Racemic 2,4-di-O-benzoyl-myo-inositol 1,3,5-orthoformate: A versatile intermediate for the preparation of myo-inositol phosphates

Article abstract of DOI:10.1016/S0008-6215(98)00061-5

The versatility of racemic 2,4-di-O-benzoyl-myo-inositol 1,3,5- orthoformate as an intermediate for the preparation of protected myo- inositol derivatives is demonstrated. Procedures described provide simple access to several protected myo-inositol derivatives which are intermediates for the preparation of myo-inositol phosphates and racemic ononitol.

Full text of DOI:10.1016/S0008-6215(98)00061-5

Carbohydrate Research 308 (1998) 165±168
Note
Racemic 2,4-di-O-benzoyl-myo-inositol
,3,5-orthoformate: a versatile intermediate for
the preparation of myo-inositol phosphates
1
Tanya Das, Mysore S. Shashidhar*
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411008, India
Received 24 November 1997; accepted in revised form 23 February 1998
Abstract
The versatility of racemic 2,4-di-O-benzoyl-myo-inositol 1,3,5-orthoformate as an intermediate
for the preparation of protected myo-inositol derivatives is demonstrated. Procedures described
provide simple access to several protected myo-inositol derivatives which are intermediates for the
preparation of myo-inositol phosphates and racemic ononitol. # 1998 Elsevier Science Ltd. All
rights reserved
Keywords: Cyclitols; Inositol; Phosphatidylinositol; Signal transduction
The involvement of myo-inositol phosphates in
cellular signal transduction pathways in living cells
of various tissues is now established [1]. The eluci-
dation of mechanisms that govern the myo-inositol
based signal transduction pathways requires the
availability of myo-inositol phosphates and their
analogues [2±12]. Suitably protected myo-inositol
derivatives are the key intermediates for the syn-
thesis of phosphorylated inositols and their ana-
logues. We herein describe the preparation of
several protected myo-inositol derivatives from
racemic 2,4-di-O-benzoyl-myo-inositol 1,3,5-ortho-
formate (1) [13] using simple procedures. Regio-
selective opening of the orthoester moiety in some
myo-inositol orthoformate derivatives has been
reported [14±16].
The synthetic utility of the dibenzoate 1 is
demonstrated by its conversion to several protected
myo-inositol derivatives (Scheme 1). The dibenzo-
ate 1, on re¯uxing with tert-butylamine in metha-
nol, a€orded myo-inositol orthoformate 2. Hence
this route is an alternative procedure for the prep-
aration of the triol 2 [17±19] without the use of
chromatography.
Heating the dibenzoate 1 in 1:5 pyridine±metha-
ꢀ
nol at 50 C resulted in the preferential solvolysis
of the axial 4-benzoate to a€ord the known diol 3
[20] in 75% yield.
Reaction of the dibenzoate 1 with an excess of
benzyl bromide in the presence of an excess of sil-
ver (I) oxide yielded the symmetrical 2-O-benzoyl-
4,6-di-O-benzyl-myo-inositol 1,3,5-orthoformate
[21], which on aminolysis gave the known 4.
Preparation of 4 (from 2), in 30±50% yield has
been reported earlier [17,18] as an intermediate
for the synthesis of myo-inositol-2-phosphate as
* Corresponding author. Fax: 91-212-33 51 53; e-mail:
shashi@dalton.ncl.res.in
0008-6215/98/$19.00 # 1998 Elsevier Science Ltd. All rights reserved
PII S0008-6215(98)00061-5

