One-step regioselective functionalization of myo-inositol by dissolution strategy

Article abstract of DOI:10.1055/s-0029-1217809

Functionalizations of hydroxy groups of myo-inositol were usually nonselective due to its poor solubility. By dissolving myo-inositol in DMSO or LiCl-N,N-dimethylacetamide, we have achieved regioselective acylation, silylation, sulfonylation, phosphinylat

Full text of DOI:10.1055/s-0029-1217809

LETTER
2287
One-Step Regioselective Functionalization of myo-Inositol by Dissolution
Strategy
R
egioselective
a
Functiona
t
o
of my
o
-Inos
e
itol Yamauchi, Minoru Hayashi, Yutaka Watanabe*
Department of Materials Science and Biotechnology, Graduate School of Science and Engineering, Ehime University,
Matsuyama 790-8577, Japan
Fax +81(89)9279921; E-mail: wyutaka@dpc.ehime-u.ac.jp
Received 4 June 2009
able to make a solution of myo-inositol. Kuhn and
Trischmann described that a DMSO solution was neces-
sary to prepare permethylated myo-inositol.15 Also, a
DMSO solution of myo-inositol was used recently to im-
Abstract: Functionalizations of hydroxy groups of myo-inositol
were usually nonselective due to its poor solubility. By dissolving
myo-inositol in DMSO or LiCl–N,N-dimethylacetamide, we have
achieved regioselective acylation, silylation, sulfonylation, phos-
phinylation to give the corresponding 1,3-di-O-substituted products prove the yield of camphor ketal during the optical reso-
in good yields.
lution of inositol. This methodology gave better yield and
diastereoselectivity than the previously reported proce-
dure using a suspension of inositol.16 The solution was
prepared by heating or sonicating a mixture of myo-ino-
sitol and a relatively large volume of DMSO (1 g myo-
inositol/20 mL DMSO). A combination of N,N-dimethyl-
acetamide (DMA) and LiCl was also found to be suitable
for solubilization of myo-inositol (1 g myo-inositol/10 mL
8% LiCl in DMA), although DMA alone was not enough.
Such combinations are often used for dissolution of
polysaccharides such as cellulose and starch. Further-
more, a combination of LiCl–N-methylpyrrolidone also
solubilized myo-inositol, while LiCl–DMF did not.
Key words: acylation, regioselectivity, substitutions, inositol,
DMA
Since the experimental disclosure of a significant role of
inositol 1,4,5-trisphosphate as an intracellular secondary
messenger in 1983,1 the synthetic chemistry of inositol
has remarkably developed,2 and a variety of natural and
related inositol derivatives such as inositol phosphates3
and inositol phospholipids4 were synthesized. myo-Inosi-
tol (1) has been derivatized to functional materials such as
liquid crystals,5 surfactants,6 metal-complexing agents,7
gelators,8 chiral synthons for syntheses of various natural
products9 and analogues.10 However, when myo-inositol
is used as the starting material, some of its hydroxy groups
need to be protected as monoketals, diketals, orthoesters
or bis(disiloxane)11 before further functionalization such
as alkylation, acylation, sulfonylation or phosphorylation
at required hydroxy groups. The direct regioselective in-
troduction of acyl, alkyl, silyl or sulfonyl12 group to myo-
inositol has not so far been achieved, preventing efficient
and economical derivatizations of the inositol for use in
various applications. For instance, the reported procedure
for the preparation of 1-O-tosyl-myo-inositol involve six
steps starting from myo-inositol.13 Similarly, 1,3-di-O-
benzoyl-myo-inositol was prepared in four steps via
orthoformate.14 We report here a regioselective synthetic
method for the preparation of 1,3-di-O-functionalized
myo-inositol derivatives from myo-inositol in one step
without protection, by the dissolution strategy.
Regioselective Functionalization at the 1- and 3-Posi-
tions of myo-Inositol
OH
OH
OR
OH
HO
HO
RO
HO
OH
OH
R–Cl, base
3
1
DMSO
or LiCl, DMA
OH
OH
1
2
Equation 1
Two chemically equivalent hydroxy groups at the 1 and 3
positions in mesomeric myo-inositol (Equation 1) are ex-
pected to have a higher reactivity than those at the remain-
ing positions. This assumption is based on the fact that
various kinds of regioselective functionalization at C1-
OH of partially protected inositol derivatives have been
achieved frequently.17 When a suspension of myo-inositol
in pyridine was treated with 2.3 equivalents of 1-naph-
thoyl chloride for 12 hours at room temperature, a com-
plex mixture of di- tri-, tetra-, penta-, and peracylated
products was obtained. The expected 1,3-di-O-naphthoyl-
myo-inositol was formed only in 6% yield. In contrast, a
homogeneous reaction medium has dramatically effected
a highly regioselective functionalization of myo-inositol.
