Conformational Preferences Research Articles

Tetratellura[36]octaphyrin(1.1.1.1.1.1.1.1) Metalation: From Dynamic Behavior to Rigid Chiral Figure-of-Eight Molecule; Activation of the C-Te Bond by Ruthenium.

The large expanded telluraporphyrin, tetratellura[36]octaphyrin(1.1.1.1.1.1.1.1), was synthesized in 7% yield by acid-catalyzed condensation of pyrrole with 2,5-bis(phenylhydroxymethyl)tellurophene and subsequent oxidation. The macrocycle acquires the chiral figure-eight conformation with two alternative spatial arrangements of the heterocyclic rings. The molecule exhibits dynamic behavior in solution, which was studied by means of 1H NMR spectroscopy. The reaction with chlorine led to a reversible oxidative addition at two distant tellurium atoms, which altered the preferred conformations. Metalation of the tetratellura[36]octaphyrin with triruthenium dodecacarbonyl selectively activated two of the eight Te-C bonds, resulting in the formation of an organometallic diruthenium compound. During the reaction, two tellurophene rings were converted to 1-ruthena-2-telluracyclohexadiene units containing octahedral ruthenium(II) centers. The rigid structure of this chiral complex allowed the separation of enantiomers.

Evaluation of All-Atom and Martini 3 Coarse-Grained Force Fields from the Structural Investigation of Nitroxide Spin Probes and Their Confinement in Beta-Cyclodextrin.

Nitroxide radicals have found wide applications as spin labels or probes, and their guest-host interactions with cyclodextrins exhibit enhanced applications in electron spin resonance (ESR) spectroscopy and imaging due to improved biostability toward reducing agents. Although the computational prediction of the guest-host binding has become increasingly common for small ligands, molecular simulations regarding the conformational preferences of hosted spin probes have not been conducted. Here we present molecular dynamics simulations at an atomistic level for a set of four TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) spin probes and thereafter develop coarse-grained models compatible with the recent version of the Martini force field (v 3.0) to tackle their encapsulation in the cavity of β-cyclodextrin (βCD) for which experimental ESR data are available. The results indicate that the atomistic descriptions perform well in relation to the structural parameters derived from X-ray diffraction as well as hydrogen bonding and hydrogen patterns and predict that the guest-host complexation is hydrophobically driven by the presence of a methyl group pair of the spin probe at the cavity center of βCD. The spin probe mobility at the binding site reveals the nitroxide group orientation toward the secondary rim of the cyclodextrin and the alternating presence of the two methyl group pairs inside the cavity, features in agreement with the experimental behavior of the ESR parameters. The coarse-grained parameterizations of TEMPO probes and βCD rely on optimizing the bonded and nonbonded parameters with references to the atomistic simulation results, and they are capable of recovering the orientation and location of the spin probe inside the cyclodextrin cavity predicted by the atomistic guest-host complexes. The results suggest the cyclodextrin host-guest system as a powerful validation suite to evaluate new coarse-grained parameterizations of small ligands and future extensions to functionalized cyclodextrins in inclusion complexes.

Effect of the Chemical Composition and Geometry of Nanotubes on the Structure and Internal Rotation Barrier of Encapsulated Ammonia‐Boron Trifluoride: A Theoretical Investigation

AbstractThe study of the structure and conformational properties of ammonia–boron trifluoride in the cavity of 24 carbon and inorganic nanotubes using the PBE/3ζ DFT approximation showed that the conformational preference of the encapsulated molecule is determined by geometry and chemical composition of the host nanostructure. The combined effect of these factors leads to the predominance of eclipsed conformation of guest molecule for four endoclusters. In other cases, the main minimum on the potential energy surface corresponds to the staggered or pseudo‐staggered forms of BF3←NH3. The guest molecule carries the electric charge and has a shortened B←N bond. These conclusions are confirmed by the results of the virtual reaction of ammonia and boron trifluoride in the cavity of individual nanotubes.

