Protecting group directed stereoselective reduction of an epi-inosose: Efficient synthesis of epi-inositol

Article abstract of DOI:10.1016/j.tetlet.2011.05.051

A facile and high yielding synthesis of epi-inositol via stereoselective reduction of a pentaprotected epi-inosose is reported. Extent of stereoselectivity during the hydride reduction appears to depend on the ability of the substrate to complex with metal ions in the reducing agent.

Full text of DOI:10.1016/j.tetlet.2011.05.051

Tetrahedron Letters 52 (2011) 3756–3758
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Tetrahedron Letters
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Protecting group directed stereoselective reduction of an epi-inosose:
efficient synthesis of epi-inositol
Madhuri T. Patil a, Shobhana Krishnaswamy b, Manash P. Sarmah a, , Mysore S. Shashidhar a,
⇑
a Division of Organic Chemistry, National Chemical Laboratory (Council of Scientific and Industrial Research-CSIR), Pune 411 008, India
b Center for Materials Characterization, National Chemical Laboratory (Council of Scientific and Industrial Research-CSIR), Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and high yielding synthesis of epi-inositol via stereoselective reduction of a pentaprotected epi-
inosose is reported. Extent of stereoselectivity during the hydride reduction appears to depend on the
ability of the substrate to complex with metal ions in the reducing agent.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 28 March 2011
Revised 10 May 2011
Accepted 12 May 2011
Available online 18 May 2011
Keywords:
Polyol
Cyclitol
Inositol
Reduction
Stereoselective
Selective reactions of organic compounds are of interest to a
large cross section of chemists due to their synthetic as well as
mechanistic implications in wide areas of research. Organic chem-
ists strive to identify and develop selective reactions of small mol-
ecules containing several functional groups, especially of the same
kind (polyols, polyamines, poly acids, etc.). Chemistry of cyclohex-
ane polyols (inositols, cyclitols) has been the subject of intense
investigations in the recent past due to the ubiquitous presence
of their derivatives in living cells and implication in biological phe-
nomena such as cellular signal transduction, calcium mobilization,
insulin stimulation, exocytosis, cytoskeletal regulation, intracellu-
lar trafficking of vesicles and anchoring of certain proteins to cell
membranes.1 Polyols are also interesting because of their structure
and reactivity in the solid state2 and they have been used as start-
ing materials for natural product synthesis.3 As expected, reactivity
and selectivity in reactions of small molecules containing several
functional groups can to some extent be tuned by varying the pro-
tecting groups utilized during a synthetic sequence. We herein
report hydride reduction of the epi-inososes 10 and 14, wherein,
the reduction of 10 was highly stereoselective to provide the epi-
inositol derivative with excellent yield, while that of 14, devoid
of any protecting group, resulted in the formation of relatively
more myo-inositol (1) due to loss of stereoselectivity. The method
of conversion of myo-inositol to epi-inositol (13) presented here
(Scheme 1) gives a single product with high yield in each step,
while most of the previous reports involved separation of isomeric
cyclitol derivatives.4 This work also illustrates the versatility of
myo-inositol orthobenzoate 25 as an intermediate for the prepara-
tion of cyclitols and their derivatives. epi-Inositol is biologically
active in its ability to affect regulation of the myo-inositol biosyn-
thetic pathway6 and it has been evaluated as a potential antide-
pressant drug that could interact with Li+ ion and myo-inositol
receptors in brain.6,7
The synthetic route for the conversion of myo-inositol to
epi-inositol is shown in Scheme 1. The racemic PMB ether4k 3 on
benzylation with NaH and excess benzyl bromide afforded the
corresponding dibenzyl ether 4. The orthobenzoate moiety in 4
was reduced with DIBAL-H to obtain a mixture of diols 5 and 6.
Benzylation of this mixture of diols afforded the pentabenzyl ether
7. The PMB ether in 7 was cleaved using HCl to afford the alcohol 8;
oxidation of 8 with IBX gave the protected epi-inosose 10. Reduc-
tion of the epi-inosose 10 with sodium borohydride was stereose-
lective to yield the corresponding epi-alcohol 11 with about 98%
selectivity (or more, see below). The pentabenzyl ether 11 was
isolated by column chromatography; global deprotection of 11
by hydrogenolysis afforded epi-inositol as a colorless solid (yield
over 9 steps, 52%). Yield of epi-inositol in the methods reported
previously4 was not more than 40%.
We also attempted to prepare epi-inositol by the hydride
reduction of the epi-inosose 14 (Scheme 2). However, unlike the
reduction of the protected inosose 10, reduction of 14 was not that
selective and yielded a mixture of epi-inositol and myo-inositol.
⇑
Corresponding author. Tel.: +91 20 2590 2055; fax: +91 20 2590 2629.
E-mail address: ms.shashidhar@ncl.res.in (M.S. Shashidhar).
Present address: Jubilant Chemsys Ltd, B-34, Sec-58, Noida 201 301, UP, India.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.051

