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Recent publications by several leading philosophers of chemistry have focused on the definition, scope, utility, and nomenclature of issues dealing with acidity and basicity. In this paper, molecular orbital theory is used to explain all acid–base reactions, concluding that the interaction of the highest occupied molecular orbital (HOMO) of one substrate, "the base," with the lowest unoccupied molecular orbital (LUMO) of a second substrate, "the acid," determines the reactivity of such systems. This paradigm provides an understanding of all acid–base reactions as well as other reactions which, on the surface, may not seem like acid–base reactions but which have fundamental underpinnings of that kind of chemistry. Rather than being unable to determine a unified understanding of acidity and basicity as suggested in the philosophy of chemistry literature, we propose that acidity and basicity fit securely in a classification of many other reactions that, using classical chemistry knowledge, pre-quantum chemistry, would not be possible. We strongly support the use of all scientific knowledge and experience in the development of the ideas in the philosophy science. We further suggest increased interactions between philosophers of science and scientists, so that all scholars benefit from the values, knowledge, and perspectives of other disciplines. [ABSTRACT FROM AUTHOR]

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

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

[Display omitted] Both concerted [4 + 2] cycloadditions and stepwise carbocation-alkene cyclizations have been proposed as means to construct the complex polycyclic cores of the artatrovirenols and daphenoid natural products during their biosyntheses. Here the energetic feasibility of each of these reactions is assessed using density functional theory calculations. While none of the previously proposed processes can be ruled out, an alternative process with a lower barrier is proposed. This process would allow for formation of a key C C bond during the cyclase phase of terpenoid biosynthesis. [ABSTRACT FROM AUTHOR]

This review summarizes approaches and caveats in computational modeling of transition-metal-catalyzed sigmatropic rearrangements involving carbene transfer. We highlight contemporary examples of combined synthetic and theoretical investigations that showcase the synergy achievable by integrating experiment and theory. 1 Introduction 2 Mechanistic Models 3 Theoretical Approaches and Caveats 3.1 Recommended Computational Tools 3.2 Choice of Functional and Basis Set 3.3 Conformations and Ligand-Binding Modes 3.4 Solvation 4 Synergy of Experiment and Theory – Case Studies 4.1 Metal-Bound or Free Ylides? 4.2 Conformations and Ligand-Binding Modes of Paddlewheel Complexes 4.3 No Metal, Just Light 4.4 How To 'Cope' with Nonstatistical Dynamic Effects 5 Outlook [ABSTRACT FROM AUTHOR]

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

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

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

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

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

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

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

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

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

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. [ABSTRACT FROM AUTHOR]

Results of quantum chemical investigations shed new light on the mechanisms of formation of the stemarene, stemodene, betaerdene, aphidicolene, and scopadulanol diterpenes from syn-copalyl diphosphate (syn-CPP). These terpenes are shown to be connected by a complex network of reaction pathways involving concerted but asynchronous dyotropic rearrangements and triple shift rearrangements. The interconnection of these pathways leads to multiple routes for formation of each diterpene, which could lead to different origins for some carbon atoms in a given diterpenes under different conditions. [ABSTRACT FROM AUTHOR]

The energetic viability of proposed mechanisms for the formation of the five-membered ring in crotinsulidane diterpenes is assessed using density functional theory calculations. A protonation-assisted coupled four-electron electrocyclization/prototropic shift mechanism is predicted to have a low (biologically relevant) barrier. [ABSTRACT FROM AUTHOR]

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

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

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

When new concepts, models, or theories are introduced in a course, their presentation should be accurate, even if depth is not the goal. In a recent publication in this Journal, the Woodward-Hoffmann rules were invoked in the context of a new laboratory experiment, but the associated description was inaccurate. Here we aim to clarify the theoretical background relevant to the described laboratory experiment, and we describe a new computational experiment that could be used to further illuminate the relevant theoretical concepts. [ABSTRACT FROM AUTHOR]

The existence of post-transition state bifurcations on potential energy surfaces for organic and biological reaction mechanisms has been known for decades, but recently, new reports of bifurcations have been occurring at a much higher rate. Beyond simply discovering bifurcations, computational chemists are developing techniques to understand what aspects of molecular structure and vibrations control the product selectivity in systems containing bifurcations. For example, the distribution of products seen in simulations has been found to be extremely sensitive to the local environment of the reacting system (i.e. the presence of a catalyst, enzyme, or explicit solvent molecules). The outlook for the future of this field is discussed, with an eye towards the application of the principles discussed here by experimental chemists to design a reaction setup to efficiently generate desired products. [ABSTRACT FROM AUTHOR]

