Capture–Collapse Heterocyclization:1,3-Diazepanes by C–N Reductive Elimination from Rhodacyclopentanones

Rhodacyclopentanones derived from carbonylative C–C activation of cyclopropyl ureas can be “captured” by pendant nucleophiles prior to “collapse” to 1,3-diazepanes. The choice of N-substituent on the cyclopropane unit controls the oxidation level of the product, such that C4–C5 unsaturated or saturated systems can be accessed selectively

New Initiation Modes for Directed Carbonylative C-C Bond Activation:Rhodium-Catalyzed (3+1+2) Cycloadditions of Aminomethylcyclopropanes

Under carbonylative conditions, neutral Rh­(I)-systems modified with weak donor ligands (AsPh₃ or 1,4-oxathiane) undergo N-Cbz, N-benzoyl, or N-Ts directed insertion into the proximal C–C bond of amino­methyl­cyclo­propanes to generate rhodacyclo­pentanone intermediates. These are trapped by N-tethered alkenes to provide complex perhydroisoindoles

Branch-Selective, Iridium-Catalyzed Hydroarylation of Monosubstituted Alkenes via a Cooperative Destabilization Strategy

Highly branch-selective, carbonyl-directed hydro­aryl­ations of mono­substituted alkenes are described. The chemistry relies upon a cationic Ir­(I) catalyst modified with an electron deficient, wide bite angle bis­phosphine ligand. This work provides a regio­isomeric alternative to the Murai hydro­aryl­ation protocol

Branch-Selective, Iridium-Catalyzed Hydroarylation of Monosubstituted Alkenes via a Cooperative Destabilization Strategy

Highly branch-selective, carbonyl-directed hydro­aryl­ations of mono­substituted alkenes are described. The chemistry relies upon a cationic Ir­(I) catalyst modified with an electron deficient, wide bite angle bis­phosphine ligand. This work provides a regio­isomeric alternative to the Murai hydro­aryl­ation protocol

Reversible C–C Bond Activation Enables Stereocontrol in Rh-Catalyzed Carbonylative Cycloadditions of Aminocyclopropanes

Upon exposure to neutral or cationic Rh­(I)-catalyst systems, amino-substituted cyclopropanes undergo carbonylative cycloaddition with tethered alkenes to provide stereochemically complex N-heterocyclic scaffolds. These processes rely upon the generation and trapping of rhodacyclopentanone intermediates, which arise by regioselective, Cbz-directed insertion of Rh and CO into one of the two proximal aminocyclopropane C–C bonds. For cyclizations using cationic Rh­(I)-systems, synthetic and mechanistic studies indicate that rhodacyclopentanone formation is reversible and that the alkene insertion step determines product diastereoselectivity. This regime facilitates high levels of stereocontrol with respect to substituents on the alkene tether. The option of generating rhodacyclopentanones dynamically provides a new facet to a growing area of catalysis and may find use as a (stereo)­control strategy in other processes

Copper-Catalyzed Racemization-Recycle of a Quaternary Center and Optimization Using a Combined Kinetics-DoE/MLR Modeling Approach

The copper-catalyzed racemization of a complex, quaternary center of a key intermediate on route to lanabecestat has been identified. Optimization and mechanistic understanding were achieved through the use of an efficient, combined kinetic-multiple linear regression approach to experimental design and modeling. The use of a definitive screening design with mechanistically relevant factors and a mixture of fitted kinetic descriptors and empirical measurements facilitated the generation of a model that accurately predicted complex reaction time course behavior. The synergistic model was used to minimize the formation of dimer byproducts, determine optimal conditions for batch operation, and highlight superheated conditions that could be accessed in flow, leading to a further increase in yield which was predicted by the original model