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Asymmetric catalysis is an advanced area of chemical synthesis, but the handling of abundantly available, purely aliphatic hydrocarbons has proven to be challenging. Typically, heteroatoms or aromatic substructures are required in the substrates and reagents to facilitate an efficient interaction with the chiral catalyst. Confined acids have recently been introduced as tools for homogenous asymmetric catalysis, specifically to enable the processing of small unbiased substrates1. However, asymmetric reactions in which both substrate and product are purely aliphatic hydrocarbons have not previously been catalysed by such super strong and confined acids. We describe here an imidodiphosphorimidate-catalysed asymmetric Wagner-Meerwein shift of aliphatic alkenyl cycloalkanes to cycloalkenes with excellent regio- and enantioselectivity. Despite their long history and high relevance for chemical synthesis and biosynthesis, Wagner-Meerwein reactions utilizing purely aliphatic hydrocarbons, such as those originally reported by Wagner and Meerwein, had previously eluded asymmetric catalysis.
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ConspectusRh2L4 catalysts have risen in popularity in the world of organic synthesis, being used to accomplish a variety of reactions, including C-H insertion and cyclopropanation, and often doing so with high levels of stereocontrol. While the mechanisms and origins of selectivity for such reactions have been examined with computational quantum chemistry for decades, only recently have detailed pictures of the dynamic behavior of reacting Rh2L4-complexed molecules become accessible. Our computational studies on Rh2L4 catalyzed reactions are described here, with a focus on C-H insertion reactions of Rh2L4-carbenes. Several issues complicate the modeling of these reactions, each providing an opportunity for greater understanding and each revealing issues that should be incorporated into future rational design efforts. First, the fundamental mechanism of C-H insertion is discussed. While early quantum chemical studies pointed to transition structures with 3-center [C-H-C] substructures and asynchronous hydride transfer/C-C bond formation, recent examples of reactions with particularly flat potential energy surfaces and even discrete zwitterionic intermediates have been found. These reactions are associated with systems bearing π-donating groups at the site of hydride transfer, allowing for an intermediate with a carbocation substructure at that site to be selectively stabilized. Second, the possible importance of solvent coordination at the Rh atom distal to the carbene is discussed. While effects on reactivity and selectivity were found to be small, they turn out not to be negligible in some cases. Third, it is shown that, in contrast to many other transition metal promoted reactions, many Rh2L4 catalyzed reactions likely involve dissociation of the Rh2L4 catalyst before key chemical steps leading to products. When to expect dissociation is associated with specific features of substrates and the product-forming reactions in question. Often, dissociation precedes transition structures for pericyclic reactions that involve electrons that would otherwise bind to Rh2L4. Finally, the importance of nonstatistical dynamic effects, characterized through ab initio molecular dynamics studies, in some Rh2L4 catalyzed reactions is discussed. These are reactions where transition structures are shown to be followed by flat regions, very shallow minima, and/or pathways that bifurcate, all allowing for trajectories from a single transition state to form multiple different products. The likelihood of encountering such a situation is shown to be associated again with the likelihood of formation of zwitterionic structures along reaction paths, but ones for which pathways to multiple products are expected to be associated with very low or no barriers. The connection between these features and reduced yields of desired products are highlighted, as are the means by which some Rh2L4 catalysts modulate dynamic behavior to produce particular products in high yield.
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A special type of C-H functionalization can be achieved through C-H insertion combined with Cope rearrangement (CHCR) in the presence of dirhodium catalysts. This type of reaction was studied using density functional theory and ab initio molecular dynamics simulations, the results of which pointed to the dynamic origins of low yields observed in some experiments. These studies not only reveal intimate details of the complex reaction network underpinning CHCR reactions but also further cement the generality of the importance of nonstatistical dynamic effects in controlling Rh2L4-promoted reactions.
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Herein, we report concise total syntheses of diterpene natural products (-)-crinipellins A and B with a tetraquinane skeleton, three adjacent all-carbon quaternary centers, and multiple oxygenated and labile functional groups. Our synthesis features a convergent Kozikowski ß-alkylation to unite two readily available building blocks with all the required carbon atoms, an intramolecular photochemical [2 + 2] cycloaddition to install three challenging and adjacent all-carbon quaternary centers and a 5-6-4-5 tetracyclic skeleton, and a controlled Cargill rearrangement to rearrange the 5-6-4-5 tetracyclic skeleton to the desired tetraquinane skeleton. These strategically enabling transformations allowed us to complete total syntheses of (-)-crinipellins A and B in 12 and 13 steps, respectively. The results of quantum chemical computations revealed that the Bronsted acid-catalyzed Cargill rearrangements likely involve stepwise paths to products and the AlR3-catalyzed Cargill rearrangements likely involve a concerted path with asynchronous alkyl shifting events to form the desired product.
