Regioselective O-acylation of myo-inositol 1,3,5-orthoesters: dependence of regioselectivity on the stoichiometry of the base

Article abstract of DOI:10.1016/j.tet.2009.01.060

A metal mediated unusual 1-3 acyl migration from C4-O to C2-OH of myo-inositol 1,3,5-orthoformate was observed during the alkylation of racemic 4-O-benzoyl-myo-inositol 1,3,5-orthoformate. This has been exploited for the selective esterification of either

Full text of DOI:10.1016/j.tet.2009.01.060

Tetrahedron 65 (2009) 2703–2710
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective O-acylation of myo-inositol 1,3,5-orthoesters: dependence
of regioselectivity on the stoichiometry of the base
*
Kana M. Sureshan, Subramanian Devaraj, Mysore S. Shashidhar
Division of Organic Chemistry, National Chemical Laboratory, Pashan Road, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 April 2008
Received in revised form 29 December 2008
Accepted 13 January 2009
Available online 20 January 2009
A metal mediated unusual 1–3 acyl migration from C4–O to C2–OH of myo-inositol 1,3,5-orthoformate
was observed during the alkylation of racemic 4-O-benzoyl-myo-inositol 1,3,5-orthoformate. This has
been exploited for the selective esterification of either the C4(6)–OH or the C2–OH of myo-inositol by
varying the amount of the base used. While the use of 1 equiv of the base (sodium hydride or potassium
tert-butoxide) for the acylation of myo-inositol orthoesters gives the corresponding C4-ester exclusively,
the use of two or more equivalents of base for the same reaction gives the C2-ester exclusively. The
relatively higher stability of the alkoxide of racemic 2-O-acyl-myo-inositol 1,3,5-orthoester as compared
to the alkoxide of 4-O-acyl-myo-inositol 1,3,5-orthoester is suggested to be responsible for the observed
isomerization.
Keywords:
Acylation
Cyclitol
Inositol
Ó 2009 Elsevier Ltd. All rights reserved.
Orthoester
Regioselectivity
Transesterification
1. Introduction
protected ketals or orthoesters of inositol are used for further se-
lective functionalization during phosphoinositol synthesis. Such
The chemistry and biology of phosphorylated inositols have
become intense areas of research during the last two decades due
to their involvement in various cellular signaling processes.1 There
are at least 26 different myo-inositol phosphates, 8 phosphoinositol
lipids and several glycoconjugates known to occur in nature. Apart
from well established roles of a few phosphoinositols in cellular
signaling and protein anchoring, the biological functions of many of
these phosphoinositols and glycoconjugates are far from well un-
derstood. Considering the facts that these derivatives occur in na-
ture in very small quantities and their isolation is often tedious due
to their transient nature (short half-life) and difficulty in purifica-
tion, it is not surprising that these molecules have attracted the
interest of synthetic chemists.1a,2 Although methodologies for
phosphoinositol synthesis starting from different starting materials
have been reported,2a,c,h,3 myo-inositol (1, Fig. 1) continues to be
a modification usually perturbs the chemical environment of dif-
ferent hydroxyl groups unevenly making them prone to better
discrimination during synthetic manipulations. While the ketali-
zation of myo-inositol gives a mixture of ketals (thus reducing the
yield of the required ketal, often less than 35%), the orthoester-
ification provides a single product, myo-inositol 1,3,5-orthoester,5
in high yield (>90%). The myo-inositol orthoesters (2–5, Fig. 1) have
two axial hydroxyl groups and one equatorial hydroxyl group (with
respect to the inositol ring) and this facilitates better discrimination
among the hydroxyl groups of orthoesters. Also, the known strat-
egies for the selective partial cleavage4c of the orthoester cage with
reducing agents in protected myo-inositol orthoesters (to re-
generate the C1(3)–OH or the C5–OH) make myo-inositol
1,3,5-orthoesters versatile intermediates for synthetic purposes.
Consequently, orthoesters have become the preferred starting
materials for the synthesis of phosphoinositols and their analogs in
recent years.5b,6 Several methodologies for regioselective pro-
tection of myo-inositol orthoester hydroxyl groups have been
reported.4c Among various protecting groups, ester protecting
groups have the advantage of mild reaction conditions for their
introduction and removal, possibilities of resolution using enzymes
or via diastereomeric derivatives.5d,6 Due to these advantages, ac-
ylation of myo-inositol derivatives forms an important synthetic
strategy. However, acyl migrations among the hydroxyl groups of
myo-inositol are sometimes annoying during the synthesis of
a
frequently used starting material for the synthesis of
phosphoinositols.
myo-Inositol being a cyclohexane hexol having six secondary
hydroxyl groups with more or less similar chemical environment,
the selective functionalization of these hydroxyl groups4 is one of
the main challenges in synthetic inositol chemistry. Often, partially
* Corresponding author. Tel.: þ91 20 2590 2055; fax: þ91 20 2590 2624.
E-mail address: ms.shashidhar@ncl.res.in (M.S. Shashidhar).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.060

2704
K.M. Sureshan et al. / Tetrahedron 65 (2009) 2703–2710
R
H
H
H
HO
2
HO
OH 6
2 R = H
1
4
O
O
O
O
O
O
O
O
3 R = Me
4 R = Bu
5 R = Ph
OH
OH
1 3O 6
O
c
b
O
O
5
3
OH5
HO
HO
HO
HO
4
2
1
H
O
HO
M
HO
HO
OH
O
OBn
OBz
10
13
9
d
e
Figure 1. myo-Inositol and its known orthoesters.
a
H
H
H
O
O
O
O
O
O
O
O
O
phosphoinositols or their derivatives. Nevertheless, in a few in-
stances, acyl migrations have been exploited for strategic and ef-
ficient synthesis of myo-inositol phosphates.7
HO
O
M
HO
O
M
O
H
O
H
2
OBn
OBz
OH
11
14
b
c
Considerable efforts have been made to understand and opti-
mize selective acylation of the three hydroxyl groups of myo-ino-
sitol orthoesters.5b,6g,8 Most of these reports deal with maximizing
the yield of a particular O-acylated (e.g., O-benzoyl) derivative of
a myo-inositol orthoester (e.g., orthoformate 2) and hence there is
no general method that could be used for the selective acylation of
C2- or C4(6)-hydroxyl group in myo-inositol orthoesters. For in-
stance, when we applied the reaction conditions reported for the
2-O-benzoylation8d of the orthoformate 2 for the preparation of the
corresponding acetate, we obtained the C4-acetate 7 (Scheme 1).
We have developed9 simple and general methodologies for selec-
tive acylation either at the C2–OH or the C4–OH by varying the
amount of the base used and the full details of this work are pre-
sented here.
b
??!
