Chelation controlled regiospecific O-substitution of myo-inositol orthoesters: Convenient access to orthogonally protected myo-inositol derivatives

Article abstract of DOI:10.1016/j.tet.2004.11.025

A general method for the completely regioselective protection of the three secondary hydroxyl groups of orthoester derivatives of myo-inositol, utilizing the subtle differences in reactivity exhibited by its alkali metal alkoxides due to differences in th

Full text of DOI:10.1016/j.tet.2004.11.025

Tetrahedron 61 (2005) 529–536
Chelation controlled regiospecific O-substitution of myo-inositol
orthoesters: convenient access to orthogonally protected
myo-inositol derivatives
*
Subramanian Devaraj, Mysore S. Shashidhar and Shailesh S. Dixit
Division of Organic Synthesis, National Chemical Laboratory, Pashan Road, Pune 411 008, India
Received 31 August 2004; revised 19 October 2004; accepted 12 November 2004
Available online 26 November 2004
Abstract—A general method for the completely regioselective protection of the three secondary hydroxyl groups of orthoester derivatives of
myo-inositol, utilizing the subtle differences in reactivity exhibited by its alkali metal alkoxides due to differences in their ability to form
chelates, is described. This method provides convenient access to orthogonally protected myo-inositol derivatives. A comparison of the
methylation of racemic 4-O-trityl-myo-inositol 1,3,5-orthoformate in the presence of sodium or lithium ions showed that stabilization of the
C4-alkoxide by chelation with lithium overrides steric hindrance offered by the C6-axial substituent in deciding the regioselectivity during
the nucleophilic O-substitution.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
regioselective protection of the three secondary hydroxyl
groups of myo-inositol orthoesters, utilizing the subtle
differences in reactivity exhibited by its alkali metal
alkoxides.
Protection of hydroxyl groups is routinely encountered in
the synthesis of cyclitol and carbohydrate derivatives.
Understanding the reasons that govern differences in
reactivity of different functional groups in the same
molecule is the key for successful regioselective functiona-
lization of complex organic molecules. Such an under-
standing becomes crucial while working with molecules
having non-equivalent functional groups of the same kind
(polyols, polyamines, polyacids, etc.).1 Phosphorylated
cyclitols and their analogs have attracted the attention of
chemists and biologists in the last two decades due to their
involvement in various biological phenomena2 such as
cellular signal transduction, calcium mobilization, insulin
stimulation, exocytosis, cytoskeletal regulation, intra-
cellular trafficking of vesicles and anchoring of certain
proteins to cell membranes. Although regio- and enantio-
selective functionalization of inositols or their derivatives
are being attempted3 and appear to show promise for the
synthesis of biologically relevant molecules, a very useful
and practical strategy for the synthesis of cyclitol deriva-
tives would be the regiospecific orthogonal protection of all
the six hydroxyl groups, wherein one hydroxyl group is
protected in each step. As a step towards achieving this goal,
we herein report a general method for the completely
myo-Inositol orthoesters (Scheme 1, 1, 2) have been used
extensively for the synthesis of phosphoinositols, their
derivatives and other compounds with interesting proper-
ties.1–4 However, the overall yield of the required protected
myo-inositol derivative is usually not good due to: (a)
formation of isomeric myo-inositol orthoester derivatives
and/or (b) use of transient protecting groups (esters,
sulfonates, allyl ether, etc.) which increase the number of
steps and decrease the overall yield. In fact, there is no
general method for the orthogonal protection of the three
hydroxyl groups of myo-inositol orthoesters (especially as
ethers) which generates only one regioisomer in each step,
in respectable yields. Such a method would provide
orthogonally protected myo-inositol orthoesters, which are
the key intermediates for the synthesis of biologically
important inositol derivatives.
The differences in the observed reactivity of the three
hydroxyl groups (and hence the observed regioselectivity)
of myo-inositol orthoesters have been attributed to various
factors shown in Scheme 1 and other parameters such as
nature of the electrophile,5 strength of the base used,5,6
solvent used for the reaction,6b,7 presence or absence of
metal ions,7,8 steric bulk of the reagent5,9 and the catalyst
used.10 These variations were utilized to obtain either
Keywords: Regioselectivity; Inositol; Cyclitol; Lithium; Chelation.
* Corresponding author. Tel./fax: C91 2025893153;
e-mail: shashi@dalton.ncl.res.in
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.025

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S. Devaraj et al. / Tetrahedron 61 (2005) 529–536
Scheme 1.
mono-O-substituted derivatives (6–12, Scheme 1) or di-O-
substituted derivatives (13–16) in poor to good isolated
yields. O-Alkylation7 and O-acylation8 of myo-inositol
orthoesters 1 and 2 in the presence of sodium hydride are
particularly interesting due to the very high regioselectivity
observed, which was thought to be due to the involvement
of chelates such as 4.11,12 We wondered whether this
property of myo-inositol derivatives could be exploited to
develop a general method for the regioselective sequential
protection of the three hydroxyl groups wherein a single
isomer is formed in each step. Our results show that
chelation of the metal ion by myo-inositol orthoesters can
override steric effects to some extent in deciding the
observed regioselectivity during O-substitution.
formation of greater amounts of the 4,6-di-O-substituted
derivatives 13 as compared to the 2,4-di-O-substituted
derivatives 15 (R5Zalkyl). This is expected since lithium,
being smaller and a better ion for coordination16 with
oxygen atoms, would stabilize the oxyanion at the C6(4)–O-
position in axial C4(6)–O-monosubstituted myo-inositol
orthoesters (10).
The results of O-substitution in myo-inositol orthoesters 1
and 2 in the presence of lithium ions are summarized in
Scheme 2. The reaction of the monobenzyl ether 17 with
benzyl bromide in the presence of lithium hydride resulted
in the formation of the corresponding symmetrical diether
20 without any trace of the unsymmetrical 2,4(6)-diether.
