A short, stereoselective synthesis of neo-inositol

Article abstract of DOI:10.1016/S0008-6215(99)00289-X

A practical synthesis of neo-inositol is described in which the target is prepared on a multigram scale in six operations from bromobenzene. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0008-6215(99)00289-X

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Carbohydrate Research 324 (2000) 200–203
Note
A short, stereoselective synthesis of neo-inositol
Tomas Hudlicky a,*, Nora Restrepo-Sa´nchez b, Pierre D. Kary a,
Luz M. Jaramillo-Go´mez b
a Department of Chemistry, Uni6ersity of Florida, PO Box 117200, Gaines6ille, FL 32611-7200, USA
b Departamento de Qu´ımica, Uni6ersidad del Valle, A.A. 25360 Cali, Colombia
Received 6 May 1999; accepted 27 October 1999
Abstract
A practical synthesis of neo-inositol is described in which the target is prepared on a multigram scale in six
operations from bromobenzene. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: neo-Inositol; Cyclitols; Inositols; Chemoenzymatic synthesis; Cyclohexadienediol
The inositols (collectively known as cycli-
tols) and their derivatives figure prominently
in numerous biological processes. For exam-
ple, inositol phosphates are involved in cellu-
lar signaling and regulation of cellular calcium
with implications in such processes as sensory
perception and fertilization [1]. The study of
inositol-containing compounds and their ef-
fects is one of the most active fields in biology
today, and there is considerable interest
among chemists in the synthesis of analogues
[2]. It can be argued that development of
synthetic routes to even the most abundant of
the nine isomers would facilitate research on
the inositols — the study of structure–activity
relationships and mechanisms through radio-
labeled compounds, for instance. We have
provided synthetic routes to five of these iso-
mers [3–5]. All but one of the nine inositols
(cis) are commercially available1, some as a
direct result of our endeavors.
neo-Inositol 1 was first described and
named by Angyal and Matheson in 1955,
when it was prepared, along with
itol, in two steps from 1,2:5,6-di-O-isopropy-
lidine- -chiro-inositol [6]. It was first identified
L-chiro-inos-
L
in nature in soil samples as its hexaphosphate
[7]. Since then, it has been isolated from Cro-
ton celtidifolius, a plant used in Brazilian folk-
lore medicine [8], and from animal tissues [9].
The crystal structure of neo-inositol has been
examined in relation to its unusual stability
[10], and molecular modeling studies have
been reported [11,12].
We have already prepared neo-inositol on a
small scale [13,14] and have reported the isola-
1 allo-Inositol, $80/100 mg (Aldrich);
$195/100 mg (Aldrich); -(−)-chiro-inositol, $195/100 mg
(Aldrich); epi-inositol, $174/100 mg (Sigma); muco-inositol,
$134/100 mg (Aldrich); myo-inositol, $75/500 g (Aldrich); neo-
inositol, $199/100 mg, scyllo-inositol, $204/100 mg (Sigma).
D-(+)-chiro-inositol,
L
* Corresponding author. Tel.: +1-904-392-9844; fax: +1-
904-846-0296.
E-mail address: hudlicky@chem.ufl.edu (T. Hudlicky)
0008-6215/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(99)00289-X