H
H
H
O
O
O
O
O
O
O
O
O
HO
12
BnO
BzO
15
BnO
HO
O
H
OBn
OBz
OBz
16
Scheme 2. Alkoxide mediated benzylation and benzoylation of 2. (a) NaH or KOtBu; (b)
benzyl bromide; (c) benzoyl chloride; (d) NaH (Ref. 6b); (e) KOtBu.
Benzoate 13 was treated with potassium tert-butoxide (or so-
dium hydride) for 5 min, and then allowed to react with benzyl
bromide when racemic 2-O-benzoyl-4-O-benzyl-myo-inositol
1,3,5-orthoformate12 (17) was obtained as the only product
(Scheme 3). The formation of 17 suggested migration of the benzoyl
group from the C4–O to the C2–OH during benzylation. When the
benzylation of 13 was carried out by the addition of sodium hydride
to a previously mixed solution of benzoate 13 and benzyl bromide
in DMF (the alkoxide was made to react as soon as it was formed),
a mixture of racemic 4-O-benzoyl-6-O-benzyl-myo-inositol 1,3,5-
orthoformate (18) and 17 were formed along with some amount of
racemic 10.6b Compound 18 was unambiguously characterized by
its aminolysis to the known6b benzyl ether. No trace of the expected
racemic 16 (Scheme 2) could be found in any of these experiments.
These results suggested that after the generation of the alkoxide (in
13) benzoyl migration competes with benzylation. It is interesting
to note that the alkylation takes place only at the C4–OH no matter
whether the acyl group has migrated or not. When 18 was treated
with sodium hydride in DMF migration of the benzoyl group was
not observed.
H
H
H
H
O
O
O
O
O
O
O
O
O
O
O
O
b
a
HO
AcO
BzO
HO
HO
H
O
HO
O
H
OAc
OH
OH
OH
6
2
7
8
Expected but
Observed
not observed
Scheme 1. Acylation of 2 showing lack of generality. (a) Pyridine, benzoyl chloride;8d
(b) pyridine, acetyl chloride.
2. Results and discussion
In our efforts toward the development of simpler methods for
the synthesis of inositol derivatives, we required to synthesize
2-O-benzyl-myo-inositol,10 the precursor for myo-inositol
1,3,4,5,6-pentakisphosphate. Benzylation of triol 2 with 1 equiv of
sodium hydride and benzyl bromide is known to give 4-O-benzyl
ether 10 (Scheme 2) while dibenzylation gives 4,6-dibenzyl ether
12 as the major product.6b These results suggest that first
deprotonation in 2 and 10 occurs at the C4- and C6-hydroxyl
groups, respectively, on their reaction with sodium hydride. This
has been attributed to the increased stability of the 4(6)-alkoxide
due to chelation of the alkali metal ion.6b However, dibenzoyla-
tion of orthoformate 2 with potassium tert-butoxide and benzoyl
chloride is reported to give the unsymmetrical dibenzoate 15 (in
contrast to the corresponding benzylation reaction) although
mono-benzoylation11 occurs at the C4–OH (similar to mono-
benzylation of 2). A mechanism involving initial benzoylation at
the C4–OH followed by the second benzoylation at the C2–OH has
been proposed (Scheme 2).11 These results imply that the treat-
ment of the 4-benzyl ether 10 with a strong base generates C6-
alkoxide 11 predominantly while the treatment of 4-benzoate 13
with a strong base generates C2-alkoxide 14 predominantly. If this
is indeed the case, alkylation (benzylation) of 13 should in prin-
ciple, give C2-O-alkylated product 16. Prompted by this logic, we
attempted benzylation of racemic 4-benzoate 13 in the presence
of potassium tert-butoxide.
H
H
H
O
O
O
O
O
O
O
O
O
a
b
HO
+
BzO
HO
17
BnO
HO
HO
OBz
OBn
OBz
13
31%
17 (94%)
18 (42%)
Scheme 3. Benzylation of 13. (a) DMF, NaH, 5 min then benzyl bromide; (b) DMF,
benzyl bromide, then NaH.
From these results, it was clear that the benzoyl migration oc-
curred prior to O-alkylation, resulting in the formation of monoalk-
oxide 20 (Scheme 4), which underwent benzylation to give 17.
Treatment of 4-benzoate 13 with 1 equiv of sodium hydride in DMF
gave 2-benzoate 6 as anticipated. Similar results were obtained when
sodium hydride was replaced with potassium tert-butoxide for all the
reactions presented above. Increasing the amount of sodium hydride
or potassium tert-butoxide did not make any difference in the ob-
served acyl migration. In some of the initial experiments, since the
recovery of 6 was not good, it was isolated as its known13 diacetate.
To examine the generality of this unusual 1,3-acyl migration,
different racemic 4-O-acyl-myo-inositol orthoesters were required.
But, there is no general method in the literature for the preparation
of racemic 4-O-acyl-myo-inositol orthoesters. Based on the

K.M. Sureshan et al. / Tetrahedron 65 (2009) 2703–2710
2705
H
an acylating agent would give the corresponding 2-O-acyl de-
rivative directly. The first equivalent of sodium hydride would acyl-
ate the C4–OH (of a myo-inositol orthoester) while the excess of
sodium hydride would effect the acyl migration to the C2–OH. If
this is indeed the case, we can achieve two different selectivities for
acylation of orthoesters of myo-inositol just by changing the stoi-
chiometry of the base used. To explore these possibilities further,
triol 2 was treated with 2 equiv of sodium hydride and 1 equiv of
benzoyl chloride in DMF and as expected, 2-benzoate 6 was
obtained as the sole product. Similarly treatment of triol 2 or 3 with
different acylating agents with different electronic and steric fea-
tures such as pivaloyl chloride (bulky), benzoyl chloride (aromatic),
lauroyl chloride (fatty acyl) and acetic anhydride (small aliphatic
acyl) in the presence of two or more equivalents of sodium hydride
gave the corresponding C2-O-acyl derivatives (6, 8, 25–28) in very
good yields (Table 1). Previously reported methods suffer from lack
of such generality and in most methods a mixture of products is
obtained where one isomer is predominantly present and requires
separation from minor products. For instance, benzoylation of triol
2 using Et3N as the base is reported to give 4-benzoate 13 while the
use of pyridine as the base gives benzoate 6.8d When these meth-
odologies were adopted for acetylation of 2 we got a mixture of 4-
acetate 7 and 4,6-di-O-acetyl-myo-inositol 1,3,5-orthoformate by
both the methods. Similarly the use of triol 3 instead of triol 2 for
benzoylation (in pyridine), gave a mixture of benzoate 28 and ra-
cemic 2,4-di-O-benzoyl-myo-inositol 1,3,5-orthoacetate. Thus pre-
vious reports are not generally applicable to either the orthoesters
or the acylating agents.
