9 (c 2.03, CHCl3) +154.8 (c 1.71, CHCl3)
6b [I(1,3,4)Bz3] +46.1 (c 1.00, MeOH) -46.2 (c 1.07, MeOH)
6c [I(1,4,6)Bz3] -46.7 (c 1.01, EtOAc) +46.3 (c 1.07, EtOAc)
6d [I(1,5,6)Bz3] +5.53 (c 1.11, EtOAc) -3.96 (c 1.21, EtOAc)
6e [I(1,4,5)Bz3] -49.8 (c 0.97, EtOAc) +50.0 (c 1.04, EtOAc)
6f [I(1,2,5)Bz3] -63.6 (c 2.75, CHCl3) +62.1 (c 1.75, CHCl3)
6g [I(2,4,5)Bz3] +9.40 (c 1.03, EtOAc) -9.74 (c 1.00, EtOAc)
6h [I(1,2,4)Bz3] -5.30 (c 0.8, THF)
+5.90 (c 1.06, THF)
respectively. Each of these regioisomers was readily
separated and purified by silica gel chromatography.
Reequilibration of any one isolated regioisomer under the
acyl migration conditions was found to provide the other
regioisomers found in the initial mixture. For example,
additional amounts of 5Da , 5Db, and 5Dc could be
obtained by the reequilibration of 5Dd .
Of the twelve monoacetonide IBz3s obtained, seven
regioisomers (5Da , 5Db/7Dc, 5Dc, 7Db, 7Dd , and 8Dc)
were individually hydrolyzed with 80% aqueous AcOH
under reflux to afford an additional six IBz3 regioisomers
6Dc-6Df and 6Lg-6Lh , respectively (Scheme 2). Thus,
the complete set of the necessary eight IBz3 regioisomers
(five D-IBz3 regioisomers and three L-IBz3 regioisomers)
was secured. Similarly, the other set of eight IBz3
regioisomers with the opposite stereochemistry (five
L-IBz3 regioisomers and three D-IBz3 regioisomers) was
obtained starting from 1L. All of these IBz3s were fully
characterized by 1H and 13C NMR spectroscopy and their
optical rotation values are listed in Table 1.
Next, all of the enantiomeric IBz3 regioisomers were
converted to the corresponding enantiomeric IP3 regio-
isomers (Scheme 2). Phosphorylation of the enantiomeric
IBz3 regioisomers with diethyl chlorophosphite in the
presence of N,N-diisopropylethylamine in DMF, followed
by oxidation with 30% hydrogen peroxide, afforded eight
enantiomeric pairs of IP′3Bz3 derivatives (9a -9h ). The
31P NMR chemical shifts and optical rotations of the eight
enantiomeric pairs of IP′3Bz3 are shown in Table 2.
In the final step of the synthesis, all protecting groups
of IP′3Bz3 derivatives (9a -9h ) were removed by succes-
sive treatment with TMSBr and then LiOH. The target
products (10a -10h ) were obtained after chromatography
on Dowex 50WX8-100 (H+), pH adjustment to 10 with
a
Reagents and conditions: (a) BzCl, pyridine, 96%; (b) AcCl,
MeOH-CH2Cl2, 0 °C; (c) BzCl (1.2 equiv), pyridine, 0 °C; (d) 60%
aq pyridine, 100 °C; (e) (i) (MeO)3CPh, TSA, DMF, rt, (ii) H2O; (f)
2,2-dimethoxypropane, TSA, DMF, rt. (Compounds in D-series only
are shown.)
(1.2 equiv) in pyridine to give a mixture of tribenzoylated
inositol monoacetonides 5Da and 5Db (ca. 1:2). Com-
pound 4Da was initially transformed to two isomers of
the necessary eight IBz3 regioisomers, 6Da (66%) and
6Lb (11%), by treatment with trimethyl orthobenzoate
and TSA in THF followed by hydrolysis. In this conver-
sion, no product that could potentially be generated via
the 4,5-trans-cyclic orthobenzoate was detected, suggest-
ing that the cis-cyclic orthobenzoate was preferentially
formed over the trans-cyclic orthobenzoate. The reaction
of tribenzoate 6Da with 2-dimethoxypropene in the
presence of a catalytic amount of TSA afforded additional
tribenzoylated inositol monoacetonides 7Da and 8Da ,
which were isolated in 58% and 30% yield, respectively.
When these three IBz3 monoacetonide derivatives were
subjected to the acyl migration conditions (60% aqueous
pyridine, 100 °C), mixtures of four regioisomers were
generated. First, the equilibration of 5Da or 5Db pro-
duced four regioisomers (5Da , 5Db, 5Dc, and 5Dd ).
Similar reactions of 7Da and 8Da afforded another set
of four regioisomers (7Da , 7Db, 7Dc, and 7Dd ) and the
third set of regioisomers (8Da , 8Db, 8Dc, and 8Dd ),
5628 J . Org. Chem., Vol. 67, No. 16, 2002

Syntheses of myo-Inositol Tris- and Tetrakisphosphates
TABLE 2. 31P NMR Ch em ica l Sh ifts a n d Op tica l
Rota tion s of IP ′3Bz3s
TABLE 4. Op tica l Rota tion s of Six En a n tiom er ic P a ir s
of IBz2
[R]2D5 (in CHCl3)
D-form L-form
[R]2D5 (in MeOH)
IP′3Bz3s
[P′ ) PO(OEt)2]
31P (δ, ppm)
IBz2
D-form
L-form
9a [I(1,5,6)P′3Bz3] 0.02, 0.07, 0.83 +75.8 (c 1.06) -71.1 (c 1.89)
9b [I(2,4,5)P′3Bz3] 0.51, 0.52, 1.16 -10.0 (c 0.98) +10.6 (c 1.92)
9c [I(1,2,5)P′3Bz3] 0.23, 0.99, 1.19 +11.9 (c 1.54) -12.7 (c 1.62)
9d [I(1,2,6)P′3Bz3] 0.21, 0.55, 1.26 -8.13 (c 2.48) +6.04 (c 0.86)
9e [I(1,2,4)P′3Bz3] 0.39, 1.07, 1.21 +19.2 (c 1.64) -19.1 (c 1.40)
9f [I(1,4,6)P′3Bz3] 0.22, 0.86, 1.03 +38.0 (c 1.12) -42.3 (c 1.77)
9g [I(1,3,4)P′3Bz3] 0.44, 0.93, 0.97 -2.53 (c 0.75) +2.59 (c 1.02)
9h [I(1,4,5)P′3Bz3] 0.29, 0.72, 0.90 +15.3 (c 0.60) -14.7 (c 1.61)
4a [I(1,6)Bz2]
4b [I(4,5)Bz2]
4c [I(1,4)Bz2]
4d [I(1,5)Bz2]
4e [I(1,2)Bz2]
4f [I(2,4)Bz2]
-74.7 (c 0.87)
-55.3 (c 1.19)
-16.7 (c 0.54)
-18.1 (c 0.50)
-96.9 (c 0.53)
+84.2 (c 0.56)
+73.3 (c 1.00)
+55.7 (c 0.93)
+16.6 (c 0.41)
+19.1 (c 0.50)
+97.2 (c 0.48)
-82.1 (c 0.48)
SCHEME 4a
TABLE 3. 31P NMR Ch em ica l Sh ifts a n d Op tica l
Rota tion s of IP 3s
[R]2D5 (in H2O, pH 10)
IP3s
[P ) PO(ONa)2]
31P (δ, ppm)
D-form
L-form
10a [I(1,5,6)P3] 6.30, 6.74, 7.24 -2.57 (c 1.01) +4.56 (c 0.95)
10b [I(2,4,5)P3] 7.28, 7.46, 7.60 -9.59 (c 1.45) +12.0 (c 0.96)
10c [I(1,2,5)P3] 7.02, 7.28, 7.48 +5.94 (c 1.62) -6.41 (c 1.58)
10d [I(1,2,6)P3] 7.04, 7.16, 7.80 -16.5 (c 1.47) +15.9 (c 0.99)
10e [I(1,2,4)P3] 7.31, 7.34, 7.59 +11.5 (c 1.51) -13.7 (c 0.75)
10f [I(1,4,6)P3] 6.05, 7.15, 7.66 -10.1 (c 0.78) +11.2 (c 1.14)
10g [I(1,3,4)P3] 6.11, 6.91, 7.61 +10.4 (c 0.59) -9.20 (c 0.74)
10h [I(1,4,5)P3] 5.67, 7.30, 7.40 -24.1 (c 0.28) +20.1 (c 0.74)
a
Reagents and conditions: (a) 80% aq AcOH, 100 °C, quant.;
(b) (i) dibenzyl diisopropylphosphoamidite, 1H-tetrazole, CH2Cl2,
(ii) mCPBA, 82-99%; (c) (i) H2 (50 psi), Pd/C, (ii) 1 N LiOH, (iii)
Dowex 50WX8-100 (H+), (iv) pH 10 (NaOH), ca. 90%.
SCHEME 3a
at 100 °C to afford the six possible isomers of chiral I(3,4)-
AceBz2 (11Da -11Df). In each case, the individual regio-
isomers were separated with flash column chromatogra-
phy in the forms of IAceBz2 with the intact acetonide
group or the IBz2 after the acid-catalyzed hydrolysis. The
acid-catalyzed hydrolysis of IAceBz2s (3D/3L and 11D/
11L) gave six enantiomeric pairs of IBz2 (4D/4L) as the
key intermediates. Thus, all possible optically active 12
regioisomers of IBz2 were successfully prepared and fully
characterized by 1H and 13C NMR spectroscopy and mass
spectrometry. Table 4 summarizes the optical rotations
of each enantiomeric pairs.
Phosphitylation of the 12 IBz2 regioisomers with
dibenzyl diisopropylphosphoamidite and 1H-tetrazole in
CH2Cl2 at room temperature and subsequent oxidation
with mCPBA afforded the six enantiomeric pairs of
inositol tetrakisphosphate (12L and 12D) in the protected
forms in 82-99% yields (Scheme 4). The 31P NMR
chemical shifts and optical rotations of the six enantio-
meric pairs of IP4Bz2 are shown in Table 5.
a
Reagents and conditions: (a) AcCl, MeOH-CH2Cl2, 0 °C; (b)
60% aq pyridine, 100 °C; (c) 2-methoxypropene, TSA, 0 °C, 73.8%.
(Compounds in D-series only are shown.)
In the final steps, all protecting groups were removed
by hydrogenolysis and treatment with LiOH to give the
desired 12 optically active regioisomers of IP4 (13L and
13D) in good yields (Scheme 4). The 31P NMR data
showed reproducible chemical shifts at ca. pH 10 and all
the signals were well-resolved. Each enantiomeric pair
of the fully deprotected IP4s showed similar optical
rotations with opposite signs. The 31P NMR data and
optical rotations of six enantiomeric pairs of IP4 are listed
in Table 6.
NaOH, and then lyophilization. All products were fully
characterized with NMR spectroscopy, and their 31P NMR
data and optical rotations are given in Table 3.
Syn th esis of Six En a n tiom er ic P a ir s of m yo-
In ositol Tetr a k isp h osp h a tes. For the conversions of
the enantiomeric starting materials 1D and 1L to the
six enantiomeric pairs of myo-IP4, two monoacetonide
IBz2s (3Da and 11Da ) were prepared in the usual
fashion. When 3Da was subjected to 60% aq pyridine at
100 °C, six possible isomers of chiral I(2,3)AceBz2 (3Da -
3Df) were obtained in substantial amounts (Scheme 3).
The kinetically controlled acetonation of chiral tetrol
4Da with 2-methoxypropene and TSA at 0 °C gave mono-
acetonated diol 11Da in 73.8% yields, which was then
subjected to the benzoyl migration in 60% aq pyridine
Con clu sion
We have successfully carried out the first total syn-
theses of the complete sets of all enantiomeric pairs of
myo-IP3 and myo-IP4 regioisomers from homochiral in-
J . Org. Chem, Vol. 67, No. 16, 2002 5629

Chung et al.
TABLE 5. 31P NMR Ch em ica l Sh ifts a n d Op tica l Rota tion s of IP ′4Bz2s
IP′4Bz2
[R]2D5 (in CHCl3)
[P′ ) PO(OBn)2]
31P (δ, ppm)
D-form
L-form
12a [I(1,2,5,6)P′4Bz2]
12b [I(1,2,3,4)P′4Bz2]
12c [I(1,2,4,5)P′4Bz2]
12d [I(1,2,4,6)P′4Bz2]
12e [I(1,4,5,6)P′4Bz2]
12f [I(1,3,4,5)P′4Bz2]
0.37, 0.91, 1.04, 1.53
0.13, 1.13, 1.18, 1.61
0.34, 0.99, 1.06, 1.35
0.39, 1.17, 1.42, 1.53
0.59, 0.72, 1.26, 1.59
0.65, 1.03, 1.19, 1.22
+21.3 (c 1.50)
-2.98 (c 1.14)
-6.06 (c 1.40)
+2.59 (c 1.75)
+6.93 (c 1.49)
-20.6 (c 1.45)
-20.8 (c 1.53)
+3.30 (c 1.76)
+6.33 (c 1.24)
-2.67 (c 1.40)
-6.38 (c 1.40)
+22.0 (c 1.35)
TABLE 6. 31P NMR Ch em ica l Sh ifts a n d Op tica l Rota tion s of IP 4s
[R]2D5 (in H2O, pH 10)
IP4
[P ) PO(ONa)2]
31P (δ, ppm)
D-form
L-form
13a [I(1,2,5,6)P4]
13b [I(1,2,3,4)P4]
13c [I(1,2,4,5)P4]
13d [I(1,2,4,6)P4]
13e [I(1,4,5,6)P4]
13f [I(1,3,4,5)P4]
4.93, 6.47, 6.97, 7.28
5.84, 7.38, 7.95, 8.12
3.98, 4.69, 5.59, 5.69
6.87, 6.96, 7.19, 7.82
5.03, 5.50, 6.25, 6.99
5.80, 6.42, 6.92, 7.38
-4.98 (c 1.93)
+19.0 (c 2.27)
-13.2 (c 1.65)
-15.2 (c 2.10)
-8.99 (c 1.85)
-4.08 (c 2.02)
+4.19 (c 2.35)
-19.9 (c 2.59)
+14.9 (c 2.08)
+14.7 (c 1.77)
+10.1 (c 2.23)
+4.68 (c 2.11)
5.61-5.66 (m, 2H, H-1 & H-6), 7.39-8.08 (m, 10H, 2Ph); 13C
NMR (CDCl3) δ 25.6, 27.1, 27.4, 27.5 (2CMe2), 73.1, 74.1, 74.5,
76.8, 76.9, 78.1 (inositol ring carbons), 111.8, 113.6 (2CMe2),
128.8-133.8 (2Ph), 165.3, 165.5 (2COPh). 2L: mp 170-172
termediates 1D and 1L, which were obtained by the CRL-
catalyzed enzymatic resolution. The chiral regioisomers
of myo-IP3 and myo-IP4, together with the available meso
compounds,16c,d are currently being utilized as molecular
probes in the studies of IP3 receptors and metabolic
enzymes. These studies are expected to provide more
detailed pictures on the structure-activity relationships
in the areas of intracellular signal transduction, eventu-
ally providing grounds for the rational design of com-
pounds with useful pharmacological activities.
