Fahmi Himo

The decarboxylative borylation of redox‐active esters promoted by bis(catecholato)diboron (B ₂ cat ₂ ) and blue light enables the synthesis of versatile organoboron building blocks from carboxylic acid materials. An LED‐illuminated NMR kinetic study revealed that the reaction is surprisingly accelerated by water, and this hidden catalysis can be attributed to a novel intermediate formed in situ, namely a hypoboric acid catecholate (HAC). This unsymmetrical diboron species can alternatively be formed by hydrolysis of B ₂ cat ₂ or transesterification between B ₂ cat ₂ and hypoboric acid (B ₂ (OH) ₄ ). Experimental and computational studies revealed and rationalized the regioselective capture of alkyl radicals by the HAC species, and the concomitant formation of a more reductive boryl radical chain carrier. The regioselectivity is characteristic of the HAC species studied, and is controlled by electronic rather than steric effects.

Molecular dynamics (MD)-based methods to predict the enantioselectivity or product specificity of enzymes typically use a near attack conformation (NAC) approach. The computational efficiency of this ground-state approach, taking minutes to hours, allows to in silico screen thousands of enzyme variants. During the computational design and screening of new variants of limonene epoxide hydrolase for improved stereoselectivity, it was noticed that, while this approach gave satisfactory prediction accuracy for most substrates, the enantioselectivity predictions were far less accurate for variants designed for cis-stilbene oxide. Here, to investigate whether inaccurate predictions with the NAC-based approach were typical for this substrate, first, a larger data set was generated by experimentally testing and computationally predicting the enantioselectivity of an additional 18 enzyme variants for cis-stilbene oxide. Subsequent MD simulations confirmed that a NAC analysis resulted in inaccurate enantioselectivity predictions throughout the data set. Density functional theory (DFT) calculations using the B3LYP-D3(BJ) functional, with an active site cluster model of >300 atoms, provided a rationale for why the NAC approach gave poor predictions with cis-stilbene oxide. The aromatic rings of the substrate influence the nucleophilic attack on the epoxide group, by providing a blend of stereoelectronic activation and steric hindrance to the transition state, which is not considered in the NAC approach. With this substrate, the DFT accurately predicted the enantioselectivity. The results offer valuable insights into the applicability of the NAC approach for predicting enzyme selectivity, suggesting that more expensive methodologies, which do explicitly consider the transition state structure, can also become required when bulky or stereoelectronically activating groups are bound to the reacting atoms.

Binding of xylene isomers to two resorcin[4]arene-based water-soluble cavitands, one fully organic and one with palladium bridges, is investigated by means of a combination of molecular dynamics simulations and quantum chemical calculations. Experimentally, the metallo-cavitand binds all three isomers but shows a preference for p-xylene, while the organo-cavitand prefers o-xylene and shows no affinity for p-xylene. The cavitands are first characterized and compared in aqueous solution in the absence of guests using classical molecular dynamics simulations. This is followed by a study of the dynamics of the various host-guest complexes. Finally, density functional theory is used to calculate the relative binding free energies. The molecular dynamics simulations show that both host and guest exhibit extensive motions in the complexed state, and the density functional theory calculations yield accurate results on the relative binding free energies.

The demand for novel enzyme-catalyzed reactions in chemical synthesis has spurred the development of many new-to-nature reactions. Additionally, detailed analysis of biosynthetic pathways can uncover unprecedented chemical/enzymatic mechanisms. In this study, we revisited the catalytic mechanism of the 2-oxoglutarate-dependent dioxygenase Pt2OGD-1, involved in the biosynthesis of huperzine alkaloids. Our experimental and computational investigations uncovered a previously unknown enzymatic C-C bond cleavage in the piperidine ring of the alkaloid scaffold, resembling an oxidative retro-aza-Prins reaction. Here, this transformation is initiated by hydrogen abstraction, followed by electron transfer at the 4-position of the heterocycle, triggering ring opening and finally resulting in the loss of a carbon atom as formaldehyde. This discovery expands the toolbox of reactions, enhances our understanding of these enzymes, and may facilitate their application in the biotechnological production of pharmaceutically relevant alkaloid scaffolds as well as the development of biocatalysts with similar activities.

Herein, we report density functional theory calculations to investigate the reaction mechanism and the selectivity of the cycloisomerization of alkynoic acids inside a gold‐functionalized resorcinarene‐based cavitand. This cavitand has experimentally been shown to catalyze the cycloisomerization of a number of substituted alkynoic acids to give the corresponding γ‐lactones. Three representative substrates, with different substitution patterns, are considered in the calculations, and for each of them, the geometries and energies of various binding modes are first characterized. Next, the cycloisomerization reaction mechanism is evaluated, which is shown to consist of an intramolecular addition of the carboxylic acid to the gold‐activated alkyne triple bond, followed by a protodeauration step. Both 5‐exo‐dig and 6‐endo‐dig cyclizations were considered, leading to γ‐ or δ‐lactones, respectively, and the involvement of the triflate counterion in the cyclization step is discussed. Finally, the influence of the cavitand walls on the reactivity is evaluated by using a model catalyst in which the walls were removed.

Nature efficiently produces a myriad of structurally diverse carbon ring frameworks from common linear precursors via cyclization reactions at specific olefinic sites in dienes or polyenes. In contrast, achieving the site-selective functionalization of diene or polyene substrates remains a formidable challenge in chemical synthesis. Herein, we report a pair of highly site-selective, regiodivergent carbocyclization reactions of dienallenes and trienallenes, enabling the efficient synthesis of cis-1,4-disubstituted cyclohexenes and trans-1,2-disubstituted cyclobutenes from a common precursor with high diastereoselectivity. Remarkably, simple achiral organophosphoric acids and amines are identified as powerful ligands for controlling these palladium-catalyzed regiodivergent carbocyclizations. This approach represents the first example of site-selective regiodivergent carbocyclization, providing a practical method for the stereospecific synthesis of thermodynamically disfavored cis-1,4-disubstituted cyclohexenes and fully substituted trans-1,2-cyclobutenes. Additionally, the methodology developed offers general insights into the development of metal-catalyzed site-selective, regiodivergent carbocyclizations of diene and polyene precursors, mimicking natural carbocyclization processes.

Density functional theory calculations are employed to investigate the detailed reaction mechanism and origins of selectivity of the diphenyl selenide-catalyzed sulfenofunctionalization of chiral α-CF ₃ allylboronic acids.

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 (B₂cat₂) 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.

Density functional theory calculations have been performed to investigate the mechanism for the BINOL-catalyzed asymmetric homologation of alkenylboronic acids with CF3-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 CF3 group of the diazomethane reagent and the gamma-substituent of the BINOL catalyst. The complex potential energy surface obtained by the calculations is analyzed by means of microkinetic simulations.