A simple and practical resolution of 1,2:4,5-di-O-isopropylidene-myo-inositol

Article abstract of DOI:10.1016/S0957-4166(03)00402-6

An efficient method for the resolution of 1,2:4,5-di-O-isopropylidene-myo-inositol has been developed. The diketal was converted to diastereomeric 3,6-di-O-mandelates by the reaction with (S)-O-acetylmandeloyl chloride. Both the diastereomers could be separated by sequential crystallization in multi-gram quantities. The enantiomers of the diol were obtained by removal of the chiral auxiliaries. Also the trans-isopropylidene was cleaved efficiently to obtain another pair of chiral diols.

Full text of DOI:10.1016/S0957-4166(03)00402-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1771–1774
A simple and practical resolution of
1,2:4,5-di-O-isopropylidene-myo-inositol
Kana M. Sureshan, Toru Yamasaki, Minoru Hayashi and Yutaka Watanabe*
Department of Applied Chemistry, Faculty of Engineering, Ehime University, Matsuyama 790-8577, Japan
Received 15 April 2003; accepted 6 May 2003
Abstract—An efficient method for the resolution of 1,2:4,5-di-O-isopropylidene-myo-inositol has been developed. The diketal was
converted to diastereomeric 3,6-di-O-mandelates by the reaction with (S)-O-acetylmandeloyl chloride. Both the diastereomers
could be separated by sequential crystallization in multi-gram quantities. The enantiomers of the diol were obtained by removal
of the chiral auxiliaries. Also the trans-isopropylidene was cleaved efficiently to obtain another pair of chiral diols. © 2003
Elsevier Science Ltd. All rights reserved.
In the last two decades we have witnessed a renaissance
in the chemistry and biology of inositols due to the
involvement of phosphorylated inositols in various bio-
logical phenomena such as cellular signal transduction,1
the anchoring of proteins to the cell membrane,2 etc.
The receptor-controlled breakdown of phosphatidyli-
nositol 4,5-bisphosphate [PI(4,5)P2] to the second mes-
methods for optical resolution and selective protection–
deprotection for this meso-cyclohexane hexol.
During the last decade, there have been many methods
reported for the selective protection and deprotection of
myo-inositol hydroxyl groups and also for the effective
phosphorylation or glycosylation of these protected
derivatives. However the search for efficient methodolo-
gies for optical resolution continues. Now the synthetic
chemistry using myo-inositol has come to the stage
where the efficiency of a particular synthetic strategy
solely depends on its effective resolution methods. The
most commonly used starting materials for the synthe-
ses of phosphoinositols are the diketal derivatives 1 and
2. The relative reactivity of hydroxyl groups in 1,2:4,5-
di-O-isopropylidene-myo-inositol, 1, has been studied
extensively.6 It is reported that phosphorylation,7
acylation,7,8 silylation,7,9 alkylation,10 etc., undergo
selectively at the 3-O-position. Also it is documented
that the trans-isopropylidene can be cleaved in presence
of the cis.11 These selectivities in this diol project it as a
good synthon for many inositol phosphates and lipid
derivatives.
sengers
diacylglycerol (DAG) is
D
-myo-inositol 1,4,5-trisphosphate (IP3) and
well-established phe-
a
nomenon.3 The cytosol soluble IP3 mobilizes Ca2+ from
endoplasmic reticulum, which ultimately leads to a cell
response. After this process, by the action of many
specific phosphatases and kinases, IP3 is recycled back
to inositol and then to the lipid PIP2 with the interme-
diacy of several myo-inositol phosphates (IPn). In addi-
tion, many phosphatidylinositol phosphates like
PI(3,5)P2, PI(3,4,5)P3, PI(4)P, PI(3)P, PI(5)P have
recently been isolated from cells. Despite, a clear under-
standing of the cellular role played by each of these
phosphates and PIPns are lacking due to the insufficient
or impractical access to these derivatives from natural
resources. This increased interest in the biological role
played by phosphoinositols necessitated better synthetic
strategies for their preparation. In addition, the dis-
closed therapeutic potential4 of inositol derivatives and
the recent use of inositol as the synthon for the synthe-
sis of many natural products5 have given further reori-
entation to the myo-inositol chemistry. This
multi-faceted importance of inositol demands better
* Corresponding author. E-mail: wyutaka@dpc.ehime-u.ac.jp
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00402-6

