Total syntheses of cyclitol based natural products from myo-inositol: brahol and pinpollitol

Article abstract of DOI:10.1016/j.tet.2009.03.024

Inositol and their derivatives are important class of biologically active natural products. Among the nine theoretically possible inositols, six are known to occur in nature. Interestingly one or more methyl ethers of these inositols have been isolated fr

Full text of DOI:10.1016/j.tet.2009.03.024

Tetrahedron 65 (2009) 3998–4006
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total syntheses of cyclitol based natural products from myo-inositol:
brahol and pinpollitol
,
y
*
*
Kana M. Sureshan , Tomohiro Murakami, Yutaka Watanabe
Department of Material Science and Biotechnology, Graduate School of Science and Engineering, Ehime University, Matsuyama-790-8577, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Inositol and their derivatives are important class of biologically active natural products. Among the nine
theoretically possible inositols, six are known to occur in nature. Interestingly one or more methyl ethers
of these inositols have been isolated from plants and these methyl inositols are presumed to have im-
portant functions in plant biology. Brahol and pinpollitol are two naturally occurring methylated inositols
reported to have allo-inositol and chiro-inositol configurations, respectively. Adopting our sulfonate in-
version strategies for synthesizing protected chiro- and allo-inositols from cheaply available myo-inositol
in combination with new methods we have achieved the total syntheses of these methylated inositols.
The proposed structure of brahol has been synthesized in six steps from myo-inositol. We have not only
disproved the proposed structure of brahol but also established its correct structure. Also, we have ef-
ficiently synthesized pinpollitol and its positional isomer from myo-inositol. These works involve several
selective protection–deprotection strategies of inositol hydroxyl groups.
Received 23 February 2009
Received in revised form 5 March 2009
Accepted 6 March 2009
Available online 19 March 2009
Keywords:
Natural product
Total synthesis
Inositol
Cyclitol
Regioselective reaction
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
OH
OH
OH
OH
HO
HO
OH
OH
MeO
HO
OH
OH
MeO
HO
OH
MeO
HO
OH
OH
2
4
1
2
5
6
3
3
4
1
1
2
Due to the involvement of various phosphorylated inositols,
inositol based lipids, and glycosylated inositols in various biological
processes including cellular signaling, protein anchoring, etc.,
a great deal of attention has been paid to the inositol chemistry.1
Inositols, being cyclohexane hexols, have nine theoretically possi-
2
1
4
6
5
3
OMe
OH
2
OH
4
OH
1
OMe
3
Chart 1. myo-Inositol and proposed structures of brahol and pinpollitol.
ble isomers. Six of these nine possible isomers, namely myo-,
D-
chiro-, -chiro-, neo-, muco-, and scyllo-inositols, are known to occur
L
naturally, myo-inositol being the most abundant. Phosphorylated,
glycosylated, and unmodified inositols have been found in animals
and plants. However, methylation is a modification of inositols
found exclusively in plants.2 Methyl ethers of all the known natu-
rally occurring inositols have been isolated and are presumed to
have important physiological functions in plants.2 Many of these
naturally occurring methyl ethers of inositols have been synthe-
sized3 either to validate the proposed structures or to provide easy
access as the isolation from natural sources is often tedious and
low-yielding.
brahol was identified as 5-O-methyl-allo-inositol 1 (Chart 1), the
first and only known natural allo-inositol derivative. A systematic
investigation to assign the structure, physicochemical properties
(absolute configuration, aD, mp), and biological activities was not
undertaken probably due to the insufficiency of the isolated ma-
terial. In an effort to supply this material in sufficient quantity in
order to study its physicochemical properties and biological profile,
we have synthesized the proposed structure of brahol.5 However,
the original structural assignment of brahol was found to be wrong
and hence we have revised the structural assignment. The full de-
tails of the synthesis and structural revision constitute part of this
report.
Ahmad4 et al. isolated a methylinositol, brahol, from the folklore
medicinal plant Stocksia brahuica for the first time. Relying on the
chemical shift values of various protons in the 1H NMR spectrum,
Gallagher isolated (þ)-pinpollitol, an unsymmetrical dimethyl
ether of D-chiro-inositol, from the pollens of the plant Pinus radi-
ata.6 The author has tentatively proposed two probable structures
for pinpollitol; 1D-1,4-di-O-methyl-chiro-inositol (2) and 1D-1,3-
di-O-methyl-chiro-inositol (3) based on the comparison of the
chemical shifts of both pinpollitol and its tetra-O-acetyl derivative
with structurally similar cyclitol derived compounds. In an elegant
* Corresponding authors.
E-mail addresses: sureshankm@yahoo.co.in (K.M. Sureshan), wyutaka@dpc.e-
hime-u.ac.jp (Y. Watanabe).
y
Present address: School of Chemistry, Indian Institute of Science Education and
Research, Thiruvananthapuram 695016, Kerala, India.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.024

K.M. Sureshan et al. / Tetrahedron 65 (2009) 3998–4006
3999
approach, Angyal et al. have synthesized 2, one of the two proposed
O
O
O
structures from pinitol and by comparing its NMR spectra with that
of pinpollitol, it has been reported that 2 is the correct structure of
pinpollitol.7 However, dimethyl ether 3 has not been synthesized.
This is important as structurally related inositol derivatives could
often have similar 1H NMR or the difference could be very subtle to
be apparent in a spectrum recorded in a low resolution NMR
spectrometer. Thus, when there are two possibilities, the practice of
ruling out the alternative possibility is as important as proving one
of the two possibilities for unambiguous establishment of the
structure. In order to provide alternate strategy for the synthesis of
2 from cheaply available myo-inositol and to rule out the other
proposed structure, we have synthesized both 2 and 3.8 This study
not only established the fact that Angyal’s structural assignment
was correct but also provided an economical route to 2. The full
details of these studies constitute part of this report. All the un-
symmetrical synthetic compounds reported here are racemic
mixtures, but for brevity only one of the enantiomers is shown.
TfO
O
O
RO
O
O
HO
O
O
b
a
5
2
1
OTf
OR
OH
O
O
O
8. R = Ac
9. R = H
7
6
OH
O
O
MeO
HO
OH
OH
MeO
O
O
HO
O
f
e
5
c or d
2
8
1
OAc
O
OAc
OH
O
O
1
11
10
Scheme 1. (a) Tf2O (2.2 equiv), Py, CH2Cl2, ꢀ20 ꢁC; (b) KOAc, DMA, 70 ꢁC; (c) MeOH,
Et3N, reflux; (d) MeOH, iso-butylamine, 60 ꢁC; (e) MeI, NaH, DMF, rt; (f) 1 N HCl, MeOH,
rt.
2. Results and discussions
myo-Inositol (4) being structurally related to 1–3 and very
cheaply available, the syntheses of 1–3 from myo-inositol are
justifiable. Since all the six secondary hydroxyl groups of inositol(s)
are expected to have more or less similar reactivity toward
methylation, other hydroxyl groups have to be protected before
methylation. The selective protection–deprotection strategies for
myo-inositol hydroxyl groups have been well explored,9 and hence
appropriately protected derivatives can easily be prepared by
adopting these known methodologies. The relative stereochemistry
at 1, 2, 4, and 5 positions of myo-inositol are preserved in com-
pounds 1 and 2 and hence 1,2:4,5-di-O-isopropylidene-myo-inosi-
tol (7)10 was chosen as the suitable protected starting material.
