Synthesis of a linear α-hydroxymethyl-pentapyrrole derivative and its cyclization to uroporphyrinogens

Article abstract of DOI:10.1016/S0040-4039(00)00293-8

A linear pentapyrrole bearing α-hydroxymeythyl group in the terminal was synthesized by the stepwise coupling of α-free pyrrole with azafulvenium ion 6. When it was treated with a catalytic amount of p-toluensulfonic acid under anaerobic condition, followed by aerial oxidation of the products, a statistical mixture of uroporphyrin I-IV octamethyl esters was obtained. It is proposed that this transformation proceeds through a spiro-pyrrolenine as a key intermediate. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00293-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2915–2918
Synthesis of a linear α-hydroxymethyl-pentapyrrole derivative
and its cyclization to uroporphyrinogens
Kunisuke Okada,∗ Hiroyuki Takakura, Keishi Nomura and Kiyoshi Saburi
Faculty of Pharmacy, Meijo University, Tenpaku, Nagoya 468-8503, Japan
Received 22 December 1999; revised 2 February 2000; accepted 10 February 2000
Abstract
A linear pentapyrrole bearing α-hydroxymeythyl group in the terminal was synthesized by the stepwise coupling
of α-free pyrrole with azafulvenium ion 6. When it was treated with a catalytic amount of p-toluensulfonic acid
under anaerobic condition, followed by aerial oxidation of the products, a statistical mixture of uroporphyrin I–IV
octamethyl esters was obtained. It is proposed that this transformation proceeds through a spiro-pyrrolenine as a
key intermediate. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: coupling reaction; linear pentapyrrole derivatives; rearrangement; spiro-pyrrolenine intermediate.
Hydroxymethylbilane (1; HMB), constructed by assembling four molecules of porphobilinogen (PBG)
with loss of four molecules of ammonia in the presence of deaminase, acts as the substrate for a second
enzyme (cosynthetase) which cyclizes the bilane with concomitant intramolecular rearrangement of the
terminal ring-D to generate uroporphyrinogen III (3; uro’gen III).1,2 The spiro-pyrrolenine 2 is a most
favorite intermediate, since the corresponding ring-D lactam 4 has been shown to function as an inhibitor
of cosynthetase.3–6
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00293-8
tetl 16573

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Based on biosynthetic mechanism of uroporhyrinogen III, we undertook the synthesis of linear
pentapyrrole derivative bearing terminal azafulvenium chromophore 21, which would be a model for the
natural intermediate in rearrangement. The synthetic strategy of precursor 17 was based on our previous
work of pyrromethane synthesis under neutral conditions: treatment of 2-mercaptobenzothiazolylmethyl-
pyrrole 5 in dry benzene with silver (I) trifrate generates the azafulvenium ion 6,7 which condenses
with α-free pyrrole 7 to give pyrromethane 8 in excellent yield. Pyrromethane 8 was converted to α-
free tripyrrole 10 by deprotection of trichloroethyl ester 8 and decarboxylation of 9. Coupling of 10
Scheme 1. Reagents and conditions: (a) AgOTf–Na2HPO4/benzene, 10 min, 97.3%; (b) Zn/80% AcOH–THF, 3 h, 97.3%; (c)
AcOH/135°C, Ar, 10 min, 83.3% (90.5%); (d) in CH3CN, 1 h, 71.9% (97.2%); (e) Zn/80% AcOH–THF, 3 h, 84.8% (98.0%);
(f) AcOH/135°C, Ar, 2 min, 52.0% (95.0%); (g) in CH3CN, 1 h, 53.3% (91.4%); (h) Zn/80% AcOH–THF, 3 h, 76.5% (90.9%);
(i) AcOH/135°C, Ar, 1 min, 21.5% (82.0%); (j) in CH3CN, 1 h, 52.9% (63.6%); (k) 0.1 N KOH–MeOH/CH2Cl2-MeOH (1:1),
15 min, 63.4% (70.3%); (l) 2-mercaptothiazole/DCC–DMAP/CH2Cl2, 4 h, 65.5% (85.6%); (m) NaBH4/CH2Cl2-MeOH (2:1),
10 min, SiO2 short column/CH2Cl2-MeOH (100:3)