A Comparative In Vitro Anticancer Evaluation and In Silico Study of New 1‐(1,3‐Oxazol‐5‐yl)piperidine‐4‐sulfonylamides

AbstractIn this work, we synthesized a series of new 1,3‐oxazole derivatives comprising the sulfonylamide group and tested their activity against the human tumor cell line panel. This study further explores the stereoelectronic characteristics of 1,3‐oxazol‐5‐sulfonylamides and new 1‐(1,3‐oxazol‐5‐yl)piperidine‐4‐sulfonylamides to connect their anticancer activity to the molecular structure. Combining in vitro and in silico methods, we analyzed how the proximity of the sulfonylamide group to the heterocyclic ring affects the structure–activity interplay. Herein, our assessment is based on the purported complexation of 1,3‐oxazoles with targeted biomolecular fragments involving the π‐stacking interaction and hydrogen bonding within the prospective complexes. Defining the probability of the prospective drug–target interactions, we detail conformational properties, donor/acceptor capabilities, electronic characteristics, and thermodynamic preference of produced sulfanylamide group containing 1,3‐oxazoles toward biomolecular fragments, identifying the nature of variations in anticancer activity.

Novel SDH Inhibitors as Antifungal Leads: From Azobenzene Derivatives to the 1,2,4-Oxadiazole Compounds.

Azo-incorporating was reported to be an effective strategy for increasing SDH inhibitory activity but for poor in vivo control effects. Herein, the azo-incorporated compounds were structurally optimized to retain a preferential conformation by replacing the azo bond with their bioisosteres. Interestingly, the 1,2,4-oxadiazole compound D2 displayed a broad fungicidal spectrum as well as fluxapyroxad. More excitedly, compound D2 showed excellent antifungal activities against rice sheath blight disease both in vitro (EC50 = 0.001 μg/mL) and in vivo (EC50 = 1.08 μg/mL, EC95 = 4.67 μg/mL). In addition, an extra π-π interaction was found between the 1,2,4-oxadiazole ring of compound D2 and the phenyl ring of residue D_Y586, which might interpret the enhanced potency of compound D2 against Rhizoctonia solani. Further structural optimizations of the 1,2,4-oxadiazole compounds gave several analogues that made a breakthrough in controlling rice blast disease. These 1,2,4-oxadiazole compounds, derived from azobenzene derivatives, could be antifungal leads especially against R. solani and Magnaporthe grisea, exemplifying an interesting mode of pesticide discovery and providing theoretical guidance for innovation of the SDHI fungicide.

U.S. against the world: Authoritarianism among American public servants

AbstractWhat is the prevalence of authoritarianism among public servants in the United States, and what are its resulting consequences? Several underlying psychological traits are associated with both authoritarianism and a desire to work in the public sector, such as an aversion to ambiguity and a preference for order and security. Scholarship also suggests that those with high authoritarian attributes may see the world through an ‘us versus them’ prism; in this case, the ‘them’ may be represented by other countries. Therefore, it is hypothesised that those with higher authoritarian attributes are more likely to work in the public sector and that public servants with higher authoritarian attributes are more likely to be sensitive to potential threats to the country. Using six surveys that cover a 20‐year period from the American National Elections Study, both hypotheses are supported. Authoritarian attributes are associated with an increased likelihood of government employment. Additionally, authoritarian public servants tend to support government wiretapping and express greater concern about terrorism. The presence of authoritarianism among public sector employees has implications for a range of governance issues, which makes it important to understand where and to what degree it is prevalent.Points for practitioners More attention should be devoted to the division and prevalence of authoritarian attributes within public servants . Checks and oversight mechanisms should be implemented for public sector employees in sensitive areas to help counterbalance potential authoritarian impulses. Organisational cultures that value openness, evidence‐based policymaking, and tolerance for dissenting viewpoints should be fostered as a counterweight to authoritarian preferences for conformity.

Conformations of α-cyclodextrin and its role on the stability of inclusion complexes in aqueous solution