H
O
O
O
O
O
O
NaH
HO
HO
-
O
O
H
Na+
19
OBz
OBz
13
BnBr
18
NaH
fast
H
X
O
O
BnBr
O
17
BzO
-
O
Na+
20
OH
Scheme 4. Pathways for benzylation of 13.
chelation mediated 4-O-alkylation of triol 2 we anticipated 4-O-
acylation of myo-inositol orthoesters on treatment with 1 equiv
each of NaH and an acylating agent.
Accordingly different racemic 4-O-acyl-myo-inositol orthoesters
(7, 13, 21–24) were prepared by the treatment of myo-inositol
orthoesters with 1 equiv of sodium hydride and 1 equiv of the re-
quired acylating agent in DMF (Scheme 5 and Table 1). In-
terestingly, all these 4-O-acyl derivatives could be successfully
converted to the corresponding 2-esters (6, 8, 25–28) by treatment
with one or more equivalent(s) of sodium hydride in DMF (Scheme
5). In some initial experiments 8 was isolated as its dibenzoate,
2-O-acetyl-4,6-di-O-benzoyl-myo-inositol 1,3,5-orthoformate (29).
Recently, both synthetic and naturally occurring O-acylated
inositols are being recognized as biologically active compounds
with a wide spectrum of therapeutic potential. Interestingly, many
of the naturally occurring myo-inositol esters are acylated at 2-OH
and/or 6-OH of myo-inositol.14 Lanceolitols, a group of 2-O-fatty-
acylated myo-inositol derivatives isolated from Solanum lanceola-
tum, have shown anti-inflammatory activity as a result of COX-2
inhibition.15 Various phosphatidylinositol mannosides, the impor-
tant component of mycobacterial cell wall, contain fatty esters on
inositol moiety.16 The phosphatidylinositol component of GPI an-
chor of proteins are decorated with a variety of fatty acyl chains at
2-position of myo-inositol, which accounts for the stability of these
anchors toward PIPLC action.17 In addition, some of the synthetic
myo-inositol esters have shown anti-oxidative18 and anti-convul-
sant19 properties. All these facts establish the importance of acyl-
ated myo-inositols and warrants efficient and selective
methodologies for acylation of myo-inositol. In this context, the
simple, general, and selective esterification methodology that we
have developed is highly relevant and invaluable. Furthermore,
recently inositols and their derivatives are increasingly being used
as synthons for natural products,20 ligands for metal complexing,21
gelators,22 catalysts for various organic transformations,23 supra-
molecular assemblies,24 etc. giving further impact for developing
efficient methodologies for their selective derivatization.
R
R
O
O
O
O
O
O
a
b
HO
R1(O)CO
2 or 3
H
O
OC(O)R1
H
O
OH
13 R = H; R1 = Ph
7 R = H; R1 = Me
21 R = H; R1 = CMe3
6 R = H; R1 = Ph
8 R = H; R1 = Me
25 R = H; R1 = CMe3
26 R = H; R1 = C11H23
27 R = Me; R1 = Me
28 R = Me; R1 = Ph
c
22 R = H; R1 = C11H23
23 R = Me; R1 = Me
24 R = Me; R1 = Ph
Scheme 5. Acylation of triols 2 and 3 and isomerization of C4-esters to C2-esters. (a)
DMF, NaH or KOBut (1 equiv), R1COCl or (R1CO)2O (1 equiv); (b) as in (a) with 2 equiv
NaH; (c) DMF, NaH.
As the 4-O-acyl derivatives 7, 13, 21–24 on treatment with one
or more equivalent(s) of sodium hydride gave the corresponding
2-O-acyl derivatives 6, 8, 25–28, it was reasonable to expect that
acylation of triol 2 or 3 in the presence of two or more equivalents
of sodium hydride or potassium tert-butoxide, with 1 equivalent of
Table 1
Acylation of triols 2 and 3
In order to get some insight into the mechanism of the acyl
migration reaction under discussion, we carried out additional
experiments and made the following observations. The results of
the crossover experiments9 involving two different inositol
orthoester derivatives suggested the acyl migration (Scheme 5) to
be an intramolecular reaction.25 Relatively weaker bases (Et3N,
i-Pr2NEt, K2CO3), that cannot generate alkoxide anion (of a race-
mic 4-O-acyl-myo-inositol orthoester) were incapable of effecting
the acyl migration suggesting that alkoxide generation is essential
for this acyl migration. Hence it is reasonable to suggest that metal
ion–inositol orthoester chelates may have a crucial role in this
unusual acyl migration. This assumption was supported by the
diminished rate of acyl migration in benzoate 13 when dibenzo-
18-crown-6-ether was added to the reaction mixture or when the
Entry
Reactant
Conditions
Product
Yield (%)
1
2
3
4
5
6
7
8
2
2
2
2
3
3
2
2
2
2
2
2
3
3
NaH (1 equiv), BzCl (1 equiv), DMF
NaH (1 equiv), Ac2O (1 equiv), DMF
NaH (1 equiv), PivCl (1 equiv), DMF
NaH (1 equiv), LaurCl (1 equiv), DMF
NaH (1 equiv), Ac2O (1 equiv), DMF
NaH (1 equiv), BzCl (1 equiv), DMF
NaH (2 equiv), BzCl (1 equiv), DMF
NaH (3 equiv), BzCl (1 equiv), DMF
NaH (7 equiv), BzCl (1 equiv), DMF
NaH (2 equiv), Ac2O (1 equiv), DMF
NaH (2 equiv), PivCl (1 equiv), DMF
NaH (2 equiv), LaurCl (1 equiv), DMF
NaH (2 equiv), Ac2O (1 equiv), DMF
NaH (2 equiv), BzCl (1 equiv), DMF
13
7
89
86
84
84
87
88
85
87
89
91
88
82
91
97
21
22
23
24
6
6
6
8
25
26
27
28
9
10
11
12
13
14

2706
K.M. Sureshan et al. / Tetrahedron 65 (2009) 2703–2710
reaction was conducted in THF (chelating solvent). Also, the time
for completion of the reaction increased when lithium hydride
was used as the base to isomerize benzoate 13; while sodium
hydride effected the acyl migration in less than 5 min, lithium
hydride took about 20 min. The observed reduction in the rate of
isomerization on changing the metal ion from sodium to lithium
could be due to the differences in stability of the corresponding
chelates. However, the lower reactivity of lithium hydride with
alcohols (to generate the corresponding alkoxide) compared to
sodium hydride as being responsible for an increase in the re-
action time cannot be excluded. Structures of the chelates that
could be involved during the acyl migration reaction are shown in
Scheme 6.
