Thermal epimerization of inositol 1,3-benzylidene acetals in the molten state

Article abstract of DOI:10.1016/j.tet.2011.07.044

1,3-O-Benzylidene-2,4,5,6-tetra-O-substituted-myo-inositol derivatives obtained by the DIBAL-H reduction of the corresponding myo-inositol 1,3,5-orthobenzoate derivatives undergo epimerization at the acetal carbon on heating, in the molten state, just abo

Full text of DOI:10.1016/j.tet.2011.07.044

Tetrahedron 67 (2011) 7280e7288
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Thermal epimerization of inositol 1,3-benzylidene acetals in the molten state
,
Bharat P. Gurale a, Shobhana Krishnaswamy b, Kumar Vanka c, Mysore S. Shashidhar a
*
a The Division of Organic Chemistry, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
b Centre for Materials Characterization, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
c The Division of Physical Chemistry, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 May 2011
Received in revised form 11 July 2011
Accepted 18 July 2011
Available online 22 July 2011
1,3-O-Benzylidene-2,4,5,6-tetra-O-substituted-myo-inositol derivatives obtained by the DIBAL-H re-
duction of the corresponding myo-inositol 1,3,5-orthobenzoate derivatives undergo epimerization at the
acetal carbon on heating, in the molten state, just above their melting point. The same epimerization
reaction does not proceed either in the crystalline state or in solution. DFT calculations suggest that the
epimeric acetal obtained by this thermal process is relatively more stable than the starting acetal. Either
of these acetals could not be obtained by the reaction of the corresponding inositol derived diol with
benzaldehyde. These observations constitute a novel reaction solely in the molten state, which are rarely
encountered in the literature. X-ray crystal structures of the epimeric acetals as well as their radical
deoxygenation reaction are also reported.
Keywords:
Cyclitols
Deoxygenation
Epimerization
Melt
Ó 2011 Elsevier Ltd. All rights reserved.
Xanthate
1. Introduction
compounds, which suggest that epimerization of these 1,3-acetals in
the molten state provides the thermodynamically more stable
Chemical reactions, which proceed with high selectivity for
product formation have attracted the attention of chemists for over
a hundred years due to their significance in research and industry.
Organic chemists invest time and effort in tailoring reactions to
maximize the yield of the product of their interest; ideally, they
would like every reaction that they carry out to yield a single
product. Although a large majority of reactions reported in the
contemporary literature pertains to reactions conducted in the
presence of solvents, there is considerable interest in reactions,
which proceed in the absence of solvents. This category includes
reactions in (i) crystals,1 (ii) non crystalline solids,2 (iii) solventless
reactions,3 and (iv) reactions in the molten state.4
Although investigation of reactions in the absence of solvents was
initially driven by curiosity, such reactions are gaining ground due to
environment related issues as well as because often they proceed
with high product (regio-, stereo-, enantio-) selectivity that cannot
be achieved in analogous solution state reactions. We had earlier
reported5 very facile benzoyl group transfer reactions in crystalline
inositol derivatives. Among solventless reactions, the least encoun-
tered are the reactions that proceed truly or solely in the molten
state.4e We herein report epimerization of inositol 1,3-acetals, which
proceed with high selectivity in the molten state. We also present
results on DFT calculations and X-ray crystal structures of relevant
product. Study of epimerization of organic compounds in condensed
phases6 is also of relevance and importance due to their potential to
generate optically active compounds without the aid of other chiral
compounds or auxiliaries. Much interest was generated in the
chemistry of inositols due to the realization of their role in various
biological phenomena and subsequent implication of the myo-ino-
sitol cycle in various diseases, such as cancer and diabetes.7
2. Results and discussion
myo-Inositol 1,3-benzylidene acetals can be prepared by the
reduction of the corresponding orthobenzoate, with DIBAL-H.8 The
extent of regioselectivity of this reduction is known to depend on
other substituents present in the myo-inositol orthoester mole-
cule.9 The orthobenzoates 3 and 4 were prepared8b,10 from myo-
inositol and reduced with DIBAL-H to obtain a single diastereomer
of the corresponding 1,3-acetal 5 and 6 (Scheme 1). The 1,3-acetals
5 and 6 were converted to the xanthates 7, 8, and 9 by adopting
routine procedures.
The xanthates of these pentaprotected myo-inositol derivatives
underwent novel radical deoxygenation reaction to provide the
corresponding dideoxy myo-inositol derivatives.11 The chemistry
of these inositol derivatives were being investigated in our labo-
ratory in order to prepare orthogonally protected inositol de-
rivatives, which can be diversified to obtain a variety of cyclitol
derivatives.9b,11
* Corresponding author. Tel.: þ91 20 25902055; fax: þ91 20 25902629; e-mail
address: ms.shashidhar@ncl.res.in (M.S. Shashidhar).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.044

B.P. Gurale et al. / Tetrahedron 67 (2011) 7280e7288
7281
Scheme 1. Synthesis of xanthates: (a) DMF, LiH, BnBr, rt, 12 h, 81% (for 2); (b) DMF, NaH,
BnBr, rt, 3 h, 98% (for 3); (c) DMF, NaH, PMBCl, rt, 96%; (d) DCM, DIBAL-H (2.2 equiv),
0
ꢀC, 80e94%; (e) THF, NaH, CS2, reflux, 1 h, MeI, rt, 16 h, 96e98%.
During the course of these investigations we observed that the
PMB ether 8 was stable in the solid state (see below) but produced
minor amounts of another organic compound while isolation from
its solution (by evaporation of the solvent) or storage (as a gum) at
ambient temperature. Isolation of this product and the scrutiny of
its spectral characteristics showed it to be an isomer of the starting
PMB ether 8. We were intrigued to see that refluxing a toluene
solution or heating a DMF solution (obtained by dissolving crystals
of 8) at 130 ꢀC however did not produce the isomer of 8 that we had
observed earlier. Hence we wondered whether the isomerization
could be occurring in the solid state. But, heating crystals of 8 just
below their melting point did not result in isomerization of 8.
Continued heating of the xanthate 8 beyond its melting point12
resulted in its isomerization to 11 (Scheme 2, about 50% conver-
sion) with concomitant formation of the corresponding diol (14, see
Experimental section).
Fig. 1. ORTEP of xanthate 8 (a) and its epimer 11 (b). Thermal ellipsoids are drawn at
30% probability and hydrogen atoms are depicted as small spheres of arbitrary radii.
as the acetal ring, while in the acetal 9 with neo-configuration, the
conformation of the two rings are retained (Figs. 2 and 3).
Additional support for the nonoccurrence of epimerization of
the acetals 7, 8, and 9 in solution was obtained by subjecting their
epimers (10, 11, and 12) to radical deoxygenation conditions and
comparing the results that we had obtained earlier11 for the de-
oxygenation of 7, 8, and 9. The xanthates 10, 11, and 12 when
subjected to radical deoxygenation conditions as reported earlier,11
yielded the corresponding mono-deoxygenated derivatives exclu-
sively (18, 19 Scheme 3), since intramolecular (acetal) hydrogen
abstraction is sterically forbidden in these molecules.
The structure of the mono-deoxy derivative 19 was established
by single crystal X-ray diffraction analysis (Fig. 4). The xanthates 7,
8, and 9 on the other hand had provided the dideoxy derivatives on
subjecting to radical deoxygenation conditions, via intramolecular
(acetal) hydrogen abstraction.11 The contrasting results of these
deoxygenation reactions with the two epimers supports our ob-
servation that the epimerization of the xanthates 7, 8, and 9 does
not occur in the solution phase. If it did, we would have observed
Scheme 2. Epimerization in the molten state: (a) 120 ꢀC, 12 h for 7 and 9, 30 h for 8.
