Regioselective functionalization of unprotected myo-inositol by electrophilic substitution

Article abstract of DOI:10.1016/j.tet.2013.03.109

Unprotected myo-inositol was treated with various electrophiles, such as aroyl chlorides, tosyl chloride and tert-butyldiphenylsilyl chloride in a solution of LiCl/DMA or DMSO to afford regioselectively 1,3-di-O-substituted or racemic 1-O-substituted deri

Full text of DOI:10.1016/j.tet.2013.03.109

Tetrahedron 69 (2013) 4657e4664
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective functionalization of unprotected myo-inositol
by electrophilic substitution
*
Yutaka Watanabe , Tsuyoshi Uemura, Satoe Yamauchi, Kousei Tomita, Takafumi Saeki,
Ryousuke Ishida, Minoru Hayashi
Department of Materials Science and Biotechnology, Graduate School of Science and Engineering, Ehime University, Matsuyama 790-8577, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Unprotected myo-inositol was treated with various electrophiles, such as aroyl chlorides, tosyl chloride
and tert-butyldiphenylsilyl chloride in a solution of LiCl/DMA or DMSO to afford regioselectively 1,3-di-O-
substituted or racemic 1-O-substituted derivatives, depending on a quantity of reagents and reaction
Received 29 January 2013
Received in revised form 28 March 2013
Accepted 31 March 2013
Available online 6 April 2013
time. a-Unbranched alkanoic acid anhydrides in LiCl/DMA in the presence of triethylamine were suitable
for acylation of myo-inositol, in contrast to the fact that acylation using alkanoyl chlorides in aprotic polar
solvents generally does not proceed well due to decomposition of the reagents by the reaction with the
solvents.
Keywords:
myo-Inositol
LiCl
Ó 2013 Elsevier Ltd. All rights reserved.
N,N-Dimethylacetamide
Regioselective substitution
Dimethyl sulfoxide
1. Introduction
not been applied to unprotected inositol, one of the important cy-
clitols. Enzymatic hexadecanoylation of myo-inositol (1) was re-
It is generally unavoidable to use protecting groups in multi-
step synthesis of target organic molecules. Polyhydroxy com-
pounds, such as carbohydrates and cyclitols have been often used
as starting material for total synthesis of natural products and so
on,1 and for preparation of synthetic tools, such as chiral ligands
and organocatalysts.2 However, straightforward introduction of
a desired functionality at the specified position as the first step is
synthetically problematic, because they have more than one hy-
droxyl group with more or less similar reactivity. The polyols are
generally transformed first to acetal derivatives for temporal pro-
tection.3 Such use of temporary protecting groups increases the
number of steps to reach the target molecule and decreases the
overall efficiency of the synthesis. Therefore, the direct function-
alization of a starting polyol is highly desirable, especially to obtain
useful materials with a variety of applications. Stannylene meth-
odology4 and its catalytic versions5 have been shown to be effective
for regioselective substitution of unprotected glycosides. The sim-
ilar borinic acid catalyzed substitution methodology was recently
reported.6 Recent approaches using chiral tertiary amines accom-
plished regioselective acylation of unprotected saccharides.7,8
However, such methodologies for the selective substitution have
ported briefly to yield 1-O-acylated product,9 whereas enzymatic
acylation has been comprehensively explored.10
myo-Inositol and chiro-inositol have been used as the starting
materials for the synthesis of physiologically important inositol
derivatives11 as well as for the total synthesis of various natural
products12 and analogues.13 Also they have been used as precursor
for liquid crystals,14 surfactant,15 metal-complexing agents16 and
gelators.17 Almost all these molecules were synthesized via inositol
monoketals, diketals, or the orthoesters.18 Common substitution
reactions, such as acylation, sulfonylation, silylation of unprotected
inositols could not be used synthetically, even though there are
many reports on the regioselective substitution of partially pro-
tected inositols at the mesomeric 1- and/or 3-OH positions adjacent
to the axial 2-OR.18 A trial of a chemical acylation of 1 by trans-
esterification under basic conditions afforded a mixture of all four
possible monoesters in low yield.15e The available chemical method
to introduce a substituent at 1-OH takes six steps as evident in the
synthesis of racemic 1-O-acyl-myo-inositol 6.y Briefly, 1,2-
cyclohexylidene ketal 2 derived from 1 in two steps, was fully
benzylated, hydrolyzed, acylated and then debenzylated to yield
the target molecule 6 (Scheme 1).15e Similarly, mesomeric 1,3-di-O-
y
* Corresponding author. Tel./fax: þ81 89 927 9921; e-mail address: wyutaka@
All compounds in the text are racemic or mesomeric. The structures portrayed
dpc.ehime-u.ac.jp (Y. Watanabe).
correspond, for convenience, to one enantiomer, but the DL-form is implied.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.109

4658
Y. Watanabe et al. / Tetrahedron 69 (2013) 4657e4664
3.4 equiv of LiCl was needed, and 8(w/v)% LiCl solution was usually
employed. Aromatic acid chlorides and pivaloyl chloride with no
proton afforded 1,3-di-O-substituted products in good to excellent
yields (Table 1). An -branched alkanoyl chloride, diphenylacetyl
a
-
a
chloride was treated with 1 in the presence of excess of pyridine and
a catalytic amount of DMAP instead of triethylamine to give 1,3-
diacyl derivative in good yield. The 1,3-di-O-silylation using tert-
butyldiphenylsilyl chloride and 1,1,3,3-tetraisopropyldisiloxanyl
dichloride was accomplished well in a solution of DMSO and pyri-
dine (5:3) in place of LiCl/DMA and triethylamine, furnishing 11f and
12, respectively. The latter product was smoothly formed in 88%
yield, while the reaction in pyridine under suspension conditions
proceeded sluggishly giving the same product in 66%.24,25 The LiCl/
DMA medium was generally better for substitution reactions than
DMSO, except for silylation, mainly because the latter solvent is
more nucleophilic to react predominantly with an electrophile
rather than with 1.
Disubstitution products thus obtained were often water soluble,
therefore, in such cases trimethylsilylation of the products was
carried out in situ after the substitution reaction followed by ex-
traction into an organic layer. The TMS ethers 12 were transformed
back without isolation to the desired products by trifluoroacetic
acid catalyzed methanolysis. Since the silylation and desilylation
both proceed quantitatively with simple operation, the procedure
is quite convenient to separate a water soluble product from LiCl
and DMA.
Scheme 1. Representative procedure for synthesis of racemic 1-O-substituted myo-
inositol.
substituted myo-inositol derivatives, 1,3-dibenzoate 11a was pre-
pared from 1 in five steps via orthoester 7 (Scheme 2).19 The
monoesters and dibenzoate were prepared as the key intermediate,
respectively, to develop an inositol-based surfactant and to search
the biological activity of inositol derivatives. If the mono- and di-
substituted inositols can be obtained directly from 1, a variety of
functional molecules as described above can be conveniently pre-
pared. In this context, we recently exploited the regioselective 1,3-
di-O-substitution method giving dibenzoate 11a, ditosylate, and so
on in excellent yields.20 The method was achieved by dissolving 1
in N,N-dimethylacetamide (DMA) containing LiCl or dimethyl
sulfoxide (DMSO). We have further studied the use of dissolution
methodology for the introduction of aliphatic substituents on the
hydroxyls at the 1 and 3 positions, and for monosubstitution at the
1-OH. We report herein the full details of the selective dis-
ubstitution and monosubstitution of myo-inositol (1).