4. Experimental section
4.1. General methods
All the deuterated solvents, myo-inositol, triethylorthoformate,
trimethylorthoacetate, benzyl bromide, sodium hydride, pivaloyl
chloride, and lauric acid were obtained from Aldrich Chemical
Company, USA and were used as received. Benzoyl chloride, acetic
anhydride, dimethylformamide, pyridine, chloroform, anhydrous
sodium sulfate, sodium bicarbonate, potassium carbonate,
triethylamine, potassium tert-butoxide, sodium chloride, and p-
toluenesulfonic acid, were obtained from SD Fine Chemicals, India.
All the solvents used, benzoyl chloride and p-toluenesulfonic acid
were purified according to the literature procedures.26 Silica gel for
flash column chromatography (230–400 mesh) was obtained from
Spectrochem India Ltd. Light petroleum refers to the 60–80 ꢀC
boiling fraction of petroleum ether. TLC was performed on E-Merck
pre-coated 60 F254 plates and the spots were rendered visible either
by shining UV light or by charring the plates after spraying concd
sulfuric acid. myo-Inositol 1,3,5-orthoesters were prepared as
reported earlier.5 Sodium hydride used in the reactions was a sus-
pension in mineral oil (60%) and was washed with dry hexane and
dried under vacuum before use. Column chromatographic separa-
tions were carried out by flash chromatography with light petro-
leum–ethyl acetate mixture, unless otherwise mentioned. IR
spectra were recorded in the solid state as Nujol mull or as KBr
H
H
H
O
O
O
O
O
O
Na
O
O
O
O
HO
HO
Ph
O
O
HO
O
O
OBz
Ph
Na
30
32
Na
31
O
O
Less stable kinetic chelates
H
H
O
O
O
O
pellets or in solution using an appropriate solvent (concd 1 mM) on
O
O
an FTIR-8400 Shimadzu spectrophotometer. NMR spectra were
BzO
BzO
recorded either on Bruker ACF 200 (200 MHz for 1H) or MSL 300
O
Na
34
O
O
OH
(300 MHz for 1H) spectrometers. Chemical shifts (
d) reported are
33
H
Na
referred to internal tetramethylsilane. Microanalytical data were
obtained using a Carlo-Erba CHNS-0 EA 1108 Elemental Analyzer, at
the National analytical facility, National Chemical Laboratory, Pune
411 008. All the melting points reported are uncorrected and were
recorded using an electro-thermal melting point apparatus. All the
compounds previously known in the literature were characterized
by comparison of their Rf values on TLC, IR, and 1H NMR spectra as
well as melting point (in case of solids) with authentic samples.
More stable thermodynamic chelates
Scheme 6. Chelates that could be involved during the isomerization shown in
Scheme 5.
The driving force for the isomerization of the C4-esters to the
corresponding C2-esters could be the formation of a relatively
stable alkoxide (such as 33, 34) of a 1,3-diaxial diol from the chelate
of a hydroxyl ester (such as 30–32). We had observed earlier that
the reaction of alkoxides of myo-inositol orthoesters (with alkyl
halides) generated using different metal hydrides (sodium vs lith-
ium) result in different regioselectivities due to variation in the
stability of the chelates involved.4d,e Involvement of metal ion–
myo-inositol orthoester chelates has been suggested to rationalize
the observed regioselectivity during the O-alkylation of myo-ino-
sitol orthoesters.6b
4.2. Benzylation of ( )-4-O-benzoyl-myo-inositol 1,3,5-
orthoformate (13)
4.2.1. Procedure I
(ꢁ)-Benzoate 138d (0.300 g, 1.02 mmol) was dissolved in DMF
(3 mL) and stirred with sodium hydride (0.024 g, 1 mmol) at room
temperature for 5 min. Benzyl bromide (0.12 mL, 1 mmol) was
added to the reaction mixture and the stirring continued for 24 h.
The reaction mixture was diluted with ethyl acetate (50 mL),
washed with water (25 mLꢂ5) followed by brine (25 mLꢂ2), dried
over anhydrous sodium sulfate; the solvents were removed under
reduced pressure using a rotary evaporator. The products were
separated by column chromatography (eluent: gradient elution
with 2–30% ethyl acetate in light petroleum) to obtain (ꢁ)-1712
(0.360 g, 94%) as colorless solid (Rf¼0.3, 20% ethyl acetate in light
petroleum) and (ꢁ)-106b (0.010 g, 4%) as a colorless gum (Rf¼0.3,
30% ethyl acetate in light petroleum).
3. Conclusion
We have described a novel and unusual 1(axial)/3(equato-
rial) acyl migration in orthoesters of myo-inositol. Generality of
this isomerization has been illustrated by using different car-
boxylic acid esters. We have exploited this acyl migration to
develop a convenient and efficient method to access 2-O- and
4-O-acyl-myo-inositol orthoesters irrespective of the nature of
the acyl group, just by varying the amount of sodium hydride
used for the reaction. To the best of our knowledge this is the
first case of the dependence of regioselectivity on the stoichi-
ometry of the base used in a reaction. Unlike previously reported
methods of acylation of inositol orthoesters, our method is very
general and can be applied to synthesize a variety of myo-inositol
esters. These results are of interest not only to organic chemists
dealing with phosphoinositol synthesis but also to a wider cross
section of biological and medicinal chemists in the context of the
use of inositols in various fields overlapping with organic
chemistry.
4.2.2. Procedure II
(ꢁ)-Benzoate 13 (0.300 g, 1.02 mmol) and benzyl bromide
(0.12 mL, 1 mmol) were dissolved in DMF (3 mL) and sodium hy-
dride (0.024 g, 1 mmol) was added and stirred at room temperature
for 24 h. The reaction mixture was diluted with ethyl acetate
(50 mL), washed with water (25 mLꢂ5) followed by brine
(25 mLꢂ2), dried over anhydrous sodium sulfate; the solvents were
removed under reduced pressure using a rotary evaporator. The
products were separated by column chromatography (eluent:

K.M. Sureshan et al. / Tetrahedron 65 (2009) 2703–2710
2707
gradient elution with 2–30% ethyl acetate in light petroleum) to
obtain (ꢁ)-1712 (0.120 g, 31%) (20% ethyl acetate in light petroleum)
and (ꢁ)-18 (0.160 g, 42%) as colorless solids, and (ꢁ)-106b (0.040 g,
14%) (20% ethyl acetate in light petroleum) as a colorless gum.
Compound 18: mp 107–110 ꢀC; Rf¼0.25 (20% ethyl acetate in light
petroleum); Found: C, 64.91; H, 5.35. C21H20O7$0.25H2O requires:
C, 64.84; H, 5.32%; HRMS: MHþ found 385.1291, C21H21O7 requires
(50.3 MHz, CDCl3) 164.9 (O–C]O), 133.7 (Ar C), 129.7 (Ar C), 128.6
(Ar C), 103.0 (HCO3), 74.2 (Ins C), 71.9 (Ins C), 68.5 (Ins C), 68.1 (Ins
C), 67.3 (Ins C), 61.0 (Ins C).
