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An asymmetric reductive amination of ketones using both arylamines and benzhydrazide in the presence of nickel catalysts was developed. A one-pot synthesis of tetrahydroquinoxalines was also developed starting directly from α-ketoaldehydes and 1,2-diaminobenzene. Formic acid was used as a safe and economic surrogate for high-pressure hydrogen gas. Strongly σ-donating bis(alkylphosphine)s are crucial ancillary ligands for both stereoselective hydride insertion and decarboxylation of the formate.

Cytochrome P450 enzymes (P450s) are ubiquitously distributed heme enzymes that play catalytic roles in the essential oxidative biotransformation of a wide range of exogenous and endogenous organic compounds. Strong inhibition of P450s through mechanism-based inactivation (MBI) essentially should not occur, because it would affect important metabolic processes adversely. However, accumulated evidence shows that the MBI of a P450 is not a rare event. MBI can also be exploited for useful applications such as reaction phenotyping. Thus, MBI is clearly one of the major problems concerning P450s, but the reaction mechanisms underlying MBI are not very clear in many cases. In this work, we used density functional theory (DFT) calculations to understand how a metabolite (benzyne) is formed from two mechanism-based inactivators of P450s: 1-aminobenzotriazole (ABT) and N-benzyl-1-aminobenzotriazole (BBT). ABT has been widely used for reaction phenotyping. Our DFT calculations show that the formation of benzyne from...

We report the use of nickel catalysts for the catalytic transfer hydrogenation of hydrazones and other ketimines with formic acid. Strongly donating bisphosphines must be used to support the catalysts. As in enzymatic catalysis, attractive weak interactions may be important for stereochemical control by the nickel/binapine catalyst.

A series of density functional theory and G4 calculations are performed to quantify the extent to which proton-coupled electron transfer (PCET) lowers the barrier for H-abstraction in the reaction between 1,1-dimethylhydrazine (UDMH) and the compound I intermediate of a cytochrome P450 enzyme. The homolytic bond dissociation energy of UDMH is larger than that of 1,4-cyclohexadiene; nevertheless, the H-abstraction barrier is significantly lower for the former substrate. The barrier lowering in the UDMH reaction caused by PCET is roughly estimated to be 9 kcal/mol. Valence bond structures are analyzed in detail to figure out how PCET lowers the barrier height.

Computational studies of molecules always require consideration of two competing factors that determine the reliability and feasibility of the computation, i.e. accuracy and computational cost. Especially when studying large molecular systems such as enzymes, how to find the best compromise between these two factors becomes a matter of major concern. The most promising route to minimising the computational cost, while maintaining good reliability of computational outcomes, is to define subsystems within a system and then apply different levels of computational methods to different subsystems. The ONIOM (Our own N-layer Integrated molecular Orbital and molecular Mechanics) method enables such hybrid calculations. In particular, the two-layer ONIOM QM/MM scheme or ONIOM2(QM:MM), which combines quantum mechanics (QM) and molecular mechanics (MM) methods, is useful for the investigation of chemical reactions occurring in complex molecular systems such as enzymes. In this chapter, some of the key concepts used in ONIOM2(QM:MM) calculations are reviewed for students and researchers beginning to explore enzymes computationally. A few recent applications of the ONIOM method to enzymatic reactions are also showcased to provide specific examples that we hope will facilitate understanding of the method.

We report the use of nickel catalysts for the catalytic transfer hydrogenation of hydrazones and other ketimines with formic acid. Strongly donating bisphosphines must be used to support the catalysts. As in enzymatic catalysis, attractive weak interactions may be important for stereochemical control by the nickel/binapine catalyst.

The metabolism of amine-containing drugs by cytochrome P450 enzymes (P450s) is prone to form a nitrosoalkane metabolic intermediate (MI), which subsequently coordinates to the heme iron of a P450, to produce a metabolic-intermediate complex (MIC). This type of P450 inhibition, referred to as mechanism-based inactivation (MBI), presents a serious concern in drug discovery processes. We applied density functional theory (DFT) to the reaction between N-methylhydroxylamine (NMH) and the compound I reactive species of P450, in an effort to elucidate the mechanism of the putative final step of the MI formation in the alkylamine metabolism. Our DFT calculations show that H-abstraction from the hydroxyl group of NMH is the most favorable pathway via which the nitrosoalkane intermediate is produced spontaneously. H-abstraction from the N–H bond was slightly less favorable. In contrast, N-oxidation and H-abstraction from the C–H bond of the methyl group had much higher energy barriers. Hence, if the conversion of NMH to nitrosoalkane is catalyzed by a P450, the reaction should proceed preferentially via H-abstraction, either from the O–H bond or from the N–H bond. Our theoretical analysis of the interaction between the MI and pentacoordinate heme moieties provided further insights into the coordination bond in the MIC. Published version

A precise understanding of the mechanism-based inactivation of cytochrome P450 enzymes (P450s) at the quantum mechanical level should allow more reliable predictions of drug–drug interactions than those currently available. Hydrazines are among the molecules that act as mechanism-based inactivators to terminate the function of P450s, which are essential heme enzymes responsible for drug metabolism in the human body. Despite its importance, the mechanism explaining how a metabolic intermediate (MI) is formed from hydrazine is not fully understood. We used density functional theory (DFT) calculations to compare four possible mechanisms underlying the reaction between 1,1-dimethylhydrazine (or unsymmetrical dimethylhydrazine, UDMH) and the reactive compound I (Cpd I) intermediate of P450. Our DFT calculations provided a clear view on how an aminonitrene-type MI is formed from UDMH. In the most favorable pathway, hydrogen is spontaneously abstracted from the N2 atom of UDMH by Cpd I, followed by a second hydrogen abstraction from the N2 atom by Cpd II. Nitrogen oxidation of nitrogen atoms and hydrogen abstraction from the C[BOND]H bond of the methyl group were found to be less favorable than the hydrogen abstraction from the N[BOND]H bond. We also found that the reaction of protonated UDMH with Cpd I is rather sluggish. The aminonitrene-type MI binds to the ferric heme more strongly than a water molecule. This is consistent with the notion that the catalytic cycle of P450 is impeded when such an MI is produced through the P450-catalyzed reaction.