An energetically viable (on the basis of results from density functional theory computations) pathway to the diterpene variediene is described. Only one of the three secondary carbocations along this pathway is predicted to be a minimum on the potential energy surface. [ABSTRACT FROM AUTHOR]

Several Brummond-Chen thermal intramolecular (2 + 2)-cycloaddition reactions were examined using density functional theory calculations. The results of these calculations indicate that it is possible for these reactions to involve diradical intermediates that form directly from zwitterionic transition state structures. The likelihood of this scenario was shown to be sensitive to both the nature of substituents and solvent polarity. [ABSTRACT FROM AUTHOR]

Catalysis is common. Rational catalyst design, however, is at the frontier of chemical science. Although the histories of physical organic and synthetic organic chemistry boast key chapters involving [3s,3s] sigmatropic shifts, catalysis of these reactions is much less common than catalysis of ostensibly more complex processes. The comparative dearth of catalysts for sigmatropic shifts is perhaps a result of the perception that transition state structures for these reactions, like their reactants, are nonpolar and therefore not amenable to selective stabilization and its associated barrier lowering. However, as demonstrated in this Account, transition state structures for [3s,3s] sigmatropic shifts can in fact have charge distributions that differ significantly from those of reactants, even for hydrocarbon substrates, allowing for barriers to be decreased and rates increased. In some cases, differences in charge distribution result from the inclusion of heteroatoms at specific positions in reactants, but in other cases differences are actually induced by catalysts. Perhaps surprisingly, strategies for complexation of transition state structures that remain nonpolar are also possible. In general, the strategies for catalysis employed can be characterized as involving either mechanistic intervention, where a catalyst induces a change from the concerted mechanism expected for a [3s,3s] sigmatropic shift to a multistep process (cutting the transformation into halves or smaller pieces) whose overall barrier is decreased relative to the concerted process, or transition state complexation, where a catalyst simply binds (holds) more tightly to the transition state structure for a [3s,3s] sigmatropic shift than to the reactant, leading to a lower barrier in the presence of the catalyst. Both of these strategies can be considered to be biomimetic in that enzymes frequently induce multistep processes and utilize selective transition state stabilization for the steps involved. In addition, transition state complexation was the principle around which catalytic antibodies were originally designed. The field of catalysis of sigmatropic shifts is now ready for rational design. The studies described here all provide evidence for the origins of rate acceleration, derived in large part from the results of quantum chemical calculations, that can now be applied to the design of new catalysts for [3s,3s] and other sigmatropic shifts. [ABSTRACT FROM AUTHOR]

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

On the basis of results from quantum chemical calculations, the feasibility of an extensive series of intramolecular proton-transfer reactions postulated to occur during terpene biosynthesis is assessed and guiding principles are proposed. [ABSTRACT FROM AUTHOR]

The results of quantum-chemical calculations aimed at assessing the viability of nonclassical carbocations proposed to be involved in the biosynthesis of atiserne, beyerene, kaurene, and trachylobane diterpenes are presented. While the proposed edge-protonated structure is much lower in energy than the proposed face-protonated structure, neither is predicted to be a viable intermediate energetically. [ABSTRACT FROM AUTHOR]

Results from density functional theory computations indicate that a 1,4-alkyl shift proposed as part of the carbocation cyclization/rearrangement leading to ledol, viridiflorol, and related sesquiterpenes is not energetically viable. Instead, a previously proposed mechanism that avoids such a shift is greatly preferred. [ABSTRACT FROM AUTHOR]

Heathcock's classic cyclization/rearrangement cascade for formation of Daphniphyllum alkaloids is subjected to analysis using density functional theory calculations. The results of these calculations are consistent with a two-step pathway involving two pericyclic reactions, a Diels-Alder cycloaddition and an ene reaction. [ABSTRACT FROM AUTHOR]

Biosynthetic production of cyclobutanes leads to many complex natural products. Recently, theoretical work employing quantum chemical calculations has shed light on many of the details of cyclobutane-formation, in particular, for terpene natural products. Specific insights and general principles derived from these theoretical studies are described herein. [ABSTRACT FROM AUTHOR]

