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Organic Chemistry Highlights

Total Synthesis

Monday, April 3, 2023
Douglass F. Taber
University of Delaware

The Dai Synthesis of Peyssonnoside A

Peyssonnoside A (3), isolated from the red alga Peyssonnelia sp., shows promising anti-microbial activity. Mingji Dai of Emory University assembled the tetracyclic core of 3 by the H-atom transfer cyclization of the dienone 1 to the cyclopropane 2 (J. Am. Chem Soc. 2022, 144, 19700. DOI: 10.1021/jacs.2c09919).

The starting material for the preparation of 1 was commercial 2-methyl cyclopentenone (4). Following the Alexakis protocol, conjugate addition with isopropyl magnesium bromide followed by trapping of the enolate so produced with 1-bromo-2-butyne led to the ketone 5 in 81% ee. Coupling with the boronic acid 6 proceeded with high regio and geometric control, to give 7. Enantioselective hydrogenation then delivered 8 in high ee, along with a minor amount of the other diastereomer, that was removed. Enol triflate formation and demethylation then set the stage for Pd-catalyzed cyclization to 1.

The H-atom mediated cyclization of 1 proceeded smoothly to give the tetracylic 2. The reaction is probably proceeding by H atom addition to the trisubstituted alkene, to give an intermediate radical that adds to the accesible face of the dienone.

Hydrogenation of 2 led to the saturated ketone, that initially resisted methylenation. Here the Lebel protocol proved useful, delivering 11, that was hydrated to give 12. At this point the synthesis converged with the alternative total synthesis of peyssonnoside A (3) reported by Karl Gademann of the University of Zurich (J. Am. Chem. Soc. 2021, 143, 14083. DOI: 10.1021/jacs.1c07135), concluding by coupling with 13 to give 3.

D. F. Taber, Org. Chem. Highlights 2023, April 3.