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

Abstract

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...

Selectivity in radical alkylation of substituted pyrroles

“…We found that 6 , which derives from the addition of the radical at C‐3, was the second major product in less than 3% yield, and that 5 , which is formed by the addition of the radical at C‐4, was not detected. ( 1 H NMR spectroscopic data of compound 6 was identical with those reported previously 30.…”

“…Radical‐molecule reactions often occur according to a complex mechanism that involves the initial formation of a prereactive Van der Waals complex that is in thermal equilibrium with the separated reactants 27–29. Consideration of these complexes has been shown to be essential for the calculation of rate constants in hydrogen abstraction reactions 30 where tunneling might be important. However, it is not expected to play any role in the present case, since we are dealing with addition reactions of a large radical.…”

Hydrogenated Pyrrolopyridines. Synthesis and Reactivity

“…Methyl and ethyl esters of the porphobilinogen lactam were obtained by intramolecular reductive cyclization of pyrroles, bearing nitrile or hydroxyiminomethyl groups at C 2 position and alkoxycarbonylmethyl or b-hydroxycarbonylethyl groups at C 3 position (Scheme 13). [26][27][28][29]…”

A Career in Biocatalysis: Kurt Faber

“…In the study of acute porphyria, molecules such as porphobilinogena key intermediate in the biosynthesis of hemewere in demand, but synthetic routes remained challenging. Instead of a ring-closure approach typically used to assemble porphyrins, an alternative route starting from pyrrole was developed, leading to a linear synthesis that could be integrated into the total synthesis of porphobilinogen (see Figure ), eventually obtained in 10 steps, including the recently reported Heck coupling reaction. , Given the light and oxygen sensitivity of many of the intermediates, the overall yield of 11% could be considered a success. , In these works, selective catalytic approaches based on palladium proved to be highly relevant. This work was performed by Kurt during a postdoctoral research stay at the Memorial University of Newfoundland in St Johns, Canada, under the supervision of Hugh J. Anderson.…”