Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, November 1, 2021
Douglass F. Taber
University of Delaware

The Zhang/Zhang Synthesis of Merrilactone A

Merrilactone A (3), isolated from the Eastern Asia tree Illicium, promotes neurite outgrowth at remarkably low concentration. A key step in the synthesis of 3 developed by Yun-wu Zhang and Yandong Zhang of Xiamen University was the oxidative cyclization of 1 to 2 (J. Am. Chem. Soc. 2021, 143, 3256. DOI: 10.1021/jacs.1c00525).

The synthesis began with commercial (R)-pulegone (4), converted via the usual bromination/Favorskii rearrangement to the ester 5. Allylation delivered 6 with high diastereoselectivity. Selective monoepoxidation of the trisubstituted alkene followed by RuO4 cleavage gave an acid, that spontaneusly cyclized to the lactone 7. Dehydration led to the alkene, that was carried on to the aldehyde 8. Diastereoselective addition of the alkynyl Grignard reagent 9 completed the assembly of the crystalline alcohol 1. The Pd-mediated borylation of 1 proceeded with high diastereocontrol to give the intermediate boronate 10, that was oxidized directly to the alcohol 2.

Exposure to mild acid removed the silyl group from 2. The primary alcohol was then converted to the selenocarbonate 11, that was cyclized to the bis-lactone 12.

The pulegone-derived methyl group of 5 directed the subsequent formation of each of the succeding stereogenic centers. To complete the synthesis, the tertiary H of 12 had to be removed. To this end, 12 was oxidized specifically to the alkene 13. Epoxidation followed by acid-catalyzed cyclization then completed the synthesis of merrilactone A (3).

It is instructive to compare this approach to the synthesis of merrilactone A (3) to the two previous strategies highlighted in these pages (Carbocyclic Natural Products by Alkene Metathesis 2007, January 29; Functional Group Interconversion: The Wang Synthesis of Merrilactone A 2019, May 13).

D. F. Taber, Org. Chem. Highlights 2021, November 1.