Total synthesis of 17-nor-deoxophylloerythroetioporphyrin

Article abstract of DOI:10.1246/bcsj.20100033

Synthesis of 17-nor-deoxophylloerythroetioporphyrin, a sedimentary nor-porphyrin, was performed through a bilene-b route in a reasonable total yield. The porphyrin prepared here can potentially be used as a biological marker for chlorophyll c-producing algae.

Full text of DOI:10.1246/bcsj.20100033

Short Articles
Bull. Chem. Soc. Jpn. Vol. 83, No. 7, 819–821 (2010)
819
Total Synthesis of 17-nor-Deoxo-
phylloerythroetioporphyrin
NH
HN
OHC
CO2t-Bu
CO2t-Bu
NH HN
NH HN
2
CO2t-Bu
CO2t-Bu
Cl
Shinya Nomoto,*1 Junya Asano,1 Kenta Asahina,1
Hajime Mita,2 and Yuichiro Kashiyama3
BnO2C
NH HN
1Department of Chemistry, University of Tsukuba,
4
1
Tsukuba 305-8571
3
2Department of Life, Environment and Materials Science,
Fukuoka Institute of Technology, Higashi-ku,
Fukuoka 811-0295
Scheme 1.
3Institute of Biogeosciences, Japan Agency for Marine-Earth
Science and Technology, Natsushima-cho,
Yokosuka 237-0061
R
CO2t-Bu
BnO2C
CO2t-Bu
NH
HN
NH
HN
+
Received February 8, 2010
AcO
E-mail: nomoto@chem.tsukuba.ac.jp
R = CO2Bn (3)
R = CO2H (7)
5
6
Synthesis of 17-nor-deoxophylloerythroetioporphyrin,
a sedimentary nor-porphyrin, was performed through a
bilene-b route in a reasonable total yield. The porphyrin
prepared here can potentially be used as a biological marker
for chlorophyll c-producing algae.
Scheme 2.
studies. We report here the first synthesis of 17-nor-deoxo-
phylloerythroetioporphyrin (17-nor-DPEP, 1).
In the synthetic path shown in Scheme 1, we adopted
a bilene-b route, since syntheses of DPEP porphyrins via
biladienes-a,c have been known to result in significant low-
ering of cyclization yields due to destabilization of linear
tetrapyrroles caused by the fused cyclopentene rings.3 Bilene-b
4 containing t-butyl esters was prepared through the condensa-
tion of dipyrrolylmethane aldehyde 2 with dipyrrolylmethane 3
with mixed ester protective groups. The bilene-b was cyclized
using orthoformate.
Dipyrrolylmethane 23b was prepared from t-butyl 3-ethyl-4-
methylpyrrole-2-carboxylate2g and benzyl 5-acetoxymethyl-4-
ethyl-3-methylpyrrole-2-carboxylate4 in a total yield of 52%.
Scheme 2 shows the synthesis of another dipyrrolylmethane 3,
which was obtained by the coupling of 5-free pyrrole 55 with
acetoxypyrrole 66 in the presence of a catalytic amount of
p-toluenesulfonic acid in 63% yield. Cleavage of the benzyl
ester of 3 by hydrogenolysis gave the corresponding carboxylic
acid 7 in a quantitative yield.
Decarboxylation and condensation of 7 with 2 was accom-
plished simultaneously by the action of 3 equivalents of
p-toluenesulfonic acid, and linear tetrapyrrole hydrochloride
4 was isolated as red crystals in 89% yield. Cleavage of the
t-butyl esters of 4 and decarboxylation of the resultant
tetrapyrrole carboxylic acid was performed using trifluoroacetic
acid, and the resulting defunctionalized tetrapyrrole was
cyclized with triethyl orthoformate. Since it had been reported
that poor results were obtained using DDQ as an oxidant, the
cyclization product was air oxidized in the presence of zinc
acetate for 2 days. After demetalation by trifluoroacetic acid
and purification by chromatography, the desired 17-nor-DPEP
(Figure 2) was obtained as violet crystals in 19% yield.
Sediments and petroleum commonly contain porphyrins,
which are principally derived from chlorophylls and are usually
found as complex mixtures with various substituents on their
pyrrole rings due to chemical modification in sediments.1 In
previous work, several nor-porphyrins, which lack an alkyl side
chain at 3-, 7-, 8-, 13-, or 17-positions, have been isolated from
geological samples and identified (Figure 1).2 The absence of
side chains of nor-porphyrins has been attributed to defunc-
tionalization of a vinyl, an acyl, and a carboxyvinyl group of
chlorophylls at the early stage of the degradation in sediments.
The individual nor-porphyrins therefore, can potentially be
used as biological markers for specific photoautotrophs.2h Since
these compounds may be of diagnostic value, there is a need
for synthetic standards for spectroscopic and chromatographic
R2
R1
5
7
3
R3
8
2
NH
N
N
NH
N
N
20
18
10
12
HN
HN
17
13
132
131
H
R4
3-nor-DPEP: R1=H, R2=Me, R3=R4=Et
7-nor-DPEP: R1=Et, R2=H, R3=R4=Et
8-nor-DPEP: R1=Et, R2=Me, R3=H, R4=Et
A 13-nor-porphyrin
17-nor-DPEP (1): R1=Et, R2=Me, R3=Et, R4=H
Figure 1. Sedimentary nor-porphyrins.
Published on the web June 24, 2010; doi:10.1246/bcsj.20100033