166
T. Das, M. S. Shashidhar/Carbohydrate Research 308 (1998) 165±168
ꢀ
Scheme 1. Reagents and conditions: (a) tert-Butylamine, MeOH, re¯ux. (b) Pyridine, MeOH, 50 C. (c) DMF, Ag
bromide. (d) p-toluenesulfonic acid, MeOH. (e) CH Cl , pyridium p-toluenesulfonate dihydropyran [21]. (f) DMF, Ag O, ICH [21].
2
O, Benzyl
2
2
2
3
well as scyllo-inositol. The present procedure gives
the symmetrical diether 4 in an overall yield of
removed using p-toluenesulfonic acid±methanol to
obtain racemic ononitol 9 [24].
7
4% starting from the dibenzoate 1 (33% from
In conclusion, the results presented provide con-
venient access to several known O-protected myo-
inositol derivatives, which can be converted to the
corresponding myo-inositol phosphates using pro-
cedures available in the literature.
myo-inositol). Removal of the orthoformate moi-
ety in 4 a€ords the 1,2,3,5-tetrol 5. The preparation
of d-myo-inositol-1-phosphate from 5 has been
reported previously [22].
The free 6-hydroxyl group of the dibenzoate 1
could be protected as the corresponding tetra-
hydropyranyl ether [21] which on aminolysis with
tert-butylamine in methanol a€orded the 2,4-diol
1. Experimental
6
.
General methods.ÐFor general experimental
conditions and procedures for the preparation of
Methanolysis of the dibenzoate 1 in the presence
of p-toluenesulfonic acid gave the tetrol 7 in excel-
lent yield. None of the steps (starting from myo-
inositol) involve column chromatography or any
expensive reagent. Meek et al. [23] have prepared
the tetrol 7 from 3,6-di-O-benzoyl-1,2:4,5-di-O-
isopropylidene-myo-inositol in two steps (overall
yield 18%.
The dibenzoate 1 could be converted into the
corresponding methyl ether 8 using methyl iodide
and silver (I) oxide in 80% yield [21]. The benzoate
groups in 8 were then removed by reaction with
tert-butylamine and the orthoformate moiety was
2-O-benzoyl-4,6-di-O-benzyl-myo-inositol
1,3,5-
orthoformate, the methyl ether 8 and 2,4-di-O-
benzoyl-6-O-tetrahydropyranyl-myo-inositol 1,3,5-
orthoformate (mixture of diastereomers) see
ref. [21]. The dibenzoate 1 was prepared as reported
earlier [13]. Anhyd p-toluenesulfonic acid [25] was
prepared according to lit. All the compounds pre-
viously reported were characterized by comparison
of their mp, IR and NMR spectroscopic data with
those available in the literature.
Preparation of myo-inositol 1,3,5-orthoformate
(2).ÐThe dibenzoate 1 (1.64 g, 4.1 mmol) was

