SYNTHESIS OF THE PORPHYRIN NUCLEUS 641 



Whatever may be the merit of these schemes, the starting products 

 are chosen from substances which have been shown to be related to 

 the synthesis of the porphyrin nucleus, and their condensations to 

 the primary precursor would be reactions of a type likely to occur 

 in the animal metabolism. Utilizing a substituted pyrrole of this 

 type as primary precursor, the remainder of the biosynthesis of the 

 porphyrin nucleus may be envisaged in the form shown in Figure 8. 



In normal hemopoiesis the monopyrrolic precursor A is decarboxy- 

 lated in the j3-substituent, the acetic acid side chain being trans- 

 formed to a methyl group, and giving precursor B (reaction 1), 

 By autocondensation, B yields the unsymmetrically substituted 

 dipyrrolic substance C with the side chain in the a-position, whether 

 — CH2COOH, — COOH, or some similar group, supplying the bridge 

 (reaction 2). By condensation of B with a monocarbon compound 

 such as formaldehyde or with a short-chain compound, which can 

 later be readily degraded to a single carbon, the symmetrically sub- 

 stituted dipyrrolic compound D is obtained (reaction 3). The latter, 

 being substituted in both a-positions, cannot give rise to a porphyrin 

 by autocondensation, the nonoccurrence of type II porphyrin being 

 thus explained. 



It is now assumed that the pyrromethene or dipyrrylmethane C, 

 but not D, undergoes an oxidative decarboxylation transforming its 

 propionic acid side chains to vinyl groups, and that the pyrromethene 

 E, resulting from this reaction, combines with D to form protopor- 

 phyrin IX and hemoglobin.* The decarboxylation of C to E, the 

 condensation of E with D, and the incorporation of iron and globin 



* Although two molecules of the a.a'-disubstituted dipyrrolic compound D cannot 

 readily condense to a type II porphyrin with elimination of two a-carbon substituents, 

 a condensation of Z) with C or £ to a type III porphyrin can readily occur. By con- 

 densation first an open-ring tetrapyrrolic body is formed. 



In the latter the rotational possibilities are restricted, and this together with the 

 great tendency of formation of the porphyrin ring allows an expulsion of one of the 

 a-substituents and ring closure. Numerous examples for reactions of this type occur- 

 ring in vitro are found in Fischer's syntheses. 