In the case of introduction of an alkanoyl group with the
a-
methylene, the acid chloride was not suitable as an electrophile
under the same reaction conditions as described above. For ex-
ample, when hexanoyl chloride was used in the presence of trie-
thylamine in LiCl-DMA, the corresponding ketene dimer was
formed predominantly.26 The chloride in the presence of pyridine
was consumed mainly in the Vilsmier-type reaction with DMA.27 To
avoid these undesirable reactions, we chose next a less reactive acid
anhydride as an acylating agent. Thus, the reaction of hexanoic
anhydride with 1 in the presence of triethylamine and catalytic
amount of dibutyltin dipivalate (15, R0¼t-Bu)28 proceeded smoothly
at 0 ꢀC to give selectively 1,3-di-O-hexanoate in 86% yield. In
a similar manner, acetic, octanoic and dodecanoic acid anhydrides
acylated myo-inositol 1 selectively in good yields. Because of the
low solubility of dodecanoic anhydride in DMA, the anhydride was
treated in a mixed solvent system of DMA and CH2Cl2 (3:2). Since
both dissolution in DMA and commercial availability of alkanoic
anhydrides with a long chain are difficult, the corresponding long
chain alkanoic acids were activated by the formation of mixed
anhydrides with pivaloyl chloride, giving a result similar to that
obtained in the case of the symmetric anhydride (Table 2, run 3 and
6). The tin(IV) reagent was important to accomplish the selective
reaction, as its absence resulted in further acylation and reduced
selectivity. When the tin diacetate (15, R0¼Ac) instead of the dipi-
valate was used, the desired 1,3-dihexanoyl product 14b was ac-
companied by the mixed ester, 1-O-acetyl-3-O-hexanoyl derivative.
A combination of a carboxylic anhydride and triethylamine is
not a practical procedure to acylate an alcohol in good yield.
Therefore, the successful acylation of 1 in DMA may be accom-
plished by an assistance of LiCl. The same combination of anhy-
dride, triethylamine, and LiCl is used for N-acylation of 2-
oxazolidinones.29 In order to explore the role of LiCl, benzoyla-
tion of alcohols with benzoic anhydride was carried out in the
presence or absence of LiCl. Promotion of the reaction by LiCl was
observed especially in the case of secondary alcohol (Table 3, run
4 and 5). Replacement of LiCl with LiClO4 reduced the yield
similar to that obtained in the absence of an additive. These re-
sults show that the chloride anion participates in the promotion
of the reaction rather than the lithium cation. A similar contri-
bution of the chloride was reported in the decomposition of
Scheme 2. Reported procedure for synthesis of 1,3-di-O-substituted myo-inositol.
2. Results and discussion
2.1. Synthesis of 1,3-di-O-substituted myo-inositol derivatives
According to the conventional procedure for acylation of an al-
cohol, inositol 1 was treated with 2.3 M equiv of 1-naphthoyl
chloride in pyridine at 0 ꢀC for 12 h to yield surprisingly a mix-
ture of acylated products including fully acylated product and two
pentacyl derivatives (Scheme 3). The result may be explained by
assuming that the low solubility of myo-inositol in pyridine retards
the initial acylation step and increase in the number of substituents
on the inositol accelerates the reaction due to increase in solubility.
On the basis of this consideration, we searched for a solvent suit-
able for dissolving the inositol, and found DMSO and LiCl-DMA21 to
be candidates for the purpose. A DMSO solution of 1 enabled
a successful isopropylidenation22 as well as a full methylation.23
As expected, inositol 1 in a solution of 8% LiCl/DMA reacted
smoothly in the presence of triethylamine at ꢁ10 ꢀC with 1-
naphthoyl chloride to give 1,3-di-O-(1-naphthoyl)-myo-inositol
11b exclusively in 83% yield, while the suspension conditions de-
scribed above gave only 6% of 11b. To dissolve 1 in DMA, at least

Y. Watanabe et al. / Tetrahedron 69 (2013) 4657e4664
4659
Scheme 3. Naphthoylation of myo-inositol under homogeneous and heterogeneous conditions.
carboxylic and carbonic mixed anhydrides by LiCl.30 It is obvious,
however that, since benzoyl chloride did not work for benzoyla-
tion (Table 3, run 6), the active species is not the chloride itself,
which may be derivatized by decomposition of the anhydride
with the chloride ion. On the other hand, it is assumed in the
synthesis of N-acyl-2-oxazolidinone that the Li cation activates
anhydride or oxazolidinone by chelation.29a Such a role of the Li
cation may also be considerable in the present reaction. Conse-
quently, the cooperative action of LiCl as a Lewis acid by the
lithium cation and nucleophilic property by the chloride ion, is
now plausible.
There have been so far two reports on the preparation of 1,3-
symmetrically substituted myo-inositols. According to the litera-
ture, ditosylate31 and dibenzoate19 were obtained from 1 in five
steps each. They are now available directly from inositol 1 without
protection. Thus, the present regioselective O-substitution method
based on a solubilization strategy opens the way to create prom-
ising materials bearing inositol with a variety of functions.
Table 1
Synthesis of 1,3-di-O-substituted myo-inositol 11 using various kinds of chlorides
OH
OH
Base
O
R
O
R
OH
OH
HO
HO
+
R-Cl
8% LiCl/DMA
or DMSO
OH
HO
OH
OH
11
1
Run
1
ReCl (equiv)
Base
(equiv)
Solv.a
Temp
Time, h
Yield, %
95b
a PhCOeCl (3)
CO-Cl
Et3N (7)
A
A
ꢁ10 ꢀC
ꢁ10 ꢀC
4
2
Et3N (7)
20
83
b
(3)
CO2-Cl
CO2-n-C6H13
3
Et3N (7)
Et3N (5)
Py (16), DMAP (cat.)
Py (exs)
Et3N (5)
Et3N (7)
Py (exs)
A
ꢁ10 ꢀC
9
85
(2.5)
c
4
5
6
7
8
9
d t-BuCOeCl (3)
e Ph2CHCOeCl (2.7)
f t-BuPh2SieCl (3)
g p-MePhSO2eCl (2.4)
h Ph2P(O)eCl (3)
i [i-Pr2Si(Cl)]2eO (2.2)
A
A
B
A
A
B
0
ꢀC
10
4
72
24
20
20
88b
80
89
ꢁ10 ꢀC
rt
0
0
ꢀC
ꢀC
87
86b
88c
rt
a
A: 8% LiCl/DMA; B: DMSO/pyridine (5:3).
The TMS derivative 13 was used for extraction with AcOEt.
The product is the disiloxanylidene derivative 12 shown below.
b
c
OTMS
O
OH
O
O
O
R
R
O
O
O
O
Sii-Pr2
Sii-Pr2
i-Pr2Si
i-Pr2Si
OTMS
OTMS
TMSO
OH
12
13

4660
Y. Watanabe et al. / Tetrahedron 69 (2013) 4657e4664
Table 2
(racemic mixture) as a major product accompanied by traces of 1,3-
Acylation of myo-inositol with alkanoic anhydrides
disubstitution product 11 (Table 4). Both products were isolated via
the trimethylsilylation and desilylation procedure. Exceptionally,
diastereomeric 1-O-(ꢁ)-menthyloxycarbonyl-myo-inositol (16f)
was extracted with AcOEt without the silylation and isolated by
silica gel chromatography.
