Asymmetric Total Synthesis and Biological Evaluation of the Natural PDE4 Inhibitor Toddacoumalone

Abstract

We describe herein the first asymmetric total synthesis and biological evaluation of the natural PDE4 inhibitor toddacoumalone and its stereoisomers. The key step of the total synthesis is a formal asymmetric [4 + 2] cycloaddition reaction catalyzed by chiral secondary amine catalysts. A variety of pyrano­quinolinones and 3-methyl­crotonaldehyde are well tolerated under the optimized reaction conditions, which paved the way for further SAR studies. Further biological evaluation showed 1a′ with the best PDE4 inhibitory activity (IC50 = 0.18 μM).

Discovery and Structural Optimization of Toddacoumalone Derivatives as Novel PDE4 Inhibitors for the Topical Treatment of Psoriasis

“…Toddacoumalone derivatives were prepared according to the synthetic methods reported by our group . The synthetic route of compounds 7 and 9 is depicted in Scheme .…”

“…In 2014, Yin and Luo discovered that natural toddacoumalone has moderate PDE4D inhibition activity . Recently, our group has achieved the first concise asymmetric total synthesis, structural elucidation, and preliminary structure–activity relationship (SAR) study of toddacoumalone . Among all stereoisomers, (2 R ,4 S )-toddacoumalone ( 1 , Figure ) showed moderate inhibitory potency (IC 50 = 180 nM) against PDE4D, providing a precious lead structure for developing novel PDE4 inhibitors.…”

Construction of α,β-Diamino Diacid Derivatives with Adjacent Acyclic Tetrasubstituted Stereocenters

“…Our group recently demonstrated that the DHA derivatives could be applied as ketimines for the construction of vicinal tetrasubstituted acyclic stereocenters . As part of our research interests in developing new strategies to construct useful building blocks, we herein disclose a Mannich-type reaction of azlactones with 2-aminoacrylates to furnish the masked α,β-diamino diacid derivatives bearing vicinal quaternary stereocenters in good yields and excellent diastereoselectivities. Moreover, this strategy could be applied to synthesize the chiral α,β-diamino diacid derivatives by employing a cinchona alkaloid dimer (DHQD) 2 PHAL as the catalyst.…”

Organocatalyzed Cascade Aza-Michael/Aldol Reaction for Atroposelective Construction of 4-Naphthylquinoline-3-carbaldehydes

“…Cascade reactions have been considered as economical and environmentally friendly processes for assembling structurally complex molecules from relatively simple materials . Over the past few decades, the cascade reactions promoted by the l -proline based secondary amine catalysts have emerged as efficient tools for the synthesis of complex targets . In the related process, the iminium–allenamine conversion was commonly used as the activation mode .…”