Chelation-driven rearrangement of primary alkyl aminopalladation products to stable trisubstituted alkyl-palladium complexes.

The formation of highly substituted carbon centers using catalysis has been a widely sought after goal, but complexes of highly substituted carbon atoms with transition metals are rare, and the factors that affect the relative stability of complexes with differentially substituted carbon atoms are poorly understood. In this study, a set of equilibrating alkyl-palladium complexes were subtly tuned to form either a primary or trisubstituted alkyl complex as the more thermodynamically favored state, depending on either the substrate or reaction conditions. An X-ray crystal structure of the trisubstituted alkyl-palladium complex is presented and compared with the corresponding primary alkyl complex. The mechanism for rearrangement and the factors that drive the change in stability are discussed.

Computational design of enone-binding proteins with catalytic activity for the Morita-Baylis-Hillman reaction.

The Morita-Baylis-Hillman reaction forms a carbon-carbon bond between the α-carbon of a conjugated carbonyl compound and a carbon electrophile. The reaction mechanism involves Michael addition of a nucleophile catalyst at the carbonyl ß-carbon, followed by bond formation with the electrophile and catalyst disassociation to release the product. We used Rosetta to design 48 proteins containing active sites predicted to carry out this mechanism, of which two show catalytic activity by mass spectrometry (MS). Substrate labeling measured by MS and site-directed mutagenesis experiments show that the designed active-site residues are responsible for activity, although rate acceleration over background is modest. To characterize the designed proteins, we developed a fluorescence-based screen for intermediate formation in cell lysates, carried out microsecond molecular dynamics simulations, and solved X-ray crystal structures. These data indicate a partially formed active site and suggest several clear avenues for designing more active catalysts.

Palladium-catalyzed alkoxyamination of alkenes with use of N-fluorobenzenesulfonimide as oxidant.

A Pd-catalyzed alkoxyamination of protected aminoalkenes promoted by N-fluorobenzenesulfonimide is described. This mild transformation allows the direct formation of ethers from carbon-carbon double bonds. An unusual switch from exo to endo selectivity in polar solvents was discovered, allowing the selective formation of either regioisomer by careful choice of reaction conditions.

Mechanism of N-fluorobenzenesulfonimide promoted diamination and carboamination reactions: divergent reactivity of a Pd(IV) species.

The mechanism of the Pd-catalyzed diamination and carboamination of alkenes promoted by N-fluorobenzenesulfonimide (NFBS) was investigated. Stereochemical labeling experiments established that the diamination reaction proceeds via overall syn addition of the two nitrogen groups, whereas carboamination is the result of an anti addition of arene and nitrogen to the alkene. The intermediate Pd-alkyl complex arising from aminopalladation was observed, and an X-ray crystal structure of its 2,2'-bipyridine (bipy) complex was obtained, revealing strong chelation of the amide protecting group to palladium. Aminopalladation was shown to be an anti-selective process in both the presence and the absence of added ligands, proceeding via external attack of the nitrogen on a Pd-coordinated alkene. The intermediate Pd-alkyl complex was converted to diamination product upon exposure to NFBS with inversion of configuration via oxidative addition followed by dissociation of the benzenesulfonimide anion and S(N)2 displacement of the Pd-C bond. Conversely, arylation of the Pd-alkyl complex proceeds via retention of stereochemistry, consistent with C-H activation of the arene at the Pd(IV) center. A small intermolecular isotope effect (k(H)/k(D) = 1.1) and a large intramolecular isotope effect (k(H)/k(D) = 4) were measured for this process, indicating that C-H activation occurs via a poorly selective product-determining coordination of the arene followed by a highly selective C-H activation. Competition between arenes reveals an unusual reactivity order of toluene > benzene > bromobenzene > anisole.

Palladium-catalyzed carboamination of alkenes promoted by N-fluorobenzenesulfonimide via C-H activation of arenes.

This report describes a unique Pd-catalyzed oxidative carboamination of protected aminoalkenes in which inexpensive unactivated nucleophilic arenes are incorporated to give carboamination products in good yields. A variety of protected amide and carbamate groups are tolerated, and various five-, six-, and seven-membered rings are formed in good yields. Under these conditions, halobenzenes are activated at the C-H bond rather than the C-X bond, and very high regioselectivity for the para substitution product is observed in all cases. We propose that this carboamination takes place via electrophilic aromatic substitution of a Pd(IV) alkyl intermediate.