Orthogonally protected cyclohexanehexols by a "one reaction - One product" approach: Efficient access to cyclitols and their analogs

Article abstract of DOI:10.1002/ejoc.201000009

Differentially protected myo-inositol derivatives were prepared from commercially available myo-inositol through regioselective O-alkylation reactions, which give a single product in each step. These derivatives were converted into six isomeric inositol derivatives carrying orthogonal hydroxy protecting groups. For all these reactions, conditions were chosen to prevent the formation of isomeric products, which obviates the need for separation of isomers and provides the required cyclitol derivative in very good yields. The synthetic potential of these derivatives was illustrated by the conversion of some of the orthogonally protected inositol derivatives into other cyclitol derivatives. Isomeric inositols were also prepared by the global deprotection of all the hydroxy groups.

Full text of DOI:10.1002/ejoc.201000009

FULL PAPER
DOI: 10.1002/ejoc.201000009
Orthogonally Protected Cyclohexanehexols by a “One Reaction – One
Product” Approach: Efficient Access to Cyclitols and Their Analogs
Rajendra C. Jagdhane[a] and Mysore S. Shashidhar*[a]
Keywords: Alkylation / Cyclitols / Inositol / Protecting groups / Regioselectivity
Differentially protected myo-inositol derivatives were pre-
obviates the need for separation of isomers and provides the
pared from commercially available myo-inositol through re- required cyclitol derivative in very good yields. The synthetic
gioselective O-alkylation reactions, which give a single prod-
uct in each step. These derivatives were converted into six
isomeric inositol derivatives carrying orthogonal hydroxy
protecting groups. For all these reactions, conditions were
chosen to prevent the formation of isomeric products, which
potential of these derivatives was illustrated by the conver-
sion of some of the orthogonally protected inositol derivatives
into other cyclitol derivatives. Isomeric inositols were also
prepared by the global deprotection of all the hydroxy
groups.
well investigated.[11] However, the scope of most of these
methods are narrow as they were developed for the prepara-
tion of one or just a few inositol derivatives (predominantly
phosphoinositols) and hence are not flexible enough to pro-
vide a large number of isomeric cyclitol derivatives. Due to
subtle differences in reactivity between the secondary hy-
droxy groups in myo-inositol (or its derivatives), most of
the reactions used for the protection of its hydroxy groups
result in the formation of isomeric products, and there are
few exceptions to this rule.[12] Although investigations on
the chemistry of myo-inositol (and its derivatives) helped
to qualitatively understand the relative reactivity of their
hydroxy groups,[11] the actual reaction conditions required
to react any one of their hydroxy groups exclusively were
seldom realized in the laboratory. Enzyme-mediated regio-
and enantiospecific reactions of myo-inositol (or its deriva-
tives)[13] are known, but they are not yet viable for organic
synthesis, because most of these involve acylation or phos-
phorylation reactions, both of which are prone to migration
among the hydroxy groups. The availability of methods for
exclusive reaction at any one hydroxy group (Scheme 1) in
myo-inositol and its derivatives would be of immense utility
to access cyclitol derivatives and many other kinds of com-
pounds that can be obtained from cyclitols.
The shortcomings mentioned above can be addressed if
orthogonally protected isomeric inositol derivatives, such as
5–7 (Scheme 1), can be synthesized in a few steps, avoiding
the formation of isomers during the reaction of the six hy-
droxy groups of myo-inositol. We herein reveal methods for
the preparation of orthogonally protected isomeric inositol
derivatives that can be used to prepare a variety of cyclitol
derivatives. This methodology is based on the fact that O-
alkylation of partially protected myo-inositol derivatives in
the presence of lithium-derived bases gives better regioselec-
tivity compared to bases derived from sodium
Introduction
Cyclohexane polyols (cyclitols, inositols, pseudosugars,
and carbasugars) and their derivatives constitute a group of
organic compounds that are crucial for the well-being of
living cells or are capable of intervention in the biological
process of diseased cells or pathogens.[1] Involvement of
phosphoinositols in cellular signal transduction pathways is
an example of the former,[2] whereas the presence of amino-
cyclitol moieties in antibiotics is an example of the latter.[3]
Apart from these, cyclitols and their derivatives are also
interesting due to their potential as starting materials for
the synthesis of natural products,[4] their ability to complex
metal ions,[5] and because of their unusual structure and
properties in the crystalline state.[6] Methodologies for the
synthesis of cyclitols and their derivatives from different
kinds of starting materials, such as naturally occurring inos-
itols (myo- and chiro-inositols and their derivatives),[7]
sugars (glucose, galactose, xylose etc.),[8] benzene and its
derivatives (toluene, naphthalene, benzoquinone),[9] and
norbornyl derivatives[10] have been reported. By and large,
formation of isomeric cyclitol derivatives is a common
shortcoming of the known synthetic methodologies and
separation of the desired isomer is often required. These
limitations result in reduction in the overall yield of the de-
sired product and wastage of chemicals, reagents and
(often) laboriously prepared synthetic intermediates. Natu-
rally occurring myo-inositol is a convenient starting mate-
rial for the synthesis of cyclitol derivatives because methods
for the preparation of its protected derivatives have been
[a] Organic Chemistry Division, National Chemical Laboratory,
Pashan Road, Pune, Maharashtra 411008, India
Fax: +91-20-2590-2629
E-mail: ms.shashidhar@ncl.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000009.
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R. C. Jagdhane, M. S. Shashidhar
FULL PAPER
Scheme 1. Synthetic sequence for the preparation of a structurally modified cyclitol or its orthogonally protected derivative.
Scheme 2. Contrast in the O-alkylation by using sodium and lithium bases.