However, for the synthesis of 3, diketal 7 cannot be an economical
starting point as methylation is required at O-5. Thus we decided to
synthesize 3 from myo-inositol 1,3,5-orthoformate. The known
methods for the efficient optical resolution of orthoesters11 and
diketal 712 allow the synthesis of 1–3 in optically pure form if
required.
hydroxyl groups. The proton signal at 5.64 ppm appeared as
a doublet of doublet (dd) with coupling constants 5.7 Hz and 2.6 Hz
and the dd signal at 5.74 ppm showed coupling constants 3.3 Hz
and 1.6 Hz. H-5 is expected to show one axial–equatorial (ae) and
one equatorial–equatorial (ee) coupling while H-2 is expected to
show two axial equatorial couplings. Since ae and ee coupling
constants do not vary much, the assignment of protons was not
straightforward. It is well known that the coupling constants vary
with the orientation of the electronegative atoms (or groups) on
the two carbons bearing coupling hydrogens.15 Taking into con-
sideration the orientation of oxygen atoms in 8, H-2 is expected to
show relatively larger coupling constants compared to H-5.16 Thus
the dd signal at 5.64 ppm is assigned to be due to H-2 and that at
5.74 ppm due to H-5.
Next task was to methylate the 5-OH selectively. Since the diol 9,
which can be prepared by basic hydrolysis of the diacetate 8, has
two axial hydroxyl groups (in 9), it is not expected to show any
regioselectivity toward methylation. Also, discrimination between
these two axial hydroxyl groups in any reaction is difficult.9 Since
the selective protection of 2-OH or selective methylation of 5-OH is
expected to be difficult, we were inclined to explore selective
deacylation of one of the acetyl groups. Both the acetoxy groups at
C-2 and C-5 are flanked by two protected hydroxyl groups; in the
case of C-2-OAc, both the protected hydroxyls on either side (C-1-O
and C-3-O) have syn relation to it whereas in the case of C-5-OAc,
one of the adjacent protected hydroxyl groups (C-4-O) has anti
relation with the acetoxy group. 3D model revealed that the methyl
groups of isopropylidene protection make C-2-OAc more sterically
protected than C-5-OAc. We were curious to know whether this
through-space protection of C-2-OAc can be exploited for the se-
lective removal of C-5-OAc and hence a regioselective de-acylation
was attempted. We envisioned that a bulky nucleophile could
easily attack the C-5-OAc compared to the sterically inaccessible
C-2-OAc. As anticipated, aminolysis of 8 with tert-butylamine
provided the monoacetate 105 in quantitative yield. The cleavage of
the acetate at C-5 was indicated by the disappearance of the signal
at 5.74 ppm. Additional evidence for C-5-OAc cleavage was
obtained from a comparison of the 3JH–H coupling constants of the
most downfield shifted dd signal (5.61 ppm) in 10 (5.1, 2.5 Hz) with
those of H-2 (5.7, 2.6 Hz) and H-5 (3.3, 1.6 Hz) in 8. Furthermore,
single crystal X-ray analysis of 10 (see Supplementary data) further
confirmed our structural assignment.17
2.1. Synthesis of 1
Methyl ether 1 can be obtained from protected allo-inositol 5
(Chart 2) by methylation followed by removal of the protecting
groups. Protected derivative 5 can be synthesized from the ditriflate
6 by nucleophilic substitution with an appropriate oxygen nucle-
ophile13 and selective protection of 2-OH group. Ditriflate 6 can be
synthesized from the diketal 7, which can be prepared from myo-
inositol.10
O
O
O
O
OH
O
HO
O
O
TfO
O
O
MeO
HO
OH
OH
HO
O
O
OH
OTf
OP
OH
O
1
5
6
7
Chart 2. Retrosynthesis of 1.
We have recently reported the synthesis of diacetate 8 during
our synthesis of allo-inositol from myo-inositol.14 The ditriflate 6
obtained by sulfonylation of diol 7 was reacted with KOAc in DMA
to obtain racemic 2,5-di-O-acetyl-1,6:3,4-di-O-isopropylidene-allo-
inositol (8)5 in 87% yield (Scheme 1). Protons on C-2 and C-5 are
shifted downfield as expected due to the acylation of the respective
Having achieved a regioselective deacylation under mild con-
dition, we were curious to know whether such a high degree of
selectivity can be achieved under relatively harsh conditions also.

4000
K.M. Sureshan et al. / Tetrahedron 65 (2009) 3998–4006
When the aminolysis with tert-butylamine was conducted at
refluxing conditions also, C-2-OAc was found to be stable. Fur-
thermore, aminolysis with less bulky iso-butylamine (yield of 10:
93%) and even more surprisingly, methanolysis using Et3N as the
base (yield of 10: 91%) also resulted in deacylation of the acetate
group at C-5 selectively, despite methoxide ion being a less bulky
nucleophile. Such a high degree of selectivity is interesting and
noteworthy as the regioselective functionalization is one of the
major foci in the synthetic chemistry of cyclitols.9
absence of any line broadening in the reported 1H NMR spectrum of
brahol we became skeptical about its proposed allo-configuration
(three axial and three equatorial oxygens).
Angyal et al. have studied and generalized18 the effect of
O-methylation in chemical shifts of protons in cyclitols. Ahmad et
al. used these generalizations for the structural assignment of
brahol. The axial orientation of methoxy substituent was assumed
based on the chemical shift of the carbon atom bearing the OMe
and the relative stereochemistry of other carbon atoms was pro-
posed by correlating with the stereochemistry of the carbon bear-
ing the OMe. As the O–CH3 resonance in the 1H NMR spectra of
methyl ethers of inositols appear in the range 3.45–3.65 ppm in
general,18 an unusual chemical shift of 3.25 ppm for O–CH3 reso-
nance in brahol points that the spectrum is up-field shifted. Thus
the reliance on the chemical shift values of a shifted spectrum for
the stereochemical assignment resulted in wrong assignment of
the structure.