α-Cyclodextrin (αCD), a cyclic carbohydrate polymer, presents a wealth of opportunities for drug delivery and various industrial applications. Its high affinity and selectivity in encapsulating target molecules have been well-documented. However, the influence of αCD's conformational variations on its encapsulation capacity remains a promising area for further exploration. This study explores the conformational dynamics of αCD and its relationship with the formation of inclusion complexes (ICs) in aqueous solutions, focusing on understanding the forces driving these dynamics and the formation of stable ICs. Classical molecular dynamics (CMD) demonstrate that αCD solvated in water can adopt two conformations: a truncated cone shape with a suitable cavity for encapsulation and a distorted cone shape with a collapsed cavity. The predominant conformation observed in the CMD trajectory of pristine αCD is the distorted cone. However, under complexation conditions with aliphatic molecules, the guest molecule's size dictates the ICs' stability, forcing αCD to maintain the truncated cone conformation. Quantum chemistry methods and electron density analyses (Quantum Theory of Atoms in Molecules and Non-Covalent Interactions index) support CMD observations by characterizing and quantifying non-covalent interactions. Findings indicate that the shift from the truncated to the distorted cone conformation in αCD is primarily driven by intramolecular non-covalent interactions and the reconfiguration of water molecules surrounding αCD. The ICs' analysis displays a significant correlation between the size of the aliphatic chain and the intensity of intermolecular interactions. The strength of these interactions can effectively disrupt the αCD intramolecular non-covalent interactions that lead to a conformational change and, consequently, the loss of the inclusion complex. In conclusion, although αCD's conformational change can affect encapsulation, guest molecules can manipulate the conformational preference. The systematic analysis of non-covalent interactions offers a way to characterize and quantify these forces, enhancing our ability to understand and predict the stability of inclusion complexes.

Synthesis of the cis‐ and trans‐3‐Fluoro Analogues of Febrifugine and Halofuginone

The novel synthesis of racemic cis‐ and trans‐3‐fluorofebrifugine and halofuginone is described. This straight‐forward seven‐step process relies on an electrophilic fluorination‐allylation sequence generating a mixture of N‐Cbz protected, diastereomeric 2‐allyl‐3‐fluoropiperidines. On separation, a Wacker oxidation‐methyl functionalisation sequence enabled introduction of the required quinazolinone portion. Finally, removal of the N‐Cbz protecting group lead to isolation of the 3‐fluorofebrifugine dihydrobromide analogues that are of potentially pharmacological use. Analysis of the NMR spectra for each stereoisomer provides information concerning the preferred conformers of the different diastereomers. Evidence indicates that the cis‐diastereomer favours a conformation where the F‐atom occupies an axial orientation. In contrast, for its trans‐stereoisomeric counterpart, the 2‐substituent overrides any F‐atom effect and it preferentially occupies a conformer where both substituents occupy equatorial positions. Finally, interconversion between the cis‐ and trans‐diastereomers was studied. In DMSO‐d6 and as their free‐bases, isomerisation of each diastereomer gave a common 65:35 ratio of trans‐ to cis‐3‐fluorofebrifugine. Determination of the reaction rate constants for the isomerisation process at different temperatures enabled calculation of the activation energy barriers, for each process, using an Arrhenius plot. The activation energy barrier for the isomerisation of the trans‐isomer was 94.3 kJ mol‐1, whereas for the cis‐isomer it was 84.5 kJ mol‐1

Comparative Bindings of Glycosaminoglycans with CXCL8 Monomer and Dimer: Insights from Conformational Dynamics and Kinetics of Hydrogen Bonds.

GAGs bind to both the monomeric and dimeric forms of CXCL8, helping to form a concentration gradient of the chemokine that facilitates the recruitment of neutrophils to an injury site and supports other biological functions. In this study, atomistic molecular dynamics simulations were conducted to investigate the binding behavior of two hexameric GAGs sulfated at two different positions, chondroitin sulfate (CS) and heparan sulfate (HS), with the monomer (SIL8) and dimer (DIL8) forms of the CXCL8 protein. The results support that the conformational diversity of CS and HS appeared to be more when binding with monomer SIL8 than dimer DIL8. CS gained more configurational entropy from glycosidic linkage flexibility when bound to SIL8 than DIL8, with a higher energy barrier, whereas HS exhibited a lower energy barrier for configurational entropy when bound to SIL8 and DIL8. The monomer SIL8 exhibited more favorable and preferential binding with GAGs compared to DIL8. Formation of hydrogen bonds with the basic amino acids of SIL8 and GAG was more rigid and required higher activation energy to break than the other identified hydrogen bondings. Water molecules involved in hydrogen bonding with GAGs, excluding those with basic amino acids of DIL8, showed longer lifetimes and slower relaxation compared to SIL8. This suggests that water-mediated interactions also favor binding of DIL8 with GAGs. Despite having more basic amino acids, DIL8 did not display stronger binding than SIL8, indicating the significant role of basic residues in stabilizing the GAG-protein interactions in the monomers. The reason could be that the greater number of nonbasic amino acids in dimeric CXCL8 stabilizes the complex by forming water-mediated hydrogen bonds, reducing the conformational preferences for binding with GAGs. In contrast, the monomeric form of CXCL8 exhibits a higher conformational preference for protein-GAG interactions.