+
(RCO)2O
2.4 equiv
1
O
RC
O
O
CR
Et3N, n-Bu2Sn(O2CR')2
15 0.1 equiv
OH
O
5.0 equiv
Monobenzoate 16a was reported to be obtained in 43% yield
accompanied with 17% of dibenzoate by the successive three-step
procedure involving full diethylborylation, partial stannylidena-
tion and then benzoylation.32 Monotosylate 16h was prepared by
multi-step procedures (four33 and six34 steps, respectively), in
which both the tosylations of partially protected inositols took long
time and needed even application of heat in one case (5 ꢀC, 24 h
then rt, 6 days for the former and rt, 4 days then 80 ꢀC, 3 h for the
latter).
The diastereomeric carbonates 16f were derived by the bor-
onetin methodology described above and optically resolved to two
stereoisomers by crystallization.35 One of them was used as the
optically active intermediate to synthesize inositol 1,4,5-
trisphosphate35 and glycosyl inositols.36 Thus, the chiral carbon-
ate is one of two generally applicable chiral inositol intermediates
including camphor ketal.37 Inositol 1-fatty acid esters are being
explored as surfactants.15a,e We have now synthesized these useful
inositol derivatives directly in one-step from myo-inositol 1 with-
out protection.
OH
8% LiCl/DMA
(ac: R'=CH3, piv: R'=t-Bu)
HO
OH
14
Run
R (anhydride)
15
Temp
Time
Yield, %
1
2
3
4
5
6
a CH3
ac
ꢁ10 ꢀC
2 h
90
86
87
70
85
76
b CH3(CH2)4
c CH3(CH2)6
d CH3(CH2)10
e cis-9-C17H33
piv
piv
piv
piv
piv
0 ꢀ
0 ꢀ
0 ꢀ
0 ꢀ
0 ꢀ
C
C
C
C
C
2.5 h
2.5 h
16 ha
12 h
5.5 h
b
c CH3(CH2)6
a
LiCl-DMA/CH2Cl2 (3:2) used in place of LiCl-DMA.
The mixed anhydride with pivalic acid used.
b
Table 3
Effect of LiCl on the reaction of benzoic anhydride
additive, Et3N
2.0 equiv
+
(PhCO)2O
PhC(O)OR
ROH
DMA,
r.t., 3 h
1.2 equiv
The 1,3-disiloxanylidene protecting group is useful for the
partial protection of vicinal diol in polyols.38 It has been well
employed for the synthesis of inositol derivatives24 as biologically
active compounds22b,39 and gelators.17a,b Considering these re-
ports, 1,6-O-disiloxanylidene inositol 17 may be recognized as
a widely applicable synthetic intermediate. Thus, the reaction of 1
with half molar equivalent of TIPDS-Cl2 in the presence of pyridine
in DMSO/DMF proceeded smoothly to give 17 in 65% yield
(Scheme 4).
Run
ROH
Additive
(equiv)
Yield,
%
1
2
3
4
Ph(CH2)3OH
Ph(CH2)3OH
Ph(CH2)3OH
PhCH(CH3)OH
PhCH(CH3)OH
PhCH(CH3)OH
d
54
61
81
6
50
6
LiClO4 (1.9)
LiCl (2.6)
d
5
LiCl (2.3)
d
6a
a
PhCOCl used in place of the anhydride.
OH
TIPDS-Cl2 Py
OH
0.5 equiv 1.2 equiv
OH
OH
OH
OH
HO
HO
Si O
O
2.2. Synthesis of 1-O-substituted DL-myo-inositol derivatives
DMSO/DMF (5:3)
Si
O
0
,12 h
OH
1
OH
17
We next tried a selective monosubstitution at the one of two
chemically equivalent 1- and 3-OH in 1. After many trials, changing
the reaction time and reducing the quantity of electrophile resulted
in the formation of regioselectively monosubstituted derivative 16
(racemic, 65%)
Scheme 4. Selective mono(disiloxanylation) of myo-inositol.
Table 4
Synthesis of 1-O-mono-substituted DL-myo-inositols
OH
OH
HO
HO
O-R
OH
HO
HO
OH
OH
Base
R-X
+
+
11
8% LiCl/DMA
or DMSO/Py
OH
OH
1
16 (racemic)
Run
ReX (equiv)
a PhCOeCl
b p-(n-C6H13O)PhC(O)eCl
c t-BuCOeCl
d [n-C5H11C(O)]2O
e n-C7H15C(O)O(O)Ct-Bu
f (ꢁ)-Menthyl-OC(O)eCl
g t-BuPh2SieCl
h p-MePhS(O)2eCl
i p-C12H25PhS(O)2eCl
j (n-BuO)2P(O)eCl
Base (equiv)
Solv.a
Temp
Time
Yield, %
16
11
1
2
3
4
5
6
7
8
9
(1.5)
Et3N (4)
Et3N (5)
Et3N (3)
Et3N (3)
Et3N (3)
Py (16)
Py (exs), DMAP (cat.)
Et3N (5)
Et3N (5)
A
A
A
A
A
A
B
A
A
A
ꢁ23 ꢀC
2 h
24 h
2.5 h
70 min
1.5 h
10 min then 14 h
20 h
10
24
78b
63
72
61
55
78
51
59
66
56
13
20
21
12
7
d
13
8
(1.3)
(1.5)
(1.2)
(1.2)b
(1.5)
(0.8)
(1.8)
(1.5)
(1.3)
0 ꢀ
C
ꢁ10 ꢀC
ꢁ15 ꢀC
ꢁ15 ꢀC
0
ꢀC then rt
rt
0 ꢀ
rt
C
16
d
10
Et3N (1.5)
0 ꢀC then rt
5 min then 16 h
a
A: 8% LiCl/DMA; B: DMSO/Pyridine (5:3).
Prepared prior to use and used without purification.
b

Y. Watanabe et al. / Tetrahedron 69 (2013) 4657e4664
4661
3. Conclusion
heated at about 120 ꢀC until the mixture became a clear solution
(about 3 min). After addition of Et3N (391 mg, 3.89 mmol), the
resulting solution was kept at ꢁ10 ꢀC, and then 1-naphthoyl chloride
(317 mg, 1.67 mmol) was added. The mixture was stirred at the same
temperature for 20 h. H2O (about 0.1 mL) was added and the mixture
was stirred for 10 min, partitioned to AcOEt and H2O layers. The
aqueous solution was extracted three times with AcOEt. The com-
bined extract was washed with H2O (ꢂ3) and brine, dried over
Na2SO4, filtered, and then evaporated. The residue was recrystallized
from AcOEt/hexane to give crystals 11b (193 mg, 71%). The remaining
dinaphthoate (32 mg, 12%) was isolated from the mother liquor by
a flash column chromatography on silica gel (MeOH/CHCl3 1:14), Rf
0.4 (MeOH/CHCl3 1:10); mp 195.5e196.0 ꢀC (AcOEt/Hexane); 1H NMR
A direct functionalization of 1- and 3-OH in myo-inositol 1 by
acyl, sulfonyl, phosphinyl and silyl groups has now been achieved
efficiently by conducting the reaction in a solution in DMA con-
taining LiCl and DMSO. The similar procedure using a limited
amount of electrophiles yielded 1-O-mono-substituted derivatives
predominantly. These inositol derivatives themselves may be used
as candidates of functional materials, such as surfactants.15 They
may be also useful intermediates for synthesis of a variety of
compounds including natural and analogous products, monomers
for polymer synthesis, and so on.
