A short and efficient route from myo - To neo -inositol

Article abstract of DOI:10.1055/s-0029-1220071

An efficient route from myo- to neo-inositol is described. The key steps of the sequence are oxidation of the hydroxy group at C-5 to the corresponding ketone, followed by a highly (dr = 7.8:1) stereoselective reduction. The route includes nine steps with an overall yield of 51% and is therefore superior to all hitherto reported methods for the preparation of neo-inositol. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1220071

LETTER
1497
A Short and Efficient Route from myo- to neo-Inositol
n
eo-Inositol fr
a
m
yo-In
b
Institut für Chemie, Universität Potsdam, Karl-Liebknecht-Str. 24-25, 14476 Potsdam, Germany
Fax +49(331)9775065; E-mail: wessig@uni-potsdam.de
Received 8 March 2010
In connection with our investigations concerning the de-
velopment of molecular rods with oligospiroketal (OSK)
backbone8 we were interested in a building block, which
could replace the hitherto used pentaerythritol but is fur-
Abstract: An efficient route from myo- to neo-inositol is described.
The key steps of the sequence are oxidation of the hydroxy group at
C-5 to the corresponding ketone, followed by a highly (dr = 7.8:1)
stereoselective reduction. The route includes nine steps with an
overall yield of 51% and is therefore superior to all hitherto reported nished with two additional substituents for solubility en-
methods for the preparation of neo-inositol.
hancement. Inositols should fulfill these demands.
Bearing in mind that ketals of vic-dihydroxycyclohexanes
are only smoothly formed if the two hydroxy groups are
in cis arrangement and that the two pairs of these cis-diol
moieties at opposing sides of the cyclohexane ring should
be positioned trans to each other to avoid a kink in the
OSK rod backbone, only allo- and neo-inositol are con-
sidered for our purpose (see boxes in Figure 1). Since the
two remaining hydroxy groups should not lower the sym-
metry of the OSK rods, neo-inositol is the only suitable
isomer for our approach (Figure 2).
Key words: inositols, cyclitols, carbocycles, stereoselective syn-
thesis, regioselectivity
Inositol is the collective term for a substance class formed
by the nine stereoisomeric hexahydroxy cyclohexanes
whose structures are summarized in Figure 1.
OH
OH
OH
HO
HO
OH
OH
HO
HO
OH
OH
HO
HO
OH
OH
1
6
5
2
3
4
OR
O
O
O
O
OH
myo-
OH
scyllo-
OH
muco-
O
O
O
O
1
4
6
5
2
3
OH
OH
OH
OR
HO
HO
OH
OH
HO
HO
OH
OH
HO
HO
OH
OH
1
6
2
3
Figure 2 OSK rods with pentaerythritol (left) and neo-inositol
(right) tetrol unit
5
4
OH
neo-
OH
L-chiro-
OH
D-chiro-
It should be noted that neo-inositol differs from myo-inos-
itol only by the relative configuration in 5-position. Only
two routes are known, which explicitly attend to the total
synthesis of neo-inositol.
OH
OH
OH
HO
HO
OH
OH
HO
HO
OH
OH
HO
HO
OH
OH
The method by Potter et al.9 starts from myo-inositol. Af-
ter protection of four hydroxy groups in 1,3,4,6-position
as BDA derivatives using butane-2,3-dione a selective
monosulfonylation of one of the remaining hydroxy
groups in 5-position with triflic anhydride is reported. The
key step of this method is a subsequent SN2 substitution of
the triflate moiety giving the neo-inositol substitution pat-
tern. Unfortunately, we could not reproduce the sulfony-
lation step. Even after numerous optimization attempts we
always obtained a mixture of mono- and disulfonylated
product. Instead of the reported 17% overall yield (5
steps) we obtained at best 5% of the desired product.
OH
OH
cis-
OH
epi-
allo-
Figure 1 Structure of the nine inositols
Some phosphorylated derivatives of inositols, especially
of myo-inositol, play an important role in signal
transduction1 and other cellular processes.2 Besides the bi-
ological significance the inositols are very interesting
building blocks for the synthesis of natural products,3 cat-
alysts,4 metal-complexing agents,5 gelators,6 and su-
pramolecular assemblies.7 On the other hand, only four of
the nine inositols occur in nature and only myo-inositol is
commercially available for an acceptable price.
