Studies on the tetramerization of substituted monopyrroles to type I porphyrins

Article abstract of DOI:10.1016/S0040-4039(02)01592-7

Investigation of the tetramerization of pyrroles bearing two different electron-donating groups as substituents led to the rapid preparation under slightly acidic conditions of a porphyrin analog family with a high ratio of type I isomer for enzymatic act

Full text of DOI:10.1016/S0040-4039(02)01592-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6967–6969
Studies on the tetramerization of substituted monopyrroles to
type I porphyrins
C. Pichon-Santander and A. I. Scott*
Center for Biological NMR, Department of Chemistry, Texas A&M University, PO Box 30012, College Station,
TX 77842-3012, USA
Received 27 June 2002; accepted 31 July 2002
Abstract—Investigation of the tetramerization of pyrroles bearing two different electron-donating groups as substituents led to the
rapid preparation under slightly acidic conditions of a porphyrin analog family with a high ratio of type I isomer for enzymatic
activity studies. © 2002 Elsevier Science Ltd. All rights reserved.
Our laboratory has been involved for many years in the
studies of different aspects of vitamin B12 biosynthesis.
In order to explore the scope of activity of the first
methyl transferases in the enzymatic pathways leading
to B , we envisioned using analogs of uroporphyrino-
side-chains (Scheme 2, 3–7). Since porphyrinogens oxi-
dize easily, it is best to prepare and isolate their oxi-
dized and more stable form, porphyrins.
Numerous works on the synthesis of type I porphyrins
1
2
2
gen I (Uro’gen I, 1, Scheme 1), which differs from the
natural substrate Uro’gen III (2) by inversion of the
acetate and propionate substitution on the ring D and
have been reported, however, most concern the prepa-
ration of etioporphyrin I (8) and coproporphyrin I (9).
Various strategies have been used, ranging from
monopyrrole tetramerization to routes involving
dipyrrolic, tripyrrolic or open-chain tetrapyrrolic inter-
mediates. Since the last methods require numerous
steps and we planned to prepare several uroporphyrin
1
was demonstrated to be a substrate. We thought to
begin our study with Uro’gen I analogs bearing sub-
stituents with one carbon longer or shorter carboxylate
(
Uro) I analogs, we decided to investigate the first one,
P
A
P
P
which involves polymerization of four pyrroles with
concomitant cyclization to porphyrinogen followed by
oxidation to porphyrin (Scheme 2). This has been
A
P
P
A
A
A
A
A
NH HN
NH HN
NH HN
NH HN
R3
R2
R3
R2
A
P
P
P
P
R2
R3
R2
R2
R3
R2
R2 R3
Uro'gen I (1)
Uro'gen II
NHHN
NHHN
NH
N
N
[
Ox]
4
x
P
A
P
R1
N
H
R4
HN
R3
R3
A
A
P
A
A
P
A
P
NH HN
NH HN
NH HN
NH HN
R2
R3
R2
R3
Porphyrinogen I
Porphyrin I
1
1
0 R1=CH2NEt2, R4=CO2H
1 R1=CH2OH, R4=H
1 R2=CH2CO2Me, R3=CH2CH2CO2Me
3 R2=CH2CO2Me, R3=(CH2)3CO2Me
R2=CH2CH2CO2Me, R3=(CH2)3CO2Me
P
P
A
A
4
Uro'gen III (2)
Uro'gen IV
5 R =CO Me, R =CH CO Me
2
2
3
2
2
6
7
8
9
1
R2=R3=CH2CO2Me
R2=R3=CH2CH2CO2Me
R2=Et, R3=Me
R2=CH2CH2CO2Me, R3=Me
2 R2=H, R3=Me
A = CH2CO2H P = CH2CH2CO2H
Scheme 1. The four isomers of uroporphyrinogen.
Keywords: pyrroles; porphyrins; tetramerization; substituent effects.
Scheme 2. Synthesis of porphyrins I by tetramerization of
*
Corresponding author. Tel.: +1-979-845-3243; fax: +1-979-845-5992;
e-mail: scott@mail.chem.tamu.edu
monopyrroles.
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01592-7

