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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 β-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.

A new reaction mechanism for the construction of dioxabicyclo[4.2.1]nonanone skeletons via a cation cascade has been proposed and examined by DFT and ab initiocomputations. This mechanism features the following steps: (1) intramolecular Friedel–Crafts-type cyclization with a methyl oxocarbenium cation formed by carboxylate disconnection, (2) electron-rich aromatic ring assisted methoxide loss followed by lactone formation, and (3) stepwise dyotropic rearrangement resulting in skeletal isomerization from a dioxabicyclo[3.2.2]nonanone to the dioxabicyclo[4.2.1]nonanone product observed experimentally. The high regioselectivity and driving force for the overall rearrangement were rationalized, and Lewis and Brønsted acid mediated reactivities were compared.

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 situgeneration 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.

Revealing the origins of kinetic selectivity is one of the premier tasks of applied theoretical organic chemistry, and for many reactions, doing so involves comparing competing transition states. For some reactions, however, a single transition state leads directly to multiple products, in which case non-statistical dynamic effects influence selectivity control. The selectivity of photochemical reactions—where crossing between excited-state and ground-state surfaces occurs near ground-state transition structures that interconvert competing products—also should be controlled by the momentum of the reacting molecules as they return to the ground state in addition to the shape of the potential energy surfaces involved. Now, using machine-learning-assisted non-adiabatic molecular dynamics and multiconfiguration pair-density functional theory, these factors are examined for a classic photochemical reaction—the deazetization of 2,3-diazabicyclo[2.2.2]oct-2-ene—for which we demonstrate that momentum dominates the selectivity for hexadiene versus [2.2.2] bicyclohexane products.

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.

Monoterpene alkaloids encompass distinct chemical diversity and wide-ranging bioactivity. Their compact complexity has made them popular as synthetic targets and has inspired many distinct strategies and tactics in the field of heterocyclic chemistry. This article documents the evolution of a synthetic program aimed at accessing the unusual sulfonamide-containing natural product altemicidin, which was generally believed to be a monoterpene alkaloid throughout our entire synthetic investigations but has recently been found to originate through an unexpected and quite disparate biosynthetic pathway. By leveraging a pyridine dearomatization/cycloaddition strategy, we developed a concise pathway to the 5,6-fused bicyclic azaindane core and, after significant experimentation, an ultimate synthesis of altemicidin itself. Tactics to productively manipulate the multiple functional groups present on this highly polar scaffold proved challenging but were eventually realized via several carefully orchestrated and chemoselective transformations–investments that paid dividends in the form of significantly shorter chemical synthesis. Surprisingly, the bond-forming logic between our presumed abiotic synthetic strategy to this alkaloid class and its subsequently identified biosynthetic pathway is eerily similar.

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 β-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.

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.

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.

Noncovalent interactions involving sulfur atoms play essential roles in protein structure and function by significantly contributing to protein stability, folding, and biological activity. Sulfur is a highly polarizable atom that can participate in many types of noncovalent interactions including hydrogen bonding, sulfur−π interactions, and S–lone pair interactions, but the impact of these sulfur-based interactions on molecular recognition and drug design is still often underappreciated. Here, we examine, using quantum chemical calculations, the roles of sulfur-based noncovalent interactions in complex naturally occurring molecules representative of thiopeptide antibiotics: glycothiohexide α and its close structural analogue nocathiacin I. While donor–acceptor orbital interactions make only very small contributions, electrostatic and dispersion contributions are predicted to be significant in many cases. In pursuit of understanding the magnitudes and nature of these noncovalent interactions, we made potential structural modifications that could significantly expand the chemical space of effective thiopeptide antibiotics.

