Resolution of synthetically useful myo-inositol derivatives using the chiral auxiliary O-acetylmandelic acid

Article abstract of DOI:10.1016/j.tetasy.2004.11.030

Efficient methods for the resolution of various myo-inositol derivatives have been developed using O-acetylmandelic acid (OAM) as the chiral auxiliary. Various methods of introduction of the chiral auxiliary have been compared. DCC mediated coupling betwe

Full text of DOI:10.1016/j.tetasy.2004.11.030

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 231–241
Resolution of synthetically useful myo-inositol derivatives using
the chiral auxiliary O-acetylmandelic acid
Kana M. Sureshan,*,ꢀ Yoko Kiyosawa, Fushe Han, Sayuri Hyodo,
Yuhki Uno and Yutaka Watanabe*
Department of Applied Chemistry, Faculty of Engineering, Ehime University, Matsuyama 790-8577, Japan
Received 2 November 2004; accepted 17 November 2004
Available online 25 December 2004
Abstract—Efficient methods for the resolution of various myo-inositol derivatives have been developed using O-acetylmandelic acid
(OAM) as the chiral auxiliary. Various methods of introduction of the chiral auxiliary have been compared. DCC mediated coupling
between the inositol derivative and O-acetylmandelic acid resulted in substantial racemization even at 0 ꢀC; while acylation with O-
acetylmandeloyl chloride in the presence of pyridine gave the diastereomers without any racemization of the chiral auxiliary. The
advantage of using OAM as a chiral auxiliary is that the absolute configuration of the resolved diastereomers can be determined by
1
analyzing the H NMR chemical shifts of various protons. The diastereomeric separation has been achieved either by fractional
crystallization or column chromatography. The enantiomers of inositol derivatives could be obtained by the removal of chiral aux-
iliaries. By employing the known selective protection–deprotection strategies, various derivatives in optically active form could be
synthesized.
ꢁ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
continues. Although various chiral auxiliaries have been
used to resolve myo-inositol derivatives, the absolute
configuration of the resulting diastereomers are usually
deduced by conversion to a derivative of known abso-
lute stereochemistry, at times through a number of
chemical transformations, which are time consuming
and costly.
The realization that phosphorylated inositols play cru-
cial roles in various biological processes such as cellular
signal transduction,1 anchoring of proteins to the cell
membrane2 etc. has accelerated the pace of research
associated with the chemistry and biology of inositols
over the last two decades. The increased interest in the
biological role played by phosphoinositols necessitated
better synthetic strategies for their preparation. In addi-
tion, the disclosed therapeutic potential3 of inositol
derivatives and the recent use of inositol as the synthon
for the synthesis of many natural products4 have given
further impact to the myo-inositol chemistry. This
multi-faceted importance of inositol demands better
methods for the resolution and selective protection–
deprotection for this meso-cyclohexane hexol. Many
methods are known for the selective protection and
deprotection of myo-inositol hydroxyl groups.5 Still
the search for efficient methodologies for its resolution
We have recently reported6 a reliable method for the
determination of the absolute configuration of inositol
derivatives and other secondary alcohols using OAM
esters as a chiral anisotropy reagent (CAR). Our study
unambiguously established that OAM could be reliably
used as a CAR in inositol and other cyclitol systems for
the determination of their absolute configuration. The
conformational model for OAM esters is similar to that
of Trostꢁs model7 for MPA (methoxy phenyl acetate)
derivatives. According to this, the OAM takes up a
syn-periplanar conformation whereby the a-hydrogen,
carbonyl carbon, and C–OAc align in a coplanar
arrangement (Fig. 1). In this conformation, the phenyl
group shields HA and HB in (R)-OAM ester and HX
and HY in (S)-OAM ester. Thus DdS–R for HA and HB
protons will be positive and for HX and HY will be neg-
ative. Therefore by measuring Dd of protons on both the
sides of OAM plane, the absolute configuration can be
determined. Due to this additional advantage, we chose
*
Corresponding authors. Tel.: +81 89 927 9921; fax: +81 89 927
9944; e-mail addresses: sureshankm@yahoo.co.in; wyutaka@dpc.
ehime-u.ac.jp
ꢀ Present address: Department of Pharmacy and Pharmacology, Uni-
versity of Bath, Bath BA2 7AY, UK.
0957-4166/$ - see front matter ꢁ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.030

232
K. M. Sureshan et al. / Tetrahedron: Asymmetry 16 (2005) 231–241
hexylidene ketal was cleaved by treatment with aqueous
δ
S-R >0
HA
acetic acid to afford the known tetrabenzoates 10L and
10D, respectively. Unfortunately, HPLC analysis (chiral-
cel OD column) of these tetrabenzoates revealed that
they are not enantiomerically pure. This suggested that
racemization of the chiral auxiliary occurred during its
introduction. Hence, other methods for the introduction
of chiral auxiliaries were sought (Table 1). DMC (2-
chloro-1,3-dimethyl-imidazolinium chloride) mediated
coupling of (S)-O-acetylmandelic acid and diol ( )-1
also resulted in serious racemization at the chiral auxil-
iary giving four different diesters. However, the use of
O-acetylmandeloyl chloride, in the presence of pyridine,
for the acylation resulted in formation of 6 and 7 in very
good yield compared to the other two methods. The
conversion into enantiomers of tetrabenzoate 10 and
their HPLC analysis revealed that they are enantiomer-
ically pure. The acid chloride method gave the diesters 6
and 7 not only in very good yield but also without any
racemization. Thus chloride method was taken as the
optimum condition for the introduction of the chiral
auxiliary.
HB
H
OAM plane
O
OAc
(Ph)
O
H
(S)-OAM
(R)-OAM
HX
S-R <0
HY
Ph
(H)
δ
Figure 1. Conformational model for (S)-OAM and (R)-OAM esters of
inositols.
O-acetylmandelic acid as the chiral auxiliary for the res-
olution of various protected myo-inositol derivatives.
We herein report methods for the resolution of synthet-
ically useful partially protected myo-inositol derivatives
1–5 using O-acetylmandelic acid4b,d,8 as the chiral
auxiliary.
R
R
R
R
O
O
O
HO
HO
O
HO
O
O
2
2
1
6
1
6
3
4
3
4
O
Si
O
_
_
+
+
2
The 1H NMR spectra of both the diastereomers 8 and 9
were analyzed to assign the absolute configuration.
According to the conformational model, H-1 and H-2
in L-3,6-di-O-[(S)-O-acetylmandeloyl]-1,2-O-isopropyl-
idene-myo-inositol and H-4 and H-5 in the diastereomer
D-3,6-di-O-[(S)-O-acetylmandeloyl]-1,2-O-isopropylide-
ne-myo-inositol are expected to be shielded by the phe-
nyl group of OAM and hence these proton signals are
expected to appear at higher fields in the respective dia-
stereomer compared to the other diastereomer. H-4 and
H-5 in the less polar diastereomer (Rf = 0.55 AcOEt/
benzene = 1/1) are shielded by 0.17 ppmand 0.25 ppm,
respectively, and H-1 and H-2 in the more polar diaste-
reomer (Rf = 0.35) are shielded by 0.24 ppmand
0.20 ppm, respectively. Thus the first (less polar) and
the second (more polar) diastereomers were assigned
to be D-3,6-di-O-[(S)-O-acetylmandeloyl]-1,2-O-isoprop-
1
6
3
5
5
_
+
O
OH
OH
4
Si
5
O
OH
OH
O
R
OH
R
1. RR = (CH2)5
2. R = Me
3. RR = (CH2)5
4. R= Me
5
2. Results and discussion
Ketalization of myo-inositol with excess ketal donor re-
agents is known to produce a mixture of ketals from
which the diketal 1 or 2 can be crystallized in 20–25%
yield. The relative reactivity of hydroxyl groups in
1,2:4,5-di-O-alkylidene-myo-inositols has been studied
extensively.9 It has been reported that phosphoryl-
ation,10 acylation,10,11 silylation10,12 and alkylation13
undergo selectively at the 3-O-position. Also, it is docu-
mented13a,14 that the trans-ketal can be cleaved in the
presence of the cis. These selectivities in diols 1 and 2
make them good synthons for many inositol phosphates
and lipid derivatives. However, methodologies for effi-
cient resolution of these diols are scarce in the literature.
Thus, we have investigated resolution of these diols
using OAM as the chiral auxiliary.
ylidene-myo-inositol
8 and L-3,6-di-O-[(S)-O-acetyl-
mandeloyl]-1,2-O-isopropylidene-myo-inositol 9, res-
pectively. The fact that 8 and 9 were converted to 10L
and 10D, respectively, further substantiated the struc-
1
tural assignments of 8 and 9 based on H NMR.