We could improve the yield of the isomeric product to about 70%
by heating molten 8 in an inert (argon) atmosphere. This isomer of
8 could be crystallized from a mixture of ethyl acetate and hexane;
single crystal X-ray diffraction studies of these crystals established
the structure of the isomer of 8 as 11 (Fig. 1 and Scheme 2; carbon
atom undergoing a change in configuration is marked in 8 and 11).
We carried out the epimerization (in the molten state) of two other
1,3-acetals 7 and 9 having the myo- and the neo-configurations,
which gave the epimerized products 10 and 12, respectively.12 All
these epimerization reactions were not feasible in the crystalline
state as well as in solution (DMF, 130 ꢀC). It is interesting to note
that epimerization of the acetals 7 and 8 having the myo-configu-
ration leads to a change in the conformation of the inositol as well

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B.P. Gurale et al. / Tetrahedron 67 (2011) 7280e7288
Fig. 2. ORTEP of hexane solvate of neo-xanthate 12 (epimer of 9). Thermal ellipsoids
are drawn at 30% probability and hydrogen atoms are depicted as small spheres of
arbitrary radii.
Fig. 4. ORTEP of 19. Thermal ellipsoids are drawn at 30% probability and hydrogen
atoms are depicted as small spheres of arbitrary radii.
acetals 7, 8, and 9 was occurring in two steps: (a) formation of the
corresponding diol followed by (b) its reaction in situ with benz-
aldehyde produced. However, heating of the diols 13e15 with
benzaldehyde under the conditions of epimerization did not result
in the formation of the corresponding 1,3 acetal. This ruled out the
epimerization of the acetal via the corresponding diol and sug-
gested that the diols 13e15 were formed only as a bi-product
during epimerization of the acetals 7, 8, and 9, but did not func-
tion as intermediates. These experiments also led to an interesting
observation. Although the two epimeric acetals (7, 10 or 8, 11 or 9,
12) cannot be prepared from the parent diol (13 or 14 or 15), they
can be accessed via the orthobenzoates and the relatively more
stable acetal (10 or 11 or 12) can only be obtained by isomerization
of its less stable epimer (see below), since reduction of the ortho-
benzoate (3 or 4) is stereoselective to yield 7 and 8 exclusively!
We also estimated the relative stability of the epimeric acetals (7
vs 10; 8 vs 11; 9 vs 12) by DFT calculations. Geometry optimization
for all the acetals was carried out with the input structures taken
from the conformation of the two rings (inositol and the acetal) as
observed in their crystals. The 1H NMR spectra of these xanthates
suggested that the conformations observed in their crystals are
retained in their solution. Estimation of the relative energies (Fig. 5)
suggested that the acetals 10, 11, and 12 are relatively more stable
compared to their epimers 7, 8, and 9, respectively. The relative
difference in stability (3.9 kcal/mol) is slightly higher for the pair of
acetals (9, 12) with the neo-configuration as compared to those
having the myo-configuration (7, 10, and 8, 11, <1.4 kcal/mol). The
differences in the stability of these 1,3-acetals could explain the
facility of epimerization under thermal conditions.
Fig. 3. (a) Molecular overlap of the xanthate 8 (black) with its epimer, the xanthate 11
(grey); (b) Molecular overlap of the xanthate 9 (black) with one of the two molecules in
the asymmetric unit of its epimer, the xanthate 12 (grey). Some functional groups are
omitted for the sake of clarity. For complete overlap of the two molecules see ESD.
Ph
H
O
H
R1O
BzO
O
O
Ph
BnO
S
a
O
R1O
a
OBn
OBn
OBn
O
SMe
O
SMe
OBn
BnO
OBn
7 R1 = Bn,
16 R1 = Bn,
9
S
8 R1 = PMB
17 R1 = PMB
S
Ph
Ph
Ph
O
O
O
SMe
a
H
O
H
H
BnO
O
S
O
a
R1O
O
R1O
SMe
O
OBn
BnO
BnO
BnO
OBn
OBn
10 R1 = Bn,
18 R1 = Bn,
12
11 R1 = PMB
19 R1 = PMB
Scheme 3. Deoxygenation of xanthates: (a) toluene, n-Bu3SnH, AIBN, reflux, 1 h,
80e92%.
formation of a mixture of the mono and the dideoxy derivatives
during the deoxygenation of the epimeric xanthates.
Since we noticed the formation of 1,3-diols (13e15, see
Experimental section) during the epimerization of the acetals 7, 8,
and 9 we wondered whether they were intermediates during the
process of epimerization. That is, whether epimerization of the
Although the mechanism of epimerization of acetals 7, 8, and 9
is not clear, we can postulate that the reaction proceeds by cleavage
of one of the acetal CeO bonds, rotation of the other CeO bond and
re-formation of the broken CeO bond (Scheme 4). It is not unlikely

B.P. Gurale et al. / Tetrahedron 67 (2011) 7280e7288
7283
Fig. 5. Geometry optimized structures of xanthates 7, 8, 9, and their epimers 10, 11, and 12.
the inositol ring could be a result of closely packed molecules in the
melt just above the melting point of the crystals. This is supported
by the fact that epimerization of the acetals at higher temperatures
resulted in increased yield of the corresponding diol, perhaps due
to loosening of the molecules in the melt, resulting in faster ring
flipping. These possibilities are schematically represented for the
epimerization of the acetal 9 (for illustration) in Scheme 4.
The process of epimerization of the acetals (7 and 8) having the
myo-configuration involve a change in the conformation of the
acetal ring as well as the inositol ring. The data available to us is not
sufficient to figure out whether these conformational changes
precede or succeed epimerization of the acetal carbon. Perusal of
the crystal structures of the acetals 7e9 as well as their epimers 11
and 12 shows that the close packing of molecules in the crystal
lattice does not allow major conformational changes required for
the epimerization reaction under discussion (Fig. 6).
Scheme 4. Plausible mechanism for the epimerization of 1,3-acetals in the molten
state.
A measurement of the unit cell parameters of the reactant
crystal at (a) ambient temperature, (b) when heated up to 90 ꢀC and
then (c) cooled down to ambient temperature did not show sig-
nificant variation, indicating that the reaction does not occur in the
crystal. This is in line with our experimental observations that the
epimerization of 7e9 sets in, subsequent to melting of the crystals.
That the nonoccurrence of epimerization in the crystalline state is
that the diol is formed as a result of flipping of the inositol ring
(20/21), since in this ‘equatorial rich’ conformation (21), re-
establishment of the broken CeO bond is not feasible. Since the
major product obtained is the epimer of the starting acetal, it is
plausible that re-formation of the broken acetal CeO bond is faster
than flipping of the inositol ring. The relatively sluggish flipping of

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B.P. Gurale et al. / Tetrahedron 67 (2011) 7280e7288
This process of epimerization is perhaps augmented by the
relative stabilities of the two epimers. In the solution state, which
allows complete freedom of movement for the molecules, the ac-
etal molecules may not achieve the required aggregation and ri-
gidity necessary for fruitful epimerization. Encountering such
unusual facile reactions in the molten state makes one wonder
whether organic chemists should consider carrying out reactions in
melt routinely, just as they carry out reactions in different solvents,
to maximize the yield and selectivity. This is especially significant
since reactions in melt are easy to carry out, do not need any spe-
cialized equipment, and are far less hazardous (in terms of gener-
ating waste) to our environment as compared to solution state
reactions. The results presented here reiterates the importance of
the phase (in which the reaction is carried out) on the facility and
selectivity of a reaction, whether or not the phase of a substance
can be defined and characterized by conventional methods and
stresses the need for investigations aimed at deeper understanding
of the phases other than solids, liquids, and vapor.
