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Substrates engineered to undergo a 1,4-C-H insertion to yield benzocyclobutenes resulted in a novel elimination reaction to yield ortho-quinone dimethide (o-QDM) intermediates that undergo Diels-Alder or hetero-Diels-Alder cycloadditions. The analogous benzylic acetals or ethers avoid the C-H insertion pathway completely and, after hydride transfer, undergo a de-aromatizing elimination reaction to o-QDM at ambient temperature. The resulting dienes undergo a variety of cycloaddition reactions with high diastereo- and regio-selectivity. This is one of the few examples of catalytic generation of o-QDM without the intermediacy of a benzocyclobutene and represents one of the mildest, ambient temperature processes to access these useful intermediates. This proposed mechanism is supported by DFT calculations. Moreover, the methodology was applied to the synthesis of (±)-isolariciresinol in 41% overall yield.

"Soft theories," i.e., "heuristic models based on reasoning by analogy" largely drove chemistry understanding for 150 years or more. But soft theories have their limitations and with the expansion of chemistry in the mid-20th century, more and more inexplicable (by soft theory) experimental results were being obtained. In the past 50 years, quantum chemistry, most often in the guise of applied theoretical chemistry including computational chemistry, has provided (a) the underlying "hard evidence" for many soft theories and (b) the explanations for chemical phenomena that were unavailable by soft theories. In this publication, we define "hard theories" as "theories derived from quantum chemistry." Both soft and hard theories can be qualitative and quantitative, and the "Houk quadrant" is proposed as a helpful categorization tool. Furthermore, the language of soft theories is often used appropriately to describe quantum chemical results. A valid and useful way of doing science is the appropriate use and application of both soft and hard theories along with the best nomenclature available for successful communication of results and ideas.

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.

The energetic viability of the previously proposed biogenetic pathway for the formation of two unique monoterpenoid indole alkaloids, voacafricine A and B, which are present in the fruits of Voacanga africana, was investigated using density functional theory computations. The results of these calculations indicate that not only is the previously suggested pathway not energetically viable but also that an alternative biosynthetic precursor is likely.

The results of quantum chemical and molecular dynamics calculations reveal that polyanionic gallium-based cages accelerate cyclization reactions of pentadienyl alcohols as a result of substrate cage interactions, preferential binding of reactive conformations of substrate/H3O+ pairs, and increased substrate basicity. However, the increase in basicity dominates. Experimental structure-activity relationship studies in which the metal vertices and overall charge of the cage are varied confirm the model derived via calculations.

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.

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.

Intramolecular C-H insertions with donor/donor dirhodium carbenes provide a concise and highly stereoselective method to set two contiguous stereocenters in a single step. Herein, we report the insertion of donor/donor carbenes into stereogenic carbon centers allowing access to trisubstituted benzodihydrofurans in a single step. This study illuminates, for the first time, the stereochemical impact on the carbene center and delineates the structural factors that enable control over both stereogenic centers. Sterically bulky, highly activated C-H insertion centers exhibit high substrate control yielding a single diastereomer and a single enantiomer of product regardless of the catalyst used. Less bulky, less activated C-H insertion centers exhibit catalyst control over the diastereomeric ratio (dr), where a single enantiomer of each diastereomer is observed with high selectivity. A combination of experimental studies and DFT calculations was used to elucidate the origin of these results. First, hydride transfer from the stereogenic insertion site proceeds with high stereoselectivity to the carbene center, thus determining the absolute configuration of the product. Second, the short lived zwitterionic intermediate can diaster-eoselectively ring-close by a hitherto unreported SE2 mechanism that is either controlled by the substrate or the catalyst. These results demonstrate that donor/donor carbenes undergo uniquely stereoselective reactions that originate from a stepwise reaction mechanism, in contrast to the analogous concerted reactions of carbenes with one or more electron-withdrawing groups attached.

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.

Basicities for derivatives of patriscabrin A and lettucenin A were calculated with density functional theory. A significant correlation is observed between the basicity and Hammett σ parameters. Protonation increases the aromatic character of the cyclic moieties of each natural product. The naturally occurring structures are predicted to be the most aromatic.

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 D94 NxxxD motif and mutation experiments confirmed an absolute requirement for D94 as well as E169.

Azobenzenes are widely used as dyes and photochromic compounds, with the Baeyer-Mills reaction serving as the most common method for their preparation. This transformation is often plagued by low yields due to the formation of undesired azoxybenzene. Here, we explore electronic effects dictating the formation of the azoxybenzene side-product. Using calculated oxidation potentials, we were able to predict reaction outcomes and improve reaction efficiency simply by modulating the oxidation potential of the arylamine component.