°C; [R]2D5 +61.2 (c 1.00, CHCl3); identical Rf, H NMR, and 13C
1
NMR data to those of 2D.
D- a n d L-1,6-Di-O-ben zoyl-2,3-O-isop r op ylid en e-m yo-
in ositol (3Da a n d 3La ) a n d D- a n d L-1,6-Di-O-ben zoyl-
m yo-in ositol (4Da a n d 4La ). To a solution of compound 2D
(5 g, 10.5 mmol) in MeOH (15 mL) and CH2Cl2 (45 mL) at 0
°C was added acetyl chloride (4 drops). After 5 h, the reaction
mixture was quenched with TEA (1 mL), evaporated, and
chromatographed on silica gel to give oily compound 3Da (2.65
g, 59%) and crystalline compound 4Da (1.30 g, 32%). A similar
reaction with compound 2L was carried out to give compounds
Exp er im en ta l Section
Gen er a l Meth od s. All nonhydrolytic reactions were carried
out in oven-dried glassware under dry argon or nitrogen
atmosphere. All commercial reagents were used as obtained
without further purification. Solvents were purified and dried
by standard methods prior to use. Melting points were
determined on a Thomas-Hoover apparatus and were uncor-
rected. NMR spectra were recorded on a Bruker AM 300, DPX
300, or DRX 500 spectrometer. Tetramethylsilane and phos-
phoric acid (85%) were used as internal and external standards
for 1H NMR and 31P NMR, respectively. When necessary,
definitive assignments of each proton for new synthetic
3La and 4La . 3Da : Rf 0.3 (EtOAc:Hex ) 1:1); [R]25 -79.8 (c
D
1.02, CHCl3); 1H NMR (CDCl3) δ 1.35, 1.51 (2s, 6H, CMe2),
2.99 (d, J ) 2.6 Hz, 1H, OH-4), 3.25 (d, J ) 3.8 Hz, 1H, OH-
5), 3.72 (ddd, J ) 3.8, 7.6, 9.6 Hz, 1H, H-5), 4.09 (ddd, J ) 2.6,
7.2, 9.6 Hz, 1H, H-4), 4.24 (dd, J ) 5.9, 7.2 Hz, 1H, H-3), 4.66
(dd, J ) 3.7, 5.9 Hz, 1H, H-2), 5.54 (dd, J ) 7.6, 7.9 Hz, 1H,
H-6), 5.60 (dd, J ) 3.7, 7.9 Hz, 1H, H-1), 7.35-8.02 (m, 10H,
2Ph); 13C NMR (CDCl3) δ 25.9, 28.0 (CMe2), 70.5, 73.7, 73.8,
74.8, 74.9, 78.6 (inositol ring carbons), 111.2 (CMe2), 126.3-
134.0 (2Ph), 166.1, 167.2 (2COPh); MS (FAB) m/z 429 (M+
+
1
compounds were based on H-1H homonuclear COSY spectra.
H). Anal. Calcd for C23H24O8: C, 64.48; H, 5.65. Found: C,
64.59; H, 5.99. 3La : [R]D25 +78.9 (c 1.70, CHCl3); identical Rf,
1H NMR, and 13C NMR data to those of 3Da . 4Da : Rf 0.2
(EtOAc); mp 108-111 °C; [R]2D5 -74.7 (c 0.87, MeOH); 1H
NMR (CD3OD) δ 3.62 (dd, J ) 2.8, 9.6 Hz, 1H, H-3), 3.67 (app.
t, J ) 9.5 Hz, 1H, H-5), 3.87 (app. t, J ) 9.5 Hz, 1H, H-4),
4.30 (app. t, J ) 2.6 Hz, 1H, H-2), 5.20 (dd, J ) 2.6, 10.4 Hz,
1H, H-1), 5.83 (app. t, J ) 10.0 Hz, 1H, H-6), 7.36-7.96 (m,
10H, 2Ph); 13C NMR (CD3OD) δ 71.8, 73.0, 74.4, 74.4, 74.9,
74.8 (inositol ring carbons), 129.5-134.5 (2Ph), 167.5, 167.9
(2COPh); MS (FAB) m/z 411 (M+ + Na), 389 (M+ + H). Anal.
Calcd for C20H20O8: C, 61.85; H, 5.19. Found: C, 61.61; H,
5.54. 4La : mp 107-110 °C; [R]2D5 +73.3 (c 1.00, MeOH);
Mass spectra (EI or FAB) were determined on a micromass
PLATFORM II, and were performed by Korea Basic Science
Center, Taejeon and Inter-University Center for Natural
Science Research Facilities, Seoul National University, Seoul,
Korea. Elemental analyses were performed with an Elementar
Vario-EL system. Optical rotations were measured with a
J ASCO DIP-360 digital polarimeter.
D- a n d L-1,6-Di-O-ben zoyl-2,3:4,5-Di-O-isop r op ylid en e-
m yo-in ositol (2D a n d 2L). Benzoylation of compound 1D23
(4.0 g, 15.4 mmol) was carried out with BzCl (8 mL, 65 mmol)
in pyridine (50 mL). After being stirred for 6 h at room
temperature, the reaction mixture was treated with water (10
mL) for 20 min, diluted with EtOAc, and washed with aq
NaHSO4, aq NaHCO3, and brine. The organic layer was
separated, dried (MgSO4), and concentrated to give a solid
product that was recrystallized from MeOH-CH2Cl2 to give
compound 2D (6.93 g, 96%). Similarly, compound 2L was
prepared from compound 1L. 2D: Rf 0.27 (EtOAc:Hex ) 1:4);
mp 169-171 °C (lit. racemate: mp 197-200 °C,22a mp 187-
189 °C22b); [R]D25 -60.6 (c 0.96, CHCl3); 1H NMR (CDCl3) δ
1.33, 1.34, 1.48, 1.51 (4s, 12H, CMe2), 3.90 (dd, J ) 8.5, 10.5
Hz, 1H, H-5), 4.32 (dd, J ) 7.8, 10.5 Hz, 1H, H-4), 4.54 (app.
t, J ) 7.3 Hz, 1H, H-3), 4.73 (dd, J ) 3.7, 6.7 Hz, 1H, H-2),
1
identical Rf, H NMR, and 13C NMR data to those of 4Da .
D- a n d L-1,4,6-Tr i-O-ben zoyl-2,3-O-isop r op ylid en e-m yo-
in ositol (5Da a n d 5La ) a n d D- a n d L-1,5,6-Tr i-O-ben zoyl-
2,3-O-isop r op ylid en e-m yo-in ositol (5Db a n d 5Lb). Mono-
benzoylation of 3Da (2 g, 2. 4 mmol) in pyridine (25 mL) was
carried out by dropwise addition of BzCl (0.66 mL, 5.8 mmol).
After being stirred for 3 h at room temperature, the reaction
mixture was treated with water (5 mL) for 5 min, diluted with
EtOAc, and washed with aq NaHSO4, aq NaHCO3, and brine.
The organic layer was separated, dried (MgSO4), concentrated,
5630 J . Org. Chem., Vol. 67, No. 16, 2002

Syntheses of myo-Inositol Tris- and Tetrakisphosphates
and chromatographed to give 5Da (640 mg, 25%) and 5Db
(1.18 g, 46%). Similarly, compounds 5La and 5Lb were
prepared from 3La . 5Da : Rf 0.5 (EtOAc:CH2Cl2:Hex ) 1:10:
5); mp 220-221 °C; [R]2D5 -54.3 (c 0.99, CH2Cl2); 1H NMR
(CDCl3) δ 1.37, 1.65 (2s, 6H, CMe2), 2.92 (d, J ) 6.3 Hz, 1H,
OH-5), 4.01 (app. q, J ) 7.2 Hz, 1H, H-5), 4.55 (app. t, 6.1 Hz,
1H, H-3), 4.79 (dd, J ) 3.7, 5.8 Hz, 1H, H-2), 5.63 (dd, J ) 6.4
8.1 Hz, 1H, H-4), 5.71 (dd, J ) 3.7, 9.7 Hz, 1H, H-1), 5.80 (dd,
J ) 7.5, 9.7 Hz, 1H, H-6), 7.26-8.12 (m, 15H, 3Ph); 13C NMR
(CDCl3) δ 25.7, 27.6 (CMe2), 70.0, 73.5, 73.9, 74.4, 75.6, 76.4
(inositol ring carbons), 111.5 (CMe2), 128.8-133.9 (3Ph), 166.7,
166.8, 167.3 (3COPh); MS (FAB) m/z 555 (M+ + Na), 533 (M+
+ H). Anal. Calcd for C30H28O9: C, 67.66; H, 5.30. Found: C,
67.44; H, 5.30. 5La : mp 221-222 °C; [R]2D5 +52.8 (c 1.10, CH2-
Cl2); identical 1H NMR and 13C NMR data to those of 5Da .
5Db: Rf 0.2 (EtOAc:CH2Cl2:Hex ) 1:10:5); mp 106-107 °C;
[R]2D5 +0.78 (c 0.5, CH2Cl2); 1H NMR (CD3OD) δ 1.39, 1.64 (2s,
6H, CMe2), 4.13 (dd, J ) 6.5, 8.3 Hz, 1H, H-4), 4.39 (app. t, J
) 6.0 Hz, 1H, H-3), 4.61 (s, 1H, OH-4), 4.81 (dd, J ) 4.0, 5.5
Hz, 1H, H-2), 5.49 (app. t, J ) 8.6 Hz, 1H, H-5), 5.82 (dd, J )
3.9, 10.2 Hz, 1H, H-1), 5.97 (dd, J ) 8.8, 10.1 Hz, 1H, H-6),
7.30-7.95 (m, 15H, 3Ph); 13C NMR (CD3OD) δ 24.7, 27.0
(CMe2), 70.3, 71.0, 72.6, 74.1, 74.6, 79.1 (inositol ring carbons),
110.7 (CMe2), 126.3-133.6 (3Ph), 165.9, 166.2, 166.3 (3COPh);
MS (FAB) m/z 533 (M+ + H). Anal. Calcd for C30H28O9: C,
67.66; H, 5.30. Found: C, 67.36; H, 5.34. 5Lb: mp 109-110
°C; [R]2D5 -0.91 (c 1.00, CH2Cl2); identical 1H NMR and 13C
NMR data to those of 5Db.
carbons), 128.4-133.4 (3Ph), 166.3, 166.6, 166.9 (3COPh); MS
(FAB) m/z 515 (M+ + Na), 493 (M+ + H). Anal. Calcd for
C
27H24O9: C, 65.85; H, 4.91. Found: C, 65.56; H, 5.06. 6Lc:
mp 112-113 °C; [R]2D5 +46.3 (c 1.07, EtOAc); identical Rf, H
1
NMR, and 13C NMR data to those of 6Dc.
D- a n d L-1,5,6-Tr i-O-b en zoyl-m yo-in osit ol (6Dd a n d
6Ld ). 6Dd : Rf 0.39 (EtOAc:Hex ) 2:1, 2 times); mp 197-198
°C; [R]2D5 +5.53 (c 1.11, EtOAc); H NMR (CD3OD) δ 3.79 (dd,
1
J ) 2.7, 9.7 Hz, 1H, H-3), 4.15 (app. t, J ) 9.7 Hz, 1H, H-4),
4.38 (app. t, J ) 2.6 Hz, 1H, H-2), 5.38 (dd, J ) 2.6, 10.5 Hz,
1H, H-1), 5.52 (app. t, J ) 9.8 Hz, 1H, H-5), 6.09 (app. t, J )
10.2 Hz, 1H, H-6), 7.24-7.96 (m, 15H, 3Ph); 13C NMR (CD3-
OD) δ 68.9, 69.7 (2C), 70.3, 71.7, 73.0 (inositol ring carbons),
126.8-131.9 (3Ph), 164.6, 164.7, 164.9 (3COPh); MS (FAB) m/z
515 (M+ + Na), 493 (M+ + H). Anal. Calcd for C27H24O9: C,
65.85; H, 4.91. Found: C, 65.47; H, 4.97. 6Ld : mp 201-202
°C; [R]2D5 -3.96 (c 1.21, EtOAc) [lit.24 [R]D +10.2 (c 2.8,
1
CHCl3)]; identical Rf, H NMR, and 13C NMR data to those of
6Dd .
D- a n d L-1,4,5-Tr i-O-b en zoyl-m yo-in osit ol (6De a n d
6Le). 6De: Rf 0.6 (EtOAc:Hex ) 2:1); mp 118-119 °C; [R]25
D
1
-49.8 (c 0.97, EtOAc); H NMR (CD3OD) δ 4.06 (dd, J ) 2.5,
10.0 Hz, 1H, H-3), 4.35 (app. t, J ) 2.5 Hz, 1H, H-2), 4.45 (app.
t, J ) 9.9 Hz, 1H, H-6), 5.16 (dd, J ) 2.4, 10.2 Hz, 1H, H-1),
5.50 (app. t, J ) 9.7 Hz, 1H, H-5), 5.80 (app. t, J ) 9.9 Hz,
1H, H-4), 7.34-8.17 (m, 15H, 3Ph); 13C NMR (CD3OD) δ 67.6,
68.5, 69.2, 72.1, 73.2, 73.5 (inositol ring carbons), 126.8-131.8
(3Ph), 164.9, 165.0, 165.1 (3COPh); MS (FAB) m/z 515 (M+
+
Na), 493 (M+ + H). Anal. Calcd for C27H24O9: C, 65.85; H, 4.91.