Revealing the Structure of Sheer N-Acetylglucosamine, an Essential Chemical Scaffold in Glycobiology.

We explored the conformational landscape of N-acetyl-α-d-glucosamine (α-GlcNAc), a fundamental chemical scaffold in glycobiology. Solid samples were vaporized by laser ablation, expanded in a supersonic jet, and characterized by broadband chirped pulse Fourier transform microwave spectroscopy. In the isolation conditions of the jet, three different structures of GlcNAc have been discovered. These are conclusively identified by comparing the experimental values of the rotational constants with those predicted by theoretical calculations. The conformational preferences are controlled by intramolecular hydrogen bond networks formed between the polar groups in the acetamido group and the hydroxyl groups and dominated in all cases by a strong OH···O═C interaction. We reported an exception to the gauche effect due to the enhanced stability observed for the Tg+ conformer. All the structures present the same disposition of the acetamido group, which explains the highly selective binding of N-acetylglucosamine with different amino acid residues. Thus, the comprehensive structural data provided here shall help to shed some light on the biological role of this relevant amino sugar.

Exploring the energetic and conformational properties of the sequence space connecting naturally occurring RNA tetraloop receptor motifs.

Folded RNAs contain tertiary contact motifs whose structures and energetics are conserved across different RNAs. The transferable properties of RNA motifs simplify the RNA folding problem, but measuring energetic and conformational properties of many motifs remains a challenge. Here, we use a high-throughput thermodynamic approach to investigate how sequence changes alter the binding properties of naturally-occurring motifs, the GAAA tetraloop•tetraloop receptor (TLR) interactions. We measured the binding energies and conformational preferences of TLR sequences that span mutational pathways from the canonical 11ntR to two other natural TLRs, the IC3R and Vc2R. While the IC3R and Vc2R share highly similar energetic and conformational properties, the landscapes that map the sequence changes for their conversion from the 11ntR to changes in these properties differ dramatically. Differences in the energetic landscapes stem from the mutations needed to convert the 11ntR to the IC3R and Vc2R rather than a difference in the intrinsic energetic architectures of these TLRs. The conformational landscapes feature several non-native TLR variants with conformational preferences that differ from both the initial and final TLRs; these species represent potential branching points along the multidimensional sequence space to sequences with greater fitness in other RNA contexts with alternative conformational preferences. Our high-throughput, quantitative approach reveals the complex nature of sequence-fitness landscapes and leads to models for their molecular origins. Systematic and quantitative molecular approaches provide critical insights into understanding the evolution of natural RNAs as they traverse complex landscapes in response to selective pressures.

In silico study on helicenes in hydrophobic natural deep eutectic solvent

This research explores the behavior of helicenes in Deep Eutectic Solvents (DES) formed by thymol and dodecanoic acid using a combined theoretical approach. COSMOtherm, Density Functional Theory (DFT), and molecular dynamics (MD) simulations were employed to elucidate the interactions between helicenes and the DES components at the molecular level. The behavior of helicenes in water was also studied as a reference system. COSMOtherm calculations provided insights into the thermodynamic properties of the system. DFT simulations allowed for the investigation of the electronic structure and bonding interactions between helicenes and DES molecules. Additionally, MD simulations offered dynamic information on the solvation behavior and conformational preferences of helicenes within the DES media. The combined approach provides a comprehensive understanding of the interactions between helicenes and thymol-dodecanoic acid DES. The research findings will contribute to the development of a theoretical framework for predicting the behavior of other functional molecules in DES environments. This knowledge has potential applications in various fields, including material science, catalysis, and drug delivery.

Sequence-dependent conformational preferences of disordered single-stranded RNA

Sequence-dependent conformational preferences of disordered single-stranded RNA

Cocrystallization of the Src-Family Kinase Hck with the ATP-Site Inhibitor A-419259 Stabilizes an Extended Activation Loop Conformation.

