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Organic Chemistry Highlights

Total Synthesis

Monday, November 4, 2013
Douglass F. Taber
University of Delaware

The Procter Synthesis of (+)-Pleuromutilin

The fungal secondary metabolite (+)-pleuromutilin (3) exerts antibiotic activity by binding to the pokaryotic ribosome. Semi-synthetic derivatives of 3 are used clinically. The central step of the first synthesis of (+)-pleuromutilin (3), devised (Chem. Eur. J. 2013, 19, 6718. DOI: 10.1002/chem.201300968) by David J. Procter of the University of Manchester, was the SmI2-mediated reductive closure of 1 to the tricyclic 2.

The starting material for the synthesis was the inexpensive dihydrocarvone 4. Ozonolysis and oxidative fragmentation following the White protocol delivered 5 in high ee. Conjugate addition with 6 followed by Pd-mediated oxidation of the resulting silyl enol ether gave the cyclohexenone 7. Subsequent conjugate addition of 8 proceeded with modest but useful diastereoselectivity to give an enolate that was trapped as the triflate 9. Sakurai addition of the derived ester 10 with 11 led to 12 and so 1 as an inconsequential 1:1 mixture of diastereomers.

The SmI2-mediated cyclization of 1 proceeded with remarkable diastereocontrol to give 2. SmI2 is a one-electron reductant that is also a Lewis acid. It seems likely that one SmI2 bound to the ester, and the second to the aldehyde. Electron transfer then led to formation of the cis-fused five-membered ring, with the newly-formed alkoxy constrained to be exo to maintain contact with the complexing Sm. Intramolecular aldol reaction of the resulting Sm enolate with the other aldehyde then formed the six-membered ring, with the alkoxy group again constrained by association with the Sm.

Hydrogenation of 13 gave 14, that could be brought to diastereomeric purity by chromatography. Elegantly, protection of the ketone simultaneously selectively deprotected one of the two silyl ethers, thus differentiating the two secondary alcohols. Reduction of the ester to the primary alcohol then delivered the diol 15. Selective esterification of the secondary alcohol followed by thioimidazolide formation and free radical reduction completed the preparation of 16.

Ketone deprotection followed by silyl ether formation and Rubottom oxidation led to the diol 17. Protection followed by the addition of 18 and subsequent hydrolysis and reduction gave the allylic alcohol 19. Coupling of the derived chloride with Me2Zn gave 20 as a single diastereomer, setting the stage for the completion of the synthesis of (+)-Pleuromutilin (3).

D. F. Taber, Org. Chem. Highlights 2013, November 4.