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The synthesis of strained carbocyclic building blocks is relevant for Medicinal Chemistry, and methylenecyclobutanes are particularly challenging with current synthetic technology. Careful inspection of the reactivity of [1.1.1]propellane and diboron reagents has revealed that bis(catecholato)diboron (B 2 cat 2 ) can produce a bis(borylated) methylenecyclobutane in a few minutes at room temperature. This reaction constitutes the first example of B-B bond activation by a special apolar hydrocarbon and also the first time that propellane is electrophilically activated by boron. Mechanistic studies including in situ NMR kinetics and DFT calculations demonstrate that the diboron moiety can be directly activated through coordination with the inverted sigma bond of propellane, and reveal that DMF is involved in the stabilization of diboronate ylide intermediates rather than the activation of the B-B bond. These results enable new possibilities for both diboron and propellane chemistry, and for further developments in the synthesis of methylenecyclobutanes based on propellane strain release., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

The acyltransferase from Pseudomonas protegens (PpATase) catalyzes in nature the reversible transformation of monoacetylphloroglucinol to diacetylphloroglucinol and phloroglucinol. Interestingly, this enzyme has been shown to catalyze the promiscuous transformation of 3-hydroxyphenyl acetate to 2',4'-dihydroxyacetophenone, representing a biological version of the Fries rearrangement. In the present study, we report a mechanistic investigation of this activity of PpATase using quantum chemical calculations. A detailed mechanism is proposed, and the energy profile for the reaction is presented. The calculations show that the acylation of the enzyme is highly exothermic, while the acetyl transfer back to the substrate is only slightly exothermic. The deprotonation of the C6-H of the substrate is rate-limiting, and a remote aspartate residue (Asp137) is proposed to be the general base group in this step. Analysis of the binding energies of various acetyl acceptors shows that PpATase can promote both intramolecular and intermolecular Fries rearrangement towards diverse compounds., (© 2023 The Authors. ChemistryOpen published by Wiley-VCH GmbH.)

Density functional theory calculations have been performed to investigate the mechanism for the BINOL-catalyzed asymmetric homologation of alkenylboronic acids with CF 3 -diazomethane. The reaction proceeds via a chiral BINOL ester of the alkenylboronic acid substrate. The calculations reveal a complex scenario for the formation of the chiral BINOL-alkenylboronate species, which is the key intermediate in the catalytic process. The aliphatic alcohol additive plays an important role in the reaction. This study provides a rationalization of the stereoinduction step of the reaction, and the enantioselectivity is mainly attributed to the steric repulsion between the CF 3 group of the diazomethane reagent and the γ-substituent of the BINOL catalyst. The complex potential energy surface obtained by the calculations is analyzed by means of microkinetic simulations.

Methylation of amines inside an introverted resorcinarene-based deep methyl ester cavitand is investigated by means of molecular dynamics simulations and quantum chemical calculations. Experimentally, the cavitand has been shown to bind a number of amines and accelerate the methylation reaction by more than four orders of magnitude for some of them. Eight different amines are considered in the present study, and the geometries and energies of their binding to the cavitand are first characterized and analyzed. Next, the methyl transfer reactions are investigated and the calculated barriers are found to be in generally good agreement with experimental results. In particular, the experimentally-observed rate acceleration in the cavitand as compared to the solution reaction is well reproduced by the calculations. The origins of this rate acceleration are analyzed by computational modifications made to the structure of the cavitand, and the role of the solvent is discussed., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

The quantum chemical cluster approach has been used for modeling enzyme active sites and reaction mechanisms for more than two decades. In this methodology, a relatively small part of the enzyme around the active site is selected as a model, and quantum chemical methods, typically density functional theory, are used to calculate energies and other properties. The surrounding enzyme is modeled using implicit solvation and atom fixing techniques. Over the years, a large number of enzyme mechanisms have been solved using this method. The models have gradually become larger as a result of the faster computers, and new kinds of questions have been addressed. In this Account, we review how the cluster approach can be utilized in the field of biocatalysis. Examples from our recent work are chosen to illustrate various aspects of the methodology. The use of the cluster model to explore substrate binding is discussed first. It is emphasized that a comprehensive search is necessary in order to identify the lowest-energy binding mode(s). It is also argued that the best binding mode might not be the productive one, and the full reactions for a number of enzyme-substrate complexes have therefore to be considered to find the lowest-energy reaction pathway. Next, examples are given of how the cluster approach can help in the elucidation of detailed reaction mechanisms of biocatalytically interesting enzymes, and how this knowledge can be exploited to develop enzymes with new functions or to understand the reasons for lack of activity toward non-natural substrates. The enzymes discussed in this context are phenolic acid decarboxylase and metal-dependent decarboxylases from the amidohydrolase superfamily. Next, the application of the cluster approach in the investigation of enzymatic enantioselectivity is discussed. The reaction of strictosidine synthase is selected as a case study, where the cluster calculations could reproduce and rationalize the selectivities of both the natural and non-natural substrates. Finally, we discuss how the cluster approach can be used to guide the rational design of enzyme variants with improved activity and selectivity. Acyl transferase from Mycobacterium smegmatis serves as an instructive example here, for which the calculations could pinpoint the factors controlling the reaction specificity and enantioselectivity. The cases discussed in this Account highlight thus the value of the cluster approach as a tool in biocatalysis. It complements experiments and other computational techniques in this field and provides insights that can be used to understand existing enzymes and to develop new variants with tailored properties.