A personal perspective on the practice of drawing polycyclic molecules and its implications for understanding and undertaking chemistry is presented.

We have developed catalyst-controlled regiodivergent rearrangements of onium-ylides derived from indole substrates. Oxonium ylides formed in situ from 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.

A primary goal of metabolomics studies is to fully characterize the small-molecule composition of complex biological and environmental samples. However, despite advances in analytical technologies over the past two decades, the majority of small molecules in complex samples are not readily identifiable due to the immense structural and chemical diversity present within the metabolome. Current gold-standard identification methods rely on reference libraries built using authentic chemical materials ("standards"), which are not available for most molecules. Computational quantum chemistry methods, which can be used to calculate chemical properties that are then measured by analytical platforms, offer an alternative route for building reference libraries, i.e., in silico libraries for "standards-free" identification. In this review, we cover the major roadblocks currently facing metabolomics and discuss applications where quantum chemistry calculations offer a solution. Several successful examples for nuclear magnetic resonance spectroscopy, ion mobility spectrometry, infrared spectroscopy, and mass spectrometry methods are reviewed. Finally, we consider current best practices, sources of error, and provide an outlook for quantum chemistry calculations in metabolomics studies. We expect this review will inspire researchers in the field of small-molecule identification to accelerate adoption of in silico methods for generation of reference libraries and to add quantum chemistry calculations as another tool at their disposal to characterize complex samples.

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-Trp•) 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.

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.

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.

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 Mtb diterpene pathway along with Rv3378c, which converts tuberculosinol pyrophosphate to 1-tuberculosinyl adenosine (1-TbAd). This pathway was shown to exist only in virulent Mycobacterium species, 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.

Compound identification by mass spectrometry needs reference mass spectra. While there are over 102 million compounds in PubChem, less than 300,000 curated electron ionization (EI) mass spectra are available from NIST or MoNA mass spectral databases. Here, we test quantum chemistry methods (QCEIMS) to generate in silico EI mass spectra (MS) by combining molecular dynamics (MD) with statistical methods. To test the accuracy of predictions, in silico mass spectra of 451 small molecules were generated and compared to experimental spectra from the NIST 17 mass spectral library. The compounds covered 43 chemical classes, ranging up to 358 Da. Organic oxygen compounds had a lower matching accuracy, while computation time exponentially increased with molecular size. The parameter space was probed to increase prediction accuracy including initial temperatures, the number of MD trajectories and impact excess energy (IEE). Conformational flexibility was not correlated to the accuracy of predictions. Overall, QCEIMS can predict 70 eV electron ionization spectra of chemicals from first principles. Improved methods to calculate potential energy surfaces (PES) are still needed before QCEIMS mass spectra of novel molecules can be generated at large scale.

Quantum chemical calculations were used to determine the energetic viability of several mechanisms for formation of ladderanes from oligocyclopropanes. Pathways involving radical cations, diradicals, and carbocations were considered, and a hybrid of carbocation and radical cation pathways was predicted to have the lowest overall barrier.

A selectivity model based on the widths of pathways to competing products, rather than barrier heights, is formulated for the butadiene + allyl cation reaction. This model was arrived at via analysis of stationary points, intrinsic reaction coordinates, potential energy surface shapes and direct dynamics trajectories, all determined using quantum chemical methods.

[This corrects the article DOI: 10.1039/C9SC05111B.].

Microsomal epoxide hydrolase (mEH) hydrolyzes a wide range of epoxide containing molecules. Although involved in the metabolism of xenobiotics, recent studies associate mEH with the onset and development of certain disease conditions. This phenomenon is partially attributed to the significant role mEH plays in hydrolyzing endogenous lipid mediators, suggesting more complex and extensive physiological functions. In order to obtain pharmacological tools to further study the biology and therapeutic potential of this enzyme target, we describe the development of highly potent 2-alkylthio acetamide inhibitors of the human mEH with IC50 values in the low nanomolar range. These are around 2 orders of magnitude more potent than previously obtained primary amine, amide and urea-based mEH inhibitors. Experimental assay results and rationalization of binding through docking calculations of inhibitors to a mEH homology model indicate that an amide connected to an alkyl side chain and a benzyl-thio function as key pharmacophore units.

