Concise chemoenzymatic synthesis of epi-inositol

Article abstract of DOI:10.1016/j.carres.2004.04.011

epi-Inositol was synthesized in six steps in 40% overall yield from a bacterial bromobenzene metabolite. The chemoenzymatic route involved toluene dioxygenase oxidation, substrate-directed catalytic osmylation, m-CPBA epoxidation, radical debromination, and Amberlite-catalized hydrolysis. The route described is amenable to scaleup and could allow access to cis-inositol, and deoxy derivatives of epi-inositol.

Full text of DOI:10.1016/j.carres.2004.04.011

Carbohydrate
RESEARCH
Carbohydrate Research 339 (2004) 1773–1778
Concise chemoenzymatic synthesis of epi-inositol
Cecilia Vitelio, Ana Bellomo, Margarita Brovetto, Gustavo Seoane
and David Gonzalez*
Departamento de Quꢀımica Orgꢀanica, Facultad de Quꢀımica, Universidad de la Repꢀublica, C.C. 1157, Montevideo, Uruguay
Received 12 December 2003; accepted 15 April 2004
Abstract—epi-Inositol was synthesized in six steps in 40% overall yield from a bacterial bromobenzene metabolite. The chemoen-
zymatic route involved toluene dioxygenase oxidation, substrate-directed catalytic osmylation, m-CPBA epoxidation, radical de-
bromination, and Amberlite-catalized hydrolysis. The route described is amenable to scaleup and could allow access to cis-inositol,
and deoxy derivatives of epi-inositol.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Keywords: Dioxygenase; Chemoenzymatic; epi-Inositol; cis-Inositol; Haloepoxide
1. Introduction
tives such as inosamines, conduramines, and deoxyflu-
oroinositols are on demand for studies as glycosidase
inhibitors28;29 and for metabolic pathway research.30–33
The chemoenzymatic approach to diverse cyclitols
and cyclitol analogs via whole-cell oxidation of aro-
matics by toluene dioxygenase has been extensively ex-
plored by Hudlicky,34–41 Carless,42–45 and Nicolosi.46–50
(Fig. 1). As a result, syntheses of five of the nine possible
inositol isomers, as well as aminofluorodeoxy deriva-
tives have been disclosed.28;51–54 The three remaining rare
Inositols are important bioactive molecules involved in
cellular communication. Particularly myo-inositol plays
a role in signal transduction, and its importance as
second messenger has been thoroughly studied.1–6 Aside
from myo-inositol, the other isomers are scarce (neo-, D-
chiro-, -chiro-, and scyllo-inositol) or nonexistent (cis-,
L
epi-, allo-, and muco-inositol) in nature, and their
chemical and biological properties have been target of
continued studies.
D- and L-chiro-inositol are potential
antidiabetic compounds.7–11 neo-Inositol phosphates
have been isolated from both mammalian tissue12 and
parasitic amoebas.13 scyllo-Inositol has been isolated
from human brain,14–17 as well as from plants,18 and its
function is under discussion. Finally, epi-inositol has
recently been evaluated as a potential antidepressant
drug that could interact with lithium and myo-inositol
receptors in the brain.15;19–27 Unfortunately, the lack of
availability of most isomers has limited the extension of
the research. In addition, many deoxygenated deriva-
OH
OH
OH
OH
HO
HO
OH
OH
HO
HO
OH
OH
OH
OH
OH
OH
epi-inositol (1)
cis-inositol (2)
conduritol D (3)
toluene
X
X
dioxygenase
chemical
oxidations
dihydroxylation
OH
cyclitols
OH hydrolytic
reactions
1 -15 g/L depending
on the strain and
the nature of X
Figure 1. Chemoenzymatic strategy towards diverse sterically con-
gested cyclitols.