2. Results and discussion
Although the O-alkylation7 of myo-inositol orthoesters
(such as 1 or 2) with alkyl halides in the presence of
1 equiv of sodium hydride resulted in exclusive reaction at
the C4(6)–O-position,13 reaction of these triols with 2 equiv
of alkyl halide7,14 in the presence of 2 equiv of sodium
hydride resulted in the formation of a mixture of 2,4- and
4,6-diethers. However, the reaction of the C4-monoether
(such as 10) with alkyl halide in the absence of metal ions
provided the unsymmetrical diether (such as 15, R5Zalkyl)
as the major product.15 These results give credence to the
postulated chelation7 of the metal ion with 4,6-diaxial
oxygens, during O-substitution of the axial monoether 10,
since acidity of the two hydroxyl groups in this monoether is
expected to be comparable in the absence of the strong
intramolecular hydrogen bond12 as present in the
corresponding triols (1 and 2). We postulated that if
chelation of the metal ions was indeed operational in these
O-substitution reactions, use of lithium instead of sodium
ions must result in better regioselectivity, resulting in the
Scheme 2. (a) LiH or BuLi, THF–DMF, alkyl halide, acyl chloride or
sulfonyl chloride. (b) (i) NaH, BnBr, DMF; (ii) BuLi, AllBr, THF–DMF;
NaH, MeI.

S. Devaraj et al. / Tetrahedron 61 (2005) 529–536
531
However, the reaction was sluggish due to the low basicity
of lithium hydride. Hence, in future experiments
n-butyllithium was used as a base to generate the inositol
orthoester oxyanions. Accordingly, the BuLi assisted
reaction of various electrophiles with myo-inositol ortho-
esters (1 or 2) and their 4-O-substituted derivatives 17–19
(Scheme 2) proceeded smoothly to afford the corresponding
4,6-di-O-substituted derivatives 20–28 in good to excellent
isolated yields along with minor amounts (5–10%) of tri-O-
substituted derivatives. Since we isolate tri-O-substituted
derivatives but no 2,4-di-O-substituted products, it appears
that tri-O-substituted products result from the initially
formed 4,6-di-O-substituted derivatives. The method being
described here is sufficiently flexible to allow the
preparation of 4,6-diethers and any combination of ether,
ester and sulfonate derivatives. The protocol for best results
is the generation of the lithium alkoxide of myo-inositol
orthoester in dry THF followed by the addition of the
appropriate electrophile in dry DMF. The yield of ditosylate
25 was not as high as those obtained for dialkylethers, but
the unsymmetrical 2,4-ditosylate was not formed. This
method is not suitable for the preparation of 4,6-diesters
since alkoxides of C4(6)–monoesters 11 undergo isomer-
ization to the corresponding C2-esters8 faster than substi-
tution at C6–O-position. The versatility of this method is
demonstrated by the rapid and efficient preparation of an
unsymmetrical tri-O-substituted derivative 29 (Scheme 2).
To the best of our knowledge, completely regiospecific
sequential tri-O-substitution of myo-inositol orthoesters is
not reported. Earlier methods7,14 for the preparation of 4,6-
di-O-substituted derivatives of 1 or 2 either resulted in a
mixture of products or were restricted to the preparation of
disulfonates6b or the dibenzyl ether 20 via a circuitous
route.17
That the myo-inositol derivatives indeed bind lithium ions
better than sodium ions as postulated above, was suggested
by the picrate extraction experiments18 (Scheme 3). Most of
the orthoester derivatives shown in Scheme 3 bind lithium
picrate 10–100 times better than sodium picrate and the diol
30 exhibits the highest binding constant for lithium picrate.
These results give credence to the suggestion that the extent
of chelation of metal ions by inositol derivatives is a major
factor in deciding the observed regioselectivity (see below)
for the O-substitution reactions shown in Scheme 2.
We also investigated the extent to which steric hindrance
due to the presence of 4,6-diaxial substituents (in 1, 2 and
their derivatives) dictate the course of the reaction and
decide the observed regioselectivity. To understand this, we
carried out (a) the reaction of the triol 1 with bulky
electrophiles (TBDMSCl, TrCl) and (b) the O-substitution
of myo-inositol orthoester carrying a bulky protecting group
(trityl) at the C4–O-position, with a small electrophile
(methyl iodide).
The reaction of 1 with TBDMSCl (1 equiv)/BuLi led to the
formation of the C4–O-protected derivative 41 (Scheme 4)
as the major product, and C2-silyl ether was not formed.
Reaction of the triol 1 with 2 equiv of TBDMSCl/LiH led to
the formation of the racemic 2,4-di-O-substituted derivative
43. This is in contrast to the corresponding reaction of the
triol 1 with alkyl halides (not having bulky alkyl groups)
which afforded the 4,6-diethers as the major product. The
difference in the observed regioselectivity in these two
reactions can be attributed to the steric hindrance offered by
the C4–O–TBDMS group for the entry of another bulky
TBDMS group at the 6-O-position. Similar steric hindrance
is also reflected in the low yield of the trityl derivative 42
obtained by tritylation of the triol 1 (as compared to the
yield of 10 on alkylation of 1 with normal alkyl halides7).
Scheme 4. (a) BuLi/THF, TBDMSCl (for 41); (b) NaH, DMF, TrCl (for
42).
The reaction of the trityl ether 42 with butyllithium followed
by methyl iodide gave a mixture of products consisting of
isomeric monomethyl ethers 44 and 45 as well as the
Scheme 3.

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S. Devaraj et al. / Tetrahedron 61 (2005) 529–536
dimethyl ether 46 (Scheme 4). The racemic C6-ether 44 was
formed in a higher proportion compared to the correspond-
ing C2-methyl ether 45 (44/45Z61:39). The use of sodium
hydride for the same reaction also resulted in a mixture of
products (44–46) but 45 was present in larger proportion as
compared to 44 (44/45Z11:89). The structure of the two
monomethyl ethers 44 and 45 were established by
unambiguous synthesis of 45 starting from the known
ditosylate 25.