Thus, when a solution of myo-inositol in a mixture of LiCl
(8%) and DMA was treated with 1-naphthoyl chloride (3
Solubility of myo-Inositol
On the basis of our consideration that dissolution of myo-
inositol is essential to accomplish direct regioselective
functionalization, we have screened several solvent sys-
tems, and found that dimethyl sulfoxide (DMSO) is suit-
SYNLETT 2009, No. 14, pp 2287–2290
x
x
.x
x
.2
0
0
9
Advanced online publication: 07.08.2009
DOI: 10.1055/s-0029-1217809; Art ID: U05909ST
© Georg Thieme Verlag Stuttgart · New York

2288
S. Yamauchi et al.
LETTER
OH
O–TMS
OR
equiv) in the presence of triethylamine (7 equiv) at –20 °C
for 20 hours the 1,3-diacylated product was selectively
furnished in 83% yield. When the quantity of the base was
decreased to five mole equivalents, the yield of the di-
naphthoate decreased to 72%. The results can be ex-
plained by invoking the suppression of a Vielsmeyer-type
side reaction18 and the acceleration of the nucleophilic at-
tack of myo-inositol hydroxy groups.19 However, attempts
to perform acylation with an acyl chloride in DMSO solu-
tion were met with failure, presumably because of a pre-
dominant Pummerer-type reaction.20
OR
OH
RO
HO
RO
TMS–Cl, Py
TFA, MeOH
O–TMS
O–TMS
TMS–O
OH
2
3
Equation 2
In order to explore the scope and generality of this regio-
selectivity enhancement by dissolution, we attempted
functionalization with different electrophilic reagents.
Silylation of myo-inositol with tert-butyldiphenylchloro-
silane in a mixture of DMSO and pyridine (5:3) took place
selectively at room temperature to give 1,3-di-O-silylated
inositol in 89% yield. However, the silylation using tert-
butyldimethylchlorosilane under similar conditions re-
sulted in a mixture of products with poor selectivity. Silyl-
ation with vicinal diol protecting reagent tetraisopropyl-
1,3-disiloxane dichloride gave bis(disiloxanyl) derivative
2h in high yield (88%; Equation 3). It is worthy to note
that the same reaction in pyridine (suspension) was report-
ed to be sluggish, low yielding (2h only in 60% yield) and
less selective (other by-products).22
Dibenzoylation was similarly accomplished in high yield
and regioselectively, but the product formed was extract-
ed after silylation in situ with TMSCl owing to the high
solubility of 1,3-di-O-benzoyl-myo-inositol in water
(Equation 2). The silyl ether 3 was transformed back,
without isolation, to the benzoate 2 (R = benzoyl) by
TFA-assisted methanolysis. When a difunctionalized
product of the general formula 2 is soluble in water, the si-
lylation followed by aqueous workup procedure is conve-
nient for the removal of LiCl and DMA, and the silylated
product thus obtained can be desilylated to obtain the ex-
pected product. It has been observed that a fraction of the
1,3-dinaphthoate obtained was found to be dissolved in
water layer during washing of the organic extract contain-
ing DMA.21 The results of the 1,3-diacylation are collect-
ed in Table 1.
Sulfonylation of myo-inositol with tosyl chloride in the
8% LiCl–DMA solvent system provided the 1,3-ditosy-
late in 79% yield. The ditosylate could be isolated without
temporary derivatization to the TMS ether. The NMR of
the reaction mixture obtained after the removal of DMA
Table 1 Synthesis of 1,3-Di-O-substituted myo-Inositols 2
Compound 2
RCl (equiv)
PhCOCl
Base (equiv)
Et3N (7)
Solventa
Temp. (°C)
–10
Time (h)
Yield (%)
95b
a
A
4
(3)
CO–Cl
b
Et3N (7)
A
–10
20
83
(3)
t-BuCOCl
(3)
c
Et3N (5)
Et3N (7)
A
A
0
10
9
88b
85
CO2–Cl
d
–10
CO2–n-C6H13
(2.5)
t-BuPh2SiCl
(3)
e
f
Py (excess)
Et3N (5)
B
A
A
B
r.t.