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K. M. Sureshan et al. / Tetrahedron: Asymmetry 14 (2003) 1771–1774
NMR analysis of the concentrated mother liquor
revealed that it contains almost pure -1,4-di-O-[(S)-
From a careful analysis of the structure it is reasonable
to think that diketal 1 is more versatile and appropriate
for the synthesis of important phosphoinositols as,
unlike in the case of 2, both the enantiomers of 1 are
equally important for the synthesis of different phos-
phates and PIPs (Scheme 1). These out-weighed impor-
tances rendered effective methodologies for the
complete (to obtain both the enantiomers in pure form)
resolution of this diketal indispensable. Many efforts
have been made for the resolution of this diketal by
different groups. However, there is no practical method
for the resolution of this diketal on a large scale. In
some cases, the resolution was carried out after a less
yielding initial protection of the 3-OH followed by a
tedious column chromatographic12 or HPLC9 separa-
tion of the diastereomers. Although the resolution of
diol 1 has been achieved on small scale, the reported
methods involve either tedious chromatographic
separation13 of the bis-camphanates or resulted in the
separation of small quantity of only one of the
diastereomers.14 During our ongoing program to
provide easy access to many inositol phosphates and
their lipid analogues, we required enantiomers of this
diketal in multi-gram quantities. Herein we report a
simple and practical method for the efficient resolution
(to have access to both the enantiomers) of this impor-
tant intermediate, which does not involve any chro-
matographic separation.
D
O-acetylmandeloyl]-2,3:5,6-di-O-isopropylidene-myo-
inositol 5.16 Further crystallization of the mother liquor
from chloroform–hexane yielded pure 5 in good yield17
(42%) as dense thick crystals [mp 177°C, [h]D=
+53.2 (c 1, CH2Cl2)]. It is noteworthy that the crystals
of 5 showed liquid crystalline property for a small
range of temperature with softening at 163–164°C and
final melting at 177°C. The chiral auxiliaries could be
removed under basic conditions to yield enantiomers of
diol 1 in quantitative yields.18 Also, to check the feasi-
bility of our synthetic strategies (Scheme 1), we pro-
ceeded for the trans-isopropylidene cleavage in presence
of the cis. In general, the reported methods for the
selective trans-ketal cleavage are less yielding (around
60%). Very recently a high yielding method using ion-
exchange resin has appeared,11c but unfortunately we
failed to reproduce their result. After a series of experi-
mentation, we arrived at optimum conditions19 for the
selective cleavage of the trans-ketal in presence of the
cis- by using a limited amount of TFA and water (2
and 1 equiv., respectively) in CH2Cl2 to obtain diols 720
and 821 in very good yields (82–87%). Thus we have
presented efficient methods for the preparation of four
highly advanced intermediates for the synthesis of
phosphorylated inositols and other natural products.
Although many resolutions of myo-inositol derivatives
by crystallization have been reported, only one of the
diastereomers can be obtained by those methods. In
many cases, in order to obtain the other diastereomer,
the mother liquor had to be converted back to the
alcohol and functionalized with the opposite chiral
auxiliary. To the best of our knowledge, this is the first
case where both the diastereomers of a myo-inositol
The diketal 1 was acylated with (S)-O-acetylmandelic
acid chloride15 in pyridine at 0°C (Scheme 2) to obtain
the diacylated derivatives (5 and 6) in quantitative
yield. Aqueous work-up followed by crystallization
from a mixture of ethyl acetate and hexane yielded pure
D-3,6-di-O-[(S)-O-acetylmandeloyl]-1,2:4,5-di-O-isoprop-
ylidene-myo-inositol, 6 (46%) as cotton like fluffy crys-
derivative
crystallizations.
can
be
obtained
by
sequential
tals {mp 215–217°C, [h]D=+64.4 (c 1, CH2Cl2)} The 1H
Scheme 1. Different phosphoinositols that can be obtained from enantiomers of diketal 1 and its diastereomeric derivatives 3 and
4 by utilizing the known selective reactions. The number in parenthesis indicates the number of transformations required for the
synthesis.