4. Experimental section
4.1. Computational details
All the density functional theory calculations were carried out
using the Turbomole suite of programs.13 The strategy adopted for
the geometry optimizations is as follows: for a given geometry,
a conformational search was first done using Molecular Mechanics
(MMþforce field) methods as implemented in the Hyperchem14
software. The best five geometries obtained from the conforma-
tional analysis were then used as input structures for the DFT cal-
culations. The conformation obtained with the lowest energy (i.e.,
the most stable conformation) has then been considered for the
relative (DE) analysis as reported in the paper. The DFT Geometry
optimizations were performed using the B-P 86 functional.15 The
electronic configuration of the atoms was described by a triple-zeta
basis set augmented by a polarization function (TURBOMOLE basis
set TZVP).16 The resolution of identity (RI),17 along with the mul-
tipole accelerated resolution of identity (marij)18 approximations
was employed for an accurate and efficient treatment of the elec-
tronic Coulomb term in the density functional calculations.
4.2. General methods
All the solvents were purified according to the literature pro-
cedures19 before use. 60% dispersion of sodium hydride in mineral
oil was used for O-alkylation reactions. 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. Work up implies washing of the organic
layer successively with water, dilute HCl (w2%), water, saturated
sodium bicarbonate solution, water followed by brine. Column
chromatographic separations were carried out on silica gel
(60e120 mesh or 230e400 mesh) with solvent system as men-
tioned in individual procedures. The compounds previously repor-
ted in the literature were characterized by comparison of their
melting points and/or 1H NMR spectra with reported data. All the
asymmetrically substituted racemic myo-inositol derivatives
(numbered with the prefix rac-) are represented in schemes by one
of the enantiomers without numbering of the inositol carbon atoms.
Fig. 6. Molecular packing in crystals of (a) 7, (b) 8, and (c) 9. The carbon atom un-
dergoing epimerization is shown as black filled circle.
not due to differences in temperature between the molten state and
the crystalline state alone, is suggested by the fact that the epi-
merization in solution at temperatures higher than the melting
point of 7e9 also did not occur.
3. Conclusions
We have presented a novel thermal epimerization of inositol
derived 1,3-acetals, which occur only in the molten state wherein
the molecules are free enough to go through the bond scission and
conformational changes, which result in the formation of the rel-
atively stable epimer. Interestingly, results presented here suggest
that in the molten state (just above the melting point of crystals),
molecules are not very free to undergo flipping of the inositol ring,
which would sterically forbid the formation of the cyclic 1,3-acetal.
Hence it is likely that in the molten state aggregated molecules
achieve the fine balance between the rigidity of the matrix, and
the molecular motion needed for their reaction to realize their
epimerization.
4.2.1. 2-O-(4-Methoxy benzyl)-4,6-di-O-benzyl-myo-inositol-1,3,5-
orthobenzoate (4). To a solution of 2 (8.93 g, 20.00 mmol) in dry
DMF (100 mL) sodium hydride (0.96 g, 24.00 mmol) was added
and stirred for 10 min. p-Methoxybenzyl chloride (3.00 mL,
22.00 mmol) was then added drop-wise and the reaction mixture
stirred for 4 h. Excess of sodium hydride was quenched by the

B.P. Gurale et al. / Tetrahedron 67 (2011) 7280e7288
7285
addition of cold water. The reaction mixture was concentrated
under reduced pressure to get a gum, which was worked up with
ethyl acetate; the organic extract was dried over anhyd sodium
sulfate. The solvent was removed under reduced pressure to afford
a gummy residue, which was purified by column chromatography
(eluent: 20% ethyl acetate/light petroleum) to obtain 4 as a colorless
solid (10.92 g, 96%). TLC Rf¼0.5 (20% ethyl acetate/light petroleum);
mp 89.4e92.0 ꢀC (crystals from a hot mixture of 30% ethyl acetate/
Ins H, J¼7.5 Hz), 3.76 (s, 3H, OCH3), 3.72e3.74 (m, 1H, Ins H), 2.51 (s,
3H, SCH3) ppm; 13C NMR (CD2Cl2, 50.3 MHz):
216.0 (C]S), 159.7
d
(Carom), 138.7 (Carom), 137.6 (Carom), 130.4 (Carom), 129.7 (Carom),
128.7 (Carom), 128.3 (Carom), 128.2 (Carom), 126.7 (Carom), 114.1
(Carom), 92.9 (PhCO2), 82.4 (Ins C), 79.7 (Ins C), 73.8 (Ins C), 71.8
(CH2), 70.9 (CH2), 68.4 (Ins C), 55.5 (OCH3), 19.5 (SCH3) ppm; ele-
mental analysis calcd (%) for C37H38O7S2 (658.82): C 67.45, H 5.81, S
9.73; found C 67.51, H 5.98, S 9.67%.
light petroleum); 1H NMR (CDCl3, 200 MHz):
d 7.60e7.68 (m, 2H, Ar
H), 7.17e7.38 (m, 15H, Ar H), 6.79e6.86 (m, 2H, Ar H), 4.40e4.70 (m,
11H, 3ꢁ CH2, and 5 Ins H), 4.10 (t, 1H, J¼1.5 Hz), 3.76 (s, 3H, CH3)
4.2.4. S-Methyl O-((1R,3r,5S,6R,7R,8S,9R)-6,8,9-tris(benzyloxy)-3-
phenyl-2,4-dioxabicyclo[3.3.1]nonan-7-yl) carbonodithioate (10, epi-
mer of 7). The solid xanthate 7 (0.20 g, 0.32 mmol) was heated at
120 ꢀC (mp of 7 is 112e114 ꢀC lit.11) under argon for 12 h and the
products were separated by column chromatography (eluent: 5e7%
ethyl acetate in light petroleum) to afford 10 (0.14 g, 70%; Rf¼0.4 in
10% ethyl acetate/light petroleum) and 1311 as gums (0.04 g, 25%;
Rf¼0.3 in 40% ethyl acetate/light petroleum). Data for 10: 1H NMR
ppm; 13C NMR (CDCl3, 50.3 MHz):
d 159.2 (Carom), 137.6 (Carom),
137.2 (Carom), 130.0 (Carom), 129.7 (Carom), 129.3 (Carom), 128.3
(Carom), 127.9 (Carom), 127.7 (Carom), 127.5 (Carom), 125.4 (Carom), 113.7
(Carom), 107.8 (PhCO3), 74.0 (Ins C), 71.9 (Ins C), 71.5 (CH2), 70.7
(CH2), 69.0 (Ins C), 65.5 (Ins C), 55.1 (CH3) ppm; elemental analysis
calcd (%) for C35H34O7 (566.64): C 74.19, H 6.05; found: C 74.11, H
6.43%.