Here, we provide an algorithm that introduces excited states into the molecular dynamics prediction of the 70 eV electron ionization mass spectra. To decide the contributions of different electronic states, the ionization cross section associated with relevant molecular orbitals was calculated by the binary–encounter–Bethe (BEB) model. We used a fast orthogonalization model/single and double state configuration interaction (OM2/CISD) method to implement excited states calculations and combined this with the GFN1-xTB semiempirical model. Demonstrated by predicting the mass spectrum of urocanic acid, we showed better accuracies to experimental spectra using excited-state molecular dynamics than calculations that only used the ground-state occupation. For several histidine pathway intermediates, we found that excited-state corrections yielded an average of 73% more true positive ions compared to the OM2 method when matching to experimental spectra and 16% more true positive ions compared to the GFN method. Importantly, the exited state models also correctly predict several fragmentation reactions that were missing from both ground-state methods. Overall, for 48 calculated molecules, we found the best average mass spectral similarity scores for the mixed excited-state method compared to the ground-state methods using either cosine, weighted dot score, or entropy similarity calculations. Therefore, we recommend adding excited-state calculations for predicting the electron ionization mass spectra of small molecules in metabolomics.

Rh-catalyzed C–H insertion reactions to form β-lactones suffer from post-transition state bifurcations, with the same transition states leading to ketones and ketenes via fragmentation in addition to β-lactones. In such a circumstance, traditional transition state theory cannot predict product selectivity, so we employed ab initiomolecular dynamics simulations to do so and provide a framework for rationalizing the origins of said selectivity. Weak interactions between the catalyst and substrate were studied using energy decomposition and noncovalent interaction analyses, which unmasked an important role of the 2-bromophenyl substituent that has been used in multiple β-lactone-forming C–H insertion reactions. Small and large catalysts were shown to behave differently, with the latter providing a means of overcoming dynamically preferred fragmentation by lowering the barrier for the recombination of the product fragments in the grip of the large catalyst active site cavity.

The reported synthesis of stemara-13(14)-en-18-ol, which revealed that the structure of this natural product was misassigned, prompted an investigation using density functional theory methods into the structural reassignment of this natural product and related diterpenoids extracted from Calceolariaplants. 1H and 13C chemical shift predictions led to the reassignment of relative configuration, and in one case the carbon skeleton, of several diterpenoids from Calceolaria. In many of these cases, the chemical shift of the vinylic hydrogen was found to be diagnostic.

Differences in entropies of competing transition states can direct kinetic selectivity. Understanding and modeling such entropy differences at the molecular level is complicated by the fact that entropy is statistical in nature; i.e., it depends on multiple vibrational states of transition structures, the existence of multiple dynamically accessible pathways past these transition structures, and contributions from multiple transition structures differing in conformation/configuration. The difficulties associated with modeling each of these contributors are discussed here, along with possible solutions, all with an eye toward the development of portable qualitative models of use to experimentalists aiming to design reactions that make use of entropy to control kinetic selectivity.

A barley diterpene synthase (HvKSL4) was found to produce (14S)-cleistantha-8,12-diene (1). Formation of the nearly planar cyclohexa-1,4-diene configuration leaves the ring poised for aromatization, but necessitates a deceptively complicated series of rearrangements steered through a complex energetic landscape, as elucidated here through quantum chemical calculations and labeling studies.

Chemical derivatization, especially silylation, is widely used in gas chromatography coupled to mass spectrometry (GC-MS). By introducing the trimethylsilyl (TMS) group to substitute active hydrogens in the molecule, thermostable volatile compounds are created that can be easily analyzed. While large GC-MS libraries are available, the number of spectra for TMS-derivatized compounds is comparatively small. In addition, many metabolites cannot be purchased to produce authentic library spectra. Therefore, computationally generated in silico mass spectral databases need to take TMS derivatizations into account for metabolomics. The quantum chemistry method QCEIMS is an automatic method to generate electron ionization (EI) mass spectra directly from compound structures. To evaluate the performance of the QCEIMS method for TMS-derivatized compounds, we chose 816 trimethylsilyl derivatives of organic acids, alcohols, amides, amines, and thiols to compare in silico-generated spectra against the experimental EI mass spectra from the NIST17 library. Overall, in silico spectra showed a weighted dot score similarity (1000 is maximum) of 635 compared to the NIST17 experimental spectra. Aromatic compounds yielded a better prediction accuracy with an average similarity score of 808, while oxygen-containing molecules showed lower accuracy with only an average score of 609. Such similarity scores are useful for annotation of small molecules in untargeted GC-MS-based metabolomics, suggesting that QCEIMS methods can be extended to compounds that are not present in experimental databases. Despite this overall success, 37% of all experimentally observed ions were not found in QCEIMS predictions. We investigated QCEIMS trajectories in detail and found missed fragmentations in specific rearrangement reactions. Such findings open the way forward for future improvements to the QCEIMS software.