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Diterpenos , Diterpenos/síntesis química , Diterpenos/química , Estereoisomerismo , Productos Biológicos/síntesis química , Productos Biológicos/química , Estructura Molecular , Reacción de Cicloadición , AlquilaciónRESUMEN
The reaction mechanism of Brønsted acid-catalyzed silane-dependent PâO reduction has been elucidated through combined computational and experimental methods. Due to its remarkable chemo- and stereoselective nature, the Brønsted acid/silane reduction system has been widely employed in organophosphine-catalyzed transformations involving P(V)/P(III) redox cycle. However, the full mechanistic profile of this type of PâO reduction has yet to be clearly established to date. Supported by both DFT and experimental studies, our research reveals that the reaction likely proceeds through mechanisms other than the widely accepted "dual activation mode by silyl ester" or "acid-mediated direct PâO activation" mechanism. We propose that although the reduction mechanisms may vary with the substitution patterns of silane species, Brønsted acid generally activates the silane rather than the PâO group in transition structures. The proposed activation mode differs significantly from that associated with traditional Brønsted acid-catalyzed CâO reduction. The uniqueness of PâO reduction originates from the dominant Si/OâP orbital interactions in transition structures rather than the P/H-Si interactions. The comprehensive mechanistic landscape provided by us will serve as a guidance for the rational design and development of more efficient PâO reduction systems as well as novel organophosphine-catalyzed reactions involving P(V)/P(III) redox cycle.
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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 ß-amyrin synthase (CqbAS1) and B,C-ring-opened triterpene synthase CqQS. Mutation of one key residue (N612K) in even evolutionarily distant Arabidopsis ß-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.
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Chenopodium quinoa , Transferasas Intramoleculares , Triterpenos , Chenopodium quinoa/metabolismo , Triterpenos/metabolismo , Transferasas Intramoleculares/genética , Transferasas Intramoleculares/metabolismoRESUMEN
Selective functionalization of the indole-C3-C bond with aromatic/heteroaromatic 1,2-diketones has been uncovered for the first time. Cobalt catalyst was found to be an effective catalyst for this unusual transformation. This ipso-C-C bond functionalization occurred in the presence of easily available weakly coordinating groups such as ketone and ester. One of the salient features of this methodology is the in situ generation of water from hexafluoro-2-propanol which acts as a reactant for the removal of the pivaloyl/ester group in a deacylative manner. The plausible mechanism has been supported by DFT calculations. Moreover, photophysical studies show the potential utility of indole-C3-acyloin and indolo-fused carbazole, which could be used in photovoltaic and optoelectronic application.
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The radical S-adenosylmethionine (rSAM) enzyme SuiB catalyzes the formation of an unusual carbon-carbon bond between the sidechains of lysine (Lys) and tryptophan (Trp) in the biosynthesis of a ribosomal peptide natural product. Prior work on SuiB has suggested that the Lys-Trp cross-link is formed via radical electrophilic aromatic substitution (rEAS), in which an auxiliary [4Fe-4S] cluster (AuxI), bound in the SPASM domain of SuiB, carries out an essential oxidation reaction during turnover. Despite the prevalence of auxiliary clusters in over 165,000 rSAM enzymes, direct evidence for their catalytic role has not been reported. Here, we have used electron paramagnetic resonance (EPR) spectroscopy to dissect the SuiB mechanism. Our studies reveal substrate-dependent redox potential tuning of the AuxI cluster, constraining it to the oxidized [4Fe-4S]2+ state, which is active in catalysis. We further report the trapping and characterization of an unprecedented cross-linked Lys-Trp radical (Lys-Trpâ¢) in addition to the organometallic Ω intermediate, providing compelling support for the proposed rEAS mechanism. Finally, we observe oxidation of the Lys-Trp⢠intermediate by the redox-tuned [4Fe-4S]2+ AuxI cluster by EPR spectroscopy. Our findings provide direct evidence for a role of a SPASM domain auxiliary cluster and consolidate rEAS as a mechanistic paradigm for rSAM enzyme-catalyzed carbon-carbon bond-forming reactions.
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Proteínas Bacterianas/química , Proteínas Hierro-Azufre/química , Lisina/química , Proteínas Ribosómicas/química , S-Adenosilmetionina/química , Streptococcus/química , Triptófano/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Sitios de Unión , Catálisis , Clonación Molecular , Espectroscopía de Resonancia por Spin del Electrón , Escherichia coli/genética , Escherichia coli/metabolismo , Expresión Génica , Vectores Genéticos/química , Vectores Genéticos/metabolismo , Proteínas Hierro-Azufre/genética , Proteínas Hierro-Azufre/metabolismo , Cinética , Lisina/metabolismo , Modelos Moleculares , Oxidación-Reducción , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , S-Adenosilmetionina/metabolismo , Streptococcus/enzimología , Streptococcus/genética , Especificidad por Sustrato , Termodinámica , Triptófano/metabolismoRESUMEN
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.