M. T. Patil et al. / Tetrahedron Letters 52 (2011) 3756–3758
Ph
3757
Ph
Ph
HO
O
O
O
O
O
O
OH
O
O
O
OH
OH
OH
i
ii
iv
iii
HO
HO
BnO
HO
HO
OH
PMBO
4
PMBO
OH
1
OBn
2
3
BnO
BnO
BnO
OR1
OBn
OBn
OR3
vi
OPMB
OH
v
OPMB
OBn
viii
R2O
BnO
OBn
BnO
OBn
R3
OBn
R1 R2
OBn
7
8 H
5 H Bn
6 Bn H
vii
OH
9 Ac
OR4
OBn
BnO
BnO
HO
OH
O
OBn
OBn
x
ix
OBn
OH
OBn
BnO
BnO
HO
OBn
OH
10
13
11 R4 = H
vii
12 R4 = Ac
Scheme 1. Reagents and conditions: (i) as in Ref. 5; (ii) as in Ref. 4k; (iii) DMF, NaH, BnBr, 16 h, 96%; (iv) DCM, 1 M DIBAL-H in toluene, 20 h; (v) DMF, NaH, BnBr, 16 h, 81%
over two steps; (vi) DCM–MeOH, concd HCl, reflux, 6 h, 93%; (vii) pyridine, DMAP, Ac2O, reflux, 18 h, 92–95%; (viii) IBX, EtOAc, reflux, 6 h, 94%; (ix) NaBH4, DCM–MeOH (4:1),
30 min, 94%; (x) 20% Pd(OH)2/C, THF, H2O, TFA, H2, 60 psi, rt, 20 h, 96%.
AcO
OAc
OAc
HO
AcO
O
OAc
OH
OAc
i
OAc
OAc AcO
OH
OAc
HO
AcO
OH
OAc
15
16
14
OAc
BnO
BnO
BnO
O
OBn
OBn
OBn
ii
OAc
OBn
OBn
OBn
BnO
BnO
BnO
OBn
9
OBn
OBn
12
10
9:12 = 2:98
M+
O
R1O
PGO
O
O
O
O
OR2
OPG
H-
OPG
OBn
OBn
BnO
BnO
PGO
OR3
OBn
OPG
17
20
R1 R2 R3
18 H Ac Bn
19 PBB Bn All
Scheme 2. Reagents and conditions: (i) (a) borohydride, H2O; (b) pyridine, DMAP,
Ac2O, reflux, 18 h; (ii) (a) NaBH4, DCM–MeOH (4:1), 30 min; (b) pyridine, DMAP,
Ac2O, reflux, 18 h, 88%.
The epi:myo ratio (at 55 °C) were 89:11, 82:18, 50:50 and 43:57
(90 °C) on reduction, respectively, with borohydrides of sodium,
potassium, lithium and sodium cyanoborohydride. These ratios
were estimated by 1H NMR spectroscopy of the mixture of hexaac-
etates 15 and 16 since the epi-hexaacetate and the myo-hexaace-
Figure 1. ORTEP diagram of 9; thermal ellipsoids are shown at 30% probability and
hydrogen atoms are depicted as small spheres of arbitrary radii.
of 14) arises due to their ability to complex the metal ions which
offers steric hindrance for the approach of the reducing agent on
one face of the inositol ring and forces the hydride to approach
the carbonyl group as shown in 20 (Scheme 2) to yield the axial
alcohol. This line of thought is supported by the fact that reduction
of the ketone 18 with a hydride reducing agent devoid of metal
ions yields the corresponding equatorial alcohol predominantly.4e
Also, the epi-inosose 14 gives a mixture of products since its chela-
tion with metal ions is not expected to be strong enough in water
to facilitate the approach of the hydride from one face of the
carbocyclic ring. The synthetic sequence for the preparation of
the epi-inosose 14 used in the present work is shown in Scheme 3.
Swern oxidation of 2110 gave a mixture of the ketone 22 and the
gem-diol 23. Methylation of a mixture of 22 and 23 gave the ketal
24 exclusively; it is interesting to note that the ketal 24 was
obtained from the ketone 22 under basic conditions. Conversion
of a carbonyl compound to the corresponding acetal under basic
tate show distinct peaks at 2.17
d (6H) and 2.21 d (3H),
respectively, in their 1H NMR spectra.4d,8
Selective reduction of the protected epi-inosose 10 to the
epi-alcohol 11 with >98% selectivity was also confirmed by conver-
sion of the crude product obtained by reduction of the protected
epi-inosose 10 to the corresponding acetate and its scrutiny by
1H NMR spectroscopy (the acetate methyl peak for the epi-isomer
12 appears at d 2.09 while the corresponding peak for the myo-iso-
mer 9 appears at d 1.92). The structure of the racemic myo-acetate
9 was established by single crystal X-ray diffraction analysis
(Fig. 1).9
Perusal of the earlier reports4d,e,k on the synthesis of epi-inositol
revealed that the hydride reduction of the protected inososes 17,
18 and 19 were also selective to yield the corresponding epi-iso-
mer. We are of the opinion that higher selectivity in hydride reduc-
tion of the fully protected epi-inososes (in contrast to the reduction

