Synthetic studies towards the SNAC ester of seco-progeldanamycin

Abstract

The ansamycin antibiotic geldanamycin is biosynthesized by Streptomyces hygroscopicus through a PKS type I. The macrolactamization in the biosynthesis is catalyzed by the amide synthase GdmF. GdmF belongs to the superfamily of arylamine N-acetyltransferases (NATs). In the present work, a convergent fragment synthesis towards the SNAC ester of seco- progeldanamycin, the natural substrate of GdmF, was developed. For the first generation synthesis, a tethered ring closing metathesis of the western and eastern fragments was investigated to introduce the central trisubstituted double bond. Key steps for the synthesis of the western fragment included Evans alkylation, Sharpless epoxidation, and Roush crotylation. For the synthesis of the east fragment, a zinc-mediated chelate-controlled isopropenylation was used. The second generation synthesis was made more convergent. For this purpose, the aromatic moiety of the western fragment was introduced via 1,2-addition followed by Barton-McCombie deoxygenation. Key steps in the synthesis of the western fragment included Myers alkylation, and anti,syn-selective Marshall propargylation followed by a hydrozirconation-iodination sequence. Coupling to the eastern fragment occurred via an achiral Nozaki-Hiyama-Kishi reaction. As an alternative to coupling the western and eastern fragments, a samarium diiodide-mediated Reformatsky reaction was investigated. In the second part of the work, truncated SNAC and pantetheine derivatives of seco-progeldanamycin were synthesized, which were successfully used for co-crystallization experiments with GdmF. Furthermore, non-hydrolyzable nitrogen and carbon analogs were synthesized. The latter were prepared using a nickel-catalyzed decarboxylative ketone synthesis.