This account discusses representative case studies for various applications of quantum chemical calculations in synthetic organic chemistry. These include confirmation of target structures, methodology development, and catalyst design. These examples demonstrate how predictions from quantum chemical calculations can be utilized to streamline synthetic efforts. [ABSTRACT FROM AUTHOR]

Quantum chemical calculations on the transformation of the bisabolyl cation into an array of sesquiterpenes (iso-y-bisabolene, trichodiene, cuprenene, laurene, isochamigrene, chamigrene, chamipinene, sesquithujene, sesquisabinene, micro- biotene, dunniene, cutnacrene, isobazzanene, bazzanene, barbatene, widdradiene, and thujopsene) are described. The bisabolyl cation is the hub of a complicated web of carbocations involved in the construction of diverse and complex molecular architectures present in a large number of Nature's sesquiterpenoids. The results of quantum chemical calculations on the multitude of rearrangements described herein provide reasonable answers to several persistent mechanistic questions in the world of terpene biosynthesis and also provide examples of general reactivity principles for terpene-forming (and other) carbocation rearrangements. [ABSTRACT FROM AUTHOR]

Selectivity in chemical reactions that form complex molecular architectures from simpler precursors is usually rationalized by comparing competing transition-state structures that lead to different possible products. Herein we describe a system for which a single transition-state structure leads to the formation of many isomeric products via pathways that feature multiple sequential bifurcations. The reaction network described connects the pimar-15-en-8-yl cation to miltiradiene, a tricyclic diterpene natural product, and isomers via cyclizations and/or rearrangements. The results suggest that the selectivity of the reaction is controlled by (post-transition-state) dynamic effects, that is, how the carbocation structure changes in response to the distribution of energy in its vibrational modes. The inherent dynamical effects revealed herein (characterized through quasiclassical direct dynamics calculations using density functional theory) have implications not only for the general principles of selectivity prediction in systems with complex potential energy surfaces, but also for the mechanisms of terpene synthase enzymes and their evolution. These findings redefine the challenges faced by nature in controlling the biosynthesis of complex natural products. [ABSTRACT FROM AUTHOR]

Covering: up to March, 2013. This article was invited following the 2012 NPR Lectureship presented to Professor Dean Tantillo at the 21st IUPAC International Conference on Physical Organic Chemistry (ICPOC 21) This Highlight describes applications of quantum chemical calculations to problems in natural products chemistry, including the elucidation of natural product structures (distinguishing between constitutional isomers, distinguishing between diastereomers, and assigning absolute configuration) and determination of reasonable mechanisms for their formation. [ABSTRACT FROM AUTHOR]

A survey of computational studies on the mechanisms of dyotropic, Schmidt, and related reactions is presented. Connections between synthetically applied versions of these processes and those predicted to occur during biosynthetic terpeneforming carbocation cascades are highlighted. [ABSTRACT FROM AUTHOR]

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

A complete pathway (structures and energies of intermediates and transition state structures connecting them) from geranylgeranyl diphosphate to taxadiene, obtained using quantum chemical calculations, is described. This pathway is fully consistent with previous labeling experiments, despite differing in several subtle ways (in terms of conformations of certain carbocation intermediates and in the concertedness and synchronicity of certain bond-forming events) from previous mechanistic proposals. Also, on the basis of the theoretical results, it is proposed that the 2-fluoro-geranylgeranyl diphosphate substrate analogue in the recently reported X-ray crystal structure of taxadiene synthase is bound in a nonproductive orientation. [ABSTRACT FROM AUTHOR]

The success of many organocatalysts depends on the proper modulation of electronic properties of amines and their derived enamines and iminium ions. We and others have been fascinated with the differences in reactivity observed for aziridines versus other amines in many reactions. Herein we report a theoretical assessment (using B3LYP/6-31 + G(d,p)) of the π-donating ability of aziridines relative to other amines and discuss the implications for enamine and iminium ion reactivity. Copyright © 2010 John Wiley & Sons, Ltd. Quantum chemical calculations reveal that N-alkenylaziridines are less basic/nucleophilic at their (β)-carbon than are corresponding systems that lack an aziridine ring and their derived iminium ions are more susceptible to attack by nucleophiles. [ABSTRACT FROM AUTHOR]