(CD2Cl2, 200 MHz)
d 7.45e7.58 (m, 2H, Ar H), 7.10e7.40 (m, 18H, Ar
H), 6.45 (s, 1H, PhCHO2), 6.06 (br s, 1H, Ins H), 4.69 (s, 2H, CH2), 4.69
(q, 4H, 2ꢁ CH2, J¼12.1 Hz), 4.50e4.64 (m, 2H, Ins H), 4.39 (t, 1H, Ins
H, J¼1.4 Hz), 4.05 (dd, 2H, Ins H, J1¼1.3 Hz and J2¼3.5 Hz), 2.41 (s,
4.2.2. 1,3-O-Benzylidene-2-O-(4-methoxy
benzyl)-4,6-di-O-benzyl
myo-inositol (6). DIBAL-H (1 M solution) in toluene (15.40 mL,
15.40 mmol) was added drop-wise over a period of 15 min to
a solution of 4 (3.96 g, 7.00 mmol) in dry dichloromethane (60 mL)
at 0 ꢀC and stirred at room temperature for 2.5 h. The reaction
mixture was poured into a stirred solution of sodium potassium
tartrate (42 g in 70 mL water) and saturated ammonium chloride
(70 mL) and stirred for 12 h. The mixture was extracted with
dichloromethane (2ꢁ100 mL), washed with brine and dried over
anhyd sodium sulfate. The solvent was removed under reduced
pressure to obtain a gummy residue, which was purified by column
chromatography (eluent: 25% ethyl acetate/light petroleum) to af-
ford 6 as a colorless solid (3.78 g, 95%). Rf¼0.4 (25% ethyl acetate/
light petroleum); mp 122.8e124.6 ꢀC (crystals from CH2Cl2); IR
(neat): nmax/cmꢂ1 3330e3510. 1H NMR (CD2Cl2, 200 MHz):
3H, CH3) ppm; 13C NMR (CD2Cl2, 125.76 MHz):
d 216.2 (C]S), 139.2
(Carom), 138.3 (Carom), 138.2 (Carom), 129.1 (Carom), 128.8 (Carom),
128.7 (Carom), 128.31 (Carom), 128.29 (Carom), 128.2 (Carom), 128.1
(Carom), 128.0 (Carom), 127.4 (Carom), 92.7 (PhCO2), 80.0 (Ins C), 78.6
(Ins C), 72.8 (CH2), 72.4 (Ins C), 71.0 (CH2), 70.5 (Ins C), 19.7 (CH3)
ppm; elemental analysis calcd (%) for C36H36O6S2 (628.80): C 68.76,
H 5.77; found C 68.51, H 6.03%.
4.2.5. Attempted epimerization of xanthate 7 in the presence of
solvents. In toluene:
A solution of the xanthate 7 (0.10 g,
0.16 mmol) in dry toluene (2 mL) was refluxed for 24 h in an at-
mosphere of argon. The solvent was removed under reduced
pressure to obtain 7 (0.10 g, 100%) as a solid. The same result was
obtained on repeating the reaction (for 12 h) in the presence of
water (0.1 mL).
In DMF: a solution of the xanthate 7 (0.10 g, 0.16 mmol) in dry
DMF (2 mL) was heated at 130 ꢀC for 24 h in an atmosphere of ar-
gon. The solvent was removed under reduced pressure and the
residue column chromatographed to obtain 7 (0.095 g, 95%) as
a solid. The same result was obtained on repeating the reaction (for
12 h) in the presence of water (0.1 mL).
d
7.42e7.51 (m, 2H, Ar H), 7.24e7.45 (m, 15H, Ar H), 6.83e6.91 (m,
2H, Ar H), 5.68 (s, 1H, PhCHO2), 4.66 (q, 4H, 2ꢁ CH2, J¼11.6 Hz), 4.59
(s, 2H, CH2), 4.33 (d, 2H, Ins H, J¼2.4 Hz), 3.94 (d, 2H, Ins H,
J¼8.2 Hz), 3.72e3.80 (m, 1H, Ins H), 3.75 (s, 3H, CH3), 3.57 (t, 1H,
J¼2.4 Hz, Ins H), 2.54 (d, 1H, J¼2.9 Hz, OH) ppm; 13C NMR (CDCl3,
50.3 MHz): d 159.7 (Carom), 138.8 (Carom),138.1 (Carom), 130.4 (Carom),
129.7 (Carom), 128.8 (Carom), 128.4 (Carom), 126.8 (Carom), 114.1
(Carom), 92.8 (PhCHO2), 82.1 (Ins C), 73.9 (Ins C), 72.0 (CH2), 70.8
(CH2), 68.5 (Ins C), 55.5 (CH3) ppm; elemental analysis calcd (%) for
C35H36O7 (568.66): C 73.92, H 6.38; found: C 73.94, H 6.12%.
4.2.6. O-((1R,3r,5S,6R,7R,8S,9R)-6,8-bis(benzyloxy)-9-((4-
methoxybenzyl)oxy)-3-phenyl-2,4-dioxabicyclo[3.3.1]nonan-7-yl) S-
methyl carbonodithioate (11, epimer of 8). The solid xanthate 8
(0.20 g, 0.30 mmol) was heated at 120 ꢀC (mp of 8 is 93e93.8 ꢀC)
under argon for 30 h and the products separated by column
chromatography (eluent: 10% ethyl acetate in light petroleum) to
afford 11 as gum (0.14 g, 72%; Rf¼0.6 in 20% ethyl acetate/light
petroleum) and 14 as a solid (0.04 g, 24%; Rf¼0.3 in 40% ethyl
acetate/light petroleum). The gummy xanthate 11 was stored un-
der n-pentane at ꢂ20 ꢀC for 12 h when it turned into a colorless
solid. Mp 77e79.2 ꢀC (crystals from a hot mixture of 10% ethyl
acetate in light petroleum); 1H NMR (CD2Cl2, 200 MHz)
4.2.3. O-((1R,3s,5S,6R,7R,8S,9R)-6,8-bis(benzyloxy)-9-((4-
methoxybenzyl)oxy)-3-phenyl-2,4-dioxabicyclo[3.3.1]nonan-7-yl)
S-methyl carbonodithioate (8). To a cooled (0 ꢀC) solution of the
alcohol 6 (1.14 g, 2.00 mmol) in dry THF (10 mL), sodium hydride
(0.40 g,10.00 mmol) was added and stirred at ambient temperature
for 30 min. Carbon disulfide (1.80 mL, 30.00 mmol) was added to
the reaction mixture and refluxed for 1 h. The reaction mixture was
allowed to cool to room temperature; methyl iodide (0.60 mL,
10.00 mmol) was added and stirred for 16 h. The reaction mixture
was diluted with ethanol (4 mL), water (8 mL), and extracted with
ethyl acetate. The organic layer was washed with saturated am-
monium chloride solution followed by brine and dried over anhyd
sodium sulfate. The gummy residue obtained after evaporation of
the solvent was purified by column chromatography (eluent: 15%
ethyl acetate/light petroleum) to obtain 8 as a colorless solid
(1.29 g, 98%). Rf¼0.4 (15% ethyl acetate/light petroleum); mp
93e93.8 ꢀC (crystals from a hot mixture of 10% ethyl acetate in light
petroleum); IR (CHCl3): nmax/cmꢂ1 1455, 1377. 1H NMR (CD2Cl2,
d
7.45e7.60 (m, 2H, Ar H), 7.16e7.43 (m, 15H, Ar H), 6.75e6.88 (m,
2H, Ar H), 6.44 (s, 1H, PhCHO2), 6.06 (br s, 1H, Ins H), 4.69 (q, 4H,
2ꢁ CH2, J¼11.9 Hz), 4.63 (s, 2H, CH2), 4.49e4.55 (m, 2H, Ins H),
4.38 (t, 1H, Ins H, J¼1.3 Hz), 4.01e4.09 (m, 2H, Ins H), 3.75 (s, 3H,
OCH3), 2.42 (s, 3H, SCH3) ppm; 13C NMR (CD2Cl2, 125.76 MHz):
d
216.2 (C]S), 159.8 (Carom), 139.2 (Carom), 138.3 (Carom), 130.2
(Carom), 130.0 (Carom), 129.1 (Carom), 128.7 (Carom), 128.3 (Carom),
128.1 (Carom), 128.0 (Carom), 127.4 (Carom), 114.1 (Carom), 92.7
(PhCO2), 80.0 (Ins C), 78.5 (Ins C), 72.7 (CH2), 72.4 (Ins C), 70.5
(CH2), 69.9 (Ins C), 55.5 (OCH3), 19.6 (SCH3) ppm; elemental
analysis calcd (%) for C37H38O7S2 (658.82): C 67.45, H 5.81; found C
200 MHz) d 7.20e7.48 (m, 17H, Ar H), 6.82e6.89 (m, 2H, Ar H), 6.20
(t, 1H, Ins H, J¼7.5 Hz), 5.75 (s, 1H, PhCHO2), 4.60 (s, 2H, CH2), 4.58
(q, 4H, 2ꢁ CH2, J¼11.9 Hz), 4.38 (d, 2H, Ins H, J¼2.3 Hz), 4.10 (d, 2H,

7286
B.P. Gurale et al. / Tetrahedron 67 (2011) 7280e7288
67.51, H 5.98%. Data for 14: mp 83.3e83.6 ꢀC (crystals from
CH2Cl2); IR (CHCl3): nmax/cmꢂ1 3300e3500. 1H NMR (CDCl3,
200 MHz) d 7.24e7.40 (m, 12H, Ar H), 6.87e6.95 (m, 2H, Ar H), 6.15
(CH2), 55.1 (CH3), 36.0 (Ins CH2), 34.2 (Ins CH2) ppm; elemental
analysis calcd (%) for C35H36O6 (552.660) C 76.06, H 6.57; found C
75.66, H 6.48%.
