Sulfonate protecting groups. Improved synthesis of scyllo-inositol and its orthoformate from myo-inositol

Article abstract of DOI:10.1016/S0008-6215(03)00052-1

A convenient high yielding method for the preparation of scyllo-inositol and its orthoformate from myo-inositol, without involving chromatography is described. myo-Inositol 1,3,5-orthoformate was benzoylated to obtain 2-O-benzoyl-myo-inositol 1,3,5-orthoformate. This diol was tosylated and the benzoyl group removed by aminolysis in a one-pot procedure to obtain 4,6-di-O-tosyl-myo-inositol 1,3,5-orthoformate. Swern oxidation of the ditosylate, followed by sodium borohydride reduction and methanolysis of tosylates gave scyllo-inositol 1,3,5-orthoformate (isolated as the triacetate). Aminolysis of the acetates followed by acid hydrolysis of the orthoformate moiety with trifluoroacetic acid gave scyllo-inositol in an overall yield of 64%.

Full text of DOI:10.1016/S0008-6215(03)00052-1

Carbohydrate Research 338 (2003) 999–1001
www.elsevier.com/locate/carres
Note
Sulfonate protecting groups.
Improved synthesis of scyllo-inositol and its orthoformate from
myo-inositol
Manash P. Sarmah, Mysore S. Shashidhar*
National Chemical Laboratory, Di6ision of Organic Synthesis, Pune 411 008, India
Received 2 December 2002; accepted 30 January 2003
Abstract
A convenient high yielding method for the preparation of scyllo-inositol and its orthoformate from myo-inositol, without
involving chromatography is described. myo-Inositol 1,3,5-orthoformate was benzoylated to obtain 2-O-benzoyl-myo-inositol
1,3,5-orthoformate. This diol was tosylated and the benzoyl group removed by aminolysis in a one-pot procedure to obtain
4,6-di-O-tosyl-myo-inositol 1,3,5-orthoformate. Swern oxidation of the ditosylate, followed by sodium borohydride reduction and
methanolysis of tosylates gave scyllo-inositol 1,3,5-orthoformate (isolated as the triacetate). Aminolysis of the acetates followed
by acid hydrolysis of the orthoformate moiety with trifluoroacetic acid gave scyllo-inositol in an overall yield of 64%. © 2003
Elsevier Science Ltd. All rights reserved.
Keywords: Cyclitol; Inositol; Inositol phosphate; Orthoesters; Sulfonates; Signal transduction
As a part of an ongoing program on the solid state
structure and reactivity of inositol derivatives,1,2 we
required scyllo-inositol (2) and its orthoformate (9).
This note describes a convenient method for the con-
version of myo-inositol to scyllo-inositol via its ortho-
formate. Development of efficient synthetic routes to
isomeric inositols is of current interest in view of the
role played by phosphoinositols in cellular signal trans-
duction pathways.3 There are several reports on the
conversion of 1 to 2 or its derivatives in overall yields
of 10–40%.4–9 However, none of these methods are
useful for the preparation of 9 since the reaction of 2
with triethyl orthoformate does not lead to the forma-
tion of 9.7,10 The only method so far known11 for the
synthesis of the orthoformate 9 involves chromato-
graphic separations and provides 9 in 28% overall yield
from myo-inositol. The method described here provides
9 in good yield (69%) and does not require chromato-
graphic purification in any of the steps. The work
reported here also illustrates the utility of sulfonate
protecting groups for the synthesis of inositol
derivatives.12–14
myo-Inositol orthoformate (3) was benzoylated with
sodium hydride and benzoyl chloride to obtain the
corresponding 2-benzoate 415 (Scheme 1). Sulfonylation
of the diol 4 with tosyl chloride in pyridine followed by
aminolysis of the benzoate gave the ditosylate 5. We
had earlier reported12 a method for the direct sulfonyla-
tion of 4- and 6-hydroxyl groups in the triol 3. How-
ever, this procedure (on the larger scale reported here)
required chromatography for the isolation of the dito-
sylate 5, and hence we preferred to use the indirect
method via benzoylation of the orthoformate 3. The
ditosylate 5 on Swern oxidation followed by reduction
with sodium borohydride, provided the scyllo-ditosy-
late 7. Methanolysis of the tosylates in 7 followed by
acetylation gave the triacetate 8. Aminolysis of the
acetates in 8 gave scyllo-inositol orthoformate 9, in an
overall yield of 69%. The orthoformate 9 on hydrolysis
with aqueous acid, provided 2 in 94% yield (overall
yield 64% from myo-inositol).
* Corresponding author. Tel./fax: +91-20-5893153
E-mail address: shashi@dalton.ncl.res.in (M.S. Shashidhar).
0008-6215/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0008-6215(03)00052-1

