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Recently, Huang and co‐workers reported a catalytic reaction that utilizes H2 as the sole reductant for a C−C coupling of allyl groups with yields up to 96 %. Here we use computational quantum chemistry to identify several key features of this reaction that provide clarity on how it proceeds. We propose the involvement of a Pd−Pd bound dimer precatalyst, demonstrate the importance of ligand π‐π interactions and counterions, and identify a new, energetically viable, mechanism involving two dimerized, outer‐sphere reductive elimination transition structures that determine both the rate and selectivity. Although we rule out the previously proposed transmetalation step on energetic grounds, we show it to have an unusual aromatic transition structure in which two Pd atoms support rearranging electrons. The prevalence of potential metal‐supported pericyclic reactions in this system suggests that one should consider such processes regularly, but the results of our calculations also indicate that one should do so with caution. [ABSTRACT FROM AUTHOR]

Investigating the reactivity of small nucleophilic scaffolds is a strategic approach for the design of new catalysts aiming at effective detoxification processes of organophosphorus compounds. The drug methimazole (MMZ) is an interesting candidate featuring two non‐equivalent nucleophilic centers. Herein, phosphoryl transfer reactions mediated by MMZ were assessed by means of spectrophotometric kinetic studies, mass spectrometry (MS) analyses, and density functional theory (DFT) calculations using the multi‐electrophilic compound O,O‐diethyl 2,4‐dinitrophenyl phosphate (DEDNPP). MMZ anion acts primarily as an S‐nucleophile, exhibiting a nucleophilic activity comparable to that of certain oximes featuring alpha‐effect. Selective nucleophilic aromatic substitution was observed, consistent with the DFT prediction of a low energy barrier. Overall, the results bring important advances regarding the mechanistic understanding of nucleophilic dephosphorylation reactions, which comprises a strategic tool for neutralizing toxic organophosphates, hence promoting chemical security. [ABSTRACT FROM AUTHOR]

The first assortment of achiral pentafluorosulfanylated cyclobutanes (SF5‐CBs) are now synthetically accessible through strain‐release functionalization of [1.1.0]bicyclobutanes (BCBs) using SF5Cl. Methods for both chloropentafluorosulfanylation and hydropentafluorosulfanylation of sulfone‐based BCBs are detailed herein, as well as proof‐of‐concept that the logic extends to tetrafluoro(aryl)sulfanylation, tetrafluoro(trifluoromethyl)sulfanylation, and three‐component pentafluorosulfanylation reactions. The methods presented enable isolation of both syn and anti isomers of SF5‐CBs, but we also demonstrate that this innate selectivity can be overridden in chloropentafluorosulfanylation; that is, an anti‐stereoselective variant of SF5Cl addition across sulfone‐based BCBs can be achieved by using inexpensive copper salt additives. Considering the SF5 group and CBs have been employed individually as nonclassical bioisosteres, structural aspects of these unique SF5‐CB "hybrid isosteres" were then contextualized using SC‐XRD. From a mechanistic standpoint, chloropentafluorosulfanylation ostensibly proceeds through a curious polarity mismatch addition of electrophilic SF5 radicals to the electrophilic sites of the BCBs. Upon examining carbonyl‐containing BCBs, we also observed rare instances whereby radical addition to the 1‐position of a BCB occurs. The nature of the key C(sp3)−SF5 bond formation step – among other mechanistic features of the methods we disclose – was investigated experimentally and with DFT calculations. Lastly, we demonstrate compatibility of SF5‐CBs with various downstream functionalizations. [ABSTRACT FROM AUTHOR]

Density functional theory was used to elucidate the mechanism and the pericyclicity of chromium‐catalyzed bicyclization reactions that purportedly involve 8‐electron electrocyclization steps. Our computational results indicate that these reactions do indeed proceed via 8‐electron electrocyclization rather than an alternative pathway involving 4‐electron electrocyclization followed by Cope rearrangement. The role of C=[M] groups on the electrocyclization, specifically its pericyclicity, was examined in detail using modern theoretical tools. [ABSTRACT FROM AUTHOR]

Herein, we describe our synthetic efforts toward the pupukeanane natural products, in which we have completed the first enantiospecific route to 2‐isocyanoallopupukeanane in 10 steps (formal synthesis), enabled by a key Pd‐mediated cyclization cascade. This subsequently facilitated an unprecedented bio‐inspired "contra‐biosynthetic" rearrangement, providing divergent access to 9‐isocyanopupukeanane in 15 steps (formal synthesis). Computational studies provide insight into the nature of this rearrangement. [ABSTRACT FROM AUTHOR]

