Pleuromutilins

Retapamulin (26 Pleuromutilin (25) Antibiotic Semi-syntiietic Microbial Antibacterial Inhibits bacterial protein 294-303... 

Rittenhouse S, Biswas S, Broskey J, McCloskey L, Moore T, Vasey S, West J, Zalacain M, Zonis R, Payne D. (2006) Selection of retapamulin, a novel pleuromutilin for topical use. Antimicrob Agents Chemother 50 3882-3885. 

Jacobs MR. (2007) Retapamulin A semisynthetic pleuromutilin compound for topical treatment of skin infections in adults and children. Future Microbiol 2 591-600. 

Lolk L, Pohlsgaard J, Jepsen AS, Hansen LH, Nielsen H, Steffansen SI, Sparving L, Nielsen AB, Vester B, Nielsen P. (2008) A click chemistry approach to pleuromutilin conjugates with nucleosides or acyclic nucleoside derivatives and their binding to the bacterial ribosome. J Med Chem 51 4957-4967. 

Jones R, Fritsche T, Sader H, Ross JE. (2006) Activity of retapamuhn (SB-275833), a novel pleuromutilin, against selected resistant gram-positive Cocci. Antimicrob Agents Chemother 50 2583-2586. 

Erkel, G. (1997) Fusidic acid, griseofulvin and pleuromutilin. In Fungal Biotechnology. Anke, T. ed.. Chapman Hall, London, pp. 128-35. 

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 (81 Scheme 28) an antibiotic isolated from several species of Basidiomycetes, e.g. Pleurotus mutilis, has been synthesized in a 30-step sequence. One of the most important steps is the fragmentation of (79) to generate the required tricyclic skeleton of this diteipene. Direct retroaldol ring opening of (79) to the respective diketone is unsuccessful, but a two-step sequence via the ketoallyl bromide (80) results in the desired transformation. 

Indications Impetigo, Bacterial skin infections Category Pleuromutilin antibacterial Half-life N/A... 

Figure 4 Exemplar structures of various antibiotic classes that bind to either the 505 or the 305 subunit. Macrolides azithromycin (1), oxazolidinones linezolid (2), aminoglycosides Kanamycin A (3), Pleuromutilin (4), phenylpropanoids chloramphenicol (5), lincosamides clindamycin (6), Sparsomycin (7), Anisomycin (8), and tetracycline (9). See Scheme 9 for thiosptrepton (38). Not pictured streptogramins such as quinupristin/dalfopristin.

Davidovich, C., Bashan, A., Auerbach-Nevo, T., Yaggie, R.D., Gontarek, R.R., Yonath, A. Induced-fit tightens pleuromutilins binding to ribosomes and remote interactions enable their selectivity. Proc. Natl. Acad. Sci. USA 2007,104(11), 4291. 

Schlunzen, E, Pyetan, E., Fucini, P., Yonath, A., Harms, J.M. Inhibition of peptide bond formation by pleuromutilins The structure of the 50s ribosomal subunit from Deinococcus mdiodurans in complex with tiamulin. Mol. Microbiol. 2004, 54(5), 1287. 

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