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M.P. Sarmah, M.S. Shashidhar / Carbohydrate Research 338 (2003) 999–1001
1. Experimental
1.3. 4,6-Di-O-tosyl-myo-inositol 1,3,5-orthoformate (5)
The 2-benzoate 4 (1.25 g, 4.25 mmol) was dissolved in
dry Py (3 mL) and toluene 4-sulfonyl chloride (2.45 g,
12.86 mmol) was added. The reaction mixture was
heated at 80–100 °C for 12 h. Pyridine was evaporated
under diminished pressure; MeOH (7 mL) and iso-
butylamine (4 mL) were added to the residue and
refluxed for 12 h and concentrated under diminished
pressure to a gum. The gum obtained was dissolved in
CHCl3 (50 mL) and worked up as usual and the
product was crystallized from CHCl3–petroleum ether
to obtain the known ditosylate 5 (2.01 g, 95%); mp
182–184 °C; lit.12 mp 183–185 °C.
1.1. General methods
For general experimental conditions, see Ref. 12. The
orthoformate 3 was prepared as reported earlier.16 All
the compounds previously reported in the literature
were characterized by comparison of their melting point
1
and H NMR spectra with those of authentic samples.
‘Usual work-up’ implies dilution of the reaction mix-
ture with a solvent (EtOAc, CHCl3 or CH2Cl2), wash-
ing of the organic layer with water, saturated sodium
bicarbonate solution followed by brine, drying over
anhydrous sodium sulfate and evaporation of the sol-
vent under diminished pressure.
1.4. 2,4-Di-O-tosyl-scyllo-inositol 1,3,5-orthoformate
(7)
1.2. 2-O-Benzoyl-myo-inositol 1,3,5-orthoformate (4)
myo-Inositol 1,3,5-orthoformate (3, 0.95 g, 5.00 mmol)
was dissolved in dry DMF (5 mL) and stirred with
sodium hydride (0.30 g, 12.50 mmol) for 5 min. Benzoyl
chloride (0.71 g, 5.05 mmol) was then added and the
stirring continued for another 5 min. The reaction
mixture was worked-up as usual (with EtOAc) and the
residue was crystallized from CHCl3–petroleum ether
to obtain the known benzoate 4 (1.25 g, 85%); mp
210–212 °C; lit.17 mp 210–213 °C.
To a cooled (−78 °C) solution of oxalyl chloride (0.56
g, 4.41 mmol) in dry dichloromethane (5 mL) was
added dropwise, a solution of dry Me2SO (0.63 g, 8.08
mmol) in dry CH2Cl2 (5 mL) and the reaction mixture
stirred for 15 min. To this mixture was added (drop-
wise) a solution of the ditosylate 5 (2.00 g, 4.02 mmol)
in dry CH2Cl2 (15 mL) and stirring was continued for 1
h. Dry Et3N (2.03 g, 20.10 mmol) was then added and
the reaction mixture was allowed to warm to room
temperature (rt) slowly. The reaction mixture was
quenched by adding a few drops of water and the
organic layer was separated, dried over anhyd Na2SO4
and the solvent was evaporated under diminished pres-
sure to obtain the ketone 6 as a white solid (1.99 g). A
small amount of 6 was purified by column chromatog-
raphy; mp 142–144 °C. IR (CHCl3): w 1774, 3490
1
cm−1. H NMR (200 MHz, CDCl3): l 2.47 (s, 6 H),
4.25–4.35 (m, 2 H), 4.50–4.60 (m, 1 H), 5.35–5.50 (m,
2 H), 5.64 (s, 1 H), 7.30–7.45 (d, 4 H, J 8), 7.80–7.95
(d, 4 H, J 8). 13C NMR (50.3 MHz, CDCl3): l 21.5,
67.7, 71.5, 72.5, 73.4, 76.3, 102.0, 127.8, 130.0, 132.0,
145.8, 195.0. Anal. Calcd for C21H20O10S2: C, 50.80; H,
4.06. Found C, 50.76; H, 4.11. The crude ketone 6 (1.99
g) was dissolved in a mixture of dry THF (10 mL) and
dry MeOH (40 mL) and reduced with sodium borohy-
dride (0.45 g, 11.84 mmol) at rt for 30 min. Solvents
were evaporated under diminished pressure and the
residue was worked up as usual (with CH2Cl2) to
obtain 7 (1.98 g, 99%); mp 150–151 °C. IR (CHCl3): w
1
3587 cm−1. H NMR (200 MHz, CDCl3): l 2.48 (s, 6
H), 2.75–2.85 (d, 1 H, D2O exchangeable, J 12), 4.20–
4.40 (m, 4 H), 5.10–5.20 (m, 2 H), 5.42 (s, 1 H),
7.35–7.45 (d, 4 H, J 9), 7.80–7.90 (d, 4 H, J 9). 13C
NMR (50.3 MHz, CDCl3): l 21.6, 65.7, 67.4, 68.7, 70.8,
101.9, 128.0, 130.1, 132.1, 145.8. Anal. Calcd for
C21H22O10S2: C, 50.59; H, 4.44. Found C, 50.48; H,
4.12.
Scheme 1. Reagents and conditions: (a) NaH, BzCl, DMF, rt;
(b) p-TsCl, pyridine, 80–100 °C; (c) iso-butylamine, MeOH,
reflux; (d) (COCl)2, Me2SO, DCM, −78 °C then Et3N, rt; (e)
NaBH4, MeOH–THF, rt; (f) NaOMe, MeOH, reflux; (g)
Ac2O, pyridine, rt; (h) TFA–water (4:1).

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1.5. scyllo-Inositol 1,3,5-orthoformate (9)
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The ditosylate 7 (2.00 g, 4.02 mmol) was refluxed with
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for 12 h. The solvents were evaporated and the solid
obtained was treated with a large excess of Ac2O (25
mL) in Py (50 mL) at rt for 24 h. The solvents were
evaporated under diminished pressure and the residue
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known triacetate 8 as a white solid (1.25 g, 98%); mp
124–126 °C; lit.11 mp 124–126 °C. The triacetate 8
(1.25 g, 3.96 mmol) was refluxed for 12 h with iso-buty-
lamine (4 mL) in MeOH (15 mL). The solvents were
evaporated and the gum obtained was washed with
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1
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The orthoformate 9 (0.10 g, 0.53 mmol) was stirred
with trifluoroacetic acid (0.75 mL) and distilled water
(0.25 mL) at rt for 1 h. The solvents were evaporated
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1
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The Department of Science and Technology, New
Delhi supported this work. MPS is the recipient of a
Senior Research Fellowship from CSIR, New Delhi.