Homorubins and homoverdins

Abstract

The syntheses are described for centrally expanded bilirubin analogs: b-homorubins with propionic and butyric acid groups in the positions corresponding to the propionic acids of bilirubin. Their syntheses were accomplished by coupling two equivalents of a reactive monopyrrole (5-(bromomethylene)pyrrolin-2-one) to a dipyrrylethane. The corresponding b-homoverdins and dehydro-b-homoverdins were prepared by dehydrogenating the rubins or their dimethyl esters using DDQ. As supported by NMR measurements and molecular mechanics calculations, the homorubins are found to engage in conformation-determining intramolecular hydrogen bonding between the dipyrrinone and carboxylic acid moieties. Likewise, the homoverdins are believed to favor intramolecularly hydrogen-bonded conformations.

(m.n)-Homorubins: syntheses and structures

“…Here and in the (2.2)- and (2.3)-homorubin, the required center dipyrrole sections differed only by the length of the carboxylic acid chain: acetic vs. the propionic and butyric of earlier work [13, 14]. Thus, as shown in Scheme 4, the α-CH 3 of the known mono-pyrrole diester 11-1 [23] was converted to the α-CHO of 22 in 66% yield by oxidation using ceric ammonium nitrate [31, 32], and 22 was coupled to afford dipyrrylethene 21 in 46% yield by the McMurry coupling procedure [13, 14, 34] using Ti°. The central C=C of 21 in ethyl acetate was smoothly hydrogenated (H 2 /Pd(C)) to give a 99% yield of dipyrrylethane tetra-ester 20e , which was saponified in ethanolic NaOH to its tetra-acid 20 in 99% yield.…”

“…This approach worked successfully in the synthesis of the first homorubin, where m = 2, with propionic acid chains at the usual locations, C(8) and C(12) [13] – and recently for the (2.3)-homorubin with butyric acid chains [14]. …”

“…Reverting to the “1 + 2 + 1” approach to linear tetrapyrrole synthesis, we employed a route similar to that used for preparing (2.2)-homorubin [13, 14] and (2.3)-homorubin [14]. Here and in the (2.2)- and (2.3)-homorubin, the required center dipyrrole sections differed only by the length of the carboxylic acid chain: acetic vs. the propionic and butyric of earlier work [13, 14].…”

“…The work indicated the presence of bilirubin-like intramolecular hydrogen bonding and a hepatobiliary metabolism similar to that of bilirubin and mesobilirubin-XIIIα. More recently we reported on a (2.3)-homorubin, with butyric acids replacing propionic, and this too, proved to be intramolecularly hydrogen bonded, although its shape was modified to accommodate the longer butyric acid [14]. …”

“…Unfortunately, we were unable to prepare the (3.1) and (3.3)-homorubins and thus report only the (3.2) of the m = 3 set. The (2.2) and (2.3)-homorubins are known [13, 14]; the (1.2) is mesobilirubin-XIIIα, also known [15]. …”