Neutral complexing agents with a cyclitol core. Effect of the relative orientation of the sidearms and end groups on the cation binding ability of myo-inositol based podands

Article abstract of DOI:10.1039/b106717f

myo-Inositol derived podands were synthesized and the extent of their binding with picrates of alkali metals, ammonia and silver was estimated. These podands bind very well with lithium and silver picrates but show moderate to poor binding toward sodium,

Full text of DOI:10.1039/b106717f

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Neutral complexing agents with a cyclitol core. Effect of the
relative orientation of the sidearms and end groups on the cation
binding ability of myo-inositol based podands
2
Kana M. Sureshan,a Mysore S. Shashidhar*a and Anjani J. Varma*b
a Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008,
India. E-mail: shashi@dalton.ncl.res.in
b Polymer Science and Engineering Unit, National Chemical Laboratory, Pune 411 008, India
Received (in Cambridge, UK) 24th July 2001, Accepted 17th October 2001
First published as an Advance Article on the web 12th November 2001
myo-Inositol derived podands were synthesized and the extent of their binding with picrates of alkali metals,
ammonia and silver was estimated. These podands bind very well with lithium and silver picrates but show moderate
to poor binding toward sodium, potassium, caesium and ammonium picrates. The ion selectivity and the strength of
binding are dependent on the relative orientation of the sidearms (1,3-diaxial, 1,2-diequatorial and 1,2-axial–
equatorial) as well as on the nature of the end group present in the podands.
complexing ability. Although inositols6 and phosphoinositols7
Introduction
have been known to form complexes with metal ions, reports on
In the last decade, there has been an upsurge of interest in
the synthesis and study of cyclitol based neutral complexing
the chemistry of inositols mainly due to the establishment of
agents began to appear only recently.8 Six secondary hydroxy
-myo-inositol 1,4,5-trisphosphate as a second messenger
groups of myo-inositol allow the preparation of crown ether
in cell signaling pathways.1 myo-Inositol is also involved in
like compounds with varying relative configuration of two of
the oxygen atoms (Scheme 1, 4, 5). Also, myo-inositol can
easily be converted to its 1,3,5-orthoformate 1 which allows the
preparation of neutral complexing agents that have two oxygen
atoms in a 1,3-cis configuration (3). It is interesting to see if
these variations result in better binding or better selectivity for
the anchoring of certain proteins to cell membranes.2 The
biological significance of myo-inositol derivatives prompted
chemists to devise methods for efficient synthesis of naturally
occurring phosphoinositols, glycophosphoinositol anchors as
well as other derivatives of cyclitols, as potential drugs or
inhibitors of enzymes involved in the myo-inositol cycle. We
complexation with metal ions.
had previously reported3 convenient methods for the prepar-
Synthesis and study of neutral complexing agents has
ation of several important O-protected myo-inositol derivatives
via myo-inositol 1,3,5-orthoformate (1, Scheme 1). From these
grown into a vast area of research9 due to their applications in
various fields of chemistry, biology, medicine and industry.
However the search for efficient, selective and biocompatible
complexing agents for metal ions continues.8 The present article
is concerned with the results on the synthesis of myo-inositol
based podands and an evaluation of their complexing ability
with picrate salts of alkali metals, ammonia and silver.
Results and discussion
We chose the orthoformate 1,10 the racemic tetrabenzyl ether
611 and the racemic isopropylidene derivative 1012 as starting
materials for the synthesis of several podands with THP and
benzyl ether end groups. The synthesis of podands from the
diols 6 and 10 was straightforward (Scheme 2). The di(ethylene
glycol) derived podands 7 and 11 with benzyl ether end
groups were prepared by the alkylation of the diols 6 and 10
with the toluene-p-sulfonate of di(ethylene glycol) monobenzyl
ether. Alkylation of 6 and 10 with THP ether derivative of
2-bromoethanol in the presence of sodium hydride provided
the podands 8 and 12. The THP ether groups were removed
(in the case of 8) by acid hydrolysis or by treatment with
ethanethiol in the presence of boron trifluoride etherate (in the
case of 12) to obtain the corresponding diols 9 and 13.