Found: C, 65.52; H, 5.06. 6Le: mp 117-119 °C; [R]2D5 +50.0
Gen er a tion a n d Sep a r a tion of IBz3 Regioisom er s fr om
5Da /5Db or 5La /5Lb. Compound 5Da or 5Db (1.40 g) in the
solvent mixture of pyridine-water (6:4, 60 mL) was heated
at 100 °C for 3 h. The solution was cooled and concentrated
under reduced pressure. Addition of acetone to the reaction
mixture followed by evaporation of the solvents was repeated
twice. The crude mixture, which contained almost equal
amounts of 5Da , 5Db, 5Dc, and 5Dd , was chromatographed
on silica gel (EtOAc:CH2Cl2:Hex ) 1:10:10 f 1:10:0 gradient).
The eluting sequence of the isomers was 5Da , 5Dc, 5Dd , and
5Db with the Rf value of 0.5, 0.4, 0.3, and 0.2 (EtOAc:CH2-
Cl2:Hex ) 1:10:5), respectively. Compounds 5Dd and 5Db
could not be cleanly separated, thus the mixture of 5Dd and
5Db was hydrolyzed in 80% aq AcOH (100 °C, 3h) and
chromatographed (MeOH:CH2Cl2 ) 1:20) on silica gel to give
meso compound 4,5,6-tri-O-benzoyl-myo-inositol16c and com-
pound 6Dd , respectively. Compound 6Dd could also be ob-
tained by direct hydrolysis of compound 5Db . Each isomer
(5Da and 5Dc) was hydrolyzed in 80% aq AcOH (100 °C, 1 h)
and concentrated to give the corresponding IBz3 products 6Dc
and 6De in quantitative yield. Compounds 6Lc, 6Ld , and 6Le
were similarly prepared from a mixture of 5La /5Lb.
1
(c 1.04, EtOAc); identical Rf, H NMR, and 13C NMR data to
those of 6De.
D- a n d L-1,2,6-Tr i-O-ben zoyl-m yo-in ositol (6Da a n d
6La ) a n d D- a n d L-1,3,4-Tr i-O-ben zoyl-m yo-in ositol (6Db
a n d 6Lb). To a solution of compound 4Da (2.50 g, 6.44 mmol)
and TSA (300 mg) in dry DMF (25 mL) at room temperature
was added trimethyl orthobenzoate (16 mL, 94 mmol). After
being stirred for 18 h, the reaction mixture was treated with
80% aq AcOH (10 mL) for 2 h at room temperature, diluted
with EtOAc, and then washed with aq NaHCO3 and water.
The organic layer was dried (MgSO4), evaporated, and chro-
matographed to provide 6Da (2.09 g, 66%) and 6Lb (349 mg,
11%). A similar reaction with 4La provided 6La and 6Db.
6Da : oil; Rf 0.17 (MeOH:CH2Cl2 ) 1:20); [R]25 -151.9 (c 2.03,
CHCl3); 1H NMR (CD3OD) δ 3.81 (app. t, J )D9.0 Hz, 1H, H-5),
3.92-4.03 (m, 2H, H-3 & H-4), 5.48 (dd, J ) 2.7, 10.5 Hz, 1H,
H-1), 5.87 (app. t, J ) 10.0 Hz, 1H, H-6), 5.96 (app. t, J ) 2.5
Hz, 1H, H-2), 7.21-8.29 (m, 15H, Ph); 13C NMR (CD3OD) δ
68.6, 69.9, 71.1, 71.5, 71.8, 72.3 (inositol ring carbons), 126.9-
132.0 (3Ph), 164.3, 164.9, 165.1 (3COPh); HRMS (FAB) m/z
calcd for C27H25O9 493.1499, found 493.1494 (M+ + H). 6La :
oil; [R]2D5 +154.8 (c 1.71, CHCl3); identical Rf, 1H NMR, and
13C NMR data to those of 6Da . 6Db: Rf 0.28 (MeOH:CH2Cl2 )
D- a n d L-1,4,5-Tr i-O-ben zoyl-2,3-O-isop r op ylid en e-m yo-
in ositol (5Dc a n d 5Lc). 5Dc: Rf 0.4 (EtOAc:CH2Cl2:Hex )
1:10:5); mp 170-171 °C; [R]2D5 -51.3 (c 0.98, CH2Cl2); 1H NMR
(CDCl3) δ 1.37, 1.57 (2s, 6H, CMe2), 3.09 (d, J ) 4.1 Hz, 1H,
OH-6), 4.43 (dt, J ) 4.2, 7.3 Hz, 1H, H-6), 4.57 (app. t, 6.7 Hz,
1H, H-3), 4.78 (dd, J ) 3.8, 6.1 Hz, 1H, H-2), 5.23 (dd, J )
7.0, 9.8 Hz, 1H, H-5), 5.58 (dd, J ) 3.7, 7.7 Hz, 1H, H-1), 5.98
(dd, J ) 7.2, 9.8 Hz, 1H, H-4), 7.26-8.18 (m, 15H, 3Ph); 13C
NMR (CDCl3) δ 25.7, 27.4 (CMe2), 71.7, 72.2, 72.9, 73.7, 76.6,
76.7 (inositol ring carbons), 111.4 (CMe2), 128.8-133.9 (3Ph),
166.3, 166.6, 167.5 (3COPh); MS (FAB) m/z 533 (M+ + H).
Anal. Calcd for C30H28O9: C, 67.66; H, 5.30. Found: C, 67.34;
H, 5.42. 5Lc: mp 170-171 °C; [R]2D5 +53.6 (c 0.77, CH2Cl2);
1:20); mp 195-196 °C; [R]2D5 +46.1 (c 1.00, MeOH); H NMR
1
(CD3OD) δ 3.81 (app. t, J ) 9.4 Hz, 1H, H-5), 4.23 (app. t, J )
9.7 Hz, 1H, H-6), 4.54 (app. t, J ) 2.5 Hz, 1H, H-2), 5.14 (dd,
J ) 2.6, 10.2 Hz, 1H, H-1), 5.35 (dd, J ) 2.5, 10.4 Hz, 1H,
H-3), 5.90 (app. t, J ) 10.0 Hz, 1H, H-4), 7.32-8.17 (m, 15H,
Ph); 13C NMR (CD3OD) δ 66.6, 69.5, 71.6 (3C), 73.1 (inositol
ring carbons), 126.8-131.8 (3Ph), 164.6, 165.1 (2C) (3COPh);
MS (FAB) m/z 493 (M+ + H); Anal. Calcd for C27H24O9: C,
65.85; H, 4.91. Found: C, 65.60; H, 4.98. 6Lb: mp 195-196
°C (lit.14e mp 184-194 °C); [R]D25 -46.2 (c 1.07, MeOH) [lit.14e
[R]546 546-38.3 (dioxane)]; Identical Rf, 1H NMR and 13C NMR
data to those of 6Db.
1
identical H NMR and 13C NMR data to those of 5Dc.
D- a n d L-1,4,6-Tr i-O-b en zoyl-m yo-in osit ol (6Dc a n d
6Lc). 6Dc: Rf 0.56 (EtOAc:Hex ) 2:1); mp 111-112 °C; [R]25
D- a n d L-1,2,6-Tr i-O-ben zoyl-3,4-O-isop r op ylid en e-m yo-
in ositol (7Da a n d 7La ) a n d D- a n d L-1,2,6-Tr i-O-ben zoyl-
4,5-O-isop r op ylid en e-m yo-in ositol (8Da a n d 8La ). To a
D
-46.7 (c 1.01, EtOAc); 1H NMR (CD3OD) δ 3.96-4.12 (m, 2H,
H-3 & H-5), 4.36 (app. t, J ) 2.5 Hz, 1H, H-2), 5.31 (dd, J )
2.5, 10.4 Hz, 1H, H-1), 5.66 (app. t, J ) 9.8 Hz, 1H, H-4), 5.96
(app. t, J ) 10.0 Hz, 1H, H-6), 7.34-8.13 (m, 15H, 3Ph); 13C
NMR (CD3OD) δ 70.2, 70.8, 71.2, 73.3, 73.5, 75.9 (inositol ring
(24) Bruzik, K. S.; Tsai, M. D. J . Am. Chem. Soc. 1992, 114, 6361-
6374.
J . Org. Chem, Vol. 67, No. 16, 2002 5631

Chung et al.
solution of compound 6Da (1.80 g, 3.65 mmol) and TSA (150
mg) in THF (50 mL) at room temperature was added 2-meth-
oxypropene (1.1 mL, 11.1 mmol) in portions with vigorous
stirring. After 5 h, the reaction mixture was quenched with
TEA (1 mL), poured into saturated aq NaHCO3 solution, and
extracted with EtOAc. The extract was dried (MgSO4), evapo-
rated, and chromatographed on silica gel (EtOAc:CH2Cl2:Hex
) 1:5:5) to give 7Da (1.13 g, 58%) and 8Da (583 mg, 30%).
Compounds 7La and 8La were similarly prepared from 6La .
7Da : Rf 0.5 (EtOAc:CH2Cl2 ) 1:10); mp 205-206 °C; [R]D25
-184.0 (c 1.05, CHCl3); 1H NMR (CDCl3) δ 1.42, 1.51 (2s, 6H,
CMe2), 2.85 (d, J ) 4.4 Hz, 1H, OH-5), 3.92 (dd, J ) 2.5, 9.3
Hz, 1H, H-3), 4.21 (ddd, J ) 4.4, 8.7, 10.0 Hz, 1H, H-5), 4.37
(dd, J ) 9.3, 10.0 Hz, 1H, H-4), 5.61 (dd, J ) 3.1, 10.0 Hz, 1H,
H-1), 5.82 (dd, J ) 8.7, 10.0 Hz, 1H, H-6), 6.19 (dd, J ) 2.5,
3.1 Hz, 1H, H-2), 7.22-8.09 (m, 15H, 3Ph); 13C NMR (CDCl3)
δ 27.1, 27.6 (CMe2), 67.5, 72.2, 72.5, 75.6, 75.9, 77.2 (inositol
ring carbons), 134.0 (CMe2), 129.0-134.2 (3Ph), 166.0, 166.1,
167.2 (3COPh); MS (FAB) m/z 533 (M+ + H). Anal. Calcd for
(3COPh); MS (FAB) m/z 515 (M+ + Na), 493 (M+ + H). Anal.
Calcd for C27H24O9: C, 65.85; H, 4.91. Found: C, 65.54; H,
5.03. 6Lg: mp 122-123 °C; [R]2D5 -9.74 (c 1.00, EtOAc) [lit.24
[R]D -8.6 (c 2.5, CHCl3)]; identical 1H NMR and 13C NMR data
to those of 6Dg.
Gen er a tion a n d Sep a r a tion of IBz3 Regioisom er s fr om
8Da a n d 8La . Compound 8Da (550 mg) in pyridine-water
(6:4, 100 mL) was heated at 100 °C, for 3 h. The solution was
cooled and concentrated under reduced pressure. The serial
operation of adding acetone to the reaction mixture followed
by evaporation of the solvents was repeated twice. The crude
mixture which contained 4 regioisomers with the Rf value of
0.6, 0.5, 0.3, and 0.2 was concentrated and chromatographed
on silica gel (EtOAc:CH2Cl2:Hex ) 1:2:6 f 1:10:2 gradient) to
give two fractions. The first fraction, which contained 8Db and
8Dc, was treated with 80% aq AcOH (100 °C, 3 h), concen-
trated, and chromatographed on silica gel to give 6Lb and 6Lh ,
respectively. 6Lb was also obtained from 4Da . The second
fraction was the mixture of 8Dd and 8Da . Similarly, 6Db and
6Dh were prepared from 8La .
C
30H28O9: C, 67.66; H, 5.30. Found: C, 67.51; H, 5.28. 7La :
mp 203-204 °C; [R]2D5 +185.2 (c 0.54, CHCl3); identical Rf, H
NMR, and 13C NMR data to those of 7Da . 8Da : Rf 0.3 (EtOAc:
1
D- a n d L-1,2,4-Tr i-O-b en zoyl-m yo-in osit ol (6Dh a n d
6Lh ). 6Dh : Rf 0.4 (EtOAc:CH2Cl2 ) 1:3); mp 187-189 °C
(lit.14e mp 186-190 °C); [R]D25 -5.3 (c 0.8, THF) [lit.14e [R]546
CH2Cl2 )1:10); mp 113-114 °C; [R]25 -138.1 (c 0.54, EtOAc);
D
1
1H NMR (CDCl3) δ 1.51, 1.56 (2s, 6H, CMe2), 2.46 (d, J ) 4.8
Hz, 1H, OH-3), 3.86 (dd, J ) 9.3, 10.3 Hz, 1H, H-5), 4.21 (app.
t, J ) 9.8 Hz, 1H, H-4), 4.35 (ddd, J ) 3.4, 4.7, 10.4 Hz, 1H,
H-3), 5.52 (dd, J ) 3.4, 9.6 Hz, 1H, H-1), 6.04 (app. t, J ) 3.3
Hz, 1H, H-2), 6.04 (dd, J ) 9.6, 10.3 Hz, 1H, H-6), 7.24-8.06
(m, 15H, Ph); 13C NMR (CDCl3) δ 27.2, 27.3 (CMe2), 69.6, 71.1,
72.5, 73.0, 76.8, 78.3 (inositol ring carbons), 113.4 (CMe2),
128.8-134.1 (3Ph), 165.9, 166.0, 166.7 (3COPh); MS (FAB) m/z
533 (M+ + H). Anal. Calcd for C30H28O9: C, 67.66; H, 5.30.
Found: C, 67.64; H, 5.32. 8La : mp 113-114 °C; [R]2D5 +136.0
-6.5 (THF)]; H NMR (CD3OD) δ 3.77 (dd, J ) 9.2, 9.8 Hz,
1H, H-5), 4.17 (dd, J ) 9.2, 10.5 Hz, 1H, H-6), 4.20 (dd, J )
2.6, 9.8 Hz, 1H, H-3), 5.23 (dd, J ) 2.6, 10.5 Hz, 1H, H-1),
5.66 (app. t, J ) 9.8 Hz, 1H, H-4), 5.93 (app. t, J ) 2.6 Hz,
1H, H-2), 7.33-8.13 (m, 15H, 3Ph); 13C NMR (CD3OD) δ 69.8,
73.0, 74.3, 74.5, 74.7, 77.1 (inositol ring carbons), 129.7-134.8
(3Ph), 167.6, 167.7, 168.3 (3COPh); MS (FAB) m/z 515 (M+
+
Na), 493 (M+ + H). 6Lh : mp 186-187 °C (lit.14e mp 188-191
°C); [R]2D5 +5.9 (c 1.06, THF) [lit. [R]546 +5.4 (THF),14e [R]2D0
+5.9 (c 2.5, THF)24]; identical Rf, 1H NMR, and 13C NMR data
to those of 6Dh .
