Iromycins:: A new family of pyridone metabolites from Streptomyces sp.: II.: Convergent total synthesis

The total synthesis of iromycin A (1a), a microbial metabolite combining a novel structure with an interesting biological activity as a NO synthase inhibitor, was accomplished using a flexible and highly convergent approach. Thus, the ring fragment was prepared as 6-bromomethylpyrone 27 by acylation of the respective beta-ketoester 13 and subsequent lactonization of the thus-obtained beta,delta-diketoester 11, followed by bromination of the 6-methyl group. In addition, the unsaturated side chain was efficiently prepared as terminal alkyne 34 which was then carboaluminated to furnish the alkenyldimethylalane 35. The assembly of these two fragments was thoroughly studied using nickel, palladium, and copper catalysts yet only succeeded in the absence of any transition metal after formation of the respective lithium alkenyltrialkylalanate. Treatment of the coupled product 41 with liquid ammonia then completed the total synthesis which furnished an 18% overall yield over the nine steps of the longest linear sequence.