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Nickel-catalyzed cross-electrophile coupling (XEC) reactions of (hetero)aryl electrophiles represent appealing alternatives to palladium-catalyzed methods for biaryl synthesis, but they often generate significant quantities of homocoupling and/or proto-dehalogenation side products. In this study, an informer library of heteroaryl chloride and aryl bromide coupling partners is used to identify Ni-catalyzed XEC conditions that access high selectivity for the cross-product when using equimolar quantities of the two substrates. Two different catalyst systems are identified that show complementary scope and broad functional-group tolerance, and time-course data suggest that the two methods follow different mechanisms. A NiBr 2 /terpyridine catalyst system with Zn as the reductant converts the aryl bromide into an arylzinc intermediate that undergoes in situ coupling with 2-chloropyridines, while a NiBr 2 /bipyridine catalyst system with tetrakis(dimethylamino)ethylene as the reductant uses FeBr 2 and NaI as additives to achieve selective cross-coupling.

In this report, we detail two distinct synthetic approaches to calyciphylline A-type Daphniphyllum alkaloids himalensine A and daphenylline, which are inspired by our analysis of the structural complexity of these compounds. Using MolComplex, a Python-based web application that we have developed, we quantified the structural complexity of all possible precursors resulting from one-bond retrosynthetic disconnections. This led to the identification of transannular bonds as especially simplifying to the molecular graph, and, based on this analysis, we pursued a total synthesis of himalensine A from macrocyclic intermediates with planned late-stage transannular ring formations. Despite initial setbacks in accessing an originally designed macrocycle, targeting a simplified macrocycle ultimately enabled investigation of this intermediate's unique transannular reactivity. Given the lack of success to access himalensine A based solely on molecular graph analysis, we revised our approach to the related alkaloid, daphenylline. Herein, we also provide the details of the various synthetic challenges that we encountered and overcame en route to a total synthesis of daphenylline. First, optimization of a Rh-mediated intramolecular Buchner/6π-electrocyclic ring-opening sequence enabled construction of the pentacyclic core. We then describe various attempts to install a key quaternary methyl group and, ultimately, our solution to leverage a [2 + 2] photocycloaddition/bond cleavage sequence to achieve this elusive goal. Finally, a late-stage Friedel-Crafts cyclization and deoxygenation facilitated the 11-step total synthesis, which was made formally enantioselective by a Rh-mediated dihydropyridone conjugate arylation. Complexity analysis of the daphenylline synthesis highlights how complexity-building/C-C cleavage combinations can be uniquely effective in achieving synthetic outcomes.

The ability to relate substituent electronic effects to chemical reactivity is a cornerstone of physical organic chemistry and Linear Free Energy Relationships. The computation of electronic parameters is increasingly attractive since they can be obtained rapidly for structures and substituents without available experimental data and can be applied beyond aromatic substituents, for example, in studies of transition metal complexes and aliphatic and radical systems. Nevertheless, the description of "top-down" macroscopic observables, such as Hammett parameters using a "bottom-up" computational approach, poses several challenges for the practitioner. We have examined and benchmarked the performance of various computational charge schemes encompassing quantum mechanical methods that partition charge density, methods that fit charge to physical observables, and methods enhanced by semiempirical adjustments alongside NMR values. We study the locations of the atoms used to obtain these descriptors and their correlation with empirical Hammett parameters and rate differences resulting from electronic effects. These seemingly small choices have a much more significant impact than previously imagined, which outweighs the level of theory or basis set used. We observe a wide range of performance across the different computational protocols and observe stark and surprising differences in the ability of computational parameters to capture para- vs meta-electronic effects. In general, σ m predictions fare much worse than σ p . As a result, the choice of where to compute these descriptors-for the ring carbons or the attached H or other substituent atoms-affects their ability to capture experimental electronic differences. Density-based schemes, such as Hirshfeld charges, are more stable toward unphysical charge perturbations that result from nearby functional groups and outperform all other computational descriptors, including several commonly used basis set based schemes such as Natural Population Analysis. Using attached atoms also improves the statistical correlations. We obtained general linear relationships for the global prediction of experimental Hammett parameters from computed descriptors for use in statistical modeling studies., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Imidazole glycerol phosphate synthase (IGPS) is a class-I glutamine amidotransferase (GAT) that hydrolyzes glutamine. Ammonia is produced and transferred to a second active site, where it reacts with N 1 -(5'-phosphoribosyl)-formimino-5-aminoimidazole-4-carboxamide ribonucleotide (PrFAR) to form precursors to purine and histidine biosynthesis. Binding of PrFAR over 25 Å away from the active site increases glutaminase efficiency by ∼4500-fold, primarily altering the glutamine turnover number. IGPS has been the focus of many studies on allosteric communication; however, atomic details for how the glutamine hydrolysis rate increases in the presence of PrFAR are lacking. We present a density functional theory study on 237-atom active site cluster models of IGPS based on crystallized structures representing the inactive and allosterically active conformations and investigate the multistep reaction leading to thioester formation and ammonia production. The proposed mechanism is supported by similar, well-studied enzyme mechanisms, and the corresponding energy profile is consistent with steady-state kinetic studies of PrFAR + IGPS. Additional active site models are constructed to examine the relationship between active site structural change and transition-state stabilization via energy decomposition schemes. The results reveal that the inactive IGPS conformation does not provide an adequately formed oxyanion hole structure and that repositioning of the oxyanion strand relative to the substrate is vital for a catalysis-competent oxyanion hole, with or without the h Val51 dihedral flip. These findings are valuable for future endeavors in modeling the IGPS allosteric mechanism by providing insight into the atomistic changes required for rate enhancement that can inform suitable reaction coordinates for subsequent investigations., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

