Sulfonate protecting groups. Regioselective O-sulfonylation of myo-inositol orthoesters

Article abstract of DOI:10.1016/S0040-4039(01)00364-1

Sulfonylation of myo-inositol 1,3,5-orthoesters with alkyl or aryl sulfonyl chlorides in the presence of sodium hydride gives the corresponding 4,6-di-O-sulfonates in good yields. These sulfonates can be cleaved with magnesium in methanol to generate the free myo-inositol derivative. This methodology was used for the preparation of racemic 2,4-di-O-benzyl-myo-inositol and 2-O-benzyl-myo-inositol, which are precursors for some phosphoinositols.

Full text of DOI:10.1016/S0040-4039(01)00364-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3037–3039
Sulfonate protecting groups. Regioselective O-sulfonylation of
myo-inositol orthoesters
Kana M. Sureshan and Mysore S. Shashidhar*
Division of Organic Synthesis, National Chemical Laboratory, Pune 411 008, India
Received 27 November 2000; revised 20 February 2001; accepted 28 February 2001
Abstract—Sulfonylation of myo-inositol 1,3,5-orthoesters with alkyl or aryl sulfonyl chlorides in the presence of sodium hydride
gives the corresponding 4,6-di-O-sulfonates in good yields. These sulfonates can be cleaved with magnesium in methanol to
generate the free myo-inositol derivative. This methodology was used for the preparation of racemic 2,4-di-O-benzyl-myo-inositol
and 2-O-benzyl-myo-inositol, which are precursors for some phosphoinositols. © 2001 Elsevier Science Ltd. All rights reserved.
The continued interest in the biological role of
phosphoinositols1 has created a need for efficient meth-
ods for the synthesis of natural as well as synthetic
derivatives and analogs of inositols. Orthoesters of
myo-inositol (1 and 2, Scheme 1) are important inter-
mediates for the synthesis of phosphoinositols2 and
other molecules with interesting properties.3 In the past
decade, there have been efforts to functionalize selec-
tively the three hydroxyl groups of orthoesters 1 and 2.
Methods for the selective functionalization of (a) only
the C-4 (or C-6) hydroxyl group;2g,4a (b) only the C-2
hydroxyl group;2f,4 (c) the C-2 and C-4 (or C-6)
hydroxyl groups2d,5 simultaneously, in 1 and 2 were
developed. However, selective functionalization of both
the C-4 and C-6 hydroxyl groups (6) in orthoesters of
myo-inositol, leaving the C-2 hydroxyl group undis-
turbed has eluded chemists. Billington and co-workers2g
benzylated 1 and obtained a mixture of diethers (the
ratio of 2,4:4,6 diethers was 1:5, isolated yield of the
4,6-diether was 27%) and the 2,4,6-triether. Most other
reports2e,f,3a,4b on the preparation of 4,6-di-O-substi-
tuted derivatives of 1 resorted to protection of the C-2
hydroxyl group prior to functionalization of the C-4
and C-6 hydroxyl groups. We now report a method to
Scheme 1.
Keywords: inositol; cyclitol; sulfonylation; chelates.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00364-1

3038
K. M. Sureshan, M. S. Shashidhar / Tetrahedron Letters 42 (2001) 3037–3039
Scheme 2. (a) DMF, NaH (1 equiv.), p-TsCl (1 equiv.); (b) DMF, NaH (5 equiv.), R2SO2Cl (2.1 equiv.); (c) DMF, NaH, BnBr;
(d) Mg/MeOH, 6 h; (e) TFA:water (4:1); (f) Mg/MeOH, 48 h.
for the presence of the metal ion for the exclusive
functionalization of the C-4 and C-6 hydroxyl groups is
also revealed by the sulfonylation of the orthoformate 1
with tosyl chloride in the presence of pyridine, which
leads to the formation of the unsymmetric ditosylate
19. Exclusive ether formation at the C-4 (or C-6)
hydroxyl groups in 1 on its reaction with alkyl halides
in the presence of sodium hydride has been attributed
to the stability of the sodium ion–orthofomate 1
chelate.2g We had earlier observed migration of O-acyl
groups from the C-4 (or C-6) position to the C-2
position in 1 and 2 as a result of the differences in the
stability of metal ion–inositol derived chelates.4a
achieve the selective sulfonylation of both the C-4 and
C-6 hydroxyl groups in 1 and 2 leaving the C-2
hydroxyl group undisturbed.
Reaction of the orthoformate 1 with 1 equiv. of p-
toluenesulfonyl chloride in the presence of 1 equiv. of
sodium hydride gave the corresponding racemic 4-O-
tosylate 7 (Scheme 2) as expected.2g The reaction of
orthoesters 1 and 2 with 2 equiv. of alkyl or arylsul-
fonyl chloride in the presence of an excess of sodium
hydride (or potassium t-butoxide) gave the correspond-
ing 4,6-di-O-sulfonates 8–12 in good yields (Table 1).
To demonstrate the utility of this method, we prepared
racemic 2,4-di-O-benzyl-myo-inositol (13) and 2-O-ben-
zyl-myo-inositol (16) from 7 and 8, respectively. The
sulfonates could be removed subsequent to benzylation
by treatment with Mg/MeOH.6 The ether 13 (83% from
1) and 16 (54% from myo-inositol), obtained7 in the
In conclusion, we have reported a simple procedure12
for the simultaneous protection of both the C-4 and
C-6 hydroxyl groups in myo-inositol orthoesters and
demonstrated its utility by preparation of important
O-protected myo-inositol derivatives. We are presently
exploring the synthesis of enantiopure inositol deriva-
tives using the methods described here, which will be
reported in due course.
present work, are intermediates for the synthesis of
D-
and
L
-myo-inositol-1,3,4,5-tetraphosphates8 and myo-
inositol-1,3,4,5,6-pentaphosphate,9 respectively. Fur-
thermore, 2-O-alkylated inositol derivatives are
important intermediates for the preparation of
inhibitors of phosphatidylinositol-specific phospholi-
pase C10 and compounds that exhibit liquid crystalline
properties.11
Table 1. Sulfonylation of myo-inositol orthoestersa
Entry Substrate R2SO2Cl
Product Yield (%)b
1
2
3
4
5
1
1
1
2
2
p-Tolyl
Methyl
1(S)-10-Camphoryl 10
p-Tolyl 11
1(S)-10-Camphoryl 12
8
9
70
84
70
78
69
A plausible reason for the high regioselectivity observed
for the sulfonylation reaction described above could be
the involvement of chelates (17, Scheme 2), which stabi-
lize the alkoxide at the axial position. This is suggested
by the fact that use of THF as a solvent for the
sulfonylation reaction or the presence of a crown ether
in the reaction mixture while using DMF as the solvent
led to loss of selectivity (Scheme 3). The requirement
a All the new compounds reported in this communication were char-
acterized by IR, 1H and 13C NMR spectroscopy as well as C, H
analysis.
b Average isolated yields from several trials; range of the yields
obtained for all the experiments was 65–85%.