The di-THP ethers 15 and 22 (Scheme 3) were prepared by the
alkylation of the diols 14 and 21 respectively, with 2-bromo-
ethanol THP ether. For the synthesis of the diol 20, we resorted
to several protection–deprotection reactions, since no good
method was available (when this work was started) for
the preparation of the 2-O-benzyl ether 21. The sequence
Scheme 1
studies, as well as others reported4 in the literature, it appeared
that the unusual selectivities encountered during O-alkylation,
O-acylation, O-sulfonylation and transesterification reactions
of the orthoformate 1 or its derivatives, were a result of their
chelation (2) with metal ions. We had also observed5 that
some O-substituted myo-inositol derivatives (such as racemic
2,4-di-O-benzoyl-myo-inositol 1,3,5-orthoformate, racemic
2,4-di-O-benzoyl-6-O-tosyl-myo-inositol 1,3,5-orthoformate,
2-O-benzoyl-4,6-di-O-benzyl-myo-inositol 1,3,5-orthoformate,
1,2,3,4,5,6-hexa-O-benzoyl-myo-inositol and racemic 1,2,3,4,5-
penta-O-benzoyl-6-O-tosyl-myo-inositol) bind well with silver
picrate. These results prompted us to synthesize simple poly-
ether derivatives of myo-inositol and examine their metal ion
2298
J. Chem. Soc., Perkin Trans. 2, 2001, 2298–2302
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b106717f

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high yielding method for the synthesis of 21 using sulfonate
protection for the axial hydroxy groups in 1, which was
adopted for the preparation of the podands 22 and 23. We
then proceeded to estimate the cation binding abilities of the
newly synthesized podands with alkali metal, ammonium
and silver picrates using literature procedures.13
Results on the solvent extraction (into CDCl3) of picrates
from their aqueous solution, by the newly synthesized podands
are shown in Table 1. The association constants (Ka) clearly
show that the podands have a high preference for binding to
lithium ions, the highest affinity being exhibited by 23. Most
of the synthetic ligands show poor binding to alkali metal
ions and the ammonium ion. Some of the inositol based ligands
also show moderate to very good affinity for silver and the
highest binding to silver is shown by 7. The ratio of association
constants for different metal picrates varies from 158 (KLi/KCs
for 15) to 7 (KLi/KNa for 7). A comparison of Ka for the THP
ethers (8, 12, 22) and the corresponding diols (9, 13, 20)
indicates the role of THP ether moieties of the ligands in bind-
ing to metal picrates. It is interesting to note that despite having
similar ionic size14 silver (0.252 nm) binds much better than
potassium (0.266 nm) with the newly synthesized podands. A
comparison of Ka for 15 and 22 reveals that the protecting
group at the 2-O position does not contribute towards the
binding of the picrates to ligand. A comparison of binding
characteristics of all the ligands reveals that the strongest
binding to lithium and silver is exhibited by podands with
benzyl ether end groups, 23 and 7 respectively.
Scheme
2
Reagents and conditions: i) DMF, NaH, BnOCH2-
CH2OCH2CH2OTs, rt. ii) BrCH2CH2OTHP, NaH, DMF, rt. iii) Acetic
acid (80%), rt, 24 h. iv) BF3ؒEt2O, EtSH, CH2Cl2, Ϫ20 ЊC, 30 min.
A comparison of the binding constants of the ligands with
the same relative orientation indicates that among the diaxial
ligands (15, 22 and 23), 23 binds Li, Na and Ag ions better.
Among the diequatorial ligands (11 and 12), the di-THP ether
12 binds more strongly with Li and Na ions while both 11 and
12 bind well to silver. In the case of axial–equatorial ligands
(7 and 8), the di-THP ether 8 shows preference for Li while 7
shows preference for Na and Ag ions. It is known that the
nature of the end groups9 and the relative configuration15 of
the donor functional groups in a ligand play a vital role in
deciding the complexing ability of the host with cations. The
fact that tetrahydropyranyl moieties are known to contribute
significantly towards complexation with metal ions9,16 and are
also present in many biologically active compounds such as
antibiotics, led us to choose THP ethers as the end group for
some of the myo-inositol based podands.
To see the effect of relative orientation of the sidearms of
the ligands on binding to metal picrates, we compared the
binding constants of isomeric ligands having different relative
orientations. Such a comparison for THP ethers (8, 12, 22)
reveals that lithium and silver ions bind better with ligand 8
having axial–equatorial orientation while sodium prefers to
bind with THP ethers having diequatorial orientation (12).