These results give credence to our postulate that in LiC
assisted reactions stabilization of the anion 52 by chelation
plays a dominant role over steric effect of the trityl group.
However, yet another possibility which cannot be ruled out
is the inability of the larger NaC to chelate at the 4,6-
positions (in 42) due to the presence of bulky trityl group
while the smaller LiC can still form a chelate at the 4,6
positions due to its smaller size. These results strongly
suggest that stabilization of the oxyanion by chelation with
lithium (53) overrides steric hindrance offered by the cis-
axial substituent in deciding the regioselectivity during the
nucleophilic O-substitution in myo-inositol orthoesters.
Hence, it appears that the major factor that controls
regioselectivity during the di-O-substitution of myo-inositol
orthoesters in the presence of metal ions is the extent of
chelation that exists between the metal ion and the two di-
axial oxygen atoms.
In principle, reaction of 2,4-diols with butyllithium or
sodium hydride can result in the formation of two anions 52
and 54 (Scheme 5). Higher isolated yields of the 4,6-
disubstituted products (Scheme 2) suggest that 52 is
preferentially formed. This could be a result of greater
stabilization of the anion 52 by metal ions due to chelation
(53) with two diaxially oriented oxygen atoms as compared
to the stabilization of the anion 54 due to chelation (55) with
the oxygen atoms in axial–equatorial orientation. This is
analogous to the formation of a strong intramolecular
hydrogen bond between the 4,6-diaxial hydroxyl groups in 1
which has been observed in its crystals, while the cis-1,2-
hydroxyl groups result in a comparatively weaker intra-
molecular hydrogen bond.12,19 Increase in the yield of the
4,6-di-O-substituted derivatives and non-formation of the
2,4-di-O-substituted derivatives (Scheme 2) in the BuLi
assisted reaction as compared to the NaH assisted reaction
suggests that LiC stabilizes the anion 52 better than NaC
does.
It is of interest to examine if the regioselectivity observed
(exclusive reaction at the C4–O-position) during the mono-
O-substitution7 of the triol (1 or 2) in the presence of NaC
and LiC, should also be attributed to chelation by the metal
ion (Scheme 1, 4). Alkylation,7 acylation8 or silylation of
the triol 1 in the presence of NaH or BuLi results in the
exclusive formation of the 4-O-substituted derivatives. The
triol 1 did not undergo alkylation with benzyl bromide in
the presence of DBU. However, use of more reactive
electrophiles (acyl halides) in the presence of tertiary
amines (e.g., triethylamine, pKaHZ10.820) is known5,6a to
give the corresponding C4–O-acylated derivatives. Benzyl-
ation of 1 in the presence of potassium carbonate resulted in
the exclusive alkylation at the 4-O-position to yield the
benzyl ether 17 in 72% isolated yield. These results imply
that chelation with metal ions is not a necessary condition
for the mono-O-substitution at the 4-positon in the triol 1.
The observed regioselectivity can be rationalized by
considering the intramolecular hydrogen bonding that is
present12 in these triols, which results in an increase of the
acidity of the C4(6)–hydroxyl group.13 If the base used is
strong enough to form even minor amounts of the anion at
C4–O-position, which is stabilized by intramolecular
hydrogen bonding, reaction brought about by such bases
result in substitution at the C4–O-position. Hence, during
the mono-O-substitution of these triols (1 and 2), in our
opinion, there is no need to invoke either chelation
(Scheme 1, 4) with metal ions or steric effect of the two
axial hydroxyl groups5 to rationalize the experimental
observations, since hydrogen present in the cis-axial
hydroxyl group is a good acceptor of hydrogen bond
which could stabilize the anion (Scheme 1, 3). Weaker bases
bring about substitution at the 2-O-position as exemplified
by benzoylation5 of 1 in the presence of pyridine (pKaHZ
5.220), alkylation of 1 under phase transfer catalytic
conditions15 and silylation21 of 1 in the presence of
imidazole. Also, silylation of 1 in the presence of metals
(palladium)22 that are not basic enough to form the 4-anion
result in a mixture of products consisting of different
regioisomers. The predominant formation of 2-O-substi-
tuted derivatives in the presence of weaker bases could be
due to the relatively higher nucleophilicity of the C2–OH as
compared to the C4(6)–OH under unionized conditions,
due to the involvement of the latter in intramolecular
H-bonding.
Scheme 5.
It is of relevance to compare the results of alkylation of the
C4-benzyl (17) and C4-trityl (42) ethers in the presence of
NaC and LiC, which could throw light on the possibility of
the relative ease of formation/stabilization of 52 and 54
under the conditions of alkylation. Since monobenzylation
of the triol 1 with NaH/BnBr yields 17 exclusively, it can
be inferred that dibenzylation of the triol 1 proceeds
exclusively via the 4-benzyl ether 17 to yield a mixture of
products consisting of 2,4 and 4,6 diethers (50, 20) in the
ratio 1:5 and the tribenzyl ether 51.7 On increasing the steric
bulk of the alkyl group at the 4-O-position with a trityl
group, predominant methylation takes place at the 2-O-
position (to give 45) which reflects the steric crowding at the
6 position. Alkylation of 17 with BuLi/BnBr on the other
hand provides the 4,6-diether 20 exclusively and the
corresponding trityl ether gives the 6-methylether 44 as
the major product, unlike in the reaction assisted by NaC.