The article offers information on the quantum mechanics and outer space. Topics include Chemical reactions must traverse hill-like barriers, energy penalties for reaching products, It takes a certain amount of energy, usually from heat, for a chemical reaction to happen, quantum mechanics sometimes offer a tunnellike third option, so that the reaction can happen even without the added energy, wave function.

A variety of (5 + 2) cycloaddition reactions involving oxidopyridinium and oxidopyrylium zwitterions are compared to investigate the effects of nitrogen-for-oxygen substitution on reactivity. Activation barriers for nitrogen-containing systems are predicted to be larger than those for analogous oxygen-containing systems. Correlations between barrier heights and synchronicity of C–C bond formation, changes to aromaticity, reactant distortion, and interaction energies between zwitterions and alkenes were assessed, leading to the conclusion that reactivity depends more on distortion effects (including aromaticity loss) than on interaction effects (such as those associated with highest occupied molecular orbital–lowest unoccupied molecular orbital (HOMO–LUMO) interactions).

We have developed catalyst-controlled regiodivergent rearrangements of onium-ylides derived from indole substrates. Oxonium ylides formed in situfrom substituted indoles selectively undergo [2,3]- and [1,2]-rearrangements in the presence of a rhodium and a copper catalyst, respectively. The combined experimental and density functional theory (DFT) computational studies indicate divergent mechanistic pathways involving a metal-free ylide in the rhodium catalyzed reaction favoring [2,3]-rearrangement, and a metal-coordinated ion-pair in the copper catalyzed [1,2]-rearrangement that recombines in the solvent-cage. The application of our methodology was demonstrated in the first total synthesis of the indole alkaloid (±)-sorazolon B, which enabled the stereochemical reassignment of the natural product. Further functional group transformations of the rearrangement products to generate valuable synthetic intermediates were also demonstrated.

Adenosine Deaminases Acting on RNA (ADARs) convert adenosine to inosine in double stranded RNA. Human ADARs can be directed to predetermined target sites in the transcriptome by complementary guide strands, allowing for the correction of disease-causing mutations at the RNA level. Here we use structural information available for ADAR2-RNA complexes to guide the design of nucleoside analogs for the position in the guide strand that contacts a conserved glutamic acid residue in ADARs (E488 in human ADAR2), which flips the adenosine into the ADAR active site for deamination. Mutating this residue to glutamine (E488Q) results in higher activity because of the hydrogen bond donating ability of Q488 to N3 of the orphan cytidine on the guide strand. We describe the evaluation of cytidine analogs for this position that stabilize an activated conformation of the enzyme-RNA complex and increase catalytic rate for deamination by the wild-type enzyme. A new crystal structure of ADAR2 bound to duplex RNA bearing a cytidine analog revealed a close contact between E488, stabilized by an additional hydrogen bond and altered charge distribution when compared to cytidine. In human cells and mouse primary liver fibroblasts, this single nucleotide modification increased directed editing yields when compared to an otherwise identical guide oligonucleotide. Our results show that modification of the guide RNA can mimic the effect of hyperactive mutants and advance the approach of recruiting endogenous ADARs for site-directed RNA editing.

Six novel oxasqualenoids (polyether triterpenes) were isolated from the red alga Laurencia viridis. Laurokanols A–E (1–5) comprise an unreported tricyclic core with a [6,6]-spiroketal system. Yucatecone (6) shows a biogenetically intriguing epimerization at C14. Quantum mechanical calculations were used to corroborate their structures and to explain key steps involved in the biogenetic mechanisms proposed for the formation of oxasqualenoids.