Methylation of the acetate 10 provided the methyl ether 115 as
3
the exclusive product. The JHH values (5.3, 2.7 Hz) for the down-
field shifted proton signal suggest that it is due to H-2. This ruled
out any possibility of acetyl migration under the alkylation condi-
tion (Williamson’s condition). Also the signal due to H-5 shifted up-
field as expected18 as a result of O-5 methylation. The single crystal
X-ray structure of 11 (see Supplementary data) provided additional
evidence for its structure.17 Finally, 5-O-methyl-allo-inositol (1) was
obtained via the global deprotection by acid hydrolysis.5
As we have proved that the structure of brahol is wrong, we
attempted to assign the structure of brahol using the reported NMR
data. But the reported data are insufficient to predict the structure
unambiguously in a straightforward manner. Thus a logistic
method was applied. There are 20 theoretically possible isomeric
monomethyl ethers for 8 inositols (Chart 3). Since comparison of all
these structures with brahol is tedious, we have short-listed the
number of possible structures based on symmetry. The reported 1H
NMR data of brahol are of an unsymmetrical methyl ether of
inositol. Of the possible 20 monomethyl ethers (1, 12–30, Chart 3), 8
(12–19) are having a plane of symmetry in them and are expected to
give a symmetrical NMR spectrum. Based on the lack of symmetry
in the reported 1H NMR spectrum of brahol, the number of plausible
structures was reduced to 12 (1, 20–30). Methyl ethers of muco- and
allo-inositols, having three axial and three equatorial dispositions
of oxygen, are expected to give broad peaks in the 1H NMR spec-
trum due to conformational exchange. Thus four of the methyl
ethers of allo- and muco-inositols (1, 20–22) were also set aside
based on the sharp signals in the reported 1H NMR spectrum of
brahol. Of the remaining eight structures, two myo-inositol methyl
ethers (23 and 24) were ruled out by comparing the reported data
of brahol with that of bornesitol (1-O-methyl-myo-inositol)19 and
ononitol (4-O-methyl-myo-inositol).3e Thus by using this analysis
based on symmetry and conformation, we could reduce the pos-
sible number of structures to six. All these six structures (Chart 4)
are of methyl ethers of inositols having two axial and four equa-
torial hydroxyl groups (epi, chiro, and neo).
2.2. Revision of the structure of brahol
The structural assignment of brahol by Ahmad et al. was proven
to be wrong by a comparison of 1H NMR spectra of our synthetic 1
with that reported for brahol.4 While brahol is reported to have
sharp signals in its 1H NMR spectrum,4 5-O-methyl-allo-inositol (1)
in D2O showed very broad signals for both protons5 and carbons.
This is not surprising based on the possible slow (with respect to
the NMR time scale) dynamic equilibrium between two chair
conformations since allo-inositol possesses three axial and three
equatorial hydroxyl groups. Although a substituted allo-inositol
would prefer a conformation where the substituted hydroxyl has
equatorial orientation, methyl being a very small substituent, the
energy barrier between two chair conformations of monomethyl
allo-inositol is expected to be small and hence it can be in dynamic
equilibrium between two conformations. A variable temperature
NMR experiment (Fig. 1) substantiated this assumption. The signals
became more and more resolved as the experimental (NMR) tem-
perature increased. Very sharp and well resolved signals were ob-
served for different protons and carbons at 80 ꢁC.5 Based on the
The six possible structures along with the reported structure of
brahol are shown in Chart 4. The numbering and orientation (with
respect to O–Me group) of the chair form of all the six methyl ethers
have been adjusted to the reported structure for easy comparison.
The coupling 3JHH constants of H-4 (dd, 3.8, 3.3 Hz) and H-3 (dd, 3.8,
3.4 Hz) of brahol have been reported in the original paper. In the
case of 25, H-30 is expected to show a dd with one large coupling
constant (and small coupling constant) due to the diaxial orienta-
tion of H-20 and H-30. Based on the lack of a large coupling constant
3
0
0
for JH-2 ,H-3 the structure 25 has been ruled out. The methoxy
protons of brahol are reported to show NOE interaction with its
neighboring methyne proton (H-4). However, such NOE interaction
is not possible in 26 because of their diaxial orientation. Also H-30
and H-40 in 26–28 should have at least one larger coupling constant
(in 26 and 28, H-30 is expected to have two large coupling constants
and H-40 one large and one small coupling constants and in 27, H-40
is expected to have two large coupling constants and H-30 one large
and one small coupling constants) due to diaxial disposition of
hydrogens. Based on the reported smaller coupling constants for
both H-3 and H-4 in brahol, structures 26–28 were ruled out. The
reported chemical shifts of axial proton, H-3 and the equatorial
proton H-2 of brahol are 3.85 ppm and 3.54 ppm, respectively. But
Figure 1. Variable temperature 1H NMR of 5-O-methyl-allo-inositol (1) in D2O.

K.M. Sureshan et al. / Tetrahedron 65 (2009) 3998–4006
4001
HO
OH
2 OH
OMe
2
OH
OH
OM2e
OH
4
OH
2
OMe
OH
OH
6
1
4
4
3
HO
HO
OH
OH
3
3
4
5
HO
HO
HO
HO
MeO
3
5
HO
5
2OH
5
5
1
HO4
HO
OH
6
HO 6
HO 6
1
3
6OMe
1
1
HO
1-O-methyl-scyllo-inositol
12
2-O-methyl-myo-inositol 5-O-methyl-myo-inositol 3-O-methyl-muco-inositol
3-O-methyl-epi-inositol
16
13
14
15
OH
OH
OH
1
OH
OH
OH
4OH
OMe
2
OH
4 OH
OH
OH
OH
OH6
1
OH
3
2
5
6
6
5
3
2
1
OMe
OH
1
HO
4
OH
HO
MeO
2
2
HO 3
MeO6
4 HO3
6
5
3HO 4
5
5
1
HO
HO
OH
OMe
OH
6-O-methyl-epi-inositol
17
1-O-methyl-cis-inositol
18
2-O-methyl-neo-inositol
19
1-O-methyl-allo-inositol
20
2-O-methyl-allo-inositol
21
OH
OMe
OH
OH
4
OH
2
OH
OH
OH
2OH
OH
3OH
4
HO 4
4
5
6
3
3
3
MeO
2OMe
2OMe
1
5
OH
5
4
HO
HO
HO
HO
OMe
HO3
5HO 6
HO 6
1
1
2
HO6
5HO6
OH1
1
HO
OH
1-O-methyl-muco-inositol 1-O-methyl-myo-inositol
4-O-methyl-myo-inositol
24
HO
5-O-methyl-allo-inositol
1
1-O-methyl-neo-inositol
25
22
23
OH
OMe
1OH
OH
OH
OMe
OH
OH
5
3OH
OH
1
5
6
5
6
4
2
4
6
2OMe
3
HO4
HO
HO
HO
HO
OH
HO
HO
5
HO
OH
4
4
1OMe
3
2
HO 3
1
HO 3
1
6
6
MeO
2
5HO
2
HO
2-O-methyl-epi-inositol
26
OH
3-O-methyl-chiro-inositol 1-O-methyl-chiro-inositol
27 28
OH
OH
1-O-methyl-epi-inositol
29
2-O-methyl-chiro-inositol
30
Chart 3. All theoretically possible structures for monomethyl ethers of inositols.
it is well known that the chemical shift values (
d
) of equatorial
When the 13C NMR spectrum of quebrachitol was standardized by
assigning its most downfield carbon signal with the chemical shift
value of the most downfield carbon signal reported for brahol, the
whole spectrum literally reproduced the reported spectrum of
brahol (Fig. 2c). Thus our study challenges the first and only report
of the natural occurrence of an allo-inositol (derivative). The
reported spectrum of brahol has found to be shifted up-field as we
have suspected. The structural assignment of brahol was done by
comparing the chemical shift values of various protons and carbons
following Angyal’s generalization on the effect of methylation on
chemical shifts of cyclitols.18 A chemical shift of 3.25 ppm for the
O–CH3 misled the authors to assume that it is having an axial
orientation in the chair form of cyclitol and the relative
protons are usually higher (lower field) than that of axial protons.
