Facile selective cleavage of a myo-inositol trans-isopropylidene acetal in the presence of a cis-isopropylidene acetal

Article abstract of DOI:10.1016/S0040-4039(01)02382-6

1,2:4,5-Di-O-isopropylidene myo-inositol acetals were selectively deprotected at the 4,5-trans position using Amberlite-120 (H⁺) resin in CHCl₃/MeOH at room temperature over 24-48 h to afford the corresponding cis-1,2-O-isopropyliden

Full text of DOI:10.1016/S0040-4039(01)02382-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1367–1368
Facile selective cleavage of a myo-inositol trans-isopropylidene
acetal in the presence of a cis-isopropylidene acetal
K. S. Ravikumar and David Farquhar*
Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
Received 28 September 2001; revised 10 December 2001; accepted 11 December 2001
Abstract—1,2:4,5-Di-O-isopropylidene myo-inositol acetals were selectively deprotected at the 4,5-trans position using Amberlite-
120 (H+) resin in CHCl3/MeOH at room temperature over 24–48 h to afford the corresponding cis-1,2-O-isopropylidene
myo-inositol acetals in near quantitative yield. © 2002 Elsevier Science Ltd. All rights reserved.
myo-Inositol is the most common inositol isomer in
nature. It is the starting material for the biosynthesis of
inositol phosphates.1–3 The 1,4,5-trisphosphate deriva-
tive, 1, possesses second messenger properties1–3 and
plays an important role in the cellular mobilization of
calcium.4 The structurally-related phosphatidylinositols,
2, play a key role in cell signal transduction pathways and
regulate such diverse biologic processes as cell growth,
cell cycle progression, apoptosis, differentiation, trans-
formation, mitogenesis, cytoskeletal rearrangement and
glucose transport.5–7
The chemical synthesis of analogs of myo-inositol
requires the use of alcohol protective groups that can be
regioselectively manipulated.1,2 It is well established12
that the 1,2- and 4,5-diol positions of myo-inositol can
be protected as isopropylidene acetals (acetonides) leav-
ing the 3- and 6-hydroxy groups free for further reaction.
In studies on the synthesis of analogs of 1 and 2, we
required the selective deprotection of the trans-acetonide
of 1,2:4,5-diacetonides of the general structure 3. The
most common method for the deprotection of acetonides
is acid-catalyzed hydrolysis13 using protic or Lewis acids.
The preferential cleavage of trans-acetonides over cis-
acetonides has been reported using catalytic amounts of
acetyl chloride14,15 in MeOH or p-toluenesulfonic acid
hydrate (PTSA)16 in acetone/water (40:1), and is based
on the slightly greater acid lability of trans-acetonides
compared with their cis-counterparts. Work up of the
During the past decade, considerable effort has been
directed at the design of analogs of inositol phosphates
both as tools to explore cell-signaling pathways and as
potential therapeutic agents to control abnormal cell
expression.8–11
O
O
HO
HO
OH
OH
HO
3
P
HO
P
OCOR
O
P
4
2
OH
OH
O
HO
P
O
HO
P
O
OCOR
O
O
O
5
HO
HO
HO
HO
O
O
P
6
1
HO
HO
OH
O
O
1
2
O
O
Amberlite-120 H+
CHCl3 / MeOH
RO
RO
HO
HO
O
O
O
O
R'O
R'O
4
3
Yield (%)
a. R = Bn
b. R = Ts
c. R = TBDPSi
d. R = Bz
R' = Bn
R' = Bn
R' = Bn
R' = Bz
93
98
97
94
Keywords: acetal; acetonide; Amberlite-120 resin; inositol; protection, deprotection.
* Corresponding author. Tel.: +(713)792-3629; fax: +(713)792-3628; e-mail: dfarquha@mail.mdanderson.org
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02382-6