The second total synthesis of neo-inositol by Hudlicky et
al.10 uses enantiomerically pure 3-bromocyclohexa-3,5-
diene-1,2-diol, the enzymatic preparation of which from
bromobenzene was previously reported.11 Besides the dif-
ficulties to scale up this first step (a run in a 2800 ml flask
gave only 160 mg product) the following steps require
some reagents, which are not commercially
SYNLETT 2010, No. 10, pp 1497–1500
Advanced online publication: 26.05.2010
DOI: 10.1055/s-0029-1220071; Art ID: G08210ST
x
x
.x
x
.2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

1498
P. Wessig et al.
LETTER
available (1,3-dibromo-5,5-dimethylimidazolidine-2,4-di-
obtained the acetate 6 with myo-configuration as main
one, DBH), highly toxic (Bu3SnH, OsO4) or expensive product together with only minor amounts of the desired
(OsO4). The reported overall yield amounts to 19%.
neo-acetate 7 and epimeric alcohols 4 and 8 (Scheme 2).
This outcome could be explained by steric hindrance of
the preferred SN2-trajectory both in conformer 5-A and 5-
B (see dashed arrows in Scheme 2).
Chung and Kwon12 reported a route to a tetraprotected
neo-inositol derivative starting from a hexaprotected myo-
inositol.13 The two key steps to switch from myo- to neo-
stereochemistry are an elimination of a trans-1,2-diol with
I2, Ph3P and imidazole, and a cis-dihydroxylation of the
resulting cyclohexene (a conduritol C derivative) using
OsO4 and NMO. The overall yield to the neo-inositol de-
rivative came to 13% or 10%, respectively, assuming that
two subsequent deprotection steps proceed with >90%
yield.
4
Tf2O, Py
89%
O
O
OTf
O
O
BnO
Nu
OBn
OBn
OBn
BnO
TfO
OBn
Nu
5-B
5-A
Conduritols are also the key intermediates in the interest-
ing work by Altenbach and co-workers.14 Unlike the route
by Chung and Kwon conduritols E with a different stere-
ochemical pattern were prepared and therefore a trans-di-
hydroxylation (carried out by a epoxidation/epoxide ring-
opening sequence) is necessary, circumventing the OsO4-
catalyzed dihydroxylation. The overall yield of the eight-
step sequence amounts to approximately 20%.
DMAA, H2O
heat
O
O
OAc
O
O
AcO
HO
OBn
OBn
OBn
OBn
OBn
OBn
6 (65%)
7 (7%)
O
O
O
OH
O
OBn
OBn
Furthermore, neo-inositol or derivatives were mentioned
in some other publications but by a critical review none of
these methods was considered an efficient access to the
target compound.15–21
OBn
OBn
OBn
OBn
8 (2%)
4 (15%)
Scheme 2 Preparation of triflate 5 and treatment with DMAA–H2O
In the face of this unsatisfactory situation we decided to
develop a new short and efficient route to neo-inositol.
Interestingly, both acetates 6 and 7 and alcohols 4 and 8
were formed at the same ratio (10:1). This suggests that
the formation of these four products passes through the
same reactive intermediate. We assume an SN1-like mech-
anism with stabilization of the intermediate carbocation at
C-5 by the neighboring two benzyloxy groups at C-4 and
C-6. Several attempts to convert 4 into the 4-nitroben-
zoate of 8 by a Mitsunobu reaction25 with DEAD, Ph3P
and 4-nitrobenzoic acid gave only a complex product mix-
ture beside unconverted reactant. Finally, we succeeded
with an oxidation–reduction sequence. To this end 4 was
oxidized to ketone 928 with Dess–Martin periodinane
(DMP)26 and was, without further purification,27 subject-
ed to numerous reduction conditions. The results are sum-
marized in Table 1. The best ratio between 829 and 4 was
obtained with sodium borohydride in refluxing methanol
(entry 4) but this ratio decreased with increasing amounts
of 9 used in the reaction (entries 5 and 6). The best com-
promise is to start the reaction at room temperature and let
the temperature increase to 40 °C by reaction heat (entry
3). Interestingly, lower reaction temperatures (entry 1) or
ethanol as solvent (entry 7) gave poorer product ratios.
Other reduction agents such as LiAlH4 (entry 9), borane
(entries 10 and 11), aluminum triisopropylate (Meerwein–
Ponndorf reduction, entry 12) or DIBAL-H (entry 13) also
consistently resulted in lower selectivity.