4. Experimental
(270 MHz, CD3OD)
d
3.61 (1H, t, J¼9.6 Hz), 4.23 (2H, t, J¼9.6 Hz), 4.73
(1H, t, J¼2.4 Hz), 5.26 (2H, dd, J¼9.6 and 2.4 Hz), 7.61 (6H, complex),
7.96(2H, d, J¼8.0 Hz), 8.11 (2H, d, J¼8.4 Hz), 8.41 (2H, d, J¼7.2 Hz), 9.00
4.1. General method
(2H, d, J¼8.4 Hz); 13C NMR (100 MHz, CDCl3)
d 69.58, 72.26 (2C), 76.30
myo-Inositol (1, Tsuno Food CO Ltd) was dried by heating at
200 ꢀC for 12 h under reduced pressure (0.5 mmHg). Anhydrous
DMA and DMSO were obtained by treating with powdered BaO and
CaH2 overnight, respectively, and subsequent distillation (about
70 ꢀC/25 mmHg and about 40 ꢀC/1 mmHg). LiCl is so hygroscopic
that it was weighed quickly in a reaction vessel and dried by ap-
plication of heat at about 400 ꢀC under reduced pressure
(0.5 mmHg) for a few min. Its DMA solution was first prepared by
addition of 1 and the solvent, and then necessary reagents for the
reaction were added. TLC Silica gel 60 F254 (Merck Ltd. Japan) was
used for analytical TLC. Flash column chromatography was per-
formed using silica gel (Fuji Silysia Chemical Ltd. BW-300).
(2C) 77.04, 125.9, 127.2, 127.6, 128.8, 128.9, 129.9, 131.9, 132.9, 134.8,
135.5 (10C), 169.0; IR (KBr) 3461 (broad), 3360 (shoulder), 1715,
1692 cmꢁ1; LRMS (FABþ, m-nitrobenzyl alcohol) m/z: 689 [Mþ1]þ;
Anal. Calcd for C28H24O8: C, 68.85; H, 4.95. Found: C, 68.56; H, 4.91.
4.2.3. Synthesis of 1,3-di-O-hexanoyl-myo-inositol (14b) in the
presence of dibutyltin dipivalate. To a DMA (1 mL) solution of 1
(100 mg, 0.55 mmol) and LiCl (80 mg, 1.89 mmol) were added
triethylamine (281 mg, 2.78 mmol) and dibutyltin dipivalate
(24 mg, 0.05 mmol), the mixture was cooled at 0 ꢀC, and then
hexanoic anhydride (173 mg, 1.33 mmol) was added slowly. The
mixture was stirred for 2.5 h, TMSCl (1 mL, 7.82 mmol) and pyridine
(2 mL) were added at the same temperature, then the reaction was
continued at rt for 2 h. The resulting mixture was cooled at 0 ꢀC,
a few drops of water was added, and stirring was continued for
10 min. After addition of ethyl acetate, the organic layer was
washed sequentially with H2O (ꢂ2), 1 N HCl, H2O, saturated
aqueous NaHCO3, H2O, and brine, tried over MgSO4, and concen-
trated. The residue in chloroform (2 mL) and methanol (4 mL) was
mixed with two drops of trifluoroacetic acid, the mixture was
stirred for 2 h at rt, and then volatile materials were distilled off
under reduced pressure. The residue was purified by a flash column
chromatography (MeOH/CHCl3 1:15) to furnish 14b (180 mg, 86%).
Rf 0.4 (MeOH/CHCl3 1:10); mp 145e147 ꢀC (AcOEt/Hexane); 1H
4.2. Representative procedures for synthesis of 1,3-di-O-
substituted myo-inositol
4.2.1. Synthesis of 1,3-di-O-benzoyl-myo-inositol (11a) via the tri-
methylsilylation procedure. To a reaction flask containing LiCl
(400 mg, 9.44 mmol) was added myo-inositol (100 mg, 0.55 mmol)
and DMA (5 mL), and the mixture was heated at about 120 ꢀC until
the mixture became a clear solution (about 3 min). After addition of
Et3N (391 mg, 3.89 mmol), the resulting solution was kept at
ꢁ10 ꢀC, and then benzoyl chloride (234 mg, 1.67 mmol) was added.
The mixture was stirred at the same temperature for 4 h, and
chlorotrimethylsilane (1 mL, 7.82 mmol) and pyridine (2 mL) were
carefully added. The mixture was stirred at 0 ꢀC for 5 h, and diluted
with H2O and AcOEt. After partition to two layers, the aqueous layer
was extracted with AcOEt (ꢂ3). The combined organic layer was
washed successively with H2O (ꢂ2), 0.5 N HCl solution, H2O, sat-
urated NaHCO3 solution, H2O, and then brine, dried over Na2SO4,
filtered and evaporated. The residue was dissolved in a small vol-
ume of CHCl3 (1 mL), and MeOH (5 mL) and CF3CO2H (74 mg,
0.64 mmol) were added. The solution was stirred for 4 h at rt, and
all the volatile materials were distilled off under reduced pressure
(1.0 mmHg). The residue was subjected to a column chromatogra-
phy on silica gel (MeOH/CHCl3 1:10) to give crystalline 1,3-di-O-
benzoate (205 mg, 95% yield). Rf 0.5 (MeOH/CHCl3 1:4); mp
NMR (270 MHz, CDCl3)
d
0.90 (6H, t, J¼6.6 Hz), 1.28e1.34 (8H,
complex), 1.65 (4H, quint, J¼7.3 Hz), 2.37 (2H, dt, J¼14.6 and 7.3 Hz)
2.43 (2H, dt, J¼14.6 and 7.3 Hz), 3.51 (1H, t, J¼9.5 Hz), 3.98 (2H, t,
J¼9.5 Hz), 4.23 (1H, t, J¼2.4 Hz), 4.87 (2H, dd, J¼9.5 and 2.4 Hz); 13C
NMR (100 MHz, CDCl3)
d 13.89 (2C), 22.31 (2C), 24.49 (2C), 31.24
(2C), 34.06 (2C), 69.23, 70.52 (2C), 72.79 (2C), 74.77, 173.54 (2C); IR
(KBr) 3503 (sharp), 3312 (broad), 1737, 1720 cmꢁ1; Anal. Calcd for
C18H32O8: C, 57.43; H, 8.57. Found: C, 57.21; H, 8.85.
