4056
H. Morishita, H. Tamiaki / Bioorg. Med. Chem. 11 (2003) 4049–4057
1
1
1
Deprotection of 13 -ketal 10 to 11. A mixture of aqu-
eous 1 M HCl solution (2 mL) and acetone (1.5 mL) was
Synthesis of 3 ,13 -ethylene ketal 17 of methyl 3-devinyl-
1
5
3-acetyl-pyropheophorbide-a (6). Ketalation of 6 gave
17 (63% yield) as the first green fraction on alumina
column chromatography (CH Cl ) and a mixture of
undesired 3 -ketal 18, 13 -ketal 19 and startingmaterial
6 as the second yellow brown fraction. 17; green solid
added to a THF solution (4 mL) of 10 (12.9 mg). After
ꢂ
stirringat 35 C under N for 3 h, the reaction mixture
2
2
2
1
1
was worked-up similarly with synthesis of 2!3, to give
2
-chloroethyl pheophorbide-a (11) as a black solid (a/
0
.53/49, 9.39/35, 8.56/50 (each 1H, s, 5-, 10-, 20-H),
1
0
1
a =6/1, 4.2 mg, 35% yield); H NMR (CDCl ) d (a/a )
(from CH Cl and hexane); H NMR (CDCl ) d 10.58,
3
2
2
3
9
9.69, 8.88 (each 1H, s, 5-, 10-, 20-H), 5.18, 5.04 (each
1
1
8.00/7.98 (1H, dd, J=12, 8 Hz, 3-CH), 6.28 (1H, dd,
1
J=1, 18 Hz, 3 -CH-trans to 3-CH), 6.25/15 (1H, s,
3 -CH), 6.19 (1H, dd, J=1, 12 Hz, 3 -CH-cis to 3-
CH), 4.47 (1H, q, J=7 Hz, 18-H), 4.32–4.11 (3H, m,
1H, d, J=16 Hz, 13 -CH ), 4.74–4.51 (5H, m, 13 -
2
1
OCH CH O, 18-H), 4.43–4.37, (3H, m, 3 -OCH , 17-
2
H), 4.13–3.98, (2H, m, 3 -OCH ), 3.85 (2H, q, J=7 Hz,
2
8-CH ), 3.67, 3.68, 3.58, 3.43 (each 3H, s, 2-, 7-, 12-
2
CH , CO CH ), 2.81–2.47, 2.42–2.13 (each 2H, m, 17-
3
2
2
1
1
1
1
2
1
7-H, 17 -CO CH ), 3.67 (2H, q, J=8 Hz, 8-CH ),
2
2
2
3
2
1
3
CH , 13 -CO CH ), 3.50 (2H, t, J=6 Hz, CH Cl),
.87/82, 3.73, 3.41/39, 3.24/22 (each 3H, s, 2-, 7-, 12-
2
CH CH ), 2.39 (3H, s, 3 -CH ), 1.82 (3H, d, J=7 Hz,
2 2 3
1
18-CH ), 1.76 (3H, t, J=7 Hz, 8 -CH ), ꢀ1.36, ꢀ3.19
3
2
3
2
3
3
2
(
.72–2.51, 2.43–2.16 (each 2H, m, 17-CH CH ), 1.82
2
3H, d, J=7 Hz, 18-CH ), 1.70 (3H, t, J=8 Hz, 8 -
3
(each 1H, s, NH); VIS (CH Cl ) l
647 (rel. 0.32),
591 (0.03), 524 (0.03), 496 (0.09), 396 nm (1.00); MS
2
2
2
max
1
+
CH ), 0.56/67, ꢀ1.61/43 (each 1H, s, NH); VIS
(FAB) found: m/z 652, calcd for C H N O : M ,
6
3
39 44
4
(
CH Cl ) l
667 (rel. 0.43), 610 (0.08), 538 (0.10),
08 (0.10), 475 (0.04), 413 (1.00), 327 nm (0.22); MS
652.
2
2
max
5
(
3
5
+
1
1
FAB) found: m/z 654, calcd for C H N O Cl: M ,
37 39 4 5
Hydrolysis of 3 ,13 -ketal 17. Similarly with synthesis of
1
1 18
6
54.