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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.
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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.
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Eunicellane diterpenoids are a unique family of natural products containing a foundational 6/10-bicyclic framework and can be divided into two main classes, cis and trans, based on the configurations of their ring fusion at C1 and C10. Previous studies on two bacterial diterpene synthases, Bnd4 and AlbS, revealed that these enzymes form cis- and trans-eunicellane skeletons, respectively. Although the structures of these diterpenes only differed in their configuration at a single position, C1, they displayed distinct chemical and thermal reactivities. Here, we used a combination of quantum chemical calculations and chemical transformations to probe their intrinsic properties, which result in protonation-initiated cyclization, Cope rearrangement, and atropisomerism. Finally, we exploited the reactivity of the trans-eunicellane skeleton to generate a series of 6/6/6 gersemiane-type diterpenes via electrophilic cyclization.
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Herein, we disclose an approach to synthesize tert-alkyl cyclopropanes by leveraging C-F bond functionalization of gem-difluorocyclopropenes using tris(pentafluorophenyl)borane catalysis. The reaction proceeds through the intermediacy of a fluorocyclopropenium ion, which was confirmed by the isolation of [Ph2(C6D5)C3]+[(C6F5)3BF]-. We found that silylketene acetal nucleophiles were optimal reaction partners with fluorocyclopropenium ion intermediates yielding fully substituted cyclopropenes functionalized with two α-tert-alkyl centers (63-93% yield). The regioselectivity of the addition to cyclopropenium ions is controlled by their steric and electronic properties and enables access to 3,3-bis(difluoromethyl)cyclopropenes in short order. The resulting cyclopropene products are readily reduced to the corresponding orphaned cyclopropanes under hydrogenation conditions. Quantum chemical calculations reveal the nature of the C-F bond cleavage steps and provide evidence for catalysis by boron and not silylated oxonium ions, though Si-F bond formation is the enthalpic driving force for the reaction.
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Polycyclic ring systems are ubiquitous three-dimensional (3D) structural motifs central to the function of many biologically active small molecules and organic materials. Indeed, subtle changes to the overall molecular shape and connectivity of atoms in a polycyclic framework (i.e., isomerism) can drastically alter its function and properties. Unfortunately, direct evaluation of these structure-function relationships typically requires the development of distinct synthetic strategies toward a specific isomer. Dynamic, "shapeshifting" carbon cages present a promising approach for sampling isomeric chemical space but are often difficult to control and are largely limited to thermodynamic mixtures of positional isomers about a single core scaffold. Here, we describe the development of a new shapeshifting C9-chemotype and a chemical blueprint for its evolution into structurally and energetically diverse isomeric ring systems. By leveraging the unique molecular topology of π-orbitals interacting through-space (homoconjugation), a common skeletal ancestor evolved into a complex network of valence isomers. This unusual system represents an exceedingly rare small molecule capable of undergoing controllable and continuous isomerization processes through the iterative use of just two chemical steps (light and organic base). Computational and photophysical studies of the isomer network provide fundamental insight into the reactivity, mechanism, and role of homoconjugative interactions. Importantly, these insights may inform the rational design and synthesis of new dynamic, shapeshifting systems. We anticipate this process could be a powerful tool for the synthesis of structurally diverse, isomeric polycycles central to many bioactive small molecules and functional organic materials.
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The template-directed C-H insertion of α,ß-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.
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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.
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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.
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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.
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We describe the various escape channels available to dirhodium carbene intermediates from cycloheptatrienyl diazo compounds located with density functional theory. An intramolecular cyclopropanation would, in principle, provide a new route to semibullvalenes (SBVs). A detailed exploration of the potential energy surface reveals that methylating carbon-7 suppresses a competing ß-hydride migration pathway to heptafulvene products, giving SBV formation a reasonable chance. During our explorations, we additionally discovered unusual spirononatriene, spironorcaradiene, and metal-stabilized 9-barbaralyl cation structures as local minima.
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Rodio , Rodio/química , Catálisis , Compuestos Azo/química , CarbonoRESUMEN
The reaction pathway of silyloxypyrone-based (5 + 2) cycloadditions was determined to be extremely dependent on the nature of the dipolarophile. Neutral alkenes were the least reactive, whereas both electron-deficient and electron-rich dipolarophiles were more reactive, thus providing evidence for ambident oxidopyrylium intermediates. Qualitative rate studies, Hammett linear free energy relationships, and theoretical calculations combined to provide evidence for a spectrum of reactivity that passes through the borderlands of concerted and stepwise.