3758
M. T. Patil et al. / Tetrahedron Letters 52 (2011) 3756–3758
and crystallographic data for compound 9) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.05.051.
O
O
O
O
O
O
O
O
O
O
ii
i
TsO
O
TsO
TsO
OH
TsO
OH
TsO
TsO
22
OH
References and notes
23
21
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Angew. Chem., Int. Ed. Engl, 1995, 34, 1933–1972; (d) Bruzik, K. S. (Ed.),
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Bhadbhade, M. M. Chem. Eur. J. 2009, 15, 261–269.
O
O
O
O
O
iii
iv
TsO
HO
14
OMe
OMe
OMe
TsO
HO
25
OMe
24
Scheme 3. Reagents and conditions: (i) DMSO, (COCl)2, DCM, Et3N, À78 °C, 82%; (ii)
DMF, Ag2O, MeI, rt, 24 h, 92%; (iii) NaOMe, MeOH, reflux, 12 h, 75%; (iv) TFA–H2O,
rt, 24 h, 99%.
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conditions is seldom encountered in the literature. The ease of for-
mation of the gem-diol 23 (and the acetal 24) is perhaps due to the
rigid trioxaadamantane frame-work in which presence of a sp2 car-
bon induces strain. The rigid trioxaadamantane frame-work also
facilitates the removal of the tosylates by S–O bond cleavage, since
nucleophilic substitution on the corresponding carbon (which is a
part of the rigid frame-work) is not possible.
In conclusion we have reported a method for the facile synthe-
sis of epi-inositol 13 involving the following novel features: highly
stereoselective reduction of the protected epi-inosose 10; use of
reaction sequence in which each step gives a single product with
excellent yields; delineation of the role of the protecting group in
the selective reduction of a ketone; and the use of tosylate as a hy-
droxyl protecting group.
Acknowledgments
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The Department of Science and Technology, New Delhi sup-
ported this work. M.T.P., S.K. and M.P.S. are recipients of Senior Re-
search Fellowships of the Council of Scientific and Industrial
Research, New Delhi.
8. Mukherjee, R.; Axt, E. M. Phytochemistry 1984, 23, 2682–2684.
9. Crystallographic data (excluding structure factors) for the structures in this
paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC code 816954.
Supplementary data
10. Sureshan, K. M.; Shashidhar, M. S.; Praveen, T.; Gonnade, R. G.; Bhadbhade, M.
M. Carbohydr. Res. 2002, 337, 2399–2410.
Supplementary data (experimental procedures for compounds
4, 7–12, 14, 24, and 25, along with all data for all new compounds