(Scheme 2).[14] In most of the reactions reported here, we lowed by inversion of the 4-hydroxy group, provided the
obtained a single product, which obviates the need for the orthogonally protected epi-inositol derivative 19. Global de-
separation of regio/stereoisomers.
protection of this derivative gave epi-inositol (20) in an
overall yield of 33% from myo-inositol. For comparison,
the reported yields of epi-inositol by using previously devel-
oped methods was in the range 6–15% from myo-inos-
Results and Discussion
We chose to use orthoesters of myo-inositol as the start- itol[7a,7b,7d] and 1–21% from other starting materi-
ing point, because they can be obtained as single products als.[8a,8b,9a,9b,9g,10a,17]
(in contrast to acetals) in high yield, and these reactions
Initially, we attempted to release the 5-hydroxy group in
can be performed on 5–100 g scales.[12a,12b,15] Due to strong the orthobenzoate 14 by its reduction with DIBAL-H.
intramolecular hydrogen bonding between the 4- and 6-hy- However, this reaction resulted in the formation of a mix-
droxy groups of myo-inositol orthoesters, and due to their ture of products from which the benzylidene acetal 26
ability to form chelates with metal ions, reaction of the (Scheme 4) could be isolated in 60% yield. Reduction of the
three hydroxy groups of these orthoesters with alkyl halides orthobenzoate moiety in the tribenzyl ether 24 with 1 equiv.
can be controlled to obtain mono-, di- or triethers exclu- of DIBAL-H is known to result in the release of the 5-
sively.[12b,16] Accordingly, the reaction of myo-inositol or- hydroxy group exclusively.[18] Attempts at inversion of the
thobenzoate with 4-methoxybenzyl chloride (assisted by so- 5-hydroxy group of benzylidene acetal 26 (by SN2 substitu-
dium hydride), allyl bromide (assisted by butyllithium) and tion on its triflate with cesium acetate, to obtain neo-inos-
4-bromobenzyl bromide (assisted by sodium hydride), in itol derivatives), resulted in a mixture of products consisting
that sequence, provided the orthogonally protected myo-in- of myo and neo isomers.
ositol orthobenzoate 14 (Scheme 3). Reduction of the or-
The orthogonally protected scyllo-inositol orthobenzoate
thobenzoate moiety with an excess of diisobutylaluminum derivative could be obtained by the sequential oxidation
hydride (DIBAL-H) gave a mixture of isomeric diols 15 and and reduction of the 2-hydroxy group in 13 (Scheme 5), fol-
16. Selective benzylation at the 1(3)-hydroxy group pro- lowed by O-alkylation with 4-bromobenzyl bromide. Re-
vided the corresponding dibenzyl ether 21, whereas ben- duction of the orthobenzoate moiety of scyllo-inositol or-
zylation by using an excess of benzyl bromide gave the trib- thobenzoate, followed by benzylation, provided scyllo-inos-
enzyl ether 17 carrying orthogonal protecting groups at the itol derivative 28 carrying three orthogonal protecting
2-, 4- and 6-positions of myo-inositol. The hydroxy groups groups.
at these positions could then be released and modified as
The synthesis of a chiro-inositol derivative carrying or-
desired. The 5-hydroxy group in the dibenzyl ether 21 could thogonal protecting groups started from the tribenzyl ether
be inverted through the mesylate 22 to obtain neo-inositol 29, which was prepared from myo-inositol orthoformate as
carrying orthogonal protecting groups (23). Cleavage of the reported earlier.[18a] Allylation of 29, followed by hydrolysis
p-methoxybenzyl (PMB) ether in the tribenzyl ether 17, fol- of the acetal, gave the symmetric diol 30. Alkylation of one
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Efficient Access to Cyclitols and Their Analogs
Scheme 3.
Scheme 4.
of the hydroxy groups in 30 with (4-chloro)benzyl bromide, to be used as starting materials for the preparation of
followed by inversion of the second hydroxy group via its differentially protected derivatives. Furthermore, such an
triflate, gave the chiro-inositol derivative 32 (Scheme 5). A approach[19] would require standardizing the reaction con-
perusal of the earlier reports reveals that much time and ditions for selective reactions of the six hydroxy groups in
effort has been invested in attempts to prepare protected each of these isomeric cyclohexanehexols and their partially
chiro-inositol derivatives such as 33 (starting from chiro-in- protected derivatives. An illustration of the utility of the
ositol), with little success.[7c,7e]
isomeric inositol derivatives carrying orthogonal protecting
This synthetic approach provides isomeric inositol deriv- groups to prepare other cyclitol derivatives is provided be-
atives that are amenable to manipulation to obtain a variety low.
of cyclitol derivatives. Inositol isomers (Figure 1) other than
The epi-inositol derivative 19 (Scheme 6) could be trans-
the myo isomer are not readily available (or relatively ex- formed into the cis-inositol derivative 42 by protection of
pensive if commercially available) in quantities large enough the axial hydroxy group followed by cleavage of the allyl
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R. C. Jagdhane, M. S. Shashidhar
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Scheme 5.
ether and inversion of the resulting hydroxy group. Global
deprotection of all the hydroxy groups provided cis-inositol
(40, isolated as its hexaacetate 43) in an overall yield of
25% from myo-inositol; for comparison, the yields in most
of the methods reported previously[7b,9b,19c,20] were lower or
required separation of isomeric inositols. Similarly, the allo-
inositol derivative 45 could be obtained from the racemic
chiro-inositol derivative 33. allo-Inositol (isolated as its
hexaacetate 46) was prepared by global deprotection of the
hydroxy groups in an overall yield of 28% from myo-inos-
itol. Free cis- and allo-inositols can be generated by the
aminolysis of the hexaacetates 43 and 46, respectively.[15b]
For comparison, yields of allo-inositol prepared in methods
reported earlier was 15% from myo-inositol[7g] and 2–16%
from other starting materials.[7b,8a,9c,9d,9e,21]
Figure 1. Structures of all nine possible inositol isomers.
Scheme 6. Preparation of inositol diastereoisomers from orthogonally protected inositols.
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Efficient Access to Cyclitols and Their Analogs
Scheme 7. Preparation of inositol derivatives from orthogonally protected inositols.
