Investigations in the Biosynthesis of the Pigments of Life: Calculations on the Formation of Uroporphyrinogen III from Hydroxymethylbilan and Description of a New Mechanism for the D‐Ring Inversion

The direct formation of a spiro tetrapyrrole intermediate from hydroxymethylbilan ( 1 ) is energetically less favorable than the formation of a cationic σ complex in the first step of the cyclization to form uroporphyrinogen III ( 2 ) [Eq.(a)]. This was shown by calculations on model compounds (A, P = H or Me). The preferred mode of cyclization in the biosynthesis of 2 , which proceeds by inversion of the D ring, can be formulated as an alternative mechanism and has stereoselective H abstraction and [1,5] sigmatropic shifts as key steps. P = (CH 2 ) 2 CO 2 H, A = CH 2 CO 2 H.