Summary: Bioactive triterpenes feature complex fused‐ring structures, primarily shaped by the first‐committed enzyme, 2,3‐oxidosqualene cyclases (OSCs) in plant triterpene biosynthesis. Triterpenes with B,C‐ring‐opened skeletons are extremely rare with unknown formation mechanisms, harbouring unchartered chemistry and biology.Here, through mining the genome of Chenopodium quinoa followed by functional characterization, we identified a stress‐responsive and neofunctionalized OSC capable of generating B,C‐ring‐opened triterpenes, including camelliol A and B and the novel (−)‐quinoxide A as wax components of the specialized epidermal bladder cells, namely the quinoxide synthase (CqQS).Protein structure analysis followed by site‐directed mutagenesis identified key variable amino acid sites underlying functional interconversion between pentacyclic β‐amyrin synthase (CqbAS1) and B,C‐ring‐opened triterpene synthase CqQS. Mutation of one key residue (N612K) in even evolutionarily distant Arabidopsis β‐amyrin synthase could generate quinoxides, indicating a conserved mechanism for B,C‐ring‐opened triterpene formation in plants. Quantum computation combined with docking experiments further suggests that conformations of conserved W613 and F413 of CqQS might be key to selectively stabilizing intermediate carbocations towards B,C‐ring‐opened triterpene formation.Our findings shed light on quinoa triterpene skeletal diversity and mechanisms underlying B,C‐ring‐opened triterpene biosynthesis, opening avenues towards accessing their chemistry and biology and paving the way for quinoa trait engineering and quality improvement. [ABSTRACT FROM AUTHOR]

Nitrogen heterocycles play a vital role in pharmaceuticals and natural products, with the six‐membered aromatic and aliphatic architectures being commonly used. While synthetic methods for aromatic N‐heterocycles are well‐established, the synthesis of their aliphatic functionalized analogues, particularly piperidine derivatives, poses a significant challenge. In that regard, we propose a stepwise dearomative functionalization reaction for the construction of highly decorated piperidine derivatives with diverse functional handles. We also discuss challenges related to site‐selectivity, regio‐ and diastereoselectivity, and provide insights into the reaction mechanism through mechanistic studies and density functional theory computations. [ABSTRACT FROM AUTHOR]

Terpene cyclization, one of the most complex chemical reactions in nature, is generally catalyzed by two classes of terpene cyclases (TCs). Cytochrome P450s that act as unexpected TC‐like enzymes are known but are very rare. In this study, we genome‐mined a cryptic bacterial terpenoid gene cluster, named ari, from the thermophilic actinomycete strain Amycolatopsis arida. By employing a heterologous production system, we isolated and characterized three highly oxidized eunicellane derived diterpenoids, aridacins A−C (1–3), that possess a 6/7/5‐fused tricyclic scaffold. In vivo and in vitro experiments systematically established a noncanonical two‐step biosynthetic pathway for diterpene skeleton formation. First, a class I TC (AriE) cyclizes geranylgeranyl diphosphate (GGPP) into a 6/10‐fused bicyclic cis‐eunicellane skeleton. Next, a cytochrome P450 (AriF) catalyzes cyclization of the eunicellane skeleton into the 6/7/5‐fused tricyclic scaffold through C2−C6 bond formation. Based on the results of quantum chemical computations, hydrogen abstraction followed by electron transfer coupled to barrierless carbocation ring closure is shown to be a viable mechanism for AriF‐mediated cyclization. The biosynthetic logic of skeleton construction in the aridacins is unprecedented, expanding the catalytic capacity and diversity of P450s and setting the stage to investigate the inherent principles of carbocation generation by P450s in the biosynthesis of terpenoids. [ABSTRACT FROM AUTHOR]

A site‐selective C(3)/C(4)‐alkylation of N‐pyridylisoquinolones is achieved by employing C−C bond activation of cyclopropanols under Ru(II)‐catalyzed/Cu(II)‐mediated conditions. The regioisomeric ratios of the products follow directly from the electronic nature of the cyclopropanols and isoquinolones used, with electron‐withdrawing groups yielding predominantly the C(3)‐alkylated products, whereas the electron‐donating groups primarily generate the C(4)‐alkylated isomers. Density functional theory calculations and detailed mechanistic investigations suggest the simultaneous existence of the singlet and triplet pathways for the C(3)‐ and C(4)‐product formation. Further transformations of the products evolve the utility of the methodology thereby yielding scaffolds of synthetic relevance. [ABSTRACT FROM AUTHOR]