(t, 1H, Ins H, J¼9.3 Hz), 4.75 (s, 2H, CH2), 4.67 (q, 4H, 2ꢁ CH2,
J¼11.2 Hz), 4.01 (t, 1H, Ins H, J¼2.7 Hz), 3.87e3.97 (m, 2H, Ins H),
3.83 (s, 3H, OCH3), 3.65 (dd, 2H, Ins H, J1¼9.6 Hz, J2¼2.6 Hz), 2.60
(s, 3H, SCH3), 2.36 (br s, 2H, 2ꢁ OH) ppm; 13C NMR (CDCl3,
4.2.9. 1,3-O-Benzylidene-2,4,6-tri-O-benzyl-5-deoxy
myo-inositol
(18). Method A: To a solution of the xanthate 10 (0.09 g, 0.14 mmol)
in dry toluene (4 mL), tri-n-butyltin hydride (0.20 mL, 0.50 mmol),
and AIBN (0.01 g) were added and heated at 100 ꢀC for 1 h. The
solvents were removed under reduced pressure and the residue
obtained was purified by column chromatography (eluent: 7% ethyl
acetate in light petroleum) to obtain 18 as a gum (0.06 g, 82%). The
gummy compound 18 was stored under n-pentane at ꢂ20 ꢀC for
12 h to afford a colorless solid. Rf¼0.4 (10% ethyl acetate/light pe-
troleum); mp 69.5e72.2 ꢀC (crystals from a hot mixture of 5% ethyl
50.3 MHz):
d 215.7 (C]S), 159.2 (Carom), 137.7 (Carom), 130.4
(Carom), 129.6 (Carom), 128.3 (Carom), 128.1 (Carom), 127.8 (Carom),
113.7 (Carom), 83.6 (Ins C), 80.0 (Ins C), 78.3 (Ins C), 74.9 (CH2), 74.8
(CH2), 71.8 (Ins C), 55.1 (CH3), 19.3 (CH3) ppm; elemental analysis
calcd (%) for C30H34O7S2 (570.72): C 63.13, H 6.00; found C 63.09, H
6.11%.
4.2.7. S-Methyl O-((1R,3r,5S,6R,7S,8S,9R)-6,8,9-tris(benzyloxy)-3-
phenyl-2,4-dioxabicyclo[3.3.1]nonan-7-yl) carbonodithioate (12,
epimer of 9). The solid xanthate 9 (0.20 g, 0.32 mmol) was heated
at 110 ꢀC (mp of 9 is 100e102 ꢀC lit.11) under argon for 12 h and
the products separated by column chromatography (eluent: 5e7%
ethyl acetate in light petroleum) to afford 12 (0.14 g, 72%; Rf¼0.4 in
10% ethyl acetate/light petroleum) and 15 (0.04 g, 24%; Rf¼0.3 in
40% ethyl acetate/light petroleum) as gums. Solid 12 could be
obtained by storing the gummy 12 in n-pentane at ꢂ20 ꢀC for 12 h.
Data for 12: mp 68.8e69.4 ꢀC (crystals from a hot mixture of 5%
ethyl acetate in light petroleum); 1H NMR (CD2Cl2, 200 MHz)
acetate in light petroleum); 1H NMR (CD2Cl2, 500 MHz)
d 7.20e7.50
(m, 20H, Ar H), 6.47 (s, 1H, PhCHO2), 4.66 (s, 2H, CH2), 4.55 (q, 4H,
2ꢁ CH2, J¼11.9 Hz), 4.52 (d, 2H, Ins H, J¼3.3 Hz), 4.46e4.48 (m, 1H,
Ins H), 3.91e3.97 (m, 2H, Ins H), 2.27e2.38 (m, 1H, Ins H), 2.05e2.11
(m, 1H, Ins H) ppm; 13C NMR (CD2Cl2, 125.76 MHz)
d 139.8 (Carom),
139.1 (Carom), 138.6 (Carom), 129.1 (Carom), 128.7 (Carom), 128.6
(Carom), 128.5 (Carom), 128.3 (Carom), 128.0 (Carom), 127.9 (Carom),
127.8 (Carom), 126.9 (Carom), 92.8 (PhCO2), 78.1 (Ins C), 72.9 (Ins C),
71.7 (CH2), 70.8 (CH2), 70.6 (Ins C), 24.2 (Ins CH2) ppm; elemental
analysis calcd (%) for C34H34O5 (522.63): C 78.14, H 6.56; found C
77.83, H 6.71%.
d
7.40e7.52 (m, 2H, Ar H), 7.22e7.40 (m, 18H, Ar H), 6.66 (t, 1H, Ins
Method B: To a solution of the xanthate 12 (0.10 g, 0.16 mmol) in
dry toluene (4 mL), tri-n-butyltin hydride (0.20 mL, 0.50 mmol),
and AIBN (0.01 g) were added and the reaction was carried out as in
method A to afford 18 as a gum (0.07 g, 84%).
