Together, the increase in [Ca2+] and the increased activity
of PKC lead to a sequence of events that culminate in DNA
synthesis and cell proliferation. In the second pathway, PI-
3-kinase has been found associated with almost every growth
factor receptor or oncogene transformation.8 PI-3-kinase
phosphorylates PI and PIP’s with a free 3-OH group to give
a class of compounds that are poor substrates for hydrolysis
by PI-PLC. The PI-3-phosphates are present in the cell in
varying amount; PI(3,4)P2 and PI(3,4,5)P3 predominate, while
PI(3)P is present in smaller amounts. PI(3,4)P2 and PI(3,4,5)-
P3 are responsible for the effects of PI-3-kinase on tumor
growth and apoptosis through activation of the pleckstrin
homology (PH) domain of certain proteins.9 The most
extensively studied examples of PH domain-regulated signal-
ing are the PH domain-dependent activation by PI(3,4)P2 and
PI(3,4,5)P3 of PI-PLCγ10 and of Akt,11,12 a proto-oncogene.
Inhibiting Akt activation induces cancer cell apoptosis,13
while activation of PI-PLCγ will result in cell proliferation
through the PI-PLC pathway. Because of the importance of
the PIPn’s in studies of cell signaling, and due to the difficulty
of isolating these materials from natural sources, efficient
synthetic routes to these molecules are required.14
First, four of the five vicinal hydroxyls of L-(-)-quebra-
chitol were protected as their acetonides. After mesylation
of the remaining 3-OH group, demethylation and concurrent
removal of the acetonides with BBr3 gave rise to a pentol
bearing an intact mesylate group at position 3. Reprotection
of the hydroxyl groups of this pentol with 2-methoxypropene
resulted in the pair of regioisomers 2 and 3. The differential
solubilities of compounds 2 and 3 in hexanes-ethyl acetate
(3/1 v/v) permit isolation of one key intermediate, compound
2, by crystallization.19 The other regioisomer, 3, was found
enriched in the mother liquor with a purity up to 96% (by
1H NMR) (Scheme 1). The availability of intermediate 3
Scheme 1. Synthesis of Key Intermediates from
L-Quebrachitol
In the literature,15 myo-inositol has been widely used as a
starting material for the synthesis of PIPn’s. To obtain the
natural D enantiomers, optical resolution of myo-inositol
intermediates is required.14a,15 Although D-glucose16 has also
served as a chiral starting material, suitable protecting groups
have to be introduced individually for different PIPn’s at the
beginning to facilitate later incorporation of phosphate groups
at selected positions. The naturally occurring cyclitol
L-(-)-quebrachitol is a byproduct of rubber manufacture.17
Although it has been widely used as a starting material for
the synthesis of 3-modified phosphatidylinositols, to our
knowledge, this is the first report demonstrating the use of
L-(-)-quebrachitol in the preparation of phosphatidylinositol
polyphosphates. Herein, we present a versatile approach to
the synthesis of selected PIPn’s from L-quebrachitol.18
allows the differential protection of 4-OH and gives ready
access to PI(3,4)P2 after inversion of the chiral center at
position 3.
The synthesis of PI(3,4)P2 from compound 3 is exemplified
here to illustrate the synthetic strategy. The inversion of the
stereochemistry at C-3 was readily accomplished through an
oxidation/reduction sequence after LAH reduction of the
mesylate (Scheme 2). Next, differential protection must be
(7) Wender, P. A.; Gribbs, C. M. In AdVances in Medicinal Chemistry;
Maryanoff, B. E., Maryanoff, C. A., Eds.; JAI Press: Greenwich, CT, 1992;
Vol. 1, pp 1-53.
Scheme 2. Inversion of the Chiral Center at C-3
(8) Toker, A.; Cantley, L. C. Nature 1997, 387, 673-676.
(9) Lemmon, M. A.; Ferguson, K. M.; Schlessinger, J. Cell 1996, 85,
621-624.
(10) Falasca, M.; Logan, S. K.; Lehto, V. P.; Baccante, G.; Lemmon,
M. A.; Schlessinger, J. EMBO J. 1998, 17, 414-422.
(11) Franke, F. F.; Kaplan, D. R.; Cantley, L. C.; Toker, A. Science 1997,
275, 665-668.
(12) French, M.; Andjelkovic, M.; Reddy, K. K.; Falck, J. R. J. Biol.
Chem. 1997, 272, 8474-8478.
(13) Franke, T. F.; Cantley, L. C. Nature 1997, 390, 116-124.
(14) For recent progress in this area, see: (a) Painter, G. F.; Grove, S.
J. A.; Gilbert, I. H.; Holmes, A. B.; Raithby, P. R.; Hill, M. L.; Hawkins,
P. R.; Stephens, L. R. J. Chem. Soc., Perkin Trans. 1 1999, 923-935. (b)
Chen, J.; Feng, L.; Prestwich, G. D. J. Org. Chem. 1998, 63, 6511-6522.
(c) Wang, D.-S.; Hus, A.-L.; Song, X.; Chiou, C.-M.; Chen, C.-S. J. Org.
Chem. 1998, 63, 5430-5437. (d) Watanabe, Y.; Nakatomi, M. Tetrahedron
Lett. 1998, 39, 1583-1586. (e) Grove, S. J. A.; Gilbert, I. H.; Holmes, A.
B.; Painter, G. F.; Hill, M. L. J. Chem. Soc., Chem. Commun. 1997, 1633-
1634, 1635-1636. (f) Gu, Q.-M.; Prestwich, G. D. J. Org. Chem. 1996,
61, 8642-8647. (g) Chen, J.; Profit, A. A.; Prestwich, G. D. J. Org. Chem.
1996, 61, 6305-6312. (h) Thum, O.; Chen, J.; Prestwich, G. D. Tetrahedron
Lett. 1996, 37, 9017-9020.
introduced at O-5 and O-6. Generally, the synthesis of a
given PIPn requires the preparation of an inositol intermediate
with temporarily protected hydroxyl groups at the positions
later to be phosphorylated. In our study, the p-methoxybenzyl
group (PMB) was applied for this purpose. By procedures
similar to those published before,20 compound 6 was
(18) This work was presented as a poster at the 217th National Meeting
of the American Chemical Society, Anaheim, CA, 1999.
(19) Kozikowski, A. P.; Fauq, A. H.; Wilcox, R. A.; Nahorski, S. R. J.
Org. Chem. 1994, 59, 2279-2281.
(20) Kozikowski, A. P.; Qiao, L.; Tu¨ckmantel, W.; Powis, G. Tetrahedron
1997, 53, 14903-14914.
(15) Billington, D. C. The Inositol Phosphates: Chemical Synthesis and
Biological Significance; VCH: New York, 1993; Chapter 3.
(16) Prestwich, G. D. Acc. Chem. Res. 1996, 29, 503-513.
(17) Kiddle, J. J. Chem. ReV. 1995, 95, 2189.
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