Stereoselective Zweifel olefination using boronate complexes carrying two different reactive π‐systems was achieved to synthesize vinyl heteroarenes and conjugated 1,3‐dienes in good yield and up to 100 % stereoselectivity, which remains unexplored until now. Most importantly, we report the unprecedented formation of E vs. Z‐vinyl heteroarenes for different heteroarenes under identical conditions. Density functional theory (DFT) investigations unveil the mechanistic dichotomy between olefin and heteroarene activation followed by 1,2‐migration, leading to E or Z‐vinyl heteroarenes respectively. We also report a previously unknown reversal of stereoselectivity by using 2,3‐Dichloro‐5,6‐dicyano‐1,4‐benzoquinone (DDQ) as an electrophile. The Zweifel olefination using a boronate complex that carries two different olefins was previously unexplored due to significant challenges associated with the site‐selective activation of olefins. We have solved this problem and reported the site‐selective activation of olefins for the stereoselective synthesis of 1,3‐dienes. [ABSTRACT FROM AUTHOR]

We report a detailed experimental and theoretical analysis of through‐space arene activation with halogens, tetrazoles and achiral esters and amides. Contrary to previously assumed direct activation through σ‐complex stabilization, our results suggest that these reactions proceed by a relay mechanism wherein the lone pair‐containing activators form exothermic π‐complexes with electrophilic nitronium ion before transferring it to the probe ring through low barrier transition states. Noncovalent interactions (NCI) plots and Quantum Theory of Atoms in Molecules (QTAIM) analyses depict favorable interactions between the Lewis base (LB) and the nitronium ion in the precomplexes and the transition states, suggesting directing group participation throughout the mechanism. The regioselectivity of substitution also comports with a relay mechanism. In all, these data pave the way for an alternate platform of electrophilic aromatic substitution (EAS) reactions. [ABSTRACT FROM AUTHOR]

The template‐directed C−H insertion of α,β‐unsaturated esters into quinoline was interrogated by using computational quantum chemistry. An energetically viable mechanism for this complex multistep transformation was elucidated, with attention paid throughout to conformational flexibility and alternative ligand binding modes. The selectivity was found to correlate with distortion from a tetrahedral geometry for the carbon atom involved in C−H insertion, a parameter that can be applied to future template design. [ABSTRACT FROM AUTHOR]

The [3s,5s]‐sigmatropic shift is an example of an orbital‐symmetry forbidden pericyclic reaction that is outcompeted by the allowed [3s,3s]‐sigmatropic shift. Density functional theory calculations are used to show that PdII‐complexed systems with strategically placed substituents engaging in key stereoelectronic effects can select for the [3s,5s] process, thereby outcompeting both orbital‐symmetry‐allowed [3s,3s]‐ and [3s,5a]‐shifts. [ABSTRACT FROM AUTHOR]

Reported herein is a reactivity of propargyl alcohols as "Three‐Carbon Synthons" in a Rh(III)‐catalyzed C−H functionalization of acetanilides, leading to the synthesis of core structures of isocryptolepine, γ‐carbolines, dihydrochromeno[2,3‐b]indoles, and diindolylmethanes (DIM) derivatives. The transformation involves a rhodium(III)‐catalyzed C−H functionalization and heteroannulation to yield indoles followed by a cascade cyclization with both external and internal nucleophiles to afford diverse products. The role of the hydroxy group, the key function of the silver additive, the origin of the reverse regioselectivity and the rate‐determining step, are rationalized in conformity with the combination of experimental, noncovalent interaction analysis and DFT studies. This protocol is endowed with several salient features, including one‐pot multistep cascade approach, exclusive regioselectivity, good functional group tolerance and synthesis of variety of molecular frameworks. [ABSTRACT FROM AUTHOR]