H, J¼4.2 Hz), 6.42 (s, 1H, PhCHO2), 4.66 (s, 2H, CH2), 4.63 (q, 4H, 2ꢁ
CH2, J¼11.9 Hz), 4.48e4.55 (m, 3H, Ins H), 4.30 (t, 2H, Ins H,
J¼4.2 Hz), 2.56 (s, 3H, CH3) ppm; 13C NMR (CD2Cl2, 125.76 MHz)
d
216.0 (C]S), 139.1 (Carom), 138.8 (Carom), 138.3 (Carom), 129.5
(Carom), 128.8 (Carom), 128.65 (Carom), 128.61 (Carom), 128.3 (Carom),
128.2 (Carom), 128.1 (Carom), 128.0 (Carom), 127.2 (Carom), 93.3
(PhCO2), 78.2 (Ins C), 77.6 (Ins C), 74.1 (CH2), 72.9 (Ins C), 71.3
(CH2), 69.9 (Ins C), 19.5 (CH3) ppm; elemental analysis calcd (%) for
C36H36O6S2 (628.80): C 68.76, H 5.77; found C 68.78, H 6.11%. Data
for 15: IR (CHCl3): nmax/cmꢂ1 3360e3550. 1H NMR (CDCl3,
4.2.10. 1,3-O-Benzylidene-2-O-(4-methoxybenzyl)-4,6-di-O-benzyl-
5-deoxy myo-inositol (19). To a solution of the xanthate 11 (0.10 g,
0.15 mmol) in dry toluene (4 mL), tri-n-butyltin hydride (0.20 mL,
0.50 mmol), and AIBN (0.01 g) were added and heated at 100 ꢀC for
1 h. The solvents were removed under reduced pressure and the
residue obtained was purified by column chromatography (eluent:
10% ethyl acetate in light petroleum) to obtain 19 as a colorless solid
(0.07 g, 85%). Rf¼0.6 (20% ethyl acetate/light petroleum); mp
99.5e101.2 ꢀC (crystals from a hot mixture of 10% ethyl acetate in
200 MHz)
d
7.25e7.45 (m, 15H, ArH), 6.88 (t, 1H, Ins H, J¼2.65 Hz),
4.84 (s, 2H, CH2), 4.68 (q, 4H, 2ꢁ CH2, J¼11.0 Hz), 4.12e4.20 (m, 1H,
Ins H), 3.98 (dd, 2H, Ins H, J1¼2.7 Hz, J2¼10.1 Hz), 3.85 (dd, 2H, Ins
H, J1¼2.8 Hz, J2¼10.1 Hz), 2.57 (s, 3H, SCH3), 2.20e2.48 (br s, 2H,
light petroleum); 1H NMR (CDCl3, 200 MHz)
d 7.24e7.50 (m, 17H, Ar
2ꢁ OH) ppm; 13C NMR (CDCl3, 125.76 MHz):
d
216.7 (C]S), 138.6
H), 6.80e6.90 (m, 2H, Ar H), 6.52 (s, 1H, PhCHO2), 4.61 (s, 2H, CH2),
4.55 (q, 4H, 2ꢁ CH2, J¼11.9 Hz), 4.51e4.58 (m, 3H, Ins H), 3.95e4.01
(m, 2H, Ins H), 3.78 (s, 3H, OCH3), 2.30e3.42 (m, 1H, Ins H),
(Carom), 137.3 (Carom), 128.5 (Carom), 128.4 (Carom), 128.2 (Carom),
128.0 (Carom), 127.73 (Carom), 127.68 (Carom), 78.4 (Ins C), 77.4 (Ins
C), 75.5 (CH2), 74.9 (Ins C), 72.5 (CH2), 70.8 (Ins C), 19.0 (CH3) ppm;
elemental analysis calcd (%) for C29H32O6S2 (540.69): C 64.42, H
5.97; found C 64.84, H 6.30%.
2.03e2.30 (m, 1H, Ins H) ppm; 13C NMR (CDCl3, 50.3 MHz):
d 159.2
(Carom), 139.0 (Carom), 138.5 (Carom), 130.0 (Carom), 129.6 (Carom),
128.9 (Carom), 128.3 (Carom), 128.2 (Carom), 127.4 (Carom), 126.5
(Carom), 113.8 (Carom), 92.5 (PhCO2), 77.4 (Ins C), 72.7 (Ins C), 71.1
(CH2), 70.0 (CH2), 69.5 (Ins C), 55.2 (CH3), 23.8 (Ins CH2) ppm; el-
emental analysis calcd (%) for C35H36O6 (552.66): C 76.06, H 6.57;
found C 75.73, H 6.34%.
4.2.8. Racemic-1-O-benzoyl-2-O-(4-methoxybenzyl)-3,5-dideoxy-
4,6-di-O-benzyl myo-inositol (17). To a solution of the xanthate 8
(1.05 g, 1.60 mmol) in dry toluene (10 mL), tri-n-butyltin hydride
(0.70 mL, 2.50 mmol), and AIBN (0.02 g, 0.15 mmol) were added
and heated at 100 ꢀC for 1 h. The solvents were removed under
reduced pressure and the residue obtained was purified by col-
umn chromatography (eluent: 15% ethyl acetate in light petro-
leum) to obtain 17 as a gum (0.82 g, 93%). Rf¼0.4 (15% ethyl
acetate/light petroleum); IR (neat): nmax/cmꢂ1 1716. 1H NMR
4.3. X-ray crystallography
Single-crystal X-ray structures were determined for crystals of 8,
11, 12, and 19. All the crystals were stable at room temperature and
the intensity data measurements were carried out at room tem-
(CDCl3, 200 MHz):
d
8.0e8.01 (m, 2H, Ar H), 7.09e7.63 (m, 15H, Ar
perature (297 K) on a Bruker SMART APEX CCD diffractometer with
ꢀ
H), 6.67e6.75 (m, 2H, Ar H), 5.11 (dd, 1H, Ins H, J¼9.4, 3.0 Hz),
4.61e4.65 (m, 2H, CH2), 4.52e4.56 (m, 2H, CH2), 4.44 (s, 2H, CH2),
3.95e4.13 (m, 2H, Ins H), 3.79e3.90 (m, 1H, Ins H), 3.74 (s, 3H,
CH3), 2.49e2.64 (m, 1H, Ins H), 2.27e2.43 (m, 1H, Ins H), 1.45e1.7
graphite-monochromatized (Mo K
a
¼0.71073 A) radiation. The X-
ray generator was operated at 50 kV and 30 mA. Data were col-
lected with a (0,
u
scan width of 0.3ꢀ at four different settings of
4
90, 180, and 270ꢀ) keeping the sample-to-detector distance fixed at
(m, 2H, Ins H) ppm; 13C NMR (CDCl3, 50.3 MHz):
d
165.9 (C]O),
6.145 cm and the detector position (2
q
) fixed at ꢂ28ꢀ. X-ray data
159.0 (Carom), 138.5 (Carom), 132.9 (Carom), 130.3 (Carom), 129.7
(Carom), 129.1 (Carom), 128.4 (Carom), 128.3 (Carom), 128.2 (Carom),
127.6 (Carom), 127.5 (Carom), 127.4 (Carom), 113.6 (Carom), 77.4 (Ins C),
74.0 (Ins C), 73.7 (Ins C), 71.9 (CH2), 71.7 (CH2), 71.4 (Ins C), 70.6
collection was monitored by the SMART program (Bruker, 2003).20
A semi-empirical absorption correction (multi-scan) based on
symmetry equivalent reflections was applied using the SADABS
program (Bruker, 2003).20 Lattice parameters were determined

B.P. Gurale et al. / Tetrahedron 67 (2011) 7280e7288
7287
Table 1
Summary of crystal data, data collection, structure solution and refinement details
8
11
12
19
Chemical formula
Mr
Temp/K
C37H38O7S2
658.79
297(2) K
Plate
0.41ꢁ0.22ꢁ0.08
Triclinic
Pꢂ1
C37H38O7S2
658.79
297(2) K
Plate
0.16ꢁ0.12ꢁ0.11
Monoclinic
P21/c
15.220(2)
26.472(4)
8.8065(13)
90
104.498(10)
90
2(C36H36O6S2)0.5(C6H14
628.77
297(2) K
Plate
0.21ꢁ0.17ꢁ0.08
Triclinic
Pꢂ1
)
C35H36O6
552.64
297(2)
Plate
0.47ꢁ0.17ꢁ0.07
Triclinic
Pꢂ1
Morphology
Crystal size
Crystal system
Space group
ꢀ
a (A)
12.1038(12)
12.1371(12)
12.8640(13)
82.429(2)
77.934(2)
64.037(2)
1659.8(3)
2
13.968(8)
15.223(9)
18.645(11)
79.963(11)
71.362(10)
67.525(9)
3465(4)
2
10.3094(12)
10.3163(12)
14.0511(16)
94.350(2)
92.309(2)
97.547(2)
1475.3(3)
2
ꢀ
b (A)
ꢀ
c (A)
a
b
g
(ꢀ)
(ꢀ)
(ꢀ)
3
ꢀ
V (A )
3435.2(9)
4
1.274
Z
Dcalcd (g cmꢂ3
)
1.318
0.210
1.247
0.198
1.244
0.084
m
(mmꢂ1
)
0.203
F(000)
696
1392
1378
588
Ab.correction
Tmin
Tmax
qmax (ꢀ)
Multi-scan
0.9199
0.9828
Multi-scan
0.9685
0.9775
25.00
Multi-scan
0.9604
0.9841
Multi-scan
0.9617
0.9946
25.00
25.00
25.00
h, k, l (min, max)
(ꢂ14,14),
(ꢂ14,14),
(ꢂ15,15)
16,279
5833
4564
0.0246
417
1.020
(ꢂ18,18),
(ꢂ31,31),
(ꢂ10,10)
32,897
6045
4898
0.0282
417
(ꢂ16,16),
(ꢂ18,18),
(ꢂ22,22)
33,588
12,169
8454
0.0428
823
1.156
(ꢂ12,12),
(ꢂ12,12),
(ꢂ16,16)
14,376
5181
3672
0.0293
371
1.019
Reflns collected
Unique reflns
Observed reflns
Rint
No. of parameters
GOF
1.041
R1[I>2
wR2[I>2
R1_all data
wR2_all data
s
(I)]
(I)]
0.0415
0.0965
0.0558
0.1065
0.0614
0.1270
0.0614
0.1270
0.28,ꢂ0.18
817424
0.0927
0.2014
0.1301
0.2178
0.0523
0.1175
0.0785
0.1297
s
ꢀꢂ3
Drmax
,
Drmin(eA
)
0.23,ꢂ0.22
0.47,ꢂ0.50
0.28, ꢂ0.19
CCDC No.
