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Organic Chemistry Highlights

Total Synthesis

Monday, November 5, 2018
Douglass F. Taber
University of Delaware

The Reisman Synthesis of (+)-Pleuromutilin

Pleuromutilin (3), isolated from the fungus Clitopilus passekerianus, shows clinically useful antibiotic activity. Sarah E. Reisman of Caltech envisioned the assembly of 3 via the reductive cyclization of 1 to 2 (J. Am. Chem. Soc. 2018, 140, 1267. DOI: 10.1021/jacs.7b13260).

The preparation of the requisite sidechain began with the alkyne 4. Addition of thiophenol delivered alkenyl sulfide 5 with good geometric control. Cu-mediated coupling of 5 with CH3MgBr followed by reduction led to the allylic alcohol 6, that was carried on to 7.

The enantiospecific preparation of the keto aldehyde 1 began with commercial dihydrocarvone (8). Ozonolytic cleavage following the procedure of White delivered 9. Conjugate addition of 10 led to the intermediate silyl enol ether, that was oxidized to the enone. Diastereoselective conjugate addition of 11 then led to 12. Allylic chlorination of 12 was effected with trichloroisocyanuric acid. Acetal hydrolysis followed by intramolecular aldol condensation was then accomplished with only minor epimerization of the secondary methyl group, to give 13. CeCl3-assisted 1,2-addition of CH3MgCl set the stage for PCC oxidation to the inverted enone. Modified Kornblum oxidation then delivered the aldehyde 14.

The (R)-3,3'-Br2-BINOL-promoted 1,2-addition of 7 to 14 led to 1.2:1 mixture of the desired diastereomer, that was carried on to 1, and the readily separated bis-epi product 15. Addition of the geometric isomer of 7 to 14 led to a 2:1 mixture of diastereomers, the major one of which was carried on to 12-epi pleuromutilin, the antibiotic activity of which is also of interest.

The SmI2-mediated cyclization of 1 to 2 proceeded smoothly under carefully defined oxygen-free aqueous conditions. With 2 in hand, there was still a serious challenge for the conversion to 3, selective diastereoselective reduction of the less reactive disubstituted alkene. An elegant solution to this problem emerged based on the Shenvi reduction protocol. After protection of the ketone as the silyl enol ether, exposure to the Shenvi conditions led to the desired intramolecular hydride transfer. The product ketone was readily reduced to 16.

The secondary alcohol of 16 was esterified with 17. Methanolysis followed global deprotection then completed the synthesis of pleuromutilin (3).

D. F. Taber, Org. Chem. Highlights 2018, November 5.