Summary: Switchgrass (Panicum virgatum) is a bioenergy model crop valued for its energy efficiency and drought tolerance. The related monocot species rice (Oryza sativa) and maize (Zea mays) deploy species‐specific, specialized metabolites as core stress defenses. By contrast, specialized chemical defenses in switchgrass are largely unknown.To investigate specialized metabolic drought responses in switchgrass, we integrated tissue‐specific transcriptome and metabolite analyses of the genotypes Alamo and Cave‐in‐Rock that feature different drought tolerance.The more drought‐susceptible Cave‐in‐Rock featured an earlier onset of transcriptomic changes and significantly more differentially expressed genes in response to drought compared to Alamo. Specialized pathways showed moderate differential expression compared to pronounced transcriptomic alterations in carbohydrate and amino acid metabolism. However, diterpenoid‐biosynthetic genes showed drought‐inducible expression in Alamo roots, contrasting largely unaltered triterpenoid and phenylpropanoid pathways. Metabolomic analyses identified common and genotype‐specific flavonoids and terpenoids. Consistent with transcriptomic alterations, several root diterpenoids showed significant drought‐induced accumulation, whereas triterpenoid abundance remained predominantly unchanged. Structural analysis verified select drought‐responsive diterpenoids as oxygenated furanoditerpenoids.Drought‐dependent transcriptome and metabolite profiles provide the foundation to understand the molecular mechanisms underlying switchgrass drought responses. Accumulation of specialized root diterpenoids and corresponding pathway transcripts supports a role in drought stress tolerance. [ABSTRACT FROM AUTHOR]

The calculation of hydrogen atom transfer (HAT) barriers within the cytochrome P450 catalytic cycle is of central importance for the prediction of metabolites formed from medicinally relevant compounds. We report the accurate estimation of hydrogen atom transfer barriers using inexpensive descriptors computed for a panel of 21 compounds. By a simple univariate linear regression between barriers previously computed using density functional theory (DFT) and newly computed "frozen radical" bond dissociation energies using the GFN2‐xTB method, a mean absolute error of 1 kcal mol−1 is achieved. Other affordable levels of theory are studied to assess differences in performance and computational cost. Multiple linear regression incorporating additional descriptors using GFN2‐xTB is shown to predict HAT barriers with mean absolute errors of 0.82 kcal mol−1. With computing times in milliseconds on modest computing hardware, this systematic approach is accessible and extensible to large scale screening workflows. [ABSTRACT FROM AUTHOR]

The fundamental challenge of C−F bond formation by reductive elimination has been met by compounds of select transition metals and fewer main group elements. The work detailed herein expands the list of main group elements known to be capable of reductively eliminating a C−F bond to include tellurium. Surprising and novel modes of both sp2 and sp3 C−F bond formation were observed alongside formation of TeIV cations during two separate attempts to synthesize/characterize fluorinated organotellurium(VI) cations in superacidic media (SbF5/SO2ClF). Following detailed low‐temperature NMR experiments, the mechanisms of the two unique reductive elimination reactions were probed and investigated using density functional theory (DFT) calculations. Ultimately, we found that an "indirect" reductive elimination pathway is likely operative whereby Sb plays a key role in fluoride abstraction and C−F bond formation, as opposed to unimolecular reductive elimination from a discrete TeVI cation. [ABSTRACT FROM AUTHOR]

Panowamycins are a group of isochroman‐based natural products first isolated from Streptomyces sp. K07‐0010 in 2012 by Satoshi Ōmura and co‐workers that exhibit modest anti‐trypanosomal activity. Herein we demonstrate the first syntheses of these natural products and their epimers. Stereoselective dirhodium‐catalyzed C−H insertion reactions with a donor/donor carbene construct the substituted isochroman core in the key bond‐forming step. The syntheses are completed without the use of protecting groups and feature a late‐stage Wacker oxidation. Incongruent NMR spectra between natural and synthetic samples revealed the structural misassignment of panowamycin A and veramycin F. Computational NMR studies suggested panowamycin A to be an alternate diastereomer, which was confirmed by synthesizing this isomer. Concurrent with this work, in 2021 Mahmud and co‐workers came to the same conclusion with an updated NMR analysis of panowamycin A. In a divergent, asymmetric sequence, we report the synthesis of panowamycin A, panowamycin B, TM‐135, and veramycin F. [ABSTRACT FROM AUTHOR]

The direct formation of aryl C−O bonds via the intramolecular dehydrogenative coupling of a C−H bond and a pendant alcohol represents a powerful synthetic transformation. Herein, we report a method for intramolecular arene C−H etherification via an umpoled alcohol cyclization mediated by an I(III) N‐HVI reagent. This approach provides access to functionalized chromane scaffolds from primary, secondary and tertiary alcohols via a cascade cyclization‐iodonium salt formation, the latter providing a versatile functional handle for downstream derivatization. Computational studies support initial formation of an umpoled O‐intermediate via I(III) ligand exchange, followed by competitive direct and spirocyclization/1,2‐shift pathways. [ABSTRACT FROM AUTHOR]

