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Organic Chemistry Highlights

Total Synthesis

Monday, March 4, 2019
Douglass F. Taber
University of Delaware

The Christmann Synthesis of Dichrocephone A

The intriguing propellane natural product dichrocephone A (3) was isolated from Dichrocephala benthamii, an herb of China and Southeast Asia. Dean J. Tantillo of the University of California, Davis and Mathias Christmann of the Freie Universitšt Berlin envisioned assembling 3 by closing 1 to the propellane skeleton 2, followed by further oxidation (Angew. Chem. Int. Ed. 2018, 57, 2419. DOI: 10.1002/anie.201711766). Dean J. Tantillo of the University of California, Davis assisted in the deduction of the actual structure of 3.

The synthesis of 1 began with commercial cyclopentane-1,3-dione (4). Allylation followed by propargylation led to 5, that was brominated with 6 and hydrated to give the prochiral triketone 7. Organocatalyzed cyclization by the Werner protocol with the Nugent phosphine (R, R)-Me-DuPhos (8) delivered 9 in outstanding enantiomeric excess despite the elevated reaction temperature. Conjugate addition with the mixed cuprate completed the assembly of 1.

The Ru-catalyzed ring-closing metathesis of 1 proceeded smoothly with Umicore M71SiPr to give the propellane 2, that was selectively reduced to 10. Addition of methyl magnesium bromide followed by hydrogenation led to 11 as a single diastereomer. Double α-methylenation of the derived ketone gave 12, that was reacted selectively with trimethylsulfoxonium iodide, then epoxidized and reduced to 13. Reductive cleavage of the cyclopropane followed by oxidation completed the synthesis of 14, the structure originally assigned to 3.

When it was clear that the structure of the natural product was not 14, the authors returned to the reported spectroscopic data, and deduced computionally that the natural product likely had the structure 3. This was confirmed by dehydration to 15, followed by Mukaiyama hydration from the more exposed face. In addition to elucidating the correct structure, this enantioselective synthesis also established the absolute configuration of the natural product.

D. F. Taber, Org. Chem. Highlights 2019, March 4.