We recently reported the discovery of phenylacetate decarboxylase (PhdB), representing one of only ten glycyl-radical-enzyme reaction types known, and a promising biotechnological tool for first-time biochemical synthesis of toluene from renewable resources. Here, we used experimental and computational data to evaluate the plausibility of three candidate PhdB mechanisms, involving either attack at the phenylacetate methylene carbon or carboxyl group [via H-atom abstraction from COOH or single-electron oxidation of COO- (Kolbe-type decarboxylation)]. In vitro experimental data included assays with F-labeled phenylacetate, kinetic studies, and tests with site-directed PhdB mutants; computational data involved estimation of reaction energetics using density functional theory (DFT). The DFT results indicated that all three mechanisms are thermodynamically challenging (beyond the range of many known enzymes in terms of endergonicity or activation energy barrier), reflecting the formidable demands on PhdB for catalysis of this reaction. Evidence that PhdB was able to bind α,α-difluorophenylacetate but was unable to catalyze its decarboxylation supported the enzyme's abstraction of a methylene H atom. Diminished activity of H327A and Y691F mutants was consistent with proposed proton donor roles for His327 and Tyr691. Collectively, these and other data most strongly support PhdB attack at the methylene carbon.

Herein we interrogate a type of heterolytic fragmentation reaction called a 'divergent fragmentation' using density functional theory (DFT), natural bond orbital (NBO) analysis, ab initio molecular dynamics (AIMD), and external electric field (EEF) calculations. We demonstrate that substituents, electrostatic environment and non-statistical dynamic effects all influence product selectivity in reactions that involve divergent fragmentation pathways. Direct dynamics simulations reveal an unexpected post-transition state bifurcation (PTSB), and EEF calculations suggest that some transition states for divergent pathways can, in principle, be selectively stabilized if an electric field of the correct magnitude is oriented appropriately.

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.

Reports of C-H insertions forming six-membered rings containing heteroatoms are rare due to Stevens rearrangements occurring after nucleophilic attack on the carbene by a heteroatom. Using donor/donor carbenes and Rh2(R-PTAD)4 as a catalyst, we have synthesized a collection of isochroman substrates in good yield, with excellent diastereo- and enantioselectivity, and no rearrangement products were observed. Furthermore, we report the first synthesis of six-membered rings containing nitrogen by C-H insertion to form tetrahydroisoquinolines. In one case, a Stevens rearrangement product was isolated at elevated temperature from a carbamate-protected amine substrate and computational evidence suggests formation through a free ylide not bound to rhodium.

Serlyticin-A is a secondary metabolite first isolated from a culture of Serratia ureilytica grown 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.

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-NH2 with a CH2 at 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=C3 alkene 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.

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 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.

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.

The introduction of functional groups with varying electron-donating/-withdrawing properties at the β-position of diketopyrrolopyrrole (DPP) has been shown to affect the optoelectronic properties of the polymers. We report the synthesis of a new diketopyrrolopyrrole monomer wherein a strong electron-donating substituent, a methoxy group, was incorporated at the β-position in an effort to modulate polymer properties. Homopolymers and co-polymers of the new β-methoxy DPP and nonderivatized DPP were synthesized, and their properties were measured by cyclic voltammetry and UV-vis-near-infrared. Density functional theory computations also were employed to predict the degree of planarity of β-methoxy oligomers to probe the significance of the newly introduced S-O conformational lock. The combined experimental and computational results showed a reduction in the gap between highest occupied molecular orbital/lowest unoccupied molecular orbital levels, a redshift toward the near-infrared region, and an increased planarity in the β-methoxy polymers.

The Cadogan cyclization is a robust but harsh method for the synthesis of 2 H-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, 2 H-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 2 H-indazole synthesis.

Among the array of complex terpene-forming carbocation cyclization/rearrangement reactions, the so-called "triple shift" reactions are among the most unexpected. Such reactions involve the asynchronous combination of three 1,n-shifts into a concerted process, e.g., a 1,2-alkyl shift followed by a 1,3-hydride shift followed by a second 1,2-alkyl shift. This type of reaction so far has been proposed to occur during the biosynthesis of diterpenes and the sidechains of sterols. Here we describe efforts to push the limits of concertedness in this type of carbocation reaction by designing, and characterizing with quantum chemical computations, systems that could couple additional 1,n-shift events to a triple shift leading, in principle to quadruple, pentuple, etc. shifts. While our designs did not lead to clear-cut examples of quadruple, etc. shifts, they did lead to reactions with surprisingly flat energy surfaces where more than five chemical events connect reactants and plausible products. Ab initio molecular dynamics simulations demonstrate that the formal minima on these surfaces interchange on short timescales, both with each other and with additional unexpected structures, allowing us a glimpse into a very complex manifold that allows ready access to great structural diversity.