817427
817425
817426
from least-squares analysis of all reflections. The structures were
solved by direct methods and refined by full matrix least squares,
based on F2, using SHELX-97 software package.21 All the hydrogen
atoms were placed in geometrically idealized positions and refined
isotropically. Molecular and packing diagrams were generated us-
ing ORTEP-3222 and Mercury CSD 2.3,23 respectively. Geometrical
calculations were performed using SHELXTL (Bruker, 2003) and
PLATON.24 The crystallographic data are summarized in Table 1.
CCDC-817424 to CCDC-817427 contain the supplementary crystal-
lographic data for this paper. This data can be obtained free of
charge from the Cambridge Crystallographic Data Center via
www.ccdc.cam.ac.uk/data_request/cif.
References and notes
1. (a) Paul, I. C.; Curtin, D. Y. Acc. Chem. Res. 1973, 6, 217e225; (b) Green, B. S.;
Lahav, M.; Rabinovich, D. Acc. Chem. Res. 1979, 12, 191e197; (c) Shklover, V. E.;
Timofeeva, T. V. Russ. Chem. Rev. 1985, 54, 619e644; (d) Ramamurthy, V.;
Venkatesan, K. Chem. Rev. 1987, 87, 433e481; (e) Ito, Y. Synthesis 1998, 1, 1e32;
(f) Keating, A. E.; Garcia-Garibay, M. A. In Molecular and Supramolecular Pho-
tochemistry; Ramamurthy, V., Schanze, K., Eds.; Marcel Dekker: New York, NY,
1998; Vol. 2, pp 195e248; (g) Braga, D.; Grepioni, F. Angew. Chem., Int. Ed. 2004,
43, 4002e4011; (h) Braga, D.; Grepioni, F. Chem. Commun. 2005, 3635e3645; (i)
Koshima, H.; Kawanishi, H.; Nagano, M.; Yu, H.; Shiro, M.; Hosoya, T.; Uekusa,
H.; Ohashi, Y. J. Org. Chem. 2005, 70, 4490e4497; (j) Mortko, C. J.; Garcia-Gar-
ibay, M. A. In Topics in Stereochemistry; Denmark, S. E., Siegel, J. S., Eds.; John:
Hoboken, NJ, USA, 2006; Vol. 25, pp 205e253; (k) Kaupp, G. In Topics in Ste-
reochemistry; Denmark, S. E., Siegel, J. S., Eds.; John: Hoboken, NJ, USA, 2006;
Vol. 25, pp 303e350; (l) Odani, T.; Okada, S.; Kabuto, C.; Kimura, T.; Shimada, S.;
Matsuda, H.; Oikawa, H.; Matsumoto, A.; Nakanishi, V. Cryst. Growth Des. 2009,
9, 3481e3487; (m) Harada, J.; Harakawa, M.; Sugiyama, S.; Ogawa, K. Crys-
tEngComm 2009, 11, 1235e1239; (n) Destro, R.; Ortoleva, E.; Soave, R.; Loconte,
L.; Presti, L. L. Phys. Chem. Chem. Phys. 2009, 11, 7181e7188; (o) Cantillo, D.;
Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.; Light, M. E.; Palacios, J. C. J. Org.
Chem. 2010, 75, 4300e4303; (p) Ghosn, M. W.; Wolf, C. J. Org. Chem. 2010, 75,
6653e6659; (q) Gonnade, R. G.; Iwama, S.; Mori, Y.; Takahashi, H.; Tsue, H.;
Tamura, R. Cryst. Growth Des. 2011, 11, 607e615 and references cited therein; (r)
Mondal, B.; Captain, B.; Ramamurthy, V. Photochem. Photobiol. Sci. 2011, 10,
891e894.
Acknowledgements
B.P.G. and S.K. thank CSIR, New Delhi, for the award of research
fellowships. B.G. and K.V. acknowledge the centre of Excellence in
Scientific Computing (COESC), Pune, for providing computational
facilities. Funding for this work by the DST, New Delhi is gratefully
acknowledged.
2. (a) Epple, M.; Ebbinghaus, S.; Reller, A.; Gloistein, U.; Cammenga, H. K. Ther-
mochim. Acta 1995, 269/270, 433e441; (b) Rothenberg, G.; Downie, A. P.; Ras-
ton, C. L.; Scott, J. L. J. Am. Chem. Soc. 2001, 123, 8701e8708; (c) Kaupp, G. Top.
Curr. Chem. 2005, 254, 95e183.
Supplementary data
3. (a) Toda, F. Acc. Chem. Res. 1995, 28, 480e486; (b) Metzger, J. O. Angew. Chem.,
Int. Ed. 1998, 37, 2975e2978; (c) Loupy, A. Top. Curr. Chem. 1999, 206, 153e207;
(d) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025e1074; (e) Cave, G. W. V.;
Raston, C. L.; Scott, J. L. Chem. Commun. 2001, 2159e2169; (f) Kaftory, M. In
Organic Solid State Reaction; Toda, F., Ed.; Kluwer Academic: Dordrecht, 2002;
pp 47e67; (g) Nakamatsu, S.; Yoshizawa, K.; Toyota, S.; Toda, F.; Matijasic, I. Org.
Biomol. Chem. 2003, 1, 2231e2234; (h) Kaupp, G.; Naimi-Jamal, M. R.;
Schmeyers, J. Tetrahedron 2003, 59, 3753e3760; (i) Matsumoto, S.; Kumazawa,
Electronic Supplementary Data (ESD) available: spectral data for
all new compounds, crystallographic and geometry optimized
colored diagrams for compounds 7e9, 11, 12 and 19 and Cartesian
co-ordinates (DFT data) for compounds 7e12. Supplementary data
related to this article can be found online at doi:10.1016/
j.tet.2011.07.044.