Cuneane is a strained hydrocarbon that can be accessed via metal-catalyzed isomerization of cubane. The carbon atoms of cuneane define a polyhedron of the C 2 v point group with six faces─two triangular, two quadrilateral, and two pentagonal. The rigidity, strain, and unique exit vectors of the cuneane skeleton make it a potential scaffold of interest for the synthesis of functional small molecules and materials. However, the limited previous synthetic efforts toward cuneanes have focused on monosubstituted or redundantly substituted systems such as permethylated, perfluorinated, and bis(hydroxymethylated) cuneanes. Such compounds, particularly rotationally symmetric redundantly substituted cuneanes, have limited potential as building blocks for the synthesis of complex molecules. Reliable, predictable, and selective syntheses of polysubstituted cuneanes bearing more complex substitution patterns would facilitate the study of this ring system in myriad applications. Herein, we report the regioselective, Ag I -catalyzed isomerization of asymmetrically 1,4-disubstituted cubanes to cuneanes. In-depth DFT calculations provide a charge-controlled regioselectivity model, and direct dynamics simulations indicate that the nonclassical carbocation invoked is short-lived and dynamic effects augment the charge model.

Enantioenriched organoboron intermediates are important building blocks in organic synthesis and drug discovery. Recently, transition metal-catalyzed enantioselective 1,2-metalate rearrangements of alkenylboronates have emerged as an attractive protocol to access these valuable reagents by installing two different carbon fragments across C═C π-bonds. Herein, we report the development of an iridium-catalyzed asymmetric allylation-induced 1,2-metalate rearrangement of bicyclo[1.1.0]butyl (BCB) boronate complexes enabled by strain release, which allows asymmetric difunctionalization of C-C σ-bonds, including dicarbonation and carboboration. This protocol provides a variety of enantioenriched three-dimensional 1,1,3-trisubstituted cyclobutane products bearing a boronic ester that can be readily derivatized. Notably, the reaction gives trans diastereoisomers that result from an anti -addition across the C-C σ-bond, which is in contrast to the syn -additions observed for reactions promoted by Pd II -aryl complexes and other electrophiles in our previous works. The diastereoselectivity has been rationalized based on a combination of experimental data and density functional theory calculations, which suggest that the BCB boronate complexes are highly nucleophilic and react via early transition states with low activation barriers.

The controlled programming of regiochemical outcomes in nucleophilic fluorination reactions with alkali metal fluoride is a problem yet to be solved. Herein, two synergistic approaches exploiting hydrogen bonding catalysis are presented. First, we demonstrate that modulating the charge density of fluoride with a hydrogen-bond donor urea catalyst directly influences the kinetic regioselectivity in the fluorination of dissymmetric aziridinium salts with aryl and ester substituents. Moreover, we report a urea-catalyzed formal dyotropic rearrangement, a thermodynamically controlled regiochemical editing process consisting of C-F bond scission followed by fluoride rebound. These findings offer a route to access enantioenriched fluoroamine regioisomers from a single chloroamine precursor, and more generally, new opportunities in regiodivergent asymmetric ( bis )urea-based organocatalysis.

The catalytic anti-Markovnikov addition of alcohols to simple alkenes is a longstanding synthetic challenge. We recently disclosed the use of organic superbase catalysis for the nucleophilic addition of alcohols to activated styrene derivatives. This article describes mechanistic studies on this reversible reaction, including thermodynamic and kinetic profiling as well as computational modeling. Our findings show the negative entropy of addition is counterbalanced by an enthalpy that is most favored in nonpolar solvents. However, a large negative alcohol rate order under these conditions indicates excess alcohol sequesters the active alkoxide ion pairs, slowing the reaction rate. These observations led to an unexpected solution to a thermodynamically challenging reaction: use of less alcohol enables faster addition, which in turn allows for lower reaction temperatures to counteract Le Chatelier's principle. Thus, our original method has been improved with new protocols that do not require excess alcohol stoichiometry, enable an expanded alkene substrate scope, and allow for the use of more practical catalyst systems. The generality of this insight for other challenging hydroetherification reactions is also demonstrated through new alkenol cyclization and oxa-Michael addition reactions.

Asymmetric catalytic azidation has increased in importance to access enantioenriched nitrogen containing molecules, but methods that employ inexpensive sodium azide remain scarce. This encouraged us to undertake a detailed study on the application of hydrogen bonding phase-transfer catalysis (HB-PTC) to enantioselective azidation with sodium azide. So far, this phase-transfer manifold has been applied exclusively to insoluble metal alkali fluorides for carbon-fluorine bond formation. Herein, we disclose the asymmetric ring opening of meso aziridinium electrophiles derived from β-chloroamines with sodium azide in the presence of a chiral bisurea catalyst. The structure of novel hydrogen bonded azide complexes was analyzed computationally, in the solid state by X-ray diffraction, and in solution phase by 1 H and 14 N/ 15 N NMR spectroscopy. With N -isopropylated BINAM-derived bisurea, end-on binding of azide in a tripodal fashion to all three NH bonds is energetically favorable, an arrangement reminiscent of the corresponding dynamically more rigid trifurcated hydrogen-bonded fluoride complex. Computational analysis informs that the most stable transition state leading to the major enantiomer displays attack from the hydrogen-bonded end of the azide anion. All three H-bonds are retained in the transition state; however, as seen in asymmetric HB-PTC fluorination, the H-bond between the nucleophile and the monodentate urea lengthens most noticeably along the reaction coordinate. Kinetic studies corroborate with the turnover rate limiting event resulting in a chiral ion pair containing an aziridinium cation and a catalyst-bound azide anion, along with catalyst inhibition incurred by accumulation of NaCl. This study demonstrates that HB-PTC can serve as an activation mode for inorganic salts other than metal alkali fluorides for applications in asymmetric synthesis.