S. Devaraj et al. / Tetrahedron 61 (2005) 529–536
533
In conclusion, we have developed a general method for the
orthogonal O-substitution of the three hydroxyl groups of
myo-inositol orthoesters wherein each step in the scheme of
reactions proceed with very high regioselectivity. We have
also shown that chelation of the metal ions with inositol
orthoester derivatives play a major role in deciding the
regioselectivity in these reactions. These results coupled
with other regioseletive reactions reported in the literature
provide convenient access to any O-substituted myo-inositol
orthoester derivative (Scheme 6). We are now working
towards the realization of a similar scheme of reactions that
allows the nucleophilic substitution of one hydroxyl group
of myo-inositol at a time that leads to orthogonally hexa-O-
substituted myo-inositol derivatives.
of their melting points and/or 1H NMR spectra with reported
data. IR spectra were recorded in CHCl3 solution or as nujol
1
mull. NMR spectra were recorded at 200 MHz for H and
50.3 MHz for 13C unless otherwise mentioned. All the
asymmetrically substituted myo-inositol derivatives
reported are racemic; however, only one of the enantiomers
in shown in all the schemes.
3.1.1. Racemic 4-O-benzyl-myo-inositol 1,3,5-ortho-
formate (17). The triol 1 (0.100 g, 0.53 mmol) and benzyl
bromide (0.63 mL, 5.26 mmol) were dissolved in DMF
(4 mL) and stirred with potassium carbonate (0.727 g,
5.26 mmol) at 106 8C for 26 h. The reaction mixture was
cooled to ambient temperature, diluted with ethyl acetate
and worked up as usual. The known benzyl ether 177
(0.106 g, 72%) was isolated after filtration of the crude
product on a short column of silica gel.
3.1.2. Racemic 4-O-(p-toluenesulfonyl)-myo-inositol
1,3,5-orthoacetate (19). To a solution of the triol 224
(0.650 g, 3.20 mmol) in dry DMF (6 mL) sodium hydride
(0.154 g, 3.84 mmol) was added and stirred for 0.5 h. Then a
solution of tosyl chloride (0.730 g, 3.84 mmol) in DMF
(6 mL) was added in one lot and stirred for 0.5 h. The
reaction mixture was worked up with ethyl acetate as usual
and the solid obtained was filtered through a short column of
silica gel to get 19 (0.837 g, 73%) as a colorless solid. Mp
137–139 8C. IR (n): 3078–3533 cmK1. 1H NMR (CDCl3): d
7.75–7.90 (d, 2H, JZ7.8 Hz), 7.35–7.50 (d, 2H, JZ7.8 Hz),
5.06–5.18 (m, 1H), 4.47–4.60 (m, 1H), 4.15–4.31 (m, 2H),
3.96–4.13 (m, 2H), 2.90–3.15 (br s, 1H, D2O exchangeable),
2.30–2.80 (br, 1H D2O exchangeable), 2.48 (s, 3H), 1.42 (s,
3H). 13C NMR ((CD3)2CO): d 145.8, 133.7, 130.4, 128.1,
108.9, 75.1, 74.4, 73.2, 69.7, 66.8, 58.7, 23.8, 20.9. Anal.
Calcd for C15H18O8S: C, 50.27; H, 5.06. Found: C, 50.08;
H, 5.06.
Scheme 6. (a) and (b) Present work; (c) Refs. 5 and 6b; (d) Ref. 21;
(e) Ref. 8; (f) Refs. 6b, 7 and 8.
3. Experimental
3.1. General
3.2. Synthesis of 4,6-di-O-substituted-myo-inositol 1,3,5-
orthoesters
Procedure A. The required 4-O-substituted myo-inositol
orthoester (1 mmol) was taken in dry THF (4 mL) and
cooled to 0 8C. n-Butyllithium (1.5 mmol) was added drop-
wise using a syringe followed by a solution of the required
alkyl halide, acyl halide or sulfonyl halide (1.2 mmol) in
DMF (2 mL). The reaction mixture was stirred for 22–28 h
and worked up with ethyl acetate. The products were
separated by column chromatography using 10–20% ethyl
acetate–light petroleum as the eluent.
All the solvents used were purified according to literature
procedures.23 All the reactions were carried out in an
atmosphere of argon. Dry DMF and dry THF were used as
solvents in all the experiments involving metal hydrides or
n-butyllithium. Sodium hydride used in experiments was
60% suspension in mineral oil. A stock solution of
n-butyllithium (1.4–1.7 M) in dry hexanes was prepared
and used in all the experiments. myo-Inositol derivatives
1,21 2,24 17,7 18,6b 30–406b,8,11,25 were prepared according
to literature procedures. Thin layer chromatography 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 with concd H2SO4. Column chromato-
graphic separations were carried out on silica gel (100–200
mesh) while flash column chromatographic separations
were carried out on silica gel (230–400 mesh) with light
petroleum–ethyl acetate mixtures as eluent. ‘Usual work-
up’ implies washing of the organic layer with water
followed by brine, drying over anhydrous sodium sulfate
followed by removal of the solvent under reduced pressure
using a rotary evaporator. The compounds previously
reported in the literature were characterized by comparison
Procedure B. The required 4-O-substituted myo-inositol
orthoester (1 mmol) was taken in DMF (3–4 mL) and
stirred for 2 h with lithium hydride (2 mmol). A solution of
the alkyl halide in DMF (2 mL) was added and the mixture
stirred for 36–40 h. The reaction mixture was then worked
up with ethyl acetate and the products were separated as in
procedure A.
Procedure C. The required triol 1 or 2 (1 mmol) was taken
in THF (5 mL) and n-butyllithium (2.3 mmol) was added at
0 8C. A solution of the appropriate alkyl halide (2.2 mmol)
in DMF (1 mL) was added and the mixture stirred for
36–45 h. The resulting mixture was then worked up with

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S. Devaraj et al. / Tetrahedron 61 (2005) 529–536
ethyl acetate. The products were separated by column
chromatography as in procedure A.