* Corresponding author. Fax: +598-2-924-1906; e-mail: davidg@
fq.edu.uy
0008-6215/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2004.04.011

1774
C. Vitelio et al. / Carbohydrate Research 339 (2004) 1773–1778
Table 1. Results obtained in the chemical dihydroxylation of diene
diols with OsO4/NMO
isomers, epi-, cis-, and scyllo-inositol, have not yet len-
ded themselves to total synthesis by this type of
chemoenzymatic strategy. The completely trans stereo-
chemistry of the later isomer is not structurally suited
for this approach. On the other hand, cis- and epi-ino-
sitol, although sterically congested, appear as attainable
targets for the direct preparation from a cis-diol. In this
report, we present our results in the development of a
short, chemoenzymatic route to epi- and cis-inositol and
some deoxygenated congeners as shown in Figure 1.
X
X
X
1. OsO4, NMO
solvent, rt
O
O
OH
OH
O
O
Me
Me
Me
Me
+
2. DMP, TsOH
O
O
O
Me
O
Me
Me
Me
4 X = Cl
5 X = Br
6 X = Cl
7 X = Br
8 X = Cl
9 X = Br
Solvent
Yield (%)
cis:trans ratio
Polar (acetone–water)
Nonpolar (toluene)
Intermediate polarity (CH2Cl2)
85
40
75
50:50
80:20
80:20
2. Results and discussion
Our first approach to the sterically congested cyclitols 1,
2, and 3 explored the directed osmylation of the known
toluene dioxygenase metabolites 4 and 5. Osmylation is
generally considered to be sterically controlled, and the
diol is formed almost exclusively on the less hindered
face of the molecule. Nevertheless, research has been
done on reversing the stereoselectivity and particularly
on the directing effect of an hydroxyl group attached to
the allylic position. Donohoe et al. have extensively
investigated the topic55–59 and have applied the results to
the synthesis of conduritol D.60 These findings indicate
that the use of an aprotic solvent instead of the classical
conditions for stoichiometric or catalytic osmylation
favors the electronic directing effect of a neighboring
Lewis base over the steric control. Brovetto et al. have
studied a series of chiral cis-cyclohexadienediols and
found that both regio- and stereoselectivity of the
osmylation were influenced by the nature of the pro-
tective groups.61 In our hands, the technique rendered a
mixture of diasteromeric tetrols favoring the syn-di-
hydroxylation in variable ratios (Table 1). The reaction
proceeded well in aprotic solvents of intermediate
polarity such as dichloromethane, although the rate was
considerably slower than the comparable reaction in
water, t-BuOH or their mixtures. Attempts to run the
reaction in solvents of very low polarity such as toluene
slowed down the reaction to unacceptable values and
decreased the overall yield without improving the dia-
stereoselectivity (Table 1).
With the bromoconduritol derivative 745 in hand, we
explored the oxidation of the remaining double bond to
target cis- and epi-inositol. We reasoned that we should
be able to achieve the desired diasterodivergence by
either epoxidizing compound 7 or the conduritol D
derivative 10 (Scheme 1). The meso epoxide 11 should
be attainable either from 10 or bromoepoxide 12. Sur-
prisingly, 7 was epoxidized faster than 10, and the route
via the bromoepoxide was finally chosen. Finally,
compound 12 was subjected to radical dehalogenation
conditions by means of SnBu3H/(PhCO2)2 to furnish the
epoxide 11.62
Several conditions were tested for the epoxide ring
opening of 11 without concomitant acetonide hydroly-
sis, but the compound proved to be systematically
unreactive. The epoxide did not react with 20% KOH in
various water–methanol mixtures either at room tem-
perature or at reflux. This fact could be explained by a
very effective blocking of the b face of the molecule by
Br
HSnBu3, (PhCO2)2,
O
m-CPBA,
O
O
O
Me
Me
Me
Me
THF, 67ºC
O
O
CH2Cl2-CHCl3, 50 ºC
Me
Me
epi
O
90 %
30 %
O
O
O
O
Me
O
Me
Me
O
Me
Me
10
7
HSnBu3, (PhCO2)2,
THF, 67ºC
11
Me
85 %
Br
O
O
m-CPBA,
Cl -CHCl , 50 ºC
HO
O
O
O
Me
Me
CH2
Me
Me
2
3
cis
70 %
O
O
O
O
O
Me
Me
Me
Me
13
12
Scheme 1. Diasterodivergent strategy towards cis- and epi-inositol.