However in the case of di(ethylene glycol) derived podands with
benzyl ether end groups (7, 11, 23) lithium and sodium ions
bind better to 23 (having diaxial orientation) while silver ions
prefer to bind to 7 (having axial–equatorial orientation). It is
interesting to note that although all the synthetic ligands have
six oxygen atoms in their side arms, in the podands 7 and 11 all
the oxygen atoms are separated by two carbon atoms (as in
poly(ethylene glycols)). Whereas, in the THP ethers 8 and 12
the two oxygen atoms present in the THP ether moiety are
separated by one carbon atom and the other oxygen atoms are
separated by two carbon atoms. In the case of podands derived
from orthoformate 1, in addition to this difference, oxygen
atoms attached to the inositol ring (at C-4 and C-6) are
separated by three carbon atoms, but are closer to each other
due to their diaxial disposition. Interestingly, these differences
lead to different selectivity patterns for binding to lithium and
silver picrates.
Scheme 3 Reagents and conditions: i) BrCH2CH2OTHP, NaH, DMF,
rt. ii) BrCH2CH2OTr (24), NaH, DMF, rt. iii) Isobutylamine, methanol,
rt. iv) BnBr, NaH, DMF, rt. v) H3BO3, benzene, reflux. vi) DMF, NaH,
BnOCH2CH2OCH2CH2OTs, rt.
of reactions involved (a) alkylation of the diol 16 with
2-bromoethanol trityl ether (24), (b) aminolysis of the benzoate
17 to the corresponding alcohol 18, (c) benzylation of 18 to
the corresponding benzyl ether 19 and (d) cleavage of the
trityl ethers in 19 to obtain the corresponding diol 20. Trityl
ethers were used in this sequence of reactions since the THP
ethers (in 22) are rather difficult to cleave in the presence of the
orthoformate moiety. We later developed3e a convenient and
We also determined the bathochromic shifts17 (Table 2)
induced by some of the synthetic myo-inositol derivatives for
J. Chem. Soc., Perkin Trans. 2, 2001, 2298–2302
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Table 1 Association constants (Ka/103 dm3 molϪ1) for the complexation of univalent cations (M) with synthetic myo-inositol derivatives (25 ЊC)
M
7
8
9
11
12
13
15
20
22
23
Lia
Na
K
Cs
NH4
Ag
156.83
23.11
5.20
7.14
1.76
221.4
5.01
6.27
5.62
1.68
52.75
3.24
4.36
1.52
1.82
42
3.14
3.33
4.11
1.63
208.87
17.09
4.85
2.6
5.76
23.37
—
3.11
0.54
1.52
40.4
201.89
14.11
5.77
1.28
2.56
23.31
0.70
205.5
14.88
5.68
1.52
2.87
331.82
30.38
3.34
6.75
2.14
b
b
—
—
b
0.08
12.62
348.12
114
112.81
74.1
73.55
12.07
14.23
57.9
a Association constants (log (Ka/dm3 molϪ1)) of 4.25 (in acetonitrile), 1.62 (in acetone) and 0.7 (in pyridine) are reported19c for the lithium ion–12-
crown-4 system. b No detectable amount of picrate was extracted.
Table 2 Optical spectroscopic results on the complexationa of alkali
metal picrates (MϩPiϪ) with synthetic myo-inositol derivatives in THF
(25 ЊC)
Co., India. Compounds 6,11 10,12 14,10 16,3d 21,3e O-benzyl-
di(ethylene glycol) toluene-p-sulfonate,21 THP ether derivative
of 2-bromoethanol,22 alkali metal and ammonium picrates13
and silver picrate19 were prepared as reported in the literature.
Compounds 6–13 are racemic, but only one of the enantiomers
is shown in Scheme 2 for brevity. All the solvents were purified
according to literature procedures, before use.23 All the NMR
spectra (200 MHz for 1H on Bruker AC 200 instrument)
were recorded in CDCl3 solution unless otherwise noted.
Infrared spectra were recorded as neat or as Nujol mull on
a Shimadzu FT-IR instrument. Elemental analyses were
performed on a Carlo Erba CHNS-0-EA-1108 instrument.
Column chromatography was performed over silica gel (200–
400 mesh) using ethyl acetate–light petroleum as the eluent
(gradient elution). The picrate binding constants reported in
Table 1 were estimated by literature procedures.13
Bathochromic shift (∆λmax/nm)b
Mϩ (λmax c/nm)
8
9
12
13
15
20
DBCd
Liϩ (332)
Naϩ (351)
Kϩ (357)
7
11
0
5
5
0
6
9
7
4
4
0
13
1
0
9
0
0
3
24
22
a Ratio of [MϩPiϪ]–[myo-inositol derivative] was 1 : 20. b No shift in λmax
was observed on mixing 6, 10 or 14 with MϩPiϪ except in the case of
14 ϩ LiϩPiϪ where ∆λmax = 4 nm. c λmax for alkali metal picrates in THF.
d Dibenzo-crown-6.
alkali metal picrates in THF, in order to gain an insight into the
nature of the metal ion–inositol derivative complexes involved.