3.2.5. Racemic 4-O-(p-toluenesulfonyl)-6-O-allyl-myo-
inositol 1,3,5-orthoformate (24). The racemic 4-tosylate
186b (0.344 g, 1 mmol) was allylated (procedure B), with
allyl bromide (0.145 g, 1.20 mmol) to obtain 24 (0.278 g,
72%) as gum. IR (n): 3200–3600 cmK1. 1H NMR (CDCl3):
d 7.75–7.85 (d, 2H, JZ8.3 Hz), 7.30–7.45 (d, 2H, JZ
8.3 Hz), 5.75–6.00 (m, 1H), 5.44 (s, 1H), 5.05–5.38 (m, 3H),
4.35–4.50 (m, 1H), 3.95–4.34 (m, 6H), 3.10–3.25 (d, 1H,
JZ10.3 Hz, D2O exchangeable), 2.47 (s, 3H). 13C NMR
(CDCl3): d 145.8, 133.9, 130.3, 128.2, 118.1, 103.3, 72.8,
72.3, 70.8, 67.5, 60.9, 21.9. The tosylate 24 obtained above
was converted to the known7 4-allyl ether 48 as follows: the
racemic 24 (0.050 g, 0.13 mmol) and sodium methoxide
(0.070 g, 1.30 mmol) were refluxed in dry methanol (2 mL)
for 2 h. The reaction mixture was cooled to ambient
temperature and worked up as usual to obtain racemic 48
(0.026 g, 87%) as a gum. The monoallyl ether 48 (0.026 g)
was characterized as its diacetate 49 (0.031 g, 89%)
obtained by acetylation with acetic anhydride (0.046 g,
0.45 mmol) in pyridine (1 mL) for 12 h to get a colorless
Procedure D. The required triol 1 or 2 (1 mmol) was taken
in DMF (2–3 mL) and lithium hydride (4 mmol) was added
at ambient temperature. A solution of the appropriate alkyl
halide (2.2 mmol) in DMF (1 mL) was added and the
mixture was stirred for 36–45 h. The reaction mixture was
then worked up with ethyl acetate and the products
separated as in procedure A.
3.2.1. 4,6-Di-O-benzyl-myo-inositol 1,3,5-orthoformate
(20). The monobenzyl ether 17 (0.283 g, 1 mmol) was
benzylated by procedure A to obtain the known dibenzyl
ether 20 (0.328 g, 89%). Mp 118–120 8C, (lit.7 Mp
124–125 8C).
3.2.2. Racemic 4-O-benzyl-6-O-allyl-myo-inositol 1,3,5-
orthoformate (21). The monobenzyl ether 17 (0.283 g,
1 mmol) was allylated by procedure A to obtain the 6-allyl
solid. Mp 87–89 8C. IR (n): 1742 cmK1 1H NMR
.
ether 21 (0.256 g, 80%) as gum. IR (n): 3220–3600 cmK1
.
1H NMR (CDCl3): d 7.33 (s, 5H), 5.75–6.00 (m, 1H), 5.47
(s, 1H), 5.16–5.35 (m, 2H), 4.50–4.70 (AB q, 2H, JZ
11.8 Hz), 4.38–4.49 (m, 1H), 4.26–4.37 (m, 2H), 3.95–4.25
(m, 5H), 3.15–3.30 (d, 1H, JZ11.2 Hz, D2O exchangeable).
13C NMR (CDCl3): d 137.9, 134.3, 128.7, 128.1, 127.8,
117.8, 103.6, 73.9, 73.3, 71.7, 71.0, 68.0, 61.7. Anal. Calcd
for C17H20O6: C, 63.74; H, 6.29. Found: C, 63.83; H, 6.47.
The monoallyl ether 21 obtained above was converted to the
known7 racemic dibenzyl ether 47 as follows: to a solution
of 21 (0.050 g, 0.20 mmol) in DMF (1 mL), sodium hydride
(0.016 g, 0.40 mmol) was added and stirred for 5 min.
Benzyl bromide (0.068 g, 0.40 mmol) was added and the
mixture stirred for 0.5 h and worked up as usual to obtain 47
(0.062 g, 97%).
(300 MHz, CDCl3): d 5.79–5.94 (m, 1H), 5.57 (d, 1H, JZ
1 Hz), 5.38–5.43 (m, 1H), 5.31–5.35 (m, 1H), 5.19–5.29 (m,
2H), 4.61–4.66 (m, 1H), 4.35–4.40 (m, 1H), 4.27–4.33 (m,
2H), 4.03–4.10 (m, 2H), 2.22 (s, 3H), 2.06 (s, 3H). Anal.
Calcd for C14H18O8: C, 53.50; H, 5.77. Found: C, 53.70; H,
5.73.
3.2.6. 4,6-Di-O-(p-toluenesulfonyl)-myo-inositol 1,3,5-
orthoformate (25). The racemic 4-tosylate 18 (0.500 g,
1.45 mmol) was taken in THF (8 mL) and n-butyllithium
(1.60 mmol) was added at K78 8C. A solution of tosyl
chloride (0.332 g, 1.75 mmol) in THF (2 mL) was added
and the mixture stirred for 2 h during which the reaction
temperature was allowed to come to ambient temperature.
The resulting mixture was then worked up with ethyl
acetate. The known ditosylate 25 (0.412 g, 57%) was
separated by column chromatography. Mp 181–182 8C,
(lit.25 Mp 183–185 8C).