4.2.4. Synthesis of 1,3-di-O-octanoyl-myo-inositol (14c) using the
mixed anhydride. To a solution of octanoic acid (216 mg, 1.50 mmol)
and triethylamine (319 mg, 3.15 mmol) in CH2Cl2 (3 mL) was added
pivaloyl chloride (233 mg, 1.80 mmol) at 0 ꢀC, and the mixture was
stirred for 2 h then evaporated to dryness. The residue was dissolved
in DMA (1 mL), and a solution of 1 (100 mg, 0.55 mmol) and LiCl
(80 mg,1.89 mmol) in DMA (1 mL), DMA (0.5 mL) washing, dibutyltin
dipivalate (24 mg, 0.05 mmol) and then triethylamine (281 mg,
2.78 mmol) were successively added at 0 ꢀC. The resulting solution
was stirred for 5.5 h at the same temperature, ethyl acetate and water
were added. The aqueous solution was extracted three times with
AcOEt, the combined extracts were successively washed with water
(ꢂ3), saturated aq NaHCO3, water and brine, dried (Na2SO4), evap-
orated. Chromatographic isolation (SiO2, MeOH/CHCl3 1:15) from the
residue gave 14c (183 mg, 76%). Rf 0. 4 (MeOH/CHCl3 1:10); 1H NMR
174.5e175.0 ꢀC (AcOEt/Hexane); 1H NMR (400 MHz, CD3OD)
d 3.44
(1H, t, J¼9.8 Hz), 4.08 (2H, t, J¼9.8 Hz), 4.43 (1H, t, J¼2.6 Hz), 5.01
(2H, dd, J¼9.8 and 2.6 Hz), 7.47 (4H, t, J¼8.0 Hz), 7.60 (2H, t,
J¼8.0 Hz), 8.00 (4H, d, J¼8.0 Hz); 13C NMR (100 MHz, CD3OD)
d
69.29, 71.89, 75.90, 76.52, 129.42 (4C), 130.88 (4C), 131.50 (2C),
134.26 (2C), 167.69 (2C); IR (KBr) 3600, 3512 (broad), 1713 cmꢁ1
;
LRMS (FABþ, m-nitrobenzyl alcohol) m/z: 389 [Mþ1]; Anal. Calcd
for C20H20O8$1/2H2O: C, 60.45; H, 5.33. Found: C, 60.09; H, 5.13.
4.2.2. Synthesis of 1,3-di-O-(1-naphthoyl)-myo-inositol (11b). To
a reaction flask containing LiCl (400 mg, 9.44 mmol) was added
inositol (100 mg, 0.55 mmol) and DMA (5 mL), and the mixture was
(270 MHz, CDCl3)
d
0.88 (6H, t, J¼5.4 Hz), 1.28 (16H, broad), 1.63 (4H,

4662
Y. Watanabe et al. / Tetrahedron 69 (2013) 4657e4664
brquint, J¼8.1 Hz), 2.36 (2H, dt, J¼10.8 and8.1 Hz) 2.36(2H, dt, J¼10.8
and 8.1 Hz), 3.52 (1H, t, J¼10.8 Hz), 3.97 (2H, t, J¼10.8 Hz), 4.20 (1H, br
t, J¼2.2 Hz), 4.88 (2H, dd, J¼9.2 and 2.2 Hz); 13C NMR (100 MHz,
added and the mixture was stirred at the same temperature for
12 h, treated with H2O (100 mL) for 10 min. After addition of AcOEt,
the organic layer was washed with H2O, saturated aq KHSO4, H2O,
saturated aq NaHCO3, H2O and brine, dried (MgSO4), evaporated.
Chromatographic isolation (SiO2, MeOH/AcOEt 1:20) gave 17
(1.52 g, 65% yield). Rf 0.5 (MeOH/AcOEt 1:20); mp 124.0e125.5 ꢀC
(lit.41 mp 118e121 ꢀC); LRMS (FABþ, m-nitrobenzyl alcohol) m/z:
423 [Mþ1].
CDCl3)
d 13.89 (2C), 22.31 (2C), 24.49 (2C), 31.24 (2C), 34.06 (2C),
69.23, 70.52 (2C), 72.79 (2C), 74.77,173.54 (2C); IR (KBr) 3600 (sharp),
3503, 3350 (broad), 1737, 1720 cmꢁ1; HRMS (FABþ, m-nitrobenzyl
alcohol) calcd for C22H41O8 [MþH] 433.2801, found 433.2794.
4.3. Synthesis of 1,6:3,4-bis-O-(tetraisopropyldisiloxane-1,3-
diyl)-myo-inositol (12)
4.6. Characterization data
To a solution of 1 (200 mg, 1.11 mmol) in DMSO (5 mL) was
added pyridine (3 mL) and TIPDS-Cl2 (771 mg, 2.44 mmol), and the
mixture was stirred for 20 h at rt. After treatment with water
4.6.1. 1,3-Di-O-(2-hexyloxycarbonyl)benzoyl-myo-inositol (11c). Rf
0.5 (MeOH/CHCl3 1:10); 1H NMR (400 MHz, CD3OD)
d 0.75 (6H, t,
J¼13.2 Hz), around 1.19 (16H, complex), 1.28 (4H, complex), 3.50
(1H, t, J¼9.6 Hz), 4.00 (2H, t, J¼9.6 Hz), 4.59 (1H, t, J¼2.4 Hz), 4.96
(2H, dd, J¼9.6 and 2.4 Hz), 7.39 (4H, complex), 7.65 (4H, complex);
HRMS (FABþ, m-nitrobenzyl alcohol) calcd for C34H45O12 [MþH]
645.2912, found 645.2970; Anal. Calcd for C34H48O12: C, 63.34; H,
6.88, Found: C, 63.09; H, 6.33.
(100 m
L) at 0 ꢀC for 10 min, the mixture was partitioned into water
and AcOEt layers, the latter of which was washed with water, sat-
urated aq KHSO4, water, saturated aq NaHCO3, water, and brine, and
dried (Na2SO4) and evaporated. The residue was recrystallized from
CH3CN and water to give the product (650 mg, 88%). Rf 0.5 (AcOEt/
hexane 1:10); mp 203e204 ꢀC (CH3CN/H2O); 1H NMR (300 MHz,
CDCl3)
d
1.04e1.10 (56H, complex), 2.48 (1H, s, OH), 2.62 (1H, s, OH),
4.6.2. 1,3-Di-O-pivaloyl-myo-inositol (11d). Rf 0.5 (MeOH/CHCl3
3.38 (1H, t, J¼9.0 Hz), 3.69 (2H, dd, J¼9.0 and 3.0 Hz), 4.00 (2H, t,
1:5); mp 166e167 ꢀC; 1H NMR (400 MHz, CD3OD)
d 1.25 (18H, s),
J¼9.0 Hz), 4.04 (1H, t, J¼3.0 Hz); 13C NMR (100 MHz, CDCl3)
d
12.07,
3.31 (1H, t, J¼9.8 Hz), 3.87 (2H, t, J¼9.8 Hz), 4.10 (1H, t, J¼2.8 Hz),
12.14, 12.71, 12.84 (8C), 17.17, 17.27, 17.44 (8C), 73.73, 75.08 (2C),
75.15, 75.57 (2C); IR (KBr) 3550, 3482 cmꢁ1; LRMS (FABþ, m-
nitrobenzyl alcohol) m/z 665 [MþH]þ; Anal. Calcd for C30H64O7Si4
(%): C, 54.17; H, 9.70. Found: C, 54.13; H, 9.42.
