The Morita-Baylis-Hillman reaction forms a carbon-carbon bond between the alpha carbon of a conjugated carbonyl compound and a carbon electrophile. The reaction mechanism involves Michael addition of a nucleophile catalyst at the carbonyl beta 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.

An enantioselective Pd-catalyzed vicinal diamination of unactivated alkenes using N-fluorobenzenesulfonimide as both an oxidant and a source of nitrogen is reported. The use of Ph-pybox and Ph-quinox ligands afforded differentially protected vicinal diamines in good yields with high enantioselectivities. Mechanistic experiments revealed that the high enantioselectivity arises from selective formation of only one of four possible diastereomeric aminopalladation products of the chiral Pd complex. The aminopalladation complex was characterized by X-ray crystallography.

A pincer for high selectivity: A mild palladium‐catalyzed hydroamination of protected amino‐1,3‐dienes is possible. This highly regioselective reaction employs a tridentate PNP pincer ligand and leads to cyclic and homoallylic protected amines in high yields. Substrates with a wide array of amine protecting groups and diene substitution patterns were cyclized to form five‐ and six‐membered heterocycles. PG=protecting group.

A new class of chiral Pd(II) complexes bearing a rigid, bidentate C,N-ligand are synthesized and characterized. The ligands are obtained in good yield via a simple five-step synthetic route beginning with cheap and commercially available amino alcohols. The structure of one of these new complexes is determined by X-ray crystallography. This data shows the expected large trans effect difference between the N and C donors (0.07 Å Pd-Cl bond length difference) as well as a boat conformation of the 6-membered chelate ring.

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.

The formation of highly substituted carbon centers using catalysis has been aw idely 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,aset of equilibrating alkylpalladium complexes were subtly tuned to form either ap rimary or trisubstituted alkylc omplex as the more thermodynamically favored state,d epending on either the substrate or reaction conditions.A nX -ray crystal structure of the trisubstituted alkyl-palladium complex is presented and compared with the corresponding primary alkylc omplex. The mechanism for rearrangement and the factors that drive the change in stability are discussed.Alkyl-metal complexes are key intermediates in aw ide variety of important organic reactions.[1] Among the more challenging goals of organic synthesis is the formation of highly substituted carbon centers,a nd metal-catalyzed reactions have the potential to be powerful tools in the realization of this goal.[2] However,s uch reactions are still quite challenging because of the scarcity of highly substituted alkyl-metal complexes.U nderstanding the factors that control the structure and stability of alkyl-metal intermediates is critical to expanding the scope of these metal-catalyzed processes.Ther elative stability of primary,s econdary,a nd tertiary alkyl-metal complexes is generally expected to follow the trend for organolithium compounds, [3] in which the highly polarized CÀLi bond results in alarge negative-charge density at the carbon atom. Increasing the substitution of the carbon atom with electron-donating alkyl groups increases the negative charge at the carbon center,a nd thus destabilizes tertiary alkyllithium compounds relative to primary alkyllithium compounds.T his model works well for many alkylmetal complexes,b ut the analysis is more complicated for transition metals such as palladium. Information on the relative stability of alkyl-palladium complexes is sparse, contradictory,a nd without clear general trends.Tw oexperimental studies of the relative stability of alkylpalladium complexes have been reported. Reger et al. [4] studied Pd complexes bearing dithiocarbamate ligands,i n which the small size of the ligands presumably minimizes any steric effects on stability.Inthis study,the stability of the alkyl complexes followed the traditional order:p rimary > secondary @ tertiary.However,alkyl groups bearing electron-withdrawing groups,such as CF 3 or CN,overrode this preference to put those groups next to the PdÀCb ond. More recently, Brookhart and co-workers [5] studied the isomerization of alkyl-palladium complexes with ad iimine ligand. Here,t he relative stability of the alkyl complexes was highly dependent on the structure of the fourth ligand. When no ligand or acetonitrile was bound in cis position to the alkyl ligand, [6] the secondary alkyl complex was more stable,b ut when bulkier ligands were pre...

No abstract

A pincer for high selectivity: A mild palladium‐catalyzed hydroamination of protected amino‐1,3‐dienes is possible. This highly regioselective reaction employs a tridentate PNP pincer ligand and leads to cyclic and homoallylic protected amines in high yields. Substrates with a wide array of amine protecting groups and diene substitution patterns were cyclized to form five‐ and six‐membered heterocycles. PG=protecting group.