The reactions shown in Scheme 7 leading to the synthesis ability to chelate with metal ions[5] helped us to develop
of ring-modified cyclitol derivatives, a deoxyinositol, a de- reaction conditions for the selective derivatization of these
oxyfluoroinositol, an azidoinositol, and an aminocyclitol, hydroxy groups. Judicious choice of alkyl halides[24] for the
illustrate the synthetic potential and flexibility of orthogo- preparation of myo-inositol ethers provided myo-inositol
nally protected inositol derivatives. Compound 49, which derivatives carrying orthogonal protecting groups. Since
can be prepared by global deprotection of 48, has shown any of these ethers could be cleaved in the presence of other
promise as a potential therapeutic agent for Alzheimer’s dis- ethers present in the same derivative, the desired myo-inos-
ease.[22] When the use of one of the intermediates (e.g., 18) itol hydroxy group can be released and inverted to obtain
for the preparation of a particular inositol derivative (52) six (of the eight possible isomers) isomeric inositol deriva-
results in lower yield (the bicyclic derivative 51 arises from tives carrying orthogonal protecting groups. Also, since
the debenzylative cycloetherification reaction),[23] the same most of the ethers used are (substituted) benzyl ethers, they
product can be obtained in higher yield by using an alterna- can all be cleaved simultaneously by hydrogenation to re-
tive intermediate (19). Perhaps, in this case, the nucleophilic lease all the hydroxy groups in one step, if necessary. These
substitution in the mesylate of 18 proceeds through an SN1 compounds can now be used for the preparation of a vari-
mechanism, which facilitates the formation of the bicyclic ety of cyclitol derivatives. Although, methods for the prepa-
derivative 51. This view is supported by the observed reten- ration of isomeric inositols have been reported in the litera-
tion of configuration at C-4 upon formation of the azide ture, none of these approaches provide access to differen-
52. Here, inversion at C-4 is prevented by participation of tially protected isomeric inositol derivatives. Chiral cyclitol
the 1-benzyloxy group (formation of 51).
derivatives can be obtained by resolution of the intermedi-
These newly synthesized cyclitol derivatives carry pro- ates; we are currently working on the desymmetrization of
tecting groups that can be cleaved in the presence of each some of the intermediates reported here to obtain differen-
other to release the desired hydroxy group, which can be tially protected chiral inositol derivatives.
further modified to give second-generation (with two modi-
fications) cyclitol derivatives. Hence, this methodology can
be used to prepare a large number of cyclitols and their
Experimental Section
derivatives starting from commercially available myo-inos-
General Methods: Sodium hydride was a 60% suspension in min-
itol. In addition, phosphorylation and glycosylation reac-
eral oil. Thin layer chromatography was performed with E. Merck
tions can be carried out on orthogonally protected cyclitol
pre-coated 60 F254 plates, and the spots were rendered visible either
derivatives (since all the protecting groups can be cleaved
by UV light or by charring the plates with chromic acid solution.
by hydrogenolysis) to obtain the corresponding cyclitol
phosphate or glycoside conjugates.
Column chromatographic separations (silica gel, 100–200 mesh)
and flash column chromatographic separations (silica gel, 230–
400 mesh) were carried out with light petroleum/ethyl acetate mix-
tures as eluent (v/v%). For column chromatographic separation of
compounds containing the PMB group or benzylidene acetal or
triflate, the silica gel used was pre-eluted with a triethylamine/light
Conclusions
An understanding of the relative reactivities of the myo-
inositol hydroxy groups[11,14,16,18b] and differences in their petroleum (1:49, 3–5 mL/g) mixture. “Usual workup” implies wash-
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R. C. Jagdhane, M. S. Shashidhar
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ing of the organic layer with water followed by brine, drying with
anhydrous sodium sulfate and removal of the solvent under re-
duced pressure using a rotary evaporator. IR spectra were recorded
(in CHCl3 solution, as a Nujol mull or as a neat film) with a Shim-
adzu FTIR-8400 or Perkin–Elmer spectrophotometer. NMR spec-
tra were recorded with a Bruker ACF 200 spectrometer (200 MHz
for 1H and 50.3 MHz for 13C) unless otherwise mentioned. Chemi-
cal shifts (δ, ppm) reported are referred to internal tetramethylsil-
ane. Microanalytical data were obtained with a FLASH 1112 Series
EA or Elementar Vario EL elemental analyzer. All the melting
points were recorded with a Büchi B-540 electrothermal melting-
point apparatus. Compounds previously reported in the literature
were characterized by comparison of their melting points and/or
1H NMR spectra with the reported data.
cooled solution of 13 (7.90 g, 18.54 mmol) in dry DMF (50 mL)
was added sodium hydride (1.48 g, 37.09 mmol) followed by a solu-
tion of 4-bromobenzyl bromide (5.10 g, 20.40 mmol) in DMF
(20 mL), and the reaction mixture was stirred at room temp. for
12 h. Excess of sodium hydride was destroyed by adding ice to the
reaction mixture, solvents were removed under reduced pressure,
and the residue was worked up as usual with dichloromethane. The
crude product was purified by flash column chromatography (ethyl
acetate/light petroleum, 1:4) on silica gel to obtain 14 (10.5 g, 95%)
as a gum. Rf = 0.38 (ethyl acetate/light petroleum, 5:17). 1H NMR
(200 MHz, CDCl3, 25 °C): δ = 7.70–7.59 (m, 2 H, Ar-H), 7.50–7.43
(m, 2 H, Ar-H), 7.37–7.18 (m, 7 H, Ar-H), 6.91–6.84 (m, 2 H, Ar-
H), 5.95–5.76 (m, 1 H, CH=CH2), 5.31–5.16 (m, 2 H, CH=CH2),
4.64 (s, 2 H), 4.59–4.35 (m, 7 H), 4.17–3.97 (m, 3 H), 3.82 (s, 3 H,
Ar-OCH3) ppm. 13C NMR (50.3 MHz, CDCl3, 25 °C): δ = 159.2
(Cipso), 137.1 (Cipso), 134.0 (Carom), 131.3 (Carom), 129.6 (Cipso),
129.3 (Carom), 129.2 (Carom), 129.0 (Carom), 127.8 (Carom), 125.2
(Carom), 121.4 (Cipso), 117.4 (C=CH2), 113.7 (CH=C), 107.7
(PhCO3), 73.6 (Ins CH), 73.4 (Ins CH), 71.8 (Ins CH), 71.7 (Ins
CH), 71.1 (CH2), 70.5 (CH2), 70.2 (CH2), 68.8 (Ins CH), 66.5 (Ins
CH), 55.1 (OCH3) ppm. C31H31BrO7 (594.13): calcd. C 62.53, H
5.25; found C 62.29, H 4.86.