Terpenes make up the largest class of natural products, with extensive chemical and structural diversity. Diterpenes, mostly isolated from plants and rarely prokaryotes, exhibit a variety of important biological activities and valuable applications, including providing antitumor and antibiotic pharmaceuticals. These natural products are constructed by terpene synthases, a class of enzymes that catalyze one of the most complex chemical reactions in biology: converting simple acyclic oligo-isoprenyl diphosphate substrates to complex polycyclic products via carbocation intermediates. Here we obtained the second ever crystal structure of a class II diterpene synthase from bacteria, tuberculosinol pyrophosphate synthase (i.e., Halimadienyl diphosphate synthase, MtHPS, or Rv3377c) from Mycobacterium tuberculosis(Mtb). This enzyme transforms (E,E,E)-geranylgeranyl diphosphate into tuberculosinol pyrophosphate (Halimadienyl diphosphate). Rv3377c is part of the Mtbditerpene pathway along with Rv3378c, which converts tuberculosinol pyrophosphate to 1-tuberculosinyl adenosine (1-TbAd). This pathway was shown to exist only in virulent Mycobacteriumspecies, but not in closely related avirulent species, and was proposed to be involved in phagolysosome maturation arrest. To gain further insight into the reaction pathway and the mechanistically relevant enzyme substrate binding orientation, electronic structure calculation and docking studies of reaction intermediates were carried out. Results reveal a plausible binding mode of the substrate that can provide the information to guide future drug design and anti-infective therapies of this biosynthetic pathway.

Reactions with post-transition-state bifurcations (PTSBs) involve initial ambimodal transition-state structures followed by an unstable region leading to two possible products. PTSBs are seen in many organic, organometallic, and biosynthetic reactions, but analyzing the origins of selectivity for these reactions is challenging, in large part due to the complex nature of the potential energy surfaces involved, which precludes analyses based on single intrinsic reaction coordinate (IRC; steepest-descent path in mass-weighted coordinate). While selectivity can be predicted using molecular dynamics simulation, connecting results from such calculations to the topography of potential energy surfaces is difficult. In the present work, a method for generating two-dimensional potential energy surfaces for PTSBs is described. The first dimension starts with the IRC for the first transition-state structure, followed by a modified reaction coordinate that reaches the second transition-state structure, which interconverts the two products of a bifurcating reaction path. The IRC for the second transition-state structure constitutes the second dimension. In addition, a method for mapping trajectories from Born–Oppenheimer molecular dynamics simulations onto these surfaces is described. Both approaches are illustrated with representative examples from the field of organic chemistry. The 2D-PESs for five asymmetric cases tested have clear tilted topography after the first transition-state structure, and the tilted direction correlates well with the selectivity observed from previous dynamic simulation. Instead of selecting reaction coordinates by chemical intuition, our method provides a general means to construct two-dimensional potential energy surfaces for reactions with post-transition-state bifurcations.

Results of density functional theory calculations on rearrangements of potential biosynthetic precursors to the sesquiterpenoid illisimonin A reveal that only some possible precursors, those with certain specific oxidation patterns, are rearrangement-competent.

The article offers information on the role of kinetic isotope effects in enzyme conversion in molecules and to understand how reactions work. Topics discussed include breaking carbon hydrogen bonds in reactions faster than breaking an analogous bond between carbon; kinetic isotope effects to hack into chemical reactions used by chemists; and the vibrational energy within carbon-hydrogen (C-H) and carbon-deuterium (C-D) bonds.

Serlyticin-A is a secondary metabolite first isolated from a culture of Serratia ureilyticagrown using squid pen as the sole carbon/nitrogen source. A previous study by Kuo et al. demonstrated that it has antioxidative and antiproliferative properties. However, the proposed chemical structure of serlyticin-A is likely incorrect based on the thermodynamic instability of its three contiguous heteroatom–heteroatom bonds. Here, we use quantum chemical calculations to predict 1H and 13C chemical shifts for serlyticin-A and demonstrate a discrepancy between the calculated and experimental chemical shifts. We then propose several reasonable alternative structures for serlyticin-A. Considering the known antioxidant and antiproliferative activity of hydroxamic acids as well as their stability and prevalence in natural products of bacterial origin, we believe that serlyticin-A is most likely 3-indolylacetohydroxamic acid (4). We provide our rationale for this assignment as well as experimental data for pure 3-indolylacetohydroxamic acid obtained via de novo synthesis. This study highlights the power of computational NMR shift prediction to revise chemical structures for natural products like serlyticin-A.