10
0
72
24
20
20
89
79
p-MeC6H4SO2Cl
(2.5)
Ph2P(O)Cl
(3)
g
h
Et3N (7)
86b
88c
[(i-Pr)2SiCl]2O
Py (excess)
r.t.
(3)
a A = 8% LiCl–DMA, B = DMSO–Py (5:3).
b Isolated via the TMS derivative.
c Bis(disiloxanyl) derivative 2h was isolated.
Synlett 2009, No. 14, 2287–2290 © Thieme Stuttgart · New York

LETTER
Regioselective Functionalization of myo-Inositol
2289
(6) (a) Kim, S. C.; Kim, T. Y.; Lee, S. Y.; Roh, S. H.; Nam,
K. D. Kongop Hwahak 1994, 5, 573. (b) Tsuzuki, W.;
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OH
OH
O
O
O
O
O
O
Sii-Pr2
Sii-Pr2
i-Pr2Si
i-Pr2Si
i-Pr2Si(Cl)-O-(Cl)Sii-Pr2
DMSO, Py (5:3)
1
2h (88%)
Equation 3
(7) (a) Sureshan, K. M.; Shashidhar, M. S.; Varma, A. J. J. Org.
Chem. 2002, 67, 6884. (b) Dixit, S. S.; Shashidhar, M. S.;
Devaraj, S. Tetrahedron 2006, 62, 4360.
(8) (a) Hosoda, A.; Miyake, Y.; Nomura, E.; Taniguchi, H.
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Chem. Rev. 2003, 103, 4477.
and other volatile materials under reduced pressure,
showed that the 1,3-disulfonate was almost exclusively
formed, however the isolated yield was about 80%. This
deviation could be due to the loss of the product during
aqueous workup as mentioned above. Similarly, phosphi-
nylation also proceeded in a highly regioselective manner
to give 1,3-diphosphinate in good yield.
In summary, the dissolution strategy has allowed to
achieve the regioselective functionalization of unprotect-
ed myo-inositol in high yield.23 The procedure reported
here provides a practical synthetic method for 1,3-difunc-
tionalized inositol derivatives. The results presented here
will be of interest not only to inositol chemists but also to
a broad section of organic chemists given the application
of inositol derivatives in a wide range of applications such
as synthons for natural products, catalysts, supramolecu-
lar assemblies etc.
(12) Suami, T.; Ogawa, S.; Oki, S. Bull. Chem. Soc. Jpn. 1971,
44, 2824.
(13) Angyal, S. J.; Bender, V.; Curtin, J. H. J. Chem. Soc. 1966,
798.
(14) Chung, S.-K.; Chang, Y.-T. Bioorg. Med. Chem. Lett. 1997,
7, 2715.
(15) Kuhn, R.; Trischmann, H. Chem. Ber. 1963, 96, 284.
(16) Wewers, W.; Gillandt, H.; Traub, H. S. Tetrahedron:
Asymmetry 2005, 16, 1723.
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research
(C) (19550166). We thank the Venture Business Laboratory (VBL)
and the Institute for Cooperative Science (INCS), Ehime University
for NMR and elemental analysis.
(17) In addition to refs. 2–4, see: (a) Angyal, S. J.; Tate, M. E.;
Gero, S. D. J. Chem. Soc. 1961, 4116. (b) Suami, T.;
Ogawa, S.; Tanaka, T.; Otake, T. Bull. Chem. Soc. Jpn.
1971, 44, 835. (c) Chung, S.-K.; Ryu, Y. Carbohydr. Res.
1994, 258, 145. (d) Kubiak, R. J.; Bruzik, K. S. J. Org.
Chem. 2003, 68, 960. (e) Watanabe, Y.; Kiyosawa, Y.;
Hyodo, S.; Hayashi, M. Tetrahedron Lett. 2005, 46, 281.
(18) (a) Braz, G. I.; Voznesenskaya, N. N.; Yakubovich, A. Y.
J. Org. Chem. USSR (Engl. Transl.) 1973, 9, 114. (b) A
related reaction of ethyl chloroformate with DMA in the
presence of triethylamine followed by reaction with benzoyl
chloride was reported: Kira, M. A.; Zayed, A. A.; Fathy,
N. M. Egypt. J. Chem. 1983, 26, 253.
References and Notes
(1) Berridge, M. J. Nature (London) 1993, 361, 315.