Preparation of Racemic 4-O-(4-Methoxybenzyl)-myo-inositol 1,3,5-
Orthobenzoate (12): To an ice-cooled solution of myo-inositol 1,3,5-
orthobenzoate (4)[15c,25] (10 g, 37.59 mmol) in DMF (80 mL), so-
dium hydride (1.50 g, 37.59 mmol) was added followed by a solu-
tion of 4-methoxybenzyl chloride (5.09 g, 37.59 mmol) in DMF
(20 mL). The reaction mixture was stirred at room temp. for 4 h.
The reaction mixture was then decomposed by the addition of ice,
solvents were removed under reduced pressure, and the residue was
worked up as usual with dichloromethane as solvent. The crude
product obtained was purified by flash column chromatography
(ethyl acetate/light petroleum, 2:3) on silica gel to obtain 12 (13.0 g,
90%) as a colorless solid. Rf = 0.38 (ethyl acetate/light petroleum,
2:3); m.p. 126–128 °C. 1H NMR (200 MHz, CDCl3, 25 °C): δ =
7.70–7.55 (m, 2 H, Ar-H), 7.45–7.32 (m, 3 H, Ar-H), 7.31–7.20 (m,
2 H, Ar-H), 7.00–6.80 (m, 2 H, Ar-H), 4.64 [q, J = 11.5 Hz, 2 H,
CH2Ph(OCH3)], 4.61–4.48 (m, 2 H), 4.44–4.32 (m, 3 H), 4.14 (m,
1 H), 3.82 (s, 3 H, OCH3), 3.80 (d, J = 10 Hz, 1 H, D2O exchange-
able, OH), 3.15 (d, J = 12 Hz, 1 H, D2O exchangeable, OH) ppm.
13C NMR (50.3 MHz, CDCl3, 25 °C): δ = 159.8 (Cipso), 136.5
(Cipso), 129.7(Carom), 129.5 (Carom), 127.9 (Carom), 127.8 (Cipso), 125.1
(Carom), 114.1 (Carom), 107.2 (PhCO3), 75.9 (Ins C), 73.4 (Ins C),
72.5 (CH2), 68.0 (Ins C), 67.6 (Ins C), 59.7 (Ins C), 55.1 (OCH3)
Preparation of Racemic 6-O-Allyl-1,3,5-tri-O-benzyl-2-O-(4-bro-
mobenzyl)-4-O-(4-methoxybenzyl)-myo-inositol (17): To an ice-co-
oled solution of the orthobenzoate 14 (4.5 g, 7.56 mmol) in dichlo-
romethane (50 mL), DIBAL-H (42 mL, 42 mmol, 1  in toluene)
was added, and the reaction mixture was stirred at room temp.
for 4 h. The reaction mixture was diluted with dichloromethane
(150 mL) and rapidly poured into a mixture of saturated solutions
of ammonium chloride (90 mL) and sodium potassium tartarate
(120 mL) with stirring and cooling. The stirring was continued at
room temp. until two layers separated. The aqueous layer was
washed with dichloromethane (2ϫ60 mL), and the combined or-
ganic layers were washed with brine, dried with anhydrous sodium
sulfate, and the solvent was removed under reduced pressure to
afford the crude product, which was purified by flash column
chromatography (ethyl acetate/light petroleum, 7:15) on silica gel
to obtain a mixture of diastereoisomeric diols 15 and 16 (3.3 g,
73%) as a gum. To an ice-cooled solution of 15 and 16 (3.3 g,
5.51 mmol) in dry DMF (30 mL), sodium hydride (1.10 g,
27.55 mmol) was added, followed by benzyl bromide (3.27 mL,
27.55 mmol), and the reaction mixture was stirred at room temp.
for 12 h. Excess of sodium hydride was destroyed by adding ice to
the reaction mixture, solvents were removed under reduced pres-
sure, and the residue was worked up as usual with dichloromethane.
The crude product was purified by flash column chromatography
(ethyl acetate/light petroleum, 1:9) on silica gel to obtain 17 (4.15 g,
97%) as a colorless solid. Rf = 0.36 (ethyl acetate/light petroleum,
1:9); m.p. 66–68 °C. 1H NMR (200 MHz, CDCl3, 25 °C): δ = 7.40–
7.17 (m, 21 H, Ar-H), 6.84–6.77 (m, 2 H, Ar-H), 6.07–5.88 (m, 1
H, CH=CH2), 5.33–5.09 (m, 2 H, CH=CH2), 4.86 (s, 2 H), 4.79–
4.53 (m, 8 H), 4.44–4.26 (m, 2 H), 4.06–3.83 (m, 3 H), 3.78 (s, 3 H,
Ar-OCH3), 3.47–3.23 (m, 3 H) ppm. 13C NMR (50.3 MHz, CDCl3,
25 °C): δ = 158.9 (Cipso), 138.7 (Cipso), 138.2 (Cipso), 138.1 (Cipso),
137.8 (Cipso), 135.3, 131.0, 130.8 (Cipso), 129.5, 129.2, 128.2, 128.1,
127.7, 127.5, 127.3, 120.9 (Cipso), 116.3 (C=CH2), 113.5, 83.5 (Ins
C), 81.2 (Ins C), 81.1 (Ins C), 80.6 (Ins C), 80.5 (Ins C), 75.7 (CH2),
75.3 (CH2), 74.8 (Ins CH), 74.3 (CH2), 73.2 (CH2), 72.75 (CH2),
72.69 (CH2), 55.0 (CH3) ppm. C45H47BrO7 (779.75): calcd. C 69.31,
H 6.08; found C 69.18, H 6.10.
ppm. IR (CHCl ): ν = 3600–3550, 3550–3400 (OH) cm–1. C H O
˜
3
21 22
7
(386.4): calcd. C 65.28, H 5.74; found C 64.92, H 5.62.