1
(c 0.99, EtOAc); identical Rf, H NMR, and 13C NMR data to
P h osp h or yla tion of IBz3 Regioisom er s (6Da -6Dh a n d
6La -6Lh ): Gen er a l P r oced u r e. To a solution of each IBz3
regioisomer (0.20 mmol) in DMF (5 mL) at -42 °C were added
dropwise N,N-diisopropylethylamine (1 mL, 5.7 mmol) and
then diethyl chlorophosphite (0.3 mL, 2.1 mmol) with vigorous
stirring. After 20 min, the reaction mixture was allowed to
slowly warm to room temperature and stirred for an additional
12 h. The mixture was cooled in an ice bath, and sodium
phosphate buffer (1 N, pH 7, 5 mL) and excess 30% H2O2 (5
mL) were added. After being stirred overnight at room
temperature, the mixture was diluted with EtOAc, and washed
with aq NaHSO4, aq NaHCO3, and brine. The organic layer
was separated, dried (MgSO4), concentrated, and chromato-
graphed to give IP′3Bz3 regioisomers (9La -9Lh and 6Da -
6Dh ) in 65-77% yields.
D- a n d L-2,3,4-Tr i-O-b en zoyl-m yo-in osit ol 1,5,6-t r is-
(d ieth yl p h osp h a te) (9Da a n d 9La ) were prepared from
compounds 6La and 6Da , respectively. 9Da : oil; [R]2D5 +75.8
(c 1.06, CHCl3); 1H NMR (CDCl3) δ 0.78-1.37 (m, 18H,
6CH2CH3), 3.54-4.32 (m, 12H, 6CH2CH3), 4.69 (dt, J ) 2.8,
8.9 Hz, 1H, H-1), 4.89 (q, J ) 9.3 Hz, 1H, H-5), 5.11 (q, J )
9.5 Hz, 1H, H-6), 5.42 (dd, J ) 2.8, 10.4 Hz, 1H, H-3), 6.04
(app. t, J ) 10.0 Hz, 1H, H-4), 6.28 (app. t, J ) 2.8 Hz, 1H,
H-2), 7.25-8.05 (m, 15H, 3Ph); 13C NMR (CDCl3) δ 15.7-16.4
(6CH2CH3), 64.2-65.1 (6CH2CH3), 69.3, 70.1, 70.4, 73.7, 76.3,
76.6 (inositol ring carbons), 126.3-134.0 (3Ph), 165.4, 165.6,
165.7 (3COPh); 31P NMR (CDCl3) δ 0.02, 0.07, 0.83; HRMS
(FAB) m/z calcd for C39H52O18P3 901.2367, found 901.2373 (M+
+ H). 9La : oil; [R]2D5 -71.1 (c 1.89, CHCl3); identical 1H NMR,
13C NMR, and 31P NMR data to those of 9Da .
those of 8Da .
Gen er a tion a n d Sep a r a tion of IBz3 Regioisom er s fr om
7Da a n d 7La . Compound 7Da (850 mg) in a solvent mixture
of pyridine-water (6:4, 100 mL) was heated at 100 °C for 3 h.
The solution was cooled and concentrated under reduced
pressure. The serial operation of adding acetone to the reaction
mixture followed by evaporation of the solvents was repeated
twice. The crude mixture, which contained almost equal
amounts of 7Da , 7Db, 7Dc, and 7Dd , was concentrated and
chromatographed on silica gel (EtOAc:Hex ) 1:4 f 1:2
gradient) to give two fractions. The first fraction contained 7Db
and 7Dc, the second 7Da and 7Dd with the Rf values of 0.4
and 0.2 (EtOAc:Hex ) 1:2), respectively. Each fraction was
treated with 80% aq AcOH (100 °C, 1 h) to give (6Df and 6Dd )
and (6Da and 6Lg) mixtures, which were separately chro-
matographed (EtOAc-CH2Cl2 gradient) to give four IBz3
isomers with Rf values of 0.6, 0.4, 0.35, and 0.5 for 6Df, 6Dd ,
6Da , and 6Lg (EtOAc:CH2Cl2 ) 1:2, 3 times). Compounds 6Lf,
6Ld , 6La , and 6Dg were similarly prepared from 7La .
D- a n d L-1,2,5-Tr i-O-ben zoyl-m yo-in ositol (6Df a n d 6Lf).
6Df: oil; [R]2D5 -63.6 (c 2.75, CHCl3); 1H NMR (CD3OD) δ 4.02
(dd, J ) 2.9, 9.9 Hz, 1H, H-3), 4.17 (app. t, J ) 9.8 Hz, 1H,
H-4), 4.36 (app. t, J ) 10.0 Hz, 1H, H-6), 5.33-5.40 (m, 2H,
H-1 & H-5), 5.97 (app. t, J ) 2.8 Hz, 1H, H-2), 7.31-8.18 (m,
15H, 3Ph); 13C NMR (CD3OD) δ 68.4, 68.7, 70.3, 71.0, 71.7,
75.3 (inositol ring carbons), 126.9-132.1 (3Ph), 164.7, 164.9,
165.4 (3COPh); HRMS (FAB) m/z calcd for C27H25O9 493.1499,
found 493.1414 (M+ + H). 6Lf: oil; [R]2D5 +62.1 (c 1.75,
CHCl3); identical H NMR and 13C NMR data to those of 6Df.
1
D- a n d L-2,4,5-Tr i-O-b en zoyl-m yo-in osit ol (6Dg a n d
D- a n d L-1,3,6-Tr i-O-b en zoyl-m yo-in osit ol 2,4,5-t r is-
(d ieth yl p h osp h a te) (9Db a n d 9Lb) were prepared from
compounds 6Lb and 6Db, respectively. 9Db: oil; [R]2D5 -10.0
(c 0.98, CHCl3); 1H NMR (CDCl3) δ 0.84-1.31 (m, 18H,
6CH2CH3), 3.57-4.23 (m, 12H, 6CH2CH3), 4.94 (app. q, J )
9.2 Hz, 1H, H-5), 5.22 (app. q, J ) 9.3 Hz, 1H, H-4), 5.34-
5.40 (m, 2H, H-1 & H-2), 5.44 (br d, J ) 10.1 Hz, 1H, H-3),
6.08 (app. t, J ) 10.0 Hz, 1H, H-6), 7.28-8.26 (m, 15H, 3Ph);
6Lg). 6Dg: mp 123-124 °C; [R]2D5 +9.40 (c 1.03, EtOAc); H
1
NMR (CD3OD) δ 3.93 (dd, J ) 2.9, 9.8 Hz, 1H, H-1), 4.14 (app.
t, J ) 9.7 Hz, 1H, H-6), 4.22 (dd, J ) 2.9, 10.2 Hz, 1H, H-3),
5.47 (app. t, J ) 9.8, 1H, H-5), 5.8 (app. t, J ) 10.1 Hz, 1H,
H-4), 5.85 (app. t, J ) 2.9 Hz, 1H, H-2), 7.35-8.16 (m, 15H,
3Ph); 13C NMR (CD3OD) δ 68.8, 70.8, 71.8, 73.9, 74.8, 75.3
(inositol ring carbons), 128.4-133.3 (3Ph), 166.6, 166.7, 166.8
5632 J . Org. Chem., Vol. 67, No. 16, 2002

Syntheses of myo-Inositol Tris- and Tetrakisphosphates
13C NMR (CDCl3) δ 15.7-16.4 (6CH2CH3), 64.2-64.8 (6CH2-
CH3), 70.1, 70.5, 70.6, 73.8, 76.0, 77.1 (inositol ring carbons),
128.7-133.9 (3Ph), 165.7, 165.8, 165.9 (3COPh); 31P NMR
(CDCl3) δ 0.51, 0.52, 1.16; MS (FAB) m/z 901 (M+ + H). 9Lb:
J ) 9.5 Hz, 1H, H-4), 5.61 (app. t, J ) 9.9 Hz, 1H, H-5), 5.91
(app. t, J ) 10.2 Hz, 1H, H-6), 6.25 (app. t, J ) 2.7 Hz, 1H,
H-2), 7.27-8.09 (m, 15H, 3Ph); 13C NMR (CDCl3) δ 15.9-16.7
(6CH2CH3), 64.5-65.4 (6CH2CH3), 71.0 (2C), 71.5, 73.9, 74.3,
76.1 (inositol ring carbons), 128.9-134.2 (3Ph), 165.6, 165.9,
166.1 (3COPh); 31P NMR (CDCl3) δ 0.44, 0.93, 0.97; MS (FAB)
m/z 901 (M+ + H). 9Lg: oil; [R]D25 +2.59 (c 1.02, CHCl3);
identical 1H NMR, 13C NMR, and 31P NMR data to those of
9Dg.
D- a n d L-2,3,6-Tr i-O-b en zoyl-m yo-in osit ol 1,4,5-t r is-
(d ieth yl p h osp h a te) (9Dh a n d 9Lh ) were prepared from
compounds 6Lh and 6Dh , respectively. 9Dh : oil; [R]2D5 +15.3
(c 0.60, CHCl3); 1H NMR (CDCl3) δ 0.77-1.26 (m, 18H,
6CH2CH3), 3.56-4.20 (m, 12H, 6CH2CH3), 4.87 (app. q, J )
9.4 Hz, 1H, H-4), 4.93 (ddd, J ) 2.9, 9.8, 10.1 Hz, 1H, H-1),
5.16 (app. q, J ) 9.3 Hz, 1H, H-5), 5.47 (dd, J ) 2.9, 10.1 Hz,
1H, H-3), 6.04 (app. t, J ) 10.0 Hz, 1H, H-6), 6.12 (app. t, J )
2.9 Hz, 1H, H-2), 7.33-8.21 (m, 15H, 3Ph); 13C NMR (CDCl3)
δ 15.9-16.6 (6CH2CH3), 64.4-65.1 (6CH2CH3), 70.2, 70.5, 71.2,
73.6, 76.5, 77.1 (inositol ring carbons), 128.9-134.3 (3Ph),
165.7, 165.9, 166.1 (3COPh); 31P NMR (CDCl3) δ 0.29, 0.72,
0.90; MS (FAB) m/z 901 (M+ + H). 9Lh : oil; [R]2D5 -14.7 (c
1.61, CHCl3); identical 1H NMR, 13C NMR, and 31P NMR data
to those of 9Dh .
P r ep a r a tion of Sod iu m Sa lts of m yo-In ositol Tr isp h os-
p h a te (10Da -10Dh a n d 10La -10Lh ): Gen er a l P r oce-
d u r e. To each compound of 9Da --Dh and 9La -9Lh (60 mg,
0.066 mmol) in CH2Cl2 (1 mL) at room temperature was added
excess bromotrimethylsilane (0.5 mL), and the solution was
stirred overnight. The solvent and excess reagent were evapo-
rated and the residue was redissolved in MeOH (3 mL), and
then treated with drops of water at 0 °C. After standing at
room temperature for 10 min, the reaction mixture was
evaporated to dryness, treated with 1 M LiOH (3 mL), and
stirred at 80 °C for 3 h. The basic solution was cooled and
loaded on Dowex 50WX8-100 (H+ form) and eluted with water.
The acidic effluent 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 sodium salts of
myo-inositol trisphosphate 10Da -10Dh and 10La -10Lh in
approximately 90% yields.
oil; [R]2D5 +10.6 (c 1.92, CHCl3); identical H NMR, 13C NMR,
1
and 31P NMR data to those of 9Db.
D- a n d L-3,4,6-Tr i-O-b en zoyl-m yo-in osit ol 1,2,5-t r is-
(d ieth yl p h osp h a te) (9Dc a n d 9Lc) were prepared from
compounds 6Lc and 6Dc, respectively. 9Dc: oil; [R]2D5 +11.9
(c 1.54, CHCl3); 1H NMR (CDCl3) δ 0.76-1.37 (m, 18H,
6CH2CH3), 3.54-3.82 (m, 12H, 6CH2CH3), 4.88 (br t, J ) 10.1
Hz, 1H, H-1), 5.06 (app. q, J ) 9.5 Hz, 1H, H-5), 5.34 (br d, J
) 10.5 Hz, 1H, H-3), 5.39 (br d, J ) 9.1 Hz, 1H, H-2), 6.02
(app. t, J ) 10.0 Hz, 1H, H-6), 6.13 (app. t, J ) 10.1 Hz, 1H,
H-4), 7.30-8.21 (m, 15H, 3Ph); 13C NMR (CDCl3) δ 15.7-16.4
(6CH2CH3), 64.2-64.9 (6CH2CH3), 70.3, 70.5, 70.9, 73.9, 75.5,
76.0 (inositol ring carbons), 128.7-133.8 (3Ph), 165.7, 165.9,
166.0 (3COPh); 31P NMR (CDCl3) δ 0.23, 0.99, 1.19; MS (FAB)
m/z 901 (M+ + H). 9Lc: oil; [R]D25 -12.7 (c 1.62, CHCl3);
identical 1H NMR, 13C NMR, and 31P NMR data to those of
9Dc.
D- a n d L-3,4,5-Tr i-O-b en zoyl-m yo-in osit ol 1,2,6-t r is-
(d iet h yl p h osp h a t e) (9Dd a n d 9Ld ) were prepared from
compounds 6Ld and 6Dd , respectively. 9Dd : oil; [R]2D5 -8.13
(c 2.48, CHCl3); 1H NMR (CDCl3) δ 0.84-1.41 (m, 18H,
6CH2CH3), 3.63-4.31 (m, 12H, 6CH2CH3), 4.70 (br t, J ) 9.5
Hz, 1H, H-1), 5.22 (app. q, J ) 9.6 Hz, 1H, H-6), 5.39 (br d, J
) 10.5 Hz, 1H, H-3), 5.50 (br d, J ) 9.1 Hz, 1H, H-2), 5.78
(app. t, J ) 9.8 Hz, 1H, H-5), 6.09 (app. t, J ) 10.3 Hz, 1H,
H-4), 7.28-8.05 (m, 15H, 3Ph); 13C NMR (CDCl3) δ 16.0-16.8
(6CH2CH3), 64.5-65.6 (6CH2CH3), 70.2, 70.9, 71.7, 74.7, 75.4,
75.8 (inositol ring carbons), 128.9-134.0 (3Ph), 166.1, 166.2
(2C) (3COPh); 31P NMR (CDCl3) δ 0.21, 0.55, 1.26; MS (FAB)
m/z 901 (M+ + H). 9Ld : oil; [R]D25 +6.04 (c 0.86, CHCl3);
identical 1H NMR, 13C NMR, and 31P NMR data to those of
9Dd .