The ability to manipulate C-C bonds for selective chemical transformations is challenging and represents a growing area of research. Here, we report a formal insertion of diazo compounds into the "unactivated" C-C bond of benzyl bromide derivatives catalyzed by a simple Lewis acid. The homologation reaction proceeds via the intermediacy of a phenonium ion, and the products contain benzylic quaternary centers and an alkyl bromide amenable to further derivatization. Computational analysis provides critical insight into the reaction mechanism, in particular the key selectivity-determining step.

CREBBP (CBP/KAT3A) and its paralogue EP300 (KAT3B) are lysine acetyltransferases (KATs) that are essential for human development. They each comprise 10 domains through which they interact with >400 proteins, making them important transcriptional co-activators and key nodes in the human protein-protein interactome. The bromodomains of CREBBP and EP300 enable the binding of acetylated lysine residues from histones and a number of other important proteins, including p53, p73, E2F, and GATA1. Here, we report a work to develop a high-affinity, small-molecule ligand for the CREBBP and EP300 bromodomains [(-)-OXFBD05] that shows >100-fold selectivity over a representative member of the BET bromodomains, BRD4(1). Cellular studies using this ligand demonstrate that the inhibition of the CREBBP/EP300 bromodomain in HCT116 colon cancer cells results in lowered levels of c-Myc and a reduction in H3K18 and H3K27 acetylation. In hypoxia (<0.1% O 2 ), the inhibition of the CREBBP/EP300 bromodomain results in the enhanced stabilization of HIF-1α.

This first asymmetric total synthesis of (+)-srilankenyne ( 1 ), a halogenated C15 tetrahydropyran acetogenin isolated from Aplysia oculifera , features a sequence-sensitive process guided by conformational analysis to solve the challenging problem of introducing halogens. A competing semipinacol rearrangement during the installation of C(12)-bromide was suppressed by our A 1,3 strain-controlled bromination protocol with support from X-ray crystallographic and computational studies. The C(10)-chloride was then placed by the Nakata chloromesylate-mediated chlorination.

Machine-readable chemical structure representations are foundational in all attempts to harness machine learning for the prediction of reactivities, selectivities, and chemical properties directly from molecular structure. The featurization of discrete chemical structures into a continuous vector space is a critical phase undertaken before model selection, and the development of new ways to quantitatively encode molecules is an active area of research. In this Account, we highlight the application and suitability of different representations, from expert-guided "engineered" descriptors to automatically "learned" features, in different prediction tasks relevant to organic and organometallic chemistry, where differing amounts of training data are available. These tasks include statistical models of stereo- and enantioselectivity, thermochemistry, and kinetics developed using experimental and quantum chemical data.The use of expert-guided molecular descriptors provides an opportunity to incorporate chemical knowledge, domain expertise, and physical constraints into statistical modeling. In applications to stereoselective organic and organometallic catalysis, where data sets may be relatively small and 3D-geometries and conformations play an important role, mechanistically informed features can be used successfully to obtain predictive statistical models that are also chemically interpretable. We provide an overview of several recent applications of this approach to obtain quantitative models for reactivity and selectivity, where topological descriptors, quantum mechanical calculations of electronic and steric properties, along with conformational ensembles, all feature as essential ingredients of the molecular representations used.Alternatively, more flexible, general-purpose molecular representations such as attributed molecular graphs can be used with machine learning approaches to learn the complex relationship between a structure and prediction target. This approach has the potential to out-perform more traditional representation methods such as "hand-crafted" molecular descriptors, particularly as data set sizes grow. One area where this is particularly relevant is in the use of large sets of quantum mechanical data to train quantitative structure-property relationships. A general approach toward curating useful data sets and training highly accurate graph neural network models is discussed in the context of organic bond dissociation enthalpies, where this strategy outperforms regression using precomputed descriptors.Finally, we describe how graph neural network predictions can be incorporated into mechanistically informed statistical models of chemical reactivity and selectivity. Once trained, this approach avoids the expensive computational overhead associated with quantum mechanical calculations, while maintaining chemical interpretability. We illustrate examples for which fast predictions of bond dissociation enthalpy and of the identities of radicals formed through cleavage of a molecule's weakest bond are used in simple physical models of site-selectivity and reactivity.

Ammonium salts are used as phase-transfer catalysts for fluorination with alkali metal fluorides. We now demonstrate that these organic salts, specifically azetidinium triflates, are suitable substrates for enantioselective ring opening with CsF and a chiral bis -urea catalyst. This process, which highlights the ability of hydrogen bonding phase-transfer catalysts to couple two ionic reactants, affords enantioenriched γ-fluoroamines in high yields. Mechanistic studies underline the role of the catalyst for phase-transfer, and computed transition state structures account for the enantioconvergence observed for mixtures of achiral azetidinium diastereomers. The N-substituents in the electrophile influence the reactivity, but the configuration at nitrogen is unimportant for the enantioselectivity.

Halopyridines are key building blocks for synthesizing pharmaceuticals, agrochemicals, and ligands for metal complexes, but strategies to selectively halogenate pyridine C-H precursors are lacking. We designed a set of heterocyclic phosphines that are installed at the 4-position of pyridines as phosphonium salts and then displaced with halide nucleophiles. A broad range of unactivated pyridines can be halogenated, and the method is viable for late-stage halogenation of complex pharmaceuticals. Computational studies indicate that C-halogen bond formation occurs via an S N Ar pathway, and phosphine elimination is the rate-determining step. Steric interactions during C-P bond cleavage account for differences in reactivity between 2- and 3-substituted pyridines.