6
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C. Pichon-Santander, A. I. Scott / Tetrahedron Letters 43 (2002) 6967–6969
shown to be the method of choice for completely
symmetrical porphyrins such as 6 and 7. However,
when the two b-substituents are not identical, a mixture
of the four possible isomers (Scheme 1) is obtained, due
to acid lability of pyrrole units at the a-position allow-
onate, methyl and ethyl, methyl side-chains, respec-
tively, in MeOH at reflux with oxidation by addition of
4b
potassium ferricyanide after 30 min. When these same
conditions were used starting with pyrroles 10 bearing
two electron-donating groups (EDG) as substituents
2a,3
ing cleavage followed by recombination reactions.
[
R =CH CO Me,
R =(CH ) CO Me
or
or
R =
R =
2
2
2
2
3
2 2
2
2
Only in very special cases, for example in the presence
of one very bulky or very strong electron-withdrawing
CH CO Me,
R =(CH ) CO Me
2
2
3
2 3
2
(
CH ) CO Me, R =(CH ) CO Me], very low yields of
2 2 2 3 2 3 2
2b
group, pure type I isomers have been obtained. How-
ever, in the model studies of syntheses of etioporphyrins
porphyrins (less than 5%) were obtained. This result
was not totally surprising as electronic effects of the
(
8) and coproporphyrins (9), type I ratio over 90% have
3b,6
substituents on pyrrolic reactivity are well known.
4
been reached. We thought this would constitute good
enough ratios for our preliminary enzymatic studies.
Higher temperatures did improve the yields by twofold,
but the relative percentage of type I isomer decreased.
The monopyrroles (10 and 11, Scheme 2) necessary for
the syntheses of the porphyrins 1, 3 to 9 and 12 were
prepared following standard published procedures.
Determinations of the type I percentages were based on
Reviewing some of the other works reported, it appears
that isomerization occurs both under basic or acidic
7
conditions and the highest ratios of type I obtained for
4
a,b
1
etioporphyrin are at neutral or nearly neutral pH.
H NMR or HPLC analyses, depending on the prod-
†
Therefore, we chose to study the polymerization–
cyclization of pyrroles 11 in chloroform, where the
ucts. The first step, porphyrinogen formation, was
accomplished in absence of oxygen to avoid oxidation
1
13
5
course of the reaction can be followed by H and
C
of intermediates, which would decrease the yields,
NMR by monitoring the disappearance of the methyl-
hydroxy (ꢀ4.4 and 56 ppm) and a-free proton (ꢀ6.4
ppm) signals at room temperature. These results are
presented in Table 1 (under the entry ‘conditions A’).
In general the reactions were rather slow, yields were
moderate and the ratios of type I isomer varied from
followed by oxidation in methanol under an oxygen
atmosphere.
Smith et al. reported a yield of 25% pure copropor-
phyrin I (9) and 36% etioporphyrin I (8) containing 8%
isomer contamination from pyrroles 10 bearing propi-
Table 1. Formation of porphyrins
Conditionsa
A
B
C
Db
Porphyrin Time
%
% type I
Time
%
% type I
Time
%
% type I
Time
%
% type I
(days)
(days)
(days)
(hours)
1
3
4
5
6
7
8
9
2
10
10
3
4
1
10 57
17 65
21 73
1
1
2
11 60
27 62
34 67
–
–
–
35 39
36 42
–
3
2
2
37 52
31 44
57 59
–
3
3
3
24
24
24
3
39 75
60 72
47 80
0
0
–
–
NA
0
–
2
0
NA
100
NA
–
65 NA
42 36
50 44
14 38
2
1
3
14 58
52 58
1
1
2
2
2
61 37
43 31
3
3
1
6
51
4
32
a
The pyrroles 11 were formed by NaBH4 reduction of the parent a-formylpyrroles (ꢀ0.2–0.4 mmol) in MeOH and used directly after work-up
for the next step. In conditions A, the products were redissolved in CDCl3 (500 mL) and the NMR tubes sealed under N . At the end of the
2
reaction, the solvent was evaporated, the residue was resuspended in MeOH and stirred overnight under O . The products were isolated by
2
1
13
preparative TLC eluted with CH Cl +1–3% MeOH. The porphyrins were characterized by H and C NMR spectroscopy and mass
2
2
c
spectrometry. Conditions B: the reactions were run in CHCl (1 mL) at reflux. Conditions C: the reactions were run in CH Cl (2 mL) over
3
2
2
Montmorillonite clay (500 mg). Conditions D: the a-hydroxymethylpyrroles 11 were dissolved in CDCl3 (400 mL) or CH Cl (800 mL) and a
2
2
diluted solution of TFA in the same solvent (100–200 mL) was added. At the end of the reaction, the solution was washed with 10% aqueous
NaHCO , the solvent evaporated to dryness and the residue oxidized as described before.
A+x%TFA; x=0.01 for 1 to 5, 8, 9, 12; x=1 for 6 and 7.
All porphyrins prepared, but porphyrins 3 and 4, are known compounds. Characterization data for 3 (major isomer): H NMR l 10.19 (s, 4H,
3
b
c
1
4
meso H), 5.08 (s, 8H, 4 CH CO Me), 4.12 (t, 8H, J=7.7 Hz, 4 CH CH CH CO Me), 3.75 (s, 24H, 8 CO CH ), 2.75 (t, 8H, J=6.7 Hz, 4
2 2 2 2 2 2 2 3
1
3
CH CH CH CO Me), 2.65 (m, 8H, 4 CH CH CH CO Me); C NMR l 174.19, 172.03, 141.95, 132.31, 98.03, 52.40, 51.63, 33.74, 32.56, 28.14,
2
2
2
2
2
2
2
2
+
1
2
4
2
5
5.76; MS (ESI) 999 (M+H) , 100%. Characterization data for 4 (major isomer): H NMR l 10.26 (s, 4H, 4 meso H), 4.47 (t, 8H, J=7.9 Hz,
CH CH CO Me); 4.14 (t, 8H, J=7.8 Hz, 4 CH CH CH CO Me), 3.76, 3.69 (2 s, 24H, 8 CO CH ), 3.34 (t, 8H, J=7.9 Hz, 4 CH CH CO Me);
2
2
2
2
2
2
2
2
3
2
2
2
1
3
.78 (t, 8H, J=6.8 Hz, 4 CH CH CH CO Me), 2.64 (m, 8H, 4 CH CH CH CO Me); C NMR l 174.06, 173.60, 140.40, 138.83, 97.31, 51.72,
2
2
2
2
2
2
2
2
+
1.64, 37.69, 33.84, 28.67, 25.73, 21.66; MS (ESI) 1055 (M+H) , 100%.
†
1
Integration of the meso-protons in the H NMR spectra (500 MHz) provides a good estimate of the type I ratio. This was confirmed in the case
of Uro I samples by HPLC analysis (silica gel column, CH Cl /MeOH, 96/4).
2
2