4.7. Acetylation of myo-inositol 1,3,5-orthoformate (2)
Acetylation of 2 (0.190 g,1 mmol) with acetic anhydride (0.1 mL)
and sodium hydride (0.024 g, 1 mmol) following the general pro-
cedure A gave the racemic acetate 7 (0.200 g, 86%) as a colorless
solid. Mp 156 ꢀC; Rf¼0.26 (40% ethyl acetate in light petroleum);
Found: C, 46.18; H, 5.45. C9H12O7 requires: C, 46.53; H, 5.21%;
385.1287; nmax(Nujol) 1724 (C]O), 3200–3600 (OH) cmꢃ1
; dH
(200 MHz, CDCl3) 7.90 (2H, d, J 12 Hz, ArH), 7.10–7.65 (8H, m, ArH),
5.70–5.85 (1H, m, Ins H-6), 5.57 (1H, s, HCO3), 4.65–4.75 (1H, m, Ins
H), 4.50–4.65 (2H, s, PhCH2), 4.40–4.50 (1H, m, Ins H), 4.30–4.40
(2H, m, Ins H), 4.25 (1H, m, Ins H), 3.00–3.55 (1H, br s, OH); dC
(50.3 MHz, CDCl3) 165.1 (O–C]O), 136.7 (Ar C), 133.1 (Ar C), 129.6
(Ar C), 128.8 (Ar C), 128.1 (Ar C), 127.6 (Ar C), 127.4 (Ar C), 103.0
(HCO3), 73.4 (Ins C-6), 72.4 (BnCH2), 71.9 (Ins C), 71.7 (Ins C), 67.9
(Ins C), 66.6 (Ins C), 61.1 (Ins C).
nmax(Nujol) 1717 (C]O), 3300–3500 (OH) cmꢃ1
; dH (200 MHz,
CDCl3) 5.40–5.55 (2H, m, Ins H-4 and HCO3), 4.55–4.65 (1H, m, Ins
H), 4.40–4.50 (1H, m, Ins H), 4.15–4.25 (2H, m, Ins H), 4.00–4.10 (1H,
m, Ins H), 3.56 (1H, br d, J 10 Hz, OH), 2.80 (1H, br d, J 7 Hz, OH), 2.11
(3H, s, CH3); dC (50.3 MHz, DMSO-d6) 170.3 (O–C]O), 102.6 (HCO3),
74.2 (Ins C-4), 71.9 (Ins C), 68.9 (Ins C), 68.4 (Ins C), 66.6 (Ins C), 59.4
(Ins C), 21.0 (CH3).
4.3. Aminolysis of ( )-18
(ꢁ)-Benzoate 18 (0.100 g, 0.26 mmol) was stirred with iso-
butylamine (1 mL) and methanol at room temperature for 24 h.
Solvent was evaporated and the residue purified by column chro-
matography to get benzyl ether (ꢁ)-106b (0.070 g, 96%) as a color-
less gum.
4.8. Pivaloylation of myo-inositol 1,3,5-orthoformate (2)
Triol 2 (0.190 g, 1 mmol) was allowed to react with pivaloyl
chloride (0.12 mL, 1 mmol) and sodium hydride (0.024 g, 1 mmol)
as in procedure A to obtain the racemic pivalate 21 (0.230 g, 84%) as
a colorless solid. Mp 128 ꢀC; Rf¼0.31 (30% ethyl acetate in light
petroleum); Found: C, 52.62; H, 6.55. C12H18O7 requires: C, 52.53; H,
4.4. Preparation of myo-inositol 1,3,5-orthoacetate (3)
myo-Inositol (12 g, 66.7 mmol) was suspended in DMF (100 mL),
trimethylorthoacetate (12 mL, 94.3 mmol), and p-toluenesulfonic
acid (1 g, 5.8 mmol) were added and stirred at 90–100 ꢀC for 1–2 h.
The acid was neutralized by the addition of triethylamine (4 mL)
and the reaction mixture was cooled to room temperature. The
solvents were evaporated under reduced pressure and the residue
obtained was chromatographed over silica gel with ethyl acetate as
the eluent to obtain myo-inositol 1,3,5-orthoacetate (3, 12.38 g,
91%) as a colorless solid. Rf¼0.5 (ethyl acetate); mp 186–187 ꢀC;
lit.5b mp 185–187 ꢀC.
6.62%; nmax(Nujol) 1717 (C]O), 3100–3600 (OH) cmꢃ1
; dH
(200 MHz, CDCl3) 5.50–5.60 (2H, m, Ins H-4 and HCO3), 4.55–4.65
(1H, m, Ins H), 4.40 (1H, m, Ins H), 4.20–4.25 (2H, m, Ins H),
4.00–4.10 (1H, m, Ins H), 3.30 (1H, br d, J 10 Hz, OH), 2.50 (1H, br d, J
6 Hz, OH),1.20 (9H, s, 3ꢂCH3); dC (50.3 MHz, CDCl3) 176.7 (O–C]O),
102.7 (HCO3), 74.1 (Ins C-4), 71.6 (Ins C), 68.2 (Ins C), 67.8 (Ins C),
67.1 (Ins C), 60.7 (Ins C), 38.7 (CMe3), 26.8 (3ꢂCH3).
4.9. Lauroylation of myo-inositol 1,3,5-orthoformate (2)
Triol 2 (0.190 g, 1 mmol) was allowed to react with lauroyl
chloride (0.23 mL, 1 mmol) as in procedure A to obtain the racemic
laurate 22 (0.310 g, 84%) as a colorless solid. Mp 82–84 ꢀC; Rf¼0.35
(30% ethyl acetate in light petroleum); Found: C, 61.20; H, 8.76.
C19H32O7 requires: C, 61.25; H, 8.67%; nmax(Nujol) 1745 (C]O),
4.5. General procedure (A) for 4-O-acylation of myo-inositol
1,3,5-orthoesters
myo-Inositol 1,3,5-orthoester (1 mmol) was dissolved in DMF
(3 mL). Sodium hydride (1 mmol) and the required acyl chloride or
acid anhydride (1 mmol) were added and the mixture stirred for
5 min. Residual sodium hydride was destroyed by the addition of
moist ethyl acetate (10 mL) or acetic acid (0.06 mL). The reaction
mixture was diluted with ethyl acetate (60 mL), washed with water
(30 mLꢂ5) followed by brine (30 mLꢂ2), dried over anhydrous
sodium sulfate; the solvents were removed under reduced pressure
using a rotary evaporator to obtain crude (ꢁ)-4-O-acyl-myo-inosi-
tol 1,3,5-orthoester. The product was isolated by column chroma-
tography (eluent: gradient elution with 2–40% ethyl acetate in light
petroleum).