Hematopoietic cell kinase (Hck) is a member of the Src kinase family and is a promising drug target in myeloid leukemias. Here, we report the crystal structure of human Hck in complex with the pyrrolopyrimidine inhibitor A-419259, determined at a resolution of 1.8 Å. This structure reveals the complete Hck active site in the presence of A-419259, including the αC-helix, the DFG motif, and the activation loop. A-419259 binds at the ATP-site of Hck and induces an overall closed conformation of the kinase with the regulatory SH3 and SH2 domains bound intramolecularly to their respective internal ligands. A-419259 stabilizes the DFG-in/αC-helix-out conformation observed previously with Hck and the pyrazolopyrimidine inhibitor PP1 (PDB: 1QCF). However, the activation loop conformations are distinct, with PP1 inducing a folded loop structure with the tyrosine autophosphorylation site (Tyr416) pointing into the ATP binding site, while A-419259 stabilizes an extended loop conformation with Tyr416 facing out into the solvent. Autophosphorylation also induces activation loop extension and significantly reduces the Hck sensitivity to PP1 but not A-419259. In cancer cells where Hck is constitutively active, the extended autophosphorylation loop may render Hck more sensitive to inhibitors like A-419259 which prefer this kinase conformation. More generally, these results provide additional insight into targeted kinase inhibitor design and how conformational preferences of inhibitors may impact selectivity and potency.

The Effect of Hyperconjugation and Hydrogen Bonding on the Conformers of Methylated Monosaccharides.

The conformational landscapes of four 1-O-methylated monosaccharides-methyl a-glucose, methyl b-glucose, methyl a-galactose, and methyl b-galactose-were characterized using jet-cooled broadband rotational spectroscopy, supported by density functional theory calculations. A newly designed, simple pulsed nozzle assembly was used to introduced the sugar samples into a jet expansion without thermal degradation, eliminating the need for a complex and expensive laser ablation system. Ten conformers were experimentally identified by assigning their rotational spectra, and the intricate methyl internal rotation splittings were analysed. Notably, methylation alters the directionality of intramolecular hydrogen bonding of a-galactose highlighting its impact on structural preference. Natural bond orbital, intrinsic bond strength, and non-covalent interaction analyses were conducted to explore the interplay between hydrogen bonding and hyperconjugation. A set of σ to σ* neutral hyperconjugative interactions were found to override a strong hydrogen bond, driving a preference for the gauche conformers.

Ring‐Size Control and Guest‐Induced Circularly Polarized Luminescence in Heteroleptic Pd3A3B3 and Pd4A4B4 Assemblies

AbstractTwo new structural motifs within the class of heteroleptic PdnAnBn assemblies, namely syn‐cis‐Pd3A3B3 bowls and bowl‐ (syn) or saddle‐ (anti) shaped cis‐Pd4A4B4 rings are introduced. All of the ten examples share a common longer fluorenone‐based bis‐monodentate ligand, equipped with meta‐pyridine donor groups. The ring size (3‐ vs. 4‐membered) and conformational preference (bowl vs. saddle) are controlled by the choice of the shorter ligand. These carry para‐pyridine donors, different aromatic backbones (benzene, thiophene or selenophene) and either no or small or bulky endohedral substituents, serving to control the nuclearity of the heteroleptic rings through different effects (ligand angle, charge distribution or backbone bulk). Moreover, the luminescence of the fluorenone ligand is conserved in the formed architectures. Emission intensity as well as host–guest properties vary depending on the inward‐pointing functions. All Pd3A3B3 assemblies are shown to bind chiral guest BINOL bis‐sulfonate which imparts its chirality to the entire host–guest complex. This results in a guest‐induced circular dichroism (CD) and circularly polarized luminescence (CPL) with dissymmetry factor glum up to 10−3.

Ring-Size Control and Guest-Induced Circularly Polarized Luminescence in Heteroleptic Pd3A3B3 and Pd4A4B4 Assemblies.