3.2.3. Racemic 4-O-benzyl-6-O-acetyl-myo-inositol 1,3,5-
orthoformate (22). The monobenzyl ether 17 (0.286 g,
1 mmol) was acetylated (procedure B, reaction time 4 h),
with acetic anhydride (0.125 g, 1.20 mmol) to obtain the
racemic 22 (0.230 g, 70%). Mp 102–104 8C. IR (n): 3300–
3570, 1737 cmK1. 1H NMR (CDCl3): d 7.16–7.45 (m, 5H),
5.51 (s, 1H), 5.35–5.46 (m, 1H), 4.62–4.72 (m, 1H), 4.57 (s,
2H), 4.05–4.43 (m, 4H), 3.20–3.40 (d, 1H, JZ11.8 Hz, D2O
exchangeable), 1.86 (s, 3H). 13C NMR (CDCl3): d 170.2,
137.5, 128.8, 128.4, 127.7, 103.5, 73.6, 72.8, 72.2, 68.6,
66.6, 61.6, 20.9. Anal. Calcd for C16H18O7: C, 59.62; H,
5.63. Found: C, 59.91; H, 5.65.
3.2.7. Racemic 4-O-(p-toluenesulfonyl)-6-O-allyl-myo-
inositol 1,3,5-orthoacetate (26). The racemic 4-tosylate
19 (0.358 g, 1 mmol) was allylated (procedure B), with allyl
bromide (0.146 g, 1.20 mmol) to obtain 26 (0.246 g, 62%)
1
as gum. IR (n): 3300–3590 cmK1. H NMR (CDCl3): d
7.75–7.84 (d, 2H, JZ8.3 Hz), 7.30–7.43 (d, 2H, JZ8.3 Hz),
5.75–6.00 (m, 1H), 5.15–5.40 (m, 2H), 5.00–5.12 (m, 1H),
4.34–4.39 (m, 1H), 3.94–4.28 (m, 6H), 2.89–3.10 (br s, 1H,
D2O exchangeable), 2.47 (s, 3H), 1.42 (s, 3H). 13C NMR
(CDCl3): d 145.6, 134.0, 133.4, 130.3, 128.2, 117.9, 109.4,
73.5, 73.2, 72.9, 72.7, 70.8, 67.5, 60.0, 24.3, 21.8. Anal.
Calcd for C18H22O8S: C, 54.26; H, 5.57. Found: C, 54.12;
H, 5.55.
3.2.4. Racemic 4-O-benzyl-6-O-(p-toluenesulfonyl)-myo-
inositol 1,3,5-orthoformate (23). The monobenzyl ether 17
(0.278 g, 1 mmol) was sulfonylated (procedure B, reaction
time 4 h), with p-toluenesulfonyl chloride (0.228 g,
1.20 mmol) to obtain the 6-tosylate 23 (0.283 g, 65%). Mp
160–162 8C. IR (n): 3300–3600 cmK1. 1H NMR (CDCl3): d
7.70–7.80 (d, 2H, JZ8.3 Hz), 7.20–7.40 (m, 7H), 5.43 (s,
1H), 5.13–5.25 (m, 1H), 4.48–4.70 (AB q, 2H, JZ11.7 Hz),
4.40–4.47 (m, 1H), 4.27–4.39 (m, 1H), 4.15–4.24 (m, 1H),
3.96–4.14 (m, 2H), 3.05–3.16 (d, 1H, JZ11.7 Hz, D2O
exchangeable), 2.44 (s, 3H). 13C NMR (CDCl3): d 145.7,
137.4, 133.1, 130.3, 128.7, 128.1, 127.9, 103.3, 73.0, 72.9,
72.8, 72.3, 71.8, 67.5, 60.9, 21.9. Anal. Calcd for
C21H22O8S: C, 58.06; H, 5.10. Found: C, 58.10; H, 4.80.
3.2.8. 4,6-Di-O-benzyl-myo-inositol 1,3,5-orthoformate
(20). The triol 1 (0.190 g, 1 mmol) was benzylated using
benzyl bromide (0.376 g, 2.20 mmol) and n-butyllithium
(procedure C) to obtain the known 207 (0.296 g, 80%). Mp
118–120 8C.
3.2.9. 4,6-Di-O-benzyl-myo-inositol 1,3,5-orthoacetate
(27). The triol 2 (0.204 g, 1 mmol) was benzylated using
benzyl bromide (0.359 g, 2.20 mmol) and n-butyllithium

S. Devaraj et al. / Tetrahedron 61 (2005) 529–536
535
(procedure C) to obtain 27 (0.268 g, 70%) as a solid. Mp 88–
3.2.14. Racemic 2,4-di-O-(t-butyldimethylsilyl)-myo-ino-
sitol 1,3,5-orthoformate (43). The triol 1 (0.150 g,
0.80 mmol) was silylated (procedure D) in dry DMF
(2 mL) using lithium hydride (0.260 g, 3.20 mmol) and
t-butyldimethylsilyl chloride (0.253 g, 1.68 mmol) to
obtain the known racemic 43 (0.174 g, 52%) as a solid.
Mp 79–81 8C, (lit.26 Mp 75–78 8C).
1
90 8C. IR (n): 3300–3600 cmK1. H NMR (CDCl3): d 7.28
(s, 10H), 4.52–4.71 (AB q, 4H, JZ11.7 Hz), 4.08–4.46 (m,
6H), 2.95–3.10 (d, 1H, JZ11.7 Hz, D2O exchangeable),
1.44 (s, 3H). 13C NMR (CDCl3): d 137.7, 128.5, 127.9,
127.7, 109.3, 73.8, 73.6, 71.7, 67.9, 60.4, 24.4. Anal. Calcd
for C22H24O6: C, 68.74; H, 6.29. Found: C, 68.97; H, 6.14.
3.2.10. 4,6-Di-O-allyl-myo-inositol 1,3,5-orthoformate
(28). The triol 1 (0.190 g, 1 mmol) was allylated using
allyl bromide (0.278 g, 2.30 mmol) and lithium hydride
(procedure D) to obtain 28 (0.251 g, 93%) as a gum. IR (n):
3.2.15. Methylation of racemic 4-O-trityl-myo-inositol
1,3,5-orthoformate (42). Racemic 42 (0.600 g, 1.40 mmol)
was methylated (procedure A) in THF (6 mL) using
n-butyllithium (1 mL, 1.68 mmol) and methyl iodide
(0.12 mL, 1.68 mmol) to obtain the 6-methyl ether 44
(0.147 g, 24%), the 2-methyl ether 45 (0.036 g, 6%) and the
dimethyl ether 46 (0.183 g, 29%). Data for 44: Mp 165–
1
3250–3700 cmK1. H NMR (500 MHz, CDCl3): d 5.82–
5.93 (m, 2H), 5.48 (s, 1H), 5.26–5.33 (dd, 2H, JZ1.4,
17.0 Hz), 5.17–5.23 (dd, 2H, JZ1.4, 10.0 Hz), 4.39–4.44
(m, 1H), 4.26–4.31 (t, 2H, JZ3.2 Hz), 4.18–4.23 (m, 2H),
4.03–4.15 (m, 5H), 3.08–3.20 (d, 1H, JZ10 Hz, D2O
exchangeable). 13C NMR (CDCl3): d 134.3, 117.5, 103.5,
73.8, 73.2, 70.7, 68.0, 61.5. Anal. Calcd for C13H18O6: C,
57.77; H, 6.71. Found: C, 57.60; H, 7.04.