Enantioselective Giese reactions employing chiral α,β-unsaturated acylammonium salts and subsequent diastereoselective trapping followed by lactamization deliver optically active δ-lactams. Alkyl iodides bearing tosylamides undergo radical initiation using triethylborane at low temperatures to provide carbon-centered radicals to initiate the described organocascade. Subsequent diastereoselective inter- or intramolecular trapping of the incipient α-radical leads to highly functionalized, enantioenriched mono- and bicyclic δ-lactams (up to 99:1 er, > 19:1 dr) bearing up to three stereogenic centers. Interestingly, benzotetramisole imparts diastereoselectivity that contradicts steric considerations alone. Results from DFT calculations rationalized the observed enantio- and diastereoselectivities, revealed an electrostatic interaction between the sulfone oxygens and the ammonium cation in the initial α-radical intermediate, and aided in application of this methodology to bicyclic δ-lactams through intramolecular trapping of the α-radical intermediate.

The Diels–Alder reaction represents one of the most thoroughly studied and well-understood synthetic transformations for the assembly of six-membered rings. Although intramolecular dehydro-Diels–Alder (IMDDA) reactions have previously been employed for the preparation of naphthalene and dihydronaphthalene substrates, low yields and product mixtures have reduced the impact and scope of this reaction. Through the mechanistic studies described within, we have confirmed that the thermal IMDDA reaction of styrene–ynes produces a naphthalene product via loss of hydrogen gas from the initially formed cycloadduct, a tetraenyl intermediate. Alternatively, the dihydronaphthalene product is afforded from the same tetraenyl intermediate via a radical isomerization process. Moreover, we have identified conditions that can be used to achieve efficient, high-yielding, and selective IMDDA reactions of styrene–ynes to form either naphthalene or dihydronaphthalene products. The operational simplicity and retrosynthetic orthogonality of this method for the preparation of naphthalenes and dihydronaphthalenes makes this transformation appealing for the synthesis of medicinal and material targets. The mechanistic studies within may impact the development of other thermal transformations.

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 initiomolecular 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.

The reaction mechanism of Brønsted acid-catalyzed silane-dependent P═O 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 P═O 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 P═O 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 P═O group in transition structures. The proposed activation mode differs significantly from that associated with traditional Brønsted acid-catalyzed C═O reduction. The uniqueness of P═O reduction originates from the dominant Si/O═P 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 P═O reduction systems as well as novel organophosphine-catalyzed reactions involving P(V)/P(III) redox cycle.

A heterocycle-to-heterocycle strategy is presented for the preparation of highly fluorescent and solvatochromic dibenzonaphthyridinones (DBNs) via methodology that leads to the formation of a tertiary, spiro-fused carbon center. A linear correlation between the results of photophysical experiments and time dependent density functional theory calculations was observed for the λmaxof excitation for DBNs with varying electronic character.

Rh2L4catalysts 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 Rh2L4catalyzed 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 Rh2L4catalyzed reactions likely involve dissociation of the Rh2L4catalyst 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 Rh2L4catalyzed 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 multipleproducts 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 Rh2L4catalysts modulate dynamic behavior to produce particular products in high yield.

Contributions from quantum mechanical tunneling to the rates of several radical coupling reactions between carbon sp2centers used as key steps in natural product total syntheses were computed using density functional theory. Contributions ranging from ∼15–52% from tunneling were predicted at room temperature, thereby indicating that tunneling plays an important role in the rates of these reactions and should perhaps be considered when designing complex synthetic schemes.

Biosynthesis of the complex diterpenoid antibiotic pleuromutilin relies on a bifunctional (di)terpene synthase, and here site-directed mutagenesis was used to knockout either of the two active sites. This enabled characterization of the novel ring contracted intermediate produced by the initiating class II diterpene cyclase active site. Quantum chemical calculations further indicate the importance of reactant configuration for this intriguing ring rearrangement.

