Synthesis of Phosphorylated Phosphatidylinositols
verted into either the phosphodiester or phosphomono-
ester functions, and (iii) the final mild deprotection of
the phosphate and inositol hydroxyl groups, compatible
with the presence of carboxylic ester functions and double
bonds in the diacylglycerol residue, and with the pro-
pensity of the neutral phosphate group toward migration
between vicinal hydroxyl functions. While most of the
earlier work focused mainly on reproducing the exact
structure of the phosphatidylinositols polar headgroups,
the more recent efforts have been devoted to replicating
the precise structure of the diglyceride, including the
presence of arachidonic acid at the 2-position of glycerol.
The first problem has been solved by various re-
search groups using different approaches including (i) the
use of enantiopure natural precursors such as D-
glucose,9c,11a,12b,14c,15g L-chiro-inositol derivatives,12g and
quinic acid,12d,e,15a,f (ii) kinetic resolution or desymmetri-
zation via enantioselective enzymatic acylations of pro-
tected myo-inositol derivatives,9b,15b,17 and (iii) separation
of diastereomeric derivatives of myo-inositol with chiral
auxiliaries.4a-d,13b,18 In our early work18 we have used the
last approach, where the resolution of the inositol enan-
tiomers is achieved by crystallization of diastereomeric
ketals of myo-inositol with D- or L-camphor. This method,
which combines in one step regioselective protection of
the cis-diol function of inositol with diastereomer separa-
tion, is both short and efficient. Hence, following our
initial reports, similar procedures have been adopted by
others in their design of PIPn synthesis.9e,12f,15k The
second problem has been solved by applying regioselec-
tive protection-deprotection sequences, typically to ob-
tain inositol derivatives protected with benzyl or related
groups. The use of benzylic groups is, however, com-
pletely unsuited in syntheses of inositol phospholipids
containing the arachidonic acid moiety in the diacyl-
glycerol residue. Synthesis of arachidonoyl PIPn, the true
naturally occurring signaling molecules, required there-
fore a complete redesign16a-c,19 of the previously developed
synthetic strategies which inevitably lengthened the
already long synthetic schemes. In addition, although
arachidonoyl PI-3,4,5-P3 has been synthesized,16 it is
unclear how the developed methodology could be used
for the synthesis of other PIPn.
F IGURE 1. Structures of phosphatidylinositol phosphates
(PIPn) 1-8. Most naturally occurring PIPn presumed to
participate in signal transduction pathways carry stearoyl and
arachidonoyl residue at the glycerol sn-1- and sn-2-positions,
respectively. All synthesized PIPn are 1,2-dipalmitoyl (DP)
glycerides except compound 7, which was also synthesized as
the 1,2-dioctanoyl (DO) derivative (7a ), and compound 8, which
was also synthesized as the dioctanoyl (8a ) and 1-stearoyl-2-
arachidonoyl (SA, 8b) derivatives.
thesis are dominated by the necessity to solve three
issues: (i) availability of myo-inositol derivatives with
high enantiomeric purity, (ii) differential regioselective
protection of inositol hydroxyl groups to be later con-
(12) PI-3,4-P2: (a) Reference 9b. (b) Thum, O.; Chen, J .; Prestwich,
G. D. Tetrahedron Lett. 1996, 37, 9017-9020. (c) Reference 9b. (d)
Reddy, K. K.; Ye, J .; Falck, J . R.; Capdevila, J . H. Bioorg. Med. Chem.
Lett. 1997, 7, 2115-2116. (e) Reddy, K. K.; Rizo, J .; Falck, J . R.
Tetrahedron Lett. 1997, 38, 4729-4730. (f) Grove, S. J . A.; Holmes, A.
B.; Painter, G. F.; Hawkins, P. T.; Stephens, L. R. J . Chem. Soc., Chem.
Commun. 1997, 17, 1635-1639. (g) Qiao, L.; Hu, Y.; Nan, F.; Powis,
G.; Kozikowski, A. P. Org. Lett. 2000, 2, 115-117.
(13) PI-3,5-P2: (a) Reference 12f. (b) Riley, A. M.; Potter, B. V. L.
Tetrahedron Lett. 1998, 39, 6769-6772. (c) Reference 11a.