Preparation of Racemic 6-O-Allyl-4-O-(4-methoxybenzyl)-myo-inos-
itol 1,3,5-Orthobenzoate (13): To a cooled (0 to –5 °C) solution of
12 (4.03 g, 10.44 mmol) in dry THF (40 mL), was added nBuLi
(7.83 mL, 12.53 mmol, 1.6  in cyclohexane) followed by a solution
of allyl bromide (0.95 mL, 10.96 mmol) in dry DMF (20 mL). The
reaction mixture was stirred at room temp. for 30 h and then de-
composed by the addition of ice. The solvents were removed under
reduced pressure, and the residue was worked up as usual with
dichloromethane. The crude product obtained was purified by flash
column chromatography (ethyl acetate/light petroleum, 5:17) on sil-
ica gel to obtain 13 (3.55 g, 80%) as a gum. Rf = 0.35 (ethyl acetate/
light petroleum, 5:17). 1H NMR (200 MHz, CDCl3, 25 °C): δ =
7.70–7.55 (m, 2 H, Ar-H), 7.44–7.23 (m, 5 H, Ar-H), 6.94–6.82 (m,
2 H, Ar-H), 6.02–5.80 (m, 1 H, CH=CH2), 5.38–5.14 (m, 2 H,
CH=CH2), 4.70–4.31 (m, 7 H), 4.25–4.05 (m, 3 H), 3.81 (s, 3 H,
Ar-OCH3), 3.10 (d, J = 12 Hz, 1 H, D2O exchangeable, OH) ppm.
13C NMR (50.3 MHz, CDCl3, 25 °C): δ = 159.2 (Cipso), 136.9
(Cipso), 134.0, 129.6 (Cipso), 129.4, 129.1, 127.9, 125.1, 117.5
(C=CH2), 113.7, 107.8 (PhCO3), 74.2 (Ins C), 74.2 (Ins C), 73.4
(Ins C), 73.0 (Ins C), 71.1 (CH2), 70.7 (CH2), 68.5 (Ins C), 60.4
(Ins C), 55.1 (OCH ) ppm. IR (Nujol): ν = 3584–3320 (OH) cm–1.
˜
3
C24H26O7 (426.46): calcd. C 67.59, H 6.15; found C 67.40, H 5.80.
Preparation of Racemic 6-O-Allyl-1,3-di-O-benzyl-2-O-(4-bromo-
benzyl)-4-O-(4-methoxybenzyl)-myo-inositol (21): To an ice-cooled
solution of a mixture of diasteroisomeric diols 15 and 16 (1.16 g,
Preparation of Racemic 6-O-Allyl-2-O-(4-bromobenzyl)-4-O-(4-
methoxybenzyl)-myo-inositol 1,3,5-Orthobenzoate (14): To an ice-
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Efficient Access to Cyclitols and Their Analogs
1.94 mmol) in DMF (12 mL), was added sodium hydride (0.086 g,
2.13 mmol) followed by benzyl bromide (0.23 mL, 1.94 mmol), and
the mixture was stirred at ambient temperature for 20 min. The
reaction was quenched by the addition of ice, solvents were re-
moved under reduced pressure, and the residue was taken into
dichloromethane and worked up as usual. The products were sepa-
rated by flash column chromatography (ethyl acetate/light petro-
leum, 1:3) on silica gel to obtain myo-alcohol 21 (0.75 g, 57%) as
a gum, which turned into a colorless solid on storing at ambient
temperature. The triether 17 (0.15 g, 20%) and the starting diols 15
and 16 (0.11 g, 10%) were also obtained. Rf = 0.32 (ethyl acetate/
(3.6 g, 48%; 78% based on recovered 30) as a gum, which turned
into a sticky solid on cooling under light petroleum (in a re-
fridgerator); unreacted starting diol 30 (2.3 g, 38%) was also reco-
vered. Rf = 0.37 (ethyl acetate/light petroleum, 1:4). 1H NMR
(200 MHz, CDCl3, 25 °C): δ = 7.40–7.28 (m, 15 H, Ar-H), 7.24–
7.18 (m, 4 H, Ar-H), 6.08–5.89 (m, 1 H, CH=CH2), 5.35–5.14 (m,
2 H, CH=CH2), 5.00–4.87 (m, 2 H), 4.84 (s, 2 H), 4.78–4.69 (dd, J
= 2.5, 11.0 Hz, 2 H), 4.61 (s, 2 H), 4.44–4.27 (m, 2 H), 4.05–3.94
(m, 2 H), 3.77 (t, J = 9.5 Hz, 1 H), 3.48–3.28 (m, 3 H), 2.24 (br. s,
1 H, D2O exchangeable, OH) ppm. 13C NMR (50.3 MHz, CDCl3,
25 °C): δ = 138.43 (Cipso), 138.4 (Cipso), 136.6 (Cipso), 134.9, 133.0
(Cipso), 128.5, 128.3, 128.1, 127.83, 127.8, 127.5, 127.39, 127.36,
1
light petroleum, 1:3); m.p. 66–69 °C. H NMR (200 MHz, CDCl3,
25 °C): δ = 7.46–7.28 (m, 13 H, Ar-H), 7.25–7.19 (m, 3 H, Ar-H), 116.4 (CH=CH2), 83.0 (Ins C), 81.6 (Ins C), 81.5 (Ins C), 80.5 (Ins
6.88–6.78 (m, 2 H, Ar-H), 6.07–5.88 (m, 1 H, CH=CH2), 5.33–5.12 C), 76.6 (Ins C), 75.6 (CH2), 75.2 (CH2), 74.4 (CH2), 74.2 (CH2),
(m, 2 H, CH=CH2), 4.90–4.50 (m, 8 H), 4.45–4.23 (m, 2 H), 3.96 71.9 (Ins C), 71.6 (CH ) ppm. IR (CHCl ): ν = 3559, 3455 (OH)
˜
2
3
(t, J = 2.4 Hz, 1 H), 3.87 (t, J = 9.5 Hz, 1 H), 3.79 (s, 3 H, Ar- cm–1. C37H39ClO6 (615.15): calcd. C 72.24, H 6.39; found C 72.58,
OCH3), 3.80–3.70 (m, 1 H), 3.44 (t, J = 9.2 Hz, 1 H), 3.36–3.26 H 6.55.
