Convergent Synthesis Of Nature Product Roseophilin And Direct Acylation Of Pyrroles With Carboxylic Acids Catalyzed By Lewis Acid

Roseophilin is a alkaloid that was isolated from the culture broth of streptomyces griseoviridis by Seto et al. in1992, exhibiting potent cytotoxicity against K562human erythroid leukemia cells and KB human epidermoid carcinoma cells. This alkaloid has unique anti-cancer property and an ansa-bridged azafulvene macrocylic core structural unit which inspired many of the synthetic teams’interest. Therefore there is an urgent need to develop an efficient synthetic route to complete the total synthesis of natural product Roseophilin.This paper developed a shortest route for the successful synthesis of natural product Roseophilin. With N-tosylpyrrole as starting material and through the Friedel-Crafts acylation, reduction, tandem pyrrole acylation-Nazarov cyclization reaction, cyclopentanone[b] pyrrole, the key intermediate was obtained. Tandem pyrrole acylation-Nazarov cyclization reaction was the highlight reaction in the entire route. The target product, the13-membered macrocyclic ring was formed with two different routes starting from cyclopentanone[b] pyrrole. Our synthetic route is the shortest and highest fielding one reported so far. The tandem acylation-Nazarov cyclization reaction which was an important step in the the total synthesis of natural product Roseophilin inspired the next part-direct acylation of pyrroles with carboxylic acids catalyzed by Lewis acid.Friedel-Crafts reaction has been widely used in the synthesis of aromatic ketones and cyclic ketones that was the important synthetic intermediates in the chemical and pharmaceutical research. So the Friedel-Crafts reaction has been a hot topic among the chemists.Several methods involving acyl chlorides, acid anhydrides, esters, Meldrum’s acid as the acylation agents and Vismeier reaction have been reported. However there are always limitations with these methods.In2004, Chuanjun Song developed a new method of pyrrole acylation using carboxylic acids and TFAA. Carboxylic acids seem to be the best choice of acylating agents reported so far, but TFAA catalyzed pyrrole acylation with carboxylic acids was not suitable with electron deficient acids. The direct acylation of pyrroles with electron deficent carboxylic acids was efficiently catalyzed by lewis acid. Different lewis catalysts have different effects, at Compared to lacking lewis, the presence of a Lewis acid was the key reason that make electron deficient carboxylic acid was acylated to pyrroles.