Pyrrole chemistry. XXVI. A synthesis of porphobilinogen from pyrrole

Demopoulos, Vassilis J.; Anderson, Hugh J.; Loader, C. E.; Faber, Kurt

doi:10.1139/v83-417

Cited by 39 publications

(23 citation statements)

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“…We have recently reported a total synthesis of porphobilinogen (I), the precursor of naturally occurring porphyrins and corrins, in nine steps from pyrrole with an overall yield of about 6% (1). In that synthesis, reduction of the cyanide group led to the partial reduction of the pyrrole ring and was a major factor in reducing the yield.…”

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confidence: 99%

“…A general outline of this approach is given in Scheme 1, and follows the philosophy outlined in the earlier paper (1). The aldoxime rather than the cyanide group was used as a precursor to the aminomethyl side chain and the lactam ethyl ester of porphobilinogen (2) was the desired final intermediate.…”

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confidence: 99%

“…For comparison, the Vilsmeier-Haack formylation of 3-methylpyrrole gave a 4 : 1 ratio of 2-and 5-substitution (8,9). The combination of the steric and electronic effects of the acetic ester group results in the less favorable ratio, as in the cyanation of the 3-acetic ester (1). Mild hydrolysis of the iminium salt did not hydrolyze the ester group and conversion to the aldehyde product was excellent.…”

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confidence: 99%

“…The acidic proton on the pyrrole nitrogen was expected to interfere with the Heck reaction (1,11,12) and was replaced by a benzoyl group by the phase-transfer benzoylation of 6 , giving 9. When compound 9 was condensed with ethyl acrylate an excellent yield of a mixture of products with (lo), and without ( l l ) , the N-benzoyl group was obtained.…”

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Pyrrole chemistry. XXVII. 2,3,4-Trisubstituted pyrroles and a second synthesis of porphobilinogen from pyrrole

Faber¹,

Anderson²,

Loader³

et al. 1984

Can. J. Chem.

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Changes in some of the key intermediates and procedures used in our earlier total synthesis of porphobilinogen from pyrrole that improve the yield to 11% are reported. Ethyl pyrrole-3-acetate was formylated by the Vilsmeier-Haack method and then iodinated. The desired 2,3,4-substituted pyrrole isomer was isolated in moderate yield and, after conversion of iodide to acrylate and aldehyde to aldoxime, reduction and work-up afforded porphobilinogen lactam ethyl ester. Hydrolysis of the latter gave porphobilinogen in ten steps from pyrrole.KURT FABER, HUGH J. ANDERSON, CHARLES E. LOADER et ANNETTE S. DALEY. Can. J. Chem. 62, 1046(1984.Grlce a des changements dans quelques intermtdiaires cles et dans quelques-unes des proctdures utilisees dans notre synthkse totale anterieure du porphobilinogkne 2 partir du pyrrole, il est possible d'amdiorer le rendement a I 1%. On a formylC le pyrroleacttate-3 d'Cthyle par la mtthode de Vilsmeier-Haack et on I'a alors iodt. L'isomkre dtsire du pyrrole substituC en 2,3,4 est isolt avec un rendement modtre; aprks conversion de I'iodure en acrylate, et de I'aldthyde en aldoxime, une reduction et une extraction permettent d'isoler I'ester Cthylique de la lactame du porphobilinogkne. L'hydrolyse de ce dernier conduit au porphobilinogine en dix ttapes 2 partir du pyrrole.[Traduit par le journal]We have recently reported a total synthesis of porphobilinogen (I), the precursor of naturally occurring porphyrins and corrins, in nine steps from pyrrole with an overall yield of about 6% (1). In that synthesis, reduction of the cyanide group led to the partial reduction of the pyrrole ring and was a major factor in reducing the yield. Attempts to develop a better procedure for this reduction, using as a model the readily available 4-carbethoxyvinylpyrrole-2-carbonitrile (see the experimental section), failed. The model appeared more susceptible to ring reduction than the porphobilinogen precursor itself under most conditions. A variation on the earlier synthesis provides both a marked increase in the overall yield of porphobilinogen and also further demonstrates the versatility ofthis approach to the synthesis of 2,3,4-trisubstituted pyrroles, a type sometimes used as porphyrin building blocks (2). The steps by which a labelled carbon or nitrogen atom could be introduced into the eventual -aminomethyl side chain are also simplified.A general outline of this approach is given in Scheme 1, and follows the philosophy outlined in the earlier paper (1). The aldoxime rather than the cyanide group was used as a precursor to the aminomethyl side chain and the lactam ethyl ester of porphobilinogen (2) was the desired final intermediate.:This synthetic approach began, as did the earlier one, with the preparation of ethyl pyrrole-3-acetate (3) in three steps from pyrrole (1). Attempts to improve this synthesis by using the Wilgerodt-Kindler rearrangement of the readily available (3, 4) 3-acetyl-1-phenylsulfonylpyrrole failed. Although the rearrangement was successful, the yield of the corresponding morpho...

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Pyrrole chemistry. XXVII. 2,3,4-Trisubstituted pyrroles and a second synthesis of porphobilinogen from pyrrole

Faber¹,

Anderson²,

Loader³

et al. 1984

Can. J. Chem.

