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.

The transamination reaction, which involves the conversion of one amine to another, traditionally relies on biological enzyme catalysts. Although chemists have recently developed a few transition metal-catalyzed methods, mimicking these enzymes to interconvert amine groups in acyclic substrates via transamination metathesis of a single C(sp²)─N bond, transamination of cyclic tertiary amines has remained a challenge in synthetic chemistry. Here, we present the development of organoautocatalyzed transamination metathesis of two C(sp²)─N bonds in a cyclic substrate that allows for the challenging transformation to take place with up to 95% yield under exceptionally mild reaction conditions at room temperature without external catalysts and/or additives. The reaction mechanism has been studied in detail through time-resolved ¹H-NMR, 2D NMR, and computational methods. Remarkably, in situ-formed pyrrolidinium salt acts as a hydrogen bond donor (HBD) organoautocatalyst in this multi-step domino process. The new organoautocatalyzed methodology gives environmentally friendly, atom-economical, straightforward, and rapid access to N-substituted 3,5-dinitro-1,4-dihydropyridines (DNDHPs), thus offering facile entry to privileged bioactive compounds.

The detailed reaction mechanism of diphenyl selenide-catalyzed sulfenofunctionalization of chiral α-CF3 allylboronic acids is investigated by means of density functional theory calculations. It is demonstrated that the reaction starts with the transfer of the SCF3 group from the (PhSO2)2NSCF3 reagent to the Ph2Se catalyst, a process that is shown to be assisted by the presence of Tf2NH acid. After a proton transfer step, the SCF3 group is transferred to the C 00000000 00000000 00000000 00000000 11111111 00000000 11111111 00000000 00000000 00000000 C double bond of the substrate to generate a thiiranium ion. Concerted deborylative opening of the thiiranium ion yields then the final product. Several representative substrates are considered by the calculations, and the origins of the stereoselectivity of the reactions are analyzed by comparing the energies and geometries of the transition states leading to the different products.

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.

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.

The catalytic alkylation of amines with alcohols is a highly atom-economical approach that produces water as the sole by-product. Existing catalytic systems lack generality and are primarily applicable to electron-poor amines or to non-oxidizable amines, such as anilines. The outstanding effectiveness of an Ir-NHC catalyst in forming C−N bonds from alcohols and amines, both aliphatic and aromatic, is presented here. The catalyst performs remarkably under mild conditions, even at room temperature, attaining complete selectivity in all tested cases toward monoalkylation, even for challenging aliphatic amines, and under base-free conditions. Thorough mechanistic investigation to understand the outstanding activity and selectivity, combining experimental, theoretical, and both in situ and ex situ X-ray absorption spectroscopy (XAS) studies, are presented.

The homologation of bioethanol to higher alcohols by means of the Guerbet reaction is a promising way to obtain biofuels. Herein, we present an efficient ruthenium-catalyzed process and a detailed investigation of the reaction mechanism using a combined experimental-computational approach. Density functional theory calculations of the free energy profiles are corroborated by designed experiments. Microkinetic simulations are performed based on the calculated energies, providing good agreement with experimental observations of the time-evolving ethanol conversion and product distribution. Analysis of the kinetics network elucidates the key steps governing the conversion and selectivity of the Guerbet process, pointing out the unexpected role of the molecular hydrogen evolution step and suggesting strategies to design new catalysts for the Guerbet reaction.

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. 

Hypervalent iodine compounds have gained widespread utility in modern organic chemistry. A number of benziodoxole derivatives have been synthesized and used as reagents to facilitate the transfer of fluorine or fluorine-containing substituents onto organic substrates. Also, novel reactions have emerged using in situ generated electrophilic hypervalent iodine species, utilizing HF as a fluorine source. Detailed knowledge about the reactivities and modes of action of these compounds is of great importance for the development of new reagents and catalytic protocols within this field. To that end, quantum chemical methods have contributed significantly to the elucidation of the mechanisms and the factors determining selectivities of this important class of reactions. In this chapter, we present examples from our recent work using density functional theory calculations aimed at shedding light at various aspects of this chemistry. We focus on the intricate mechanisms for the syntheses of various benziodoxole reagents and on the understanding of the reaction mechanisms and sources of regio- and enantioselectivity for organo-catalyzed electrophilic fluorine transfer reactions employing in situ generated hypervalent iodine reagents. These studies have yielded novel mechanistic insights with potential implications for other reactions involving the incorporation of fluorine or fluorine-containing groups with hypervalent iodine reagents/catalysts.