Pleuromutilin

The chemical modification of biologically active natural products is essential for determining their structure–activity profile and for improving their potency. The complexity of a lead structure often imposes severe limitations on the type of transformations that can be accomplished. Pleuromutilin, a naturally occuring antibacterial isolated from various basidomycete microorganisms (e.g. Pleurotus mutilus and Pleurotus passeckerianus),1 is a case in point. Most of the modifications have concerned the ester side-chain on C-14 and have led to two more potent drugs Tiamulin and Valnemulin, now in veterinary use (Fig. 1).2 On a structure of this complexity, it is not easy to manipulate the unactivated and relatively hindered olefin on C-12 without extensive protection of the remaining functional groups. We have now found that the radical chain xanthate transfer process3 is of sufficient mildness to allow the direct creation of new C–C bonds on the olefin in Pleuromutilin without the need for any prior protection.

Retapamulin (SB-275833) 16 is a semi-synthetic derivative of the fungal metabolite pleuromutilin 17, which exerts its antimicrobial activity by binding to the 50S bacterial ribosome. A 1% retapamulin ointment (called Altabax in the US and Altargo in Europe) developed by GlaxoSmithKline (GSK) was approved by the FDA in April 2007 and the EMEA in June 2007 for the topical treatment of impetigo caused by Staphylococcus aureus or Streptococcus pyogenes. Further information on other pleuromutilin derivatives undergoing clinical evaluation can be found in Section 3.

The hydrindane skeleton is found in many biologically active natural products. We wished to develop a stereoselective approach to the cis-hydrindane skeleton 1 that would allow stereocontrolled installation of substituents around the bicyclic structure. A flexible approach to 1 would facilitate approaches to a number of natural products, many of which display important biological activity (Fig. 1). The sesquiterpene glycosides, dendronobilosides A and B, display immunomodulatory activity, and are closely related to faurinone 2. Pleuromutilin 3 has an inhibitory effect against the bacteria Staphylococcus aureous and is known to prevent bacterial protein synthesis. Bakkenolides, such as 4,display a variety of biological activities including selective cytotoxicity.