Biosynthesis of porphyrins and related macrocycles. Part 40. Synthesis of a spiro-lactam related to the proposed spiro-intermediate for porphyrin biosynthesis: inhibition of cosynthetase

Abstract

Routes are developed for synthesis of the tripyrrolic macrocyclic spiro-lactam 39. A minor product from the synthesis, thought earlier to be an atropisomer, has been shown by molecular mechanics calculations and re-investigation to be a dimer.

The octa-acid derived from 39 closely resembles the spiro-pyrrolenine 2 proposed as a biosynthetic intermediate for uroporphyrinogen Ill. This octa-acid acts as a strong inhibitor of cosynthetase (uroporphyrinogen Ill synthase) whilst other similar systems which lack some of its functionality do not. These results strongly support the view that the spiro system 2 is indeed the biosynthetic intermediate for formation of uroporphyrinogen III 3 from hydroxymethylbilane 1.