Synthesis of -pleuromutilin

Sam Zard of the Ecole Polytechnique in Paliseau has developed elegant and affordable free-radical methods for C-C bond construction. In the context of the total synthesis of pleuromutilin, he recently reported (Organic Lett. 5 325, 2003) that the free radical cyclization of 12 proceeded smoothly to give the eight-membered ring product 13. The ketone 12 is easily prepared from m-toluic acid. It is a tribute to the efficacy of the cyclization procedure that the conformation drawn, the conformation required for cyclization, is the less stable chair available to 12. 

Acidic hydrolysis of MOM ethers is not easy 3% concentrated HQ in aqueous EtOH and trifluoroacetic acid in dichloromethane at room temperature are typical conditions taken from the solo synthesis of Pleuromutilin by Gibbons [Scheme 4.238J.444 At the other extreme are the remarkably easy scission of a phenolic MOM group activated by an adjacent carbonyl in Muxfeldfs synthesis of Terramycin [Scheme 4.239J44-15 and the use of an acidic exchange resin in re-fluxing methanol to cleave a MOM ether and a dioxolane used in a synthesis of 7-deoxypancratistatin [Scheme 4.240].446... 

In a synthesis of (+)-pleuromutilin, only a 1 1 mixture of diastereomeric vinylic alcohols (86% yield) was obtained by addition of vinylmagnesium bromide to the precursor ketone. Equilibration of the easily separated undesired alcohol to a 1 1 mixture was achieved by a twofold sulfoxide - sulfenate rearrangement [C6H5SC1, then (EtO)3P in refluxing methanol] raising the overall yield of the desired diastereomer to 70% after two cycles81. 

SCHEME 21.8. Radical cycUzation cascade for the synthesis of pleuromutilin. 

For a study of this strategy in the synthesis of the antibiotic pleuromutilin (isolated from the Basidiomycetes Pleurotus mutitus. active against Oram-positive bacteria) see ref 920. 

Uccello DP, Miller SM, Dieterich NA, et al. The synthesis of C-13 functionalized pleuromutilins via C-H amidation and subsequent novel rearrangement product. Tetrahedron Lett. 2011 52 4247-4251. 

In studies toward the synthesis of the antibacterial natural product pleuromutilin (Scheme 25.66), Procter et al. reported a cascade double annulation process using Sml2 to generate an initial ketyl radical from 137. After a subsequent cyclization, the resulting new ketyl radical was reduced to form the organosamarium (III) intermediate 138, which in turn promoted a diastereoselective intramolecular aldol reaction to give 139. ° ... 

Inhibition of protein synthesis (aminoglycosides, phenicols, lincosamides, macrolides, streptogramins, pleuromutilins, tetracyclines)... 

The antibiotic pleuromutilin (51), isolated from Pleurotus mutilis, has been synthesized by Gibbons. This neat synthesis has as its basis a sequential Michael strategy which produces in one step, i.e. (48) + (49) (50), the indane nucleus with four of the eight stereocentres of (51)... 

Pleuromutilin, a protein synthesis inhibitor, was first isolated from the genus Pleurotus and discovered as potent diterpene antibiotics in 1950. ° Later, several derivatives were discovered and have been used in veterinary and clinic environments. For example, tiamulin was the first pleuromutilin compound to be approved for veterinary use in 1979, followed by valnemulin in 1999. In 2007, retapamu-lin, a topical antibiotic developed by GlaxoSmithKline (London, U.K.), became the first pleuromutilin antibiotics approved for use in humans. It is marketed as an ointment under the brand names Altabax and Altargo. Retapamulin was approved by the U.S. Food and Drug Administration (FDA) for the treatment of bacterial skin infections such as... 

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