The eunicellane diterpenoids are a unique family of natural products seen in marine organisms, plants, and bacteria. We used a series of biochemical, bioinformatics, and theoretical experiments to investigate the mechanism of the first diterpene synthase known to form the eunicellane skeleton. Deuterium labeling studies and quantum chemical calculations support that Bnd4, from Streptomyces sp. (CL12‐4), forms the 6,10‐bicyclic skeleton through a 1,10‐cyclization, 1,3‐hydride shift, and 1,14‐cyclization cascade. Bnd4 also demonstrated sesquiterpene cyclase activity and the ability to prenylate small molecules. Bnd4 possesses a unique D94NxxxD motif and mutation experiments confirmed an absolute requirement for D94 as well as E169. [ABSTRACT FROM AUTHOR]

Gold‐catalyzed dehydro‐Diels‐Alder reactions of ynamide derivatives allow efficient access to a variety of N‐containing aromatic heterocycles. A dual gold catalysis mechanism was postulated for transformations involving the formation of C−C bonds by reaction between a terminal alkyne and an enynamide fragment. In this article, complete experimental and computational investigations into the mechanism of such a transformation are reported. Support for a dual gold catalysis was found and it was shown that the concerted or stepwise nature of the cyclization event depends on the substitution of the ynamide moiety. The reaction was found to proceed in three stages: 1) formation of a σ,π‐digold complex from the terminal alkyne, 2) cyclization to produce a gem‐diaurated aryl complex, and 3) catalyst transfer to free the product and regenerate the σ,π‐digold complex. [ABSTRACT FROM AUTHOR]

Recent computational studies highlighting the importance of accounting for dynamic effects on organic reactivity are discussed, accompanied by descriptions of the factors that led the author to pursue these projects. [ABSTRACT FROM AUTHOR]

In the early 1960s, as part of R. B. Woodward's isoxazole route to vitamin B12, Subramania Ranganathan uncovered two coupled sets of stereospecific reactions, a thermal set and a photochemical set. These four reactions illustrated the alternating configurations that were the major data points that prompted the solution of the no‐mechanism problem. Though Ranganathan's reactions played a major role, according to Woodward, in the development of the Woodward–Hoffmann rules, they were published only as part of the documentation of a lecture given by Woodward in 1966. The authors of this paper have uncovered Subramania Ranganathan's 1964 postdoctoral report and have used modern quantum chemical theory to predict the 1H NMR spectra for Ranganathan's key compounds, providing support for the structure assignments made by Woodward and Ranganathan. A similar set of alternating, stereospecific reactions was observed by E. J. Corey and Alfred Hortmann in their 1963 total synthesis of dihydrocostunolide. We also have applied the computational process used for Ranganathan's compounds to Hortmann's compounds, now also including the calculation of coupling constants, and find computational support for Corey and Hortmann's structure assignments. [ABSTRACT FROM AUTHOR]

Fungal meroterpenoids are a diverse group of hybrid natural products with impressive structural complexity and high potential as drug candidates. In this work, we evaluate the promiscuity of the early structure diversity‐generating step in fungal meroterpenoid biosynthetic pathways: the multibond‐forming polyene cyclizations catalyzed by the yet poorly understood family of fungal meroterpenoid cyclases. In total, 12 unnatural meroterpenoids were accessed chemoenzymatically using synthetic substrates. Their complex structures were determined by 2D NMR studies as well as crystalline‐sponge‐based X‐ray diffraction analyses. The results obtained revealed a high degree of enzyme promiscuity and experimental results which together with quantum chemical calculations provided a deeper insight into the catalytic activity of this new family of non‐canonical, terpene cyclases. The knowledge obtained paves the way to design and engineer artificial pathways towards second generation meroterpenoids with valuable bioactivities based on combinatorial biosynthetic strategies. [ABSTRACT FROM AUTHOR]

Between 1910 and 1947, Robert Robinson (primarily), among others, published numerous proposed structures for strychnine. Robinson published 17 of his strychnine papers with his doctoral advisor William Henry Perkin, Jr. though all but two appeared after Robinson had taken his first permanent academic position. This Essay analyzes 20 key publications leading up to Robinson's (correct, then incorrect, then correct again though not definitively) proposal and Woodward's assignment of the actual structure of strychnine. We subjected the assignment of the strychnine structure to a modern computational quantum chemistry workflow. By computing, with density functional theory, 1H and 13C NMR chemical shifts for the literature‐proposed strychnine structures, we were able to rule out most incorrect structures. 13C NMR predictions were better at this, but 1H NMR chemical shifts were helpful. A comparison is made between the consequences of publishing erroneous ideas in the first half of the 20th century and doing so in the 21st century. [ABSTRACT FROM AUTHOR]