C. Vitelio et al. / Carbohydrate Research 339 (2004) 1773–1778
1775
OH
OH
Dowex 1X8-200
O
O
strongly acidic cation
OH
OH
HO
HO
OH
OH
O
O
H2O, 100 ºC
Me
Me
HO
O
O
OH
Me
Me
11
14
epi-inositol (1)
90% yield
Scheme 2. Acetonide deprotection and attendant epoxide ring opening in H2O.
the acetonide groups. On the other hand, when 11 was
boiled in water containing either an acidic or basic resin,
it readily deprotected, and the resulting epoxitetrol 14
was smoothly opened to render epi-inositol (1) that
remained in solution. Filtration of the resin and evap-
oration of the water rendered crystalline epi-inositol in
90% yield with identical 1H NMR and 13C NMR spectra
to those previously reported (Scheme 2).63–66 The order
of the events in this one-pot reaction was confirmed by
performing the experiment in D2O and analyzing
aliquots by NMR at different times. Under all the con-
ditions tested, the epoxide ring-opening was effected
prior to the acetonide group deprotection.
A similar strategy was followed in an attempt to syn-
thesize cis-inositol. We reasoned that bromoepoxide 12
would react in a similar way to that of the analogous
epoxide 11 to furnish the inosose 15. In addition, related
inosose 17 was reported previously by Mandel and
Hudlicky for the opening of chloroepoxide 16 with alu-
mina and water.67 Unfortunately, 15 turned out to be
unstable under the reaction conditions and could only be
obtained in minute amounts, since it degraded promptly
to render aromatic derivatives. Conversely, deoxygen-
ated derivatives of type 18 can be smoothly converted
into ketone 19 without observed degradation (Seoane,
G., and Fonseca, G., unpublished data) (Scheme 3).
We have completed a chemoenzymatic synthesis of
epi-inositol in six steps (five synthetic operations) from
bromobenzene in an overall yield of 40% from meta-
bolite 5 (Scheme 4). The preparation is amenable to
scaleup and also potentially stereodivergent to the syn-
thesis of cis-inositol and inosamines. Research on the
syntheses of these compounds is in progress and will be
disclosed in forthcoming reports.
Dowex 1X8-200
O
strongly acidic cation
Br
O
H2O, 100 ºC
OH
OH
HO
HO
O
O
Me
Me
or
Al2O3 (basic)
H2O, 80 ºC
O
OH
O
Me
15
12
Me
O
Cl
O
Al2O3 (basic)
HO
HO
OH
OH
O
H2O, 80 ºC, 30 min
Me
Me
84 %
O
HO
3. Experimental
OH
17
OH
16
3.1. General methods
O
Cl
O
NaHCO3/H2O,
HO
O
100 ºC, 5 min.
O
O
Me
Me
Me
Me
All nonhydrolytic reactions were carried out under a
nitrogen atmosphere with standard techniques for the
exclusion of moisture. All solvents were distilled prior to
use. Melting points were determined on a Leitz Wetzlar
O
80 %
19
18
Scheme 3. Hydrolytic ring opening of conduritol haloepoxides.
Br
Br
Br
O
O
Me
Me
m-CPBA,
toluene
1. OsO4, NMO, CH2Cl2, rt
2. DMP, TsOH, rt
OH
OH
CH2Cl2-CHCl3, 50 ºC
dioxygenase
O
70 %
75 %
3 g/L
O
Me
Me
5
7
Br
O
OH
O
DOWEX 1X8-200
strongly acidic cation
H2O, 100 ºC
O
O
Me
Me
O
O
Me
Me
HO
HO
OH
epi-inositol (1)
OH
OH
HSnBu3, (PhCO2)2,
THF, 67ºC
O
O
85 %
90 %
O
O
Me
Me
Me
Me
12
11
Scheme 4. Total chemoenzymatic synthesis of epi-inositol from bromobenzene.