Herein we describe our exploration, using density functional theory calculations, of a conjugate addition–rearrangement sequence that leads to medium-ring cyclic amines. On the basis of the results of our calculations, we conclude that the rearrangement step is rate determining. In addition, we analyze the role of a carbanion lone pair in the rearrangement step, concluding that it functions as a substituent on a [3,3] sigmatropic shift, rather than a nucleophile; thus, the Woodward–Hoffmann rules are not circumvented in this reaction via involvement of orthogonal orbitals on an atom involved in the rearrangement.

The rapidly growing appreciation of enzymes’ catalytic and substrate promiscuity may lead to their expanded use in the fields of chemical synthesis and industrial biotechnology. Here, we explore the substrate promiscuity of enoyl-acyl carrier protein reductases (commonly known as FabI) and how that promiscuity is a function of inherent reactivity and the geometric demands of the enzyme’s active site. We demonstrate that these enzymes catalyze the reduction of a wide range of substrates, particularly α,β-unsaturated aldehydes. In addition, we demonstrate that a combination of quantum mechanical hydride affinity calculations and molecular docking can be used to rapidly categorize compounds that FabI can use as substrates. The results here provide new insight into the determinants of catalysis for FabI and set the stage for the development of a new assay for drug discovery, organic synthesis, and novel biocatalysts.

Results of kinetic experiments and quantum chemical computations on a series of platinum-promoted polycyclization reactions are described. Analyses of these results reveal a reactivity model that reaches beyond the energetics of the cascade itself, incorporating an ensemble of pre-cyclization conformations of the platinum–alkene reactant complex, only a subset of which are productive for bi- (or larger) cyclization and lead to products. Similarities and differences between this scenario, including reaction coordinates for polycyclization, for platinum- and enzyme-promoted polycyclization reactions are highlighted.

S-Adenosyl methionine (SAM) is employed as a [4Fe-4S]-bound cofactor in the superfamily of radical SAM (rSAM) enzymes, in which one-electron reduction of the [4Fe-4S]-SAM moiety leads to homolytic cleavage of the S-adenosyl methionine to generate the 5′-deoxyadenosyl radical (5′dAdo•), a potent H-atom abstractor. HydG, a member of this rSAM family, uses the 5′dAdo•radical to lyse its substrate, tyrosine, producing CO and CN that bind to a unique Fe site of a second HydG Fe–S cluster, ultimately producing a mononuclear organometallic Fe-l-cysteine-(CO)2CN complex as an intermediate in the bioassembly of the catalytic H-cluster of [Fe–Fe] hydrogenase. Here we report the use of non-native tyrosine substrate analogues to further probe the initial radical chemistry of HydG. One such non-native substrate is 4-hydroxy phenyl propanoic acid (HPPA) which lacks the amino group of tyrosine, replacing the CαH-NH2with a CH2at the C2 position. Electron paramagnetic resonance (EPR) studies show the generation of a strong and relatively stable radical in the HydG reaction with natural abundance and 13C2-HPPA, with appreciable spin density localized at C2. These results led us to try parallel experiments with the more oxidized non-native substrate coumaric acid, which has a C2═C3alkene substitution relative to HPPA’s single bond. Interestingly, the HydG reaction with the cis-p-coumaric acid isomer led to the trapping of a new radical EPR signal, and EPR studies using cis-p-coumaric acid along with isotopically labeled SAM reveal that we have for the first time trapped and characterized the 5′dAdo•radical in an actual rSAM enzyme reaction, here by using this specific non-native substrate cis-p-coumaric acid. Density functional theory energetics calculations show that the cis-p-coumaric acid has approximately the same C–H bond dissociation free energy as 5′dAdo•, providing a possible explanation for our ability to trap an appreciable fraction of 5′dAdo•in this specific rSAM reaction. The radical’s EPR line shape and its changes with SAM isotopic substitution are nearly identical to those of a 5′dAdo•radical recently generated by cryophotolysis of a prereduced [4Fe-4S]-SAM center in another rSAM enzyme, pyruvate formate-lyase activating enzyme, further supporting our assignment that we have indeed trapped and characterized the 5′dAdo•radical in a radical SAM enzymatic reaction by appropriate tuning of the relative radical free energies via the judicious selection of a non-native substrate.