166 8C. IR (n): 3323–3541 cmK1 1H NMR (CDCl3): d
.
7.43–7.55 (m, 6H), 7.23–7.40 (m, 9H), 5.29 (s, 1H), 4.43–
4.52 (m, 1H), 4.02–4.10 (m, 1H), 4.14–4.24 (m, 2H), 3.72–
3.83 (m, 1H), 3.46 (s, 3H), 3.08–3.18 (m, 1H), 2.85 (br s,
1H, D2O exchangeable). 13C NMR (CDCl3): d 143.8, 128.6,
128.0, 127.5, 102.8, 88.0, 75.8, 73.7, 72.4, 69.0, 68.0, 61.3,
57.6. Anal. Calcd for C27H26O6: C, 72.63; H, 5.87. Found:
C, 72.30; H, 6.10. Data for 45: mp 191–193 8C. IR (n):
3304–3541 cmK1. 1H NMR (CDCl3): d 7.25–7.50 (m, 15H),
5.32 (d, 1H, JZ1.1 Hz), 4.54–4.62 (m, 1H), 4.31–4.45 (m,
2H), 3.79–3.89 (m, 2H, 1H D2O exchangeable), 3.57–3.65
(m, 1H), 3.48 (s, 3H), 3.41–3.51 (m, 1H). 13C NMR
(CDCl3): d 142.7, 128.5, 128.2, 128.1, 102.3, 89.9, 71.1,
70.3, 69.9, 69.0, 68.1, 67.8, 56.9. Anal. Calcd for C27H26O6:
C, 72.63; H, 5.87. Found: C, 72.43; H, 5.44. Data for 46: mp
251–253 8C. 1H NMR (CDCl3): d 7.45–7.55 (m, 5H), 7.20–
7.40 (m, 10H), 5.34 (s, 1H), 4.44–4.52 (m, 1H), 4.28–4.36
(m, 1H), 4.08–4.15 (m, 1H), 3.99–4.07 (m, 1H), 3.74–3.80
(m, 1H), 3.53 (s, 3H), 3.31 (s, 3H), 3.07–3.14 (m, 1H). 13C
NMR (CDCl3): d 143.9, 128.6, 128.1, 127.5, 102.8, 88.0,
75.9, 70.1, 69.7, 69.4, 69.2, 68.5, 57.7, 56.7. Anal. Calcd for
C28H28O6: C, 73.03; H, 6.13. Found: C, 72.99; H, 6.10. The
proportion of 44 and 45 formed on using butyllithium and
sodium hydride for the methylation of 42 were estimated as
follows: racemic 42 (0.100 g, 0.23 mmol) was methylated
(procedure A) in THF (1 mL) using n-butyllithium
(0.15 mL, 0.25 mmol) and methyl iodide (0.02 mL,
0.25 mmol) in DMF (0.18 mL). The mixture of monoethers
44 and 45 (0.042 g) was separated by column chromato-
graphy and their proportion (44/45Z61:39) estimated by 1H
NMR spectroscopy. Use of sodium hydride (0.010 g,
0.25 mmol) instead of butyllithium in the above experiment
provided a mixture of the two ethers (0.053 g) in the ratio
44/45Z11:89 and the dimethyl ether 46 (0.030 g, 28%).
3.2.11. Racemic 2-O-methyl-4-O-benzyl-6-O-allyl-myo-
inositol 1,3,5-orthoformate (29). Racemic 17 (0.281 g,
1 mmol) was taken in THF (4 mL) and cooled to 0 8C.
n-Butyllithium (1.1 mL, 1.50 mmol) was added slowly
followed by allyl bromide (0.145 g, 1.20 mmol) in dry
DMF (2 mL) and the mixture stirred for 22 h. Then excess
sodium hydride (0.100 g, 2.50 mmol) and methyl iodide
(0.355 g, 2.50 mmol) were added and the mixture stirred for
4 h and worked up with ethyl acetate. The triether 29
(0.267 g, 80%) was separated (as gum) by flash column
1
chromatography. H NMR (CDCl3): d 7.20–7.50 (m, 5H),
5.75–6.05 (m, 1H), 5.51 (s, 1H), 5.14–5.40 (m, 2H), 4.51–
4.76 (AB q, 2H, JZ11.7 Hz), 4.24–4.50 (m, 5H), 4.00–4.23
(m, 2H), 3.78 (s, 1H), 3.48 (s, 3H). 13C NMR (CDCl3): d
137.9, 134.4, 128.7, 128.1, 127.8, 117.9, 103.4, 74.2, 74.0,
71.9, 71.1, 70.2, 70.0, 69.6, 68.3, 56.9. Anal. Calcd for
C18H22O6: C, 64.66; H, 6.63. Found: C, 64.76; H, 6.89.
3.2.12. Racemic 4-O-(t-butyldimethylsilyl)-myo-inositol
1,3,5-orthoformate (41). The triol 1 (0.500 g, 2.63 mmol)
was silylated (procedure A) in THF (25 mL) using
n-butyllithium (1.7 mL, 2.63 mmol) and a solution of
TBDMSCl (0.476 g, 3.15 mmol) in THF (5 mL). The
known racemic 41 (0.584 g, 73%) was isolated by column
chromatography. Mp 74–76 8C, (lit.22 Mp 73–74 8C).