4.66 (2H, dd, J¼9.8 and 2.8 Hz); 13C NMR (100 MHz, CD3OD)
d 26.21
(6C), 38.55 (2C), 67.58, 70.34 (2C), 73.53 (2C), 75.24, 178.3 (2C); IR
(KBr) 3518 (broad), 3380 (broad), 1716 cmꢁ1; Anal. Calcd for
C16H28O8$1/2H2O: C, 53.77; H, 8.18. Found: C, 53.60; H, 7.89.
4.4. Representative procedure for synthesis of 1-O-
substituted DL-myo-inositol: synthesis of DL-1-O-benzoyl-myo-
inositol (16a)
4.6.3. 1,3-Di-O-diphenylacetyl-myo-inositol (11e). Rf 0.6 (AcOEt/Hex
1:1); mp 149 ꢀC (AcOEt/hexane); 1H NMR (400 MHz, CD3OD/CDCl3
1:2)
J¼2.6 Hz), 4.85 (2H, dd, J¼9.7 and 2.6 Hz), 5.17 (2H, s), 7.23e7.33
(20H, complex); 13C NMR (100 MHz, CD3OD/CDCl3 1:2)
56.31 (2C),
d
3.32 (1H, t, J¼9.7 Hz), 3.86 (2H, t, J¼9.7 Hz), 4.14 (1H, t,
To a solution of 1 (96 mg, 0.54 mmol), LiCl (400 mg, 9.44 mmol)
and triethylamine (225 mg, 2.22 mmol) in DMA (5 mL) cooled at
ꢁ23 ꢀC was slowly added benzoyl chloride (117 mg, 0.83 mmol),
and the mixture was stirred for 2 h at the same temperature and
then methanol was added. After 10 min, TMSCl (2 mL) and pyridine
(4 mL) were added, the mixture was stirred for 3 h at rt, cooled to
d
67.64, 69.83 (2C), 73.72 (2C), 74.54, 126.71 (2C), 126.82 (2C), 127.98
(4C), 128.09 (4C), 128.14 (4C), 128.22 (4C), 138.18, 138.23, 172.07
(2C); IR (KBr) 3590 (sharp), 3476 (broad), 3350 (broad), 1725 cmꢁ1
;
Anal. Calcd for C34H32O8$1/2H2O: C, 70.41; H, 5.68. Found: C, 70.35;
H, 5.89.
0
ꢀC, and then H2O (0.1 mL) was added. After being stirred for
10 min, the solution was partitioned to AcOEt and H2O layers. The
organic solution was washed with H2O (ꢂ3), 0.5 N HCl solution,
H2O, saturated NaHCO3 solution, H2O, and then brine, dried
(MgSO4), filtered and then evaporated. The residue was dissolved in
CHCl3 (1 mL) and MeOH (2 mL), and CF3CO2H (one drop) were
added. The solution was stirred for 2 h at rt, and all the volatile
materials were distilled off under reduced pressure (1.0 mmHg).
The residue was subjected to a column chromatography on silica
gel (MeOH/CHCl3 1:4) to give crystalline 1-O-benzoate 16a (120 mg,
78%) and 11a (29 mg, 13%). Rf 0.3 (MeOH/CHCl3 1:4); mp
194e195 ꢀC (MeOH/hexane);40 1H NMR (270 MHz, DMSO-d6þD2O)
4.6.4. 1,3-Di-O-tert-butyldiphenylsilyl-myo-inositol (11f). Rf 0.5
(MeOH/AcOEt 1:20); mp 81 ꢀC; 1H NMR (270 MHz, CDCl3)
d 1.02
(18H, s), 2.17 (1H, s), 2.36 (1H, s), 2.55 (1H, s), 3.03 (1H, t, J¼9.3 Hz),
3.21 (2H, dd, J¼9.3 and 2.7 Hz), 3.51 (1H, t, J¼2.7 Hz), 3.91 (2H, t,
J¼9.3 Hz), 7.27 (8H, t, J¼8.4 Hz), 7.39 (4H, m), 7.56 (8H, m); 13C NMR
(100 MHz, CDCl3)
d 19.27 (2C), 26.94 (6C), 72.29, 72.81 (2C), 73.53,
73.99 (2C), 127.7, 129.9, 133.0, 135.7 (24C); IR (KBr) 3575 (sharp),
3422 (broad) cmꢁ1; Anal. Calcd for C38H48O6Si2: C, 69.47; H, 7.36.
Found: C, 69.29; H, 7.34.
4.6.5. 1,3-Di-O-p-toluenesulfonyl-myo-inositol (11g). Rf 0.5 (AcOEt);
mp 244e245 ꢀC (n-C3H7OH) {lit.31 mp 233e234 ꢀC (EtOH)}; 1H
d
3.07 (1H, t, J¼9.7 Hz), 3.30 (1H, t, J¼9.7 Hz), 3.42 (1H, t, J¼9.7 Hz),
3.94 (1H, t, J¼9.7 Hz), 3.94 (1H, br), 4.65 (1H, dd, J¼9.7 and 2.4 Hz),
7.49 (2H, t, J¼7.4 Hz), 7.62 (1H, t, J¼6.2 Hz), 7.99 (2H, d, J¼8.4 Hz);
NMR (270 MHz, CD3OD)
d
2.59 (6H, s), 3.23 (1H, t, J¼9.7 Hz), 3.87
(2H, t, J¼9.7 Hz), 4.22 (1H, t, J¼2.6 Hz), 4.35 (2H, dd, J¼9.7 and
13C NMR (100 MHz, D2O)
d 69.93, 70.44, 70.75, 72.21, 74.10, 74.44,
2.6 Hz), 7.55 (4H, d, J¼8.4 Hz), 7.96 (4H, d, J¼8.4 Hz); 13C NMR
128.74 (2C), 128.94 (2C), 129.64, 134.05, 167.81; IR (KBr) 3500
(100 MHz, CD3OD) d 20.25 (2C), 68.86, 69.81 (2C), 73.80, 81.04 (2C),
(sharp), 3425 (broad), 3330 (broad), 3240 (broad),1705,1688 cmꢁ1
;
127.9, 129.5, 133.8, 145.0 (12C); IR (KBr) 3422 (broad), 1354,
1176 cmꢁ1; Anal. Calcd for C20H24O10S2: C, 49.17; H, 4.95. Found: C,
49.09; H, 4.95.
LRMS (FABþ, m-nitrobenzyl alcohol) m/z 285 [Mþ1]; Anal. Calcd for
C13H16O7: C, 54.66; H, 5.60. Found: C, 54.93; H, 5.67.
4.5. Synthesis of DL-1,6-O-(tetraisopropyldisiloxane-1,3-diyl)-
myo-inositol (17)
4.6.6. 1,3-Di-O-diphenylphosphinyl-myo-inositol
(MeOH/CHCl3 1:3); mp 173e174 ꢀC (benzene); 1H NMR (400 MHz,
CDCl3)
3.16 (1H, t, J¼9.2 Hz), 3.93 (2H, ddd, J¼9.2, 7.3 and 2.6 Hz),
4.06 (2H, t, J¼9.2 Hz), 4.40 (1H, t, J¼2.6 Hz), 7.39 (12H, complex),
7.81 (8H, m); 13C NMR (100 MHz, CDCl3)
70.84, 70.95, 70.99, 74.05,
76.93, 77.22, 128.4, 128.6, 129.4, 130.3, 130.8, 131.6, 131.7, 132.0,
132.1,132.2, 132.3; 31P NMR (162 MHz, CDCl3)
34.43; IR (KBr) 3386
(11h). Rf
0.4
d
To a solution of myo-inositol (400 mg, 2.22 mmol) in DMSO
(10 mL) prepared by heating was added DMF (6 mL) and pyridine
(211 mg, 2.66 mmol), and the solution was cooled at 0 ꢀC. 1,3-
Dichloro-1,1,3,3-tetraisopropyldisiloxane (350 mg, 1.11 mmol) was
d
d

Y. Watanabe et al. / Tetrahedron 69 (2013) 4657e4664
4663
(broad) cmꢁ1; HRMS (FABþ, m-nitrobenzyl alcohol), calcd for
C30H31O8P2 [MþH] 581.1494, found, 581.1476.