(2) (a) Billington, D. C. The Inositol Phosphates, Chemical
Synthesis and Biological Significance; Wiley-VCH:
Weinheim, 1993. (b) Watanabe, Y. Selective Reactions and
Total Synthesis of Inositol Phosphates, In Studies in Natural
Products Chemistry, Stereoselective Synthesis (Part K), Vol.
18; Atta-Ur-Rahman, Ed.; Elsevier: Amsterdam, 1996,
391–456.
(3) (a) Reitz, A. B. Inositol Phosphates and Derivatives,
Synthesis, Biochemistry, and Therapeutic Potential;
American Chemical Society: Washington DC, 1991.
(b) Potter, B. V. L.; Lampe, D. Angew. Chem., Int. Ed. Engl.
1995, 34, 1933. (c) Morgan, A. J.; Komiya, S.; Xu, Y.;
Miller, S. J. J. Org. Chem. 2006, 71, 6923.
(4) (a) Gigg, J.; Gigg, R. Top. Curr. Chem. 1990, 154, 77.
(b) Prestwich, G. D. Acc. Chem. Res. 1996, 29, 503.
(c) Bruzik, K. S. Phosphoinositides: Chemistry,
Biochemistry and Biomedical Applications; American
Chemical Society: Washington DC, 1998. (d) Xu, Y.;
Sculimbrene, B. R.; Miller, S. J. J. Org. Chem. 2006, 71,
4919.
(5) (a) Praefcke, K.; Kohne, B.; Psaras, P.; Hempel, J.
J. Carbohydr. Chem. 1991, 10, 523. (b) Praefcke, K.;
Marquardt, P.; Kohne, B.; Stephan, W. J. Carbohydr. Chem.
1991, 10, 539. (c) Praefcke, K.; Blunk, D. Liquid Cryst.
1993, 14, 1181.
(19) McCormick, C. L.; Dawsey, T. R.; Newman, J. K.
Carbohydr. Res. 1990, 208, 183.
(20) (a) Bordwell, F. G.; Pitt, B. M. J. Am. Chem. Soc. 1955, 77,
572. (b) Dilworth, B. M.; McKervey, M. A. Tetrahedron
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(21) When a solution of dinaphthoate in EtOAc was washed with
H2O, the dinaphthoate could be recovered completely in the
organic layer. However, the presence of DMA in the solution
resulted in the loss of about 10% of the dinaphthoate into the
aqueous layer.
(22) Watanabe, Y.; Mitani, M.; Morita, T.; Ozaki, S. J. Chem.
Soc., Chem. Commun. 1989, 482.
(23) myo-Inositol was dried prior to the reaction. Commercial
myo-inositol was first dried by heating at 200 °C for 12 h
under reduced pressure (0.5 mmHg) and secondly, the
inositol was treated three times with pyridine (1 g Ins/5 mL
Py) under atmospheric pressure to remove azeotropically a
trace of H2O. The resulting inositol was finally heated at 120
°C for 12 h under reduced pressure (0.5 mmHg). Anhydrous
DMA and DMSO were obtained by treating with powdered
CaH2 and BaO overnight, respectively, and subsequent
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2290
S. Yamauchi et al.
LETTER
distillation (1 and 20 mmHg). LiCl is so hygroscopic that it
was weighed in a reaction vessel and dried by application of
heat at about 300–400 °C under reduced pressure (0.5
mmHg).
m-nitrobenzyl alcohol): m/z = 389 [M + H]+. Anal. Calcd for
C20H20O8·1/2H2O: C, 60.45; H, 5.33. Found: C, 60.09; H,
5.13.