The effects of including (a) implicit solvent in geometry optimizations, (b) conformationally flexible molecules in test sets, and (c) empirical dispersion D3(BJ) on scaling factors for predicting 1H and 13C NMR chemical shifts were explored. Scaling factors with optimizations performed in the gas phase and with a Polarizable Continuum Model (PCM) solvent model were obtained for 12 organic solvents, including 2,2,2‐trifluroethanol and chlorobenzene, for which scaling factors have been developed for the first time. Scaling factors for aromatic solvents were split into primary and secondary scaling factors to account for CH–π effects. Including empirical dispersion D3(BJ) did not lead to significant improvement. [ABSTRACT FROM AUTHOR]

Quantum chemical methods are useful for probing the energetic viability of chemical mechanisms involved in natural product biosynthesis. Typical computational approaches are described and representative examples of mechanistic studies on radical, pericyclic, and carbocation rearrangement reactions that lead to polycyclic skeletons of complex natural products showcase the utility of such methods in providing understanding and shaping future experimental studies. The importance of inherent substrate reactivity is highlighted and cautions for interpreting computational results are discussed. This article is categorized under:Structure and Mechanism > Reaction Mechanisms and CatalysisTheoretical and Physical Chemistry > Reaction Dynamics and KineticsStructure and Mechanism > Computational Biochemistry and Biophysics [ABSTRACT FROM AUTHOR]

The harmful impact caused by pesticides on human health and the environment necessitates the development of efficient degradation processes and control of prohibited stocks of such substances. Organophosphates (OPs) are among the most used agrochemicals in the world and their degradation can proceed through several possible pathways. Investigating the reactivity of OPs with nucleophilic species allows one to propose new and efficient catalyst scaffolds for use in detoxification. In light of the remarkable catalytic activity of imidazole (IMZ) at promoting dephosphorylation processes of OPs, the reactivity of 4(5)‐hydroxymethylimidazole (HMZ) with diethyl‐2,4‐dinitrophenylphosphate (DEDNPP) and Paraoxon are evaluated by combining experimental and theoretical approaches. It is observed that HMZ is an efficient and regiospecific catalyst with reactivity modulated by competing tautomers. To propose an optimal IMZ‐based catalyst, quantum chemical calculations were performed for monosubstituted 4(5)IMZ derivatives that might cleave DEDNPP. Both inductive effects and hydrogen bonding by the substituents are shown to influence barriers and mechanisms. [ABSTRACT FROM AUTHOR]

The classical/nonclassical nature of cationic ammonium intermediates proposed to be involved in cinchona alkaloid solvolysis and related reactions is investigated. While these intermediates are found to possess highly distorted geometries in which the central nitrogen atom and three of the attached groups are essentially coplanar, we do not find evidence of a nonclassical bonding array. Instead, we find evidence that the intermediate resembles a classical, albeit strained, aziridinium structure, which is still able to account for experimental observations. [ABSTRACT FROM AUTHOR]

The synthesis of structurally complex and highly strained natural products provides unique challenges and unexpected opportunities for the development of new reactions and strategies. Herein, the synthesis of (+)‐[5]‐ladderanoic acid is reported. En route to the target, unusual and unexpected strain release driven transformations were uncovered. This occurrence required a drastic revision of the synthetic design that ultimately led to the development of a novel stepwise cyclobutane assembly by an allylboration/Zweifel olefination sequence. [ABSTRACT FROM AUTHOR]

Abstract: Herein, we report the first enantioselective synthesis of dichrocephones A and B, which are cytotoxic triquinane sesquiterpenes with a dense array of stereogenic centers within a strained polycyclic environment. Key features include the application of a catalytic asymmetric Wittig reaction, followed by stereoselective functionalization of the propellane core into a pentacyclic intermediate. Double reductive ring cleavage yielded the proposed structure of dichrocephone A. Mismatched spectroscopic data for our synthetic material compared to the natural isolate led us to revise the previously proposed configuration based on biosynthetic considerations and NMR calculations. Implementation of these findings culminated in the synthesis of dichrocephones A and B. [ABSTRACT FROM AUTHOR]