T. Das, M. S. Shashidhar/Carbohydrate Research 308 (1998) 165±168
167
re¯uxed in MeOH (44 mL) with tert-butylamine
2.2 mL, 20.5 mmol) for 3 h. The product was crys-
tallized from MeOH (0.78 g, 100%). mp 300±
and anhyd p-toluenesulfonic acid (0.04 g,
0.2 mmol) was added and the reaction mixture
stirred for 40 h at room temperature. The solvent
was then evaporated and the residue puri®ed by
®ltration over a short column of silica gel (1:1
EtOAc±light petroleum) to give the tetrol 7 (0.36 g,
(
ꢀ
ꢀ
3
01 C , lit. 300±302 C [17].
Preparation of 2-O-benzoyl-myo-inositol 1,3,5-
orthoformate (3).ÐThe dibenzoate
3
MeOH (90 mL) for 24 h at 50 C. The reaction
mixture was allowed to attain room temperature
and the solvent evaporated. The residue was crys-
1
(1.5 g,
.8 mmol) was heated with pyridine (18 mL) in
ꢀ
ꢀ
93%). mp 193±195 C, lit. 198±201 C [23].
ꢀ
Preparation of racemic 4-O-methyl-myo-inositol
(ononitol) (9).ÐThe methyl ether 8 (0.42 g,
1.0 mmol) was stirred with tert-butylamine
(0.8 mL) in MeOH (1O mL) at room temperature
for 19 h and the product obtained (0.25 g) was
treated with p-toluenesulfonic acid (0.14 g,
0.74 mmol) and MeOH (8 mL) as in the prepara-
tion of the tetrol 5. Crude 9 was puri®ed by silica
gel column chromatography (1:9 MeOH±EtOAc)
tallized (MeOH±CHCl ) to obtain the diol 3
3
ꢀ ꢀ
(
0.58 g, 53%), mp 210±213 C, lit. 202±204 C [20].
A further quantity of 3 (0.24 g, 22%) could be
obtained by silica gel column chromatography of
the mother liquor (eluent: 30% EtOAc±light pet-
roleum) along with some triol 2 (0.09 g, 13%).
Preparation of 4,6-di-O-benzyl-myo-inositol 1,3,5-
orthoformate (4).Ð2-O-benzoyl-4,6-di-O-benzyl-
myo-inositol 1,3,5-orthoformate (0.47 g, 1.0 mmol)
was re¯uxed with tert-butylamine (0.8 mL) and
MeOH (10 mL) for 20 h. The solvent was removed
under reduced pressure and the residue was pur-
ꢀ
ꢀ
(0.19 g, 98%). mp 165±168 C, lit. 165±166 C [24].
Acknowledgements
Financial support from the DST, New Delhi, is
gratefully acknowledged. T.D. thanks UGC, New
Delhi, for a fellowship.
i®ed by crystallization from CHCl ±light petro-
3
ꢀ
leum mixture (0.34 g, 92%), mp 124±125 C, lit.
ꢀ
1
25 C [18].
Preparation of 4,6-di-O-benzyl-myo-inositol (5).Ð
References
The crude dibenzyl ether 4 (0.83 g, 2.3 mmol) prior
to crystallization was dissolved in MeOH (20 mL)
and stirred at room temperature with p-toluene-
sulfonic acid (0.4 g) for 24 h. The pure product was
[1] M.J. Berridge and R.F. Irvine, Nature, 341 (1989)
197±205.
[
2] S. Ozaki and L. Lei, Chemo-enzymatic Synthesis of
Optically Active myo-Inositol Phosphates, in Z.J.
Witczak and K.A. Nieforth (Eds.), Carbohydrates
in Drug Design, Marcel Dekker, New York, 1997,
pp 343±384.
obtained by column chromatography over silica gel
ꢀ
(R 0.4 in EtOAc) (0.75 g, 93%), mp 137±138 C,
lit. 138.5±139 C [18].
f
ꢀ
Preparation
inositol 1,3,5-orthoformate (6).Ð2,4-Di-O-benzoyl-
-O-tetrahydropyranyl-myo-inositol 1,3,5-ortho-
formate (0.33 g, 0.7 mmol) was re¯uxed in MeOH
8 mL) with tert-butylamine (0.6 mL) for 9 h. The
of
4-O-tetrahydropyranyl-myo-
[
3] K.S. Bruzik, PhosphatidylinositolÐSpeci®c Phos-
pholipase C as a Target for Drug Design, in Z.J.
Witczak and K.A. Nieforth (Eds.), Carbohydrates
in Drug Design, Marcel Dekker, New York, 1997,
pp 385±432.
6
(
product (mixture of diastereomers) was puri®ed by
column chromatography over silica gel (1:1
EtOAc±light petroleum) (0.17 g, 91%), mp 201±
[4] B.V.L. Potter and D. Lampe, Angew. Chem. Int.
Ed. Eng., 34 (1995) 1933±1972.
[5] J.J. Kiddle, Chem. Rev., 95 (1995) 2189±2202.
ꢀ
� 1 1
[
[
[
[
6] M.S. Shashidhar, Proc. Indian Acad. Sci. (Chem.
Sci.), 106 (1994) 1231±1251.
7] K.S. Bruzik and M.-D. Tsai, Bioorg. Med. Chem.,
2
CDCl ±Me SO-d ) 1.5±1.9 (m, 6 H, CH X 3), 3.1±
03 C. IR: 3160±3380 cm . H-NMR: (200 MHz,
3
2
6
2
3
1
3
.4 (broad s, D O exchangeable, OH), 3.5±3.7 (m,
2
H), 3.8 (d, 1 H, D O exchangeable, OH, J 7 Hz),
2
.8±4.0 (m, 1 H), 4.0±4.3 (m, 3 H), 4.3±4.6 (m, 2
2
(1994) 49±72.
8] S.L. Becauge and R.P. Iyer, Tetrahedron, 49 (1993)
0441±10448.
1
H), 4.6±4.8 (m, 2 H), 5.5 (s, 1 H, O CH). Anal.
3
9] D.C. Billington, The Inositol Phosphate ChemicalÐ
Synthesis and Biological Signi®cance, VCH, New
York, 1993.
Calcd for C H O : C, 52.55, H, 6.57; found: C,
18
12
7
5
2.90, H, 6.26.
Preparation of racemic 2,4-di-O-benzoyl-myo-
inositol (7).ÐThe dibenzoate 1 (0.4 g, 1.0 mmol)
[
10] T. Hudlicky and M. Cebulak, Cyclitols and Their
Derivatives: A Handbook of Physical, Spectral and
Synthetic Data, VCH, New York, 1993.
was dissolved in CH Cl (4 mL) and MeOH (4 mL)
2
2