1776
C. Vitelio et al. / Carbohydrate Research 339 (2004) 1773–1778
Microscope Heating Stage apparatus model 350. Optical
rotations were measured on a Perkin–Elmer 241polar-
imeter using a 7-mL cell. Infrared spectra were recorded
on a Matheson Excalibur spectrometer. Mass spectra
were performed on a Shimadzu GS-MS QP 1100 EX
instrument using the electron-impact mode. Nuclear
magnetic resonance spectra were recorded on Bruker
Avance DPX-400 instrument with Me4Si as the internal
standard and chloroform-d as solvent unless otherwise
indicated in the experimental section. Combustion
analyses were performed by Atlantic Microlab, Inc.
(Norcross, Georgia 30091). Analytical TLC was per-
formed on silica gel 60F-254 plates and visualized with
UV light (254 nm) and/or anisaldehyde–H2SO4–AcOH
as the detecting agent. Flash column chromatography
was performed using silica gel (Kieselgel 60, EM Re-
agents, 230–400 mesh).
gel, 1:9 EtOAc–hexanes) rendered 12 (220 mg, 70%) as a
20
D
white crystalline solid: mp 100–120 ꢁC (d); ½aŠ +42 (c
0.36, CH2Cl2); IR (KBr): m 2993, 2944, 2891, 1378, 1243,
1220 (C–O–C), 1107, 1055, 884, 797, 788 cmÀ1
;
1H
NMR (400 MHz, CDCl3): d 4.66 (bd, 1H, J3;4 5.3 Hz,
H-3), 4.40 (m, 1H, H-6), 4.24 (m, 2H, H-4, and H-5),
3.66 (s, 1H, H-2), 1.61 (s, 3H), 1.53 (s, 3H), 1.45 (s, 3H),
1.40 (s, 3H), 13C NMR (100 MHz, CDCl3): d 111.4,
110.8, 74.8, 72.7, 72.4, 69.5, 63.0, 27.7 (di), 26.4 (di); MS
m=z (relative intensity): 305 (Mþ-CH3, 23%), 247 (2), 187
(2), 159 (4), 97 (9), 85 (6), 69 (6), 59 (14), 43 (100). Anal.
Calcd for C12H17BrO5: C, 44.88; H, 5.34. Found: C,
45.02; H, 5.23.
3.1.3. Preparation of (1R,2S,3S,4R,5S,6R)-2,3-epoxy-
3,4,5,6-di-O-isopropylidenecyclohexane (11).62 Tributyl-
tin hydride (146 mg, 0.50 mmol) was added to a mixture
of benzoyl peroxide (25 mg, 0.10 mmol) and the epoxide
bromide 12 (120 mg, 0.37 mmol) in dry THF (6 mL). The
reaction mixture was refluxed for 4 h. The solvent was
evaporated, and the residue was purified by flash chro-
matography (silica gel, 1:9 EtOAc–hexanes) to afford
the pure product as a white solid (76 mg, 85%). 1H
NMR (400 MHz, CDCl3): d 4.46 (d, 2H, J3;4 ¼ J6;5
4.7 Hz, H-3, and H-6), 4.23 (d, 2H, H-4, and H-5), 3.40
(s, 2H, H-1, and H-2), 1.52 (s, 6H), 1.40 (s, 6H), 13C
NMR (100 MHz, CDCl3): d 110.4, 72.3, 71.2, 54.2, 27.2
(di), 26.3 (di).