Among the array of complex terpene-forming carbocation cyclization/rearrangement reactions, the so-called "triple shift" reactions are among the most unexpected. Such reactions involve the asynchronous combination of three 1,n-shifts into a concerted process, e.g., a 1,2-alkyl shift followed by a 1,3-hydride shift followed by a second 1,2-alkyl shift. This type of reaction so far has been proposed to occur during the biosynthesis of diterpenes and the sidechains of sterols. Here we describe efforts to push the limits of concertedness in this type of carbocation reaction by designing, and characterizing with quantum chemical computations, systems that could couple additional 1,n-shift events to a triple shift leading, in principle to quadruple, pentuple, etc. shifts. While our designs did not lead to clear-cut examples of quadruple, etc. shifts, they did lead to reactions with surprisingly flat energy surfaces where more than five chemical events connect reactants and plausible products. Ab initio molecular dynamics simulations demonstrate that the formal minima on these surfaces interchange on short timescales, both with each other and with additional unexpected structures, allowing us a glimpse into a very complex manifold that allows ready access to great structural diversity.

Covering: up to 2018With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw nuclear magnetic resonance (NMR) data, independently of, and in parallel with, classical publishing outlets. A comprehensive compilation of historic to present-day cases as well as contemporary and future applications show that addressing the urgent need for a repository of publicly accessible raw NMR data has the potential to transform natural products (NPs) and associated fields of chemical and biomedical research. The call for advancing open sharing mechanisms for raw data is intended to enhance the transparency of experimental protocols, augment the reproducibility of reported outcomes, including biological studies, become a regular component of responsible research, and thereby enrich the integrity of NP research and related fields.

Correction for 'The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research' by James B. McAlpine et al., Nat. Prod. Rep., 2018, DOI: .

A post-transition state bifurcation (PTSB) involved in a Pummerer-type rearrangement is characterized using density functional theory (DFT) calculations on potential energy stationary points and direct dynamics simulations. A sensitivity of the ratio of products produced via this PTSB to solvent dielectric constant is revealed and implications of such a dependence for selectivity control of organic reactions are discussed.

Questions of relevance to those working in the field of natural products synthesis that can be answered, at least in part, using computational chemistry approaches are described. Illustrative examples are provided, as are descriptions of limitations.

A concise, one-step route to indazolones from primary alkyl amines and o-nitrobenzyl alcohols is reported. The key step in this readily scalable indazolone forming process involves base-mediated in situ o-nitrobenzyl alcohol → o-nitrosobenzaldehyde conversion. Although this functional group interconversion is known to be useful for 2 H-indazole synthesis, its reactivity was modulated for indazolone formation.

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.

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.

The first chemical synthesis of pentacyclic onocerane triterpenoids has been achieved. A putative biomimetic tricyclization cascade is employed to forge a fused decalin-/oxepane ring system. The synthetic route proceeds to (+)-cupacinoxepin in seven steps and to (+)-onoceranoxide in eight steps in the longest linear sequence, when starting from geranyl chloride and (+)-sclareolide. The bioinspired epoxypolyene cyclization is supported by computational and enzymatic studies.

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.

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.

Enzymes have been through millions of years of evolution during which their active-site microenvironments are fine-tuned. Active-site residues are commonly conserved within protein families, indicating their importance for substrate recognition and catalysis. In this work, we systematically mutated active-site residues of l-threonine dehydrogenase from Thermoplasma volcanium and characterized the mutants against a panel of substrate analogs. Our results demonstrate that only a subset of these residues plays an essential role in substrate recognition and catalysis and that the native enzyme activity can be further enhanced roughly 4.6-fold by a single point mutation. Kinetic characterization of mutants on substrate analogs shows that l-threonine dehydrogenase possesses promiscuous activities toward other chemically similar compounds not previously observed. Quantum chemical calculations on the hydride-donating ability of these substrates also reveal that this enzyme did not evolve to harness the intrinsic substrate reactivity for enzyme catalysis. Our analysis provides insights into connections between the details of enzyme active-site structure and specific function. These results are directly applicable to rational enzyme design and engineering.

Intramolecular chirality transfer [2 + 2] cycloaddition of enantiomerically enriched allenoates and alkenes is presented. The use of a chiral catalyst was found to be critical to achieve high levels of diastereoselectivity compared to use of an achiral catalyst. The method developed leads to highly substituted cyclobutanes that would be difficult to prepare by alternative methods.