The late-stage functionalization (LSF) of pharmaceutical and agrochemical compounds by the site-selective activation of C-H bonds provides access to diverse structural analogs and expands synthetically-accessible chemical space. We report a C-H functionalization LSF strategy that hinges on the use of an alkyne linchpin to assemble conjugates of sp 2 -rich marketed pharmaceuticals and agrochemicals with sp 3 -rich 3D fragments and natural products. This is accomplished through a template-assisted inverse Sonogashira reaction that displays high levels of selectivity for the meta position. This protocol is also amenable to distal structural modifications of α-amino acids. The transformation of alkyne functionality to other functional groups further highlights the applicative potential. Computational and experimental mechanistic studies shed light on the detailed mechanism. Turnover-limiting 1,2-migratory insertion of the bromoalkyne coupling partner occurs after relatively fast C-H activation. While this insertion occurs unselectively, regioconvergence results from one of the adducts undergoing a 1,2-trialkylsilyl migration to form the alkynylated product. A heterobimetallic Pd-Ag transition structure is essential for product formation in the β-bromide elimination step.

Reactive intermediates frequently play significant roles in the biosynthesis of numerous classes of natural products although the direct observation of these biosynthetically relevant species is rare. We present here direct evidence for the existence of complex, thermally unstable, tricyclic oxonium ions that have been postulated as key reactive intermediates in the biosynthesis of numerous halogenated natural products from Laurencia species. Evidence for their existence comes from full characterization of these oxonium ions by low-temperature NMR spectroscopy supported by density functional theory (DFT) calculations, coupled with the direct generation of 10 natural products on exposure of the oxonium ions to various nucleophiles.

The development of catalytic enantioselective methods is routinely carried out using easily accessible and prototypical substrates. This approach to reaction development often yields asymmetric methods that perform poorly using substrates that are sterically or electronically dissimilar to those used during the reaction optimization campaign. Consequently, expanding the scope of previously optimized catalytic asymmetric reactions to include more challenging substrates is decidedly nontrivial. Here, we address this challenge through the development of a systematic workflow to broaden the applicability and reliability of asymmetric conjugate additions to substrates conventionally regarded as sterically and electronically demanding. The copper-catalyzed asymmetric conjugate addition of alkylzirconium nucleophiles to form tertiary centers, although successful for linear alkyl chains, fails for more sterically demanding linear α,β-unsaturated ketones. Key to adapting this method to obtain high enantioselectivity was the synthesis of modified phosphoramidite ligands, designed using quantitative structure-selectivity relationships (QSSRs). Iterative rounds of model construction and ligand synthesis were executed in parallel to evaluate the performance of 20 chiral ligands. The copper-catalyzed asymmetric addition is now more broadly applicable, even tolerating linear enones bearing tert- butyl β-substituents. The presence of common functional groups is tolerated in both nucleophiles and electrophiles, giving up to 99% yield and 95% ee across 20 examples., Competing Interests: The authors declare no competing financial interest., (Copyright © 2019 American Chemical Society.)

Despite numerous advances in spectroscopic methods through the latter part of the 20th century, the unequivocal structure determination of natural products can remain challenging, and inevitably, incorrect structures appear in the literature. Computational methods that allow the accurate prediction of NMR chemical shifts have emerged as a powerful addition to the toolbox of methods available for the structure determination of small organic molecules. Herein, we report the structure determination of a small, stereochemically rich natural product from Laurencia majuscula using the powerful combination of computational methods and total synthesis, along with the structure confirmation of notoryne, using the same approach. Additionally, we synthesized three further diastereomers of the L. majuscula enyne and have demonstrated that computations are able to distinguish each of the four synthetic diastereomers from the 32 possible diastereomers of the natural product. Key to the success of this work is to analyze the computational data to provide the greatest distinction between each diastereomer, by identifying chemical shifts that are most sensitive to changes in relative stereochemistry. The success of the computational methods in the structure determination of stereochemically rich, flexible organic molecules will allow all involved in structure determination to use these methods with confidence.

The unique structure of furanocembranoid natural product providencin has stimulated biosynthetic hypotheses, especially concerning the formation of its cyclobutanol ring. One such hypothesis involves a photochemically induced Norrish-Yang cyclization in bipinnatin E. We have used computations to assess the feasibility and the stereochemical outcome of this proposed biosynthetic transformation. Density functional theory calculations reveal that the proposed Norrish-Yang cyclization in bipinnatin E is possible and that the stereoselectivity of this step is consistent with that of the natural product.

Potassium fluoride (KF) is an ideal reagent for fluorination because it is safe, easy to handle and low-cost. However, poor solubility in organic solvents coupled with limited strategies to control its reactivity has discouraged its use for asymmetric C-F bond formation. Here, we demonstrate that hydrogen bonding phase-transfer catalysis with KF provides access to valuable β-fluoroamines in high yields and enantioselectivities. This methodology employs a chiral N-ethyl bis-urea catalyst that brings solid KF into solution as a tricoordinated urea-fluoride complex. This operationally simple reaction affords enantioenriched fluoro-diphenidine (up to 50 g scale) using 0.5 mol % of recoverable bis-urea catalyst.

We have compiled an experimental data set (SWITCH10) of equilibrium constants for a series of hydrogen-bond-dependent conformational switches. These organic molecules possess common functionalities and are representative in terms of size and composition of systems routinely studied computationally. They exist as two well-defined conformations which serve as a useful tool to benchmark computational estimates of experimental Gibbs energy differences. We examine the performance of HF theory and a variety of density functionals (B3LYP, B3LYP-D3, CAM-B3LYP, ωB97X-D, M06-2X) against these experimental benchmarks. Surprisingly, despite a strong similarity between the two switch conformations, the average errors (0.4-1.7 kcal·mol -1 ) obtained across the data set for all methods are larger than obtained with HF calculations. B3LYP was found to outperform implicitly and explicitly dispersion-corrected functionals, with an average error smaller by 1 kcal·mol -1 . Unsystematic errors in the optimized structures were found to contribute to the relatively poor performance obtained, while quasi-rigid rotor harmonic oscillator thermal contributions are important in improving the accuracy of computed Gibbs energy differences. These results emphasize the challenge of quantitative accuracy in computing solution-phase thermochemistry for flexible systems and caution against the often used (but unstated) assumption of favorable error cancellation in comparing conformers or stereoisomers.

