K. Kasireddy et al. / Tetrahedron Letters 45 (2004) 2743–2746
2745
C14H29
C14H29
O
O
HO
HO
C14H29
O
O
C14H29
O
O
c
a
b
C14H29
C14H29
Br
OBn
15a and 15b
OBn
OH
18a and 18b
17a and 17b
16a and 16b
d
C14H29
C14H29
O
O
N
7a and 7b
Scheme 3. Reagents and conditions: (a) NaH, C14H29Br, DMF, 60 °C, 10 h; (b) 10% Pd/C, H2, 50 psi, ethyl acetate, 12 h; (c) Ph3P, CBr4, CH2Cl2,
0 °C to rt, 2 h; (d) 2 M dimethylamine in methanol, MeOH, pressure bottle, 90 °C, 60 h.
OH
14
C
C
H
O
O
14 29
+
O
O
H
14 29
Br
Ethanol
Br
N
7, 7a and 7b
reflux
O
O
O
O
-
OH
-
Br
+
Br
N
+
O
O
N
3, 3a and 3b
Scheme 4.
propane 7a and 7b were accomplished starting from
commercially available (S) and (R)-1-O-benzyl glycerol
15a and 15b, respectively (Scheme 3). Williamson
etherification of 1-O-benzyl glycerol 15a and 15b with
tetradecyl bromide in presence of NaH in DMF afforded
1,2-bis-tetradecyloxy-3-O-benzylpropane desired prod-
ucts 16a (75%) and 16b (80%), respectively. Debenzyl-
ation of 16a and 16b via hydrogenation over 10% Pd/C
catalyst in ethyl acetate gave 1,2-bis-tetradecyloxy pro-
pane-3-ol 17a and 17b in 92% yields, respectively. The
alcohol 17a and 17b on reaction with Ph3P/CBr4 in
CH2Cl2 afforded 1,2-bis-tetradecyloxy-3-bromopropane
18a and 18b in 90% and 87% yields, respectively. The
bromo compound 18a and 18b on heating with 10-fold
excess of 2 M methanolic dimethylamine solution in
pressure bottle gave (R)-1,2-bis-tetradecyloxy-3-di-
methylamine propane 7a (88% yield) and (S)-1,2-bis-
tetradecyloxy-3-dimethylamine propane 7b (80% yield),
respectively.
cardiolipin analogues to deliver antisense oligonucleo-
tode (AON) and RNAi into the targeted cells in vitro
and in vivo is under investigation and will be reported
elsewhere.
References and notes
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The optically pure (R) and (S) isomers 3a (78% yield), 3b
(80% yield) as well as racemic (R,S) of spacer cationic
cardiolipin 3 (69% yield) (Scheme 4) were obtained by
quanternization of tertiary amine compounds 7a, 7b,
and 7, respectively, with dibromo derivative 14 in eth-
anol at reflux temperature for 5 days.
The method developed is novel and efficient to synthe-
size a series of cationic cardiolipin and its analogues.
The solubility of compound 3 is increased in polar sol-
vents compared to compound 2, because of incorpora-
tion of oxyethylene group. The process is scalable from
gram to kilogram scale. Cationic cardiolipin analogues
will be used to formulate a broad range of therapeutic
agents, including antisense oligonucleotode as well as
gene transfection agents. Application of these cationic
4. Felgner, P. L. Adv. Drug Delivery Rev. 1990, 5, 167–187.
5. (a) Weiss, B.; Nitachko, H.; Wright, R.; Schlessinger, S.
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