Commencing with myo-inositol (1) we prepared the ortho
ester 2 according to literature.22 Unlike the previously re-
ported methods23 we succeeded in directly converting 2
without further purification into the completely protected
myo-inositol 3 by alkylation with benzyl chloride. The
subsequent reductive ring opening of the ortho ester moi-
ety liberated the axial hydroxy group in 5-position and
provided the five-fold protected myo-inositol 4 in excel-
lent yield (Scheme 1).24
OH
HO
HO
OH
OH
HC(OEt)3
TsOH (cat.)
DMF
O
O
5
1
4
O
6
5
2
3
4
3
OH
1
6
2
OH
OH
OH
2
1
BnCl, NaH
DMF
78% (2 steps)
DIBAL–H
CH2Cl2
O
O
O
O
OH
O
OBn
OBn
93%
OBn
OBn
OBn
OBn
3
4
Scheme 1 Optimized preparation of 4
To obtain a pure neo-configured derivative, the product
mixture (8 + 4) was first partly deprotected by treatment
with HCl in refluxing methanol followed by separation
with flash column chromatography (CHCl3–EtOAc) giv-
ing 1030 with an overall yield of 76% based on 4.
At this point an epimerization at C-5 suggests itself to
switch from myo to neo configuration. For this purpose 4
was converted into the triflate 5, which was treated with a
mixture of dimethylacetamide–water.9 Surprisingly we
Synlett 2010, No. 10, 1497–1500 © Thieme Stuttgart · New York

LETTER
neo-Inositol from myo-Inositol
1499
Table 1 Reduction of Ketone 9
In summary, we developed a short and efficient route
from myo-inositol (1) to neo-inositol (12), which is clearly
superior to all hitherto described methods. The overall
yield of the nine-step sequence amounts to 51%. Further-
more, three intermediate products were used in the next
reaction step without purification (2, 8, 9).
Entry Reagent
Solvent Temp na
drb
Yield (%)
1
2
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
MeOH
Et2O
0 °C
r.t.
0.3 5.4:1
0.5 6.5:1
43.1 7.8:1
97
93
98
94
83
46
76
89
3
r.t.c
Acknowledgment
4
reflux 0.7 9.5:1
reflux 19.0 7.6:1
reflux 45.0 6.5:1
reflux 0.7 7.1:1
The financial support of this work by the Deutsche Forschungs-
gemeinschaft (We 1850/7-1) is gratefully acknowledged.
5
6
7
References and Notes
d
(1) (a) Almeida, A.; Layton, M.; Karadimitris, A. Biochim.
Biophys. Acta, Mol. Basis Dis. 2009, 1792, 874.
(b) Berridge, M. J. Biochim. Biophys. Acta, Mol. Cell Res.
2009, 1793, 933. (c) Burton, A.; Hu, X.; Saiardi, A. J. Cell.
Physiol. 2009, 220, 8. (d) Phosphoinositides: Chemistry,
Biochemistry and Biomedical Applications, ACS Symposium
Series 718; Bruzik, K. S., Ed.; American Chemical Society:
Washington DC, 1999. (e) Hinchliffe, K.; Irvine, R. Nature
(London) 1997, 390, 123. (f) Derridge, M. J. Nature
(London) 1993, 361, 315.
8
r.t.
0.7 1.2:1
0.3 4.8:1
0.7 4.4:1
0.7 1.7:1
e
9
LiAlH4
r.t.
–
10
11
12
13
BH3·THF
BH3·THF
THF
0 °C
r.t.
27
21
97
95
THF
Al(Oi-Pr)3 i-PrOH
reflux 0.3 4.3:1
0.5 1:1.3
DIBAL-H CH2Cl2 0 °C
(2) (a) Deranieh, R. M.; Greenberg, M. L. Biochem. Soc. Trans.
2009, 37, 1099. (b) Ferguson, M. A. J.; Williams, A. F. Ann.
Rev. Biochem. 1988, 57, 285.
a Amount of 9 in mmol.
b Ratio 8 (neo)/4 (myo) determined via 1H NMR.
c The temperature increased to 40 °C during reaction.
d CeCl3 (1 equiv) was added.
(3) (a) Kwon, Y.-K.; Lee, C.; Chung, S.-K. J. Org. Chem. 2002,
67, 3327. (b) Suzuki, T.; Suzuki, S. T.; Yamada, I.; Koashi,
Y.; Yamada, K.; Chida, N. J. Org. Chem. 2002, 67, 2874.
(c) Suzuki, T.; Tanaka, S.; Yamada, I.; Koashi, Y.; Yamada,
K.; Chida, N. Org. Lett. 2000, 2, 1137. (d) Chida, N.;
Yoshinaga, M.; Tobe, T.; Ogawa, S. Chem. Commun. 1997,
1043. (e) Chida, N.; Ogawa, S. Chem. Commun. 1997, 807.