1368
K. S. Ra6ikumar, D. Farquhar / Tetrahedron Letters 43 (2002) 1367–1368
crude reaction mixtures required the addition of triethyl-
amine to neutralize acid, and column chromatography
on silica gel to isolate pure product.17
Acknowledgements
This work was supported by a grant from the Univer-
sity of Texas System Cancer Center Drug Discovery
Group and by NIH Cancer Center Support Grant
CA16672.
To avoid sensitive work up conditions and chromato-
graphic purification procedures, an alternative
approach was sought for the selective deprotection of
the trans-acetonide group of 1,2:4,5-diacetonides. Since
the deprotection of acetonides has been reported18 with
aqueous acetic acid, attempts were made to selectively
cleave the trans-acetonide of 3a using a weakly acidic
ion-exchange resin, Amberlite IRC-50, in CHCl3/
MeOH (2:1) solution. No reaction was evident after 24
h at room temperature. However, when a strongly
acidic ion-exchange resin, Amberlite 120 H+, was sub-
stituted, smooth cleavage of the trans-acetonide
occurred and the reaction was complete in 24 h. The
product, 4a, was isolated in near quantitative yield by
filtration of the reaction mixture and evaporation of the
solvent. No traces of the cis-diol, the tetradiol, or the
starting material were apparent. In a similar manner,
3b–d were quantitatively converted over 24–48 h to the
corresponding trans-diols, 4b–d. This mild and simple
procedure avoids the generation of unwanted by-prod-
ucts in the selective deprotection of the trans-acetonide
of myo-inositol 1,2:4,5-diacetonides and, therefore, pre-
cludes the requirement for chromatographic purifica-
tion procedures. It should be generally useful in the
field of myo-inositol chemistry.
References
1. Billington, D. C. The Inositol Phosphates: Chemical Syn-
thesis Biological Significance; New York, 1993.
2. Reitz, A. B. Inositol Phosphate Derivatives: Synthesis,
Biochemistry, Therapeutic Potential; ACS Symposium
Series 463, 1991.
3. Potter, B.; Lampe, D. Angew. Chem., Int. Ed. Engl. 1995,
34, 1933–1972.
4. Berridge, M. Am. J. Nephrol. 1997, 17, 1–11.
5. Rameh, L. E.; Cantley, L. C. J. Biol. Chem. 1999, 274,
8347–8350.
6. Leevers, S. J.; Vanhaesebroeck, B.; Waterfield, M. D.
Curr. Opin. Cell. Biol. 1999, 11, 219–225.
7. Vanhaesebroeck, B.; Alessi, D. R. Biochem. J. 2000, 346,
561–576.
8. Johnson, S. C.; Dahl, J.; Shih, T. L.; Schedler, D. J.;
Anderson, L.; Benjamin, T. L.; Baker, D. C. J. Med.
Chem. 1993, 36, 3628–3635.
9. Qiao, L.; Nan, F.; Kunkel, M.; Gallegos, A.; Powis, G.;
Kozikowski, A. P. J. Med. Chem. 1998, 41, 3303–3306.
10. Hu, Y.; Meuillet, E. J.; Berggren, M.; Powis, G.;
Kozikowski, A. P. Bioorg. Med. Chem. Lett. 2001, 11,
173–176.
11. Powis, G.; Aksoy, I. A.; Melder, D. C.; Aksoy, S.;
Eichinger, H.; Fauq, A. H.; Kozikowski, A. P. Cancer
Chemotherapy Pharmacol. 1991, 29, 95–104.
12. Gigg, J.; Gigg, R.; Payne, S.; Conant, R. Carbohydr. Res.
1985, 142, 132–134.
13. Greene, T. W.; Wuts, P. G. Protective Groups in Organic
Synthesis; Wiley-Interscience, 1999; pp. 207–215.
14. Kozikowski, A. P.; Fauq, A. H.; Wilcox, R. A.;
Nahorski, S. R. J. Org. Chem. 1994, 59, 2279–2281.
15. Kozikowski, A. P.; Fauq, A. H. J. Am. Chem. Soc. 1990,
112, 7403–7404.
Selective deprotection of a myo-inositol 4,5-trans-ace-
tonide in the presence of a 1,2-cis-acetonide: Amberlite-
120 (H+) resin was washed successively with 1N H2SO4,
deionized water, acetone, and air-dried. 3-O-Tosyl-6-O-
benzyl-1,2:4,5-isopropylidene myo-inositol, 3b (0.50 g, 1
mmol) was dissolved in CHCl3/MeOH (2:1, 20 mL) and
Amberlite-120 (H+) resin (0.5 g) was added. The reac-
tion was stirred at room temperature under an inert
(argon) atmosphere for 36 h. The mixture was filtered
through Celite and the solvent was evaporated in
vacuo. The pure diol, 3-O-tosyl-6-O-benzyl-1,2-iso-
propylidene myo-inositol, was obtained as a white solid
1
(0.455 g, 98%). Mp 153°C. H NMR (CDCl3) l 1.23 (s,
3H), 1.45 (s, 3H), 2.44 (s, 3H), 2.72 (d, J=2.68 Hz,
1H), 2.78 (d, J=2.23 Hz, 1H), 3.43 (td, J=7.05, 2.00
Hz, 1H), 3.49–3.54 (dd, J=9.40, 6.68 Hz, 1H), 3.94 (td,
J=9.35, 2.45 Hz, 1H), 4.15 (t, J=5.93 Hz, 1H), 4.33 (t,
J=4.61 Hz, 1H), 4.64 (d, J=9.54 Hz, 1H), 4.66 (d,
J=11.37 Hz, 1H), 4.89 (d, J=11.52 Hz, 1H), 7.28–7.35
(m, 7H), 7.85 (d, J=8.26 Hz, 2H); 13C NMR (CDCl3)
l 21.66 (q), 25.63 (q), 27.72 (q), 69.97 (t), 72.91 (d),
73.31 (d), 74.26 (d), 78.92 (d), 79.11 (d), 81.05 (d),
110.42 (s), 127.91 (d), 128.01 (d), 128.05 (d), 128.44 (d),
129.74 (d), 133.69 (s), 137.82 (s), 145.05 (s).
16. Gigg, J.; Gigg, R.; Payne, S.; Conant, R. J. Chem. Soc.,
Perkin Trans. 1 1987, 423–429.
17. Electropositive substituents such as benzyl or TBDPSi
underwent trans-acetonide deprotection faster in the
presence of catalytic amounts of acetyl chloride in
CHCl3/MeOH than electron-withdrawing substituents
such as tosyl or benzoyl groups.
18. Lewbart, M. L.; Schneider, J. J. J. Org. Chem. 1969, 34,
3505–3512.