The λmax (345 nm) observed for the complexation of 15 with
lithium picrate is close to the value reported18 for the
complexation of lithium picrate with tetra(ethylene glycol)
dimethyl ether, indicating the existence of similar complexes in
both the cases. Potassium picrate in THF is known to exist as a
tight ion pair (λmax 357 nm). A crown ether which shifts the λmax
of potassium picrate in THF to 361 nm is indicative17 of a
crown-complexed tight ion pair, while a shift to 380 nm (λmax of
free picrate anion) would indicate a crown-separated ion pair
(as in the case of DBC, λmax = 379 nm). We obtained a λmax of
364 nm for the binding of potassium picrate to 12 (and λmax
of 352–362 nm for the binding of sodium picrate to other
ligands under study), which suggests the presence of podand-
complexed tight ion pairs.
General procedure for the O-alkylation of myo-inositol
derivatives
To a solution of the required inositol derivative (0.5–2 mmol)
in dry DMF (5 mL, unless otherwise noted) was added
sodium hydride (2–8 mmol, 60% emulsion in mineral oil)
followed by the appropriate alkyl bromide (2–6 mmol) or the
glycol toluene-p-sulfonate (2–6 mmol). The resulting mixture
was stirred at ambient temperature (24 h, unless otherwise
noted) and then diluted with chloroform (50 mL) and washed
successively with water and brine. The organic layer was dried
over anhydrous Na2SO4 and concentrated to a gum under
reduced pressure. The crude product so obtained was purified
by column chromatography.
Racemic 1,2-di-O-[2-(2-benzyloxyethoxy)ethyl]-3,4,5,6-tetra-
O-benzyl-myo-inositol (7). The diol 6 (0.27 g, 0.5 mmol), DMF
(3 mL), sodium hydride (0.17 g, 4.25 mmol) and 2-(2-benzyl-
oxyethoxy)ethyl toluene-p-sulfonate (0.39 g, 1.1 mmol) were
used (reaction time 1 h) to obtain 7 (0.44 g, 98%) as a thick
colorless oil. δH 3.30–3.50 (m, 3H), 3.50–3.85 (m, 14H),
3.85–4.10 (m, 5H), 4.55 (2s, 4H), 4.65–5.05 (m, 8H), 7.20–7.50
(m, 30H). δC 69.3, 69.9, 70.3, 70.7, 72.3, 72.8, 75.1, 75.3, 75.6,
77.4, 80.5, 81.3, 81.6, 83.3, 127.0, 127.2, 127.5, 128.0, 138.0,
138.2, 138.7, 138.9. Anal. calcd for C56H64O10: C, 74.96; H, 7.20.
Found C, 74.63; H, 7.62%.
Conclusions
We have reported novel myo-inositol based neutral complexing
agents, which show good selectivity for binding to lithium and
silver ions. The association constants for these podands are
much higher than those observed for glyme and some crown
ethers.19 It is known20 that complexing agents that bind lithium
ions strongly have applications in lithium ion selective
electrodes, while the relatively weakly binding compounds are
useful in lithium batteries. Since these ligands show affinity for
lithium ion, which is known to inhibit the catalytic activity of
myo-inositol-1-phosphatase, the results presented here could
aid in the development of cyclitol derivatives, which are useful
in biology and medicine related to the myo-inositol cycle.
Racemic 1,2-di-O-[2-(tetrahydropyran-2-yloxy)ethyl]-3,4,5,6-
tetra-O-benzyl-myo-inositol (8). The diol 6 (1.08 g, 2 mmol),
sodium hydride (0.32 g,
8 mmol) and tetrahydro-2-(2-
bromoethoxy)-2H-pyran (1.01 g, 4.8 mmol) were used to obtain
8 (1.50 g, 94%) as a colorless oil. δH 1.3–2.00 (m, 12H), 3.2–3.6
(m, 7H), 3.60–4.20 (m, 11H), 4.60–5.00 (m, 10H), 7.10–7.50 (m,
20H). δC 19.2, 19.6, 25.0, 25.1, 25.3, 30.4, 61.7, 61.8, 66.6, 66.9,
67.0, 69.7, 69.8, 70.2, 71.9, 72.0, 72.3, 72.4, 72.7, 75.2, 75.4,
75.7, 75.8, 80.5, 80.6, 80.7, 80.9, 81.0, 81.4, 81.7, 83.0, 83.4,
98.4, 98.5, 98.7, 126.5, 127.0, 127.2, 127.3, 127.4, 127.45, 127.5,
127.6, 127.9, 128.0, 138.1, 138.3, 138.7, 138.8, 138.85, 138.9,
139.0. Anal. calcd for C48H60O10ؒ0.6H2O: C, 71.35; H, 7.64.
Found C, 71.63; H, 8.01%.
