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Organic Chemistry Highlights

Total Synthesis

Monday, September 5, 2022
Douglass F. Taber
University of Delaware

The Herzon Synthesis of Euonyminol

Euonyminol (3) was isolated from the thunder duke vine, Tripterygium wilfordii, used in traditional Chinese medicine. In the course of a synthesis of 3, Seth B. Herzon of Yale University established the key cyclic quaternary center by the Cu-catalyzed cyclization of the α-diazo acetoacetate 1 to the enol ether 2 (J. Am. Chem. Soc. 2021, 143, 699, DOI: 10.1021/jacs.0c12998; J. Org. Chem. 2021, 86, 17011, DOI: 10.1021/acs.joc.1c02167).

The preparation of the ester 1 began with commerical carvone 4. Following the method of Floreancig, α-oxygenation led to the undesired diastereomer 5, but that could be corrected by deprotonation/protonation. Epoxidation then gave 6. Addition of 7 followed by cyclization and protection led to 8, that was oxidized to 9. Acylation with diketene 10 followed by diazo transfer completed the assembly of 1.

The Cu-catalyzed cyclization of 1 proceeded with substantial diastereocontrol to give the crystalline vinylogous carbonate 2. The authors rationalized this by postulating significant charge separation in the transition state 11. Stabilization of the incipient carbocation by the nonbonding electrons on the adjacent ether then blocked bond formation from that face, leading to the observed outcome.

Ozonolysis of 2 followed by Baeyer-Villiger oxidation, hydrolysis and esterification gave the monoacetate 12. Desilylation followed by oxidation and the addition of vinyl magnesium bromide and acetonide formation then led to the alkyne 13, that cyclized under free radical conditions to the stannane 14, completing the carbon skeleton of 3. The later oxidative phase of the synthesis depended on the 1,3-diol being protected by a bridging bis-silyloxy group. With that group in place, however, the radical cyclization led to the alternative cyclopentane. Only the acetonide 13 cyclized to the desired cyclohexane.

Destannylation and deprotection of 14 gave the intermediate diol, that was carried on to the requisite cyclic siloxane 15. Oxidation to the enone followed by methyl lithium addition and epoxidation then gave 16, with the stage set for the completion of the synthesis of euonyminol (3).

D. F. Taber, Org. Chem. Highlights 2022, September 5.