3.2.13. Racemic 4-O-trityl-myo-inositol 1,3,5-ortho-
formate (42). To a solution of the triol 1 (1 g, 5.30 mmol)
in DMF (15 mL) was added sodium hydride (0.233 g,
5.83 mmol) and stirred for 0.5 h. A solution of trityl chloride
(1.630 g, 5.83 mmol) in DMF (8 mL) was added drop-wise
and the mixture stirred for 1 h. The reaction mixture was
worked up with ethyl acetate and the crude product was
purified by filtration over a short column of silica gel to
obtain 42 (0.900 g, 40%) as a solid. Mp 217–218 8C. IR (n):
3350–3700 cmK1. 1H NMR (CDCl3): d 7.20–7.60 (m, 15H),
5.28 (s, 1H), 4.53–4.62 (m, 1H), 4.16–4.40 (m, 3H), 3.84–
3.89 (d, 1H, JZ9.8 Hz, D2O exchangeable), 3.69–3.77 (m,
1H), 3.02–3.20 (m, 2H, 1H D2O exchangeable). 13C NMR
(CDCl3): d 142.6, 128.4, 128.2, 128.0, 102.3, 89.8, 74.1,
73.1, 70.1, 67.7, 67.4, 60.9. Anal. Calcd for C26H24O6: C,
72.21; H, 5.59. Found: C, 72.19; H, 5.73.
3.2.16. Racemic 2-O-methyl-4-O-trityl-myo-inositol
1,3,5-orthoformate (45). To a solution of the ditosylate
25 (0.300 g, 0.60 mmol) in DMF, sodium hydride (0.036 g,
0.90 mmol) was added followed by methyl iodide (0.06 mL,
0.90 mmol). The reaction mixture was stirred for 15 min
and worked up with ethyl acetate as usual to get 2-O-
methyl-4,6-di-O-(p-toluenesulfonyl)-myo-inositol 1,3,5-
1
orthoformate (0.287 g, 93%). Mp 141–143 8C. H NMR
(CDCl3): d 7.75–7.95 (d, 4H, JZ8.2 Hz), 7.30–7.50 (d, 4H,
JZ8.2 Hz), 5.40–5.48 (d, 1H, JZ1.6 Hz), 5.05–5.19 (t, 2H,
JZ4 Hz), 4.26–4.37 (m, 2H), 4.13–4.22 (m, 1H), 3.59–3.68
(m, 1H), 3.42 (s, 3H), 2.48 (s, 6H). The methyl ether
(0.450 g, 0.90 mmol) and sodium methoxide (0.486 g,

536
S. Devaraj et al. / Tetrahedron 61 (2005) 529–536
4. Shashidhar, M. S. ARKIVOC 2002, VII, 63 and references
cited therein.
´
5. Flores-Mosquera, M.; Martın-Lomas, M.; Chiara, J. L.
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9 mmol) were refluxed in dry methanol/THF (4:1) for 6 h.
The solvents were evaporated and the solid obtained was
chromatographed over silica gel using 1:1 ethyl acetate–
light petroleum as eluent to obtain 2-O-methyl-myo-inositol
1,3,5-orthoformate (0.124 g, 69%). Mp 179–181 8C. 1H
NMR ((CD3)2CO): d 5.36–5.41 (d, 1H, JZ1.2 Hz), 4.98–
5.10 (br s, 2H, D2O exchangeable), 4.39–4.52 (m, 2H),
4.24–4.31 (m, 2H), 4.15–4.23 (m, 1H), 3.75–3.82 (m, 1H),
3.46 (s, 3H). To a solution of the diol obtained above
(0.080 g, 0.40 mmol) in DMF was added sodium hydride
(0.024 g, 0.60 mmol) and trityl chloride (0.167 g,
0.60 mmol) and the reaction mixture stirred at ambient
temperature for 1 h and worked up as usual with ethyl
acetate. Column chromatography over silica gel gave the
trityl ether 45 (0.054 g, 31%). Mp 191–193 8C.
6. (a) Chung, S.-K.; Chang, Y.-T.; Lee, J. W.; Ji, Y.-K. Korean
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11. Also see: Praveen, T.; Das, T.; Sureshan, K. M.; Shashidhar,
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Acknowledgements
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Chim. Acta 1998, 81, 695. (c) Das, T.; Praveen, T.; Shashidhar,
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Financial support for this work was generously provided by
the Department of Science and Technology, New Delhi.
S.D. and S.S.D. are recipients of Senior Research Fellow-
ships from the Council of Scientific and Industrial Research,
New Delhi.
14. (a) Riley, A. M.; Murphy, C. T.; Lindley, C. J.; Westwick, J.;
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¨
15. Baudin, G.; Glanzer, B. I.; Swaminathan, K. S.; Vasella, A.
Helv. Chim. Acta 1988, 71, 1367.
Supplementary data
16. (a) Chemistry of the Metal Chelate Compounds; Martell, A. E.;
Calvin, M. 1952; Prentice Hall: New York, NY, Chapter 5, pp
181–206. (b) Comprehensive Co-ordination Chemistry; Wilk-
inson, G., Ed.; Pergamon Press, 1987; Chapter 23, Vol. 3,
pp 1–80.
1H NMR spectra of the mixture of monomethyl ethers (44
and 45) obtained by the methylation of 42 using
butyllithium/methyl iodide and sodium hydride/methyl
iodide can be found, in the online version, at doi:10.1016/
j.tet.2004.11.025
17. Falck, J. R.; Barma, D. K.; Venkataraman, S. K.; Baati, R.;
Mioskowski, C. Tetrahedron Lett. 2002, 43, 963.
18. Moore, S. S.; Tarnowski, T. L.; Newcomb, M.; Cram, D. J.
J. Am. Chem. Soc. 1977, 99, 6398.
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Chemistry; Oxford University Press: New York, NY, 2001;
pp 199–202.
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