Leeper Group



Some 3,4-disubstituted pyrroles Finian J. Leeper and James M. Kelly,
"Synthesis of 3,4-Disubstituted Pyrroles. A Review"
Org. Prep. Proc. Int., 2013, 45 171-210. Full Text.

Pyrrole rings are present in a number of natural products and synthetic pharmaceuticals. Natural products include porphobilinogen 1, the precursor of all the natural tetrapyrroles (e.g. heme, chlorophyll and vitamin B12), the myrmicarin family of alkaloids, e.g. myrmicarin 217 2, isolated from the ant Myrmicaria opaciventris, pyrrolnitrin 3, an antifungal antibiotic, and prodigiosin 4, a tripyrrole with potent anti-cancer activity, while the prime example of a pyrrolic pharmaceutical is atorvastatin 5 (trade name Lipitor) the best selling drug in pharmaceutical history.

Bearing up to five substituents, the pyrrole core has proven to be a challenging target for chemical synthesis but, arguably, the most challenging substitution pattern is 3,4-disubstituted. This is because starting with unsubstituted pyrrole it is easy to add substituents on to the nitrogen atom under base-catalysed conditions and electrophilic substitution usually occurs preferentially at the a-positions (C-2 and C-5). Therefore achieving substitution only at the b-positions (C-3 and C-4) is difficult. Furthermore the classic syntheses of pyrrole rings, shown in Scheme 2, generally work best for the more highly substituted pyrroles. This review, therefore, will be concentrating on the synthesis of 3,4-disubstituted pyrroles. 1,3,4-Trisubstituted pyrroles are also included because appropriate substituents on the nitrogen atom can serve as protecting groups and be removed later (though this was often not done in the papers cited). Syntheses of pyrroles with other substitution patterns have been reviewed elsewhere.

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Department of Chemistry
University of Cambridge