D- a n d L-3,5,6-Tr i-O-b en zoyl-m yo-in osit ol 1,2,4-t r is-
(d ieth yl p h osp h a te) (9De a n d 9Le) were prepared from
compounds 6Le and 6De, respectively. 9De: oil; [R]2D5 +19.2
(c 1.64, CHCl3); 1H NMR (CDCl3) δ 0.74-1.37 (m, 18H,
6CH2CH3), 3.44-4.21 (m, 12H, 6CH2CH3), 4.96 (app. t, J )
1.9, 10.1 Hz, 1H, H-1), 5.31-5.43 (m, 3H, H-2, H-3 & H-4),
5.75 (app. t, J ) 9.5 Hz, 1H, H-5), 5.99 (app. t, J ) 10.1 Hz,
1H, H-6), 7.33-8.24 (m, 15H, 3Ph); 13C NMR (CDCl3) δ 15.7-
16.4 (6CH2CH3), 64.1-64.9 (6CH2CH3), 70.4, 70.9, 71.5, 73.9,
75.0, 75.7 (inositol ring carbons), 128.7-133.9 (3Ph), 165.6,
165.7, 165.8 (3COPh); 31P NMR (CDCl3) δ 0.39, 1.07, 1.21;
D- a n d L-m yo-In ositol 1,5,6-tr isp h osp h a te sod iu m sa lt
(10Da a n d 10La ) were prepared from compounds 9Da and
9La , respectively. 10Da : [R]2D5 -2.57 (c 1.01, H2O) [lit. [R]20
D
+2.2 (c 2.3, H2O, free acid),14v [R]D20 -2.8 (c 1.43, H2O, sodium
salt)14q]; 1H NMR (D2O, pH 10) δ 3.63 (dd, J ) 3.4, 8.4 Hz,
1H, H-3), 3.86-3.92 (m, 2H, H-4 & H-5), 3.98 (br t, J ) 6.8
Hz, 1H, H-5), 4.33 (br q, J ) 8.9 Hz, 1H, H-6), 4.45 (br s, 1H,
H-2); 13C NMR (D2O, pH 10) δ 70.3, 71.6, 73.5, 74.4 (2C), 77.3;
31P NMR (D2O, pH 10) δ 6.30, 6.74, 7.24. 10La : [R]2D5 +4.56 (c
0.95, H2O) [lit.14v [R]D20 -4.6 (c 1.4, H2O, free acid)]; identical
1H NMR, 13C NMR, and 31P NMR data to those of 10Da .
D- a n d L-m yo-In ositol 2,4,5-tr isp h osp h a te sod iu m sa lt
(10Db a n d 10Lb) were prepared from compounds 9Db and
9Lb, respectively. 10Db: [R]2D5 -9.59 (c 1.45, H2O) [lit.14h
[R]546 -8.05 (H2O, cyclohexylammonium salt)]; 1H NMR (D2O,
pH 10) δ 3.46 (dd, J ) 1.9, 9.8 Hz, 1H, H-1), 3.69 (dt, J ) 2.4,
9.7 Hz, 1H, H-3), 3.80 (q, J ) 8.3 Hz, 1H, H-6), 3.92 (app. t, J
) 9.3 Hz, 1H, H-5), 4.19 (q, J ) 8.7 Hz, 1H, H-4), 4.43 (br d,
J ) 7.3 Hz, 1H, H-2); 13C NMR (D2O, pH 10) δ 72.1, 72.3, 74.0,
75.0, 75.6, 77.8; 31P NMR (D2O, pH 10) δ 7.28, 7.46, 7.60.
10Lb: [R]2D5 +12.0 (c ) 0.96, H2O) [lit.14h [R]546 +9.5 (H2O,
cyclohexylammonium salt)]; identical 1H NMR, 13C NMR, and
31P NMR data to those of 10Db.
HRMS (FAB) m/z calcd for
C39H52O18P3 901.2367, found
901.2352 (M+ + H). 9Le: oil; [R]D25 -19.1 (c 1.40, CHCl3);
identical 1H NMR, 13C NMR, and 31P NMR data to those of
9Dd .
D- a n d L-2,3,5-Tr i-O-b en zoyl-m yo-in osit ol 1,4,6-t r is-
(d ieth yl p h osp h a te) (9Df a n d 9Lf) were prepared from
compounds 6Lf and 6Df, respectively. 9Df: oil; [R]2D5 +38.0 (c
1.12, CHCl3); 1H NMR (CDCl3) δ 0.72-1.30 (m, 18H, 6CH2CH3),
3.48-4.15 (m, 12H, 6CH2CH3), 4.76 (ddd, J ) 3.0, 7.8, 10.2
Hz, 1H, H-1), 5.16-5.27 (m, 2H, H-4 & H-6), 5.47 (dd, J )
3.0, 10.2 Hz, 1H, H-3), 5.67 (app. t, J ) 9.9 Hz, 1H, H-5), 6.25
(app. t, J ) 2.9 Hz, 1H, H-2), 7.35-8.27 (m, 15H, 3Ph); 13C
NMR (CDCl3) δ 15.8-16.6 (6CH2CH3), 64.3-65.4 (6CH2CH3),
69.6, 70.8, 71.9, 74.1, 75.4, 76.0 (inositol ring carbons), 128.9-
134.2 (3Ph), 165.7, 165.8, 166.1 (3COPh); 31P NMR (CDCl3) δ
0.22, 0.86, 1.03; MS (FAB) m/z 901 (M+ + H). 9Lf: oil; [R]2D5
-42.3 (c 1.77, CHCl3); identical 1H NMR, 13C NMR, and 31P
NMR data to those of 9Df.
D- a n d L-2,5,6-Tr i-O-b en zoyl-m yo-in osit ol 1,3,4-t r is-
(d ieth yl p h osp h a te) (9Dg a n d 9Lg) were prepared from
compounds 6Lg and 6Dg, respectively. 9Dg: oil; [R]2D5 -2.53
(c 0.75, CHCl3); 1H NMR (CDCl3) δ 0.70-1.27 (m, 18H,
6CH2CH3), 3.56-4.12 (m, 12H, 6CH2CH3), 4.64 (dt, J ) 2.7,
9.2 Hz, 1H, H-3), 4.91 (dt, J ) 2.9, 9.99 Hz, 1H, H-1), 5.14 (q,
D- a n d L-m yo-In ositol 1,2,5-tr isp h osp h a te sod iu m sa lt
(10Dc a n d 10Lc) were prepared from compounds 9Dc and
9Lc, respectively. 10Dc: [R]2D5 +5.94 (c 1.62, H2O); H NMR
1
(D2O, pH 10) δ 3.51 (br d, J ) 9.6 Hz, 1H, H-3), 3.77-3.94 (m,
3H, H-4, H-5 & H-6), 4.01 (br t, J ) 9.4 Hz, 1H, H-1), 4.65 (br
d, J ) 7.2 Hz, 1H, H-2); 13C NMR (D2O, pH 10) δ 72.2, 72.4,
J . Org. Chem, Vol. 67, No. 16, 2002 5633

Chung et al.
73.8 (2C), 75.4, 79.0; 31P NMR (D2O, pH 10) δ 7.02, 7.28, 7.48.
contained 3De (185 mg). The third and fourth-eluted materials
could not be cleanly separated but contained compounds 3Dd
and 3Dc (245 mg). The mixture of 3Dd and 3Dc was treated
with 80% aq AcOH (100 °C, 3h), concentrated, and chromato-
graphed (MeOH:CH2Cl2 ) 1:20) on silica gel to give compound
4Dc and the more polar compound 4Lb, respectively. The fifth-
and sixth-eluted materials were compounds 3Db (165 mg) and
3Da (290 mg). Each isomer (3Da , 3Db, 3Dd , and 3De) was
treated with 80% aq AcOH (100 °C, 3 h) and concentrated to
give the corresponding IBz2 products 4Da , 4Db, 4Dc, and 4Dd
in quantitative yield. Compounds 4La , 4Lb, 4Db, 4Lc, and
4Ld were similarly prepared from compound 3La .
D- a n d L-4,5-Di-O-ben zoyl-2,3-O-isop r op ylid en e-m yo-
in ositol (3Db a n d 3Lb). 3Db: oil; Rf 0.23 (EtOAc:CH2Cl2 )
1:3); [R]2D5 -38.5 (c 1.15, CHCl3); 1H NMR (CDCl3) δ 1.38, 1.65
(2s, 6H, CMe2), 3.74 (br s, 1H, OH), 4.03-4.08 (m, 2H, H-1 &
OH), 4.18 (app. t, J ) 8.7 Hz, 1H, H-6), 4.40 (dd, J ) 5.6, 7.3
Hz, 1H, H-3), 4.51 (app. t, J ) 4.6 Hz, 1H, H-2), 5.25 (app. t,
J ) 9.2 Hz, 1H, H-5), 5.73 (dd, J ) 7.3, 9.8 Hz, 1H, H-4), 7.26-
7.96 (m, 10H, 2Ph); 13C NMR (CDCl3) δ 26.1, 27.9 (CMe2), 70.8,
72.4, 73.8, 74.8, 75.9, 76.8 (inositol ring carbons), 111.2 (CMe2),
128.7-133.7 (2Ph), 166.0, 167.2 (2COPh); HRMS (FAB) m/z
calcd for C23H25O8 429.1491, found 429.1442 (M+ + H). 3Lb:
[R]D25 +38.8 (c 1.25, CHCl3); identical Rf, 1H NMR, and 13C
NMR data to those of 3Db.
10Lc: [R]2D5 -6.41 (c 1.58, H2O); identical H NMR, 13C NMR,
1
and 31P NMR data to those of 10Dc.
D- a n d L-m yo-In ositol 1,2,6-tr isp h osp h a te sod iu m sa lt
(10Dd a n d 10Ld ) were prepared from compounds 9Dd and
9Ld , respectively. 10Dd : [R]2D5 -16.5 (c 1.47, H2O) [lit. [R]25
D
-19.5 (c 1.1, H2O, free acid),14r [R]D29 -16.9 (c 0.56, H2O,
1
lithium salt)14t]; H NMR (D2O, pH 10) δ 3.46 (br q, J ) 10.4
Hz, 2H, H-3 & H-5), 3.82 (app. t, J ) 9.6 Hz, 1H, H-4), 3.91
(br t, J ) 9.7 Hz, 1H, H-1), 4.21 (q, J ) 8.6 Hz, 1H, H-6), 4.66
(br d, J ) 5.9 Hz, 1H, H-2); 13C NMR (D2O, pH 10) δ 72.5,
72.8, 73.9, 75.9 (3C); 31P NMR (D2O, pH 10) δ 7.04, 7.16, 7.80.
10Ld : [R]2D5 +15.9 (c 0.99, H2O); identical H NMR, 13C NMR,
1
and 31P NMR data to those of 10Dd .
D- a n d L-m yo-In ositol 1,2,4-tr isp h osp h a te sod iu m sa lt
(10De a n d 10Le) were prepared from compounds 9De and
9Le, respectively. 10De: [R]2D5 +11.5 (c 1.51, H2O); H NMR
1
(D2O, pH 10) δ 3.47 (q, J ) 8.2 Hz, 2H, H-3 & H-5), 3.83-3.98
(m, 2H, H-1 & H-6), 4.15 (q, J ) 8.6 Hz, 1H, H-4), 4.52 (br d,
J ) 7.4 Hz, 1H, H-2); 13C NMR (D2O, pH 10) δ 71.8, 72.9, 73.6,
75.8 (2C), 77.27; 31P NMR (D2O, pH 10) δ 7.31, 7.34, 7.59.
10Le: [R]2D5 -13.7 (c 0.75, H2O); identical H NMR, 13C NMR,
1
and 31P NMR data to those of 10De.
D- a n d L-m yo-In ositol 1,4,6-tr isp h osp h a te sod iu m sa lt
(10Df a n d 10Lf) were prepared from compounds 9Df and 9Lf,
respectively. 10Df: [R]2D5 -10.1 (c 0.78, H2O) [lit.14o [R]2D0 -8.9
(c 0.90, H2O, sodium salt)]; 1H NMR (D2O, pH 10) δ 3.56 (app.
t, J ) 9.1 Hz, 1H, H-5), 3.70 (dd, J ) 2.6, 9.6 Hz, 1H, H-3),
3.92 (br t, J ) 7.5 Hz, 1H, H-1), 4.13-4.26 (m, 2H, H-4 & H-6),
4.36 (br s, 1H, H-2); 13C NMR (D2O, pH 10) δ 71.2, 71.8, 73.8,
74.8, 75.7, 76.7; 31P NMR (D2O, pH 10) δ 6.05, 7.15, 7.66.
10Lf: [R]2D5 +11.2 (c 1.14, H2O) [lit.14o [R]D20 +9.4 (c 0.85, H2O,
sodium salt)]; identical 1H NMR, 13C NMR, and 31P NMR data
to those of 10Df.