Photoswitches capable of accessing two geometric states are highly desirable, especially if their design is modular and incorporates a pharmacophore tethering site. We describe a redox isomerization strategy for synthesizing p-formylazobenzenes from p-nitrobenzyl alcohol. The resulting azo-aldehydes can be readily converted to photoswitchable compounds with excellent photophysical properties using simple hydrazide click chemistry. As a proof of principle, we synthesized a photoswitchable surfactant enabling the photocontrol of an emulsion with exceptionally high spatiotemporal precision.

The formation of fused pyrazoles via intramolecular 1,3-dipolar cycloadditions of diazo intermediates with pendant alkynes is described. A subsequent thermal [1s, 5s] sigmatropic shift of these pyrazole systems resulted in a ring contraction, forming spirocyclic pyrazoles. The limitations of this rearrangement were explored by changing the substituents on the nonmigrating aromatic ring and by using substrates lacking an aromatic linkage to the propargyl group.

Tryptophan, an essential amino acid, is metabolized into a variety of small molecules capable of impacting human physiology, and aberrant tryptophan metabolism has been linked to a number of diseases. There are three principal routes by which tryptophan is degraded, and thus methods for measuring metabolic flux through these pathways can be used to understand the factors that perturb tryptophan metabolism and potentially to measure disease biomarkers. Here, we describe a method utilizing 6-fluorotryptophan as a probe for detecting tryptophan metabolites in ex vivo tissue samples via 19F nuclear magnetic resonance. As a proof of concept, we demonstrate that 6-fluorotryptophan can be used to measure changes in tryptophan metabolism resulting from antibiotic-induced changes in gut microbiota composition. Taken together, we describe a general strategy for monitoring amino acid metabolism using 19F nuclear magnetic resonance that is operationally simple and does not require chromatographic separation of metabolites.

The Davis–Beirut reaction provides access to 2H-indazoles from aromatic nitro compounds. However, N-aryl targets have been traditionally challenging to access due to competitive alternate reaction pathways. Previously, the key nitroso imine intermediate was generated under alkaline conditions, but as reported here, the photochemistry of o-nitrobenzyl alcohols empowered Brønsted acid catalyzed conditions for accessing N-aryl targets. Anilines and alkyl amines give different outcomes under optimized conditions; the proposed mechanism was studied using quantum chemical calculations.

A series of computational laboratory experiments aimed at teaching students principles of rational drug design are described and evaluated. These experiments range from an introduction to viewing protein–ligand complexes to optimizing geometries of potential drugs with quantum chemistry and automated docking. Student feedback indicates that such a course increased their appreciation for the roles of chemists in the drug discovery–development process.

The Cadogan cyclization is a robust but harsh method for the synthesis of 2H-indazoles, a valuable class of nitrogen heterocycles. Although nitrene generation by exhaustive deoxygenation is widely accepted as the operating mechanism in the reductive cyclization of nitroaromatics, non-nitrene pathways have only been theorized previously. Here, 2H-indazole N-oxides were synthesized through an interrupted Cadogan/Davis–Beirut reaction and are presented as direct evidence of competent oxygenated intermediates; mechanistic implications for both reactions are discussed. Isolation and characterization of these N-oxides enabled a formal Cadogan cyclization at room temperature for 2H-indazole synthesis.

A method for the diastereoselective synthesis of highly substituted β-enamino ketones from anhydrides and ketone-derived imines is reported. Cyclic, enolizable anhydrides undergo a base-promoted conjugate addition reaction with α,β-unsaturated N-tosyl ketimines, followed by an intramolecular acylation to give formal [4 + 2] cycloaddition products. The carboxylic acid-containing products are formed with modest selectivity for the cis-diastereomer and can be fully epimerized to the trans-diastereomer upon esterification.