Asymmetric Alkyne Transformation via Gold/Organo Synergistic Catalysis

ConspectusThe construction of polyfunctionalized chiral molecules represents a compelling frontier in chemical research. In this context, gold-catalyzed asymmetric alkyne transformations─achieved through the cleavage and functionalization of one or two π bonds─stand out as versatile protocols. This method features high atom economy and bond-forming efficiency, facilitating the rapid assembly of structurally diverse and complex chiral compounds. Although remarkable chemo- and regioselectivity have been established over the past decades with the development of sophisticatedly designed gold catalysts, controlling the enantioselectivity remains a challenge. This is primarily due to the outer-sphere catalytic model, which is based on the innately linear coordination geometry of gold complexes. Furthermore, achieving stereocontrol in alkyne multifunctionalization involving the cleavage of two π bonds is more complicated due to the potential catalyst dissociation during the cascade process. On the other hand, the efficiency of chiral gold catalysts has often been unpredictable, as the steric and electronic demands vary significantly across different substrates. Consequently, the development of a modular and practical strategy that leverages commercially available catalysts to achieve high enantioselectivity in alkyne functionalization remains highly desirable.In this Account, we summarize our recent efforts in developing a synergistic gold/organo catalysis strategy to address these challenges. This protocol relies on the chiral-organocatalyst-mediated asymmetric interception of two distinct classes of prochiral gold-associated intermediates: gold enolates and allylic gold species. First, leveraging the gold-catalyzed oxidative generation of gold carbenes from alkynes, we realized diverse asymmetric carbene geminal difunctionalization transformations through chiral Brønsted acid-promoted enantioselective Mannich addition of transient gold enolate species, leading to chiral dihydrofuran-3-ones and chiral α-alkoxy-β-amino ketone derivatives. Moreover, asymmetric geminal dialkylation of gold carbene species derived from unactivated internal alkynes furnishes polyfunctionalized chiral linear and cyclic ketones that incorporate quaternary stereocenters. Second, the allylic gold species, which is derived from the vinylgold intermediate via an aromatization-driven double-bond migration process, has been isolated and characterized by X-ray crystallography for the first time by our group. This key intermediate has engaged in a range of asymmetric ene-type reactions with different electrophiles in the presence of chiral quinine-derived squaramide (QN-SQA) cocatalysts, including aldol and Mannich-type addition reactions, formal Michael-type addition, stepwise [4 + 2] annulation, and divergent amination reactions. In all of these transformations, the achiral gold complexes promoted the formation of the key prochiral gold-associated intermediates under mild conditions, and the exceptionally high stereocontrol is achieved in the later interception stage facilitated by the chiral organocatalysts. A hallmark of this synergistic approach is its modularity and practicality. By an appropriate combination of achiral gold complexes with readily available chiral organocatalysts, we circumvent the lengthy search for complex chiral ligands, enabling a variety of novel asymmetric alkyne transformations by simply switching the trapping reagents with the aid of readily accessible matched chiral organocatalysts. This flexible platform not only solves long-standing stereochemical problems in alkyne functionalization but also opens new avenues for the design of distinct catalytic manifolds in asymmetric synthesis.