The base-catalyzed rearrangement of arylindenols is a rare example of a suprafacial [1,3]-hydrogen atom transfer. The mechanism has been proposed to proceed via sequential [1,5]-sigmatropic shifts, which occur in a selective sense and avoid an achiral intermediate. A computational analysis using quantum chemistry casts serious doubt on these suggestions: These pathways have enormous activation barriers, and in constrast to what is observed experimentally, they overwhelmingly favor a racemic product. Instead we propose that a suprafacial [1,3]-prototopic shift occurs in a two-step deprotonation/reprotonation sequence. This mechanism is favored by 15 kcal mol -1 over that previously proposed. Most importantly, this is also consistent with stereospecificity since reprotonation occurs rapidly on the same π-face. We have used explicitly solvated molecular dynamics studies to study the persistence and condensed-phase dynamics of the intermediate ion-pair formed in this reaction. Chirality transfer is the result of a particularly resilient contact ion-pair, held together by electrostatic attraction and a critical NH···π interaction which ensures that this species has an appreciable lifetime even in polar solvents such as DMSO and MeOH.

Cation radical Diels-Alder cycloadditions proceed via an acyclic intermediate that exists on a flat region of the potential energy surface. Competition between cyclization and C-C bond rotation results in varying levels of suprafacial stereoselectivity. Quasi-classical trajectories were used to explore reaction dynamics on this surface. Even though there is no discernible energy barrier toward cyclization, a dynamically stepwise process is found, for which the acyclic intermediate is found to reside for several hundreds of femtoseconds. In a small number of cases, exceptionally long lifetimes (>1000 fs) are found, leading to a loss of alkene stereochemistry.

The acetylacetone-benzaldimine Mannich reaction catalyzed by Mg(II) and Ca(II) salts of chiral phosphoric acids (CPA) has been investigated computationally by QM/MM methods. Enantioselectivity in this reaction is both larger than and in the opposite sense to that observed for the same reaction catalyzed by the protic CPA catalyst alone. We present a mechanistic model from which the characteristic differences between these metal and metal-free catalysts, which can coexist in the same reaction mixture, can be understood. Alkaline earth salts with chiral phosphate counterions are found to be more catalytically active than the protic form, and the Ca(II) and Mg(II) CPA salts react via different mechanisms, with a higher coordination number favored by calcium over magnesium. In the well-ordered chiral cavities around these metal centers, asymmetric induction arises from the steric interaction with the imine protecting group in the unfavorable pathway, with both substrates adopting well-defined conformations. These mechanistic models have allowed us to rationalize the stereochemical outcome across a range of bimolecular reactions promoted by divalent metal phosphates formed with different CPAs.

The first enantioselective synthesis of (-)-himalensine A has been achieved in 22 steps. The synthesis was enabled by a novel catalytic, enantioselective prototropic shift/furan Diels-Alder (IMDAF) cascade to construct the ACD tricyclic core. A reductive radical cyclization cascade was utilized to build the B ring, and end-game manipulations featuring a molecular oxygen mediated γ-CH oxidation, a Stetter cyclization to access the pendant cyclopentenone, and a highly chemoselective lactam reduction delivered the natural product target.

A highly efficient and stereoselective route to potential synthetic intermediates for ocellenyne and related C 15 acetogenin natural products with 6,10-syn- and 6,10-anti-2,5-dioxabicyclo[2.2.1]heptane core structures has been developed by means of an iterative biogenesis-inspired oxonium ion formation/fragmentation sequence. In accordance with chemical transformations, the most likely stereostructure for (E)-ocellenyne on the basis of GIAO 13 C NMR calculations possesses a 6,10-anti-2,5-dioxabicyclo[2.2.1]heptane core, as predicted from a plausible biosynthetic pathway, instead of the spectroscopically proposed 6,10-syn-2,5-dioxabicyclo[2.2.1]heptane skeleton.

Quantum chemical studies of C-ethylation of 1-methyl- and 1,4,4-trimethyl-tropane-derived enamines predict good (89:11 er, B3LYP) and high (98:2 er, B3LYP) levels, respectively, of asymmetric induction in the resulting α-alkylated aldehydes. The nonracemic tropanes were synthesized using Mannich cyclization strategies (Robinson-Schöpf and by way of a Davis-type N-sulfinyl amino bisketal, respectively), and ethylation of the derived enamines was found to support the predicted sense and magnitude of asymmetric induction (81:19 er and 95:5 er, respectively). A comparison of several computational methods highlights the robustness of predicted trends in enantioselectivity, enabling theory to guide synthesis.

Ligand binding is one of the most fundamental properties of proteins. Ligand functions fall into three basic types: substrates, regulatory molecules, and cofactors essential to protein stability, reactivity, or enzyme-substrate complex formation. The regulation of potassium ion movement in bacteria is predominantly under the control of regulatory ligands that gate the relevant channels and transporters, which possess subunits or domains that contain Rossmann folds (RFs). Here we demonstrate that adenosine monophosphate (AMP) is bound to both RFs of the dimeric bacterial Kef potassium efflux system (Kef), where it plays a structural role. We conclude that AMP binds with high affinity, ensuring that the site is fully occupied at all times in the cell. Loss of the ability to bind AMP, we demonstrate, causes protein, and likely dimer, instability and consequent loss of function. Kef system function is regulated via the reversible binding of comparatively low-affinity glutathione-based ligands at the interface between the dimer subunits. We propose this interfacial binding site is itself stabilized, at least in part, by AMP binding.