1,3-Di-O-(1-naphthoyl)-myo-inositol (2b): As described
above, a solution of inositol (100 mg, 0.55 mmol) and LiCl
(400 mg, 9.44 mmol) in DMA (5 mL) was prepared. After
addition of Et3N (391 mg, 3.89 mmol), the resulting solution
was kept at –10 °C, and then 1-naphthoyl chloride (317 mg,
1.67 mmol) was added. The mixture was stirred at the same
temperature for 20 h. H2O (about 0.1 mL) was added and the
mixture was stirred for 10 min, and then partitioned to
EtOAc and H2O layers. The aqueous solution was extracted
with EtOAc (3 ×). The combined extract was washed with
H2O (3 ×) and brine, dried over Na2SO4, filtered, and then
evaporated. The residue was recrystallized from EtOAc–
hexane to give crystals of 2b (193 mg, 71%). The remaining
dinaphthoate (32 mg, 12%) was isolated from the mother
liquor by a flash column chromatography on silica gel
(MeOH–CHCl3, 1:14): Rf 0.4 (MeOH–CHCl3, 1:10); mp
195.5–196.0 °C (EtOAc–hexane). 1H NMR (270 MHz,
CD3OD): d = 3.61 (1 H, t, J = 9.6 Hz, InsH5), 4.23 (2 H, t,
J = 9.6 Hz, InsH4,6), 4.73 (1 H, t, J = 2.4 Hz, InsH2), 5.26 (2
H, dd, J = 9.6, 2.4 Hz, InsH1,3), 7.61 (6 H, complex, aromatic
Typical Procedure for the Synthesis of 1,3-Di-O-benzoyl-
myo-inositol (2a): To a reaction flask containing LiCl (400
mg, 9.44 mmol) were added inositol (100 mg, 0.55 mmol)
and DMA (5 mL), and the mixture was heated at about 120
°C until the mixture became a clear solution (about 3 min).
After addition of Et3N (391 mg, 3.89 mmol), the resulting
solution was kept at –10 °C, and then benzoyl chloride (234
mg, 1.67 mmol) was added. The mixture was stirred at the
same temperature for 4 h, and pyridine (2 mL) and TMSCl
(1 mL, 7.82 mmol) were carefully added. The mixture was
stirred at 0 °C for 5 h, and diluted with H2O and EtOAc.
After partition to two layers, the aqueous layer was extracted
with EtOAc (3 ×), and the organic layers combined with the
initial organic one were washed successively with H2O (2 ×),
0.5 N HCl solution, H2O, sat. NaHCO3 solution, H2O, and
then brine. The organic layer was dried over Na2SO4, filtered
and evaporated. The residue was dissolved in a small volume
of CHCl3 (1 mL), and MeOH (5 mL) and CF3CO2H (74 mg,
0.64 mmol) were added. The solution was stirred for 4 h at
r.t., and the volatile materials were all distilled off under
reduced pressure (1.0 mmHg). The residue was subjected to
a column chromatography on silica gel (MeOH–CHCl3,
1:10) to give crystalline 1,3-di-O-benzoate (205 mg, 95%
yield): Rf 0.5 (MeOH–CHCl3, 1:5); mp 174.5–175.0 °C
(EtOAc–hexane). 1H NMR (400 MHz, CD3OD): d = 3.44 (1
H, t, J = 9.8 Hz, InsH5), 4.08 (2 H, t, J = 9.8 Hz, InsH4,6), 4.43
(1 H, t, J = 2.6 Hz, InsH2), 5.01 (2 H, dd, J = 9.8, 2.6 Hz,
InsH1,3), 7.47 (4 H, t, J = 8.0 Hz, Hm), 7.60 (2 H, t, J = 8.0
Hz, Hp), 8.00 (4 H, d, J = 8.0 Hz, Ho). 13C NMR (100 MHz,
CD3OD): d = 69.29, 71.89, 75.90, 76.52 (6 × C, InsC),
129.42 (4 × C, Car3), 130.88 (4 × C, Car2), 131.50 (2 × C,
H3,6,7), 7.96 (2 H, d, J = 8.0 Hz, aromatic H5), 8.11 (2 H, d,
J = 8.4 Hz, aromatic H4), 8.41 (2 H, d, J = 7.2 Hz, aromatic
H2), 9.00 (2 H, d, J = 8.4 Hz, aromatic H8). 13C NMR (100
MHz, CDCl3): d = 69.58 (C, InsC2), 72.26 (2 × C, InsC4,6),
76.30 (2 × C, InsC1,3), 77.04 (C, InsC5), 125.9, 127.2, 127.6,
128.8, 128.9, 129.9, 131.9, 132.9, 134.8, 135.5 (10 × C,
aromatic), 169.0 (C=O). MS (FAB+, m-nitrobenzyl alcohol):
m/z = 689 [M + H]+. Anal. Calcd for C28H24O8: C, 68.85; H,
4.95. Found: C, 68.56; H, 4.91.
The other compounds were identified similarly by spectros-
copic data (1H NMR and 13C NMR, FAB–MS) and
elemental analysis.
C
ar1), 134.26 (2 × C, Car4), 167.69 (2 × C, CO). MS (FAB+,
Synlett 2009, No. 14, 2287–2290 © Thieme Stuttgart · New York