H. Tamiaki et al. / Bioorg. Med. Chem. Lett. 26 (2016) 3034–3037
3035
conformation and induce its less
p
-conjugation with the chlorin
The aforementioned procedures of Wittig reaction were useful
system to shift hypsochromically the redmost maximum (= intrin-
sic site energy) of the synthetic models due to a small electronic
effect of the additional methyl group(s).
Methyl pyropheophorbide-d (3a) was prepared by modification
of Chl-a extracted from commercially available Spirulina powder
through oxidation of methyl pyropheophorbide-a (1a) [see step
for preparation of 3-(2-methyl-)1-propenyl-chlorins 1b–d. Ethyli-
3
denation of 3a with MeCH@PPh gave a 1:3 mixture of cis- and
1
7
trans-isomers 1c/b (16% isolated yield). The isomers were easily
separated by a single run of isocratic HPLC (see ESI). Their charac-
terization was performed by various spectroscopies: especially
proton coupling constants of 3-CH@CH were 11 and 16 Hz for
cis-1c and trans-1b, respectively (ESI). The stereoselectivity is
consistent with the reported ratio for benzylidenation of 3a.10
Similarly as in acidic dehydration of methyl bacteriopheophor-
bide-d (4a) possessing a 1-hydroxyethyl group at the 3-position
(
i) of Scheme 1] or alternatively obtained from cultured cells of
Acaryochloris marina producing Chl-d (the 3-formyl-substituted
9
Chl-a). It was previously revealed that semi-synthetic 3-formyl-
chlorin 3a reacted with a variety of (meta-)stable Wittig reagents
to readily give the corresponding olefins.1
0,11
In contrast, treat-
to 1a [step (v) of Scheme 1], 3-(1-hydroxypropyl)chlorin 4b
18
ment of 3a with one equivalent of the unstable Wittig reagent,
prepared by Grignard reaction of 3a with EtMgBr [step (iv)]19
was converted to thermodynamically stable trans-1b exclusively
+
À
methylenetriphenylphosphorane prepared by CH
MeOLi was reported to afford a trace amount of its desired
3 3
PPh I and
but no cis-1c was obtained. Simple isopropylidenation of 3a with
1
0,12
17
1
a
and even using an excess amount CH
2
@PPh
3
(from
2 3
Me C@PPh directly afforded 1d (14%), while isopropylation of
CH
16%).
When CH
3
PPh+
3
3,14
Br and BuLi) led to the production of 1a in a low yield
À
3a with iPrMgCl followed by acidic dehydration of the resulting
secondary alcohol 4d gave 1d in the overall yield of less than a
few% with more troublesome procedures.
19
1
(
The chemical yield was improved as follows.
PPh+
I was mixed with 1.5 equivalents of potassium
À
3
3
tert-butoxide in dichloromethane at room temperature, the reac-
tion mixture was quickly changed from white to brilliant yellow
Since the 3-acetyl group was known to be more reactive than
2
0
the 13-keto-carbonyl group,
the methylenation of 3e was
(
or orange) color to give CH
2
@PPh
3
. Just after its preparation, a
examined using the above Wittig reaction procedures but no
desired product was found in the reaction mixture. 3-Iso-
propenyl-chlorin 1e was prepared by methylenation of 3e with
relatively small amount of 3a was added and stirred for a few
minutes to afford 1a in an isolated yield of 46% by purification of
column chromatography and successive recrystallization [see step
1
6
more reactive Tebbe reagent (15%). As the reference compound,
(
ii) of Scheme 1 and ESI]. From the reaction mixture no compound
3-ethyl-chlorin 2a was synthesized by catalytic hydrogenation of
1a [step (viii) of Scheme 1].
9
bearing 13-C@CH was available, because the 13-keto carbonyl
2
group was less reactive than the 3-formyl group. Such simple
procedures are efficient for the regioselective Wittig reaction of
Methyl pyropheophorbides-a 1a–e and 2a were readily dis-
solved in dichloromethane to give intense visible absorption
bands. The Qy and Soret bands of 1a–d and 2a at longer and shorter
wavelengths, respectively, were sharp (see Fig. 2), indicating
3
a to 1a. Recently we reported similar methylenation of 3a with
a commercially available Tebbe reagent (61% isolated yield) [step
1
6
(
vii) of Scheme 1]. The yield is larger than that by the present
that they were monomeric in the diluted solution (ca. 10 lM).
Wittig reaction, but the Tebbe reaction must be performed
carefully. Since the Tebbe reagent was more reactive than the
Wittig reagent, the former readily reacted with the 13-C@O to give
Isopropenylated chlorin 1e showed also sharp but relatively
broadened bands, whose spectral shape was apparently different
from the others. This is ascribable to a distortion of the chlorin
1
21
the 13 -methylenated analog of 1a after the prolonged reaction.
p-plane by the sterically demanding isopropenyl group.
Scheme 1. Synthesis of methyl (di)methyl-pyropheophorbides-a 1b–e from methyl pyropheophorbide-a (1a) through methyl pyropheophorbide-d (3a), methyl
1
2
+ À
3
mesopyropheophorbide-a (2a) from 1a, and 1a from 3a: (i) OsO
EtMgBr/THF, or iPrMgCl/THF; (v) p-MeC SO O/PhMe (90 °C); (vi) Pr
HÁH
viii) H –Pd/C/THF–Me CO.
4
–NaIO
4
/THF–H
2
O; (ii) R R CHPPh
–MeN(O)(CH CH
I –tBuOK/CH
2
Cl
2
; (iii) HBr/AcOH, H
2
O, CH
2
N
2
/Et
2 2
O; (iv) MeMgI/Et O,
6
H
4
3
2
4
NRuO
4
2
2
2
) O/CH Cl ; (vii) Cp
2
2
2
Ti(–Cl–)(–CH –)AlMe
2
2
–C H
5 5
N/PhMe–THF (À20 °C);
(
2
2
Tamiaki, Hitoshi
