Syntheses of linear tetrapyrroles as potential inhibitors for uroporphyrinogen III synthase

Abstract

Living systems depend on a variety of metal complexes of tetrapyrrolic macrocycles to carry out many biologically important functions. Among these pigments of life are heme, chlorophyll and vitamin B[12]- All these substances are biosynthetically derived from the same macrocyclic precursor, uroporphyrinogen III. In Nature, the latter is constructed from a linear tetrapyrrole, hydroxymethylbilane, by an enzyme named uroporphyrinogen III synthase or cosynthetase. In order to elucidate the mechanism of action of cosynthetase, a variety of linear tetrapyrrolic compounds have been synthesized as potential inhibitors for the enzyme. Four new hydroxymethylbilane derivatives (D ring N-methyl hydroxymethylbilane 30, acetyl bilane 62, trifluoroacetyl bilane 64, and 19-carbobenzoxy hydroxymethylbilane methyl ester 69) have been synthesized, together with the known formylbilane 26. These syntheses employed the established "2 + 2" approach, and the key step was acid-catalyzed condensation of two dipyrromethane precursors bearing the desired array of substituents. Aminomethylbilane 5 has been prepared through the tripyrrene / a, c-biladiene route. The benzyl ester in the tripyrrene precursor was cleaved by vigorous acid treatment, a modification of a recently reported procedure. Borohydride reduction of biladiene-a,c salt led to aminomethylbilane lactam methyl ester whose lactam ring and side-chain esters were saponified to afford the aminomethylbilane. An alternative approach to aminomethylbilanes has been developed. It is based on catalytic hydrogenation of a bilene-a derivative in which the terminal α position was unprotected. The required bilene-a was constructed by acid-catalyzed condensation of an appropriate tripyrrane-α-carboxylic acid with an α-formyl-pyrrole. The new route is demonstrated in the syntheses of amino-methylbilane and 18-butyrate aminomethylbilane 78...