So we suspected a reversal of configuration at these positions is
reasonable. More clearly, the chemical shift of H-2 (3.54 ppm) is
closer to that of other two axial hydrogens (H-1 and H-6, 3.40 ppm)
while the chemical shift of H-3 (3.85 ppm) is closer to the value for
other equatorial hydrogen (H-4, 4.06 ppm). The lower chemical
shift value for H-5 is as expected since O-methylation brings about
an up-field shift of
a-hydrogens irrespective of their orientation
(axial or equatorial).18 These facts suggest that 30 is the more
plausible structure of brahol.
A comparison of the spectra of 30 (L-2-O-methyl-chiro-inositol:
L-quebrachitol) and brahol established that they are same (Fig. 2).
OH
OH
2
4
OH
3.54
H
3
4.06 (dd, 3.8, 3.3Hz)
3.85 (dd, 3.8,3.4Hz)
H
3.40H
H
HO
6
H3.20
CH3
1
5
O
HO
H
3.40
3.25
reported structure of brahol and chemical shifts of protons
H
OH
H
OH
4'
H
H
H
4'
OH
2'
OH
4'
OH
2'
2'
OH
H
3'
OH
HO
3'
HO
3'
H
H
H
H
H
6'
H
O
H
H
6'
H
6'
H
1'
5'
O
HO
H
CH3
1'
OH
5'
HO
1'
OH
5'
HO
CH3
H
OH
O
CH3
H
25
26
27
H
OH
H
OH
OH
2'
4'
OH
2'
2'
OH
H
OH
3'
H
HO
4'
3'
H
HO
3'
H
H
4'
H
OH
6'
O
OH
6'
H
HO
O
H
HO
6'
HO
H
5'
HO
CH3
1'
HO
1'
H
1'
H
5'
5'
O
H
CH3
H
H
H
CH3
28
29
30
Chart 4. Structural comparison of brahol with 25–30. The numbering similar to brahol has been followed for 25–30 and the orientation has been fixed as in brahol by taking the
carbon bearing OMe as the reference point.

4002
K.M. Sureshan et al. / Tetrahedron 65 (2009) 3998–4006
Figure 2. (a) 1H NMR of quebrachitol standardized with respect to the OMe signal reported brahol. (b) 13C NMR spectrum of quebrachitol standardized with respect to the most
downfield signal reported brahol. (c) 13C NMR spectra of quebrachitol standardized with dioxane as the internal standard.
stereochemistries of other carbons were determined by correlating
(NOE, JHH values) with this. However, due to the reliance on
which on nucleophilic substitution with KOAc in N,N-dimethyl-
acetamide (DMA) gave the racemic 1-O-acetyl-2,3:5,6-di-O-iso-
propylidene-chiro-inositol (33) in quantitative yield. Single crystal
X-ray structure of (ꢀ)-3322confirmed its structure (see Supple-
mentary data). Methanolysis of the acetate 33 provided diol (ꢂ)-31
(85% from 7), which on methylation provided (ꢂ)-1,2:4,5-di-O-
isopropylidene-3,6-di-O-methyl-chiro-inositol (34) in good (99%)
yield. Hydrolytic removal of the isopropylidene groups under acidic
conditions provided (ꢂ)-1,4-di-O-methyl-chiro-inositol (2, 73%),
which on acetylation provided the tetraacetate 35 (93%) (Scheme 2).
3
a shifted spectrum, the assignment of axial orientation for the OMe
was wrong. Since the relative stereochemistry of the reference
center was incorrect, the relative stereochemistries of all other
carbons also were wrong and this culminated in a wrong structural
assignment for brahol. Although Angyal’s generalizations are ex-
tremely useful for the structural assignment, care must be taken to
standardize the NMR chemical shifts with a known standard peak
other than HOD as the chemical shift of HOD varies with concen-
tration, temperature, and pH.20
2.4. Synthesis of 3
2.3. Synthesis of 2
Dimethyl ether 3 can be synthesized from the protected diol 36
by methylation followed by deprotection of the hydroxyl groups.
The diol 36 can be synthesized by nucleophilic substitution of the
differentially protected myo-inositol derived triflate 37 with an
appropriate oxygen nucleophile (acetate), followed by the removal
of protecting group P2. Acetyl and benzyl were chosen as the pro-
tecting group P2 and P1, respectively, so that both the acetyl groups
(newly introduced acetate at the inversion site and P2) can be
cleaved simultaneously to provide the diol 36. It has been known
that 1-OH and 3-OH are more nucleophilic than 5-OH in myo-ino-
sitol toward various electrophilic reagents.9 Thus the triflate 37 can
be obtained from triol 38 by sequential protection of 1-OH with
protecting group P1 (Bn), triflylation of 3-OH, and protection of the
5-OH with protecting group P2 (Ac). Triol 38 can be prepared from
orthoformate 39 by protection of its three hydroxyl groups with P1
(Bn) followed by acid hydrolysis of the orthoester cage. Ortho-
formate 39 can be obtained from myo-inositol in good yield
(Chart 6).23
Methylation of diol 31 followed by the deprotection of the iso-
propylidene groups is expected to provide dimethyl ether 2. Diol 31
can be obtained from the triflate 32, which can be obtained from
diketal 7 (Chart 5).
OH
O
O
O
MeO
HO
OH
HO
O
O
TfO
O
O
HO
O
O
OMe
OH
OH
OH
OH
O
O
O
2
31
32
7
Chart 5. Retrosynthesis of 2.
The diol 31, the precursor for the synthesis of 2, was synthesized
from myo-inositol diketal 7.21 Regioselective sulfonylation of race-
mic diol 7 with triflic anhydride provided the monotriflate 32,

K.M. Sureshan et al. / Tetrahedron 65 (2009) 3998–4006
4003
OR
OR
O
O
O
O
OR1
O
RO
OMe
OR
O
O
OR
O
O
OMe
O
d
e
b
R2O
MeO
HO
MeO
O
O
2. R =H
33. R1 = Ac; R2 = H
31. R1 = R2 = H
f
7.R = H
35. R = Ac
34
a
c
32.R = Tf
Scheme 2. (a) Tf2O (1.1 equiv), py, CH2Cl2, ꢀ20 ꢁC; (b) KOAc, DMA, 70 ꢁC; (c) NaOMe, MeOH, reflux; (d) MeI, NaH, DMF, rt; (e) TFA, H2O, rt; (f) Ac2O, py, rt.
undertaken to separate and identify these byproducts. The hy-
droxyl groups at 3- and 5-position were exposed by methanolytic
removal of the acetate protecting groups. Methylation of diol 46
provided the dimethyl ether 47 (63%), which on hydrogenolysis
OP1
OP1
OH
HO
OP1
OP1
TfO
OP1
OP1
MeO
HO
OH
OH
P1O
P1O
OH
36
OP2
OP1
OMe
3
provided 1,3-di-O-methyl-chiro-inositol (3, 89%). Tetrol
3 on
37
acetylation afforded the tetraacetate 48 in 93% yield (Scheme 3).