In this work we describe a simple uniform methodology
that is applicable to synthesis of all naturally occurring
PIPn, including the unsaturated derivatives and phos-
phorothioate analogues20 of PIPn.
(14) PI-4,5-P2: (a) Dreef, C. E.; Elie, C. J . J .; Hoogerhout, P.; Van
der Marel, G. A.; van Boom, J . H. Tetrahedron Lett. 1988, 29, 6513-
16. (b) Watanabe, Y.; Nakamura, T.; Mitsumoto, H. Tetrahedron Lett.
1997, 38, 7407-7419. (c) Chen, J .; Prestwich, G. D. J . Org. Chem. 1998,
63, 430-431. (d) Falck, J . R.; Krishna, U. M.; Capdevila, J . H.
Tetrahedron Lett. 1999, 40, 8771-8774. (e) Reference 12g.
(15) PI-3,4,5-P3: (a) Falck, J . R.; Abdali, A. In Inositol Phosphates
and Derivatives. Synthesis, Biochemistry, and Therapeutic Potential;
Reitz, A. B., Ed.; ACS Symp. Ser. 463; American Chemical Society:
Washington, DC, 1991; pp 145-154. (b) Gou, D.-M.; Chen, C.-S. J .
Chem. Soc., Chem. Commun. 1994, 18, 2125-6. (c) Watanabe, Y.;
Hirofuji, H.; Ozaki, S. Tetrahedron Lett. 1994, 35, 123-124. (d)
Reference 9b. (e) Watanabe, Y.; Tomioka, M.; Ozaki, S. Tetrahedron
1995, 51, 8969-8976. (f) Reddy, K. K.; Saady, M.; Falck, J . R. J . Org.
Chem. 1995, 60, 3385-3390. (g) Chen, J .; Profit, A. A.; Prestwich, G.
D. J . Org. Chem. 1996, 61, 6305-6312. (h) Reference 9b. (i) Reference
12f. (j) Reference 9e. (k) J iang, T.; Sweeney, G.; Rudolf, M. T.; Klip,
A.; Traynor-Kaplan, A.; Tsien, R. Y. J . Biol. Chem. 1998, 273, 11017-
11024. (l) Reference 12g. (m) Estevez, V. A.; Prestwich, G. D. J . Am.
Chem. Soc. 1991, 113, 9885-9887.
(16) Unsaturated PI-3,4,5-P3: (a) Gaffney, P. R. J .; Reese, C. B.
Bioorg. Med. Chem. Lett. 1997, 7, 3171-3176. (b) Gaffney, P. R. J .;
Reese, C. R. J . Chem. Soc., Perkin Trans. 1 2001, 10, 192-205. (c)
Watanabe, Y.; Nakatomi, M. Tetrahedron 1999, 55, 9743-9754.
(17) (a) Ozaki, S.; Lei, L. In Carbohydrates in Drug Design; Witczak,
Z. J ., Nieforth, K. A., Eds.; Marcel Dekker: New York, p 343-384. (b)
Sculimbrene, B. R.; Miller, S. J . J . Am. Chem. Soc. 2001, 123, 10125-
10126.
Resu lts a n d Discu ssion
The synthetic approach reported here is based on the
following strategic consecutive steps (Schemes 1-3): (a)
regioselective silylation of the 1-hydroxyl of inositol-
camphor ketal; (b) removal of the ketal group; (c) regio-
selective benzoylation of the phosphomonoester positions;
(d) exhaustive “capping” of all the remaining hydroxyl
groups; (e) deacylation at the phosphomonoester posi-
(18) (a) Bruzik, K. S.; Salamonczyk, G. M. Carbohydr. Res. 1989,
195, 67-73. (b) Bruzik, K. S.; Tsai, M.-D. J . Am. Chem. Soc. 1992,
114, 6361-6374. (c) Pietrusiewicz, K. M.; Salamonczyk, G. M.; Bruzik,
K. S.; Wieczorek, W. Tetrahedron 1992, 48, 5523-42.
(19) Watanabe, Y. In Phosphoinositides: Chemistry, Biochemistry
and Biomedical Applications; ACS Symp. Ser. No. 718; American
Chemical Society: Washington, DC, 1998; pp 197-211.
(20) Kubiak, R. J .; Bruzik, K. S. Bioorg. Med. Chem. Lett. 1997, 7,
1231-1234.
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