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K.; Ogura, K. Bull. Chem. Soc. Jpn. 2003, 76, 2179e2182; (j) Bu, X.; Jing, H.; Wang,
L.; Chang, T.; Jin, L.; Liang, Y. J. Mol. Catal. A: Chem. 2006, 259, 121e124; (k)
2945e2953; (c) Swarbrick, J. M.; Gaffney, P. R. J. J. Org. Chem. 2010, 75,
4376e4386.
Rodriguez, B.; Bruckmann, A.; Rantanen, T.; Bolm, C. Adv. Synth. Catal. 2007, 349,
2213e2233; (l) Pravst, I.; Zupan, M.; Stavber, S. Tetrahedron 2008, 64,
5191e5199; (m) Dolotko, O.; Wiench, J. Z.; Dennis, K. W.; Pecharsky, V. K.;
Balema, V. P. New J. Chem. 2010, 34, 25e28.
4. (a) Broido, A.; Houminer, Y.; Patai, S. J. Chem. Soc. B 1966, 411e414; (b) Pincock, R.
E.; Wilson, K. R.; Kiovsky, T. E. J. Am. Chem. Soc. 1967, 89, 6890e6897; (c) Kras-
noselsky, M.; Patai, S. J. Chem. Soc. B 1969, 24e27; (d) Michman, M.; Frenkel, M. J.
Chem. Soc. C 1971, 3856e3859; (e) Kaupp, G.; Naimi-Jamal, M. R. Eur. J. Org. Chem.
2002, 1368e1373; (f) Beristain, M. F.; Fomine, S.; Ogawa, T. Mol. Cryst. Liq. Cryst.
2006, 447, 251e263; (g) Kaupp, G. J. Phys. Org. Chem. 2008, 21, 630e643.
5. Murali, C.; Shashidhar, M. S.; Gonnade, R. G.; Bhadbhade, M. M. Chem.dEur. J.
2009, 15, 261e269 and references cited there in.
6. (a) Sakurai, R.; Suzuki, S.; Hashimoto, J.; Baba, M.; Itoh, O.; Uchida, A.; Hattori,
T.; Miyano, S.; Yamaura, M. Org. Lett. 2004, 6, 2241e2244; (b) Sakurai, R.; Itoh,
O.; Uchida, A.; Hattori, T.; Miyano, S.; Yamaura, M. Tetrahedron 2004, 60,
10553e10557; For an example of epimerization in solution; (c) Ikuma, N.; Tsue,
H.; Tsue, N.; Shimono, S.; Uchida, Y.; Masaki, K.; Matsuoka, N.; Tamura, R. Org.
Lett. 2005, 7, 1797e1800.
7. (a) Michell, R. H. Biochim. Biophys. Acta 1975, 415, 81e87; (b) Berridge, M. J.;
Irvine, R. F. Nature 1984, 312, 315e321; (c) Potter, B. V. L. Nat. Prod. Rep. 1990, 7,
1e24; (d) Katso, R.; Okkenhaug, K.; Ahmadi, K.; White, S.; Timms, J.; Waterfield,
M. D. Annu. Rev. Cell Dev. Biol. 2001, 17, 615e675; (e) Nicholson, K. M.; Anderson,
N. G. Cell. Signalling 2002, 14, 381e395; (f) Shamsuddin, A. M.; Vucenic, I. Curr.
Cancer Ther. Rev. 2005, 1, 259e269; (g) Wymann, M. P.; Schneiter, R. Nat. Rev.
2008, 9, 162e176; (h) Liu, X.; Moody, E. C.; Hecht, S. S.; Sturla, S. J. Bioorg. Med.
Chem. 2008, 16, 3419e3427; (i) Sureshan, K. M.; Riley, A. M.; Rossi, A. M.; Tovey,
S. C.; Dedos, S. G.; Taylor, C. W.; Potter, B. V. L. Chem. Commun. 2009, 1204e1206
and references cited there in.
10. Bhosekar, G.; Murali, C.; Gonnade, R. G.; Shashidhar, M. S.; Bhadbhade, M. M.
Cryst. Growth Des. 2005, 5, 1977e1982.
11. Murali, C.; Gurale, B. P.; Shashidhar, M. S. Eur. J. Org. Chem. 2010, 755e764.
12. Further increase in the reaction temperature led to increased formation of the
diol 14, 2-O-(4-methoxybenzyl)-4,6-di-O-benzyl-5-O-(methylthio)thiocarbonyl
myo-inositol. As observed during the epimerization of 8, formation of minor
amounts of the diols 13 [2,4,6-tri-O-benzyl-5-O-[(methylthio)thiocarbonyl]
myo-inositol] and 15 [1,3,5-tri-O-benzyl-2-O-[(methylthio)thiocarbonyl] neo-
inositol] were observed during the epimerization of 7 and 9.
€
€
13. (a) Ahlrichs, R.; Bar, M.; Baron, H.-P.; Bauernschmitt, R.; Bocker, S.; Ehrig, M.;
€
Eichkorn, K.; Elliott, S.; Furche, F.; Haase, F.; Haser, M.; Horn, H.; Huber, C.;
Huniar, U.; Kattannek, M.; Kolmel, C.; Kollwitz, M.; May, K.; Ochsenfeld, C.;
Ohm, H.; Schafer, A.; Schneider, U.; Treutler, O.; von Arnim, M.; Weigend, F.;
Weis, P.; Weiss, H. TURBOMOLE (Version 5.3); Universitat Karlsruhe: Karlsruhe,
€
€
€
€
€
Germany, 2000; (b) Schafer, A.; Huber, C.; Ahlrichs, R. J. Chem. Phys. 1994, 100,
5829e5835; (c) Andrae, D.; Haeussermann, U.; Dolg, M.; Stoll, H.; Preuss, H.
Theor. Chim. Acta 1990, 77, 123e141.
14. Hyperchem (version 5); Hypercube, Gainesville, FL, 32601.
15. (a) Becke, A. D. Phys. Rev. A: At., Mol., Opt. Phys. 1988, 38, 3098e3100; (b) Per-
dew, J. P. Phys. Rev. B: Condens. Matter Mater. Phys. 1986, 33, 8822e8824.
€
16. Schafer, A.; Horn, H.; Ahlrichs, R. J. Chem. Phys. 1992, 97, 2571e2577.
€
€
17. Eichkorn, K.; Treutler, O.; Ohm, H.; Haser, M.; Ahlrichs, R. Chem. Phys. Lett. 1995,
240, 283e290.
18. Sierka, M.; Hogekamp, A.; Ahlrichs, R. J. Chem. Phys. 2003, 118, 9136e9148.
19. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 2nd ed.;
Pergamon: Oxford, UK, 1988.
20. Bruker. SADABS (Version 2.05), SMART (Version 5.631) and SAINT (Version 6.45);
Bruker AXS: Madison, Wisconsin, USA, 2003.
8. (a) Gilbert, I. H.; Holmes, A. B.; Pestchanker, M. J.; Young, R. C. Carbohydr. Res.
1992, 234, 117e130; (b) Murali, C.; Shashidhar, M. S.; Gopinath, C. S. Tetrahedron
2007, 63, 4149e4155.
9. (a) Swarbrick, J. M.; Cooper, S.; Bultynck, G.; Gaffney, P. R. J. Org. Biomol. Chem.
2009, 7, 1709e1715; (b) Jagdhane, R. C.; Shashidhar, M. S. Eur. J. Org. Chem. 2010,
21. Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, 64, 112e122.
22. Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
23. Macrae, C. F.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Shields, G. P.; Taylor, R.;
Towler, M.; van de Streek, J. J. Appl. Crystallogr. 2006, 39, 453e457.
24. Spek, A. L. J. Appl. Crystallogr. 2003, 36, 7e13.