Diols 8 and 9 allow access to the 4-OH and 5-OH of ino-
sitol for phosphorylation or other derivatization. To
have access to another pair of hydroxyl groups (3-OH
and 6-OH), the diols 8 and 9 were re-protected again
to di-cyclohexylidene derivatives 6 and 7, respectively,
in very good yields. Diol 8 on treatment with 1,1-
dimethoxycyclohexane in the presence of catalytic
amount of camphorsulfonic acid provided the diastereo-
merically pure diketal 6 in very good yield. Similarly,
compound 9 was converted to 7. Removal of the chiral
auxiliary from 6 and 7 by hydrazinolysis provided diols
DCC mediated coupling of the racemic diol 1 with ex-
cess of (S)-O-acetylmandelic acid gave a chromato-
graphically inseparable mixture of diastereomers 6 and
7 in moderate yield (Scheme 1). However, the selective
cleavage of the more labile trans-cyclohexylidene using
15
pyridiniumpolyhydrogenfluoride
mation of diols 8 and 9, which could be separated by
resulted in the for-
column chromatography.
17
To check the enantiomeric excess of the individual dia-
stereomers 8 and 9, they were converted to the known16
tetra-O-benzoyl-myo-inositols 10L and 10D. The acetyl-
mandeloyl groups were removed by hydrazinolysis and
the tetrols 3D and 3L obtained were benzoylated, under
standard conditions, and finally the acid labile cyclo-
1D and 1L in enantiomerically pure forms.
Next, we turned our attention to the resolution of di-iso-
propylidene-myo-inositol, ( )-2 to see whether we can
separate the diastereomers at the diketal stage itself.
The acylation of the diketal ( )-2 with (S)-O-acetyl-

K. M. Sureshan et al. / Tetrahedron: Asymmetry 16 (2005) 231–241
233
O
O
O
O
OR
O
HO
O
O
RO
O
O
a/b/c
+
_
+
RO
OH
OR
O
O
O
d
7
6
1
O
O
O
O
RO
HO
O
O
OR
e
e
HO
HO
O
O
OH
OH
+
OR
RO
OH
OH
HO
8
OH
h
OH
9
OH
h
OH
3D
3L
f, g
OH
7
6
f,g
e
e
OH
O
O
HO
OBz
OBz
BzO
BzO
OH
HO
O
O
OH
BzO
OBz
O
OH
1D
HO
O
OBz
OBz
O
O
1L
10L
10D
R = (S)-PhCH(OAc)(CO)-
Scheme 1. Reagents and conditions: (a) (S)-O-acetylmandeloyl chloride, pyr, DMAP, 0 ꢀC; (b) (S)-O-acetylmandelic acid, DCC, CH2Cl2, 0 ꢀC; (c)
(S)-O-acetylmandelic acid, DMC, CH2Cl2, pyr, 0 ꢀC; (d) pyr(HF)x, ethylene glycol, MeCN; (e) N2H4ÆH2O, ethanol, rt; (f) BzCl, Et3N, DMAP,
CH2Cl2, 0 ꢀC, 21 h; (g) 80% AcOH, reflux, 3 h; (h) 1,1-dimethoxy cyclohexane, CSA, CH2Cl2, reflux.
Table 1. Comparison of different methods for O-acetylmandeloylation of ( )-1
Reagents and conditions
% Yield (6 + 7)
% Eea 1D, 1L
1
2
3
O-Acetylmandelic acid, DCC, DMAP, CH2Cl2, 0 ꢀC
O-Acetylmandelic acid, DMC, pyr, CH2Cl2, 0 ꢀC
O-Acetylmandeloyl chloride, pyr, DMAP, CH2Cl2, 0 ꢀC
60
71
98
72, 76
Substantial racemization
100, 100
a Determined by conversion to 10 and HPLC analysis.
mandeloyl chloride18 in pyridine gave diastereomers 11
and 12 in good yield (Scheme 2). However, diesters 11
and 12 were inseparable by chromatography as in the
case of their cyclohexylidene counterparts. However,
crystallization froma mixture of ethyl acetate and hex-
ane yielded one of the diastereomers in pure form (by
1H NMR) in 46% yield (92% of the theoretical maxi-
mum) as cotton-like fluffy crystals. Further crystalliza-
tion of the concentrated mother liquor from
chloroform–hexane yielded the second diastereomer in
very pure formin good yield (42%) as dense thick crys-
tals. Thus both the diastereomers could be separated by
sequential crystallizations.
ylidene-myo-inositol are expected to be shielded by the
phenyl group of OAM. H-5 and H-6 in the first diaste-
reomer (crystallized from ethyl acetate–hexane) are
shielded by 0.22 ppmand 0.02 ppm, respectively, and
H-2 and H-3 in the second diastereomer (crystallized
fromchloroform–hexane) are shielded by 0.22 ppmand
0.37 ppm, respectively. Thus the first and the second dia-
stereomers were assigned to be L-1,4-di-O-[(S)-O-acetyl-
mandeloyl]-2,3:5,6-di-O-isopropylidene-myo-inositol
and
D-1,4-di-O-[(S)-O-acetylmandeloyl]-2,3:5,6-di-O-
isopropylidene-myo-inositol, respectively. Later, these
assignments were substantiated by solving the single
crystal X-ray structure of the second diastereomer.19
The absolute configuration of 11 and 12 were determined
by analyzing their H NMR spectra. H-2 and H-3 in D-
1,4-di-O-[(S)-O-acetylmandeloyl]-2,3:5,6-di-O-isopropyl-
idene-myo-inositol and H-5 and H-6 in the diastereomer
L-1,4-di-O-[(S)-O-acetylmandeloyl]-2,3:5,6-di-O-isoprop-
The chiral auxiliaries could be removed by hydrazinoly-
sis to yield enantiomers of diol 2 in quantitative yields.
Also, to check the synthetic versatility of diastereomers
11 and 12, we attempted cleavage of the trans-isopropyl-
idene in presence of the cis. In general, the reported
1

234
K. M. Sureshan et al. / Tetrahedron: Asymmetry 16 (2005) 231–241
+_
2
a
O
O
O
RO
O
O
O
OR
O
+
OR
RO
O
11
12
O
O
c
c
O
OR
OH
RO
HO
O
b
b
RO
OR
O
O
O
OH
b
OH
b
14
13
HO
O
O
OH
O
O
OH
HO
2L
4L
O
4D
2D
R = (S)-PhCH(OAc)(CO)-
Scheme 2. Reagents and conditions: (a) (S)-(+)-O-acetylmandeloyl chloride (2.1 equiv), pyr, 0 ꢀC, 2 h; (b) N2H4ÆH2O, EtOH, rt, 3 h; (c) TFA
(2 equiv), H2O (1 equiv), CH2Cl2, 0 ꢀC to rt, 50 min.
methods for the selective trans-ketal cleavage are low
yielding (around 60%). Recently a high yielding method
using ion exchange resin has been reported.14b Unfortu-
nately, we were unable to cleave the trans-ketal fromthe
diester 11 or 12 by this method. After some experimen-
tation we arrived at an optimum condition for the selec-
tive cleavage of the trans-ketal from 11 or 12 using a
limited amount of TFA and water (2 and 1 equiv,
respectively) in CH2Cl2 to get diols 13 and 14 in good
yields (82–87%). Since 11 and 12 were separated by crys-
tallization, the enantiomeric purity of the diols 2D and
2L alone does not rule out the possible racemization at
the chiral auxiliary during its introduction. For this rea-
son, the inseparable mixture of 11 and 12 obtained was
subjected to trans-isopropylidene cleavage to obtain
chromatographically separable diols 13 and 14, which
were individually converted to enantiomers of tetra-
benzoate and their enantiomeric excesses established
by HPLC analysis. This ruled out racemization of the
chiral auxiliary. Since diketals 1 and 2 and their deriva-
tives are identical in terms of reactivity and selectivity,
resolution of ( )-2 is more appealing as both the result-
ing diastereomers 11 and 12 can be separated by sequen-
tial crystallization.
alents of O-acetylmandeloyl chloride in pyridine gave a
mixture of many products. Stannylene mediated reac-
tions have often been employed for regioselective func-
tionalization of polyol derivatives.21 Gigg et al.