In agreement with Angyal’s report, the structural identity of
pinpollitol as 1,4-di-O-methyl-chiro-inositol has been proven based
on comparison of 1H NMR of pinpollitol and its tetraacetate with
that of dimethyl ethers (2 and 3) and their tetraacetates (35 and 48).
OH
OH
OH
O
HO
HO
OH
OH
HO
OH
O
HO
P1O
OP1
OH
O
OH
38
4
39
3. Conclusions
Chart 6. Retrosynthesis of 3.
In conclusion, we have reported the efficient syntheses of three
methyl inositols from myo-inositol via sulfonate inversion strategy.
The synthesis of the reported structure of brahol, 5-O-methyl-allo-
inositol, and a comparison of its spectral data with that of the
natural product revealed that the structural assignment of brahol
was wrong. We have reassigned the structure of brahol to be 2-O-
methyl-chiro-inositol based on the spectral data and logistical ap-
proach. Also, we have synthesized both the proposed plausible
structures of pinpollitol; 1,3-di-O-methyl-chiro-inositol and 1,4-di-
O-methyl-chiro-inositol. Agreeing with previous report, a compari-
son of the spectral data of the natural product with the synthetic
compounds unambiguously established that the correct structure is
1,4-di-O-methyl-chiro-inostol. In addition to achieving the total
synthesis of these methyl inositols and establishing the structures
of these natural compounds, our syntheses involved several
regioselective protection–deprotection of inositol hydroxyl groups
and several useful synthetic transformations, which will be of in-
terest to a broad cross-section of organic chemists as inositol and
other cyclitols are increasingly being recognized as synthons for
many natural products,27 metal complexing agents,28 gelators,29
catalysts,30 supramolecular assemblies,31 chiral auxiliary,32 etc.
2,4,6-Tri-O-benzyl-myo-inositol 4124 was prepared from myo-
inositol 1,3,5-orthoformate (39)23 via benzylation to tribenzyl ether
4024a,25 followed by acid hydrolysis. Benzylation of triol 41 with one
equivalent of NaH and benzyl bromide provided the known26
tetrabenzyl ether 42 selectively. Triol 41 being a meso compound,1-
OH and 3-OH are chemically equivalent. The lack of symmetry in
the NMR spectrum of 42 is indicative of benzylation at 1(3)-posi-
tion (benzylation at 5-OH give a meso compound). Sulfonylation of
the diol 42 gave the triflate 43 (81%) as anticipated based on the
enhanced reactivity of 3-OH over 5-OH.9 A deshielded dd signal
with 3JHH coupling constants 7.6 Hz and 2.0 Hz, the typical J values
for H-3 of inositol, confirm the sulfonylation at O-3. In addition,
coupling of H-5 with OH (J¼2.4 Hz) further supports the fact that
5-OH is unaffected during sulfonylation. The hydroxyl group in
triflate 43 was protected as acetate (98%). Nucleophilic substitution
of triflate 44 with KOAc provided racemic 1,2,3,5-tetra-O-benzyl-
4,6-di-O-acetyl-chiro-inositol (45, 30%) and
a
mixture of
unidentified products. This could be either due to the partial hy-
drolysis of the diacetate 45 or due to the action of other pathways
like SN1 or elimination reactions. However, a detailed study was not
4. Experimental
4.1. General
OBn
OBn
O
O
O
HO
HO
OBn
OBn
OH
c
a,b
d
All chemicals were purchased from Aldrich chemical company.
All experiments were conducted under nitrogen atmosphere.
Melting points were determined with a Yanaco Micro Melting Point
Apparatus and are uncorrected. Flash column chromatography was
performed using silica gel (Fuji Silysia, Silica gel BW-300). 1H and
13C NMR spectra were recorded on a Bruker-DPX-400 instrument.
Chemical shifts (dH values relative to tetramethylsilane and dC
values relative to CDCl3) and coupling constants (J values) are given
in parts per million and hertz, respectively. Elemental analyses
were carried out on a YANACO MT-5 elemental analyzer. Usual
work-up refers to evaporation of the reaction solvent followed by
dissolution of the residue in ethyl acetate and washing successively
with water, dil HCl, satd NaHCO3 solution, and brine followed by
drying over anhydrous MgSO4 and concentration under reduced
pressure.
BnO
4
BnO
BnO
BnO
OBn
OBn
OH
OR
OH
40
41
42
OBn
OBn
MeO
RO
RO
TfO
OR
OR
OBn
OBn
OBn
OBn
j
g
e
BnO
BnO
f
OMe
OR
OR
45. R = Ac
46. R =H
43. R =H
3. R =H
48. R = Ac
h
i
f
44. R = Ac
47. R = Me
Scheme 3. (a) CH(OEt)3, p-TSA, DMF, 100 ꢁC, 2 h; (b) BnBr, NaH, DMF, rt; (c) 1 M HCl,
MeOH, reflux, 1 h; (d) BnBr, NaH, DMF, rt, 10 min; (e) Tf2O, py, 0 ꢁC; (f) Ac2O, py, 0 ꢁC;
(g) KOAc, DMA, 70 ꢁC; (h) Et3N, MeOH, reflux, 1 h; (i) MeI, NaH, DMF, 0 ꢁC; (j) Pd/C, H2,
MeOH, EtOAc, rt.

4004
K.M. Sureshan et al. / Tetrahedron 65 (2009) 3998–4006
4.2. 3-O-Acetyl-1,2:4,5-di-O-isopropylidene-allo-inositol (10)
4.7. ( )-1,2:4,5-Di-O-isopropylidene-3,6-di-O-methyl-chiro-
inositol (34)
4.2.1. Method A
The diacetate 814 (344 mg, 1 mmol) was stirred with tert-
butylamine (1 mL, 9.5 mmol) in methanol (9 mL) at rt for 2 h, when
the TLC showed disappearance of starting material. The solvents
were evaporated and the residue was chromatographed using ethyl
acetate and hexane as eluent to get pure monoacetate 105 (299 mg,
99%). Anal. Calcd for C14H22O7: C, 55.62; H, 7.33. Found: C, 55.46; H,
7.46.
To a solution of diketal 31 (260 mg, 1 mmol) in DMF (8 mL) at
0 ꢁC, sodium hydride (60 mg, 2.5 mmol) was added and stirred for
5 min. Then, methyl iodide (187 mL, 3 mmol) was added and stirred
for 3 h gradually warming the reaction mixture to rt. The excess
NaH was destroyed by adding few drops of methanol and the
mixture was diluted with ethyl acetate, washed successively with
water, dil HCl, and satd NaHCO3 solution, and brine. The organic
layer was dried over MgSO4 and evaporated under reduced pres-
sure to get the dimethyl ether 34 (285 mg, 99%). A small fraction
(50 mg) of this material was passed through a small pad of silica
column to get analytically pure 34.8 Mp 99 ꢁC. Anal. Calcd for
C14H24O6: C, 58.32; H, 8.39. Found: C, 58.14; H, 8.47.