(f) Chida, N.; Nakazawa, K.; Ninomiya, S.; Amano, S.;
Koizumi, K.; Inaba, J.; Ogawa, S. Carbohydr. Lett. 1995, 1,
335. (g) Chida, N.; Koizumi, K.; Kitada, Y.; Yokoyama, C.;
Ogawa, S. J. Chem. Soc., Chem. Commun. 1994, 1, 111.
(4) Akiyama, T.; Hara, M.; Fuchibe, K.; Sakamoto, S.;
Yamaguchi, K. Chem. Comm. 2003, 1734.
e A third unidentified product was also detected.
The three benzyl groups could be quantitatively removed
by catalytic hydrogenation (H2, Pd/C). Unfortunately, it
turned out to be difficult to remove traces of charcoal due
to the scarce solubility of neo-inositol. Therefore, we con-
verted the crude product into the hexaacetate 11, which
could easily be purified by recrystallization. In the final
step the six acetyl groups were removed by
saponification14 giving the desired neo-inositol 12 with
nearly quantitative yield (Scheme 3).
(5) Sureshan, K. M.; Shashidhar, M. S.; Varma, A. J. J. Org.
Chem. 2002, 67, 6884.
(6) Hosoda, A.; Miyake, Y.; Nomura, E.; Taniguchi, H. Chem.
Lett. 2003, 32, 1042.
(7) Sureshan, K. M.; Gonnade, R. G.; Shashidhar, M. S.;
Puranik, V. G.; Bhadbhade, M. M. Chem. Commun. 2001,
881.
(8) (a) Müller, P.; Nikolaus, J.; Schiller, S.; Herrmann, A.;
Möllnitz, K.; Czapla, S.; Wessig, P. Angew. Chem. 2009,
121, 4497. (b) Wessig, P.; Möllnitz, K. J. Org. Chem. 2008,
73, 4452. (c) Wessig, P.; Möllnitz, K.; Eiserbeck, C. Chem.
Eur. J. 2007, 13, 4859.
O
O
see
O
DMP
O
O
Table 1
4
HO
(CH2Cl2)
~ 99%
OBn
OBn
OBn
OBn
OBn
OBn
8
(+4)
77%
9
1. HCl, MeOH, reflux
2. FSC
OBn
OH
(9) Riley, A. M.; Jenkins, D. J.; Potter, B. V. L. Carbohydr. Res.
1998, 314, 277.
(10) Hudlicky, T.; Restrepo-Sanchez, N.; Kary, P. D.; Jaramillo-
Gomez, L. M. Carbohydr. Res. 2000, 324, 200.
(11) Hudlicky, T.; Stabile, M. R.; Gibson, D. T.; Whited, G. M.
Org. Synth. 1999, 76, 77.
OAc
OAc
1. H2, Pd/C
2. Ac2O, Py
BnO
AcO
OH
OAc
96%
OBn
OH
OAc
OAc
10
11
1. NaOMe, MeOH
2. aq NaOH, reflux
96%
(12) Chung, S. K.; Kwon, Y. U. Bioorg. Med. Chem. Lett. 1999,
OH
9, 2135.
OH
OH
HO
HO
OH
OH
(13) Gigg, J.; Gigg, R.; Payne, S.; Conant, R. Carbohydr. Res.
1985, 142, 132.
(14) Podeschwa, M.; Plettenburg, O.; vom Brocke, J.; Block, O.;
Adelt, S.; Altenbach, H. J. Eur. J. Org. Chem. 2003, 1958.
(15) Mandel, M.; Hudlicky, T. J. Chem. Soc., Perkin Trans. 1
1993, 741.
HO
OH
HO
OH
OH
12
Scheme 3 Preparation of neo-inositol 12
Synlett 2010, No. 10, 1497–1500 © Thieme Stuttgart · New York

1500
P. Wessig et al.
LETTER
Rf = 0.7 (hexanes–EtOAc, 2:1). 1H NMR (500 MHz,
(16) Mandel, M.; Hudlicky, T. J. Chem. Soc., Perkin Trans. 1
1993, 1537.
(17) Kowarski, C. R.; Sarel, S. J. Org. Chem. 1973, 38, 117.
(18) Carpintero, M.; Fernandez Mayoralas, A.; Jaramillo, C.