Experimental
General
Di(ethylene glycol) and 2-bromoethanol were obtained from
Fluka, UK. Dihydropyran, sodium hydride, myo-inositol,
benzyl bromide, trityl chloride and toluene-p-sulfonyl chloride
were obtained from Aldrich, USA. All the solvents and picric
acid were obtained from SD Fine Chemicals, India. Silica gel
for column chromatography was obtained from Spectrochem
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J. Chem. Soc., Perkin Trans. 2, 2001, 2298–2302

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Racemic
1,2-di-O-(2-hydroxyethyl)-3,4,5,6-tetra-O-benzyl-
sodium hydride (0.24 g, 6 mmol) and tetrahydro-2-(2-bromo-
myo-inositol (9). The di-THP ether 8 (0.40 g, 0.5 mmol) was
stirred in aqueous acetic acid (80%, 10 mL) at ambient temper-
ature for 24 h. The reaction mixture was then diluted with
chloroform (50 mL), washed with water and brine, and dried
over anhydrous Na2SO4 and the solvent was evaporated under
reduced pressure. The crude product was purified by column
chromatography to get 9 (0.25 g, 79.6%) as a white solid, mp
61 ЊC. νmax 3100–3600 cmϪ1. δH 3.20–3.40 (d of t, 2H), 3.50 (t,
2H), 3.55–3.80 (m, 8H), 3.85–4.10 (m, 4H), 4.70–4.75 (m, 2H),
4.75–4.80 (m, 1H), 4.85–5.00 (m, 5H), 7.20–7.45 (m, 20H). δC
61.6, 61.9, 71.9, 73.1, 75.0, 75.6, 77.0, 80.2, 81.1, 81.3, 81.5,
83.2, 127.4, 127.5, 127.6, 127.8, 128.1, 128.3, 137.7, 138.2,
138.5. Anal. calcd for C38H44O8: C, 72.59; H, 7.05. Found C,
72.89; H, 7.40%.
ethoxy)-2H-pyran (1.25 g, 6 mmol) as described in the general
procedure (gum, 0.96 g, 86%). νmax 2800–3000 cmϪ1. δH 0.15
(d, 6H), 0.95 (d, 9H), 1.4–1.9 (m, 12H), 3.40–3.60 (m, 4H),
3.60–4.00 (m, 7H), 4.1 (m, 2H), 4.2–4.3 (m, 3H), 4.35 (m, 1H),
4.4–4.5 (m, 1H), 4.55–4.65 (m, 2H), 5.55 (s, 1H). δC Ϫ5.1, 17.9,
18.7, 18.9, 19.0, 24.9, 25.1, 25.5, 29.9, 30.0, 30.2, 60.5, 61.3,
61.4, 61.6, 61.8, 65.7, 65.9, 66.2, 66.4, 66.9, 67.0, 67.6, 68.1,
68.8, 72.3, 73.0, 74.7, 74.9, 75.2, 98.2, 98.3, 98.6, 98.7, 102.2,
102.7. Anal. calcd for C27H48O10Siؒ0.5H2O: C, 56.90; H, 8.67.
Found C, 56.92; H, 8.86%.