Abstract: Sesterterpenoids are a relatively rare class of plant terpenes. Sesterterpene synthase (STS)‐mediated cyclization of the linear C25 isoprenoid precursor geranylfarnesyl diphosphate (GFPP) defines sesterterpene scaffolds. So far only a very limited number of STSs have been characterized. The discovery of three new plant STSs is reported that produce a suite of sesterterpenes with unprecedented 6/11/5 and 6/6/7/5 fused ring systems when transiently co‐expressed with a GFPP synthase in Nicotiana benthamiana. Structural elucidation, feeding experiments, and quantum chemical calculations suggest that these STSs catalyze an unusual cyclization path involving reprotonation, intramolecular 1,6 proton transfer, and concerted but asynchronous bicyclization events. The cyclization is diverted from those catalyzed by the characterized plant STSs by forming unified 15/5 bicyclic sesterterpene intermediates. Mutagenesis further revealed a conserved amino acid residue implicated in reprotonation. [ABSTRACT FROM AUTHOR]

The mechanism of the reaction at room temperature between an unactivated 2-alkyl aziridine and carbon dioxide to generate the corresponding oxazolidinone in glass has been studied. Theoretical calculations suggest that this reaction should not proceed at room temperature in the absence of a catalyst. In cases where a reaction was observed, kinetic studies show that the reaction displays a zero-order dependence with respect to aziridine, indicating that free aziridine is not involved in the rate-determining step. An ammonium salt generated in situ acts as a catalyst. The amount of this catalyst is diminutive, which prevented spectroscopic identification, and it is not readily removed from the starting material using chromatography. [ABSTRACT FROM AUTHOR]

C-H functionalization, mechanism, Pd catalysts, quantum chemistry, templates Keywords: C-H functionalization; mechanism; Pd catalysts; quantum chemistry; templates EN C-H functionalization mechanism Pd catalysts quantum chemistry templates 1 1 1 05/16/23 20230511 NES 230511 B Like an octopus b trapping its prey with wriggling arms, a palladium catalyst binds its quinoline substrate through multiple conformations en route to selective activation of a particular C-H bond. Cover Feature: Mechanism and Origins of Site-Selectivity of Template-Directed C-H Insertion of Quinolines (Chem. Eur. J. 27/2023). [Extracted from the article]

Meroterpenes derived from dimethylorsellinic acid (DMOA) and farnesyl pyrophosphate have attracted much biosynthetic attention, yet only recently have synthetic solutions to any family members appeared. A key point of divergence in DMOA-derived meroterpene biosynthesis is the protoaustinoid A carbocation, which can be diverted to either the berkeleyone, andrastin, or terretonin structural classes by cyclase-controlled rearrangement pathways. Shown herein is that the protoaustinoid bicyclo[3.3.1]nonane nucleus can be reverted to either andrastin or terretonin ring systems under abiotic reaction conditions. The first total syntheses of members of these natural product families are reported as their racemates. [ABSTRACT FROM AUTHOR]

Medium-sized rings, particularly the corresponding cyclic peptides, are challenging synthetic targets. In the present study, we report an approach to medium-sized cyclic peptides through targeted formation and collapse of cyclol intermediates. This methodology operates on β-amino imides derived from 2,5-diketopiperazines and offers a straightforward transition from frequently examined scaffolds in drug discovery to a rarely visited class of medium-sized rings. [ABSTRACT FROM AUTHOR]

Metal carbenes appended with two electron-donating groups, known as 'donor/donor' carbenes, undergo diastereo- and enantioselective rhodium-catalyzed C−H insertion reactions with ether substrates to form benzodihydrofurans. Unlike the reactions of metal carbenes with electron-withdrawing groups attached, the attenuated electrophilicity enables these reactions to be conducted in Lewis basic solvents (e.g., acetonitrile) and in the presence of water. The diazo precursors for these species are prepared in situ from hydrazone using a mild and chemoselective oxidant (MnO2). Although this sequence often can be performed in one-pot, control experiments have elucidated why a 'two-pot' process is often more efficient. A thorough screening of achiral catalysts demonstrated that sterically encumbered catalysts are optimal for diastereoselective reactions. Although efficient insertion into allylic and propargylic C−H bonds is observed, competing dipolar cycloaddition processes are noted for some substrates. The full substrate scope of this useful method of benzodihydrofuran synthesis, mechanisms of side reactions, and computational support for the origins of stereoselectivity are described. [ABSTRACT FROM AUTHOR]