T. Hudlicky et al. / Carbohydrate Research 324 (2000) 200–203
201
Scheme 1. (i) Toluene dioxygenase; (ii) dimethoxypropane, p-TsOH, acetone; then DBH, H2O, acetone; (iii) 10% aq KOH, DME,
t
5 h, rt; (iv) rt“reflux; (v) Bu3SnH, AlBN, benzene, reflux, 18 h; (vi) OsO4, NMO, BuOH, acetone–water; (vii) concd HCl,
MeOH, 48 h.
tion mixture to reflux effected the hydrolysis2.
tion of neo-inositol as a side-product in the
The regioselectivity of the oxirane opening can
be attributed in part to the atomic charge
distribution being more positive at C-3 than
C-4 [20,21], in part to the steric requirements
for pseudo trans-diaxial opening and the bulk
of the acetonide group. Radical debromina-
tion of 6a to 7, followed by dihydroxylation
with osmium tetroxide and 4-methylmorpho-
line N-oxide (NMO) yielded tetrol 8. Depro-
tection in methanolic HCl or water containing
a catalytic amount of sodium benzoate readily
provided neo-inositol 1 in 77% yield.
This efficacious, high-yielding route pro-
vided neo-inositol selectively in only six opera-
tions from bromobenzene, without the need
for column chromatography. We have pre-
pared 3.8 g of analytically pure neo-inositol3
from approximately 20 g of the bromocyclo-
hexadiene-cis-diol 3 in a 17% overall yield.
synthesis of
D
-chiro-inositol [5]. Chung and
Kwon have synthesized neo-inositol and other
inositols from myo-inositol [15]. Recently, as
the work described in this paper was in pro-
gress, a practical multigram synthesis of neo-
inositol from myo-inositol was reported by
Riley and co-workers [16]. Herein, we report a
practical synthesis of neo-inositol from
bromobenzene.
neo-Inositol was prepared as shown in
Scheme 1. The major thrust of the strategy
arose from our synthesis of deoxyfluoro inosi-
tols [17] and from our efforts in the synthesis
of the sphingosines [18]. The present synthesis
represents a substantial scale-up of those pro-
cedures already reported.
We have used the biooxidation of aromatic
compounds as a technique to prepare diverse
chiral starting materials for many of the syn-
theses we have undertaken in our laboratories
over the past few years [3]. In this case, bro-
mobenzene 2 was enzymatically hydroxylated
to the corresponding cyclohexadiene-cis-diol 3
[19] in \99% ee by treatment with Es-
cherichia coli JM109 (pDTG601). The diol
was subsequently protected as its acetonide
and converted to bromohydrin 4 by means of
1,3-dibromo-5,5-dimethylhydantoin (DBH) in
acetone–water [17,18].
1. Experimental
(3R,4S,5S,6S)-1-Bromo-5,6-O-isopropyli-
dene-1-cyclohexene-3,4,5,6-tetrol (6a).—Bro-
mohydrin 4 [17,18] (40 g, 0.10 mol) was dis-
2 Lewis acid-catalyzed cleavage (BF3) of epoxide 5 with
benzyl alcohol yields 6b, prepared in conjunction with a
project on the synthesis of oligo inositols and used here only
to check purity by HPLC.
Treatment of 4 with excess aqueous KOH
at room temperature generated the epoxide 5
[17], which was not isolated; heating the reac-
3 The 6.3 g batch of neo-inositol obtained in the final step
is of a purity suitable for further transformations. The overall
yield in this instance is 28%.

202
T. Hudlicky et al. / Carbohydrate Research 324 (2000) 200–203
for 12 h at 100 °C under reduced pressure: mp
313 °C (dec), lit. 315 °C (dec) [6]; [h]2D7 0° (c
0.01, H2O); IR (KBr): w 3250–2910, 1392,
solved in 1,2-dimethoxyethane (DME, 350
mL), then aq KOH (10%, 176 mL) was slowly
added. The reaction mixture was stirred at
ambient temperature until thin-layer chro-
matography (TLC) analysis (19:1 CH2Cl2–
EtOAc) showed no remaining bromohydrin (5
h). The flask was fitted with a reflux condenser
and the mixture was heated at reflux
overnight. When the reaction mixture had
cooled to room temperature (rt), NH4Cl was
added and the solvent was removed in vacuo.
The crude product was dissolved in EtOAc,
washed with water, and dried over MgSO4.
Removal of the solvent yielded 22 g of mate-
rial of sufficient purity to use directly in the
next step.
1
1283, 1258, 1131, 1058, 1037 cm−1; H NMR
(500 MHz, Me2SO-d6): l 4.34 (d, 2 H, OH),
4.21 (bs, 4 H, OH), 3.71 (bs, 2 H), 3.43 (bs, 4
H); MS: C6H13O6 requires 181.07121; found
[M+H] 181.07121; m/z (CI): 181 [M+H]+,
361 [2M+H]+, 554 [3M+4H]+, 163 [(M+
H)–OH]+, 127 [(M+H)–3 OH]+. Anal.
Calcd for C24H48O24·H2O [4:1 hydrate]: C,
39.02; H, 6.50. Found: C, 39.16; H, 6.69.
Acknowledgements
We thank NSF (CHE-9521489), EPA
(R826133), and TDC Research, Inc., for fund-
ing. Special thanks are due to Dr Mary Ann
Endoma for preparing substantial quantities
of the bromocyclohexadiene-cis-diol by fer-
mentation.
(3R,4S,5S,6R) - 5,6 - O - Isopropylidene - 1-
cyclohexene-3,4,5,6-tetrol (7).—To diol 6a
[17] (22 g, 0.08 mol) dissolved in benzene (125
mL) and MeOH (65 mL) was added a spatula-
tip of AlBN and n-BuSn3H (56 mL, 0.2 mol).
After stirring at reflux overnight, the reaction
mixture was concentrated in vacuo and the
residue was dissolved in MeCN. The mixture
was washed with hexanes; as the hexane phase
contained some of the diol it was extracted
with another portion of MeCN. The com-
bined MeCN extracts were evaporated to dry-
ness to yield 15 g of material of sufficient
purity to use in the next step.
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.

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