D- a n d L-1,4-Di-O-ben zoyl-2,3-O-isop r op ylid en e-m yo-
in ositol (3Dd a n d 3Ld ). 3Dd : Rf 0.39 (EtOAc:CH2Cl2 ) 1:3);
mp 231-234 °C; [R]2D5 +8.44 (c 0.54, CHCl3:MeOH ) 5:1); H
1
NMR (DMSO-d6) δ 1.24, 1.45 (2s, 6H, CMe2), 3.54 (ddd, J )
5.4, 8.5, 10.4 Hz, 1H, H-5), 3.84 (ddd, J ) 5.1, 8.4, 8.5 Hz, 1H,
H-4), 4.44 (dd, J ) 5.5, 7.9 Hz, 1H, H-1), 4.54 (dd, J ) 3.9, 5.5
Hz, 1H, H-2), 5.27 (dd, J ) 3.9, 8.4 Hz, 1H, H-3), 5.35 (dd, J
) 7.9, 10.4 Hz, 1H, H-6), 5.36 (d, J ) 5.4 Hz, 1H, OH-5), 5.52
(d, J ) 5.1 Hz, 1H, OH-4), 7.53-8.07 (m, 10H, 2Ph); 13C NMR
(DMSO-d6) δ 25.7, 27.3 (CMe2), 70.9, 71.2, 72.5, 73.4, 76.0, 76.1
(inositol ring carbons), 109.3 (CMe2), 128.5-133.4 (2Ph), 165.0,
165.1 (2COPh); MS (FAB) m/z 429 (M+ + H); Anal. Calcd for
D- a n d L-m yo-In ositol 1,3,4-tr isp h osp h a te sod iu m sa lt
(10Dg a n d 10Lg) were prepared from compounds 9Dg and
9Lg, respectively. 10Dg: [R]2D5 +10.4 (c 0.59, H2O) [lit. [R]22
C
23H24O8: C, 64.48; H, 5.65. Found: C, 64.29; H, 5.92. 3Ld :
D
-6 (c 0.5, H2O, ammonium salt),14c [R]D +13.6 (c 2, H2O, pH
8.2, potasium salt),14k [R]D26 +37 (c 0.42, H2O, pH 7.8, triethyl-
ammonium salt)14p]; 1H NMR (D2O, pH 10) δ 3.54 (app. t, J )
9.0 Hz, 1H, H-5), 3.81 (app. t, J ) 9.5 Hz, 1H, H-6), 3.95 (m,
2H, H-1 & H-3), 4.16 (q, J ) 8.5 Hz, 1H, H-4), 4.45 (br s, 1H,
H-2); 13C NMR (D2O, pH 10) δ 71.4, 72.8, 73.6, 74.1, 75.4 (2C);
31P NMR (D2O, pH 10) δ 6.11, 6.91, 7.61. 10Lg: [R]2D5 -9.20
(c 0.74, H2O) [lit.14p [R]D26 -40 (c 0.42, H2O, pH 7.8, triethyl-
mp 232-234 °C; [R]2D5 -6.82 (c 0.52, CHCl3:MeOH ) 5:1);
identical Rf, H NMR, and 13C NMR data to those of 3Dd .
1
D- a n d L-1,5-Di-O-ben zoyl-2,3-O-isop r op ylid en e-m yo-
in ositol (3De a n d 3Le). 3De: Rf 0.45 (EtOAc:CH2Cl2 ) 1:3);
mp 85-88 °C; [R]2D5 -44.6 (c 0.68, CHCl3); 1H NMR (CDCl3) δ
1.32, 1.49 (2s, 6H, CMe2), 3.45 (br s, 1H, OH-4), 3.58 (br s,
1H, OH-6) 0.4.22-4.36 (m, 3H, H-3, H-4 & H-6), 4.65 (dd, J )
3.9, 6.1 Hz, 1H, H-3), 5.14 (dd, J ) 7.0, 9.0 Hz, 1H, H-5), 5.56
(dd, J ) 3.9, 7.7 Hz, 1H, H-1), 7.34-8.08 (m, 10H, 2Ph); 13C
NMR (CDCl3) δ 25.5, 27.7 (CMe2), 71.4, 72.4, 73.2, 73.6, 78.8,
79.1 (inositol ring carbons), 110.8 (CMe2), 128.8-133.9 (2Ph),
166.4, 167.9 (2COPh); MS (FAB) m/z 429 (M+ + H). Anal.
Calcd for C23H24O8: C, 64.48; H, 5.65. Found: C, 64.18; H,
5.83. 3Le: mp 85-88 °C; [R]2D5 +44.6 (c 0.55, CHCl3); identi-
1
ammonium salt)]; identical H NMR, 13C NMR, and 31P NMR
data to those of 10Dg.
D- a n d L-m yo-In ositol 1,4,5-tr isp h osp h a te sod iu m sa lt
(10Dh a n d 10Lh ) were prepared from compounds 9Dh and
9Lh , respectively. 10Dh : [R]2D5 -24.1 (c 0.28, H2O), [lit. [R]22
D
-24 (c 0.15, H2O, pH 6.9),14g [R]D -24 (c 0.5, H2O, pH 9.3,
potasium salt),14k [R]D24 -20 (c 0.05, H2O, pH 9, sodium
salt),14s [R]2D4 -3.19 (c 0.26, H2O, sodium salt)14w]; 1H NMR
(D2O, pH 10) δ 3.58 (dd, J ) 2.8, 9.6 Hz, 1H, H-3), 3.66-3.79
(m, 3H, H-1, H-5 & H-6), 4.03 (q, J ) 8.5 Hz, 1H, H-4), 4.21
(s, 1H, H-2); 13C NMR (D2O, pH 10) δ 70.8, 72.0, 72.7, 74.8,
75.3, 77.3; 31P NMR (D2O, pH 10) δ 5.67, 7.30, 7.40. 10Lh :
1
cal Rf, H NMR, and 13C NMR data to those of 3De.
D- a n d L-4,6-Di-O-ben zoyl-2,3-O-isop r op ylid en e-m yo-
in ositol (3Df a n d 3Lf). 3Df: Rf 0.58 (EtOAc:CH2Cl2 ) 1:3);
mp 98-100 °C; [R]2D5 -15.7 (c 0.38, CHCl3); H NMR (CDCl3)
1
δ 1.39, 1.64 (2s, 6H, CMe2), 2.73 (br s, 1H, OH-1), 2.92 (br s,
1H, OH-5), 3.88 (app. t, J ) 7.9 Hz, 1H, H-5), 4.13 (dd, J )
3.8, 9.0 Hz, 1H, H-1), 4.45 (app. t, J ) 6.2 Hz, 1H, H-3), 4.58
(dd, J ) 4.2, 5.8 Hz, 1H, H-2), 5.50 (dd, J ) 8.0, 9.1 Hz, 1H,
H-6), 5.55 (dd, J ) 6.7, 7.8 Hz, 1H, H-4), 7.40-8.08 (m, 10H,
2Ph); 13C NMR (CDCl3) δ 25.7, 27.6 (CMe2), 69.3, 73.0, 75.8,
76.1 (2C), 76.9 (inositol ring carbons), 111.2 (CMe2), 128.8-
[R]2D5 +20.1 (c 0.74, H2O), [lit. [R]22 +27 (c 0.15, H2O, pH
D
6.4),14g [R]D24 +17 (c 0.03, H2O, pH 10, sodium salt)14s]; identi-
1
cal H NMR, 13C NMR, and 31P NMR data to those of 10Dh .
Gen er a tion a n d Sep a r a tion of IBz2 Regioisom er s fr om
3Da a n d 3La . Compound 3Da (1.26 g, 2.94 mmol) in pyri-
dine-water (6:4, 50 mL) was heated at 100 °C for 3 h. The
reaction mixture was cooled and concentrated under reduced
pressure. The serial operation of EtOH addition and evapora-
tion was repeated twice. The oily residue was triturated with
CH2Cl2 and precipitated solid (3Dd , 110 mg) was filtered off.
The filtrate was concentrated and chromatographed on silica
gel (EtOAc:CH2Cl2:Hex ) 1:4:5). The first-eluted material was
compound 3Df (120 mg), and the second-eluted fraction
133.8 (2Ph), 166.5, 167.5 (2COPh); MS (FAB) m/z 429 (M+
+
H). Anal. Calcd for C23H24O8: C, 64.48; H, 5.65. Found: C,
64.39; H, 5.65. 3Lf: mp 99-101 °C; [R]2D5 +13.3 (c 0.67,
1
CHCl3); identical Rf,, H NMR, and 13C NMR data to those of
3Df.
D- a n d L-4,5-Di-O-ben zoyl-m yo-in ositol (4Db a n d 4Lb).
4Db: oil: Rf 0.17 (MeOH:CH2Cl2 ) 1:10); [R]25 -55.3 (c 1.19,
D
MeOH); 1H NMR (CD3OD) δ 3.69 (dd, J ) 2.7, 9.7 Hz, 1H,
5634 J . Org. Chem., Vol. 67, No. 16, 2002

Syntheses of myo-Inositol Tris- and Tetrakisphosphates
H-3), 3.94 (dd, J ) 2.7, 10.0 Hz, 1H, H-3), 4.13 (app. t, J ) 9.7
Hz, 1H, H-6), 4.17 (app. t, J ) 2.7 Hz, 1H, H-2), 5.41 (app. t,
J ) 9.8 Hz, 1H, H-5), 5.77 (app. t, J ) 10.0 Hz, 1H, H-4), 7.31-
7.92 (m, 10H, 2Ph); 13C NMR (CD3OD) δ 71.5, 72.4, 73.3, 74.2,
75.1, 76.1 (inositol ring carbons), 129.4-134.2 (2Ph), 167.7,
167.9 (2COPh); HRMS (FAB) m/z calcd for C20H21O8 389.1236,
found 389.1229 (M+ + H). 4Lb: oil; [R]2D5 +55.7 (c 0.93,
from compound 11Dc completely. Each isomer (11Da , 11Dc,
11Dd , 11De, and 11Df) was treated with 80% aq AcOH (100
°C, 3 h) and concentrated to give the corresponding IBz2
products (4Da , 4De, 4Lb, 4Lf, and 4Dd ) in quantitative yield,
respectively. Compounds 4La , 4Le, 4Db, 4Df, and 4Ld were
similarly prepared from compound 11La .
D- a n d L-1,2-Di-O-ben zoyl-3,4-O-isop r op ylid en e-m yo-
in ositol (11Dc a n d 11Lc). 11Dc: Rf 0.22 (EtOAc:CH2Cl2 )
1
MeOH); identical Rf, H NMR, and 13C NMR data to those of
1:3); mp 168-170 °C; [R]2D5 -81.7 (c 0.57, CHCl3); 1H NMR
(CDCl3) δ 1.38, 1.46 (2s, 6H, CMe2), 3.12 (br s, 1H, OH), 3.50
(br s, 1H, OH), 3.82 (dd, J ) 2.1, 9.7 Hz, 1H, H-3), 3.96 (app.
t, J ) 9.2 Hz, 1H, H-4), 4.15 (app. t, J ) 9.6 Hz, 1H, H-5),
4.23 (app. t, J ) 9.8 Hz, 1H, H-6), 5.34 (dd, J ) 3.1, 9.9 Hz,
1H, H-1), 6.10 (app. t, J ) 2.6 Hz, 1H, H-2), 7.26-8.03 (m,
10H, 2Ph); 13C NMR (CDCl3) δ 26.8, 27.2 (CMe2), 67.7, 72.8,
73.7, 74.6, 75.3, 76.5 (inositol ring carbons), 113.3 (CMe2),
128.7-133.8 (2Ph), 165.8, 166.4 (2COPh); MS (FAB) m/z 429
(M+ + H). Anal. Calcd for C23H24O8: C, 64.48; H, 5.65. Found:
C, 64.41; H, 5.98. 11Lc: mp 169-170 °C; [R]2D5 +81.8 (c 0.52,
4Db.
D- a n d L-1,4-Di-O-ben zoyl-m yo-in ositol (4Dc a n d 4Lc).
4Dc: Rf 0.17 (MeOH:CH2Cl2 ) 1:20); mp 222-225 °C; [R]D25
1
-16.7 (c 0.54, MeOH); H NMR (CD3OD) δ 3.62 (app. t, J )
9.4 Hz, 1H, H-5), 3.84 (dd, J ) 2.7, 10.0 Hz, 1H, H-3), 4.14
(app. t, J ) 9.7 Hz, 1H, H-6), 4.25 (app. t, J ) 2.6 Hz, 1H,
H-2), 4.97 (dd, J ) 2.6, 10.2 Hz, 1H, H-1), 5.51 (app. t, J ) 9.8
Hz, 1H, H-4), 7.45-8.16 (m, 10H, 2Ph); 13C NMR (CD3OD) δ
71.5, 72.1, 72.3, 74.7, 76.4, 77.1 (inositol ring carbons), 129.5-
134.4 (2Ph), 168.0, 168.3 (2COPh); MS (FAB) m/z 389 (M+
+
H). Anal. Calcd for C20H20O8: C, 61.85; H, 5.19. Found: C,
1
CHCl3); identical Rf, H NMR, and 13C NMR data to those of
61.73; H, 5.49. 4Lc: mp 223-225 °C; [R]2D5 +16.6 (c 0.41,
1
MeOH); identical Rf, H NMR, and 13C NMR data to those of
11Dc.
D- a n d L-5,6-Di-O-ben zoyl-3,4-O-isop r op ylid en e-m yo-
in ositol (11Dd a n d 11Ld ). 11Dd : Rf 0.25 (EtOAc:CH2Cl2 )
1:3); mp 122-125 °C; [R]2D5 +58.6 (c 0.23, CHCl3); 1H NMR
(CDCl3) δ 1.49 (s, 6H, CMe2), 2.94 (d, J ) 1.4 Hz, 1H, OH-2),
3.22 (d, J ) 8.1 Hz, 1H, OH-1), 3.73 (dd, J ) 1.9, 9.6 Hz, 1H,
H-3), 3.97 (app. dt, J ) 3.0, 8.4, 8.4 Hz, 1H, H-1), 4.42 (app. t,
J ) 9.7 Hz, 1H, H-4), 4.50 (br s, 1H, H-2), 5.61 (app. t, J ) 9.7
Hz, 1H, H-6), 5.69 (app. t, J ) 9.4 Hz, 1H, H-5), 7.32-7.97
(m, 10H, 2Ph); 13C NMR (CDCl3) δ 26.9, 27.4 (CMe2), 67.9, 71.8,
73.4, 73.6, 76.5, 77.6 (inositol ring carbons), 113.3 (CMe2),
128.7-133.8 (2Ph), 166.1, 167.7 (2COPh); MS (FAB) m/z 451
(M+ + Na), 429 (M+ + H). Anal. Calcd for C23H24O8: C, 64.48;
H, 5.65. Found: C, 64.15; H, 5.95. 11Ld : mp 122-124 °C; [R]
4Dc.
D- a n d L-1,5-Di-O-ben zoyl-m yo-in ositol (4Dd a n d 4Ld ).