820
Bull. Chem. Soc. Jpn. Vol. 83, No. 7 (2010)
© 2010 The Chemical Society of Japan
CH3CH2-3,8
2H-131
CH3CH2-3,8
CH3-2,7,
of hydrogen for 20 h at room temperature. The catalyst was
filtered off and the solvent was removed under reduced pressure
to afford 7 in a quantitative yield (431 mg). The product turns
dark brown in air.
12,18
CHCl3
H2O TMS
5-(2-t-Butoxycarbonyl-1,4,5,6-tetrahydro-3-methylcyclo-
penta[b]pyrrol-6-yl)-3-methylpyrrole-2-carboxylic Acid (7):
1
White solid; mp 169-170 °C; H NMR (270 MHz, CDCl3): ¤
3H-5,10,20
1.56 (s, 9H), 2.20 (s, 3H), 2.36 (s, 3H), 2.60-2.85 (m, 4H), 4.30
(m, 1H), 5.97 (d, J = 2.8 Hz, 1H), 10.3 (br s, 1H), 11.7 (br s,
1H); 13C NMR (CDCl3): ¤ 12.13, 13.35, 23.21, 28.58, 34.10,
36.65, 81.56, 109.04, 119.12, 122.99, 123.27, 128.63, 129.85,
141.81, 144.18, 164.00, 165.77; HRMS (ESI) m/z Calcd for
C19H25N2O4: 345.1539 [M + H]+, found: 345.1544 [M + H]+;
Anal. Found: C, 65.37; H, 7.22; N, 7.71%. Calcd for
C19H24N2O4: C, 66.26; H, 7.02; N, 8.13%.
H-17
2H-132
2H-NH
10
9
8
7
6
5
4
3
δ
2
1
0
-1 -2 -3
Figure 2. 1H NMR spectrum of synthetic 17-nor-DPEP.
Synthesis of Bilene-b Hydrochloride 4.
A methanol
solution (0.3 mL) of p-toluenesulfonic acid monohydrate
(37.1 mg, 0.195 mmol) was added to a solution of 23
(20.8 mg, 0.0580 mmol) and 7 (20.4 mg, 0.0592 mmol) in
dichloromethane (4 mL), and the reaction mixture was stirred
under a nitrogen atmosphere in the dark for 2 h at room
temperature. The solution was washed with 5% aqueous
sodium hydrogen carbonate and water and dried over magne-
sium sulfate. After evaporation of the solvent the residual oil
was dissolved in dichloromethane (5 mL), and HCl gas was
bubbled into the solution for 10 s. The oily product obtained
after evaporation of the solvent was triturated with ether to give
4 in 89% yield (35.1 mg).
In the present study, we have shown that 17-nor-DPEP, a
sedimentary nor-porphyrin found and identified in geological
samples, can be synthesized through a bilene-b route in a
reasonable total yield. Since it is possible to consider that
chemical transformation in sediments generated 17-nor-DPEP
from chlorophyll c by defunctionalization of the carboxyvinyl
group at the C-17 position,2h the authentic sample prepared
here has the important potential use as a biomarker for
chlorophyll c-producing algae.
Experimental
Synthesis of Dipyrrolylmethane 3.
t-Butyl 6-acetoxy-
1,19-Di-t-butoxycarbonyl-2,7-diethyl-3,8,12,18-tetrameth-
yl-15,17-ethanobilene-b Hydrochloride (4): Red crystals;
mp 170 °C (dec); 1H NMR (270 MHz, CDCl3): ¤ 1.01 (t,
J = 7.6 Hz, 3H), 1.08 (t, J = 7.4 Hz, 3H), 1.55 (s, 9H), 1.56 (s,
9H), 2.05 (s, 3H), 2.26 (s, 6H), 2.32 (s, 3H), 2.43-2.75 (m, 6H),
2.96-3.03 (m, 2H), 4.25 (s, 2H), 4.79-4.83 (m, 1H), 6.14 (s,
1H), 7.10 (s, 1H), 9.66 (br s, 1H), 10.5 (br s, 1H), 13.7 (br s,
1H), 14.0 (br s, 1H); HRMS (ESI) m/z Calcd for C39H53N4O4:
641.3977 [M]+, found: 641.3979 [M]+.
1,4,5,6-tetrahydro-3-methylcyclopenta[b]pyrrole-2-carboxylate6
(2.46 g, 8.81 mmol) and benzyl 3-methylpyrrole-2-carboxylate5
(1.88 g, 8.73 mmol) were dissolved in acetic acid (125 mL) and