The Nazarov cyclization is investigated in solution and within K 12 [Ga 4 L 6 ] supramolecular organometallic cage by means of computational methods. The reaction needs acidic condition in solution but works at neutral pH in the presence of the metallocage. The reaction steps for the process are analogous in both media: (a) protonation of the alcohol group, (b) water loss and (c) cyclization. The relative Gibbs energies of all the steps are affected by changing the environment from solvent to the metallocage. The first step in the mechanism, the alcohol protonation, turns out to be the most critical one for the acceleration of the reaction inside the metallocage. In order to calculate the relative stability of protonated alcohol inside the cavity, we propose a computational scheme for the calculation of basicity for species inside cavities and can be of general use. These results are in excellent agreement with the experiments, identifying key steps of catalysis and providing an in-depth understanding of the impact of the metallocage on all the reaction steps., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Human PAICS is a bifunctional enzyme that is involved in the de novo purine biosynthesis, catalyzing the conversion of aminoimidazole ribonucleotide (AIR) into N -succinylcarboxamide-5-aminoimidazole ribonucleotide (SAICAR). It comprises two distinct active sites, AIR carboxylase (AIRc) where the AIR is initially converted to carboxyaminoimidazole ribonucleotide (CAIR) by reaction with CO 2 and SAICAR synthetase (SAICARs) in which CAIR then reacts with an aspartate to form SAICAR, in an ATP-dependent reaction. Human PAICS is a promising target for the treatment of various types of cancer, and it is therefore of high interest to develop a detailed understanding of its reaction mechanism. In the present work, density functional theory calculations are employed to investigate the PAICS reaction mechanism. Starting from the available crystal structures, two large models of the AIRc and SAICARs active sites are built and different mechanistic proposals for the carboxylation and phosphorylation-condensation mechanisms are examined. For the carboxylation reaction, it is demonstrated that it takes place in a two-step mechanism, involving a C-C bond formation followed by a deprotonation of the formed tetrahedral intermediate (known as isoCAIR) assisted by an active site histidine residue. For the phosphorylation-condensation reaction, it is shown that the phosphorylation of CAIR takes place before the condensation reaction with the aspartate. It is further demonstrated that the three active site magnesium ions are involved in binding the substrates and stabilizing the transition states and intermediates of the reaction. The calculated barriers are in good agreement with available experimental data.

A water-soluble cavitand bearing a benzotriazole upper rim was prepared and characterized. It exists as a dimeric velcraplex in D 2 O, but forms host-guest complexes with hydrophobic and amphiphilic guests. Alkanes (C5 to C10), cyclic ketones (C6-C10), cyclic alcohols (C6-C8) and various amphiphilic guests form 1 : 1 cavitand complexes. A cyclic array of hydrogen bonds, bridged by solvent/water (D 2 O) molecules, stabilizes the vase conformation of the complexes. With longer alkanes (C12-C15), symmetrical dialkyl amine, urea and phosphate, 2 : 1 host:guest capsules are formed. Computations indicate that additional waters on the upper rim create a self-complementary hydrogen-bonding pattern for capsule formation., (© 2022 Wiley-VCH GmbH.)

Imine reductases (IREDs) are NADPH-dependent enzymes (NADPH=nicotinamide adenine dinucleotide phosphate) that catalyze the reduction of imines to amines. They exhibit high enantioselectivity for a broad range of substrates, making them of interest for biocatalytic applications. In this work, we have employed density functional theory (DFT) calculations to elucidate the reaction mechanism and the origins of enantioselectivity of IRED from Amycolatopsis orientalis. Two substrates are considered, namely 1-methyl-3,4-dihydroisoquinoline and 2-propyl-piperideine. A model of the active site is built on the basis of the available crystal structure. For both substrates, different binding modes are first evaluated, followed by calculation of the hydride transfer transition states from each complex. We have also investigated the effect of mutations of certain important active site residues (Tyr179Ala and Asn241Ala) on the enantioselectivity. The calculated energies are consistent with the experimental observations and the analysis of transition states geometries provides insights into the origins of enantioselectivity of this enzyme., (© 2021 The Authors. Published by Wiley-VCH GmbH.)

