A direct approach to the functionalized propellane core of pleuromutilin

ORGN 652

Stephen D. Lotesta, slotesta@princeton.edu, Junjia Liu, junjial@princeton.edu, and Erik J. Sorensen, ejs@princeton.edu. Department of Chemistry, Princeton University, 63 Frick Laboratory, Washington Road, Princeton, NJ 08544
Derivatives of pleuromutilin continue to be of interest due to their unique prokaryotic ribosomal binding properties which lead to high levels of antibacterial activity. A short route to the core of pleuromutilin could help identify a minimal scaffold needed to retain antibacterial activity. A direct 9 step approach to the functionalized propellane core of this natural product is described (Scheme 1). From known enone 1, a tandem cuprate addition/cyclocondensation reaction was used to establish hydrindenone 2. Further manipulations, which included hydrocyanation and asymmetric homopropargylation reactions, gave alkynal 3 as a single diastereomer. Various ring closing strategies were employed in an effort to obtain the propellane system (4).