4,6-Di-O-(2-trityloxyethyl)-myo-inositol 1,3,5-orthoformate
(18). The trityl ether 17 was prepared using the diol 16 (0.29 g,
1 mmol), sodium hydride (0.09 g, 2.25 mmol) and the trityl ether
24 (0.81 g, 2.2 mmol) as described in the general procedure
(0.63 g, 72%), mp 123–126 ЊC. νmax 1722 cmϪ1. δH 3.0–3.35
(m, 4H), 3.55–3.85 (m, 4H), 4.3–4.7 (m, 5H), 5.55 (br s, 1H),
5.65 (s, 1H), 7.0–7.75 (m, 33H), 8.2 (d, 2H). δC 63.4, 64.5, 68.2,
69.1, 70.4, 74.7, 86.5, 103.2, 126.9, 127.1, 127.7, 128.3, 128.5,
129.8, 133.1, 143.8, 165.8. The benzoate 17 (0.63 g, 0.72 mmol)
and isobutylamine (1 mL) were stirred in dry methanol (10 mL)
at ambient temperature for 10 h. Methanol was evaporated
under reduced pressure, and the resulting syrup was purified by
column chromatography to obtain 18 (0.54 g, 98%) as a white
solid, mp 67 ЊC. νmax 3500 cmϪ1. δH 3.0–3.3 (m, 5H), 3.5–3.8
(m, 4H), 4.05–4.15 (m, 1H), 4.20–4.30 (m, 2H), 4.35–4.40
(m, 2H), 4.45–4.55 (m, 1H), 5.5 (s, 1H), 7.1–7.3 (m, 17 H),
7.35–7.50 (m, 13H). δC 61.4, 63.4, 67.8, 69.3, 73.0, 74.7, 86.5,
103.2, 126.9, 127.7, 128.5, 143.8. Anal. calcd for C49H46O8: C,
77.13; H, 6.08. Found C, 77.52; H, 6.32%.
Racemic 1,2-O-isopropylidene-3,6-di-O-benzyl-4,5-di-O-[2-
(2-benzyloxyethoxy)ethyl]-myo-inositol (11). The podand 11
was prepared using the diol 10 (0.20 g, 0.5 mmol), DMF
(3 mL), sodium hydride (0.17 g, 4.2 mmol) and 2-(2-
benzyloxyethoxy)ethyl toluene-p-sulfonate (0.39 g, 1.1 mmol)
as described in the general procedure (reaction time 1 h). The
podand 11 was obtained as colorless oil (0.34 g, 90%). δH 1.32
(s, 3H), 1.45 (s, 3H), 3.20 (t, 1H), 3.50–3.75 (m, 16H), 3.90–4.05
(m, 4H), 4.2 (t, 1H), 4.55 (2s, 4H), 4.70–4.95 (m, 4H), 7.20–7.50
(m, 20H). δC 25.4, 27.3, 61.3, 69.3, 70.2, 70.6, 71.5, 71.7, 72.1,
72.8, 73.3, 74.2, 78.6, 81.0, 81.7, 82.6, 109.2, 126.5, 127.0, 127.1,
127.2, 127.5, 127.7, 127.9, 128.3, 138.2, 138.5. Anal. calcd for
C45H56O10: C, 71.38; H, 7.46. Found C, 71.12; H, 7.70%.
Racemic 1,2-O-isopropylidene-3,6-di-O-benzyl-4,5-di-O-[2-
(tetrahydropyran-2-yloxy)ethyl]-myo-inositol (12). The THP
ether 12 was prepared using the diol 10 (0.30 g, 0.75 mmol),
DMF (3 mL), sodium hydride (0.32 g, 8 mmol) and tetrahydro-
2-(2-bromoethoxy)-2H-pyran (0.84 g, 4 mmol) as described in
the general procedure (colorless oil, 0.45 g, 91.4%). δH 1.32
(s, 3H), 1.45 (s, 3H), 1.4–1.9 (m, 12H), 3.2 (t, 1H), 3.35–3.75
(m, 8H), 3.8–4.00 (m, 8H), 4.2 (m, 1H), 4.55–4.7 (m, 2H), 4.7–
4.95 (m, 4H), 7.1–7.5 (m, 10H). δC 19.0, 25.1, 25.3, 27.2, 30.2,
61.6, 66.5, 71.5, 71.6, 72.9, 73.3, 74.3, 78.6, 80.9, 81.6, 82.7,
98.4, 109.2, 126.9, 127.5, 127.8, 127.9, 138.8, 139.0. The di-THP
ether 12 has the tendency to retain water (as revealed by its
IR spectrum, νmax 3100–3600 cmϪ1 and Anal. calcd for
C37H52O10ؒ3.5H2O: C, 61.74; H, 8.26. Found C, 61.56; H,
8.17%). The podand 12 is not very stable (even when stored in a
refrigerator) and decomposes to give unidentified products.
Consequently, the picrate extraction data given in Table 1 are
not for an analytically pure sample of 12.
