Pd(0)-Catalyzed Asymmetric Cyclization/Coupling Cascade of Alkyne-Tethered Unsaturated Carbonyls: Development and Mechanism Elucidation

While the Pd(0)-catalyzed cyclization of alkyne-tethered unsaturated carbonyl substrates has been reported, the mechanism has not been well elucidated, and the potential asymmetric version remains to be developed. Here, we disclose that a chiral Pd(0) complex can efficiently promote the desymmetrizative cyclization of alkyne-tethered cyclohexadienones in CH₃OH, and the resultant Pd­(II) intermediates further undergo an array of tandem coupling reactions, including Suzuki, Sonogashira, and even chemoselective reduction by CH₃OH in the absence of additional coupling partners. As a result, a broad spectrum of hydrobenzofuran derivatives, having a tetra- or trisubstituted <i>exo</i>-alkene motif, is constructed with moderate to outstanding enantioselectivity in an exclusive <i>cis</i>-difunctionalization pattern. In addition, this enantioselective protocol can be well expanded to linear alkyne-tethered unsaturated carbonyls, and a new desymmetrizative and asymmetric cyclization/coupling cascade of bis-alkyne-tethered enones is further realized efficiently, furnishing diversely structured frameworks with high stereoselectivity. Moreover, kinetic transformation for various racemic alkyne-tethered enones can be accomplished under similar catalytic conditions, and unusual kinetic reactions by chemoselectively undertaking Suzuki or Sonogashira coupling, or reduction by CH₃OH, occur sequentially, finally yielding two types of chiral products, both with high enantioselectivity via either ligand- or substrate-based control. The experimental results demonstrate that the current Pd(0)-based strategy is superior to the classical Pd­(II)-catalyzed carbopalladation/cyclization process of the identical substrates with regard to enantioselectivity and synthetic versatility. Moreover, density functional theory calculations are conducted to rationalize the Pd(0)-catalyzed oxidative cyclometalation pathway in the key cyclization step, which leads to the observed <i>cis</i>-difunctionalized products exclusively.