reported22 that tin mediated benzylation of 1,2-O-iso-
propylidene-myo-inositol 4 yields 3,6-di-O-benzyl-1,2-
O-isopropylidene-myo-inositol predominantly. By anal-
ogy, we anticipated similar selectivity during acylation
also. Thus the tetrol ( )-3 was converted into the stann-
ylene acetals by treatment with Bu2SnO in refluxing tolu-
ene in a Dean–Stark apparatus. Subsequent treatment
with excess (more than 2 equiv) of O-acetylmandeloyl
chloride at low temperature (ꢀ20 ꢀC) gave both
D- and L-3,6-di-O-acetylmandelate derivatives (1:1) as
expected with minor amounts of 3-O-monoesters
(D/L = 1:1). The diesters could be separated by column
chromatography, but not the monoesters. NMR analy-
sis revealed that the diesters were contaminated with
other positional isomers. At relatively higher tempera-
ture (0 ꢀC) no monoester was isolated but a mixture of
triacylated derivatives were formed. When the solvent
for the acylation was changed to dichloromethane,
interestingly, both the diastereomers 8 and 9 (Scheme
3) were obtained without any contaminated regioiso-
mers. Also, one of the diastereomers has been found
to formpredominantly over the other. In all the
attempts, the L-diastereomer, 9 was obtained in higher
yield than the corresponding D-diastereomer, 8. In addi-
tion, the ratio of monoester was found to be in the
reverse order as expected. By using 2.5 equiv of acyl
chloride we obtained 42% of 9, 10% of 8 and 20% of
15 without any contamination of 16. Similar results were
obtained when a structurally similar isopropylidene
derivative ( )-4 was used (Table 2). Irrespective of the
amount of acyl chloride used, only 1.2–1.5 equiv of acyl
chloride were consumed in the reaction. From these
results, it is obvious that the first acylation is at the 3-
Although diketal derivatives are synthetically versatile,
the major disadvantage of using the diketal 1 or 2 as
starting material is that the diketalization of inositol
yields a mixture of ketals, where the yield of the required
diketal 1 or 2 is only about 20–25%. On the other hand,
monoketalization of myo-inositol gives only a single
monoketal 3 or 4 in very good yield (>90%).5 Unfortu-
nately, few attempts16,20 have been made in the past
either to resolve this tetrol or to use this tetrol for phos-
phoinositol synthesis. It is known that diacylation and
disilylation of tetrol 3 gives 3,6-di-O-silylated deriva-
tives.5 However, our treatment of ( )-3 with two equiv-

K. M. Sureshan et al. / Tetrahedron: Asymmetry 16 (2005) 231–241
235
O-position in both the D- and L-forms of tetrol 3 or 4. It
is also evident that the 6-OH of monoester 16/18 is more
reactive toward the second acylation (in DCM), than
that of 15/17. These product ratios are very appealing,
since optically active and differently protected deriva-
tives can be obtained in high yields taking into consider-
ation the very high yield of monoketals 3 and 4 from
myo-inositol.
phatidylinositolphosphates (PtdInsPns: PtdIns(5)P,
PtdIns(3,5)P2, PtdIns(4,5)P2, PtdIns(3,4,5)P3) contain a
phosphate group at the 5-O-position of myo-inositol.
Efficient syntheses of 5-O-phosphorylated inositol phos-
pholipids and phosphates are challenging since the intro-
duction of a phosphate group, selectively, at O-5 is not
trivial in inositol derivatives with two or more hydroxyl
groups. Although 5-OH can be selectively exposed (for
subsequent phosphorylation) from 20 or 21, this involves
two additional steps (silylation and selective desilylation)
in the synthesis. The synthesis of 5-O-phosphorylated
phosphoinositols can be improved if the diastereomers
after phosphitylation/phosphorylation of DL-19 are sepa-
rable. Phosphitylation of DL-19 with dibenzyl N,N-
diisopropylphosphoramidite yielded diastereomeric
phosphites 22 and 23 (Scheme 4), which were separated
by column chromatography. The absolute configurations
of 22 and 23 were confirmed by analyzing their NMR
spectra. Further confirmation of their absolute configu-
rations was made by unambiguous syntheses of phosph-
ites 22 and 23 fromenantiomerically pure L-19 and D-19,
respectively. Phosphites 22 and 23 were separately oxi-
dized, using m-CPBA, to the phosphates 24 and 25,
respectively. Use of these two compounds is advanta-
geous in the comprehensive synthesis of 5-O-phosphory-
lated PtdInsPns and InsPns in terms of the number of
steps and yield. Either 1,2-diols or 3,4-diols can be ex-
posed from 24 and 25 by selective cleavage of TIPDS
or cyclohexylidene groups as necessary. Since selectivity
Diol 5 is another important protected derivative, which
can be obtained in very good yield (>90%) from myo-
inositol.23 Efficient methods for the resolution of such
a derivative are essential for the economical synthesis
of various phosphoinositols and other derivatives. We
have previously attempted the resolution of this diol
using OAM as the chiral auxiliary. Acylation of the diol
( )-5 with 1 equiv of O-acetylmandeloyl chloride gave
the D- and L-1,2-O-cyclohexylidene-3,4-O-(tetraisopro-
pyl-disiloxane-1,3-diyl)-6-O-[O-acetylmandeloyl]-myo-
inositol as a mixture of inseparable diastereomers 19.
Silylation of the remaining hydroxyl group, with TES-
Cl, gave the fully protected diastereomers, which could
easily be separated by column chromatography. The
usefulness of this method has been exemplified by the
efficient syntheses of various phosphoinositols.24
Many of the important biologically active inositol phos-
phates (InsPns: Ins(5)P, Ins(1,5)P2, Ins(1,4,5)P3
Ins(1,3,4,5)P4, Ins(1,4,5,6)P4, Ins(1,3,4,5,6)P5) and phos-
R
R
O
HO
HO
O
3. RR = (CH2)5
4. R = Me
+_
OH
OH
1. Bu2SnO, toluene, reflux, 1h
2. AcMndCl, solvent, -20--25oC, 1h
R
R
R
R
R
O
O
R
R
R
O
O
O
OR1
OH
O
OR1
OH
R1O
HO
O
R1O
HO
O
LS
LSS
+
+
DSS
OH
DS
OH
+
R1O
OR1
OH
HO
OH
OH
9. RR = (CH2)5
13. R = Me
16. RR = (CH2)5
18. R = Me
8. RR = (CH2)5
14. R = Me
15. RR = (CH2)5
17. R = Me
R
1 = (S)-PhCH(OAc)(CO)-
Scheme 3.
Table 2. Comparison of different conditions of O-acetylmandeloylation of ( )-3
Tetrol
Solvent, temp
Equiv of AcMnd-Cl
% Yield 9/13
% Yield 8/14
% Yield 15 + 16/17 + 18 (DS/LS)
3
3
3
3
4
4
4
Toluene, ꢀ20 ꢀC
3.0
3.0
1.8
2.5
4.0
3.0
2.5
38
31
21
42
27
27
40
34
31
7
12 (1/1)
—
Toluene, 0 ꢀCa
CH2Cl2, ꢀ20 ꢀC
CH2Cl2, ꢀ20 ꢀC
Toluene, ꢀ20 ꢀC
Toluene, ꢀ20 ꢀC
CH2Cl2, ꢀ20 ꢀC
60 (2/1)
20 (D only)
26 (3/2)
23 (1/1)
44 (6/1)
10
27
27
7
a At 0 ꢀC mixture of triacylated derivatives were isolated but not monoesters.

236
K. M. Sureshan et al. / Tetrahedron: Asymmetry 16 (2005) 231–241
O
O
O
O
O
O
Si
O
O
O
Si
Si
O
O
O
DL
Si
Si
Si
O
O(S)-OAM
O
O(S)-OAM
O
O(S)-OAM
OH
OTES
OTES
19
20
21
O
O
O
O
O
Si
O
Si
O
O
O
Si
a
DL19
+
(S)-OAMO
Si
O
O(S)-OAM
OR
OR
22. R = P(OBn)2
24. R = P(O)(OBn)2
23. R = P(OBn)2
25. R = P(O)(OBn)2
b
b
Scheme 4. Reagents and conditions: (a) dibenzyl N,N-diisopropylphosphoramidite (1.6 equiv), tetrazole (2.0 equiv), CH2Cl2, 0 ꢀC to rt, 1 h, 96%;
(b) m-CPBA (1.4 equiv), CH2Cl2, ꢀ78 ꢀC–rt, 1 h.
can be achieved between two hydroxyl groups of these
two gem diols, many important inositol phosphates and
phosphatidylinositol phosphates can be synthesized in
economical routes. Unlike most of the resolved diastereo-
mers, both 24 and 25 can be used for phosphoinositol
syntheses. The practical use of these two compounds
for the comprehensive syntheses of PtdInsPns and InsPns
is underway.
Flash column chromatography was performed using sil-
ica gel (Fuji Silysia, Silica gel BW-300). 1H, 31P and 13
C
NMR spectra were recorded on a Bruker-DPX-400
instrument or JEOL JNM-GSX270 instrument. Chemi-
cal shifts (dH values relative to tetramethylsilane, dC val-
ues relative to CDCl3 and dP values relative to H3PO4)
and coupling constants (J values) are given in parts
per million and hertz, respectively. Optical rotations
were recorded in a JASCO P-1010 Polarimeter. Elemen-
tal analyses were carried out on a YANACO MT-5 ele-
mental analyzer. Usual work-up refers to evaporation of
the reaction solvent followed by dissolution of the resi-
due 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.
3. Conclusion
In conclusion, we have achieved efficient methods for
the optical resolution of important myo-inositol deriva-
tives using OAM as the chiral auxiliary. The advantage
of this method is that the absolute configuration can be
1
determined by analyzing the H NMR of both the dia-
stereomers. UV activity of the products (advantageous
for chromatographic separation) and low cost of man-
delic acid (both R and S) are added advantages of using
acetylmandelic acid over other frequently used chiral
auxiliaries, like camphanic acid, menthoxy acetic acid
etc. By applying the known selective reactions, many
optically active inositol derivatives can be synthesized
in an economical way. We hope that these resolution
methods will be useful, not only to the inositol chemists
but also to a wider cross section of organic chemists, as
inositols are increasingly being used as synthons for
many natural products,4 metal complexing agents,25
gelators,26 catalysts,27 supramolecular assemblies,28 chi-
ral auxiliary,29 etc.