The cycloisomerization of enynes catalyzed by Pd(OAc) 2 and bis-benzylidene ethylenediamine (bbeda) is a landmark methodology in transition-metal-catalyzed cycloisomerization. However, the mechanistic pathway by which this reaction proceeds has remained unclear for several decades. Here we describe mechanistic investigations into this reaction using enynamides, which deliver azacycles with high regio- and stereocontrol. Extensive 1 H NMR spectroscopic studies and isotope effects support a palladium(II) hydride-mediated pathway and reveal crucial roles of bbeda, water, and the precise nature of the Pd(OAc) 2 pre-catalyst. Computational studies support these mechanistic findings and lead to a clear picture of the origins of the high stereocontrol that can be achieved in this transformation, as well as suggesting a novel mechanism by which hydrometalation proceeds.

We describe the first theoretical study of a landmark example of chiral anion phase-transfer catalysis: the enantioselective ring-opening of meso-aziridinium and episulfonium cations promoted by asymmetric counteranion-directed catalysis (ACDC). The mechanism of ion-pairing, ring-opening, and catalyst deactivation have been studied in the condensed phase with both classical and quantum methods using explicitly and implicitly solvated models. We find that the stability of chiral ion-pairs, a prerequisite for asymmetric catalysis, is dominated by electrostatic interactions at long range and by CH···O interactions at short range. The decisive role of solvent upon ion-pair formation and of nonbonding interactions upon enantioselectivity are quantified by complementary computational approaches. The major enantiomer is favored by a smaller distortion of the substrate, demonstrated by a distortion/interaction analysis. Our computational results rationalize the stereoselectivity for several experimental results and demonstrate a combined classical/quantum approach to perform realistic modeling of chiral counterion catalysis in solution.

An ONIOM(QM/MM) study on the mechanism of the Michael addition to triple bonds catalyzed by chiral diiminophosphorane catalysts has been performed to understand the stereoselectivity of the product olefin. Our results are consistent with the experimental enantioselectivity, but more importantly, reveal that the Z vs E preference depends on the influence of the catalyst upon the geometry of the allenyl enolate formed in the addition step. These intermediates show an innate preference for a (Z)-configuration, although this can be suppressed by steric interactions due to a catalyst. This leads to two distinct mechanisms in which the kinetic basis for (E) or (Z)-stereoselectivity is determined by a different step. Bifunctional iminophosphorane catalysts are found to use steric interactions to override innate stereoelectronic effects of the allenyl enolate reactive intermediate.

Combined experimental and computational efforts have demonstrated the utility of divergent photocyclization/1,4-sigmatropic rearrangement reactions for developing a general strategy toward the synthesis of cubebane-, spiroaxane-, and guaiane-type sesquiterpenes and related analogues. The configuration of the bridgehead substituent, the choice of solvent, and the wavelength of irradiation all impact diastereoselectivity in this tandem reaction process.

Cp X Rh(III)-catalyzed C-H functionalization reactions are a proven method for the efficient assembly of small molecules. However, rationalization of the effects of cyclopentadienyl (Cp X ) ligand structure on reaction rate and selectivity has been viewed as a black box, and a truly systematic study is lacking. Consequently, predicting the outcomes of these reactions is challenging because subtle variations in ligand structure can cause notable changes in reaction behavior. A predictive tool is, nonetheless, of considerable value to the community as it would greatly accelerate reaction development. Designing a data set in which the steric and electronic properties of the Cp X Rh(III) catalysts were systematically varied allowed us to apply multivariate linear regression algorithms to establish correlations between these catalyst-based descriptors and the regio-, diastereoselectivity, and rate of model reactions. This, in turn, led to the development of quantitative predictive models that describe catalyst performance. Our newly described cone angles and Sterimol parameters for Cp X ligands served as highly correlative steric descriptors in the regression models. Through rational design of training and validation sets, key diastereoselectivity outliers were identified. Computations reveal the origins of the outstanding stereoinduction displayed by these outliers. The results are consistent with partial η 5 -η 3 ligand slippage that occurs in the transition state of the selectivity-determining step. In addition to the instructive value of our study, we believe that the insights gained are transposable to other group 9 transition metals and pave the way toward rational design of C-H functionalization catalysts.

Directing group-assisted regioselective C-H olefination with electronically biased olefins is well studied. However, the incorporation of unactivated olefins has remained largely unsuccessful. A proper mechanistic understanding of olefination involving unactivated alkenes is therefore essential for enhancing their usage in future. In this Article, detailed experimental and computational mechanistic studies on palladium catalyzed C-H olefination with unactivated, aliphatic alkenes are described. The isolation of Pd(II) intermediates is shown to be effective for elucidating the elementary steps involved in catalytic olefination. Reaction rate and order determination, control experiments, isotopic labeling studies, and Hammett analysis have been used to understand the reaction mechanism. The results from these experimental studies implicate β-hydride elimination as the rate-determining step and that a mechanistic switch occurs between cationic and neutral pathway. Computational studies support this interpretation of the experimental evidence and are used to uncover the origins of selectivity.

