Stereocontrolled Syntheses of the Nemorensic Acids Using 6-Diazoheptane-2,5-dione in Carbonyl Ylide Cycloadditions

Levulinic acid-derived 6-diazoheptane-2,5-dione (9) serves as a common precursor in a formal
synthesis of frontalin 19, and in syntheses of cis-nemorensic acid 1, 4-hydroxy-cis-nemorensic acid
2, 3-hydroxy-cis-nemorensic acid 3, and nemorensic acid 4. The key step in these syntheses is the
Rh2(OAc)4-catalyzed tandem carbonyl ylide formation−intermolecular 1,3-dipolar cycloadditions
of diazodione 9 with formaldehyde, alkynes or allene, which occur with high regioselectivity.
Subsequent oxidative cleavage of the ring originally derived from the cyclic carbonyl ylide
intermediate provides a straightforward access to polysubstituted tetrahydrofurans, and in
particular an efficient entry to the nemorensic acids. Enantioselective cycloadditions with diazodione
9, using chiral rhodium catalysts, gave cycloadducts in up to 51% ee.