Pd -Catalyzed C(alkenyl)-H Activation Facilitated by a Transient Directing Group.

Palladium(II)-catalyzed C(alkenyl)-H alkenylation enabled by a transient directing group (TDG) strategy is described. The dual catalytic process takes advantage of reversible condensation between an alkenyl aldehyde substrate and an amino acid TDG to facilitate coordination of the metal catalyst and subsequent C(alkenyl)-H activation by a tailored carboxylate base. The resulting palladacycle then engages an acceptor alkene, furnishing a 1,3-diene with high regio- and E/Z-selectivity.

Thiol Reactivity of -Aryl α-Methylene-γ-lactams: A Reactive Group for Targeted Covalent Inhibitor Design.

Kinase activity can be modulated reversibly or irreversibly by the reaction of targeted covalent inhibitors with nucleophilic residues in protein active sites. Herein, we present thiol reactivity studies that support α-methylene-γ-lactams as tunable surrogates for the highly reactive α-methylene-γ-lactones. The reactivity of the α-methylene is modulated via the N substituent, and the reaction rates toward glutathione were determined via mass spectrometry.

Multifaceted Substrate-Ligand Interactions Promote the Copper-Catalyzed Hydroboration of Benzylidenecyclobutanes and Related Compounds.

A unified synthetic strategy to access tertiary four-membered carbo/heterocyclic boronic esters is reported. Use of a Cu(I) catalyst in combination with a modified dppbz ligand enables regioselective hydroboration of various trisubstituted benzylidenecyclobutanes and carbo/heterocyclic analogs. The reaction conditions are mild, and the method tolerates a wide range of medicinally relevant heteroarenes.

Cu-Catalyzed Hydroboration of Benzylidenecyclopropanes: Reaction Optimization, (Hetero)Aryl Scope, and Origins of Pathway Selectivity.

The copper-catalyzed hydroboration of benzylidenecyclopropanes, conveniently accessed in one step from readily available benzaldehydes, is reported. Under otherwise identical reaction conditions, two distinct phosphine ligands grant access to different products by either suppressing or promoting cyclopropane opening via β-carbon elimination. Computational studies provide insight into how the rigidity and steric environment of these different bis-phosphine ligands influence the relative activation energies of β-carbon elimination versus protodecupration from the key benzylcopper intermediate.

A Transient-Directing-Group Strategy Enables Enantioselective Reductive Heck Hydroarylation of Alkenes.

Metal-coordinating directing groups have seen extensive use in the field of transition-metal-catalyzed alkene functionalization; however, their waste-generating installation and removal steps limit the efficiency and practicality of reactions that rely on their use. Inspired by developments in asymmetric organocatalysis, where reactions rely on reversible covalent interactions between an organic substrate and a chiral mediator, we have developed a transient-directing-group approach to reductive Heck hydroarylation of alkenyl benzaldehyde substrates that proceeds under mild conditions. Highly stereoselective migratory insertion is facilitated by in situ formation of an imine from catalytic amounts of a commercially available amino acid additive.

Sterically Shielded, Stabilized Nitrile Imine for Rapid Bioorthogonal Protein Labeling in Live Cells.

In pursuit of fast bioorthogonal reactions, reactive moieties have been increasingly employed for selective labeling of biomolecules in living systems, posing a challenge in attaining reactivity without sacrificing selectivity. To address this challenge, here we report a bioinspired strategy in which molecular shape controls the selectivity of a transient, highly reactive nitrile imine dipole. By tuning the shape of structural pendants attached to the ortho position of the N-aryl ring of diaryltetrazoles-precursors of nitrile imines, we discovered a sterically shielded nitrile imine that favors the 1,3-dipolar cycloaddition over the competing nucleophilic addition.