3200–3600 (OH) cmꢃ1
; dH (200 MHz, CDCl3) 5.55 (1H, m, Ins H-4),
5.50 (1H, s, HCO3), 4.60 (1H, m, Ins H), 4.40 (1H, m, Ins H), 4.20 (2H,
m, Ins H), 4.05 (1H, m, Ins H), 3.50 (1H, br s, OH), 2.85 (1H, br s, OH),
2.30 (2H, t, J 9 Hz, COCH2), 1.50–1.70 (2H, m, COCH2CH2), 1.15–1.45
(16H, m, 8ꢂCH2), 0.80–0.95 (3H, t, J 9 Hz, CH3); dC (50.3 MHz, CDCl3)
171.9 (O–C]O),102.8 (HCO3), 74.1 (Ins C-4), 71.6 (Ins C), 68.2 (Ins C),
67.7 (Ins C), 67.2 (Ins C), 60.6 (Ins C), 33.9 (CH2), 31.7 (CH2), 29.4
(CH2), 29.1 (CH2), 28.9 (CH2), 24.5 (CH2), 22.5 (CH2), 13.9 (CH3).
4.10. Acetylation of myo-inositol 1,3,5-orthoacetate (3)
4.6. Benzoylation of myo-inositol 1,3,5-orthoformate (2)
Triol 3 (0.204 g, 1 mmol) was acetylated with acetic anhydride
(0.1 mL, 1 mmol) as in the general procedure A to obtain the race-
mic acetate 23 (0.215 g, 87%) as a colorless solid. Mp 181–183 ꢀC;
Rf¼0.3 (40% ethyl acetate in light petroleum); Found: C, 46.66; H,
5.69. C10H14O7$0.6H2O requires: C, 46.71; H, 5.96%; nmax(Nujol)
Orthoformate 2 (0.190 g, 1 mmol) was benzoylated with benzoyl
chloride (0.12 mL) and sodium hydride (0.024 g, 1 mmol) as in the
general procedure A to obtain (ꢁ)-4-O-benzoyl-myo-inositol 1,3,5-
orthoformate8d (13, 0.260 g, 88%) as
a
colorless solid. Mp
1728–1747 (C]O), 3261 (OH), 3458 (OH) cmꢃ1
; dH (200 MHz,
149–152 ꢀC; Rf¼0.31 (30% ethyl acetate in light petroleum); nmax
-
CDCl3) 5.40–5.55 (1H, m, Ins H-4), 4.50–4.60 (1H, m, Ins H),
4.35–4.45 (1H, m, Ins H), 4.15–4.30 (2H, m, Ins H), 3.95–4.10 (1H, m,
Ins H), 3.60 (1H, br s, OH), 3.10 (1H, br s, OH), 2.10 (3H, s, COCH3),
1.45 (3H, s, H3CCO3); dC (50.3 MHz, CDCl3) 170.3 (O–C]O), 108.7
(MeCO3), 75.2 (Ins C-4), 72.8 (Ins C), 69.1 (Ins C), 68.7 (Ins C), 66.7
(Ins C), 58.5 (Ins C), 24.8 (H3CCO3), 21.3 (COCH3).
(Nujol) 1720 (C]O), 3200–3600 (OH) cmꢃ1
; dH (200 MHz, CDCl3)
d
7.90–8.05 (2H, d, J 12 Hz, Ar H), 7.30–7.70 (3H, m, Ar H), 5.75–5.85
(1H, m, Ins H-4), 5.55–5.60 (1H, s, HCO3), 4.60–4.75 (1H, m, Ins H),
4.50–4.60 (1H, m, Ins H), 4.30–4.45 (1H, m, Ins H), 4.15–4.30 (2H, m,
Ins H), 3.30 (1H, d, J 19 Hz, OH), 2.50 (1H, d, J 7 Hz, OH); dC

2708
K.M. Sureshan et al. / Tetrahedron 65 (2009) 2703–2710
4.11. Benzoylation of myo-inositol 1,3,5-orthoacetate (3)
7.10–7.30 (4H, m, Ar H), 5.85 (2H, t, J 6 Hz, Ins H-4 and Ins H-6), 5.70
(1H, s, HCO3), 5.5 (1H, m, Ins H-2), 4.90–5.00 (1H, m, Ins H-5),
4.50–4.60 (2H, m, Ins H-1 and Ins H-3), 2.25 (3H, s, COCH3); dC
(50.3 MHz, CDCl3) 170.5 (O–C]O of Ac), 165.0 (2ꢂO–C]O of Bz),
133.4 (Ar C), 129.3 (Ar C), 128.6 (Ar C), 128.3 (Ar C), 103.2 (HCO3),
69.3 (Ins C), 68.4 (Ins C), 67.0 (Ins C), 63.4 (Ins C), 20.7 (CH3).
Triol 3 (0.204 g, 1 mmol) was benzoylated with benzoyl chloride
(0.12 mL), as above (general procedure A) to obtain the racemic
benzoate 24 (0.270 g, 88%) as a colorless solid. Mp 108 ꢀC; Rf¼0.33
(35% ethyl acetate in light petroleum); Found: C, 58.79; H, 5.52.
C15H16O7 requires: C, 58.42; H, 5.23%; nmax(Nujol) 1717 (C]O),
3200–3600 (OH) cmꢃ1
;
dH (200 MHz, CDCl3) 7.90–8.10 (2H, m, Ar
4.14.2. Using potassium tert-butoxide
H), 7.55–7.65 (1H, m, Ar H), 7.35–7.50 (2H, m, Ar H), 5.65–5.70 (1H,
m, Ins H-4), 4.55–4.65 (1H, m, Ins H), 4.45–4.50 (1H, m, Ins H),
4.30–4.35 (1H, m, Ins H), 4.15–4.25 (2H, m, Ins H), 3.6 (1H, br s, OH),
3.15 (1H, br s, OH), 1.50 (3H, s, CH3); dC (50.3 MHz, CH3OH with D2O
as external lock) 167.7 (O–C]O), 134.6 (Ar C), 131 (Ar C), 129.8 (Ar
C), 109.8 (MeCO3), 74.5 (Ins C-4), 71.2 (Ins C), 69.2 (Ins C), 64.7 (Ins
C), 24.9 (CH3).
The racemic acetate 7 (0.232 g, 1 mmol) was isomerized with
potassium tert-butoxide (0.112 g, 1 mmol) as in the general pro-
cedure B and benzoylated as in the procedure given in Section
4.14.1, to obtain 29 (0.420 g, 95%) as a colorless solid.