3.1.1. Preparation of (2R,3R,4S,5S)-1-bromo-2,3,4,5-di-
O-isopropylidene-6-cyclohexene (7).45 To a solution of 1-
bromo-4,6-cyclohexadiene-2,3-diol (5, 500 mg, 2.62
mmol) in CH2Cl2 (10 mL) was added N-methylmorph-
oline N-oxide (465 mg, 3.97 mmol) and a catalytic
amount of OsO4 (0.1mL of a 10% solution in tert-butyl
alcohol). The mixture was stirred overnight at room
temperature, protected from light. After removal of
CH2Cl2, the crude product from the osmylation was
treated with DMP (3 mL, 22.26 mmol) in acetone
(3.0 mL) and p-TsOH (689 mg, 4.00 mmol). Stirring was
continued during 45 min at rt. At the end of that time
the acetone was evaporated, and the residue was dis-
solved in CH2Cl2 (15 mL). The resulting solution was
washed with aq Na2CO3 (10 mL) and brine, dried over
MgSO4, and filtered. The solvent was evaporated to give
the crude mixture, which was chromatographed (silica
gel, 1:9 EtOAc–hexanes) to furnish 7 (1.2 g, 75%) as a
white solid: 1H NMR (400 MHz, CDCl3): d 6.22 (d, 1H,
J6;5 3.8 Hz, H-6), 4.56 (m, 2H, H-3, and H-5), 4.45 (m,
1H, H-4), 4.41 (m, 1H, H-2), 1.53 (s, 3H), 1.49 (s, 3H),
1.42 (s, 3H), 1.39 (s, 3H), 13C NMR (100 MHz, CDCl3):
d 128.8, 124.7, 111.5 (di), 75.9, 74.3, 73.1, 72.3, 27.2 (di),
26.8 (di).
3.1.4. Preparation of cyclohexane-1,2,3,4,5,6-hexaol (epi-
inositol) (1).63
A mixture of epoxide 11 (76 mg,
0.31mmol), Dowex 1X8-200 resin (75 mg) and H 2 O was
stirred at reflux for 24 h. After completion of the reac-
tion, the resin was filtered off, and the solvent was re-
moved under reduced pressure to give epi-inositol (1)
1
(50 mg, 90%) as a white solid: mp 270 ꢁC (d); H NMR
(400 MHz, D2O): d 4.03 (d, 2H, J2;1 ¼ J4;5 2.6 Hz, H-2,
and H-4), 3.80 (t, 1H, J6;1 9.9 Hz, H-6), 3.69 (t, 1H, J3;2
2.9 Hz, H-3), 3.45 (dd, 2H, H-1, and H-5), 13C NMR
(100 MHz, D2O): d 74.9, 72.2, 70.5, 67.3.
Acknowledgements
3.1.2. (1R,2S,3S,4S,5R,6R)-1-Bromo-1,2-epoxy-3,4,5,6-
di-O-isopropylidenecyclohexane (12). cis-Diacetonide 7
(300 mg, 0.98 mmol) was dissolved in 1:1 CH2Cl2–
CHCl3 (10 mL). 3-Chloroperoxybenzoic acid (485 mg,
1.96 mmol) was added to the stirred solution, and the
system was allowed to react at reflux temperature for
6 h. After completion of the reaction, the mixture was
diluted with CH2Cl2 (10 mL) and poured onto aq
Na2CO3 (10 mL). The organic layer was separated, and
the aqueous phase was further extracted with CH2Cl2
(3 · 10 mL). The combined organic layers were washed
with brine, dried over MgSO4, and filtered. Concentra-
tion and purification by flash chromatography (silica
The authors acknowledge Mr. Horacio Pezzaroglo and
Mr. Eleuterio Umpierrez for recording spectra and Prof.
Stephen Angyal for reading the manuscript.
The following organizations contributed to support
this work: OPCW/IFS partnership programme (Re-
search Grant F/3078-1and F/3078-2), CONICYT-BID
(project FCE5065) and PEDECIBA (URU 97/016).
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