72.9, 74.0, 75.6, 76.4, 175.3; IR (KBr) 3496, 3370, 3235 (broad)
1711 cmꢁ1; Anal. Calcd for C19H28O8: C, 51.79; H, 7.97. Found: C,
51.59; H, 7.81.
4.6.7. 1,3-Di-O-acetyl-myo-inositol (14a). Rf 0.4 (MeOH/CHCl3 1:3);
mp 173e174 ꢀC (benzene/AcOEt); 1H NMR (270 MHz, D2O)
d
2.20
4.6.13. DL-1-O-Octanoyl-myo-inositol (16e). Rf 0.4 (MeOH/CHCl3
(6H, s, CH3), 3.50 (1H, t, J¼9.6 Hz), 3.90 (2H, t, J¼9.6 Hz), 4.29 (1H,
1:3); 1H NMR (270 MHz, CD3OD/CDCl3 2:1)
d 0.87 (3H, br t,
t, J¼2.8 Hz), 4.88 (2H, dd, J¼9.6 and 2.8 Hz); 13C NMR (100 MHz,
J¼7.6 Hz), 1.27 (8H, complex), 1.62 (2H, br quint, J¼7.6 Hz), 2.40 (2H,
t, J¼7.6 Hz), 3.24 (1H, t, J¼9.6 Hz), 3.43 (1H, br dd, J¼9.6 and 2.1 Hz),
3.64 (1H, t, J¼9.6 Hz), 3.82 (1H, t, J¼9.6 Hz), 4.05 (1H, br t, J¼2.1 Hz),
4.63 (1H, dd, J¼9.6 and 2.1 Hz); 13C NMR (100 MHz, CD3OD/CDCl3
D2O/CD3OD)
d 21.52 (2C), 68.68, 71.26 (2C), 71.41 (2C), 74.85,
174.3; Calcd for C10H16O8: C, 45.46; H, 6.10. Found: C, 45.26; H,
6.11.
2:1)
d 13.4, 22.4, 24.6, 28.8, 28.9, 31.5, 33.8, 70.2, 70.4, 71.6, 72.6,
4.6.8. 1,3-Di-O-dodecanoyl-myo-inositol (14d). Rf 0.4 (MeOH/CHCl3
1:10); mp 126e128 ꢀC (hexane/AcOEt); 1H NMR (270 MHz, CDCl3)
74.0, 74.9, 174.1; HRMS (ESI): calcd for C14H26O7 [M], 306.1679;
found 306.1692.
d
0.88 (6H, t, J¼5.4 Hz), 1.26 (32H, broad), 1.64 (4H, br quint,
J¼8.1 Hz), 2.37 (2H, dt, J¼10.8 and 8.1 Hz) 2.43 (2H, dt, J¼10.8 and
8.1 Hz), 3.50 (1H, t, J¼10.8 Hz), 3.98 (2H, t, J¼10.8 Hz), 4.23 (1H, br
t, J¼2.2 Hz), 4.87 (2H, dd, J¼10.8 and 2.2 Hz); 13C NMR (100 MHz,
4.6.14. Diastereomeric mixture of 1-O-(ꢁ)-menthyloxycarbonyl-
myo-inositol (16f).35 Rf 0.4 (MeOH/CHCl3 1:4); 1H NMR (400 MHz,
CD3OD) (diastereomeric 69:31 mixture)
d
0.69 (3H, d, J¼6.9 Hz),
CDCl3)
d
14.10 (2C), 22.68 (2C), 24.88 (2C), 29.20 (2C), 29.37 (2C),
0.82 (6H, complex), 0.95e1.34 (5H, complex), 1.60 (2H, br d), 1.95
(1H, m), 3.13 (1H, t, J¼9.2 Hz), 3.14 (1H, t, J¼9.3 Hz), 3.32 (2H, br d,),
3.51 (2H, br t), 3.53 (1H, t, J¼9.2 Hz), 3.71 (2H, br d), 3.99 (1H, br t),
4.02 (1H, br t), 4.33 (1H, dd, J¼10.0 and 2.0 Hz), 4.36 (1H, br dd),
4.43 (1H, dt, J¼11.1 and 4.5 Hz); LRMS (FABþ, m-nitrobenzyl alco-
hol), C167H30O8, m/z: 363 [Mþ1].
29.39 (2C), 29.57 (2C), 29.66 (2C), 29.69 (2C), 31.92 (2C), 34.15
(2C), 69.23, 70.55 (2C), 72.78 (2C), 74.80, 173.47 (2C); IR (KBr)
3595 (sharp), 3504 (sharp), 3378 (broad), 3275 (shoulder), 1742,
1720 cmꢁ1
C30H57O8 [MþH] 545.4053, found 545.4047.
;
HRMS (FABþ, m-nitrobenzyl alcohol) calcd for
4.6.9. 1,3-Di-O-(cis-9-octadecenoyl)-myo-inositol
(14e). Rf
0.5
4.6.15. DL-1-O-tert-Butyldiphenylsilyl-myo-inositol (16g).22b Rf 0.5
(MeOH/CHCl3 1:4); mp 163e165 ꢀC (hexane/AcOEt); 1H NMR
(MeOH/CHCl3, 1:10); 1H NMR (400 MHz, CDCl3)
d
0.89 (6H, t,
J¼8.0 Hz), 1.27e1.30 (40H, complex), 1.62 (4H, br quint, J¼8.0 Hz),
2.00, 2.01 (4Hꢂ2, dt, J¼12.0 and 8.0 Hz) 2.36 (2H, dt, J¼10.8 and
8.1 Hz), 2.42 (2H, dt, J¼14.6 and 8.0 Hz), 2.69 (1H, br s, OH), 3.53
(1H, t, J¼10.0 Hz), 3.94 (2H, t, J¼10.0 Hz), 4.17 (1H, br t), 4.89 (2H,
dd, J¼10.0 and 1.2 Hz), 5.09 (1H, br s, OH), 5.34 (4H, m); 13C NMR
(400 MHz, D2O) d 1.09 (9H, s), 2.98e3.02 (2H, complex), 3.51 (1H,
dd, J¼9.6 and 2.8 Hz), 3.60 (1H, t, J¼9.6 Hz), 3.68 (1H, t,
J¼2.8 Hz), 3.81 (1H, t, J¼9.6 Hz), 7.33e7.42 (6H, complex), 7.78
(4H, d, J¼6.4 Hz); LRMS (FABþ, m-nitrobenzyl alcohol) m/z: 441
[MþNa].
