RESUMO
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.
RESUMO
Rh-catalyzed carbonylative C-C bond activation of cyclopropylamides generates configurationally stable rhodacyclopentanones that engage tethered alkenes in (3+1+2) cycloadditions. These studies provide the first examples of multicomponent cycloadditions that proceed through C-C bond activation of "simple" electron poor cyclopropanes.
RESUMO
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.
RESUMO
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.
RESUMO
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.
Assuntos
Ciclopropanos/química , Compostos Heterocíclicos/síntese química , Ródio/química , Alcenos/química , Catálise , Ciclização , Compostos Heterocíclicos/química , Estrutura Molecular , EstereoisomerismoRESUMO
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.