Biomimetic Synthesis of Symmetrical Tetrasubstituted Pyrroles

Significance

The reported biosynthesis of a natural product containing a pyrrole core, chromo­pyrrolic acid (T. Nishizawa et al. J. Am. Chem. Soc. 2006, 128, 724), was the encouragement which triggered the biomimetic synthesis of similar products. Envisioned, and accomplished, was the synthesis of highly substituted pyrroles from the reaction of commercially available amino acids by oxidation, deamination, and cyclization mediated by transition metals. Initial tests with one equivalent of Cu(OAc)₂ in refluxing toluene afforded a 30% yield of the desired product. The reaction was optimized by testing different additives and bases, resulting in the conditions shown. Similar yields were obtained with three equivalents of Cu(OAc)₂ without additives (62% vs. 79% yield). The scope was well studied with both aliphatic and aromatic amino acids as starting materials, although aliphatic amino acids generally afforded lower yields. Additionally, the natural products ­lycogarubin C and chromopyrrolic acid were synthesized using this methodology.

Comment

The reported one-step biomimetic procedure is of interest because of easily available starting materials and simple synthetic operation. The products, symmetrical pyrroles, were obtained in reasonably high yields. The synthesis of two unsymmetrical pyrroles was also tested, with a 37% yield obtained of one and 0% yield of another, indicating a likely limitation of the methodology. Unfortunately, reaction times were not mentioned except in the initial optimization stage (10 h). Additionally, ‘dry air’ is reportedly used, meaning an inert gas atmosphere is not required; but it is not clear whether rigorous exclusion of moisture is necessary. As the reactions were carried out on a 0.28 mmol scale, it is also not clear if it is amenable to scale-up.