168
T. Das, M. S. Shashidhar/Carbohydrate Research 308 (1998) 165±168
[
11] F. Kaufman, D.J.R. Massy, W. Pirson, and P.
Wyss, Inositol Phosphates and Derivatives: Synthesis,
Biochemistry and Therapeutic Potential, in A.B.
Reitz (Ed.), ACS Symp. Ser. 463, 1991, pp 202±253.
12] D.C. Billington, Chem. Soc. Rev., 18 (1989) 83±122.
13] T. Banerjee and M.S. Shashidhar, Tetrahedron
Lett., 35 (1994) 8053±8056.
[19] G. Baudin, B.I. Glanzer, K.S. Swaminathan, and
A. Vasella, Helv. Chim. Acta., 71 (1988) 1367±
1378.
[20] S. Ozaki, Y. Koga, L. Ling, Y. Watanabe, Y.
Kimura, and M. Hirata, Bull. Chem. Soc. Jpn., 67
(1994) 1058±1063.
[21] T. Das and M.S. Shashidhar, Carbohydr. Res., 297
(1997) 243±249.
[22] K. Laumen and O. Ghisalba, Biosci. Biotech. Bio-
chem., 58 (1994) 2046±2049.
[23] J.L. Meek, F. Davidson, and F.W. Hobbs Jr., J.
Am. Chem. Soc., 110 (1988) 2317±2318.
[24] B.A. Klyaschitskid, A.K. Starostina, L.F. Linberg,
V.I. Shvets, and R.P. Evstigneeva, Zh. Org. Khim.,
7 (1971) 492±497.
[25] D.D. Perrin and L.F. Armarego, Puri®cation of
Laboratory Chemicals, Pergamon Press, Oxford,
1992.
[
[
[
[
[
[
[
14] I.H. Gilbert and A.B. Holmes, Tetrahedron Lett.,
31 (1990) 2633±2644.
15] I.H. Gilbert, A.B. Holmes, M.J. Pestchanker, and
R.C. Young, Carbohydr. Res., 234 (1992) 117±130.
16] S.-M. Yeh, G.H. Lee, Y. Wang, and T.-Y. Luh, J.
Org. Chem., 62 (1997) 8315±8318.
17] H.-W. Lee and Y. Kishi, J. Org. Chem., 50 (1985)
4402±4404.
18] D.C. Billington, R. Baker, J.J. Kulagowski, I.M.
Mawer, J.P. Vacca, S.J. deSolms, and J.R. Hu€, J.
Chem. Soc. Perkin Trans., I (1989) 1423±1429.