4.15. Isomerization of ( )-4-O-pivaloyl-myo-inositol 1,3,5-
orthoformate (21) with sodium hydride
4.12. General procedure (B) for the isomerization of ( )-4-O-
acyl-myo-inositol 1,3,5-orthoesters to 2-O-acyl-myo-inositol
1,3,5-orthoesters
The racemic pivalate 21 (0.100 g, 0.36 mmol) was treated with
sodium hydride (0.010 g, 0.4 mmol) in DMF (2 mL) as in the general
procedure B to obtain 2-pivalate 25 (0.090 g, 90%) as a colorless
solid. Mp 159 ꢀC; Rf¼0.28 (25% ethyl acetate in light petroleum);
Found: C, 52.95; H, 6.46. C12H18O7 requires: C, 52.55; H, 6.62%;
(ꢁ)-4-O-Acyl-myo-inositol 1,3,5-orthoester (1 mmol) was dis-
solved in DMF (3 mL) and stirred with sodium hydride or potassium
tert-butoxide (1 mmol) for 5 min. The reaction mixture was then
diluted with ethyl acetate (50 mL), washed with water (30 mLꢂ5)
followed by brine (30 mLꢂ2) and dried over anhydrous sodium
sulfate and the solvent was evaporated under reduced pressure to
obtain 2-O-acyl-myo-inositol 1,3,5-orthoester. In some experi-
ments, the product was isolated as its diacetate or dibenzoate
derivative.
nmax(Nujol) 1721 (C]O), 3100–3500 (OH) cmꢃ1
; dH (200 MHz,
CDCl3) 5.50 (1H, s, HCO3), 5.25 (1H, m, Ins H-2), 4.60 (2H, m, Ins H),
4.30 (3H, m, Ins H), 4.20 (2H, br, 2ꢂOH), 1.30 (9H, s, 3ꢂCH3); dC
(50.3 MHz, CDCl3) 179.3 (O–C]O), 102.2 (HCO3), 71.5 (2ꢂIns C),
68.5 (Ins C-2), 67.8 (2ꢂIns C), 63.0 (Ins C-5), 38.9 (CMe3), 26.8
(3ꢂCH3).
4.16. Isomerization of ( )-4-O-lauroyl-myo-inositol 1,3,5-
orthoformate (22) with sodium hydride
4.13. Isomerization of ( )-4-O-benzoyl-myo-inositol 1,3,5-
orthoformate (13)
The racemic laurate 22 (0.100 g, 0.27 mmol) was treated with
sodium hydride (0.010 g, 0.4 mmol) in DMF (2 mL) as in the general
procedure B to obtain 2-laurate 26 (0.093 g, 93%) as a colorless
solid. Mp 89 ꢀC; Rf¼0.3 (25% ethyl acetate in light petroleum);
Found: C, 61.01; H, 8.73. C19H32O7 requires: C, 61.25; H, 8.67%;
4.13.1. Using sodium hydride
Benzoate 13 (0.294 g, 1 mmol) was isomerized to 2-benzoate 6
(0.265 g, 90%) as described in the general procedure B; mp 211 ꢀC;
lit.8a mp 210–213 ꢀC.
nmax(Nujol) 1747 (C]O), 3466 (OH) cmꢃ1
; dH (200 MHz, CDCl3) 5.50
(1H, s, HCO3), 5.30 (1H, m, Ins H-2), 4.55–4.65 (2H, m, Ins H),
4.20–4.40 (5H, m, 2ꢂOH, 3ꢂIns H), 2.5 (2H, t, J 10 Hz, COCH2),
1.55–1.75 (2H, m, COCH2CH2), 1.15–1.45 (16H, m, 8ꢂCH2), 0.80–0.95
(3H, t, J 11 Hz, CH3); dC (50.3 MHz, CDCl3) 174.3 (O–C]O), 102.2
(HCO3), 71.6 (2ꢂIns C), 68.4 (Ins C-2), 67.7 (2ꢂIns C), 62.9 (Ins C-5),
34.1 (aliph C), 31.7 (aliph C), 29.3 (aliph C), 29.1 (aliph C), 28.8 (aliph
C), 24.7 (aliph C), 22.4 (aliph C), 13.8 (CH3).
4.13.2. Using potassium tert-butoxide
Benzoate 13 (0.294 g, 1 mmol) was treated with potassium tert-
butoxide (0.112 g, 1 mmol) as above. After 5 min pyridine (5 mL)
and acetic anhydride (1 mL) were added and the reaction mixture
was stirred overnight, at room temperature. The reaction mixture
was then diluted with chloroform (100 mL), washed successively
with water (50 mLꢂ5), cold dil HCl (30 mLꢂ2), satd sodium bi-
carbonate solution (50 mLꢂ2), and brine (50 mLꢂ2). The organic
layer was dried over anhydrous sodium sulfate and the solvent
evaporated under reduced pressure to obtain 2-O-benzoyl-4,6-di-
O-acetyl-myo-inositol 1,3,5-orthoformate (0.350 g, 93%) as a color-
less solid. Mp 142 ꢀC; lit.13 mp 142–143 ꢀC.
4.17. Isomerization of ( )-4-O-acetyl-myo-inositol 1,3,5-
orthoacetate (23)
4.17.1. Using sodium hydride
The racemic acetate 23 (0.246 g, 1 mmol) was treated with so-
dium hydride (0.024 g, 1 mmol) in DMF (3 mL) as in the general
procedure B to get 2-acetate 27 (0.22 g, 89%) as a colorless solid. Mp
66–68 ꢀC; Rf¼0.25 (30% ethyl acetate in light petroleum); Found: C,
45.37; H, 5.88. C10H14O7$H2O requires: C, 45.43; H, 6.10%; HRMS:
MNaþ found 269.0637, C21H21O7Na requires 269.0637; nmax(Nujol)
4.14. Isomerization of ( )-4-O-acetyl-myo-inositol 1,3,5-
orthoformate (7)
4.14.1. Using sodium hydride
The racemic acetate 7 (0.232 g, 1 mmol) was treated with so-
dium hydride as in the general procedure B and benzoylated with
benzoyl chloride (10 mmol) and pyridine (10 mL) to obtain 2-
O-acetyl-4,6-di-O-benzoyl-myo-inositol 1,3,5-orthoformate (29,
0.390 g, 89%) and 2,4,6-tri-O-benzoyl-myo-inositol 1,3,5-ortho-
formate8b (0.030 g, 6%) as colorless solids, after chromatography
(eluent: gradient elution with 2–20% ethyl acetate in light petro-
leum). Compound 29: mp 212 ꢀC; Rf¼0.27 (15% ethyl acetate in light
petroleum); Found: C, 62.51; H, 4.11. C23H20O9 requires: C, 62.72; H,
1732 (C]O), 3100–3600 (OH) cmꢃ1
; dH (200 MHz, CDCl3) 5.30 (1H,
m, Ins H-2), 5.00 (2H, d, J 9 Hz, 2ꢂOH), 4.40–4.60 (2H, m, 2ꢂIns H),
4.30 (2H, m, 2ꢂIns H), 4.10–4.25 (1H, m, Ins H-5), 2.20 (3H, s,
COCH3), 1.45 (3H, s, CCH3); dC (50.3 MHz, CDCl3) 170.1 (O–C]O),
107.6 (O3CMe), 72.3 (2ꢂIns C), 68.5 (Ins C-2), 66.9 (2ꢂIns C), 61.9
(Ins C-5), 29.1 (COCH3), 23.6 (CCH3).
