SYNTHESIS 99 



structure for bilirubin. At first a symmetrical arrangement of the 

 side chains was assumed, but later {255Jf) it was discovered that each 

 of the two types of pyrromethenes, a-hydroxy-a'-methylpyrromethene 

 {A) and a-hydroxy-a'-unsubstituted pyrromethene {B), was actually 

 again a mixture of two isomers, all of which were subsequently syn- 

 thesized. The arrangement of the side chains is thus nonsymmetrical 

 and the same as in protoporphyrin IX and hematin (Fig. 5). 



Using the shorter term bilinic acid suggested by Piloty (2153) for the 

 dipyrrylmethane bilirubinic acid, the rather unwieldy names of Fischer 

 "xanthobilirubinic, isoxanthobilirubinic, neoxanthobilirubinic, and isoneo- 

 xanthobilirubinic acids" may be suitably replaced by the more self-descriptive 

 terms "dehydrobilinic, isodehydrobilinic, nordehydrobilinic and isonor- 

 dehydrobilinic acids," respectively, the prefix "nor" being customarily used 

 to describe the lack of a methyl group. The iso compounds have the ethyl, 

 the others the methyl group, in the neighborhood of the hydroxyl. 



1.3. Synthesis 



The nonsymmetrical structure of the naturally occurring bile 

 pigments made their synthesis difficult. It also proved impossible 

 to obtain vinyl-substituted bile pigments in the way this had been 

 achieved in the porphyrin class (by reduction of acetyl side chains 

 to hydroxyethyl and dehydration to vinyl). While the problem of 

 the synthesis of bile pigments from simple pyrrole compounds had 

 been solved in principle by Fischer and co-workers by 1935, biliverdin 

 and bilirubin were first synthesized from hemin by Lemberg (1681, 

 1715). Biliverdin was isolated and shown to be dehydrobilirubin by 

 Lemberg (167^,1676 J680,1691,169£); it is reduced to bilirubin by 

 zinc in ammonia or by enzyme systems (1715). 



Table I summarizes the historical development of the synthesis of 

 bile pigments. Biliverdin and bilirubin were finally synthesized by 

 Fischer and Plieninger (863) in 1942 (Fig. 6). By treatment of 

 opsopyrrolecarboxylic acid with hydrogen perdxide in pyridine, it is 

 transformed into two isomeric a-hydroxy pyrroles (1) which are sep- 

 arated and the constitution of which has been proved independently. 

 Their propionic acid side chains are transformed into the urethan 

 side chains (3) and (4), as described in the figure, and the two hydroxy- 

 pyrroles then condensed separately with a-formylopsopyrrolecarbox- 

 ylic acid obtained from the starting material in the Gattermann- 

 Koch reaction (2). Thus two pyrromethenes are obtained in reac- 

 tions 5 and 7, into one of which a formyl group is introduced (6). 



