Conformationally Restricted and Flexible Phospholipids
SCHEME 4a
SCHEME 5 a
a
Reaction conditions: (a) LiCl, DMSO, H2O, reflux, 6 h, 86%;
(b) DIBAL, CH2Cl2, -78 °C, then NaBH4, MeOH, rt, 30 min, 69%;
(c) TBDPSCl, imidazole, DMF, rt, 20 h, 78%; (d) ozone, -78 °C,
then NaBH4, >99%.
SCHEME 6 a
a
Reaction conditions: (a) 1a : diphenylchlorophosphate, imida-
zole, CH2Cl2, rt, 14 h, then cat. PtO2, H2, 8 h, rt, 91%; 1c: 2-chloro-
1,3,2-dioxaphospholane 2-oxide, Et3N, benzene, rt, 20 h, then NH3,
benzene/acetonitrile 4 h, rt, 62%; (b) 2-chloro-1,3,2-dioxaphos-
pholane-2-oxide, Et3N, benzene, rt, 20-21 h, then NH3, benzene
5.5 h, rt, 62%.
18 in 87% yield. Diol 18 is a versatile intermediate, since
different nonpolar tails can be incorporated. For example,
palmitoyl and palmitoleoyl tails were attached each in
99% yield. The desilylation of 19a and 19b afforded the
corresponding alcohols 20a and 20b in 93% and 99%
yield, respectively. Our first choice for phospholipid
headgroup was a phosphatidic acid which was introduced
by treating first the alcohol 20a with diphenyl chloro-
phosphate followed by the catalytic hydrogenation to
afford 1a in 92% yield (Scheme 4). The phosphoethano-
lamine derivatives 1b and 1c were obtained by convert-
ing the corresponding alcohols 20a and 20b to rather
unstable dioxaphospholane intermediates which were
ring-opened in 62% yield using ammonia.9 The phospho-
lipids with saturated tails, 1a and 1c, were practically
insoluble in common organic solvents which prevented
complete characterization by NMR. However, unsatur-
ated 1b was quite soluble in chloroform or methanol.
Syn th esis of F lexible P h osp h olip id s 2. Alcohol 12
was prepared by modification of the method described
by Nugent and co-workers.10 Diethyl diallylmalonate 14
was first decarboxylated in 86% yield (Scheme 5).11
Reduction of ethyl ester 13 to the corresponding alcohol
12 was achieved with DIBALH followed by NaBH4 in 69%
yield.12 After the hydroxyl group was protected as a silyl
ether in 78% yield, the terminal alkenes in 21 were
cleaved by first treating the diene with ozone followed
by reduction of the ozonide with NaBH4 to give diol 22
in quantitative yield. The diol 22 is a versatile intermedi-
ate that can be conjugated with different nonpolar tails
a
Reaction conditions: (a) 23a: palmitoyl chloride, Et3N, CH2Cl2,
1 h, rt, 70%; 23b: palmitoleic acid, DCC, DMAP, CH2Cl2, 20 h,
77%; (b) TBAF, THF, rt, 4-16 h, rt, 79% (24a ), 60% (24b).
SCHEME 7a
a
Reaction conditions: (a) 2a : diphenylchlorophosphate, imi-
dazole, CH2Cl2, rt, 17 h, then cat. PtO2, H2, AcOH, rt, 6 h, 85%;
2c: 2-chloro-1,3,2-dioxaphospholane 2-oxide, Et3N, benzene, rt, 18
h, then NH3, acetonitrile/benzene 1.5 h, 43%; (b) 2-chloro-1,3,2-
dioxaphospholane 2-oxide, Et3N, benzene, rt, 18 h, then NH3, rt,
4.5 h, 81%.
(8) On the basis of 1H NMR in CDCl3, the lactol/hydroxy-aldehyde
ratio in 17 is about 95:5 at room temperature. We have not yet explored
the possibility of converting 17 into differentially acylated phospho-
lipids.
(9) Menger, F. M.; Chen, X. Y.; Brocchini, S.; Hopkins H. P.;
Hamilton, D. J . J . Am. Chem. Soc. 1993, 115, 660.
(10) Nugent, W. A.; Feldman, J .; Calabrese, J . C. J . Am. Chem. Soc.
1995, 117, 8992.
(11) (a) Krapcho A. P.; Weimaster, J . F.; Eldridge, J . M.; J ahngen,
E. G. E., J r; Lovey, A. J .; Stephens, W. P. J . Org. Chem. 1978, 43,
138. (b) Battersby, A. R.; Westwood, S. W. J . Chem. Soc., Perkin Trans.
1 1987, 1679. (c) Van Ornum, S. G.; Cook, J . M. Tetrahedron Lett. 1966,
40, 7185.
and polar headgroups. For example, the diol 22 was
successfully acylated with palmitoyl chloride in 67% yield
(Scheme 6). When palmitoleoyl chloride was used as an
acylating agent, the diester 23b was isolated in less that
50% yield. However, when the corresponding acid was
used instead, the desired 23b was obtained in 77% yield.
Removal of silyl protecting groups gave alcohols 24a and
24b in 79% and 60% yield, respectively. Different head-
(12) Even if excess DIBALH was used, some intermediate aldehyde
was always obtained. However, subsequent treatment with NaBH4
converted all material to desired alcohol 12.
J . Org. Chem, Vol. 68, No. 26, 2003 10075