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. 

Pleuromutilin (Scheme 17.9) is an antibiotic from Pleurotus or Clitopilus basidiomycete strains which kills mainly Gram-positive bacteria and mycoplasms. Metabolism of pleuromutilin and derivatives results in hydroxylation by microsomal cytochrome P-450 at the 2- or 8-position and inactivates the antibiotics. Modification of the 8-position of pleuromutilin and analogs was of interest as a means of preventing the metabolic hydroxylation. Microbial hydroxylation at the... 

FIGURE 16.20 Anti-infective drugs. Microbial hydroxylation of pleuromutilin 81 or mutilin 82. 

More extensive migration and also bond fracture within (4.112) [the carbonium ion preceding (4.107) is thought to occur in the biosynthesis of pleuromutilin (4.113). Again it is the mevalonoid (4-pro-R)-hydrogen which migrates from C-9 to C-8, and in a subsequent step (see Scheme 4.24) it is a C-5 (/ ro-5)-proton which moves from C-11 to C-4 (the labels from [2- " C]mevalonate = ) [102]. 

Scheme 40 Rhodium- and silver-catalyzed C—H amination of pleuromutilin carbamate 39.

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

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