In diesem Kurzaufsatz wird die Bedeutung der inhärenten Substratreaktivität von Terpen ‐ Synthasen diskutiert. Der Fokus liegt auf neuen experimentellen Validierungen von Vorhersagen, die anhand von Berechnungen der Reaktivität von Carbokationen in der Gasphase getroffen wurden. Ich weiß, was ich will: Dieser Kurzaufsatz diskutiert die Bedeutung der inhärenten Substratreaktivität bei Umsetzungen mit Terpen ‐ Synthasen. Experimentelle Studien stützen Vorhersagen aus der Quantenchemie, dass in der Gegenwart von Terpen ‐ Synthasen Carbokationen ihre inhärente Reaktivität ausspielen. [ABSTRACT FROM AUTHOR]

The importance of inherent substrate reactivity for terpene synthase enzymes is discussed, with a focus on recent experimental tests of predictions derived from computations on gas-phase reactivity of carbocations. [ABSTRACT FROM AUTHOR]

Imidazole (IMZ) rings catalyze many biological dephosphorylation processes. The methyl positioning effect on IMZs reactivity has long intrigued scientists and its full understanding comprises a promising tool for designing highly efficient IMZ-based catalysts. We evaluated all monosubstituted methylimidazoles (xMEI) in the reaction with diethyl 2,4-dinitrophenyl phosphate by kinetics studies, NMR analysis and DFT calculations. All xMEI showed remarkable rate enhancements, up to 1.9×105 fold, compared with spontaneous hydrolysis. Unexpectedly, the electron-donating methyl group acts to decrease the reactivity of the xMEI compared to IMZ, except for 4(5)methylimidazole, (4(5)MEI). This behavior was attributed to both electronic and steric effects. Moreover, reaction intermediates were monitored by NMR and surprisingly, the reactivity of the two different 4(5)MEI tautomers was distinguished. [ABSTRACT FROM AUTHOR]

Caryolene formation occur asynchronously in a concerted way through carbocationic rearrangements involving the generation of a secondary or a tertiary carbocation whether the reaction proceeds in the absence or in the presence of NH3, respectively. Both caryolene formation mechanisms are analyzed within the general framework of the reaction force; the reaction force constant is used to gain insights into the synchronicity of the mechanisms and the reaction electronic flux helps to characterize the electronic activity taking place during the reaction. DFT calculations at the B3LYP/6-31+G(d,p) level show a clear difference in the mechanisms of the base promoted or base free caryolene formation reactions. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

When activated by an acylating agent, pyridine boronic esters react with organometallic reagents to form a dihydropyridine boronic ester. This intermediate allows access to a number of valuable substituted pyridine, dihydropyridine, and piperidine products. [ABSTRACT FROM AUTHOR]

Substitution of a histidine, comprising part of the catalytic base group in the ent-copalyl diphosphate synthases found in all seed plants for gibberellin phytohormone metabolism, by a larger aromatic residue leads to rearrangements. Through a series of 1,2-hydride and methyl shifts of the initially formed bicycle predominant formation of (-)-kolavenyl diphosphate is observed. Further mutational analysis and quantum chemical calculations provide mechanistic insight into the basis for this profound effect on product outcome. [ABSTRACT FROM AUTHOR]

Adenosine to inosine RNA editing catalyzed by ADAR enzymes is common in humans, and altered editing is associated with disease. Experiments using substrate RNAs with adenosine analogues at editing sites are useful for defining features of the ADAR reaction mechanism. The reactivity of ADAR2 was evaluated with RNA containing the emissive adenosine analogue thieno[3,4-d]-6-aminopyrimidine (thA). This nucleoside was incorporated into a mimic of the glutamate receptor B (GluR B) mRNA R/G editing site. We found that thA is recognized by AMV reverse transcriptase as A, and is deaminated rapidly by human ADAR2 to give thI. Importantly, ADAR reaction progress can be monitored by following the deamination-induced change in fluorescence of the thA-modified RNA. The observed high thA reactivity adds to our understanding of the structural features that are necessary for an efficient hADAR2 reaction. Furthermore, the new fluorescent assay is expected to accelerate mechanistic studies of ADARs. [ABSTRACT FROM AUTHOR]

A biomimetic total synthesis of santalin Y, a structurally complex but racemic natural product, is described. The key step is proposed to be a (3+2) cycloaddition of a benzylstyrene to a 'vinylogous oxidopyrylium', which is followed by an intramolecular Friedel-Crafts reaction. This cascade generates the unique oxafenestrane framework of the target molecule and sets its five stereocenters in one operation. Our work provides rapid access to santalin Y and clarifies its biosynthetic relationship with other colorants isolated from red sandalwood. [ABSTRACT FROM AUTHOR]

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