Synthesis of optically active ferrocene-containing platensimycin derivatives with a C6-C7 substitution pattern

Concurrently with the emergence of purely organic derivatives of the naturally occurring antibiotic platensimycin (1a), herein, we describe the design, synthesis and biological evaluation of both the enantiomers of a C6-C7 ferrocene-fused platensimycin derivative 2b. (S,S_P)- and (R,R _P)-2b were prepared in nine steps starting from commercially available 4-ferrocenyl-4-oxobutyric acid via highly diastereoselective Michael additions of optically active planar-chiral ferrocene-fused cyclohexanone derivatives (5) with acrylate ester as the key step. Manual superimposition of (S,S_P)-2b on platensimycin bound to the active site of its target enzyme FabF suggests that the former fits nicely in the active site and the C6-C7-fused ferrocene occupies a pocket similarly to the C8-C9-fused tetracyclic cage of 1a. Antimicrobial activities of (S,S_P)- and (R,R _P)-2b were tested against various Gram-positive and Gram-negative bacterial strains. An efficient synthetic route to optically active planar chiral ferrocene-containing bioorganometallics (2b) inspired by the antibiotic platensimycin lead structure has been developed. The absolute configurations were confirmed by X-ray crystallography. Docking experiments with (S,S _P)-2b showed the existence of a pocket for the ferrocene fused at C6-C7 position of the cyclohexenone moiety. Compounds 2b represent a new family of compounds with an as yet unexplored substitution pattern compared to the reported purely organic analogues of platensimycin.