Pd-Catalyzed Decarboxylative Olefination: Stereoselective Synthesis of Polysubstituted Butadienes and Macrocyclic P-glycoprotein Inhibitors

The
efficient and stereo­selective synthesis of polysubstituted
butadienes, especially the multifunctional butadienes, represents
a great challenge in organic synthesis. Herein, we wish to report
a distinctive Pd(0) carbene-initiated decarboxylative olefination
approach that enables the direct coupling of diazo esters with vinylethylene
carbonates (VECs), vinyl oxazolidinones, or vinyl benzoxazinones to
afford alcohol-, amine-, or aniline-containing 1,3-dienes in moderate
to high yields and with excellent stereo­selectivity. This protocol
features operational simplicity, mild reaction conditions, a broad
substrate scope, and gram-scalability. Notably, a structurally unique
allylic Pd­(II) intermediate was isolated and characterized. DFT calculation
and control experiments demonstrated that a rare Pd(0) carbene intermediate
could be involved in this reaction. Moreover, the polysubstituted
butadienes as novel building blocks were unprecedentedly assembled
into macrocycles, which efficiently inhibited the P-glycoprotein and
dramatically reversed multidrug resistance in cancer cells by 190-fold.