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Organic Chemistry Highlights

Total Synthesis

Monday, October 2, 2023
Douglass F. Taber
University of Delaware

The Garg Synthesis of Lissodendoric Acid A

Lissodendoric acid A (4), isolated from the marine sponge Lissodendoryx florida, reduced reactive oxygen species (ROS) in a Parkinson's disease model. Neil K. Garg of UCLA devised an approach to 4 based on the generation of the cyclic allene from 1, and in situ cycloaddition to the 2-pyrone 2 to give 3 (Science 2023, 379, 261. DOI: 10.1126/science.ade0032).

The 2-pyrone 2 was prepared from the commercial acid 5. Bis tosylation followed by quenching with t-butanol led to the ester 6. Coupling with the organozinc 7 then completed the preparation of 2.

The bromide 1 was assembled from the commercial triflate 8. Coupling with the organozirconium reagent 9 gave 10. The absolute configuration was then set by enantioselective reduction to the allylic alcohol. Coupling of the derived ester with the PhMe2SiLi led to 1 in 90% ee.

The cyclic allene 11 has two alkenes, and each has two faces. Further, the barrier to racemization of the allene is estimated to be only ~ 14 kcal/mol. Nevertheless, the cycloaddition proceeded predominantly across just one face of one of the alkenes, and with substantial maintenance of the enantiomeric excess.

To complete the synthesis, it was necessary to selectively reduce one of the two alkenes. To this end, the cyclic amine was oxidized to the unsaturated lactam, then reduced in a conjugate sense with "CuH", leading to 12. Extrusion of CO2 followed by removal of two of the three Boc groups and acylation with acryloyl chloride gave 13. Ring-closing metathesis led to 14. Reduction followed by removal of the t-butyl ester completed the synthesis of lissodendoric acid A (4).

D. F. Taber, Org. Chem. Highlights 2023, October 2.