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“…It was recrystallized from hexane-AcOEt to give colorless needles, mp 66-68°C, (lit. 27) mp 64-65°C Methyl 4-Cyanomethylpyrrole-2-carboxylate (30) DBU (0.21 ml, 1.4 mmol) was added to a solution of 26a (65 mg, 0.20 mmol) in toluene (1 ml) and the mixture was stirred at room temperature for 1 h. It was concentrated under reduced pressure and the residual brown oil was subjected to column chromatography on silica gel [hexane-Et 2 O (4 : 1)] to give 30 (33 mg, 99%) as a white solid. It was recrystallized from hexane-AcOEt to give colorless prisms, mp 92-93°C.…”

Section: Tert-butyl (2s4r)-4-hydroxy-4-methyl-1-p-toluenesulfonylpyrmentioning

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Conversion of 4-Oxoproline Esters to 4-Substituted Pyrrole-2-carboxylic Acid Esters

Yagi

Arakawa

Tanaka

et al. 2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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167During our study of the synthesis of several compounds using 4-hydroxyproline (1) as a starting material, 1) when a ptoluenesulfonyl (Ts, tosyl) group was introduced to the nitrogen atom of 1 by the Schotten-Baumann method employing TsCl and aqueous NaOH according to Portoghese's method 2) in order to obtain compound 2, thereby prolonging the reaction, we encountered a side reaction that caused the elimination of sulfinic acid and aromatization, giving pyrrole-2-carboxylic acid (3) (Chart 1). We therefore considered that the aromatization could be utilized for the synthesis of pyrrole-2-carboxylic acid derivatives such as methyl 4-methylpyrrole-2-carboxylate (4), which is a trail pheromone of Atta texana. [3][4][5][6] Although aromatizations of the N-tosylproline derivatives giving pyrrole-2-carboxylic acid derivatives, [7][8][9] as well as other syntheses of the pyrrole-2-carboxylic acid derivatives, [10][11][12] have been reported by many workers, synthesis of the pyrrole-2-carboxylic acid derivatives using 4-oxoproline derivatives has not been reported. Therefore, we performed alkylation and alkylidenaion of N-tosyl-4-oxoproline ester, followed by aromatization of the products to give 4-substituted proline-2-carboxylic acid esters 7 (Chart 2). This method made it possible to introduce not only a simple alkyl group but also an alkyl possessing a functional group into 4-position of the pyrrole-2-carboxylic acid derivatives.Thus we report here the conversion of 4-oxoproline esters 5 and 6 to the 4-substituted proline-2-carboxylic acid esters 7.Base Treatments of N-Tosyl-4-oxoproline Esters We chose the methyl and/or tert-butyl esters of N-tosyl-4-oxoproline 5 13) and 6 14) as substrates for the ketone reactions, and synthesized them from 1 according to the previously reported methods.2) Next, we attempted the base treatments of 5 and 6 using appropriate bases to cause enolization and aromatization. As a result, 4-hydroxypyrrole-2-carboxylic acid esters 8 and 9 were successfully obtained in 76% and 60% yields, respectively. Only the benzyl ester of 4-hydroxypyrrole-2-carboxylic acid 15) has been reported previously; 8 and 9 are new compounds (Chart 3). The Grignard Reactions of N-Tosyl-4-oxoproline Ester and Conversion into the Pyrrole DerivativesGrignard reactions were attempted with the tert-butyl ester of N-tosyl-4-oxoproline 6, in order to prevent the reaction at the ester moiety. When the Grignard reagent was employed without addition of other reagent, the by-products were remarkably formed and yields of the desired products were much lower (mixture of epimers Ͻ70%). In order to prevent the aldol reaction and the aromatization of 6, which seemed to be the side reactions, additions of CeCl 3 16,17) into the reaction systems were examined. Consequently, the numbers of the com- Conversion of 4-Oxoproline Esters to 4-Substituted Pyrrole-2-carboxylic Acid EstersYasushi ARAKAWA,* Naomi YAGI, Yukimi ARAKAWA, Ken-ichi TANAKA, and Shigeyuki YOSHIFUJI Faculty of Pharmaceutical Sciences, Hokuriku University; Kanagaw...

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Inhibition Studies of Porphobilinogen Synthase fromEscherichia coli Differentiating between the Two Recognition Sites

et al. 2001

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Porphobilinogen synthase condenses two molecules of 5-aminolevulinate in an asymmetric way. This unusual transformation requires a selective recognition and differentiation between the substrates ending up in the A site or in the P site of porphobilinogen synthase. Studies of inhibitors based on the key intermediate first postulated by Jordan allowed differentiation of the two recognition sites. The P site, whose structure is known from X-ray crystallographic studies, tolerates ester functions well. The A site interacts very strongly with nitro groups, but is not very tolerant to ester functions. This differentiation is a central factor in the asymmetric handling of the two identical substrates. Finally, it could be shown that the keto group of the substrate bound at the A site is not only essential for the recognition, but that an increase in electrophilicity of the carbon atom also increases the inhibition potency considerably. This has important consequences for the recognition process at the A site, whose exact structure is not yet known.

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Pyrrole chemistry. XXVI. A synthesis of porphobilinogen from pyrrole

Cited by 39 publications

References 13 publications

Pyrrole chemistry. XXVII. 2,3,4-Trisubstituted pyrroles and a second synthesis of porphobilinogen from pyrrole

Pyrrole chemistry. XXVII. 2,3,4-Trisubstituted pyrroles and a second synthesis of porphobilinogen from pyrrole

Conversion of 4-Oxoproline Esters to 4-Substituted Pyrrole-2-carboxylic Acid Esters

Inhibition Studies of Porphobilinogen Synthase fromEscherichia coli Differentiating between the Two Recognition Sites

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