Total Synthesis of Prodigiosin, Prodigiosene, and Desmethoxyprodigiosin: Diels-Adler Reactions of Heterocyclic Azadienes and Development of an Effective Palladium(II)-Promoted 2,2'-Bipyrrole Coupling Procedure

Article abstract of DOI:10.1021/jo00242a013

The total synthesis of prodigiosin (1), a red pigment first isolated from Serratia marcescens, possessing the characteristic pyrrolylpyrromethene skeleton of a class of naturally occurring polypyrroles exhibiting antimicrobial and cytotoxic properties, is detailed.The approach is based application of an inverse electron demand Diels-Adler reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate in a 1,2,4,5-tetrazine--->1,2-diazine--->pyrrole strategy for preparation of prodigiosin pyrrole ring B and the subsequent implementation of an effective intramolecular palladium(II)-promoted 2,2'-diaryl coupling for construction of the prodigiosin 2,2'-bipyrrole AB ring system.In situ generated activated ester derivatives of pyrrole-1-carboxylic acid or the use of pyrrole-1-carboxylic acid anhydride proved suitable for the generation of mixed 1,1'-carbonyldipyrrole compounds for use in the palladium(II)-promoted mixed, 2,2'-bipyrrole coupling.Extensions of this approach to the preparation of the naturally occurring parent pyrrolylpyrromethene, prodigiosene (2a), and 2-methyl-3-pentylprodigiosene (2e, desmethoxyprodigiosin) are detailed.A comparison of the in vitro cytotoxic properties of prodigiosin (1), prodigiosene (2a), and 2-methyl-3-pentylprodigiosene (2e) are reported and reveal exceptional cytotoxic potency (3.7*10^-4 μg/mL = 3.7*10^-10 g/mL) for prodigiosin against 9PS (P388) mouse leukemia which may be attributed to the presence of the prodigiosin C-6 methoxy substituent.