This Account describes the use of quantum-chemical calculations to elucidate mechanisms and develop catalysts to accomplish highly selective cyclization reactions. Chemistry is awash with cyclic molecules, and the creation of rings is central to organic synthesis. Cyclization reactions, the formation of rings by the reaction of two ends of a linear precursor, have been instrumental in the development of predictive models for chemical reactivity, from Baldwin's classification and rules for ring closure to the Woodward and Hoffmann rules based on the conservation of orbital symmetry and beyond. Ring formation provides a productive and fertile testing ground for the exploration of catalytic mechanisms and chemo-, regio-, diastereo-, and enantioselectivity using computational and experimental approaches. This Account is organized around case studies from our laboratory and illustrates the ways in which computations provide a deeper understanding of the mechanisms of catalysis in 5-endo cyclizations and how computational predictions can lead to the development of new catalysts for enhanced stereoselectivities in asymmetric cycloisomerizations. We have explored the extent to which several cation-directed 5-endo ring-closing reactions may be considered as electrocyclic and demonstrated that reaction pathways and magnetic parameters of transition structures computed using quantum chemistry are inconsistent with this notion, instead favoring a polar mechanism. A rare example of selectivity in favor of 5-endo-trig ring closure is shown to result from subtle substrate effects that bias the reactant conformation out-of-plane, limiting the involvement of cyclic conjugation. The mode of action of a chiral ammonium counterion was deduced via conformational sampling of the transition state assembly and involves coordination to the substrate via a series of nonclassical hydrogen bonds. We describe how computational mechanistic understanding has led directly to the discovery of new catalyst structures for enantioselective cycloisomerizations. Calculations have revealed that stepwise C-C bond formation and proton transfer dictate the exclusive endo diastereoselectivity of the intramolecular Michael addition to form 2-azabicyclo[3.3.1]nonane skeletons catalyzed by primary amines. These insights have led to development of a highly enantioselective catalyst with higher atom economy than previous generations. This Account also explores transition-metal-catalyzed cycloisomerizations, where our theoretical investigations have uncovered an unexpected reaction pathway in the [5 + 2] cycloisomerization of ynamides. This has led to the design of new phosphoramidite ligands to enable double-stereodifferentiating cycloisomerizations in both matched and mismatched catalyst-substrate settings. Computational understanding of the factors responsible for the regio-, enantio-, and diasterocontrol is shown to generate tangible predictions leading to an acceleration of catalyst development for selective cyclizations.

Transition state force fields (TSFF) treated the TS structure as an artificial minimum on the potential energy surface in the past decades. The necessary parameters were developed either manually or by the Quantum-to-molecular mechanics method (Q2MM). In contrast with these approaches, here we propose to model the TS structures as genuine saddle points at the molecular mechanics level. Different methods were tested on small model systems of general chemical reactions such as protonation, nucleophilic attack, and substitution, and the new procedure led to more accurate models than the Q2MM-type parametrization. To demonstrate the practicality of our approach, transferrable parameters have been developed for Mo-catalyzed olefin metathesis using quantum mechanical properties as reference data. Based on the proposed strategy, any force field can be extended with true transition state force field (TTSFF) parameters, and they can be readily applied in several molecular mechanics programs as well.

Dehydration over acidic zeolites is an important reaction class for the upgrading of biomass pyrolysis vapors to hydrocarbon fuels or to precursors for myriad chemical products. Here, we examine the dehydration of ethanol at a Brønsted acid site, T12, found in HZSM-5 using density functional theory (DFT). The geometries of both cluster and mixed quantum mechanics/molecular mechanics (QM:MM) models are prepared from the ZSM-5 crystal structure. Comparisons between these models and different DFT methods are conducted to show similar results among the models and methods used. Inclusion of the full catalyst cavity through a QM:MM approach is found to be important, since activation barriers are computed on average as 7 kcal mol(-1) lower than those obtained with a smaller cluster model. Two different pathways, concerted and stepwise, have been considered when examining dehydration and deprotonation steps. The current study shows that a concerted dehydration process is possible with a lower (4-5 kcal mol(-1)) activation barrier while previous literature studies have focused on a stepwise mechanism. Overall, this work demonstrates that fairly high activation energies (∼50 kcal mol(-1)) are required for ethanol dehydration. A concerted mechanism is favored over a stepwise mechanism because charge separation in the transition state is minimized. QM:MM approaches appear to provide superior results to cluster calculations due to a more accurate representation of charges on framework oxygen atoms.

We report a hybrid density functional theory-molecular mechanics study of the mechanism of the addition of nitroalkanes and phosphonates to benzaldehyde catalyzed by a chiral phosphacene catalyst developed by Ooi and co-workers. Our results are consistent with a reaction mechanism in which a catalyst molecule simultaneously interacts by hydrogen bonds with the nucleophile and the electrophile, transferring a proton to the aldehyde in concert with carbon-carbon bond formation. Despite the C2 symmetry of this class of organocatalyst, substrate recognition, and asymmetric induction in both reaction classes studied relies on interactions with nonequivalent N-H bonds that break symmetry. The origin of the stereo and diastereoselectivity is discussed in terms of steric effects and of the conformations adopted by the reactants, and the most favorable transition structure results from minimal geometric distortion energies. A rational model for predicting the major stereoisomer of reactions catalyzed by this chiral phosphacene, based on the qualitative assessment of steric interactions, is given.

Bromodomains are protein modules that bind to acetylated lysine residues. Their interaction with histone proteins suggests that they function as "readers" of histone lysine acetylation, a component of the proposed "histone code". Bromodomain-containing proteins are often found as components of larger protein complexes with roles in fundamental cellular process including transcription. The publication of two potent ligands for the BET bromodomains in 2010 demonstrated that small molecules can inhibit the bromodomain-acetyl-lysine protein-protein interaction. These molecules display strong phenotypic effects in a number of cell lines and affect a range of cancers in vivo. This work stimulated intense interest in developing further ligands for the BET bromodomains and the design of ligands for non-BET bromodomains. Here we review the recent progress in the field with particular attention paid to ligand design, the assays employed in early ligand discovery, and the use of computational approaches to inform ligand design.

The intramolecular Diels-Alder reactions of cycloalkenones and terminal dienes occur with high endo stereoselectivity, both thermally and under Lewis-acidic conditions. Through computations, we show that steric repulsion and tether conformation govern the selectivity of the reaction, and incorporation of either BF3 or α-halogenation increases the rate of cycloaddition. With a longer tether, isomerization from a terminal diene to the more stable internal diene results in a more facile cycloaddition.