4Dd : Rf 0.18 (MeOH:CH2Cl2 ) 1:15); mp 183-185 °C; [R]D25
1
-18.0 (c 0.50, MeOH); H NMR (CD3OD) δ 3.30 (dd, J ) 2.7,
9.8 Hz, 1H, H-3), 3.98 (app. t, J ) 9.7 Hz, 1H, H-4), 4.26 (app.
t, J ) 2.5 Hz, 1H, H-2), 4.29 (app. t, J ) 9.9 Hz, 1H, H-6),
5.02 (dd, J ) 2.7, 10.3 Hz, 1H, H-1), 5.17 (app. t, J ) 9.6 Hz,
1H, H-5), 7.45-8.14 (m, 10H, 2Ph); 13C NMR (CD3OD) δ 70.5,
71.7, 72.5, 73.1, 76.4, 78.4 (inositol ring carbons), 129.6-134.4
(2Ph), 167.8, 168.0 (2COPh); MS (FAB) m/z 389 (M+ + H).
Anal. Calcd for C20H20O8: C, 61.85; H, 5.19. Found: C, 61.55;
H, 5.47. 4Ld : mp 183-185 °C; [R]2D5 +19.1 (c 0.50, MeOH);
identical Rf, H NMR, and 13C NMR data to those of 4Dd .
1
25
D
1
-57.3 (c 0.24, CHCl3); identical Rf, H NMR, and 13C NMR
D- a n d L-1,6-Di-O-ben zoyl-3,4-O-isop r op ylid en e-m yo-
in ositol (11Da a n d 11La ). To a solution of compound 4Da
(1.24 g, 3.20 mmol) and TSA (72 mg) in DMF (12 mL) at 0 °C
was added 2-methoxypropene (0.8 mL, 8.1 mmol). After 30
min, the reaction mixture was warmed to room temperature,
stirred for additional 6 h, poured into aq NaHCO3 at 0 °C with
vigorous stirring, and extracted with EtOAc. The organic layer
was dried (MgSO4), concentrated, and chromatographed on
silica gel to give 11Da (1.01 g, 73.8%). The byproducts
including compound 2D and the monoacetonated IBz2 deriva-
tives were treated in boiling aq AcOH (80%) to give the starting
material 4Da , quantitatively. Similarly, compound 11La was
prepared from compound 4La . 11Da : Rf 0.46 (EtOAc:CH2Cl2
data to those of 11Dd .
D- a n d L-2,6-Di-O-ben zoyl-3,4-O-isop r op ylid en e-m yo-
in ositol (11De a n d 11Le). 11De: Rf 0.53 (EtOAc:CH2Cl2
)
1:3); mp 197-198 °C; [R]2D5 -62.8 (c 0.52, CHCl3); 1H NMR
(CDCl3) δ 1.30, 1.43 (2s, 6H, CMe2), 2.95 (br s, 1H, OH), 3.16
(br s, 1H, OH), 3.69 (dd, J ) 2.0, 9.6 Hz, 1H, H-3), 4.03-4.11
(m, 2H, H-1 & H-5), 4.19 (app. t, J ) 9.8 Hz, 1H, H-4), 5.45
(app. t, J ) 9.2 Hz, 1H, H-6), 5.93 (app. t, J ) 2.6 Hz, 1H,
H-2), 7.40-8.08 (m, 10H, 2Ph); 13C NMR (CDCl3) δ 26.7, 27.2
(CMe2), 69.6, 71.6, 71.9, 75.6, 76.8, 78.7 (inositol ring carbons),
113.4 (CMe2), 128.9-134.0 (2Ph), 166.4, 167.8 (2COPh); MS
(FAB) m/z 429 (M+ + H). Anal. Calcd for C23H24O8: C, 64.48;
H, 5.65. Found: C, 64.55; H, 5.90. 11Le: mp 199-201 °C; [R]
) 1:3); mp 219-221 °C; [R]2D5 -73.1 (c 0.7, CHCl3); H NMR
1
25
D
1
+62.2 (c 0.50, CHCl3); identical Rf, H NMR, and 13C NMR
(CDCl3) δ 1.48, 1.50 (2s, 6H, CMe2), 2.79 (br s, 1H, OH-2), 2.89
(br s, 1H, OH-5), 3.71 (dd, J ) 2.0, 9.7 Hz, 1H, H-3), 4.09 (app.
t, J ) 9.3, H, H-5), 4.32 (app. t, J ) 9.8 Hz, 1H, H-4), 4.69 (br
s, 1H, H-2), 5.36 (dd, J ) 2.9, 10.0 Hz, 1H, H-1), 5.81 (dd, J )
9.1, 10.0 Hz, 1H, H-6), 7.29-7.97 (m, 10H, 2Ph); 13C NMR
(CDCl3) δ 26.9, 27.4 (CMe2), 66.4, 72.2, 74.0, 75.2, 75.9, 76.9
(inositol ring carbons), 113.3 (CMe2), 128.8-133.9 (2Ph), 166.1,
167.1 (2COPh); MS (FAB) m/z 429 (M+ + H). Anal. Calcd for
data to those of 11De.
D- a n d L-1,5-Di-O-ben zoyl-3,4-O-isop r op ylid en e-m yo-
in ositol (11Df a n d 11Lf). 11Df: Rf 0.67 (EtOAc:CH2Cl2
)
1:3); mp 191-192 °C; [R]2D5 -13.0 (c 0.29, CHCl3:MeOH )
1
5:1); H NMR (CDCl3, with a few drops of CD3OD) δ 1.47 (s,
6H, CMe2), 3.78 (dd, J ) 1.9, 9.6 Hz, 1H, H-3), 4.30 (app. t, J
) 9.7 Hz, 1H, H-6), 4.36 (app. t, J ) 9.9 Hz, 1H, H-4), 4.60
(app. t, J ) 2.4 Hz, 1H, H-2), 5.14 (dd, J ) 3.0, 9.9 Hz, 1H,
H-1), 5.44 (dd, J ) 9.1, 10.0 Hz, 1H, H-5), 7.42-8.14 (m, 10H,
2Ph); 13C NMR (CDCl3, with a few drops of CD3OD) δ 26.5,
27.0 (CMe2), 65.5, 71.5, 73.5, 74.5, 76.2, 77.2 (inositol ring
carbons), 112.7 (CMe2), 128.5-133.5 (2Ph), 166.6, 166.7
(2COPh); MS (FAB) m/z 429 (M+ + H). Anal. Calcd for
C
23H24O8: C, 64.48; H, 5.65. Found: C, 64.60; H, 6.02. 11La :
mp 218-220 °C; [R]2D5 +71.8 (c 0.32, CHCl3); identical Rf, H
1
NMR, and 13C NMR data to those of 11Da .
Gen er a tion a n d Sep a r a tion of IBz2 Regioisom er s fr om
11Da a n d 11La . Compound 11Da (1.036 g, 2.42 mmol) in a
mixed solvent of pyridine-water (6:4, 50 mL) was heated at
100 °C for 3 h. The reaction mixture was cooled and concen-
trated under reduced pressure. The serial operation of EtOH
addition and evaporation were repeated twice. The crude
mixture, which contained almost equal amounts of six regio-
isomers, was chromatographed on silica gel (EtOAc:Hex )
1:5 f EtOAc gradient). The eluted sequence of the isomers
was 11Df, 11De, 11Da , 11Dd , 11Dc, and 11Db with the Rf
value of 0.67, 0.53, 0.33, 0.25, 0.22, and 0.21 (EtOAc:CH2Cl2
) 1:3). Of the six isomers, compound 11Db was not separated
C
23H24O8: C, 64.48; H, 5.65. Found: C, 64.15; H, 5.97. 11Lf:
mp 191-193 °C; [R]2D5 +15.1 (c 0.26, CHCl3:MeOH ) 5:1);
identical Rf, H NMR, and 13C NMR data to those of 11Df.
1
D- a n d L-1,2-Di-O-ben zoyl-m yo-in ositol (4De a n d 4Le).
4De: Rf 0.19 (MeOH:CH2Cl2 ) 1:10); mp 219-222 °C; [R]D25
1
-96.9 (c 0.53, MeOH); H NMR (CD3OD) δ 3.43 (app. t, J )
9.1 Hz, 1H, H-5), 3.78-3.88 (m, 2H, H-3 & H-4), 4.02 (app. t,
J ) 9.8 Hz, 1H, H-6), 5.11 (dd, J ) 2.8, 10.2 Hz, 1H, H-1),
5.85 (app. t, J ) 2.6 Hz, 1H, H-2), 7.32-8.01 (m, 10H, 2Ph);
J . Org. Chem, Vol. 67, No. 16, 2002 5635

Chung et al.
13C NMR (CD3OD) δ 71.4, 72.8, 73.9, 74.6, 74.7, 76.5 (inositol
ring carbons), 129.5-134.6 (2Ph), 167.5 (2C) (2COPh); MS
(FAB) m/z 389 (M+ + H). Anal. Calcd for C20H20O8: C, 61.85;
H, 5.19. Found: C, 61.90; H, 5.43. 4Le: mp 220-222 °C; [R]
+2.59 (c 1.75, CHCl3); 1H NMR (CDCl3) δ 4.26-5.17 (m, 17H,
H-1 & 8CH2Ph), 5.25-5.47 (m, 3H, H-3, H-4 & H-6), 5.60 (br
d, J ) 9.2 Hz, 1H, H-2), 5.71 (app. t, J ) 9.5 Hz, 1H, H-5),
6.71-8.12 (m, 50H, 10Ph); 13C NMR (CDCl3) δ 69.5, 69.5, 69.6,
69.7, 70.0, 70.1, 70.2, 70.4, 70.4, 70.6 (8CH2Ph), 70.6, 71.7, 74.2,
75.2, 75.6 (2C) (inositol ring carbons), 127.7-136.1 (10Ph),
165.7, 165.9 (2COPh); 31P NMR (CDCl3) δ 0.39, 1.17, 1.42, 1.53;
MS (FAB) m/z 1429 (M+ + H). 12Ld : oil; [R]2D5 -2.67 (c 1.40,
CHCl3); identical 1H NMR, 13C NMR, and 31P NMR data to
those of 12Dd .
25
D
1
+97.2 (c 0.48, MeOH); identical Rf, H NMR, and 13C NMR
data to those of 4De.
D- a n d L-2,4-Di-O-ben zoyl-m yo-in ositol (4Df a n d 4Lf).
4Df: Rf 0.24 (MeOH:CH2Cl2 ) 1:10); mp 191-193 °C; [R]D25
1
+84.2 (c 0.56, MeOH); H NMR (CD3OD) δ 3.60 (app. t, J )
9.4 Hz, 1H, H-5), 3.73 (dd, J ) 2.7, 9.8 Hz, 1H, H-1), 3.85 (app.
t, J ) 9.5 Hz, 1H, H-6), 4.01 (dd, J ) 2.8, 10.1 Hz, 1H, H-3),
5.53 (app. t, J ) 9.9 Hz, 1H, H-4), 5.75 (app. t, J ) 2.8 Hz,
1H, H-2), 7.43-8.14 (m, 10H, 2Ph); 13C NMR (CD3OD) δ 70.2,
72.0, 74.8, 75.0, 76.8, 77.4 (inositol ring carbons), 129.5-134.3
(2Ph), 168.0, 168.2 (2COPh); MS (FAB) m/z 389 (M+ + H).
Anal. Calcd for C20H20O8: C, 61.85; H, 5.19. Found: C, 61.49;
H, 5.42. 4Lf: mp 196-199 °C; [R]2D5 -82.1 (c 0.48, MeOH);
D- a n d L-2,3-Di-O-ben zoyl-m yo-in ositol 1,4,5,6-tetr a k is-
(d iben zyl p h osp h a te) (12De a n d 12Le) were prepared from
compounds 4Le and 4De, respectively. 12De: oil; [R]2D5 +6.93
1
(c 1.49, CHCl3); H NMR (CDCl3) δ 4.37-5.12 (m, 18H, H-1,
H-5 & 8CH2Ph), 5.15-5.28 (m, 2H, H-4 & H-6), 5.42 (dd, J )
2.9, 9.8 Hz, 1H, H-3), 6.25 (app. t, J ) 2.8 Hz, 1H, H-2), 6.79-
8.00 (m, 50H, 10Ph); 13C NMR (CDCl3) δ 69.5, 69.6, 69.9, 70.0,
70.1, 70.1, 70.2 (8CH2Ph), 69.2 (2C), 73.7, 75.8, 76.0, 76.4
(inositol ring carbons), 127.9-136.3 (10Ph), 165.4, 165.5
(2COPh); 31P NMR (CDCl3) δ 0.59, 0.72, 1.26, 1.59; MS (FAB)
m/z 1429 (M+ + H). 12Le: oil; [R]D25 -6.38 (c 1.40, CHCl3);
identical 1H NMR, 13C NMR, and 31P NMR data to those of
12De.
1
identical Rf, H NMR, and 13C NMR data to those of 4Df.
P h osp h or yla tion of IBz2 Regioisom er s (4Da -4Df a n d
4La -4Lf): Gen er a l P r oced u r e. To a solution of each IBz2
regioisomer (0.1 mmol) and 1H-tetrazole (142 mg, 2 mmol) in
CH2Cl2 (5 mL) at room temperature was added dibenzyl
diisopropylphosphoramidite (0.34 mL, 1 mmol). After 7 h, an
excess amount of mCPBA (800 mg) was added to the mixture
at 0 °C. After being stirred overnight at room temperature,
the mixture was diluted with CH2Cl2 and washed with aq Na2-
SO3, aq NaHCO3, and brine. The organic layer was dried
(MgSO4), concentrated, and chromatographed to give IP′4Bz2
regioisomers (12La -12Lf and 12Da -12Df) in 82-99% yields.
D- a n d L-3,4-Di-O-ben zoyl-m yo-in ositol 1,2,5,6-tetr a k is-
(d iben zyl p h osp h a te) (12Da a n d 12La ) were prepared from
compounds 4La and 4Da , respectively. 12Da : oil; [R]2D5 +21.3
(c 1.50, CHCl3); 1H NMR (CDCl3) δ 4.34 (dd, J ) 9.1, 11.8 Hz,
1H, CHaHbPh), 4.59 (br t, J ) 9.4 Hz, 1H, H-1), 4.68 (dd, J )
7.3, 11.8 Hz, 1H, CHaHbPh), 4.82-5.27 (m, 17H, H-3, H-5, H-6
& 7CH2Ph), 5.64 (br d, J ) 9.0 Hz, 1H, H-2), 6.16 (app. t, J )
10.1 Hz, 1H, H-4), 6.83-7.96 (m, 50H, 10Ph); 13C NMR (CDCl3)
δ 69.5, 69.6, 70.0, 70.1, 70.2, 70.4, 70.5 (8CH2Ph), 70.4, 74.2,
75.2, 75.3, 75.9, 76.9 (inositol ring carbons), 127.9-136.3
(10Ph), 165.7, 165.8 (2COPh); 31P NMR (CDCl3) δ 0.37, 0.91,
1.04, 1.53; MS (FAB) m/z 1451 (M+ + Na), 1429 (M+ + H).
