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) 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 condensation 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.

Farnesyl pyrophosphate regulates adipocyte functions as an endogenous PPARγ agonist

The cholesterol biosynthetic pathway produces not only sterols but also non-sterol mevalonate metabolites involved in isoprenoid synthesis. Mevalonate metabolites affect transcriptional and post-transcriptional events that in turn affect various biological processes including energy metabolism. In the present study, we examine whether mevalonate metabolites activate PPARγ (peroxisome-proliferator-activated receptor γ), a ligand-dependent transcription factor playing a central role in adipocyte differentiation. In the luciferase reporter assay using both GAL4 chimaera and full-length PPARγ systems, a mevalonate metabolite, FPP (farnesyl pyrophosphate), which is the precursor of almost all isoprenoids and is positioned at branch points leading to the synthesis of other longer-chain isoprenoids, activated PPARγ in a dose-dependent manner. FPP induced the in vitro binding of a co-activator, SRC-1 (steroid receptor co-activator-1), to GST (glutathione transferase)–PPARγ. Direct binding of FPP to PPARγ was also indicated by docking simulation studies. Moreover, the addition of FPP up-regulated the mRNA expression levels of PPARγ target genes during adipocyte differentiation induction. In the presence of lovastatin, an HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitor, both intracellular FPP levels and PPARγ-target gene expressions were decreased. In contrast, the increase in intracellular FPP level after the addition of zaragozic acid, a squalene synthase inhibitor, induced PPARγ-target gene expression. The addition of FPP and zaragozic acid promotes lipid accumulation during adipocyte differentiation. These findings indicated that FPP might function as an endogenous PPARγ agonist and regulate gene expression in adipocytes.