J. Org. Chem. 1997, 62, 1916.
CDCl3): d = 3.95–3.97 (m, 2 H), 4.51 (d, 2J = 11.6 Hz, 2 H),
4.52–4.54 (m, 2 H), 4.64 (d, 2J = 4.8 Hz, 1 H), 4.67 (d,
2J = 11.6 Hz, 2 H), 4.73 (s, 2 H), 4.76 (t, 3J = 1.3 Hz, 1 H),
5.52 (d, 3J = 4.8 Hz, 1 H), 7.24–7.41 (m, 15 H). 13C NMR
(125 MHz, CDCl3): d = 69.8 (CH), 71.1 (CH2), 72.2 (CH),
72.3 (CH2), 81.6 (CH), 85.5 (CH2), 127.8 (CH), 127.9 (CH),
127.9 (CH), 128.3 (CH), 128.4 (CH), 136.8 (C), 137.3 (C),
202.7 (C). HRMS: m/z [M + H]+ calcd for C28H28O6 + H:
461.1964; found: 461.1986.
(19) Heo, J. N.; Holson, E. B.; Roush, W. R. Org. Lett. 2003, 5,
1697.
(20) Angyal, S. J.; Matheson, N. K. J. Am. Chem. Soc. 1955, 77,
4343.
(21) Nakajima, M.; Tomida, I.; Kurihara, N.; Takei, S. Chem.
Ber. 1959, 92, 173.
(29) Ketone 9 (19.84 g, 43.08 mmol) was dissolved in anhyd
MeOH (800 mL) and NaBH4 (1.98 g, 52.39 mmol, 1.2
equiv) was added. The reaction mixture was stirred about 20
min until gas and heat evolution ceased. This mixture was
directly used in the next step. To obtain spectroscopic data a
small sample (2 mL) was taken from the mixture, and the
solvent was evaporated. The resulting residue was treated
with 0.1 M aq HCl solution and extracted thrice with Et2O.
The combined organic layers were dried and evaporated
giving a pale yellow oil (49 mg, 0.10 mmol, 98%) with a
ratio of 8 (neo) to 4 (myo) of 7.8:1 (determined by 1H NMR);
Rf (8) = 0.46 (hexanes–EtOAc, 2:1); Rf (4) = 0.44 (hexanes–
EtOAc, 2:1). 1H NMR (8): d = 2.74 (br s, 1 H), 3.91–3.96
(m, 2 H), 4.30–4.32 (m, 1 H), 4.34–4.37 (m, 2 H), 4.43–4.47
(m, 1 H), 4.52 (s, 2 H), 4.59 (d, 2J = 11.9 Hz, 2 H), 4.63 (d,
2J = 4.5 Hz, 1 H), 4.67 (d, 2J = 11.9 Hz, 2 H), 5.52 (d,
2J = 4.5 Hz, 1 H), 7.25–7.39 (m, 15 H). 1H NMR (4):
matches with literature.24
(30) The reaction mixture of the previous step, containing 8 + 4,
was treated with concd HCl (60 mL) and refluxed for 3 h.
The solvents were evaporated, and the resulting residue was
treated with H2O and extracted thrice with CH2Cl2. The
combined organic layers were dried, evaporated, and the
resulting residue purified by flash chromatography (silica,
CHCl3 →CHCl3–EtOAc, 1:2) giving 10 as colorless crystals
(14.96 g, 33.21 mmol, 77%); mp 97–98 °C; Rf = 0.26
(CHCl3–EtOAc, 1:2).
(22) Lee, H. W.; Kishi, Y. J. Org. Chem. 1985, 50, 4402.
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Commun. 1987, 1011. (b) Andersch, P.; Schneider, M. P.
Tetrahedron: Asymmetry 1993, 4, 2135. (c) Billington, D.
C.; Baker, R.; Kulagowski, J. J.; Mawer, I. M.; Vacca, J. P.;
de Solms, S. J.; Huff, J. R. J. Chem. Soc., Perkin Trans. 1
1989, 1423.
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(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277.
(27) Ketone 9 was obtained as an oil, which was partly
decomposed upon flash column chromatography on silica
gel.
(28) Alcohol 4 (20.18 g, 43.63 mmol) was dissolved in anhyd
CH2Cl2 (500 mL) and Dess–Martin periodinane (20.59 g,
48.55 mmol, 1.1 equiv) was added. The resulting mixture
was stirred at r.t. until complete conversion of 4 was
monitored by TLC. The organic layer was washed several
times with an aq solution of Na2S2O3/NaHCO3, dried, and
evaporated. Ketone 9 was obtained as an oil (19.85 g, 43.10
mmol, 99%) and can be used without further purification;
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