D- a n d L-2,6-Di-O-ben zoyl-m yo-in ositol 1,3,4,5-tetr a k is-
(d iben zyl p h osp h a te) (12Df a n d 12Lf) were prepared from
compounds 4Lf and 4Df, respectively. 12Df: oil; [R]2D5 -20.6
(c 1.45, CHCl3); 1H NMR (CDCl3) δ 4.30 (dd, J ) 9.9, 11.7 Hz,
1H, CHaHbPh), 4.43 (dd, J ) 9.5, 11.8 Hz, 1H, CHcHdPh), 4.56-
4.71 (m, 3H, H-3, CHaHbPh & CHcHdPh), 4.79-5.10 (m, 14H,
H-1, H-5 & 6CH2Ph), 5.18 (app. q, J ) 9.6 Hz, 1H, H-4), 6.03
(app. t, J ) 9.9 Hz, 1H, H-6), 6.41 (app. t, J ) 2.7 Hz, 1H,
H-2), 6.82-8.08 (m, 50H, 10Ph); 13C NMR (CDCl3) δ 69.6, 69.7,
69.8, 69.9, 70.1, 70.4 (8CH2Ph), 70.5, 70.9, 73.8, 73.9, 76.2, 76.6
(inositol ring carbons), 128.0-136.2 (10Ph), 165.4, 165.7
(2COPh); 31P NMR (CDCl3) δ 0.65, 1.03, 1.19, 1.22; MS (FAB)
m/z 1429 (M+ + H). 12Lf: oil; [R]D25 +22.0 (c 1.35, CHCl3);
identical 1H NMR, 13C NMR, and 31P NMR data to those of
12Df.
P r ep a r a t ion of Sod iu m Sa lt s of m yo-In osit ol Tet r a -
k isp h osp h a te (13Da -13Df a n d 13La -13Lf): Gen er a l P r o-
ced u r e. To a solution of each IBz2P4 regioisomer, 12Da -12Df
and 12La -12Lf (100 mg, 0.07 mmol) in a solvent mixture of
EtOH-MeOH (1:1, 8 mL), was added 10% Pd/C (45 mg). The
mixture was stirred under H2 (50 psi) for 1 day. The catalyst
was filtered off and the solution was concentrated under
reduced pressure and treated with 1 N LiOH (6 mL) at 80 °C
for 5 h. The basic solution was cooled and loaded on Dowex
50WX8-100 (H+ form) and eluted with water. The acidic
effluent was collected, washed with CH2Cl2 three times, and
lyophilized to dryness. The residue was redissolved in a small
amount of water (1 mL) and the pH was adjusted to 10 with
NaOH and lyophilized again to give the sodium salts of myo-
inositol tetrakisphosphate (13Da -13Df and 13La -13Lf) in
approximately 90% yields.
12La : oil; [R]2D5 -20.8 (c 1.53, CHCl3); identical H NMR, 13C
1
NMR, and 31P NMR data to those of 12Da .
D- a n d L-5,6-Di-O-ben zoyl-m yo-in ositol 1,2,3,4-tetr a k is-
(d iben zyl p h osp h a te) (12Db a n d 12Lb) were prepared from
compounds 4Lb and 4Db, respectively. 12Db: oil; [R]D25
1
-2.98 (c 1.14, CHCl3); H NMR (CDCl3) δ 4.36-4.73 (m, 5H,
H-3 & 2CH2Ph), 4.83-5.31 (m, 13H, H-1 & 6CH2Ph), 5.34 (app.
q, J ) 9.6 Hz, 1H, H-4), 5.67 (m, 2H, H-2 & H-5), 6.09 (app. t,
J ) 10.1 Hz, 1H, H-6), 6.82-7.93 (m, 50H, 10Ph); 13C NMR
(CDCl3) δ 69.6, 69.7, 70.0, 70.1, 70.6, 70.7 (8CH2Ph), 71.1 (2C),
74.2 (2C), 75.7, 77.1 (inositol ring carbons), 127.9-136.1
(10Ph), 165.8, 165.9 (2COPh); 31P NMR (CDCl3) δ 0.13, 1.13,
1.18, 1.61; MS (FAB) m/z 1451 (M+ + Na), 1429 (M+ + H).
12Lb: oil; [R]2D5 +3.30 (c 1.76, CHCl3); identical H NMR, 13C
1
D- a n d L-m yo-In ositol 1,2,5,6-tetr a k isp h osp h a te sod iu m
sa lt (13Da a n d 13La ) were prepared from compounds 12Da
and 12La , respectively. 13Da : [R]2D5 -4.98 (c 1.93, H2O, pH
9.5); 1H NMR (D2O, pH 10) δ 3.49 (br d, J ) 9.5 Hz, 1H, H-3),
3.84-3.95 (m, 2H, H-4 & H-5), 4.01 (br t, J ) 10.0 Hz, 1H,
H-1), 4.36 (app. q, J ) 9.2 Hz, 1H, H-6), 4.57 (br d, J ) 6.9
Hz, 1H, H-2); 13C NMR (D2O, pH 10) δ 72.1, 73.7, 74.0, 75.3,
76.0, 78.2 (inositol ring carbons); 31P NMR (D2O, pH 10) δ 4.93,
6.47, 6.97, 7.28. 13La : [R]2D5 +4.19 (c 2.35, H2O, pH 8.6);
identical 1H NMR, 13C NMR, and 31P NMR data to those of
13Da .
NMR, and 31P NMR data to those of 12Db.
D- a n d L-3,6-Di-O-ben zoyl-m yo-in ositol 1,2,4,5-tetr a k is-
(d iben zyl p h osp h a te) (12Dc a n d 12Lc) were prepared from
compounds 4Lc and 4Dc, respectively. 12Dc: oil; [R]2D5 -6.06
1
(c 1.40, CHCl3); H NMR (CDCl3) δ 4.33-5.15 (m, 18H, H-1,
H-5 & 8CH2Ph), 5.35-5.46 (m, 3H, H-2, H-3 & H-4), 6.12 (app.
t, J ) 9.9 Hz, 1H, H-6), 6.79-8.15 (m, 50H, 10Ph); 13C NMR
(CDCl3) δ 69.7, 69.7, 69.9, 70.0, 70.1 (8CH2Ph), 70.3, 70.5, 74.1,
76.1 (2C), 77.1 (inositol ring carbons), 128.0-136.1 (10Ph),
165.7, 165.9 (2COPh); 31P NMR (CDCl3) δ 0.34, 0.99, 1.06, 1.35;
MS (FAB) m/z 1451 (M+ + Na), 1429 (M+ + H). 12Lc: oil; [R]
D- a n d L-m yo-In ositol 1,2,3,4-tetr a k isp h osp h a te sod iu m
sa lt (13Db a n d 13Lb) were prepared from compounds 12Db
and 12Lb, respectively. 13Db: [R]2D5 +19.0 (c 2.27, H2O, pH
25
D
1
+6.33 (c 1.24, CHCl3); identical H NMR, 13C NMR, and 31P
NMR data to those of 12Dc.
9.2) [lit.15i [R]D20 -6.6 (c 3.95, H2O, free acid)]; H NMR (D2O,
1
D- a n d L-3,5-Di-O-ben zoyl-m yo-in ositol 1,2,4,6-tetr a k is-
(d iben zyl p h osp h a te) (12Dd a n d 12Ld ) were prepared from
compounds 4Ld and 4Dd , respectively. 12Dd : oil; [R]D25
pH 10) δ 3.52 (app. t, J ) 8.3 Hz, 1H, H-5), 3.87-3.97 (m, 3H,
H-1, H-3 & H-6), 4.21 (app. q, J ) 8.6 Hz, 1H, H-4), 4.69 (br
5636 J . Org. Chem., Vol. 67, No. 16, 2002

Syntheses of myo-Inositol Tris- and Tetrakisphosphates
d, J ) 8.8 Hz, 1H, H-2); 13C NMR (D2O, pH 10) δ 73.0, 73.2,
74.1, 75.5, 76.2, 76.5 (inositol ring carbons); 31P NMR (D2O,
pH 10) δ 5.84, 7.34, 7.95, 8.12. 13Lb: [R]2D5 -19.9 (c 2.59,
H2O, pH 9.0) [lit.15i [R]D20 +4.8 (c 1.73, H2O, free acid)];
identical 1H NMR, 13C NMR, and 31P NMR data to those of
13Db.
adjusted by addition of cyclohexylammine)]; 1H NMR (D2O,
pH 10) δ 3.82 (br s, 1H, H-2), 4.05-4.11 (m, 2H, H-4 & H-6),
4.25-4.45 (m, 3H, H-1, H-3 & H-5); 13C NMR (D2O, pH 10) δ
72.3, 74.0 (2C), 75.2 (2C), 75.5 (inositol ring carbons); 31P NMR
(D2O, pH 10) δ 5.03, 5.50, 6.25, 6.99. 13Le: [R]25 +10.1 (c
D
2.23, H2O, pH 8.9) [lit. [R]24 +9.8 (c 1.43, H2O, pH 11.1,
D
D- a n d L-m yo-In ositol 1,2,4,5-tetr a k isp h osp h a te sod iu m
sa lt (13Dc a n d 13Lc) were prepared from compounds 12Dc
and 12Lc, respectively. 13Dc: [R]2D5 -13.2 (c 1.65, H2O, pH
9.8) [lit. [R]D -13.3 (c 1.0, H2O, pH 10, sodium salt),15h [R]D
-27.2 (c 0.50, H2O, pH 8.6, triethylammonium hydrogen
carbonate salt)15g]; 1H NMR (D2O, pH 10) δ 3.59 (br d, J ) 8.7
Hz, 1H, H-3), 3.88-3.97 (m, 3H, H-1, H-5 & H-6), 4.28 (app.
q, J ) 8.9 Hz, 1H, H-4), 4.61 (br d, J ) 8.1 Hz, 1H, H-2); 13C
NMR (D2O, pH 10) δ 71.1, 72.1, 74.5, 74.8, 77.3, 78.3 (inositol
ring carbons); 31P NMR (D2O, pH 10) δ 3.98, 4.69, 5.59, 5.69.
13Lc: [R]2D5 +14.9 (c 2.08, H2O, pH 9.8) [lit. [R]D +12.1 (c 1.0,
H2O, pH 10, sodium salt),15h [R]D +25.8 (c 0.31, H2O, pH 8.6,
sodium salt, adjusted by addition of cyclohexylammine),15e [R]D
1
-6.2 (c 2.15, H2O, pH 9.5, sodium salt)15c]; identical H NMR,
13C NMR, and 31P NMR data to those of 13De.
D- a n d L-m yo-In ositol 1,3,4,5-tetr a k isp h osp h a te sod iu m
sa lt (13Df a n d 13Lf) were prepared from compounds 12Df
and 12Lf, respectively. 13Df: [R]2D5 -4.08 (c 2.02, H2O, pH
9.7) [lit. [R]D24 -13 (c 1.0, H2O, ammonium salt),15a [R]2D3 -3.5
(c 5.5, H2O, pH 8.3, potassium salt),14k,m [R]D25 -2.5 (c 1,
H2O, cyclohexylammonium salt),15b [R]D24 -4.51 (c 0.13, H2O,
1
sodium salt)14w]; H NMR (D2O, pH 10) δ 3.84-3.95 (m, 4H,
H-1, H-3, H-5 & H-6), 4.30 (app. q, J ) 9.3 Hz, 1H, H-4), 4.66
(br s, 1H, H-2); 13C NMR (D2O, pH 10) δ 70.1, 73.0, 73.7, 74.2,
74.5, 78.0 (inositol ring carbons); 31P NMR (D2O, pH 10) δ 5.80,
6.42, 6.92, 7.38. 13Lf: [R]2D5 +4.68 (c 2.11, H2O, pH 8.9) [lit.15b
1
triethylammonium hydrogen carbonate salt)15g]; identical H
NMR, 13C NMR, and 31P NMR data to those of 13Dc.
D- a n d L-m yo-In ositol 1,2,4,6-tetr a k isp h osp h a te sod iu m
sa lt (13Dd a n d 13Ld ) were prepared from compounds 12Dd
and 12Ld , respectively. 13Dd : [R]2D5 -15.2 (c 2.10, H2O, pH
[R]2D5 +2.6 (c 1, H2O, cyclohexylammonium salt)]; identical H
1
NMR, 13C NMR, and 31P NMR data to those of 13Df.
1
9.5); H NMR (D2O, pH 10) δ 3.49-3.55 (m, 2H, H-3 & H-5),
Ack n ow led gm en t. This work was supported by the
Korea Science & Engineering Foundation/Center for
Biofunctional Molecules and the Ministry of Education/
Basic Science Research Institute.
3.88 (app. t, J ) 9.6 Hz, 1H, H-1), 4.19-4.30 (m, 2H, H-4 &
H-6), 4.64 (br d, J ) 7.1 Hz, H-2); 13C NMR (D2O, pH 10) δ
72.1, 72.6, 75.5 (2C), 75.8, 77.9 (inositol ring carbons); 31P NMR
(D2O, pH 10) δ 6.87, 6.96, 7.19, 7.82. 13Ld : [R]25 +14.7 (c
1.77, H2O, pH 9.5); identical 1H NMR, 13C NMR, anDd 31P NMR
data to those of 13Dd .
Su p p or t in g In for m a t ion Ava ila b le: 1H spectra of
compounds 6Da , 6Df, 9Da -9Dh , 10Dc, 10De, 3Db, 4Db,
12Da -12Df, 13Da , and 13Dd . This material is available
free of charge via the Internet at http://pubs.acs.org.
D- a n d L-m yo-In ositol 1,4,5,6-tetr a k isp h osp h a te sod iu m
sa lt (13De a n d 13Le) were prepared from compounds 12De
and 12Le, respectively. 13De: [R]2D5 -8.99 (c 1.85, H2O, pH
9.5) [lit.15e [R]D24 -10.2 (c 2.46, H2O, pH 10.7, sodium salt,
J O0257694
J . Org. Chem, Vol. 67, No. 16, 2002 5637