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Fig. 1. The Me ester regions of acetic acid (AMe) and propionic acid (PMe) side chain of the 400 MHz NMR spectra (CDCl3),
involved in the isomers of uroporphyrin octamethyl ester, are described. [A] is the spectrum of a mixture of uroporphyrin
octamethyl esters obtained from 20 and [B] is the spectrum of a statistical mixture of uroporphyrin octamethyl esters of type I,
II, III and IV (1:1:4:2): marked a=III (1.5H); b=I (1.5H)+IV (1.5H); c=III (1.5H); d=IV (1.5H); e=III (3H); f=II (1.5H)
with azafluvenium ion 6 in dry acetonitrile proceeded smoothly at room temperature to give 11 in
high yield. Similar deprotection of ester 11 and decarboxylation of 12 followed by coupling reaction
of 13 with 6 produced tetrapyrrole 14 as shown in Scheme 1.8 In the same way, 14 was transformed to
the desired linear pentapyrrole 17 through carboxylic acid 15 and α-free pyrrole derivative 16 even in
low yield. Finally, conversion of methylsulfonylethyl ester moiety of 17 to hydroxymethyl function was
performed by alkaline hydrolysis of 17 to give 18, which was followed by formation of amide with 2-
mercaptothiazoline and selective reduction with sodium borohydride in dichloromethane–methanol (2:1),
giving rise to unstable α-hydroxymethylpentapyrrole derivative 20.9
To a solution of 20 (6.2 mg) in dichloromethane (3 ml) was added a cataytic amount of p-
toluenesulfonic acid (0.1 mg) and the mixture was stirred at room temperature under argon atmosphere
for 20 h. A large amount of powdered sodium acetate was added to the mixture which was further stirred
for 1 h under oxygen atmosphere for oxidation of the products. The major product (2.2 mg), separated
from the mixture on silica gel TLC (CH2Cl2:MeOH 100:3), was characterized as a statistical mixture of
four isomers of urophorphyrin octamethyl esters (I:II:III:IV=1:1:4:2). 1H NMR spectrum of the product
between 3.67–3.85 ppm was absolutely identical with that of an authentic sample as shown in Fig. 1.
We propose that α-hydroxymethyl-pentapyrrole derivative 20 is dehydrated under acidic conditions to
Scheme 2.

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generate the pentapyrrole 21 bearing azafulvenium chromophore in the terminal position of the molecule.
As illustrated in Scheme 2, compound 21 will then cyclize in two ways, to afford 22 and 23, the precursor
of uro’gen I and uro’gen III octamethyl ester, respectively, during formation of the mixture of uro’gen
IIV octamethyl esters as discussed in the previous paper.10 It is obvious that one of a possible route in
the transformation from 20 to uro’gen III octamethyl ester involves azafulvene 21 and spiro-pyrrolenine
intermediate 23. This process is a model for the biosynthetic pathway from HMB 1 to uro’gen III 3.
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8. Typical procedure for deprotection of ester (b), decarboxylation (c) and coupling reaction (d) are as follows: (b) to a solution
of 8 (150 mg, 0.19 mmol) in THF-80% AcOH (5:1, 3.6 ml) was added Zn powder (750 mg) and the mixture was stirred
vigorously for 3 h at rt. After filtration followed by concentration of the reaction mixture, the resulting residue was purified
by flash column chromatography on silica gel (CH2Cl2:MeOH=100:2) to give 9 (121.5 mg, 97.3%); (c) a solution of 9 (325.0
mg, 0.495 mmol) in AcOH (32.5 ml) was heated at 135°C for 10 min under argon in the dark. After cooling, the reaction
mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel
(CH2CCl2:MeOH=100:1) to give10 (252.3 mg, 83.3%, corrected yield 90.5%) along with starting material 9 (26.2 mg); (d)
to a solution of 10 (112 mg, 0.183 mmol) and 5 (211.6 mg, 0.366 mmol) in CH3CN (5 ml) were added AgOTf (141 mg,
0.549 mmol) and Na2HPO4 (233.9 mg, 1.65 mmol) under Ar and the mixture was stirred at rt for 1 h. After dilution with
CH2CCl2 (50 ml), the mixture was washed with saturated aq. soln of NaHCO3, brine and concentrated. The residue was
purified by flash column chromatography on silica gel (CH2CCl2:MeOH=200:1) to give 11 (134.6 mg, 71.9%; corrected
yield 97.2%) along with 10 (29.12 mg).
9. After passing the reaction mixture through a short silica gel column (H:10 mm, φ:10 mm) which was washed with degassed
CH2Cl2:MeOH (2:1, 5 ml) under Ar, the combined eluates were concentrated under reduced pressure. The residue was used
directly for the next reactions.
10. Takakura, H.; Nomura, K.; Tanino, H.; Okada, K. Tetrahedron Lett. 1999, 40, 2989–2992.