A Dialdehyde Cyclization Cascade: An Approach to Pleuromutilin

摘要

Resistance to antibiotics is a major concern worldwide and has led to an urgent need to identify antibacterial agents with modes of action distinct from the established classes. The antibacterial natural product pleuromutilin (1) is such a candidate (Scheme 1). Pleuromutilin derivatives are known to bind to the peptidyl transferase site on the 50S ribosomal subunit of bacteria thereby preventing bacterial protein synthesis. The poor pharmacokinetic properties of the pleuromutilin class are, however, a major problem. Only recently has a pleuromutilin derivative been approved for use in humans: retapamulin (an ester derivative at Cl4) is used as a topical agent for bacterial skin infections and other pleuromutilin analogues are currently being developed. Although analogues of pleuromutilin are available by minor modification of the natural product, a concise approach to the core of pleuromutilin would allow the preparation of analogues of the natural product displaying improved pharmacokinetic properties.