Zaragozic Acid (Part II)
Hashimoto, Hirata, Nakamura, Watanabe, Kataoka, Kurosaki, Anada, Kitagaki and Shiro. Chem. Eur. J., 2006, Early View. DOI: 10.1002/chem.200601212.
A second appearance for zaragozic acid on this blog (the first was by Rizzacasa), and a second synthesis by this group (the first). However, there’s been lots of work on this natural product family, most of which construct the ketal using the same approach (Heathcock’s route was an exception). In this synthesis, however, they’ve used a carbonyl ylide cyclisation, an exceptionally elegant route to that complex bridged system.
To make the cyclisation substrate, they needed a diazo group adjacent to a carbonyl; I’m impressed with the way they did this, using a protocol developed by Wenkert.
I’m just surprised that the diazo group stays intact! They initially did quite a bit of screening, and had to determine the levels of diastereomeric control. For this they cyclised the product, and the diazo group still stays on! I was quite taken with this transformation, but it obviously shows that I need to brush up on my diazo chemistry…
They were then set for the cyclisation, which was rigorously screened to find the right dipolarophile, catalyst and solvent, and settled upon those shown, completing the transformation in a remarkably good yield. Left with the olefin and the methyl ester, a dihydoxylation and cleavage of the extraneous carbon unit left the complex bridged system complete.
Appendage of the sidechains was initially commenced with a Kocienskiâ€“Julia olefination, but returned starting material! Thus, they then tried some metathesis, again screening conditions; Blechert’s catalyst was most successful (effectively a derivative of Hoveyda’s catalyst). This consituted a formal synthesis of the target, but they finished the job anyway, following Carreira and Du Bois’s route. Now that’s a load of screening!