Two new structural motifs within the class of heteroleptic PdnAnBn assemblies, namely syn-cis-Pd3A3B3 bowls and bowl- (syn) or saddle- (anti) shaped cis-Pd4A4B4 rings are introduced. All of the ten examples share a common longer fluorenone-based bis-monodentate ligand, equipped with meta-pyridine donor groups. The ring size (3- vs. 4-membered) and conformational preference (bowl vs. saddle) are controlled by the choice of the shorter ligand. These carry para-pyridine donors, different aromatic backbones (benzene, thiophene or selenophene) and either no or small or bulky endohedral substituents, serving to control the nuclearity of the heteroleptic rings through different effects (ligand angle, charge distribution or backbone bulk). Moreover, the luminescence of the fluorenone ligand is conserved in the formed architectures. Emission intensity as well as host-guest properties vary depending on the inward-pointing functions. All Pd3A3B3 assemblies are shown to bind chiral guest BINOL bis-sulfonate which imparts its chirality to the entire host-guest complex. This results in a guest-induced circular dichroism (CD) and circularly polarized luminescence (CPL) with dissymmetry factor glum up to 10-3.

Dative Bonding in Quasimetallatranes Containing Group 15 Donors (Y = N, P, and As) and Group 14 Acceptors (M = Si, Ge, Sn, and Pb).

Metallatranes and their analogous fused ring [3.3.0] bicyclic compounds, quasimetallatranes, have emerged as fascinating molecular systems with intriguing structural, bonding, and conformational properties. We present a comprehensive investigation aimed at unraveling the nature of dative bonding and exploring the conformational flexibility of these compounds. We extensively characterize the dative bond between the metal center and the electron pair donor, using a range of modeling techniques. Our analyses involve structural optimizations, molecular orbital examinations, and covalency ratio calculations, which provide a thorough understanding of the bonding interactions responsible for the stability of these systems. The results confirmed the presence of dative bonds, supported by the close proximity between the metal and the electron-donating group, and the observation of overlapping electron density. Our studies reveal a correlation between the size of the electron-donor and the coordinating metal atom, and the strength of the dative interaction, as indicated by the bond length and the Wiberg bond indices. This bond strength, in turn, influences the conformational preferences adopted by these compounds. This investigation sheds light on the fundamental aspects of the fused ring [3.3.0] bicyclic quasimetallatrane compounds and offers valuable insights into their unique properties.

Understanding the gelation properties of the fluorophenyl glycosides of arabinoside gelators: experimental and theoretical studies.

In supramolecular gelation, fluorinated gelators are important due to the unique properties displayed by these compounds that arise out of the presence of fluorine atoms. Generally, incorporation of fluorine leads to higher mechanical strength of the gels compared to their non-fluorinated counterparts and this property is enhanced with increasing the number of fluorine atoms. Herein, we show that the incorporation of fluorine into the phenyl ring of phenyl arabinoside allows the molecule to act as a gelator, unlike the non-fluorinated compound. We also show that the mechanical strength and stiffness of the gels is not only dependent on the positions of the fluorine atoms but also guided by their number. Detailed experimental studies, supported by computational studies, allowed us to rationalize the observed supramolecular interactions and propose reasons based on the conformational preferences of these compounds that allow additional hydrogen bonds and π-π interactions which guide the self-assembly, in addition to the primary H-bonding interactions. This, in turn, affects the mechanical behavior of these gels.

Quantum Chemical Characterization of Rotamerism in Thio-Michael Additions for Targeted Covalent Inhibitors.

Myotonic dystrophy type I (DM1) is the most common form of adult muscular dystrophy and is a severe condition with no treatment currently available. Recently, small-molecule ligands have been developed as targeted covalent inhibitors that have some selectivity for and covalently inhibit cyclin-dependent kinase 12 (CDK12). CDK12 is involved in the transcription of elongated RNA sections that results in the DM1 condition. The covalent bond is achieved after nucleophilic addition to a Michael acceptor warhead. Previous studies of the conformational preferences of thio-Michael additions have focused on characterizing the reaction profile based on the distance between the sulfur and β-carbon atoms. Rotamerism, however, has not been investigated extensively. Here, we use high-level quantum chemistry calculations, up to coupled cluster with single, double, and perturbative triple excitations [CCSD(T)], to characterize the nucleophilic addition of an archetypal nucleophile, methanethiolate, to various nitrogen-containing Michael acceptors which are representative of the small-molecule covalent inhibitors. By investigating the structural, energetic, and electronic properties of the resulting enolates, as well as their reaction profiles, we show that synclinal additions are generally energetically favored over other additions due to the greater magnitude of attractive noncovalent interactions permitted by the conformation. The calculated transition states associated with the addition process indicate that synclinal addition proceeds via lower energetic barriers than antiperiplanar addition and is the preferred reaction pathway.