K. M. Sureshan, M. S. Shashidhar / Tetrahedron Letters 42 (2001) 3037–3039
3039
3. (a) Angyal, S. J. Carbohydr. Res. 2000, 325, 313; (b)
Paquette, L. A.; Tae, J.; Gallucci, J. C. Org. Lett. 2000,
2, 143; (c) Tae, J.; Rogers, R. D.; Paquette, L. A. Org.
Lett. 2000, 2, 139; (d) Tse, B.; Kishi, Y. J. Am. Chem.
Soc. 1993, 115, 7892.
4. (a) Sureshan, K. M.; Shashidhar, M. S. Tetrahedron Lett.
2000, 41, 4185; (b) Lee, H. W.; Kishi, Y. J. Org. Chem.
1985, 50, 4402.
5. Banerjee, T.; Shashidhar, M. S. Tetrahedron Lett. 1994,
35, 8053.
6. Sridhar, M.; Kumar, B. A.; Narender, R. Tetrahedron
Lett. 1998, 39, 2847.
Scheme 3. (a) THF, NaH (5 equiv.), p-TsCl (2.1 equiv.); (b)
DMF, 18-C-6, NaH (5 equiv.), p-TsCl (2.1 equiv.); (c) pyri-
dine, p-TsCl, 100°C, 24 h.
7. Compound 13: mp 120°C, lit.2g mp 119–120.5°C, yield
(from 1) reported in Refs. 2g and 8 are 36 and 63%,
respectively. Compound 16: mp 251°C, lit.9 mp 248–
250°C, the yield (from myo-inositol) reported in Ref. 9 is
10%.
Acknowledgements
8. Laumen, K.; Ghisalba, O. Biosci. Biotechnol. Biochem.
1999, 63, 1374.
9. Lu, P.-J.; Gou, D.-M.; Sheih, W. R.; Chen, C.-S. Bio-
chemistry 1994, 33, 11586.
10. Garigapati, V. R.; Roberts, M. F. Tetrahedron Lett. 1993,
34, 5579.
11. Praefcke, K.; Blunk, D.; Hempel, J. Mol. Cryst. Liq.
Cryst. 1994, 243, 323.
K.M.S. is the recipient of a Senior Research Fellowship
from the CSIR, New Delhi. The authors would like to
thank Dr. T. Praveen for the discussions, Ms. S. B.
Banoo for the technical assistance and the Department
of Science and Technology, New Delhi for financial
support.
12. Procedure for sulfonylation: Sodium hydride (5 mmol,
previously washed with dry petroleum ether) was sus-
pended in dry DMF (5 mL) and stirred with the
orthoester (1 or 2, 1 mmol) at ambient temperature under
a nitrogen atmosphere (1–2 min). A solution of the
sulfonyl chloride (2.1 mmol) in dry DMF (4 mL) was
added in one portion with stirring. After 5 min the
reaction mixture was diluted with chloroform and washed
with water. The combined aqueous layers were acidified
(dil. HCl) and again extracted with chloroform. The
combined chloroform extracts were washed successively
with cold dil. HCl, saturated NaHCO3 solution and
brine. The organic layer was dried over anhydrous
sodium sulfate and the solvent evaporated under reduced
pressure. The crude product obtained was purified by
crystallization or column chromatography over silica gel.
The regioselectivity observed in this reaction was sensitive
to the presence of moisture in the reaction mixture.
Hence, all the reactions were carried out using freshly
dried DMF, clean sodium hydride, and orthoester (1 or
2) either crystallized from dry methanol or filtered
through a column of silica gel using ethyl acetate as the
eluant.
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