4.2. Preparation of O-acetylmandeloyl chloride
To an ice cooled solution of DMF (316 mg, 1.43 mmol)
and oxalyl chloride (402 mg, 3.17 mmol) in dichlorome-
thane (5 mL) was added dropwise a solution of (S)-O-
acetylmandelic acid (560 mg, 2.88 mmol) in dichlorome-
thane (5 mL), and the mixture was stirred at 0 ꢀC for
15 min. When the effervescence was ceased (about
15 min), the volatile materials were evaporated off under
reduced pressure and the residual DMF solution was ex-
tracted with hexane (6 · 3 mL). The combined hexane
extracts were evaporated under reduced pressure, to ob-
tain (S)-O-acetylmandeloyl chloride.
4.3. DL-3,6-Di-O-[(S)-O-acetylmandeloyl]-1,2:4,5-di-O-
cyclohexylidene-myo-inositol 6 and 7
4. Experimental
4.1. General
To a cooled (ꢀ5 to ꢀ10 ꢀC; ice–salt bath) solution of
( )-1,2:4,5-di-O-cyclohexylidene-myo-inositol (1.00 g,
2.94 mmol) in dry pyridine (15 mL) was added a solu-
tion of (S)-O-acetylmandeloyl chloride (1.87 g,
8.82 mmol) in dichloromethane (15 mL). The mixture
was stirred for 2.5 h at ꢀ5 ꢀC under nitrogen atmo-
All experiments were conducted under nitrogen atmo-
sphere. Melting points were determined with a Yanaco
Micro Melting Point Apparatus and are uncorrected.

K. M. Sureshan et al. / Tetrahedron: Asymmetry 16 (2005) 231–241
237
sphere and then quenched by the addition of water.
Compound 9: mp = 118.0–120.0 ꢀC (fromAcOEt/hex-
26
After being stirred for 30 min, usual work-up followed
by purification of the residue thus obtained by chroma-
tography (AcOEt/hexane, 1:4) yielded D- and L-3,6-di-O-
[(S)-O-acetylmandeloyl]-1,2:4,5-di-O-cyclohexylidene-
myo-inositol 6 and 7, 2.00 g, 98%) as an inseparable mix-
ture of diastereomers. 1H NMR (270 MHz, CDCl3):
1.23–1.77 (40H, complex, cyclohexylidene H), 2.17 (s,
6H, Me), 2.19 (s, 3H, Me), 2.20 (s, 3H, Me), 3.24 (dd,
1H, J = 9.8, 11.2 Hz, Ins H-5), 3.45 (dd, 1H, J = 9.8,
11.2 Hz, Ins H-5), 3.82 (dd, 1H, J = 6.8, 4.9 Hz, Ins H-
1), 4.05 (dd, 2H, J = 10.7, 9.3 Hz, Ins H-4), 4.14 (dd,
1H, J = 4.4, 6.8 Hz, Ins H-1), 4.39 (t, 1H, J = 4.4 Hz,
Ins H-2), 4.57 (t, 1H, J = 4.4 Hz, Ins H-2), 5.02 (dd,
1H, J = 4.4, 10.7 Hz, Ins H-3), 5.06 (dd, 1H, dd,
J = 4.4, 10.7 Hz, Ins H-3), 5.20 (dd, 1H, J = 6.8,
11.2 Hz, Ins H-6), 5.22 (dd, 1H, J = 6.84, 11.2 Hz, Ins
H-6), 6.00 (s, 1H, benzylic-H), 6.08 (s, 1H, benzylic-
H), 6.11 (s, 2H, benzylic-H), 7.33–7.54 (m, 20H, aro-
matic-H); 13C NMR (67.9 MHz, CDCl3): 20.57, 20.64,
20.72, 23.21, 23.34, 23.61, 23.76, 24.81, 34.62, 34.77,
35.99, 36.17, 36.25, 37.15, 37.40, 71.80, 74.08, 74.14,
74.40, 74.57, 75.18, 75.72, 75.95, 76.04, 78.23, 78.56,
110.99, 111.43, 113.35, 113.86, 127.82, 128.13, 128.17,
128.57, 128.64, 129.08, 129.17, 133.28, 133.43, 133.96,
167.70, 167.74, 168.12, 168.34, 169.88, 170.04, 170.19.
ane); ½aŠ ¼ þ45:6 (c 1.05, CHCl3); 1H NMR
D
(400 MHz, CDCl3): 1.20–1.63 (m, 10H, cyclohexylid-
ene), 2.18 (s, 3H, Me) 2.20 (s, 3H, Me), 3.51 (t, 1H,
J = 9.3 Hz, Ins H-5), 3.89 (dd, 1H, J = 7.8, 4.9 Hz, Ins
H-1), 4.07 (t, 1H, J = 9.3 Hz, Ins H-4), 4.23 (t, 1H,
J = 4.4 Hz, Ins H-2), 5.03 (dd, 1H, J = 4.4, 9.3 Hz, Ins
H-3), 5.13 (t, 1H, J = 10.3, 7.8 Hz, Ins H-6), 5.93
(s, 1H, benzylic-H), 6.00 (s, 1H, benzylic-H), 7.30–7.53
(m, 10H, aromatic-H); 13C NMR (100 MHz, CDCl3):
20.62, 20.66, 23.29, 23.66, 24.79, 34.81, 37.24, 70.50,
71.56, 72.62, 74.49, 74.79, 75.46, 76.68, 77.07, 111.10,
127.50, 127.91, 128.65, 128.72, 129.14, 133.20, 168.48,
168.59, 170.63, 170.92; FABMS (m/z): 636
(M+H+Na)+. Anal. Calcd for C32H36O12Æ1/2 H2O: C,
61.83; H, 6.00. Found: C, 61.84; H, 6.18.
4.5. D-1,2-O-Cyclohexylidene-myo-inositol 3D
A solution of D-3,6-di-O-[(S)-O-acetylmandeloyl]-1,2-O-
cyclohexylidene-myo-inositol, 8 (117 mg, 0.20 mmol,
1.0 equiv) and hydrazine monohydrate (50 mg,
1.0 mmol) in EtOH (2 mL) was stirred at room temper-
ature for 3 h. Volatile materials were removed under
reduced pressure and the residue was chromato-
graphed (MeOH–CHCl3, 1:3) to afford 3D (47 mg,
26
D
96%). Mp = 175–177 ꢀC; ½aŠ ¼ ꢀ27:1 (c 0.70, MeOH).
4.4. Selective cleavage of trans-cyclohexylidene from DL-
3,6-di-O-[(S)-O-acetylmandeloyl]-1,2:4,5-di-O-cyclohexyl-
idene-myo-inositol
4.6. L-1,2-O-Cyclohexylidene-myo-inositol 3L
Compound 3L was prepared by hydrazinolysis of 9 by
following the procedure described for the preparation
To a solution of 6 and 7 (1.19 g, 1.72 mmol) and ethylene
glycol (106 lL, 1.89 mmol) in anhydrous acetonitrile
(7 mL) was added pyridinium poly(hydrogen fluoride)
(1.03 mL, 36.16 mmol) at 0 ꢀC, and the mixture was stir-
red at the same temperature for 10 min and then at room
temperature for another 4 h. When the starting material
was disappeared (TLC), solid NaHCO3 was added and
stirred for another 30 min to neutralize the acid and then
worked-up as usual. Purification by chromatography
(AcOEt/benzene, 4:7) yielded the less polar D-3,6-di-O-
[(S)-O-acetylmandeloyl]-1,2-O-cyclohexylidene-myo-in-
ositol 8 (358 mg, 34% yield, Rf = 0.55, AcOEt/benzene,
1:1) and further elution gave L-3,6-di-O-[(S)-O-acetyl-
mandeloyl]-1,2-O-cyclohexylidene-myo-inositol 9 (505
mg, 48% yield, Rf = 0.35, AcOEt/benzene, 1:1).
26
D
of 3D (Section 4.5). Mp 180–181 ꢀC; ½aŠ ¼ þ26:9 (c
0.78, MeOH).
4.7. L-1,4,5,6-Tetra-O-benzoyl-myo-inositol 10L
To a solution of 3D (36 mg, 0.14 mmol), Et3N (308 lL,
2.2 mmol), and a catalytic amount of DMAP in CH2Cl2
(1.0 mL) was added, BzCl (128 lL, 1.10 mmol) at 0 ꢀC
and the mixture was stirred for 2 h at rt and worked-
up as usual. The residue thus obtained was dissolved
in 80% aqueous AcOH and the solution was refluxed
for 3 h. Acetic acid was evaporated off and the residue
was dissolved in ethyl acetate and worked-up as usual.