K. M. Sureshan et al. / Tetrahedron: Asymmetry 14 (2003) 1771–1774
1773
Scheme 2. Reagents and conditions: (i) (S)-(+)-O-acetylmandeloyl chloride (2.1 equiv.), pyr, 0°C, 2 h; (ii) i-butylamine (5 equiv.),
MeOH, reflux, 30 min; (iii) TFA (2 equiv.), H2O (1 equiv.), CH2Cl2, 0°C–rt, 50 min.
In conclusion, we have achieved the optical resolution
of an important intermediate for the synthesis of many
myo-inositol phosphates. The advantage of the method
reported here is that it excludes tedious chromato-
graphic separation. Both the enantiomers can be
obtained in very good yield on a multi-gram scale. We
hope this resolution method will be useful not only for
the inositol chemists but also for chemists working on
natural product synthesis. Presently we are investigat-
ing the synthetic utility of these diols and diester deriva-
tives to achieve phosphoinositols as depicted in Scheme
1 and other derivatives, which will be reported in a full
account elsewhere.
Melder, D. C.; Aksoy, S.; Eichinger, H. Cancer
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Acknowledgements
8. Shashidhar, M. S.; Volwerk, J. J.; Griffith, O. H.; Keana,
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We thank the JSPS for a postdoctoral fellowship
(K.M.S.) and Grant-in-Aid (No. 02170) and the Naito
Foundation for financial support. We also thank Ven-
ture Business Laboratory and Advanced Instrumenta-
tion Center for Chemical Analysis, Ehime University
for NMR and elemental analysis, respectively.
References
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15. DCC-mediated coupling between acid and 1 resulted in
racemization to a small extent in our hand. This could be
the reason for the separation of only one of the
diastereomer (6) in low (18%) yield even after column
chromatography and multiple crystallizations in the
3. Berridge, M. J. Nature 1993, 361, 315.
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K. M. Sureshan et al. / Tetrahedron: Asymmetry 14 (2003) 1771–1774
reported case.14 Although, DCC method had been used
obtain a solid (1.23 g). Compound 6 (563 mg, 46%) could
be obtained by crystallization from a mixture of ethyl
acetate and hexane (1:3 v/v). The concentrated mother
liquor was redissolved in a mixture of CHCl3 (10 mL)
and hexane (20 mL) to yield crystals of 5 (514 mg, 42%).
in inositol, it appears that special care (like low tempera-
ture) is needed to avoid racemization where as chloride
method had been used in inositol successfully (e.g.
Garegg, P. J.; Lindberg, B.; Kvarnstrom, I.; Svensson, S.
C. T. Carbohydr. Res. 1985, 139, 209). To make sure that
no racemization occurred in our case, the mixture of
diastereomers was converted into chromatographically
18. 1-L
: mp 160–162°C, [h]2D5=+22.3 (c 1, CH3CN). Lit.12 mp
159–161°C, [h]2D5=+22 (c 1.08, CH3CN); 1-
161°C, [h]2D5=−21.8 (c 1, CH3CN).
D: mp 159–
separable diols 7 and 8 and converted to the known 1-
D
19. Selective cleavage of trans ketal: To a solution of 5 or 6
(612 mg, 1 mmol) in CH2Cl2 (5 mL), added water (18 mL,
1 mmol) and TFA (140 mL, 2 mmol) at 0°C and stirred
under a nitrogen atmosphere. The reaction was followed
by TLC and when the reaction was complete (50 min–1
h), the mixture was dissolved in ethyl acetate, washed
with satd NaHCO3 and brine. The organic layer was
dried over anhd. Na2SO4 and evaporated under reduced
pressure. The resulting residue was chromatographed
over silica gel (flash, ethyl acetate:benzene 1:3) to obtain
the corresponding diol 7 or 8 in the yield range 82–87%.
20. Mp 100–101°C, [h]2D5=+53 (c 1, CH2Cl2).
and 1- -1,4,5,6-tetra-O-benzoyl-myo-inositols respec-
L
tively both with >99% ee (HPLC, Chiralcel OD).
1
16. All new compounds were characterized by H, 13C NMR
and elemental analysis.
17. Separation of 5 and 6: To a solution of ( ) diol 1 (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 dropwise 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
anhd. Na2SO4 and evaporated under reduced pressure to
21. Mp 119–120°C, [h]2D5=+71 (c 1, CH2Cl2).