2-O-Benzyl-4,6-di-O-(2-trityloxyethyl)-myo-inositol
1,3,5-
orthoformate (19). The benzyl ether 19 was prepared using 18
(0.38 g, 0.5 mmol), DMF (2 mL), sodium hydride (0.06 g, 1.5
mmol) and benzyl bromide (0.24 mL, 2 mmol) as described
(reaction time 3 h) in the general procedure (0.38 g, 90%), mp
53 ЊC. δH 3.0–3.30 (m, 4H), 3.5–3.8 (m, 4H), 4.05 (s, 1H), 4.35
(d, 4H), 4.40–4.50 (m, 1H), 4.7 (s, 2H), 5.6 (s, 1H), 7.10–7.30
(m, 21H), 7.35–7.55 (m, 14H). δC 63.4, 68.0, 69.2, 70.7, 71.6,
74.9, 86.5, 103.2, 126.9, 127.7, 128.3, 128.6, 137.9, 143.8. Anal.
calcd for C56H52O8: C, 78.83; H, 6.15. Found C, 78.62; H,
6.35%.
2-O-Benzyl-4,6-di-O-(2-hydroxyethyl)-myo-inositol
1,3,5-
orthoformate (20). To a solution of the trityl ether 19 (0.20 g,
0.23 mmol) in benzene (25 mL) was added boric acid (0.90 g)
and the mixture was refluxed for 48 h. The reaction mixture was
then diluted with chloroform (50 mL), washed several times
with water and finally with brine. The organic layer was dried
over anhydrous Na2SO4 and the solvent evaporated under
reduced pressure. The crude product thus obtained was purified
by column chromatography to get the diol 20 (0.07 g, 85.6%) as
a gum. νmax 3100–3600 cmϪ1. δH 3.25 (br s, 2H), 3.6 (s, 8H), 3.9
(s, 1H), 4.15–4.35 (m, 4H), 4.4–4.5 (m, 1H), 4.75 (s, 2H), 5.55 (s,
1H), 7.25–7.5 (m, 5H). δC 61.2, 66.8, 67.4, 70.0, 71.2, 71.5, 74.7,
76.9, 77.5, 102.9, 127.7, 127.9, 128.3, 137.6. Anal. calcd for
C18H24O8ؒ0.5H2O: C, 57.29; H, 6.63. Found C, 57.51; H, 6.80%.
Racemic 1,2-O-isopropylidene-3,6-di-O-benzyl-4,5-di-O-(2-
hydroxyethyl)-myo-inositol (13). The di-THP ether 12 (0.33 g,
0.5 mmol) was dissolved in dry dichloromethane (3 mL)
containing 5% v/v of ethanethiol and stirred with BF3ؒEt2O
(6 µL, 0.05 mmol) at Ϫ20 ЊC and the resulting solution was
allowed to warm up to 0 ЊC over a period of 30 min. The
reaction mixture was poured into a saturated solution of
sodium bicarbonate and extracted with dichloromethane. The
organic layer was dried over anhydrous Na2SO4 and evaporated
under reduced pressure. The crude product obtained was
chromatographed to isolate the diol 13 as a gum (0.21 g, 86%).
νmax 3200–3600 cmϪ1. δH 1.3 (s, 3H), 1.45 (s, 3H), 3.25 (t, 2H),
3.4–4.1 (m, 13H), 4.25 (m, 1H), 4.55–5.00 (m, 4H), 7.2–7.5
(m, 10H). δC 25.7, 27.7, 62.2, 62.3, 72.7, 73.4, 73.9, 74.5, 74.6,
77.3, 77.5, 79.1, 80.4, 81.9, 82.5, 109.8, 125.0, 127.0, 127.6,
127.9, 128.2, 128.4, 128.5, 128.7, 137.6, 137.9. Anal. calcd for
C27H36O8: C, 66.39; H, 7.37. Found C, 66.70; H, 7.24%.
2-O-Benzyl-4,6-di-O-[2-(tetrahydropyran-2-yloxy)ethyl]-
myo-inositol 1,3,5-orthoformate (22). The THP ether 22 was
prepared using the diol 21 (0.09 g, 0.32 mmol), sodium hydride
(0.06 g, 1.5 mmol) and tetrahydro-2-(2-bromoethoxy)-2H-
pyran (0.22 g, 1.05 mmol) as described in the general procedure
(gum, 0.17 g, 98.7%). δH 1.4–1.9 (m, 12H), 3.40–3.90 (m, 12H),
3.90–4.00 (s, 1H), 4.25–4.40 (m, 4H), 4.45–4.50 (m, 1H), 4.50–
4.65 (m, 2H), 4.70 (s, 2H), 5.55 (s, 1H), 7.20–7.50 (m, 5H).
