1
070
Med Chem Res (2011) 20:1068–1073
separated and dried over anhydrous sodium sulphate, fil-
tered and evaporated under reduced pressure to obtain
anhydrous sodium sulphate and the solvent removed by
evaporation under reduced pressure to obtain 4.22 g (yield
72% Rf = 0.5, 50% ethylacetate in hexane) of
octadecylaldehyde.
7
.2 g (yield 57.55% R = 0.4, 50:50 ethylacetate:hexane
f
(
v/v)) of 2-dihexadecylamino-ethanol.
0
00
00
Synthesis of 2-N,N -dihexadecylamino-acetaldehyde To a
solution of pyridinium chloro chromate (3.9 g, 18.2 mmol)
dissolved in 50 ml of anhydrous DCM added in portions a
solution of 2-dihexadecylamino-ethanol (6.2 g, 12 mmol)
in 10 ml of anhydrous DCM and stirred for one and half
hour. To the reaction mixture 50 ml of dry ether was added
and the supernatant solution decanted from black gum. The
residue was extracted thoroughly with 3 9 50 ml of
anhydrous ether and the combined organic solvents were
dried over anhydrous sodium sulphate and the solvent
removed by evaporation under reduced pressure to obtain
Synthesis of 5 ,20 -diheptadecyl-porphyrin (Lipid 2) The
preparation is same as described in the ‘‘Synthesis of
0
00
N,N -dihexadecyl-porphyrin-5 -ylmethyl-amine (Lipid 1)’’
section, except that instead of dihexadecylamino-acet-
aldehdye, octadecylaldehyde is used here. The product
obtained was recrystallized from chloroform/methanol
(85:15) followed by flash chromatography using ethyl
acetate:hexane as eluent, distillation to obtain 0.86 g (yield
7% R = 0.5, 50% ethylacetate in hexane) of 5,20-dihep-
f
1
tadecyl-porphyrin. H NMR (300 MHz, CDCl ): d 0.96 (t,
3
0
terminal-CH 9 2, 6H, 17 and 17 ), 1.33 (m, (–CH –)
9
3
2
15
0 0
2, 60H, 2–16 and 2 –16 ), 1.9 (t, = C–CH 9 2, 4H, 1 and
2
4
g (yield 64.8% R = 0.5, 50% ethylacetate in hexane) of
f
0 00 00
dihexadecylamino-acetaldehyde.
1 ), 4.3 (s, = CH– 9 2, 2H, 10 and 15 ), 5.0 (s, pyrrole-
0
0
00
NH– 9 2, 2H), 7.3 (s, pyrrole CH = CH 9 4, 8H, 2 , 3 ,
00 00 00 00 00 00
0
00
Synthesis of N,N -dihexadecyl-porphyrin-5 -ylmethyl-
amine (Lipid 1)
7 , 8 , 12 , 13 , 17 and 18 ). ESI–MS: m/z
?
?
A
solution of pyrrole (1.05 g,
M [C H N ] , calcd 786.65, found 786. Anal. Calcd for
53 81 5
1
5.7 mmol), formaldehyde (0.35 g, 11.8 mmol) and
C H N : C, 82.38; H, 10.50; N, 7.12. Found: C, 82.35; H,
54 82 4
dihexadecylamino-acetaldehyde (2.1 g, 3.94 mmol) in
anhydrous DCM was purged with nitrogen gas for 15 min
and to this anhydride zinc chloride is added. The reaction
mixture was stirred for 1 h at room temperature followed
by filtration to separate the catalyst. To the filtrate DDQ
10.40; N, 7.25.
Results and discussion
(
0.895 g, 3.94 mmol) was added and the mixture was
Synthesis of lipids
refluxed for an additional 1 h. Solvent was removed under
reduced pressure. The product obtained was recrystallized
from chloroform/methanol (85:15) followed by flash
chromatography using ethyl acetate:hexane as eluent to
The key structural elements common to the porphyrin-
based lipids 1 and 2 described herein include (a) the
presence of hydrophobic chains as anchoring groups (i)
linked to the positively charged nitrogen atom directly
which in turn attached to the porphyrin group through a
spacer or (ii) linked directly to the porphyrin group (b) the
presence of porphyrin group which is having positively
charged nitrogen atom. The details of the synthetic pro-
cedures for the novel porphyrin-based lipids 1 and 2 shown
in Chart 1 are described in the ‘‘Experimental section’’. As
outlined in Schemes 1 and 2, the chemistry involved in
preparing these new lipids are straightforward. However,
given their antibacterial activity, the overall yields of these
lipids need to be improved in future. Scheme 1 outlines the
general synthetic strategies adopted for preparing lipid 1.
The steps involved were (a) reacting hexadecyl bromide
with ethanol amine to produce an intermediate tertiary
amine alcohol. (b) Oxidizing the intermediate tertiary
amine alcohol to aldehyde of tertiary amine using pyridi-
nium chloro chromate. (c) The tertiary amine aldehyde
intermediate is treated with formaldehyde and pyrrole in
presence of acid catalyst to get the lipid 1. Synthesis of
lipid 2 essentially consists of similar steps as in synthesis of
lipid 1 except that instead of reacting with tertiary amine
obtain 0.26 g (yield 8% R = 0.5, 50% ethylacetate in
f
1
hexane) of dihexadecyl-porphyrin-5-ylmethyl-amine.
H
NMR (300 MHz, CDCl ) d 0.96 (t, terminal-CH 9 2, 6H,
3
3
0 0
6 and 16 ), 1.33 (m, (–CH –) 9 2, 56H, 2–15 and 2 –
2 14
1
0
0
1
5 ), 2.1 (t, (–CH –N–CH –), 4H, 1 and 1 ), 3.3 (s, =C–
2
2
0
0
00
00
00
CH –N, 2H, 21 ), 4.3 (s, =CH– 9 3, 3H, 10 ,15 and 20 ),
2
5
.0 (s, pyrrole-NH– 9 2, 2H), 7.3 (s, pyrrole –CH=CH– 9 4,
00
0
0
00
00
?
00
00
00
00
8
H, 2 , 3 , 7 , 8 , 12 , 13 , 17 , 18 ). ESI–MS: m/z
?
M [C H N ] , calcd 787.65, found 789. Anal. Calcd for
5
3 81 5
C H N : C, 80.76; H, 10.36; N, 8.88. Found: C, 80.66; H,
53 81 5
1
0.48; N, 8.86.
Synthesis of octadecylaldehyde To a solution of pyridi-
nium chloro chromate (4.7 g, 2.1 mmol) dissolved in
2
00 ml of anhydrous DCM, a solution of steryl alcohol
(
4 g, 1.4 mmol) in 20 ml of anhydrous DCM is added in
one portion and stirred the mixture for one and half an
hour. To this mixture 200 ml of dry ether is added and the
supernatant solution decanted from block gum. The residue
was extracted thoroughly with 3 9 50 ml of anhydrous
ether and the combined organic solvents were dried over
1
23