stirred in the presence of p-toluenesulfonic acid monohydrate
(185 mg, 0.973 mmol) for 18 h at room temperature. The
reaction mixture was diluted with chloroform (100 mL) and
washed with water (500 mL). The aqueous layer was extracted
with chloroform (200 mL), and the combined organic layer was
washed with 10% aqueous sodium carbonate solution and dried
with magnesium sulfate. The oil obtained after evaporation of
the solvent was chromatographed (eluted with dichloro-
methane) on silica gel to afford 3 after recrystallization from
ethanol in 63% yield (2.39 g). The product turns dark yellow in
air.
Synthesis of 17-nor-DPEP (1). Bilene-b hydrochloride 4
(20.0 mg, 29.5 mmol) was dissolved in trifluoroacetic acid
(2 mL) and the solution was stirred under a nitrogen at-
mosphere in the dark for 10 min at room temperature. After the
solution was diluted with dichloromethane (30 mL), a dichloro-
methane solution (10 mL) of triethyl orthoformate (0.016 mL,
0.096 mmol) was added dropwise over a 30 min period and the
mixture was stirred for 4 h. A saturated methanol solution
(15 mL) of zinc acetate was added to the reaction mixture,
which was stirred for 2 days. The solution was washed with
water and dried with sodium sulfate. A black oil obtained by
removal of the solvent was dissolved in trifluoroacetic acid and
the solution was stirred for 5 min. The mixture was diluted with
dichloromethane (10 mL), washed with 5% aqueous sodium
hydrogen carbonate and water, and dried with magnesium
sulfate. Removal of the solvent afforded an oil, which was
chromatographed on neutral alumina (eluted with dichloro-
methane) to yield 1 in 19% yield (2.50 mg).
t-Butyl
1,4,5,6-tetrahydro-3-methylcyclopenta[b]pyrrole-2-carbox-
ylate (3):
Pale orange solid; mp 178-180 °C; 1H NMR
6-(2-Benzyloxycarbonyl-3-methyl-5-pyrrolyl)-
(270 MHz, CDCl3): ¤ 1.55 (s, 9H), 2.26 (s, 3H), 2.31 (s, 3H),
2.53-2.67 (m, 2H), 2.77-2.88 (m, 2H), 4.21 (m, 1H), 5.29 (s,
2H), 5.84 (d, J = 2.9 Hz, 1H), 7.31-7.42 (m, 5H), 8.46 (br s,
1H), 8.58 (br s, 1H); 13C NMR (CDCl3): ¤ 11.71, 13.12, 23.23,
28.63, 37.67, 38.89, 65.78, 80.41, 110.31, 118.21, 122.47,
124.09, 128.05, 128.09, 128.56, 129.24, 130.50, 132.03,
136.44, 138.48, 138.78, 152.79, 161.31, 161.58; HRMS
(ESI) m/z Calcd for C26H31N2O4: 435.2089 [M + H]+, found:
435.2093 [M + H]+; Anal. Found: C, 71.30; H, 7.13; N,
6.28%. Calcd for C26H30N2O4: C, 71.87; H, 6.96; N, 6.45%.
1
17-nor-DPEP (1): Violet crystals; mp >300 °C; H NMR
Synthesis of Dipyrrolylmethanecarboxylic Acid 7.
solution of dipyrrolylmethane diester 3 (510 mg, 1.17 mmol) in
THF (75 mL) was stirred with 10% Pd-C under an atmosphere
A
(600 MHz, CDCl3): ¤ ¹3.50 (s, 1H), ¹2.70 (s, 1H), 1.84 (t,
J = 7.8 Hz, 3H), 1.87 (t, J = 7.8 Hz, 3H), 3.56 (s, 3H), 3.57 (s,
3H), 3.66 (s, 3H), 3.78 (s, 3H), 3.95-4.06 (m, 4H), 4.11 (q,

S. Nomoto et al.
Bull. Chem. Soc. Jpn. Vol. 83, No. 7 (2010)
821
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9.90 (s, 1H), 9.99 (s, 1H), 10.0 (s, 1H); HRMS (ESI) m/z
Calcd for C30H33N4: 449.2622 [M + H]+, found: 449.2621
[M + H]+.
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