(100 MHz, CDCl3)
d 14.09 (2C), 22.66 (2C), 24.85 (2C), 27.21 and
27.22 (4C), 29.17 (2C), 29.23 (2C), 29.30 (2C), 29.32 (4C), 29.53 (2C),
29.76 (2C), 29.78 (2C), 31.89 (2C), 34.12 (2C), 69.26, 70.54 (2C),
72.72 (2C), 74.76, 129.64 and 129.96 (4C), 173.43 (2C); IR (KBr) 3598
(sharp), 3504 (sharp), 3366 (broad), 1740, 1723 cmꢁ1; HRMS (FABþ,
m-nitrobenzyl alcohol) calcd for C42H77O8 [MþH] 709.5618, found
709.5626.
4.6.16. DL-1-O-p-Toluenesulfonyl-myo-inositol (16h).33,34 Rf
(MeOH/CHCl3 1:4); mp 228e231 ꢀC (dec. AcOH/H2O, lit.34 mp
224 ꢀC); 1H NMR (270 MHz, D2O)
2.48 (3H, s) 3.26 (1H, t,
0.5
d
J¼9.4 Hz), 3.49 (1H, dd, J¼9.4 and 2.8 Hz), 3.62 (1H, t, J¼9.4 Hz),
3.78 (1H, t, J¼9.4 Hz), 4.00 (1H, t, J¼2.8 Hz), 4.40 (1H, dd, J¼9.4
and 2.8 Hz), 7.52 (2H, d, J¼7.9 Hz), 7.90 (2H, d, J¼7.9 Hz); IR (KBr)
3500 (sharp), 3436 (sharp), 3345 (broad), 3235 (broad), 1358,
4.6.10. DL-1-O-p-Hexyloxybenzoyl-myo-inositol
(MeOH/CHCl3 1:5); mp 183e184 ꢀC (MeOH); 1H NMR (270 MHz,
CD3OD)
(16b). Rf
0.3
1173 cmꢁ1
.
d
0.83 (3H, t, J¼6.8 Hz), 1.23 (4H, complex), 1.39 (2H, m),
4.6.17. DL-1-O-p-Dodecylbenzenesulfonyl-myo-inositol (16i). Rf 0.3
(MeOH/CHCl3 1:4); 1H NMR (400 MHz, CD3OD)
0.66e1.64 (25H,
1.70 (2H, quint, J¼6.8 Hz), 3.19 (1H, t, J¼9.2 Hz), 3.36 (1H, dd, J¼9.2
and 2.8 Hz), 3.40 (1H, t, J¼9.2 Hz), 3.88 (1H, t, J¼9.2 Hz), 3.94 (2H,
t, J¼6.8 Hz), 4.07 (1H, t, J¼2.8 Hz), 4.72 (1H, dd, J¼9.2 and 2.8 Hz),
6.87 (2H, d, J¼9.0 Hz), 7.96 (2H, d, J¼9.0 Hz); 13C NMR (100 MHz,
d
complex), 3.13 (1H, t, J¼9.4 Hz), 3.33 (1H, br t, J¼9.4 Hz), 3.58 (1H, t,
J¼9.4 Hz), 3.77 (1H, t, J¼9.4 Hz), 4.06 (1H, br t), 4.28 (1H, br t,
J¼9.4 Hz), 7.38e7.58 (2H, m), 7.90 (2H, d, J¼7.6 Hz); IR (KBr) 3500
(sharp), 3433 (sharp), 3335 (broad), 3250 (shoulder), 1358,
CD3OD)
d 12.98, 22.28, 25.41, 28.84, 31.35, 67.91, 74.73, 75.18,
70.67, 71.69, 72.69, 75.19, 113.69 (2C), 122.14, 131.69 (2C), 163.31,
166.35; IR (KBr) 3477 (sharp), 3358 (broad), 3250 (broad), 3160
(broad), 1691 cmꢁ1; Anal. Calcd for C19H28O8: C, 59.36; H, 7.34.
Found: C, 59.14; H, 7.07.
1175 cmꢁ1
C24H41O8S [MþH] 314.1239, found 314.1235.
;
HRMS (FABþ, m-nitrobenzyl alcohol) calcd for
4.6.18. DL-1-O-Dibutylphosphoryl-myo-inositol (16j). Rf 0.4 (MeOH/
CHCl3 1:4); 1H NMR (400 MHz, CD3OD)
d
1.00 (6H, td, J¼3.4 and
4.6.11. DL-1-O-Pivaloyl-myo-inositol (16c). Mp 202e203 ꢀC (MeOH/
1.6 Hz), 1.48 (4H, m), 1.71 (4H, m), 3.23 (1H, t, J¼9.5 Hz), 3.41 (1H,
dd, J¼9.5 and 2.7 Hz), 3.67 (1H, t, J¼9.5 Hz), 3.83 (1H, t, J¼9.5 Hz),
4.10 (1H, ddd, J¼12.2, 9.5 and 2.7 Hz), 4.14e4.22 (5H, complex);
AcOEt) (lit.42 202e204 ꢀC); 1H NMR (270 MHz, CD3OD)
d 1.24 (9H,
s), 3.20 (1H, t, J¼9.2 Hz), 3.39 (1H, dd, J¼9.7 and 2.7 Hz), 3.62 (1H,
t, J¼9.7 Hz), 3.82 (1H, t, J¼9.7 Hz), 4.00 (1H, t, J¼2.7 Hz), 4.58 (1H,
dd, J¼9.7 and 2.7 Hz); IR (KBr) 3545, 3460, 3392 (broad)
13C NMR (100 MHz, CD3OD)
d 14.22 (2C), 20.01 (2C), 33.62 (2C),
69.39 (2C), 72.80, 73.06, 72.13, 74.15, 76.47, 80.87; 31P NMR
1714 cmꢁ1
.
(162 MHz, CD3OD)
d
ꢁ1.10; IR (KBr) 3400 (broad), 3324 (broad)
cmꢁ1; LRMS (FABþ, m-nitrobenzyl alcohol) m/z: 373 [Mþ1].
4.6.12. DL-1-O-Hexanoyl-myo-inositol (16d). Rf 0.4 (MeOH/CHCl3
1:3); mp 160.0e161.5 ꢀC (MeOH/AcOEt); 1H NMR (270 MHz,
Acknowledgements
CD3OD)
d
0.91 (3H, br t, J¼7.7 Hz), 1.33 (4H, complex), 1.64 (2H, br
quint, J¼7.7 Hz), 2.41 (2H, t, J¼7.7 Hz), 3.20 (1H, t, J¼9.7 Hz), 3.39
(1H, dd, J¼9.7 and 2.6 Hz), 3.62 (1H, t, J¼9.7 Hz), 3.81 (1H, t,
J¼9.7 Hz), 4.02 (1H, t, J¼2.6 Hz), 4.61 (1H, dd, J¼9.7 and 2.6 Hz);
This work was supported by Grant in-Aid for Scientific Research
(C) (23510257). We thank Venture Business Laboratory (VBL) and
Institute for Cooperative Science (INCS), Ehime University for NMR
and elemental analysis.
13C NMR (100 MHz, CD3OD)
d 14.2, 23.3, 25.5, 32.4, 35.0, 71.6, 71.8,

4664
Y. Watanabe et al. / Tetrahedron 69 (2013) 4657e4664
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