4.17.2. Using potassium tert-butoxide
The racemic acetate 23 (0.246 g, 1 mmol) was treated with po-
tassium tert-butoxide (0.112 g,1 mmol) in DMF (3 mL) with stirring,
4.54%; nmax(Nujol) 1730 (C]O) cmꢃ1
7.75–7.95 (4H, d, J 12 Hz, Ar H), 7.40–7.55 (2H, t, J 12 Hz, Ar H),
;
dH (200 MHz, CDCl3)

K.M. Sureshan et al. / Tetrahedron 65 (2009) 2703–2710
2709
as in the general procedure B, to get 27 (0.21 g, 85%) as the only
4.23. Acetylation of myo-inositol 1,3,5-orthoformate (2)
product.
Triol 2 (0.190 g, 1 mmol) was acetylated with sodium hydride
(0.048 g, 2 mmol) and acetic anhydride (0.1 mL, 1 mmol) as in the
general procedure C to obtain 8 (0.210 g, 91%) as a colorless solid.6c
4.18. Isomerization of ( )-4-O-benzoyl-myo-inositol 1,3,5-
orthoacetate (24)
4.18.1. Using sodium hydride
4.24. Pivaloylation of myo-inositol 1,3,5-orthoformate (2)
The racemic benzoate 24 (0.20 g, 0.65 mmol) was treated with
sodium hydride (0.156 g, 0.65 mmol) in DMF (2 mL) as in the gen-
eral procedure B to obtain 2-benzoate 28 (0.190 g, 95%) as a color-
less solid. Mp 160 ꢀC; Rf¼0.4 (35% ethyl acetate in light petroleum);
Found: C, 58.07; H, 5.37. C15H16O7 requires: C, 58.42; H, 5.23%;
Triol 2 (0.190 g, 1 mmol) was allowed to react with pivaloyl
chloride (0.12 mL, 1 mmol) as in procedure C, in the presence of
sodium hydride (0.048 g, 2 mmol) to obtain 25 (0.241 g, 88%) as
a colorless solid.
nmax(Nujol) 1711 (C]O), 3100–3600 (OH) cmꢃ1
; dH (200 MHz,
CDCl3) 8.1–8.2 (2H, d, J 9 Hz, Ar H), 7.60 (1H, t, J 9 Hz, Ar H), 7.40–
7.55 (2H, m, Ar H), 5.5 (1H, t, 3 Hz, Ins H-2), 4.55–4.65 (2H, m, 2ꢂIns
H), 4.45–4.50 (2H, m, 2ꢂIns H), 4.3 (1H, m, Ins H-5), 4.25 (2H, d, J
6 Hz, 2ꢂOH), 1.50 (3H, s, CH3); dC (50.3 MHz, CH3OH with D2O as
external lock) 167.7 (O–C]O), 134.6 (Ar C), 131 (Ar C), 129.8 (Ar C),
109.8 (MeCO3), 74.5 (2ꢂIns C), 71.2 (Ins C-2), 69.2 (2ꢂIns C), 64.7
(Ins C-5), 24.9 (CH3).
4.25. Lauroylation of myo-inositol 1,3,5-orthoformate (2)
Triol 2 (0.190 g, 1 mmol) was allowed to react with lauroyl
chloride (0.23 mL, 1 mmol) in the presence of sodium hydride
(0.048 g, 2 mmol) as in procedure C to obtain 26 (0.303 g, 82%) as
a colorless solid.
4.26. Acetylation of myo-inositol 1,3,5-orthoacetate (3)
4.18.2. Using potassium tert-butoxide
The racemic benzoate 24 (0.100 g, 0.32 mmol) was treated with
potassium tert-butoxide (0.037 g, 0.33 mmol) in DMF (1 mL) as in
the general procedure B to obtain 28 (0.090 g, 90%) as the only
product.
Triol 3 (0.204 g, 1 mmol) was acetylated with acetic anhydride
(0.1 mL, 1 mmol) as in procedure C to obtain 27 (0.225 g, 91%) as
a colorless solid.
4.27. Benzoylation of myo-inositol 1,3,5-orthoacetate (3)
4.19. General procedure (C) for 2-O-acylation of myo-inositol
1,3,5-orthoesters
Triol 3 (0.204 g, 1 mmol) was benzoylated with benzoyl chloride
(0.12 mL) as above to obtain 28 (0.300 g, 97%) as a colorless solid.
myo-Inositol 1,3,5-orthoester (1 mmol) was dissolved in DMF
(3 mL). Sodium hydride (2 mmol) and acyl chloride (or acid anhy-
dride) were added and the mixture stirred for 5 min. Residual so-
dium hydride was destroyed by the addition of moist ethyl acetate
(10 mL) or acetic acid (0.06 mL). The reaction mixture was diluted
with ethyl acetate (60 mL), washed with water (30 mLꢂ5), satu-
rated sodium bicarbonate (30 mLꢂ2) followed by brine (30 mLꢂ2)
and dried over anhydrous sodium sulfate; the solvents were re-
moved under reduced pressure using a rotary evaporator, to obtain
2-O-acyl-myo-inositol 1,3,5-orthoester. The products were isolated
by column chromatography (eluent: gradient elution with 2–40%
ethyl acetate in light petroleum).
Acknowledgements
K.M.S. and S.D. thank CSIR for research fellowships. This work
was funded by the Department of Science and Technology, New
Delhi, India. Technical assistance by Madhuri Patil and Rajendra
Jagdhane is much appreciated.
References and notes
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4.20. Benzoylation of myo-inositol 1,3,5-orthoformate (2)
Triol 2 (0.190 g, 1 mmol) was benzoylated with benzoyl chloride
(0.12 mL) and sodium hydride (0.048 g, 2 mmol) as in the general
procedure C to obtain 6 (0.250 g, 85%) and (ꢁ)-dibenzoate 15
(0.030 g, 8%) as colorless solids.
4.21. Reaction of myo-inositol 1,3,5-orthoformate (2) with
3 equiv of sodium hydride and 1 equiv benzoyl chloride
Triol 2 (0.190 g, 1 mmol) was dissolved in DMF (3 mL). Sodium
hydride (0.072 g, 3 mmol) and benzoyl chloride (0.12 mL) were
added and stirred for 5 min. Work up of the reaction mixture (as in
procedure C) followed by column chromatography gave 6 (0.256 g,
87%) as the only product.
4.22. Reaction of myo-inositol 1,3,5-orthoformate (2) with
excess sodium hydride and 1 equiv benzoyl chloride
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