(m, 2 H), 2.52 (br. s, 1 H, D2O exchangeable, OH) ppm. 13C NMR
Preparation of Racemic 1-O-Acetyl-3-O-allyl-2,4,6-tri-O-benzyl-5-
(50.3 MHz, CDCl3, 25 °C): δ = 159.1 (Cipso), 138.2 (Cipso), 138.1
O-(4-chlorobenzyl)-chiro-inositol (32): To a cooled solution (–15 °C)
of 31 (1.43 g, 2.32 mmol) in pyridine/dichloromethane (5:15 mL)
(Cipso), 137.9 (Cipso), 135.2, 131.1, 130.9 (Cipso), 129.6, 129.3, 128.3,
127.6, 127.4, 127.38, 121.0 (Cipso), 116.7 (C=CH2), 113.7, 80.63 (Ins
was added trifluoromethanesulfonic anhydride (0.58 mL,
C), 80.6 (Ins C), 80.5 (Ins C), 80.4 (Ins C), 75.0 (Ins C), 74.9 (CH2),
3.49 mmol), and the reaction mixture was stirred for 2 h, during
74.8 (Ins C), 74.1 (CH2), 73.3 (CH2), 72.7 (CH2), 72.6 (CH2) ppm.
which time the mixture was allowed to warm to ambient tempera-
IR (Nujol): ν = 3603–3344 cm–1. C H BrO (689.63): calcd. C
˜
38 41
7
ture. The reaction mixture was decomposed by the addition of ice,
then solvents were removed under reduced pressure, and the residue
was worked up with dichloromethane as usual. The product was
purified by column chromatography on silica gel to obtain the cor-
responding triflate (1.6 g, 90%) as a gum. The triflate (1.6 g), benz-
ene (12 mL), cesium acetate (1.23 g, 6.43 mmol) and 18-crown-6
(1.13 g, 4.28 mmol), were refluxed for 2 h. The reaction mixture
was cooled to ambient temperature and decomposed by the ad-
dition of ice, then diluted with dichloromethane and worked up as
usual. The product was purified by flash column chromatography
(ethyl acetate/light petroleum, 1.5:8.5) to afford the chiro-acetate
32 (0.98 g, 70%) as a gum and 4-O-allyl-1,3,5-tri-O-benzyl-2-O-(4-
chlorobenzyl)cyclohex-1(6)-ene-1,2,3,4,5-pentol (ethyl acetate/light
petroleum, 1:13) as a colorless solid (0.32 g, 25%).
66.18, H 5.99; found C 66.16, H 6.35.
Preparation of 5-O-Allyl-2,4,6-tri-O-benzyl-myo-inositol (30): To an
ice-cooled solution of 29[18a] (8.50 g, 18.39 mmol) in DMF (50 mL),
was added sodium hydride (2.20 g, 55.17 mmol) followed by allyl
bromide (3.18 mL, 36.78 mmol), and the mixture was stirred at am-
bient temperature for 4 h. Excess of sodium hydride was destroyed
by the addition of ice, the solvents were removed under reduced
pressure, and the residue was worked up with ethyl acetate as usual
to obtain the crude product (10.2 g). To the crude allyl ether
(10.2 g), methanol (25 mL) and concd. HCl (5 mL) were added,
and the mixture was refluxed for 5 h. The reaction mixture was
cooled to ambient temperature, acid was neutralized by the ad-
dition of solid sodium hydrogen carbonate, and the mixture was
filtered through a bed of Celite. The filtrate was concentrated under
reduced pressure and worked up with ethyl acetate as usual. The
product was purified by flash column chromatography (ethyl acet-
ate/light petroleum, 1:3) to afford the 1,3-diol 30 (8.5 g, 94%) as a
gum. Rf = 0.36 (ethyl acetate/light petroleum, 3:7). 1H NMR
(200 MHz, CDCl3, 25 °C): δ = 7.42–7.30 (m, 15 H, Ar-H), 6.09–
5.90 (m, 1 H, CH=CH2), 5.36–5.15 (m, 2 H, CH=CH2), 4.92 (d, J
= 11 Hz, 2 H), 4.81 (s, 2 H), 4.75 (d, J = 11 Hz, 2 H), 4.36 (dt, J
= 5.7, 1.4 Hz, 2 H), 4.00 (t, J = 2.7 Hz, 1 H), 3.75 (t, J = 9.3 Hz,
2 H), 3.60–3.45 (m, 2 H), 3.34 (t, J = 9.2 Hz, 1 H), 2.28 (d, J =
5.4 Hz, 2 H, D2O exchangeable, 2 OH) ppm. 13C NMR (50.3 MHz,
CDCl3, 25 °C): δ = 138.5 (Cipso), 138.4 (Cipso), 134.9, 128.4, 128.3,
128.0, 127.8, 127.7, 127.6, 116.7 (C=CH2), 83.2 (Ins C), 82.0 (Ins
C), 78.9 (Ins C), 75.4 (CH2), 75.1 (CH2), 74.2 (CH2), 72.3 (Ins C)
Data for 32: Rf = 0.40 (ethyl acetate/light petroleum, 1:4). 1H NMR
(200 MHz, CDCl3, 25 °C): δ = 7.39–7.27 (m, 17 H, Ar-H), 7.24–
7.17 (m, 2 H, Ar-H), 6.10–5.90 (m, 1 H, CH=CH2), 5.36–5.14 (m,
3 H, CH=CH2, 1-H), 4.84 (q, J = 12.8 Hz, 2 H), 4.74–4.47 (m, 6
H), 4.45–4.23 (m, 2 H), 3.95–3.79 (m, 2 H), 3.73 (t, J = 3.6 Hz, 1
H), 3.66–3.55 (m, 2 H), 1.99 (s, 3 H, OC-CH3) ppm. 13C NMR
(50.3 MHz, CDCl3, 25 °C): δ = 169.6 (C=O), 138.6 (Cipso), 137.9
(Cipso), 137.7 (Cipso), 136.7 (Cipso), 135.2, 133.2 (Cipso), 128.9,
128.34, 128.29, 128.27, 128.2, 128.1, 127.8, 127.63, 127.6, 116.4
(CH=CH2), 81.5 (Ins C), 81.3 (Ins C), 79.2 (Ins C), 77.3 (Ins C),
76.0 (CH2), 74.5 (CH2), 74.0 (Ins CH), 73.1 (CH2), 72.6 (CH2),
72.1 (CH ), 67.8 (Ins C), 20.8 (OC-CH ) ppm. IR (neat): ν = 1747
˜
2
3
(C=O) cm–1. C39H41ClO7 (657.19): calcd. C 71.28, H 6.29; found
ppm. IR (Nujol): ν = 3594–3233 (OH) cm–1. C H O (490.59):
C 71.32, H 6.49.
