Enantioselective Alkyne Conjugate Addition Enabled by Readily Tuned Atropisomeric P,N-Ligands

Abstract

By the nature of its structure, the 5-membered chiral biaryl heterocyclic scaffold represents a departure from 6-membered P,N-ligands that facilitates tuning and enables ligand evolution to address issues of selectivity and reactivity. In this vein, the Cu-catalyzed enantioselective conjugate alkynylation of Meldrum's acid acceptors is reported using Me-StackPhos. Enabled by this new ligand, the reaction tolerates a wide range of alkynes furnishing the products in high yields and excellent enantioselectivity. The transformation provides access to highly useful chiral β-alkynyl Meldrum's acid building blocks as demonstrated by an efficient enantioselective synthesis of the preclinical agent OPC 51803.

A Facile Enantioselective Alkynylation of Chromones

“…With the goal of developing an enantioselective chromone alkynylation, we set out to explore the proposed transformation using our Stack ligands . These ligands were designed to have a stabilizing intramolecular catalyst–catalyst interaction between the naphthyl and C 6 F 5 groups, and the groups on the backbone were originally incorporated to establish a chiral pocket with quadrants of differing steric demand . The backbone aryl groups can be modified to include electron‐withdrawing/donating substituents and we sought to determine if these modifications could impact the reaction, possibly by intermolecular π–π or π–cation interactions.…”

“…These ligands were designed to have a stabilizing intramolecular catalyst–catalyst interaction between the naphthyl and C 6 F 5 groups, and the groups on the backbone were originally incorporated to establish a chiral pocket with quadrants of differing steric demand . The backbone aryl groups can be modified to include electron‐withdrawing/donating substituents and we sought to determine if these modifications could impact the reaction, possibly by intermolecular π–π or π–cation interactions. Although the phosphine's aryl groups are also positioned in proximity, and P‐aryl‐substrate interactions are known, the backbone aryls are unique to this imidazole‐based P,N‐ligand class and offer tunability without directly impacting the nature of the metal–ligand bond as does phosphine modification.…”

Lactone Synthesis by Enantioselective Orthogonal Tandem Catalysis

“…Studies from our laboratory have been directed at using heterocyclic chiral biaryl ligands in enantioselective transformations and we postulated that our Stack ligands might also control other types of selectivity. We recently reported conjugate addition to Meldrum's acid derivatives in water, and we decided that this would be a suitable reaction platform from which to build a subsequent catalytic transformation to form the six‐membered lactone 7 . To achieve this, our ligands would need to reverse the innate substrate regioselectivity reported by Jiao and Fillion [Eq.…”

“…The Ag I catalyst appears to be a much better catalyst than the corresponding Cu I catalyst for the heterofunctionalization step, and it is probable that this species is predominantly responsible for the second phase of the reaction sequence. The process begins with the formation of the copper acetylide 14 , which then adds to the Meldrum's acid substrate 6 to form the alkynylated product 15 as the copper enolate . After hydrolysis, the alkyne product 8 is formed and enters into the Ag catalytic cycle.…”

Lactone Synthesis by Enantioselective Orthogonal Tandem Catalysis

“…[23] Studies from our laboratory have been directed at using heterocyclic chiral biaryl ligands in enantioselective transformations [24][25][26][27][28][29] and we postulated that our Stack ligands might also control other types of selectivity. We recently reported conjugate addition to Meldrumsa cid derivatives in water, [30] and we decided that this would be asuitable reaction platform from which to build asubsequent catalytic transformation to form the six-membered lactone 7. To achieve this,our ligands would need to reverse the innate substrate regioselectivity reported by Jiao and Fillion [Eq.…”