The crude product was chromatographed (AcOEt/hex-
ane, 1:2) to obtain L-1,4,5,6-tetra-O-benzoyl-myo-inosi-
tol 10L (80 mg, 97%). The optical purity was checked
by HPLC on a Chiralcel OD column. Compound
10L >99% ee, 29 min (i-PrOH/hexane, 1:5).
Compound 8: mp = 100.0–103.0 ꢀC (fromAcOEt/hex-
26
ane); ½aŠ ¼ þ67:0 (c 0.81, CHCl3); 1H NMR
D
(400 MHz, CDCl3) 1.36–1.80 (m, 10H, cyclohexylidene),
2.18 (s, 3H, Me) 2.20 (s, 3H, Me), 3.26 (t, 1H,
J = 9.8 Hz, Ins H-5), 3.90 (t, 1H, J = 9.8 Hz, Ins H-4),
4.13 (dd, 1H, J = 7.8, 4.9 Hz, Ins H-1), 4.43 (t, 1H,
J = 4.9 Hz, Ins H-2), 4.95 (dd, 1H, J = 4.9, 9.8 Hz, Ins
H-3), 5.10 (dd, 1H, J = 9.8, 7.8 Hz, Ins H-6), 5.98 (s,
1H, benzylic-H), 6.00 (s, 1H, benzylic-H), 7.30–7.53
(m, 10H, aromatic-H); 13C NMR (100 MHz, CDCl3)
20.68, 20.76, 23.45, 23.75, 24.86, 34.94, 37.32, 70.43,
71.95, 72.75, 72.30, 74.70, 74.81, 75.46, 77.00, 111.63,
127.81, 127.91, 128.82, 129.38, 129.50, 133.46, 133.74,
168.13, 168.38, 170.67, 170.77; FABMS (m/z): 613
(M+H)+, 635 (M+Na)+. Anal. Calcd for C32H36O12:
C, 62.74; H, 5.92. Found C, 62.45; H, 6.11.
4.8. D-1,4,5,6-Tetra-O-benzoyl-myo-inositol 10D
Compound 10D was similarly obtained in 65% overall
yield starting from 9 following the procedure described
in Section 4.7. Compound 10D >99% ee, 18 min (i-
PrOH/hexane, 1:5).
4.9. D-3,6-Di-O-[(S)-O-acetylmandeloyl]-1,2:4,5-di-O-
cyclohexylidene-myo-inositol 6
A solution of diol 8 (83.7 mg, 0.14 mmol), 1,1-
dimethoxycyclohexane (82.4 lL, 0.547 mmol), and

238
K. M. Sureshan et al. / Tetrahedron: Asymmetry 16 (2005) 231–241
camphorsulfonic acid (3.2 mg, 0.014 mmol) in CH2Cl2
(1 mL) was stirred under reflux for 8 h. Usual work-up
followed by chromatographic purification (AcOEt/
hexane, 2:7) yielded 6 (86 mg, 91%) as white crystalline
powder. Mp = 162.0–162.4 ꢀC (fromAcOEt/hexane);
(17 mg, 36%). Mp = 175.1–175.4 ꢀC (fromAcOEt/hex-
23
ane); ½aŠ ¼ ꢀ26:0 (c 0.562, CHCl3); 1H NMR
D
(270 MHz, CDCl3): 1.42–1.70 (m, 22H, cyclohexylid-
ene-H, –OH), 3.31 (dd, 1H, J = 9.8, 10.7 Hz, Ins H-5),
3.82 (t, 1H, J = 9.8 Hz, Ins H-4), 3.88 (dd, 1H,
J = 10.7, 6.3 Hz, Ins H-6), 4.02 (dd, 1H, J = 4.9,
9.8 Hz, Ins H-3), 4.07 (dd, 1H, J = 4.9, 6.3 Hz, Ins H-
1), 4.48 (t, 1H, J = 4.9 Hz, Ins H-2).
23
1
½aŠ ¼ þ65:0 (c 0.846, CHCl3); H NMR (270 MHz,
D
CDCl3): 1.25–1.76 (m, 20H, cyclohexylidene-H), 2.17
(s, 3H, Me), 2.19 (s, 3H, Me), 3.24 (dd, 1H, J = 9.8,
11.2 Hz, Ins H-5), 4.05 (t, 1H, J = 9.8 Hz, Ins H-4),
4.14 (dd, 1H, J = 6.8, 4.9 Hz, Ins H-1), 4.53 (t, 1H,
J = 4.9 Hz, Ins H-2), 5.02 (dd, 1H, J = 4.9, 9.8 Hz, Ins
H-3), 5.22 (dd, 1H, J = 6.8, 11.2 Hz, Ins H-6), 6.00 (s,
1H, benzylic-H), 6.11 (s, 1H, benzylic-H), 7.26–7.53
(m, 10H, aromatic-H); 13C NMR (67.9 MHz, CDCl3):
20.53, 20.67, 20.96, 23.33, 23.43, 23.49, 23.75, 24.80,
34.77, 35.98, 36.11, 37.39, 71.75, 74.05, 74.14, 74.56,
74.61, 75.72, 76.05, 78.25, 111.4, 113.4, 127.8, 128.1,
128.3, 128.5, 128.6, 129.0, 129.1, 133.3, 134.0, 167.7,
168.3, 169.8, 170.2.
4.12. L-1,2:4,5-Di-O-cyclohexylidene-myo-inositol 1L
Diol 1L was obtained by hydrazinolysis (74%) or alka-
line hydrolysis (99%) of 7 by following the procedure de-
scribed in Section 4.11. Mp = 179.5–180.1 ꢀC (from
23
AcOEt/hexane); ½aŠ ¼ þ25:5 (c 0.548, CHCl3).
D
4.13. L-3,6-Di-O-[(S)-O-acetylmandeloyl]-1,2:4,5-di-O-
isopropylidene-myo-inositol 11 and D-3,6-di-O-[(S)-O-
acetylmandeloyl]-1,2:4,5-di-O-isopropylidene-myo-inosi-
tol 12
4.10. L-3,6-Di-O-[(S)-O-acetylmandeloyl]-1,2:4,5-di-O-
cyclohexylidene-myo-inositol 7
To a solution of diol ( )-2 (520 mg, 2 mmol) in pyridine
(10 mL), a solution of (S)-O-acetyl mandeloyl chloride
(893 mg, 4.2 mmol) in CH2Cl2 (5 mL) was added drop-
wise at 0 ꢀC and stirred for 3 h gradually allowing the
reaction mixture to attain room temperature. After
3 h, ethyl acetate was added and washed successively
with water, dil HCl, satd solution of NaHCO3, and
brine. The organic layer was dried over anhydrous
Na2SO4 and evaporated under reduced pressure to ob-
tain a solid (1.23 g). Crystallization froma mixture of
ethyl acetate and hexane (1:3 v/v) yielded diastereomer
12 (563 mg, 46%) in pure form. The concentrated
mother liquor was recrystallized from a mixture of
CHCl3 (10 mL) and hexane (20 mL) to get 11 (514 mg,
Compound 7 was obtained in 93% from L-3,6-di-O-[(S)-
O-acetylmandeloyl]-1,2-O-cyclohexylidene-myo-inositol
9 by following the procedure described in Section 4.9.
24
D
Mp = 165.2–165.7 ꢀC (fromAcOEt/hexane);
½aŠ ¼
1
þ27:1 (c 0.258, CHCl3); H NMR (270 MHz, CDCl3):
1.25–1.64 (m, 20H, cyclohexylidene-H), 2.17 (s, 3H,
Me), 2.19 (s, 3H, Me), 3.45 (dd, 1H, J = 10.3, 11.2 Hz,
Ins H-5), 3.82 (dd, 1H, J = 6.8, 4.9 Hz, Ins H-1),
4.08 (t, 1H, J = 10.3 Hz, Ins H-4), 4.39 (t, 1H,
J = 4.4 Hz, Ins H-2), 5.06 (dd, 1H, J = 4.9, 10.3 Hz,
Ins H-3), 5.20 (dd, 1H, J = 6.8, 11.2 Hz, Ins H-6),
6.00, (s, 1H, benzylic-H), 6.11 (s, 1H, benzylic-H),
7.34–7.53 (m, 10H, aromatic-H); 13C NMR
(67.9 MHz, CDCl3): 20.63, 20.70, 23.22, 23.55, 23.61,
24.71, 24.88, 34.64, 36.25, 37.15, 71.81, 74.10, 74.17,
74.18, 74.42, 75.21, 75.98, 78.58, 111.0, 113.9, 127.8,
128.2, 128.57, 128.64, 129.1, 129.2, 133.5, 134.0, 167.7,
168.1, 170.0, 170.07.