The electrophilic fluorination of geminal alkyl substituted vinyl-Bmida derivatives proceeds via bora-Wagner-Meerwein rearrangement. According to DFT modelling studies this rearrangement occurs with a low activation barrier via a bora-cyclopropane shaped TS. The Bmida group has a larger migration aptitude than the alkyl moiety in the Wagner-Meerwein rearrangement of the presented electrophilic fluorination reactions., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

A combined experimental-computational approach has been used to study the cyclopropanation reaction of N -hydroxyphthalimide diazoacetate (NHPI-DA) with various olefins, catalyzed by a ruthenium-phenyloxazoline (Ru-Pheox) complex. Kinetic studies show that the better selectivity of the employed redox-active NHPI diazoacetate is a result of a much slower dimerization reaction compared to aliphatic diazoacetates. Density functional theory calculations reveal that several reactions can take place with similar energy barriers, namely, dimerization of the NHPI diazoacetate, cyclopropanation (inner-sphere and outer-sphere), and a previously unrecognized migratory insertion of the carbene into the phenyloxazoline ligand. The calculations show that the migratory insertion reaction yields an unconsidered ruthenium complex that is catalytically competent for both the dimerization and cyclopropanation, and its relevance is assessed experimentally. The stereoselectivity of the reaction is argued to stem from an intricate balance between the various mechanistic scenarios., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

We describe new container host molecules - deep cavitands with benzimidazole walls and ionic feet - to recognize highly hydrophilic guest molecules in water. The aromatic surfaces of the cavity recognize hydrophobic portions of the guest while bound water molecules mediate hydrogen bonding in the complex. Spectroscopic (NMR) evidence indicates slow in/out exchange on the chemical shift timescale and thermodynamic (ITC) methods show large association constants (Ka up to 6 × 10 4 M -1 ) for complexation of small, water-soluble molecules such as THF and dioxane. Quantum chemical calculations are employed to optimize the host-guest geometries and elucidate the hydrogen bonding patterns responsible for the binding.

The mechanism of the Kinugasa reaction, that is, the copper-catalyzed formation of β-lactams from nitrones and terminal alkynes, is re-evaluated by means of density functional theory calculations and in light of recent experimental findings. Different possible mechanistic scenarios are investigated using phenanthroline as a ligand and triethylamine as a base. The calculations confirm that after an initial two-step cycloaddition promoted by two copper ions, the resulting five-membered ring intermediate can undergo a fast and irreversible cycloreversion to generate an imine and a dicopper-ketenyl intermediate. From there, the reaction can proceed through a nucleophilic attack of a ketenyl copper intermediate on the imine and an intramolecular cyclization, rather than through the previously suggested (2 + 2) Staudinger synthesis.

Quantum chemical calculations are today an extremely valuable tool for studying enzymatic reaction mechanisms. In this mini-review, we summarize our recent work on several metal-dependent decarboxylases, where we used the so-called cluster approach to decipher the details of the reaction mechanisms, including elucidation of the identity of the metal cofactors and the origins of substrate specificity. Decarboxylases are of growing potential for biocatalytic applications, as they can be used in the synthesis of novel compounds of, e.g. , pharmaceutical interest. They can also be employed in the reverse direction, providing a strategy to synthesize value-added chemicals by CO 2 fixation. A number of non-redox metal-dependent decarboxylases from the amidohydrolase superfamily have been demonstrated to have promiscuous carboxylation activities and have attracted great attention in the recent years. The computational mechanistic studies provide insights that are important for the further modification and utilization of these enzymes in industrial processes. The discussed enzymes are: 5-carboxyvanillate decarboxylase, γ-resorcylate decarboxylase, 2,3-dihydroxybenzoic acid decarboxylase, and iso -orotate decarboxylase., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Broad substrate tolerance and excellent regioselectivity, as well as independence from sensitive cofactors have established benzoic acid decarboxylases from microbial sources as efficient biocatalysts. Robustness under process conditions makes them particularly attractive for preparative-scale applications. The divalent metal-dependent enzymes are capable of catalyzing the reversible non-oxidative (de)carboxylation of a variety of electron-rich (hetero)aromatic substrates analogously to the chemical Kolbe-Schmitt reaction. Elemental mass spectrometry supported by crystal structure elucidation and quantum chemical calculations verified the presence of a catalytically relevant Mg 2+ complexed in the active site of 2,3-dihydroxybenoic acid decarboxylase from Aspergillus oryzae (2,3-DHBD_Ao). This unique example with respect to the nature of the metal is in contrast to mechanistically related decarboxylases, which generally have Zn 2+ or Mn 2+ as the catalytically active metal., (© 2020 The Authors. ChemBioChem published by Wiley-VCH GmbH.)