2!3, deprotection of 17 gave 3 -ketal of 13 - O-oxo-
18
labelled methyl 3-acetyl-pyropheophorbide-a (84%
yield, 88Æ1%- O) as the main brown fraction of alu-
1
1
Synthesis of 3 -ethylene acetal and 13 -ethylene ketal 12
1
5
of methyl pyropheophorbide-d (5). Ketalation of 5
gave 12 (50% yield) as the first fraction on an alumina
mina column; brown solid (from CH Cl and hexane);
2
2
1
H NMR (CDCl ) d 10.19, 9.54, 8.59 (each 1H, s, 5-, 10-,
20-H), 5.28, 5.12 (each 1H, d, J=16 Hz, 13 -CH ), 4.49
(1H, q, J=7 Hz, 18-H), 4.31 (1H, d, J=9 Hz, 17-H),
4.45–4.35, 4.12–4.02 (each 2H, m, 3 -OCH CH O), 3.72
2
(2H, q, J=8 Hz, 8-CH ), 3.69, 3.60, 3.52, 3.30 (each 3H,
2
3
1
1
column (CH Cl ) and a mixture of undesired 3 -acetal
2
13, 13 -ketal 14 and startingmaterial 5 as the second
yellow brown fraction. 12; green solid (from CH Cl
2
2
1
1
2
2
2
1
and hexane); H NMR (CDCl ) d 10.04, 9.68, 8.91
3
(
each 1H, s, 5-, 10-, 20-H), 7.44 (1H, s, 3-CH), 5.20,
1
s, 2-, 7-, 12-CH , CO CH ), 2.77–2.50, 2.40–2.18 (each
2
3
3
1
5
m, 3 -, 13 -OCH CH O, 18-H), 4.44–4.41 (1H, m, 17-
.05 (each 1H, d, J=16 Hz, 13 -CH ), 4.73–4.48 (9H,
1
2H, m, 17-CH CH ), 2.33 (3H, s, 3 -CH ), 1.81 (3H, d,
2 2 3
2
1
1
J=7 Hz, 18-CH ), 1.71 (3H, t, J=8 Hz, 8 -CH ),
3
2
2
3
H), 3.84 (2H, q, J=7 Hz, 8-CH ), 3.64, 3.61, 3.59, 3.40
2
0.33,ꢀ1.83 (each 1H, s, NH); VIS (CH Cl ) l
662
(rel. 0.50), 606 (0.08), 538 (0.10), 506 (0.09), 474 (0.04),
2
2
max
(
each 3H, s, 2-, 7-, 12-CH , CO CH ), 2.85–2.53, 2.39–
3
2
3
2
2
1
.21 (each 2H, m, 17-CH CH ), 1.83 (3H, d, J=7 Hz,
2
410 (1.00), 319 nm (0.20); IR (CH Cl ) 1734 (17 -C¼O),
2
2
2
1
16
18
ꢀ1
8-CH ), 1.75 (3H, t, J=7 Hz, 8 -CH ), ꢀ1.40, ꢀ3.17
1696 (13-C¼ O), 1663 (13-C¼ O), 1622 cm (C¼C);
+
3
3
1
36 40 4 4
8
(
5
each 1H, s, NH); VIS (CH Cl ) l
649 (rel. 0.34),
95 (0.03), 525 (0.02), 497 (0.09), 396 nm (1.00); MS
MS (FAB) found: m/z 610, calcd for C H N O O:
M , 610.
2
2
max
+
(
FAB) found: m/z 638, calcd for C H N O : M ,
37 42 4 6
6
38.
Similarly with synthesis of 10!11, deprotection of the
1
18
above 3 -ketal afforded O-unlabelled ketone 6 (46%
yield).
1
1 18
Synthesis of 3 -13 - O-oxo-labelled methyl pyropheo-
phorbide-d (15). Similarly with synthesis of 2!3, depro-
tection of 12 (9.2 mg) gave 15 (6.0 mg, 75% yield)
purified by FCC with 5–7 (v/v)% Et O–CH Cl as the
Ketal-protection of methyl bacteriopheophorbide-d (7) to
1
5
20. Accordingto the reported procedure, reaction of
7 (9.6 mg) with ethylene glycol and TMSCl gave ex-
2
2
2
1
1 18
1 18
1 16
main red brown fraction; 3 ,13 - O-15 : 3 - O/13 - O:
1 16
1
16
1 18
1
1
3
- O/13 - O-8: 3 ,13 - O-5=84:6:9:1; black solid
1
pected 13 -ketal 20 and also undesired trimethyl silyl
ether 22 and its ketal 21. The reaction mixture was pur-
(
from CH Cl and hexane); H NMR and VIS, see data
2
2
2
1
of 5 in ref 17; IR (CH Cl ) 1734 (17 -C¼O), 1697 (13-
ified with an alumina column. 13 -Ketal (un)protected
1
2
18
2
1
6
18
ꢀ1
C¼ O), 1669 (13-C¼ O), 1649 (3-C¼ O), 1616 cm
C¼C); MS (FAB) found: m/z 554, calcd for
chlorin 21 and 22 possessingthe 3 -TMSO group
were eluted with CH Cl as the first and second frac-
(
C H N O O : M , 554.
2
2
1
2
8
+
tions, respectively. As the third fraction, a mixture of 7
and 20 was eluted (CH Cl ) together and desired
20 could not be isolated because of their similar
3
3
34
4
2
2
2
1
1 18
Synthesis of 3 ,13 - O-labelled methyl 3-devinyl-3-hy-
1
7
droxymethyl-pyropheophorbide-a (16). Reduction of
1
polarities.
1 18
1 18
1 16
1
5 gave 16 (90% yield); 3 ,13 - O-16: 3 - O/13 - O:
1 16
1
16
1 18
1
1
1 18
3
VIS, see data of the correspondingunlabelled chlorin in
- O/13 - O-9: 3 ,13 - O¼84:6:9:1; H NMR and
Synthesis of 13 - O-labelled methyl bacteriopheophor-
bide-d (26). 3-(1-Hydroxyethyl)-chlorin 7 (50.6 mg) was
dissolved in pyridine (3 mL). Acetic anhydride (0.2 mL)
was added into the pyridine solution. After stirringfor
24 h at room temperature, the reaction mixture was
poured into water and successively extracted with
1
18
2
ref 17; IR (THF) 3427 (3 - O-H), 1741 (17 -C¼O),
1
6
18
ꢀ1
1
MS (FAB) found: m/z 556, calcd for C H N O O :
701 (13-C¼ O), 1670 (13-C¼ O), 1620 cm (C¼C);
1
33 36 4 2 2
8
+
M , 556.