˜
30 34
6
calcd. C 73.45, H 6.99; found C 73.30, H 7.29.
Data for 4-O-Allyl-1,3,5-tri-O-benzyl-2-O-(4-chloro)benzylcyclohex-
1(6)-ene-1,2,3,4,5-pentol: Rf = 0.38 (ethyl acetate/light petroleum,
1:9); m.p. 87–89 °C. 1H NMR (200 MHz, CDCl3, 25 °C): δ = 7.45–
7.28 (m, 15 H, Ar-H), 7.24–7.15 (m, 4 H, Ar-H), 6.10–5.90 (m, 1
H), 5.37–5.30 (m, 2 H), 5.00–4.57 (m, 9 H), 4.50–4.30 (m, 2 H),
4.28–4.16 (m, 2 H), 3.72 (dd, J = 7.3, 7.5 Hz, 1 H), 3.56 (dd, J =
7.3, 7.2 Hz, 1 H) ppm. 13C NMR (50.3 MHz, CDCl3, 25 °C): δ =
153.7 (Cipso), 138.52 (Cipso), 138.46 (Cipso), 136.9 (Cipso), 136.4
(Cipso), 135.1, 133.2 (Cipso), 129.5, 128.5, 128.4, 128.34, 128.30,
128.1, 127.9, 127.8, 127.7, 127.6, 116.8 (CH=CH2), 96.9 (Ins C),
83.2 (Ins C), 82.5 (Ins C), 80.2 (Ins C), 78.4 (Ins C), 75.6 (CH2),
Preparation of Racemic 5-O-Allyl-1-O-(4-chlorobenzyl)-2,4,6-tri-O-
benzyl-myo-inositol (31): To an ice-cooled solution of 30 (6.00 g,
12.24 mmol) in dry DMF (30 mL), was added sodium hydride
(0.54 g, 13.47 mmol) followed by a solution of 4-chlorobenzyl bro-
mide (2.64 g, 12.86 mmol) in DMF (20 mL), and the reaction mix-
ture was stirred at room temp. for 12 h. Excess of sodium hydride
was destroyed by the addition of ice, solvents were removed under
reduced pressure, and the residue was worked up with ethyl acetate
as usual. The product was separated by flash column chromatog-
raphy (ethyl acetate/light petroleum, 1:4) on silica gel to obtain 31
Eur. J. Org. Chem. 2010, 2945–2953
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2951

R. C. Jagdhane, M. S. Shashidhar
74.12 (CH2), 74.06 (CH2), 72.4 (CH2), 69.7 (CH2) ppm. Preparation of Racemic 1,3,5-Tri-O-benzyl-4-O-(4-chlorobenzyl)-6-
FULL PAPER
C37H37ClO5 (597.14): calcd. C 74.42, H 6.25; found C 74.46, H
5.86.
O-(4-methoxybenzyl)-allo-inositol (45): Dichloromethane (1.5 mL)
and oxalyl chloride (0.18 mL, 2.07 mmol) were taken in a two-
necked round-bottomed flask (50 mL) and cooled to –78 °C. A
solution of dimethyl sulfoxide (0.18 mL, 2.84 mmol) in dichloro-
methane (1.5 mL) was added, and the reaction mixture was stirred
at –78 °C for 20 min. To the resulting mixture, a solution of the
chiro-alcohol 44 (0.60 g, 0.86 mmol) in dichloromethane (5.0 mL)
was added dropwise, and the mixture was stirred at –78 °C for 2 h.
Triethylamine (0.66 mL, 4.73 mmol) was added at –78 °C, and the
mixture was stirred at ambient temperature for 2 h. The reaction
mixture was diluted with dichloromethane and worked up as usual
to obtain the crude ketone (0.70 g). To an ice-cooled solution of the
crude ketone (0.70 g) in a THF/methanol (8:2 mL) mixture, sodium
borohydride (0.16 mL, 4.3 mmol) was added, and the mixture was
stirred at ambient temperature for 30 min. Saturated ammonium
chloride solution was added to the reaction mixture, solvents were
removed under reduced pressure, and the residue was worked up
as usual with dichloromethane. The product was purified by flash
column chromatography (ethyl acetate/light petroleum, 1:4) to af-
ford racemic allo-alcohol 45 as a gum (0.58 g, 96%). Rf = 0.37
(ethyl acetate/light petroleum, 1:4). 1H NMR (200 MHz, CDCl3,
25 °C): δ = 7.45–7.27 (m, 15 H, Ar-H), 7.24–7.02 (m, 6 H, Ar-H),
6.85–6.77 (m, 2 H, Ar-H), 4.81–4.30 (m, 11 H), 4.05–3.63 (m, 5 H),
3.80 (s, 3 H, Ar-OCH3), 3.56 (br. s, OH, 1 H, D2O exchangeable)
ppm. 13C NMR (50.3 MHz, CDCl3, 25 °C): δ = 159.3 (Cipso), 138.5
(Cipso), 138.1 (Cipso), 137.4 (Cipso), 133.0 (Cipso), 129.4 (Carom), 129.0
(Carom), 128.30 (Carom), 129.27 (Carom), 128.2 (Carom), 127.7
(Carom), 127.5 (Carom), 127.4 (Carom), 113.7 (Carom), 78.4 (InsC),
77.8 (InsC), 76.0 (InsC), 75.3 (InsC), 73.6 (CH2), 73.2 (CH2), 72.7
Preparation of Racemic 4-O-Allyl-1,3,5-tri-O-benzyl-2-O-(4-chloro-
benzyl)-6-O-(4-methoxybenzyl)-chiro-inositol (33): A mixture of
chiro-acetate 32 (1.75 g, 2.66 mmol), isobutylamine (2 mL) and
methanol (12 mL) was refluxed for 4 h. The solvent was removed
under reduced pressure, and the residue was worked up with ethyl
acetate as usual, to afford the corresponding crude alcohol (1.65 g).