Quantum chemical calculations on carbocation intermediates encountered during the conversion of ent-copalyl diphosphate to the diterpenes beyerene, kaurene, trachylobane, and atiserene are described. Based on the results of these computations, it is suggested that previously proposed secondary carbocation intermediates are avoided. In some cases, complex rearrangements in which up to three alkyl or hydride shifting events are coupled into concerted processes are predicted to occur instead. The potential effects of electron-rich active site groups on the inherent reactivity of key carbocations are discussed, as are complex rearrangements coupled to deprotonation events. Based on computed electrostatic potential maps, it also is proposed that ammonium ions that were previously designed as mimics of several carbocations are actually better mimics of transition state structures for carbocation deprotonation. [ABSTRACT FROM AUTHOR]

Quantum chemical calculations reveal how functional group arrays present in known enzyme active sites could accelerate an intramolecular Diels−Alder reaction proposed to occur during the biosynthesis of a complex terpenoid natural product. [ABSTRACT FROM AUTHOR]

Herein we describe density functional theory calculations on nitroso acetal-to-aminal rearrangements reported by Denmark and co-workers. Our calculations indicate that various structural (ring strain, hyperconjugation, anomeric effects) and environmental (both specific and nonspecific solvation) factors greatly influence the ease of rearrangement. Our calculations also indicate that both concerted and stepwise mechanisms are energetically viable. [ABSTRACT FROM AUTHOR]

Terpenes comprise a class of natural products that includes molecules with thousands of distinct structurally and stereochemically complex molecular architectures. The core hydrocarbon frameworks of these molecules are constructed via carbocation rearrangements promoted by terpene synthase (cyclase) enzymes. Although many mechanistic details for such reactions have been uncovered, the factors that control which carbocation intermediates and transition-state structures form are not well understood. Here we show that rearrangement pathways that pass through particular transition-state structures can bifurcate after the transition state. The resulting pathways lead to terpenes with distinctly different skeletons from each other. Although these types of bifurcating pathways have been described previously for some small molecules, the possibility that they may have an important role in the production of complex molecules in nature has, to our knowledge, not previously been considered. [ABSTRACT FROM AUTHOR]

Quantum chemical calculations on cyclization mechanisms for several sesquiterpene families proposed to be closely related to each other in a biogenic sense (the bisabolene, curcumene, acoradiene, zizaene (zizaene, isozizaene, epi-zizaene, and epi-isozizaene) cedrene (α/β-cedrenes and 7-epi-α/β-cedrenes), duprezianene, and sesquithuriferol families) are described. On the basis of the results of these calculations, we suggest that the conformation of the bisabolyl cation attainable in an enzyme active site is a primary determinant of the structure and relative stereochemistry of the sesquiterpenes formed. We also suggest that substantial conformational changes of initially formed conformers of the bisabolyl cation are necessary in order to form zizaene and epi-cedrene. Given that the productive conformation of the bisabolyl cation does not necessarily reflect the original orientation of farnesyl diphosphate bound in the corresponding enzyme active site, we conclude that folding of farnesyl diphosphate alone does not always dictate the structure and relative stereochemistry of cyclization products. In addition, the potential roles of dynamic matching in determining product distributions and enzyme-promoted formation of secondary carbocations are discussed. [ABSTRACT FROM AUTHOR]

Recent theoretical studies on concerted carbocation rearrangements that involve multiple asynchronous chemical events are described. The relevance of such rearrangements to natural products biosynthesis is highlighted. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Quantum chemical calculations were used to characterize [4,5] sigmatropic shifts in systems containing butadiene and pentadienyl substructures. Cationic, anionic, and radical systems with various tethers connecting these substructures were examined. In many cases, concerted [4,5] sigmatropic shifts with asynchronous bond making and breaking events were observed. The fundamental connections between [4,5] sigmatropic shifts and (5+4) cycloadditions are highlighted. [Copyright &y& Elsevier]

Three mechanistic possibilities for the formation of the oxetane (D ring) of Taxol were examined at various levels of theory [B3LYP/6-31+G(d,p), mPW1PW91/6-31+G(d,p), and MP2/6-31+G(d,p)] including one mechanism involving an unusual oxabicyclobutonium ion intermediate. The mechanisms examined differ considerably in terms of their predicted inherent activation barriers, and the requirements for acceleration of each by an enzyme active site are outlined. Our calculations provide an important starting point for future studies in this area. Also examined were previously published calculations on simple oxabicyclobutonium ions, as well as the all-carbon analog of the pathway involving the oxabicyclobutonium ion. [ABSTRACT FROM AUTHOR]