4.2.2. Method B
The diacetate 8 (172 mg, 0.5 mmol) was stirred with iso-butyl-
amine (0.5 mL, 4.55 mmol) in methanol (5 mL) at rt for 1 h. The
solvents were evaporated and the residue was chromatographed
using ethyl acetate and hexane as eluent to get pure monoacetate
10 (140 mg, 93%).
4.8. ( )-1,4-Di-O-methyl-chiro-inositol (2)
4.2.3. Method C
Diketal 34 (235 mg, 0.81 mmol) was stirred in a mixture of tri-
fluoroacetic acid (TFA) and water (2.5 mL, 4:1 v/v) at rt for 3 h. The
solvents were evaporated and the residue was chromatographed
using ethyl acetate as the eluent to get pure dimethyl ether 28
(124 mg, 73%).
The diacetate 8 (172 mg, 0.5 mmol) was refluxed with triethyl-
amine (0.5 mL) in methanol (5 mL) at rt for 1 h. The solvents were
evaporated and the residue was chromatographed using ethyl ac-
etate and hexane as eluent to get pure monoacetate 10 (138 mg,
91%).
4.9. ( )-1,2,4,5-Tetra-O-acetyl-3,6-di-O-methyl-chiro-
inositol (35)
4.3. 2-O-Acetyl-1,6:3,4-di-O-isopropylidene-5-O-methyl-allo-
inositol (11)
To a solution of tetrol 2 (100 mg, 0.48 mmol) in pyridine (5 mL)
at 0 ꢁC, acetic anhydride (472
mL, 5 mmol) was added dropwise and
To a solution of acetate 10 (302 mg, 1 mmol) in DMF (6 mL) at
0 ꢁC, sodium hydride (29 mg,1.2 mmol) was added and the solution
was stirred for 5 min. Then, methyl iodide (125 mL, 2 mmol) was
the mixture was stirred overnight gradually warming the reaction
mixture to rt. Pyridine was evaporated under reduced pressure and
the residue was dissolved in ethyl acetate, washed successively
with water, dil HCl, satd NaHCO3 solution, and brine. The organic
layer was dried over anhydrous MgSO4 and evaporated under re-
duced pressure. The residue thus obtained was chromatographed
using ethyl acetate/hexane as the eluent to provide pure tetraace-
tate 358 (168 mg, 93%).
added and the mixture was stirred at rt for 3 h, when the TLC
showed complete disappearance of the starting material. The
mixture was diluted with ethyl acetate, washed with water, dil HCl,
and satd NaHCO3 solution, and brine. The organic layer was dried
and evaporated under reduced pressure to provide pure methyl
ether 115 (310 mg, 98%). Further purification was done by crystal-
lization from a mixture of ethyl acetate and hexane. Anal. Calcd for
C15H24O7: C, 56.95; H, 7.65. Found: C, 56.79; H, 7.78.
4.10. 2,4,6-Tri-O-benzyl-myo-inositol 1,3,5-orthoformate (40)
To a solution of triol 3923 (760 mg, 4 mmol) in DMF (20 mL) at
0 ꢁC, NaH (360 mg, 15 mmol) was added and the mixture was
stirred under argon atmosphere for 10 min. Then, BnBr (1.8 mL,
15 mmol) was added at 0 ꢁC and the mixture was stirred for 3 h
gradually warming the reaction mixture to rt. The excess NaH and
BnBr were quenched by adding methanol and the mixture was
diluted with ethyl acetate and washed successively with water, cold
dil HCl, satd NaHCO3 solution, and brine. The organic layer was
dried over anhydrous MgSO4 and evaporated to dryness to get
a gummy material, which was further purified by column chro-
matography using ethyl acetate and hexane as eluent to get the
known tribenzyl ether 4024a,25 (1.638 g, 89%).
4.4. 5-O-Methyl-allo-inositol (1)
The acetate 11 (280 mg, 0.88 mmol) was stirred in a mixture of
1 N HCl (1 mL) and methanol (4 mL) at rt overnight. Evaporation of
the solvents followed by co-evaporation with toluene provided
pure methyl ether 15 (171 mg, 100%). Anal. Calcd for C7H14O6: C,
43.30; H, 7.27. Found: C, 43.09; H, 7.41.
4.5. ( )-1-O-Acetyl-2,3:5,6-di-O-isopropylidene-chiro-
inositol (33)
The monotriflate 3214 (542 mg, 1.38 mmol) was stirred with
potassium acetate (677 mg, 6.9 mmol) in DMA (12 mL) at 70 ꢁC for
12 h. The reaction mixture was diluted with ethyl acetate, washed
successively with water, dil HCl, satd NaHCO3, and brine. The or-
ganic layer was dried and evaporated under reduced pressure. The
crude residue was chromatographed to get the known mono-
acetate 3314 (380 mg, 91%).
4.11. 2,4,6-Tri-O-benzyl-myo-inositol (41)
A suspension of tribenzyl ether 40 (920 mg, 2 mmol) in a mix-
ture of methanol (15 mL) and 1 N HCl (2 mL) was refluxed for 1 h.
Evaporation of the solvent provided the known triol 4124 (900 mg)
in quantitative yield.
4.6. ( )-1,2:4,5-Di-O-isopropylidene-chiro-inositol (31)
4.12. 1,2,4,6-Tetra-O-benzyl-myo-inositol (42)
The acetate 33 (358 mg, 1.18 mmol) was refluxed with sodium
methoxide (6 mg, 0.11 mmol) in methanol (10 mL) for 2 h. Metha-
nol was evaporated and the residue was chromatographed to get
pure diol 3114 (290 mg, 94%).
To a solution of triol 41 (900 mg, 2 mmol) in DMF (15 mL) at
0 ꢁC, NaH (52 mg, 2.2 mmol) was added and the mixture was stir-
red under argon atmosphere for 10 min. Then, BnBr (240
mL,
2 mmol) was added at 0 ꢁC and the mixture was stirred for 3 h

K.M. Sureshan et al. / Tetrahedron 65 (2009) 3998–4006
4005
gradually warming the reaction mixture to rt. The mixture was
diluted with ethyl acetate and washed successively with water, cold
dil HCl, satd NaHCO3 solution, and brine. The organic layer was
dried over anhydrous MgSO4 and evaporated to dryness to get
a gummy material, which was further purified by column chro-
matography using ethyl acetate and hexane (3:7 v/v) as eluent to
get pure tetrabenzyl ether 4226 (767 mg, 71%).
(COCH3), 67.3, 71.9, 73.1, 73.3, 73.6, 74.6, 74.7, 75.5, 77.2, 79.4, 79.4,
127.5, 127.6, 127.7, 127.8, 127.83, 127.9, 127.90, 127.92, 128.3, 128.4,
128.43, 137.8, 137.9, 138.1, 138.6, 169.8 (OCOCH3), 170.02 (OCOCH3).