To an ice-cooled solution of the alcohol (1.65 g) and tetrabutylam-
monium iodide (0.02 g) in DMF (15 mL), sodium hydride (0.32 g,
7.98 mmol) was added followed by PMBCl (0.90 g, 6.65 mmol).
The mixture was stirred at ambient temperature for 4 h, then the
reaction mixture was decomposed by the addition of ice, the solvent
was removed under reduced pressure, and the residue was worked
up with dichloromethane as usual. The product was purified by
column chromatography (ethyl acetate/light petroleum, 2:23) on sil-
ica gel to obtain the racemic chiro-PMB ether 33 (1.85 g, 95%
yield) as a gum. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 7.40–7.17
(m, 17 H, Ar-H), 7.16–7.10 (m, 2 H, Ar-H), 7.05–7.00 (m, 2 H, Ar-
H), 6.82–6.77 (m, 2 H, Ar-H), 6.06–5.96 (m, 1 H), 5.32–5.25 (m, 1
H), 5.18–5.13 (m, 1 H), 4.84 (q, J = 10.7 Hz, 2 H), 4.69 (d, J =
11.9 Hz, 1 H), 4.60–4.31 (m, 8 H), 4.25 (d, J = 11.9 Hz, 1 H), 3.85–
3.77 (m, 1 H), 3.79 (s, 3 H, Ar-OCH3), 3.75–3.68 (m, 3 H), 3.61–
3.58 (m, 1 H), 3.51 (t, J = 3.36 Hz, 1 H) ppm. 13C NMR
(125.6 MHz, CDCl3, 25 °C): δ = 159.1 (Cipso), 139.0 (Cipso), 138.8
(Cipso), 138.2 (Cipso), 137.3 (Cipso), 135.6, 133.2 (Cipso), 130.5 (Cipso),
128.3, 129.1, 128.4, 128.3, 128.0, 127.9, 127.7, 127.6, 127.5, 116.4
(CH=CH2), 113.7, 82.0 (Ins C), 81.9 (Ins C), 79.6 (Ins C), 79.5 (Ins
C), 75.9 (CH2), 74.9 (Ins C), 74.6 (CH2), 74.5 (Ins C), 73.3 (CH2),
72.9 (CH2), 72.8 (CH2), 72.3 (CH2), 55.2 (OCH3) ppm. C45H47ClO7
(735.30): calcd. C 73.50, H 6.44; found C 73.64, H 6.58.
(CH ), 72.2 (CH ), 55.2 (OCH ) ppm. IR (Neat): ν = 3505 (OH)
˜
2
2
3
cm–1. C42H43ClO7 (695.24): calcd. C 72.56, H 6.23; found C 72.87,
H 6.42.
Preparation of Racemic 1,3,5-Tri-O-benzyl-2-O-(4-chlorobenzyl)-6-
O-(4-methoxybenzyl)-chiro-inositol (44): To an ice-cooled solution
of the chiro-allyl ether 33 (1.85 g, 2.51 mmol) in toluene (20 mL),
(dppp)NiCl2 (0.07 g, 0.12 mmol) and DIBAL-H (7.55 mL,
7.55 mmol, 1  in toluene) were added, and the mixture was stirred
at room temp. for 3 h. The reaction mixture was diluted with
dichloromethane (80 mL), cooled to 0 °C and methanol (4 mL) and
10% HCl (5 mL) were added. The mixture was stirred at room
temp. for 3 h, and the precipitate formed was filtered by passing
through a bed of Celite and washed with dichloromethane. The
filtrate was concentrated under reduced pressure, and the residue
was taken up in dichloromethane, washed successively with aq. so-
dium hydrogen carbonate, water, brine and dried with anhydrous
sodium sulfate. The solvent was removed under reduced pressure,
and the product was purified by column chromatography (ethyl
acetate/light petroleum, 1:4) to afford the racemic chiro-alcohol 44
(1.50 g, 86%) as a gum. Rf = 0.38 (ethyl acetate/light petroleum,
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data for com-
pounds 18–20, 22, 23, 26–28, 41–43, 46–48, and 50–54.
Acknowledgments
R. J. thanks the Council of Scientific and Industrial Research, New
Delhi, for a Senior Research Fellowship. Financial assistance for
this work was provided by the Department of Science and Technol-
ogy, New Delhi.
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1:4). H NMR (200 MHz, CDCl3, 25 °C): δ = 7.40–7.27 (m, 13 H,
Ar-H), 7.25–7.12 (m, 6 H, Ar-H), 7.08–6.99 (m, 2 H, Ar-H), 6.85–
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(m, 2 H), 3.80 (s, 3 H, Ar-OCH3), 3.71–3.57 (m, 3 H), 2.53 (br. s,
1 H, D2O exchangeable, OH) ppm. 13C NMR (50.3 MHz, CDCl3,
25 °C): δ = 159.1 (Cipso), 138.9 (Cipso), 138.3 (Cipso), 138.1 (Cipso),
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(CHCl ): ν = 3609–3322 (OH) cm–1. C H ClO (695.24): calcd.
˜
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C 72.56, H 6.23; found C 72.83, H 6.08.
2952
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2945–2953

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Published Online: April 8, 2010
Eur. J. Org. Chem. 2010, 2945–2953
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