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Organic Chemistry Highlights

Total Synthesis

Monday, June 1, 2009
Douglass F. Taber
University of Delaware

The Johnson Synthesis of Zaragozic Acid C

The zaragozic acids, exemplified by Zaragozic Acid C (3), are picomolar inhibitors of cholesterol biosynthesis. Jeffrey S. Johnson of the University of North Carolina developed (J. Am. Chem. Soc. 2008, 130, 17281. DOI: 10.1021/ja808347q) an audacious silyl glyoxylate cascade approach to the oxygenated backbone fragment 1. Intramolecular aldol cyclization converted 1 to 2, setting the stage for the construction of 3.

The lactone 2 includes five stereogenic centers, two of which are quaternary. The authors were pleased to observe that exposure of 4 to vinyl magnesium bromide (5) led, via condensation, silyl transfer, condensation, and again silyl transfer, to a species that was trapped with t-butyl glyoxylate (6) to give 7 as a single diastereomer. This one step assembled three of the stereogenic centers of 2, including both of the quaternary centers. The alcohol 7 so prepared was racemic, so the wrong enantiomer was separated by selective oxidation. Intramolecular aldol reaction of the derived α-benzyloxy acetate 1 then completed the construction of 2.

Addition of the alkyl lithium 8, again as a single enantiomerically-pure diasteromer, to 2 gave the hemiketal 9. Exposure of 9 to acid initially gave a mixture of products, but this could be induced to converge to the tricyclic ester 10. To convert 10 to 11, the diastereomer that was needed for the synthesis, two of the stereogenic centers had to be inverted. This was accomplished by exposure to t-BuOK/t-amyl alcohol, followed by re-esterification. The inversion of the secondary hydroxyl group was thought to proceed by retro-aldol/re-aldol condensation.

Debenzylation of 11 followed by acetylation delivered 12, an intermediate in the Carreira synthesis of the zaragozic acids. Following that precedent, the ring acetates of 12 were selectively removed, leaving the acetate on the side chain. Boc protection was selective for the endo ring secondary hydroxyl, leaving the exo ring secondary hydroxyl available for condensation with the enantiomerically-pure acid 13. Global deprotection then completed the synthesis of Zaragozic Acid C (3).

The key to the success of this synthesis of the complex spiroketal 3 was the assembly of 7 in one step as a single diastereomer from the readily-available building blocks 4, 5, and 6. This process, reminiscent of group transfer polymerization, will be a useful complement to the cascade organocatalyzed aldol condensations that have recently been developed.

D. F. Taber, Org. Chem. Highlights 2009, June 1.