Anal. Calcd for C38H40O8: C, 73.06; H, 6.45. Found: C, 72.91; H, 6.69.
4.16. 1,2,3,5-Tetra-O-benzyl-chiro-inositol (46)
A mixture of diacetate 45 (190 mg, 0.3 mmol) and triethylamine
(1 mL) was refluxed in methanol (8 mL) for 1 h. The solvents were
evaporated and the residue was dissolved in ethyl acetate, washed
with water, dil HCl, satd NaHCO3 solution, and brine. The organic
layer was dried over MgSO4 and evaporated under reduced pres-
sure to provide the diol 46 (137 mg, 83%). 1H NMR (CDCl3,
400 MHz): 2.34 (s, OH), 2.47 (s, OH), 3.69 (dd, 9.6, 4.0 Hz, H-2),
3.80–3.91 (m, 3H, H-3, H-4 and H-5), 3.94 (dd, 4.0, 2.0 Hz, H-6), 3.99
(dd, 4.4, 2.8 Hz, H-1), 4.66 (AB q, 57.2, 12.0 Hz, PhCH2), 4.67 (AB q,
98.0, 12.0 Hz, PhCH2), 4.67 (AB q, 24.8, 11.6 Hz, PhCH2), 4.86 (AB q,
87.6, 10.8 Hz, PhCH2), 7.20–7.40 (m, 20H, Ph); 13C NMR (CDCl3,
100.4 MHz): 68.1, 72.98, 72.99, 73.6, 75.3, 76.0, 79.5, 79.7, 81.1,
127.56, 127.61, 127.64, 127.91, 127.95, 128.0, 128.14, 128.4, 128.6,
138.1, 138.50, 138.53, 138.9. Anal. Calcd for C34H36O6: C, 75.53; H,
6.71. Found: C, 75.52; H, 6.88.
4.13. 1,2,4,6-Tetra-O-benzyl-3-O-trifluoromethanesulfonyl-
myo-inositol (43)
To a solution of tetrabenzyl ether 42 (750 mg, 1.39 mmol) in
pyridine (12 mL) at 0 ꢁC, trifluoromethanesulfonic anhydride
(252 mL, 1.5 mmol) was added dropwise and the solution was stir-
red at that temperature for 2 h. The mixture was then diluted with
ethyl acetate and washed with cold dil HCl, satd NaHCO3 solution,
and brine. The organic layer was dried over anhydrous MgSO4 and
evaporated under reduced pressure. The crude material thus
obtained was further purified by column chromatography using
ethyl acetate/hexane as eluent to get the 3-triflate 43 (757 mg,
81%). 1H NMR (CDCl3, 400 MHz): 2.41 (d, 2.4 Hz, OH), 3.44 (dd, 9.6,
2.4 Hz, H-1), 3.53 (dd, 9.2, 2.4 Hz, H-5), 3.90 (dd, 10.0, 8.8 Hz, H-6),
4.00 (dd, 10.0, 9.6 Hz, H-4), 4.16 (dd, 2.4, 2.0 Hz, H-2), 4.62 (dd, 7.6,
2.0 Hz, H-3), 4.64–4.96 (m, 8H, 4ꢃPhCH2), 7.20–7.40 (m, 20H, Ar);
13C NMR (CDCl3, 100 MHz): 73.2 (Ins C), 74.7 (Ins C), 75.3 (Ins C),
75.5 (2ꢃIns C), 76.2 (Ins C), 78.1, 79.8, 80.3, 86.7 (Ins C-3), 117.5 (q,
CF3), 127.6, 127.9, 128.0, 128.1, 128.4, 128.48, 128.51 (Ph),137.5, 137.6,
137.7, 138.3 (4ꢃipso C). Anal. Calcd for C35H35F3O8S: C, 62.49; H,
5.24. Found: C, 62.19; H, 5.30.
4.17. 4,6-Di-O-methyl-1,2,3,5-tetra-O-benzyl-chiro-
inositol (47)
To a solution of diol 46 (130 mg, 0.24 mmol) in DMF (3 mL), NaH
(24 mg, 1 mmol) was added at 0 ꢁC and stirred for 5 min. Then,
methyl iodide (63 mL, 1 mmol) was added and stirred for additional
1 h. The reaction was quenched by addition of few drops of meth-
anol. The mixture was diluted with ethyl acetate, washed with
water, dil HCl, satd NaHCO3 solution, and brine. The organic layer
was dried over anhydrous MgSO4 and evaporated under reduced
pressure. The residue was purified by column chromatography to
yield pure dimethyl ether 47 (100 mg, 73%). 1H NMR (CDCl3,
270 MHz): 3.21 (s, 3H, CH3), 3.34 (dd, 3.42, 2.93 Hz, H-6), 3.51 (t,
9.28 Hz, H-4), 3.68 (s, 3H, CH3), 3.65–3.85 (m, 4H, 4ꢃInsH), 4.40–
4.90 (m, 8H, 4ꢃPhCH2), 7.20–7.40 (m, 20H, Ph); 13C NMR (CDCl3,
100.4 MHz): 58.8 (CH3), 61.3 (CH3), 73.2, 73.4, 73.5, 74.2, 75.8, 77.2,
77.7, 79.3, 79.7, 82.2, 83.8, 127.4, 127.5, 127.58, 127.61, 127.9, 128.0,
128.02, 128.26, 128.31, 138.4, 138.77, 138.8, 139.2. Anal. Calcd for
C36H40O6: C, 76.03; H, 7.09. Found: C, 75.81; H, 7.27.
4.14. 5-O-Acetyl-1,2,4,6-tetra-O-benzyl-3-O-trifluoro-
methanesulfonyl-myo-inositol (44)
To a solution of the triflate 43 (750 mg, 1.11 mmol) in pyridine
(10 mL) at 0 ꢁC, acetic anhydride (142
mL, 1.5 mmol) was added
dropwise and the mixture was stirred under argon atmosphere for
3 h gradually warming the mixture to rt. Pyridine was then evap-
orated and the residue was dissolved in ethyl acetate, washed
successively with water, dil HCl, satd NaHCO3 solution, and brine.
The organic layer was dried over anhydrous MgSO4 and evaporated
under reduced pressure. The residue was further purified by col-
umn chromatography using ethyl acetate/hexane as eluent to
provide pure acetate 44 (781 mg. 98%). 1H NMR (CDCl3, 400 MHz):
1.76 (s, 3H, COCH3), 3.52 (dd, 9.77, 2.44 Hz, H-1), 3.96 (t, 9.77 Hz, H-
6), 4.08 (t, 9.28 Hz, H-4), 4.17 (t, 2.44 Hz, H-2), 4.48–4.96 (m, 9H, H-
3, 4ꢃPhCH2), 5.08 (dd, 9.77, 9.28 Hz, H-5), 7.22–7.39 (m, 20H, Ar);
13C NMR (CDCl3, 100 MHz): 20.7 (CH3), 73.2 (Ins C), 73.5 (Ins C), 75.4
(Ins C), 75.5 (Ins C), 75.7 (Ins C), 76.3, 76.9, 78.4 (q, CF3), 79.9, 86.7,
118.4 (q, CF3), 127.68, 127.74, 127.8, 127.9, 128.0, 128.2, 128.35,
128.43, 128.6 (Ph), 137.3, 137.4, 137.6, 138.1 (4ꢃipso C), 169.6 (CO).