42%) as dense crystals. Compound 11: mp = 177 ꢀC;
26
½aŠ ¼ þ53:2 (c 1, CH2Cl2); 1H NMR (400 MHz,
D
CDCl3): 1.00 (s, 3H, Me), 1.35 (s, 3H, Me), 1.41 (s,
3H, Me), 1.44 (s, 3H, Me), 2.16 (s, 3H, OAc), 2.18 (s,
3H, OAc), 3.45 (dd, 1H, J = 11.2, 10.3 Hz, Ins H-5),
3.79 (dd, 1H, J = 6.8, 4.4 Hz, Ins H-1), 4.06 (dd, 1H,
J = 9.8, 10.5 Hz, Ins H-4), 4.33 (t, 1H, J = 4.4 Hz, Ins
H-2), 5.07 (dd, 1H, J = 4.4, 10.5 Hz, Ins H-3), 5.22
(dd, 1H, J = 11.2, 6.8 Hz, Ins H-6), 6.05 (s, 1H,
PhCHOAc), 6.11 (s, 1H, PhCHOAc), 7.34–7.47
(m, 10H, aromatic-H); 13C NMR (100 MHz, CDCl3):
20.5, 20.6, 25.3, 26.7, 26.8, 27.2, 71.4, 73.97, 74.02,
74.2, 74.5, 75.4, 75.5, 79.0, 110.0, 113.1, 127.8, 128.1,
128.4, 128.6, 129.0, 129.1, 133.3, 133.8, 167.6, 168.2,
169.8, 169.9. Anal. Calcd for C32H36O12: C, 62.74; H,
4.11. D-1,2:4,5-Di-O-cyclohexylidene-myo-inositol 1D
4.11.1. By hydrazinolysis route. A mixture of 6
(174 mg, 0.25 mmol) and hydrazine hydrate (122 mg,
2.51 mmol) in DMF (3 mL) was stirred for 1.5 h at
room temperature. The mixture was taken in ethyl ace-
tate and washed several times with water to remove
DMF completely, and then with brine, dried, concen-
trated, and flash-chromatographed (AcOEt/CHCl3/hex-
ane 5:5:1) to get 1D (64 mg, 74%).
5.92%. Found C, 62.69; H, 5.96. Compound 12:
26
D
mp = 215–217 ꢀC; ½aŠ ¼ þ64:4 (c 1, CH2Cl2); 1H
NMR (400 MHz, CDCl3): 1.22 (s, 3H, Me), 1.29 (s,
3H, Me), 1.31 (s, 3H, Me), 1.57 (s, 3H, Me), 2.17 (2s,
2 · 3H, 2 · OAc), 3.24 (dd, 1H, J = 11, 9.3 Hz, Ins H-
5), 4.03 (dd, 1H, J = 9.3, 10.5 Hz, Ins H-4), 4.15 (dd,
1H, J = 6.8, 4.9 Hz, Ins H-1), 4.53 (dd, 1H, J = 4.4,
4.9 Hz, Ins H-2), 5.08 (dd, 1H, J = 4.4, 10.5 Hz, Ins H-
3), 5.21 (dd, 1H, J = 11, 6.8 Hz, Ins H-6), 6.00 (s, 1H,
PhCHOAc), 6.11 (s, 1H, PhCHOAc), 7.33–7.50 (m, 10
H, aromatic-H); 13C NMR (100 MHz, CDCl3): 20.6,
20.7, 25.7, 26.5, 26.7, 27.7, 71.3, 74.0, 74.3, 74.5, 75.0,
75.6, 76.4, 78.6, 110.7, 112.6, 127.9, 128.2, 128.5,
4.11.2. By alkaline hydrolysis route. To an ice cooled
solution of 6 (95 mg, 0.136 mmol) in dioxane/H2O
(10:1, 1 mL) added powdered KOH (153 mg,
2.73 mmol), and the mixture was stirred for 2 h at room
temperature. CH2Cl2 was added and the organic layer
was washed with water and brine, dried (Na2SO4), and
concentrated. The residue was recrystallized from
AcOEt/hexane to give crystals of diketal 1D (29.5 mg,
63%). The mother liquor was chromatographed
(AcOEt/hexane 1:1) to get an additional amount of 1D

K. M. Sureshan et al. / Tetrahedron: Asymmetry 16 (2005) 231–241
239
128.6, 129.1, 129.2, 133.3, 133.9, 167.7, 168.4, 169.9,
170.2. Anal. Calcd for C32H36O12: C, 62.74; H, 5.92.
Found C, 62.39; H, 6.21.
Ins H-4), 4.17 (t, 1H, J = 4.4 Hz, Ins H-2), 5.09 (dd,
1H, J = 4.4, 9.8 Hz, Ins H-3), 5.16 (dd, 1H, J = 9.8,
7.3 Hz, Ins H-6), 5.91 (s, 1H, PhCHOAc), 5.96 (s, 1H,
PhCHOAc), 7.31–7.54 (m, 10H, aromatic-H); 13C
NMR (100 MHz, CDCl3): d 20.62, 20.69, 25.71, 27.53,
70.30, 71.78, 72.24, 73.25, 74.65, 74.88, 75.88, 76.83,
110.41, 127.56, 127.86, 128.66, 128.80, 129.24, 129.37,
133.01, 133.04, 168.56, 168.57, 170.75, 170.99. Anal.
Calcd for C29H32O12ÆH2O: C, 58.97; H, 5.80. Found
C, 59.00; H, 5.77.
4.14. L- and D-1,2:4,5-Di-O-isopropylidene-myo-inositol
Compound 2L and 2D were obtained by hydrazinolysis
of 11 and 12, respectively, by following the procedure
described in Section 4.5. 2L: yield 93%, mp = 160–
25
162 ꢀC, ½aŠ ¼ þ22:3 (c 1, CH3CN). Lit.30 mp
D
25
D
159–161 ꢀC, ½aŠ ¼ þ22 (c 1.08, CH3CN). Compound
25
2D: yield 89%, mp = 159–161 ꢀC, ½aŠ ¼ ꢀ21:8 (c 1,
4.17. D-1,2-O-Isopropylidene-myo-inositol 4D
D
CH3CN).
A solution of 14 (41 mg, 0.072 mmol) and hydrazine
monohydrate (17 mg, 0.36 mmol) in EtOH (2 mL) was
stirred at room temperature for 3 h. Volatile materials
were removed under reduced pressure and the residue
4.15. D-3,6-Di-O-[(S)-O-acetylmandeloyl]-1,2-O-isoprop-
ylidene-myo-inositol 14
To a solution of 12 (612 mg, 1 mmol) in CH2Cl2 (5 mL),
was added water (18 lL, 1 mmol) and TFA (140 lL,
2 mmol) at 0 ꢀC and stirred under nitrogen atmosphere.
The reaction was followed by TLC and when the reac-
tion was complete (50 min to 1 h), the mixture was dis-
solved in ethyl acetate, washed with satd NaHCO3 and
brine. The organic layer was dried over anhyd Na2SO4
and evaporated under reduced pressure. The resulting
residue was chromatographed over silica gel (ethyl
acetate/benzene, 1:3) to get the diol 14 (469 mg,
was chromatographed (MeOH–CHCl3, 1:3) to afford
27
4D (11 mg, 70%). Mp = 178–180 ꢀC; ½aŠ ¼ ꢀ50:0 (c
D
0.08, MeOH); 1H NMR (400 MHz, CDCl3): 1.48 (s,
3H, Me), 1.62 (s, 3H, Me), 3.34 (t, 1H, J = 9.8 Hz, Ins
H-5), 3.66 (dd, 1H, J = 7.8, 9.8 Hz, Ins H-4), 3.71 (t,
1H, J = 9.8 Hz, Ins H-6), 3.93 (dd, 1H, J = 9.8, 4.4 Hz,
Ins H-1), 4.15 (dd, 1H, J = 4.4, 7.8 Hz, Ins H-3), 4.57
(t, 1H, J = 4.4 Hz, Ins H-2).
4.18. L-1,2-O-Isopropylidene-myo-inositol 4L
82%, Rf 0.48; AcOEt–benzene, 1:1). mp = 119–120 ꢀC;
24
½aŠ ¼ þ71 (c 1, CH2Cl2); 1H NMR (400 MHz, CDCl3):
Tetrol 4L was prepared from 13 by following the proce-
dure described for 4D (Section 4.17); mp = 180–181 ꢀC;
D
1.33 (s, 3H, Me), 1.56 (s, 3H, Me), 2.04 (d, J = 2.9 Hz, 4-
OH), 2.19 (s, 3H, OAc), 2.21 (s, 3H, OAc), 2.24 (d, 1H,
J = 3.9 Hz, 5-OH), 3.26 (dt, 1H, J = 9.8, 3.9 Hz, Ins H-
5), 3.88 (dt, 1H, J = 9.8, 2.9 Hz, Ins H-4), 4.15 (dd, 1H,
J = 7.3, 4.4 Hz, Ins H-1), 4.43 (t, 1H, J = 4.4 Hz, Ins H-
2), 4.98 (dd, 1H, J = 4.4, 9.8 Hz, Ins H-3), 5.11 (dd, 1H,
J = 9.8, 7.3 Hz, Ins H-6), 5.99 (s, 1H, PhCHOAc), 6.10
(s, 1H, PhCHOAc), 7.26–7.52 (m, 10H, aromatic-
H). 13C NMR (100 MHz, CDCl3): 20.70, 20.78, 25.87,
27.64, 70.23, 72.05, 72.42, 73.54, 74.64, 74.66, 75.89,
76.77, 110.98, 127.81, 127.88, 128.83, 128.85, 129.41,
129.49, 133.43, 133.68, 168.10, 168.45, 170.69, 170.74.
