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Organic Chemistry Highlights

Total Synthesis

Monday, August 5, 2019
Douglass F. Taber
University of Delaware

The Herzon Synthesis of Myrocin G

Myrocin C (5), isolated from the cellulose-decomposing fungus Myrothecium verrucaria, has antiproliferative and antimicrobial activity. Seth B. Herzon of Yale University hypothesized that 5 would readily open to its active form, 4, which he named myrocin G. He then developed the remarkable cascade coupling of 1 with 2 that delivered 3, and thus 4 (J. Am. Chem. Soc. 2018, 140, 16058. DOI: 10.1021/jacs.8b10891).

The preparation of 2 began with the Rawal Cr-catalyzed coupling of 6 with 7 to give 8. Methylenation followed by deprotection of the enone and iodination led to 9, that was protected, then acylated with 10, leading to 11. Desilylation followed by acylation led, after deprotection, to the enone 12, that was silylated to give 2.

The absolute configuration of 15 was set by the diamine-mediated combination of 13 with 14. Iodination followed by cyclopropanation then completed the preparation of the crystalline 16.

The combination of 16 with 2 began with exposure to n-BuLi to generate 1, conducted at -78 C. A solution of 2 was added dropwise at that same temperature, followed by warming. The apparent sequence of events was the initial formation of the alkoxide 17. Silyl transfer generated 18, that then cyclized to 19. Allyloxycarbonyl transfer led to 20. Proton transfer followed by β-elimination then delivered 3 in a remarkable 38% yield based on 2. Desilylation completed the synthesis of myrocin G (4).

D. F. Taber, Org. Chem. Highlights 2019, August 5.