Anal. Calcd for C37H37F3O9S: C, 62.18; H, 5.22. Found: C, 61.98; H,
5.25.
4.18. 1,3-Di-O-methyl-chiro-inositol (3)
A solution of tetrabenzyl ether 47 (90 mg, 0.16 mmol) in a mix-
ture of methanol and ethyl acetate (5 mL, 1:1 v/v) was stirred with
10% Pd on charcoal (18 mg, 20 wt %) under atmosphere of hydrogen
(H2 balloon) at rt for 24 h. The mixture was filtered through
a membrane filter by washing well with methanol and water. The
combined filtrate and washings were evaporated under reduced
pressure to obtain pure dimethyl ether 3 (29 mg, 89%). 1H NMR
(D2O, 400 MHz): 3.28 (t, 9.4 Hz, H-3), 3.48 (s, 3H, OCH3), 3.60 (s, 3H,
OCH3), 3.63 (t, 9.6 Hz, H-4), 3.64 (t, 3.6 Hz, H-1), 3.69 (dd, 9.6,
3.6 Hz, H-5), 3.86 (dd, 10.2, 3.6 Hz, H-2), 4.22 (t, 3.6 Hz, H-6); 13C
NMR (D2O, 100.4 MHz, std dioxane 66.5 ppm): 58.5, 59.8, 67.8, 70.6,
71.9, 81.5, 83.0. Anal. Calcd for C8H16O6: C, 46.15; H, 7.75. Found: C,
45.89; H, 7.86.
4.15. 4,6-Di-O-acetyl-1,2,3,5-tetra-O-benzyl-chiro-inositol (45)
The triflate 44 (770 mg, 1.08 mmol) and potassium acetate
(491 mg, 5 mmol) were dissolved in dimethylacetamide (6 mL) and
the mixture was stirred at 70 ꢁC for 12 h. The mixture was diluted
with ethyl acetate and washed with water and brine. The organic
layer was dried over anhydrous MgSO4 and evaporated under re-
duced pressure. Purification by column chromatography provided
the diacetate 45 (202 mg, 30%). 1H NMR (CDCl3, 400 MHz): 1.93 (s,
3H, COCH3), 2.01 (s, 3H, COCH3), 3.71 (t, 3.9 Hz, H-1), 3.74–3.80
(2ꢃdd, H-2 and H-5), 3.88 (t, 9.8 Hz, H-3), 4.31–4.89 (m, 8H,
4ꢃPhCH2), 5.31 (t, 9.8 Hz, H-4), 5.35 (t, 3.9 Hz, H-6), 7.20–7.40 (m,
20H, Ph); 13C NMR (CDCl3, 100.4 MHz): 20.90 (COCH3), 20.95
4.19. 1,2,3,5-Tetra-O-acetyl-4,6-di-O-methyl-chiro-
inositol (48)
To a solution of dimethyl ether 3 (20 mg, 0.1 mmol) in pyridine
(2 mL) at 0 ꢁC was added acetic anhydride (95
mL, 1 mmol) and the
mixture was stirred for 3 h gradually warming the mixture to rt.
The excess pyridine and acetic anhydride were evaporated and the

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672–674; 3-O-Methyl-scyllo-inosamine: Ref. 2k.
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residue was dissolved in ethyl acetate, washed with water, dil HCl,
satd NaHCO3 solution, and brine. The organic layer was dried over
anhydrous MgSO4 and evaporated under reduced pressure. The
crude acetate was further purified by column chromatography us-
ing ethyl acetate and hexane as eluent to get pure tetraacetate 48
(34 mg, 93%). 1H NMR (CDCl3, 400 MHz): 1.99 (s, 3H, COCH3), 2.08
(s, 3H, COCH3), 2.14 (s, 6H, 2ꢃCOCH3), 3.47 (s, 3H, OCH3), 3.49 (s, 3H,
OCH3), 3.68 (t, 3.4 Hz, H-1), 3.68 (t, 9.8 Hz, H-3), 5.12 (dd, 10.3,
2.9 Hz, H-2), 5.20 (10.3, 3.4 Hz, H-5), 5.34 (9.8 Hz, H-4), 5.49 (t,
3.9 Hz, H-6); 13C NMR (CDCl3, 100.4 MHz): 20.65 (COCH3), 20.82
(COCH3), 20.86 (COCH3), 21.02 (COCH3), 59.32 (OCH3), 60.57 (OCH3),
67.24, 69.23, 71.26, 72.62, 76.55, 78.66, 169.73 (OCOCH3), 169.75
(OCOCH3), 170.04 (OCOCH3), 170.11 (OCOCH3). Anal. Calcd for
C16H24O10: C, 51.06; H, 6.43. Found: C, 50.98; H, 6.54.
12. Sureshan, K. M.; Yamasaki, T.; Hayashi, M.; Watanabe, Y. Tetrahedron: Asym-
metry 2003, 14, 1771–1774.
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14. Sureshan, K. M.; Ikeda, K.; Asano, N.; Watanabe, Y. Tetrahedron 2008, 64, 4072–
4080.
Acknowledgements
15. Haasnoot, C. A. G.; De Leeuw, F. A. A. M.; Altona, C. Tetrahedron 1980, 36, 2783–
2792.
We thank JSPS for a postdoctoral fellowship (K.M.S.) and Grant-
in-aid (No. 02170). Also we thank Venture Business Laboratory and
Advanced Instrumentation Center for Chemical Analysis, Ehime
University for NMR and elemental analysis, respectively.
16. Assuming the ideal dihedral angle of 60ꢁ for both ae and ee, the calculated
3
(using Haasnoot–Altona equation) JHH values for H1–H2, H2–H3, H5–H6, and
H4–H5 are 2.2, 3.8, 2.2, and 0.65 Hz, respectively. The small variation between
3
observed and calculated JHH values could be due to the slight deviation of
torsion from the ideal torsion of 60ꢁ.
17. Sureshan, K. M.; Watanabe, Y. Carbohydr. Res. 2005, 340, 2311–2318.
18. Angyal, S. J.; Odier, L. Carbohydr. Res. 1983, 123, 23–29.
Supplementary data
19. Jaramillo, C.; Chiara, J.-L.; Martin-Lomas, M. J. Org. Chem. 1994, 59, 3135–3141.
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Teyral, J.; Capen, R.; Huang, M.; Sturgess, A. W.; Hennessey, J. P.; Washabaugh,
M.; Sitrin, R.; Abeygunawardana, C. Anal. Biochem. 2005, 337, 235–245; (c) Son,
T.-D.; Chachaty, C. Biochim. Biophys. Acta 1973, 335, 1–13.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.03.024.
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