Anal. Calcd for C29H32O12: C, 60.83; H, 5.63. Found
C, 61.13; H, 5.74.
27
½aŠ ¼ þ56:0 (c 0.25, MeOH).
D
4.19. Resolution of ( )-1,2-O-cyclohexylidene-myo-inosi-
tol via stannylene mediated O-acetylmandeloylation
Racemic 1,2-O-cyclohexylidene-myo-inositol (( )-3,
300 mg, 1.15 mmol) and dibutyltin oxide (631 mg,
2.54 mmol) were suspended in 20 mL of dry toluene in
a 50 mL two-necked round-bottomed flask, fitted with
a Dean–Stark apparatus. The mixture was refluxed for
1 h, during which the water generated was removed.
The solvent was evaporated under reduced pressure
and the residue was dissolved in dichloromethane
(15 mL). To this solution, a solution of (S)-O-acetyl-
mandeloyl chloride (2.88 mmol) in dichloromethane
(10 mL) was added slowly at ꢀ20 ꢀC, and the mixture
was stirred at the same temperature for 1 h. A solution
4.16. L-3,6-Di-O-[(S)-O-acetylmandeloyl]-1,2-O-isoprop-
ylidene-myo-inositol 13
To a solution of 11 (612 mg, 1 mmol) in CH2Cl2 (5 mL),
was added water (18 lL, 1 mmol) and TFA (140 lL,
2 mmol) at 0 ꢀC and stirred under nitrogen atmosphere.
The reaction was followed by TLC and when the reac-
tion was complete (50 min to 1 h), the mixture was dis-
solved in ethyl acetate, washed with satd NaHCO3 and
brine. The organic layer was dried over anhyd Na2SO4
and evaporated under reduced pressure. The resulting
residue was chromatographed over silica gel to get the
diol 13 (498 mg, 87%, Rf = 0.39; AcOEt–benzene, 1:1).
of
N,N-dimethyl-1,3-propanediamine
(236 mg,
2.31 mmol) in dichloromethane (4 mL) was added to
quench the excess acid chloride and stirred for 30 min
and then acetic acid (264 lL, 4.62 mmol) in dichloro-
methane (4 mL) was added and stirred at the same tem-
perature, for 10 min. The mixture was taken in a
separating funnel and was washed with water (3 times)
and brine, dried over anhydrous MgSO4, and concen-
trated under reduced pressure. The residue was purified
by flash column chromatography on silica gel (AcOEt/
benzene, 2:3) and recrystallized fromAcOEt/hexane to
give 8 (71 mg, 10%), 9 (296 mg, 42%), and D-3-O-[(S)-
O-acetylmandeloyl]-1,2-O-cyclohexylidene-myo-inositol,
15 (100 mg, 20%, Rf = 0.10, AcOEt/benzene, 1:1). Com-
24
1
Mp = 100–101 ꢀC; ½aŠ ¼ þ53 (c 1, CH2Cl2); H NMR
D
(400 MHz, CDCl3): 1.10 (s, 3H, Me), 1.44 (s, 3H, Me),
2.19 (s, 3H, OAc), 2.20 (s, 3H, OAc), 2.91 (d, 1H,
J = 2.4 Hz, C4-OH), 3.02 (d, 1H, J = 2.9 Hz, C5-OH),
3.54 (dt, 1H, J = 9.8, 2.9 Hz, Ins H-5), 3.93 (dd, 1H,
J = 7.3, 4.4 Hz, Ins H-1), 4.08 (dt, 1H, J = 9.8, 2.4 Hz,
pound 15: mp = 150.0–152.0 ꢀC (fromAcOEt/hexane);
26
½aŠ ¼ þ57:4 (c 1.22, CHCl3); 1H NMR (270 MHz,
D

240
K. M. Sureshan et al. / Tetrahedron: Asymmetry 16 (2005) 231–241
CDCl3): 1.33–1.73 (m, 10H, cyclohexylidene-H), 2.22 (s,
3H, Me), 2.35 (d, 1H, J = 3.4 Hz, –OH), 2.80 (br s, 1H,
–OH), 3.02 (br s, 1H, –OH), 3.32 (dt, 1H, J = 9.8, 2.4 Hz,
Ins H-5), 3.64 (ddd, 1H, J = 9.8, 2.9 Hz, Ins H-4), 3.83
(dt, 1H, J = 9.8, 3.4 Hz, Ins H-6), 4.02 (dd, 1H,
J = 9.8, 4.9 Hz, Ins H-1), 4.42 (dd, 1H, J = 4.9, 4.4 Hz,
Ins H-2), 4.98 (dd, 1H, J = 4.4, 9.8 Hz, Ins H-3), 5.98
(s, 1H, benzylic-H), 7.35–7.55 (m, 5H, aromatic-
H); 13C NMR (100 MHz, CD3OD): 21.35, 25.40,
25.82, 26.89, 36.72, 39.67, 72.65, 75.00, 75.84, 75.95,
77.03, 77.14, 80.90, 112.45, 129.86, 130.51, 131.05,
135.96, 170.94, 172.77; FABMS (m/z): 459 (M+Na)+.
20.68, 23.63, 23.91, 25.04, 35.06, 37.40, 63.32, 63.80,
73.40, 73.84, 73.87, 74.97, 75.51, 75.90, 76.01, 110.63,
127.26, 127.33, 127.42, 127.53, 127.61, 128.07, 128.14,
128.28, 128.32, 128.47, 128.89, 134.52, 138.39,
138.70, 167.92, 169.43; FABMS (m/z): 924 (M+H)+,
23
D
945 (M+Na)+. Compound 23: ½aŠ ¼ þ27:4 (c 1.06,
1
CHCl3); H NMR (400 MHz, CDCl3): d 1.00–1.13 (m,
28H, i-Pr), 1.37 (br, 2H, cyclohexylidene-H), 1.57 (br,
6H, cyclohexylidene-H), 1.64 (br, 2H, cyclohexylidene-
H), 2.13 (s, 3H, C(O)CH3), 3.76 (td, 1H, J = 8.4Hz,
Ins H-5), 3.84 (dd, J = 4.0, 8.4 Hz, 1H, Ins H-3), 4.13
(dd, 1H, J = 6.8, 4.0 Hz, Ins H-1), 4.15 (t, 1H,
J = 8.4 Hz, Ins H-4), 4.33 (t, J = 4.0 Hz, Ins H-2),
4.60–4.68 (m, 3H, ArCH2), 4.78 (dd, J = 8.4, 12.6 Hz,
1H, ArCH2), 5.29 (dd, J = 6.8, 8.4 Hz, 1H, Ins H-6),
6.11 (s, 1H, benzylic-H), 7.20–7.41 (m, 15H, aromatic-
H); 31P NMR (162 MHz, CDCl3): d 140.79; 13C NMR
(100 MHz, CDCl3): 12.00, 12.54, 12.58, 12.83, 17.17,
17.24, 17.28, 17.34, 17.54, 20.69, 23.63, 23.73, 25.01,
34.68, 37.04, 63.39, 63.62, 73.02, 74.19, 75.07, 75.12,
75.38, 75.96, 76.05, 110.70, 127.36, 127.39, 127.47,
127.51, 128.01, 128.13, 128.19, 128.26, 128.30, 128.51,
128.96, 133.91, 138.27, 138.52, 167.76, 169.60; FABMS
(m/z): 924 (M+H)+, 946 (M+Na)+.
4.20. Resolution of ( )-1,2-O-isopropylidene-myo-inositol
via stannylene mediated O-acetylmandeloylation
A
mixture of 1,2-O-isopropylidene-myo-inositol
(108 mg, 0.49 mmol) and dibutyltin oxide (268 mg,
1.08 mmol) in dry toluene was refluxed for 1 h in a flask
equipped with a Dean–Stark apparatus, and then the
toluene was distilled off. The residue was re-dissolved
in toluene (3.0 mL) and a solution of O-acetylmandeloyl
chloride in toluene (2.5 mL) was added at ꢀ20 ꢀC and
the solution was stirred at this temperature for 1.5 h.
A
solution of N,N-dimethyl-1,3-propanediamine
(100 mg, 123 lL, 0.98 mmol) in dichloromethane
(2 mL) was added to quench the excess acid chloride
and stirred for 30 min and then acetic acid (58.8 mg,
56 lL, 0.98 mmol) in dichloromethane (2 mL) was
added and stirred at the same temperature, for 10 min.