The Diels-Alder reactions of the cycloalkenes, cyclohexene through cyclopropene, with a series of dienes--1,3-dimethoxybutadiene, cyclopentadiene, 3,6-dimethyltetrazine, and 3,6-bis(trifluoromethyl)tetrazine--were studied with quantum mechanical calculations and compared with experimental values when available. The reactivities of cycloalkenes as dienophiles were found by a distortion/interaction analysis to be distortion controlled. The energies required for cycloalkenes to be distorted into the Diels-Alder transition states increase as the ring size of cycloalkenes increases from cyclopropene to cyclohexene, resulting in an increase in activation barriers. The reactivities of the dienes are controlled by both distortion and interaction energies. In normal Diels-Alder reactions with cycloalkenes, the electron-rich 1,3-dimethoxybutadiene exhibits stronger interaction energies than cyclopentadiene, but the high distortion energies required for 1,3-dimethoxybutadiene to achieve transition-state geometries overtake the favorable interaction, resulting in higher activation barriers. In inverse-electron-demand Diels-Alder reactions of 3,6-dimethyltetrazine and 3,6-bis(trifluoromethyl)tetrazine, the reactivities are mainly controlled by interaction energies.

Cross-metathesis (CM) has recently emerged as a viable strategy for protein modification. Here, efficient protein CM has been demonstrated through biomimetic chemical access to Se-allyl-selenocysteine (Seac), a metathesis-reactive amino acid substrate, via dehydroalanine. On-protein reaction kinetics reveal a rapid reaction with rate constants of Seac-mediated-CM comparable or superior to off-protein rates of many current bioconjugations. This use of Se-relayed Seac CM on proteins has now enabled reactions with substrates (allyl GlcNAc, N-allyl acetamide) that were previously not possible for the corresponding sulfur analogue. This CM strategy was applied to histone proteins to install a mimic of acetylated lysine (KAc, an epigenetic marker). The resulting synthetic H3 was successfully recognized by antibody that binds natural H3-K9Ac. Moreover, Cope-type selenoxide elimination allowed this putative marker (and function) to be chemically expunged, regenerating an H3 that can be rewritten to complete a chemically enabled "write (CM)-erase (ox)-rewrite (CM)" cycle.

The site selectivities and stereoselectivities of C-H oxidations of substituted cyclohexanes and trans-decalins by dimethyldioxirane (DMDO) were investigated computationally with quantum mechanical density functional theory (DFT). The multiconfiguration CASPT2 method was employed on model systems to establish the preferred mechanism and transition state geometry. The reaction pathway involving a rebound step is established to account for the retention of stereochemistry. The oxidation of sclareolide with dioxirane reagents is reported, including the oxidation by the in situ generated tBu-TFDO, a new dioxirane that better discriminates between C-H bonds on the basis of steric effects. The release of 1,3-diaxial strain in the transition state contributes to the site selectivity and enhanced equatorial C-H bond reactivity for tertiary C-H bonds, a result of the lowering of distortion energy. In addition to this strain release factor, steric and inductive effects contribute to the rates of C-H oxidation by dioxiranes.

The synthesis and alkylation of chiral, nonracemic tropane- and homotropane-derived enamines is examined as an approach to enantioenriched α-alkylated aldehydes. The two bicyclic N auxiliaries, which differ by a single methylene group, give opposite senses of asymmetric induction on alkylation with EtI and provide modestly enantioenriched 2-ethylhexanal (following hydrolysis of the alkylated iminium). The observed stereoselectivity is supported by density functional studies of ethylation for both enamines.

We report a completely substrate-controlled approach to the asymmetric total synthesis of representative dioxabicyclic bromoallene marine natural products with either a 2,10-dioxabicyclo[7.3.0]dodecene or 2,9-dioxabicyclo[6.3.0]undecene skeleton from commercially available glycidol as a common starting material. The former include (-)-isolaurallene (1), the enantiomeric form of natural (+)-neolaurallene (2), and (+)-itomanallene A (3c), and the latter are (+)-laurallene (4) and (+)-pannosallene (5a). In addition, our first syntheses of 3c and 5a established the structure and absolute stereochemistry of both natural products. Our general approach to establish the α,α'-relative stereochemistry of the medium-ring (oxonene or oxocene) and tetrahydrofuran, respectively, involved the judicious pairing of our protecting-group-dependent intermolecular amide enolate alkylation (either chemoselective chelation-controlled or dianion alkylation) with either our intramolecular amide enolate or nitrile anion alkylation. Remarkable selectivity was achieved through the use of the appropriate alkylation steps, and this approach offered us optional access to any of these dioxabicyclic bromoallene marine natural products. In addition, a computational analysis was performed to investigate conformational effects on the rate of oxonene formation via RCM, a key step in these approaches. The results suggested an alternative rationale for reactivity based on the avoidance of eclipsing torstional interactions in the AS2-type ring conformation.

The thermal pericyclic cascade rearrangement of Zincke aldehydes (5-(dialkylamino)-2,4-pentadienals) to afford Z-α,β,γ,δ-unsaturated amides discovered by the Vanderwal group has been studied in depth using quantum mechanical methods. Two mechanistic possibilities that had previously been put forth to explain this internal redox process, one that had been discounted by experiment and the other that had withstood experimental scrutiny, were evaluated. Both of these mechanisms suffered from energetic barriers that appeared too high to allow rearrangement to proceed under the conditions used; however, computational study of a third possibility that implicates the intermediacy of vinylketenes revealed that it is the most likely pathway of rearrangement. Further computational studies accounted for the relative rates of rearrangement in substituted Zincke aldehydes, predicted the feasibility of related processes for other donor-acceptor dienes, and provided insight into the rearrangement of allylamine-derived Zincke aldehydes that provide either dihydropyridones or polycyclic lactams by further pericyclic processes.