C. Pichon-Santander, A. I. Scott / Tetrahedron Letters 43 (2002) 6967–6969
6969
moderate to good. Heating does speed up the reactions
and gives a slight increase in yields (Table 1, conditions
B), but no better type I ratios. Another problem
appears to be the lack of reproducibility of the results
with important variations in reaction times, yields and
type I ratios, most probably brought about by the
presence of traces of acid in the solvent and/or glass-
ware. Hence, we decided to study the effect of an acid
catalyst on the reaction.
scale synthesis of porphyrins with a high ratio of type I
isomer. This method represents the best and most rapid
approach to prepare a porphyrin analog family for
enzymatic activity studies.
Acknowledgements
We thank the NIH (NIDDK) for financial support and
Dr. Patricio J. Santander for providing some of the
monopyrrole precursors.
Addition of Montmorillonite clay (Table 1, conditions
C) afforded better yields in a more reasonable time, but
the type I ratios remained poor. The second acid cata-
lyst studied was trifluoroacetic acid (TFA), which offers
the possibility of monitoring the course of the reaction
by NMR without additional work-up. Thus, it was
determined that the best yields and type I ratios of
porphyrin 4 were consistently obtained in the presence
of 0.01% TFA. The monopyrrole 11 was completely
consumed in 1 h, but the amount of porphyrin 4 was
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5
0% higher if the work-up and oxidation were carried
out after 3 h, allowing enough time for the polymeriza-
tion–cyclization to porphyrinogen to reach completion
before oxidation.
The conditions just described were then applied to
produce our desired porphyrins (1, 3–7) and the model
porphyrins (8, 9, 12) (Table 1, conditions D). The
porphyrins I bearing two different EDG substituents (1,
3
and 4) were obtained in good yields with 20–28%
isomer contamination. If one of the substituents was an
electron-withdrawing group (5), no porphyrin was ever
isolated under the tested conditions. Completely sym-
metrical porphyrins (6 and 7) were easily obtained in
excellent yields at a concentration of TFA raised to 1%,
no isomerization being possible as fragmentation/
recombination of pyrroles units led to the same prod-
ucts. Model porphyrins (8, 9, 12) showed more
susceptibility to isomerization and contamination with
other isomers was greater than 50%.
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