After addition of CHCl3, the organic layer was washed
with brine (twice), dried, and evaporated. The residue
was chromatographed on SiO2 (AcOEt/benzene, 1:1)
to give 13 (75.7 mg, 27%, Rf = 0.40), 14 (75.8 mg, 27%,
4.22. Dibenzyl {L-6-O-[(S)-O-acetylmandeloyl]-1,2-O-
cyclohexylidene-3,4-O-(tetraisopropyldisiloxan-1,3-diyl)-
myo-inositol-5}-phosphate 24
To a solution of phosphite 22 (78.1 mg, 0.085 mmol) in
dry CH2Cl2 (1.1 mL) was added m-CPBA (20.8 mg,
0.12 mmol) at ꢀ78 ꢀC and the mixture was stirred for
5 min at ꢀ78 ꢀC and then the temperature was raised
to rt and stirring was continued for another 30 min.
The reaction was quenched by stirring with 10% aq
Na2SO3 for 30 min. Usual work-up followed by chro-
matography (AcOEt/hexane, 1:3) yielded the phosphate
Rf = 0.48), and
(44.7 mg, 23%, Rf = 0.10).
a
mixture of monomandelates
4.21. Phosphitylation of DL-6-O-[(S)-O-acetylmandeloyl]-
1,2-O-cyclohexylidene-3,4-O-(tetraisopropyldisiloxan-
1,3-diyl)-myo-inositol DL-19
24 (75.5 mg, 95%, Rf = 0.35) as a colorless oil.
25
D
½aŠ ¼ þ41:7 (c 1.80, CHCl3); 1H NMR (400 MHz,
CDCl3): d 0.97–1.13 (m, 28H, i-Pr), 1.35–1.87 (m,
10H, cyclohexylidene-H), 2.09 (s, 3H, C(O)CH3), 3.66
(dd, 1H, J = 7.6, 5.2 Hz, Ins H-1), 3.82 (dd, 1H,
J = 9.6, 4.2 Hz, Ins H-3), 4.10–4.18 (m, 2H, Ins H-2
and H-4), 4.24 (td, 1H, J = 9.6 Hz, Ins H-5), 5.00–5.06
(q, 4H, J = 7.6, 8.0 Hz, benzylic-H), 5.32 (dd, 1H,
J = 9.6, 7.6 Hz, Ins H-6), 6.22 (s, 1H, benzylic-H),
7.25–7.44 (m, 15H, aromatic-H); 31P NMR: d ꢀ0.50;
13C NMR (100 MHz, CDCl3): 11.83, 12.50, 12.52,
12.79, 16.99, 17.03, 17.11, 17.17, 17.21, 17.26, 17.45,
20.70, 23.55, 23.87, 24.99, 34.93, 37.27, 69.12, 69.18,
73.09, 73.86, 73.97, 75.12, 75.27, 75.76, 77.61, 110.72,
127.85, 127.97, 128.16, 128.19, 128.29, 128.33, 128.35,
128.47, 128.91, 134.39, 135.86, 136.12, 167.98, 169.34;
FABMS (m/z): 939 (M+H)+, 961 (M+Na)+.
To a solution of DL-19 (120 mg, 0.18 mmol) and tetra-
zole (25.5 mg, 0.36 mmol) in CH2Cl2 (2.0 mL) at 0 ꢀC
was added a solution of (BnO)2PNi-Pr2 (100 mg,
0.29 mmol) in CH2Cl2 (0.4 mL) and stirred for 30 min
at rt. Usual work-up followed by chromatography
(AcOEt/hexane, 1:10) yielded phosphites 22 [71.8 mg,
44%, Rf = 0.41 (AcOEt/hexane, 1:10), colorless oil] and
23 [64.2 mg, 39%, Rf = 0.32 (AcOEt/hexane, 1:10), col-
25
orless oil]. Compound 22: ½aŠ ¼ þ24:3 (c 1.56, CHCl3);
D
1H NMR (400 MHz, CDCl3): 0.97–1.13 (m, 28H, i-Pr),
1.33–1.88 (m, 10H, cyclohexylidene-H), 2.03 (s, 3H,
–C(O)CH3), 3.67 (dd, J = 4.4, 7.6 Hz, 1H, Ins H-1),
3.76 (td, 1H, J = 9.2 Hz, Ins H-5), 3.82 (dd, J = 4.4,
9.8 Hz, 1H, Ins H-3), 4.11 (t, J = 9.2 Hz, 1H, Ins H-4),
4.18 (t, J = 4.4 Hz, 1H, Ins H-2), 4.79 (q, J = 6.2 Hz,
1H, ArCH2), 4.82 (dd, J = 7.0, 12.4 Hz, 1H, ArCH2),
4.89 (1H, dd, J = 7.2, 12.4 Hz, ArCH2), 4.98 (1H, dd,
J = 9.2, 12.4 Hz, ArCH2), 5.30 (dd, J = 7.6, 9.2 Hz,
1H, Ins H-6), 6.17 (s, 1H, benzylic-H), 7.28–7.40 (m,
15H, aromatic-H); 31P NMR (162 MHz, CDCl3):
140.13; 13C NMR (100 MHz, CDCl3): 12.09, 12.58,
12.60, 12.87, 17.16, 17.23, 17.25, 17.27, 17.31, 17.54,
4.23. Dibenzyl {D-6-O-[(S)-O-acetylmandeloyl]-1,2-O-
cyclohexylidene-3,4-O-(tetraisopropyldisiloxan-1,3-diyl)-
myo-inositol-5}-phosphate 25
Oxidation of the phosphite 23 (58.8 mg, 0.064 mmol,
1.0 equiv) with m-CPBA (15.6 mg, 0.091 mmol,
1.4 equiv) as in the above procedure gave the phosphate
25 (57.6 mg, 96%, Rf = 0.32, AcOEt/hexane, 1:3) as

K. M. Sureshan et al. / Tetrahedron: Asymmetry 16 (2005) 231–241
241
24
D
1
S. J.; Potter, B. V. L. J. Chem. Soc., Perkin Trans. 1 1997,
1279; (f) Garegg, P. J.; Lindberg, B.; Kvarnstrom, I.;
Svensson, S. C. T. Carbohydr. Res. 1985, 139, 209; (g)
Mills, S. J.; Potter, B. V. L. J. Org. Chem. 1996, 61, 8980;
(h) Mills, S. J.; Backers, K.; Erneux, C.; Potter, B. V. L.
Org. Biomol. Chem. 2003, 1, 3546; (i) Chida, N.; Koizumi,
K.; Kitada, Y.; Yokoyama, C.; Ogawa, S. J. Chem. Soc.,
Chem. Commun. 1994, 111.
colorless oil. ½aŠ ¼ þ12:0 (c 1.34, CHCl3); H NMR
(400 MHz, CDCl3): 0.98–1.14 (m, 28H, i-Pr), 1.29 (br,
2H, cyclohexylidene-H), 1.53 (br, 6H, cyclohexylidene-
H), 1.73 (br, 2H, cyclohexylidene-H), 2.17 (s, 3H,
C(O)CH3), 3.88 (dd, 1H, J = 9.8, 3.6 Hz, Ins H-3),
4.18–4.22 (m, 2H, Ins H-4 & H-1), 4.30 (td, 1H,
J = 7.6 Hz, Ins H-5), 4.36 (t, 1H, J = 3.6 Hz, Ins H-2),
4.82–4.99 (m, 4H, benzylic-H), 5.35 (t, 1H, J = 7.6 Hz,
Ins H-6), 6.12 (s, 1H, PhCH(OAc)), 7.20–7.45 (m,
15H, aromatic-H); 31P NMR: d ꢀ1.37; 13C NMR
(100 MHz, CDCl3): 11.84, 12.57, 12.60, 12.85, 17.11,
17.15, 17.21, 17.22, 17.30, 17.33, 17.36, 17.57, 20.79,
23.62, 23.78, 25.06, 34.46, 36.79, 69.02, 69.14, 72.66,
74.08, 74.24, 74.83, 75.21, 75.79, 79.48, 110.83, 127.83,
127.85, 127.97, 128.21, 128.26, 128.29, 128.38, 128.42,
128.66, 129.09, 134.04, 135.87, 135.98, 167.87, 169.80;
FABMS (m/z): 939 (M+H)+, 961 (M+Na)+.
9. Chung, S.-K.; Ryu, Y. Carbohydr. Res. 1994, 258, 145.
10. Chung, S.-K.; Chang, Y.-T.; Ryu, Y. Pure Appl. Chem.
1996, 68, 931.
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Acknowledgements
15. Watanabe, Y.; Kiyosawa, Y.; Tatsukawa, A.; Hayashi, M.
Tetrahedron Lett. 2001, 42, 4641.
We thank JSPS for a fellowship (K.M.S.) and Grant-in-
aid (No. 02170). Also we thank Yamakawa Chemical
Industry Co. Ltd for the generous gift of mandelic acid.
16. (a) Ling, L.; Ozaki, S. Tetrahedron Lett. 1993, 34, 2501; (b)
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18. DCC mediated coupling between O-acetylmandelic acid
and 2 resulted in racemization to some extent as in the case
of cyclohexylidene derivative. This could be the reason for
the low yield (18%) and separation of only one of the
diastereomer (even after column chromatography and
multiple crystallizations) in the reported8e case.
19. (a) Sureshan, K. M.; Miyasou, T.; Hayashi, M.; Watan-
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