δC 19, 25.0, 29.3, 30.2, 61.6, 66.3, 66.4, 67.4, 67.8, 68.7, 70.3,
71.1, 74.5, 98.4, 98.6, 102.8, 127.4, 128.0, 137.8. Anal. calcd
for C28H40O10: C, 62.65; H, 7.52. Found C, 62.55; H, 7.65%.
2-O-tert-Butyldimethylsilyl-4,6-di-O-[2-(tetrahydropyran-2-
yloxy)ethyl]-myo-inositol 1,3,5-orthoformate (15). The THP
ether 15 was prepared using the diol 14 (0.61 g, 2 mmol),
J. Chem. Soc., Perkin Trans. 2, 2001, 2298–2302
2301

View Article Online
Trans. 1, 1989, 1423; (b) S.-M. Yeh, G. H. Lee, Y. Wang and T.-Y.
Luh, J. Org. Chem., 1997, 62, 8315.
5 T. Praveen, T. Das, K. M. Sureshan, M. S. Shashidhar, U. Samanta,
D. Pal and P. Chakrabarti, J. Chem. Soc., Perkin Trans. 2, accepted
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153; (b) K. Mernissi-Arifi, G. Schlewer and B. Spiess, J. Inorg.
Biochem., 1995, 57, 127.
8 (a) L. A. Paquette, J. Tae, E. R. Hickey and R. D. Rogers, Angew.
Chem., Int. Ed., 1999, 38, 1409; (b) L. A. Paquette, J. Tae,
B. M. Branan, S. W. E. Eisenberg and J. E. Hofferberth, Angew.
Chem., Int. Ed., 1999, 38, 1412; (c) B. Tse and Y. Kishi, J. Am. Chem.
Soc., 1993, 115, 7892; (d ) L. A. Paquette, J. Tae and J. C. Gallucci,
Org. Lett., 2000, 2, 143; (e) J. Tae, R. D. Rogers and L. A. Paquette,
Org. Lett., 2000, 2, 139.
9 Comprehensive Supramolecular Chemistry Vol. 1. Molecular
recognition: Receptors for Cationic Guests, Ed. G. W. Gokel,
Pergamon Press, New York, 1996.
2-O-Benzyl-4,6-di-O-[2-(2-benzyloxyethoxy)ethyl]-myo-inosi-
tol 1,3,5-orthoformate (23). The podand 23 was prepared using
the diol 21 (0.28 g, 1 mmol), DMF (3 mL), sodium hydride
(0.2 g, 5 mmol) and O-benzyldi(ethylene glycol) toluene-p-
sulfonate (0.80 g, 2.3 mmol) as described (reaction time 1 h) in
the general procedure (oil, 0.58 g, 91.2%). δH 3.50–3.75 (m,
16H), 3.95 (m, 1H), 4.3 (t, 2H), 4.35 (m, 2H), 4.50 (m, 1H),
4.55 (s, 4H), 4.70 (s, 2H), 5.55 (s, 1H), 7.20–7.50 (m, 15H).
δC 67.3, 67.8, 69.0, 69.3, 70.4, 71.2, 73.0, 74.7, 102.9, 127.5,
128.1, 138.0. Anal. calcd for C36H44O10ؒ0.5H2O: C, 66.94;
H, 7.03. Found C, 66.65; H, 7.23%.
1-Bromo-2-trityloxyethane (24). 2-Bromoethanol (2.4 mL,
32 mmol), trityl chloride (12 g, 43 mmol) and N,N-diisopropyl-
ethylamine (15 mL) were mixed in dichloromethane (50 mL) at
0 ЊC. The reaction mixture was stirred at ambient temperature
for 24 h. Conventional work up of the reaction mixture yielded
the trityl ether 24 (10.6 g, 90%), mp 127 ЊC.24
10 H. W. Lee and Y. Kishi, J. Org. Chem., 1985, 50, 4402.
11 R. Gigg and C. D. Warren, J. Chem. Soc. C, 1969, 2367.
12 R. Gigg, S. Payne and R. Conant, J. Chem. Soc., Perkin Trans. 1,
1987, 423.
Acknowledgements
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This work was supported by the Department of Science
and Technology, New Delhi (research grant No. SP/S1/G-30/94
to MSS and AJV). KMS thanks the Council of Scientific
and Industrial Research, New Delhi, for a Senior Research
fellowship. Technical assistance by Ms S. V. Deshpande is
appreciated.
17 M. Bourgoin, K. H. Wong, J. Y. Hui and J. Smid, J. Am. Chem. Soc.,
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