Retention Of Configuration Research Articles

Benchmark Ab Initio Mapping of the F- + CH2ClI SN2 and Proton-Abstraction Reactions.

The experimental and theoretical studies of gas-phase SN2 reactions have significantly broadened our understanding of the mechanisms governing even the simplest chemical processes. These investigations have not only advanced our knowledge of reaction pathways but also provided critical insights into the fundamental dynamics of chemical systems. Nevertheless, in the case of the prototypical X- + CH3Y → Y- + CH3X [X, Y = F, Cl, Br, and I] SN2 reactions, the effect of the additional halogenation of CH3Y has not been thoroughly explored. Thus, here, we perform the first high-level ab initio characterization of the F- + CH2ClI SN2 and proton-abstraction reactions utilizing the explicitly-correlated CCSD(T)-F12b method. Two possible SN2 channels leading to the Cl- + CH2FI and I- + CH2FCl products are distinguished, in which we investigate four different pathways of back-side attack Walden inversion, front-side attack, double inversion, and halogen-bonded complex formation. In order to obtain the benchmark energies of the geometries of the stationary points, determined at the CCSD(T)-F12b/aug-cc-pVTZ level of theory, additional computations are carried out considering the basis set effects, post-CCSD(T) correlations, and core corrections. Using the benchmark data, we assess the accuracy of the MP2, DF-MP2, MP2-F12, and DF-MP2-F12 methods as well. By comparing the present F- + CH2ClI system with the corresponding F- + CH3Y [Y = Cl and I] reactions, this study demonstrates that further halogenation of CH3Y significantly promotes the corresponding proton-abstraction and SN2 retention channels as well as the halogen-bonded complex formation, and as a consequence, the traditional back-side attack Walden-inversion mechanism becomes less pronounced.

Theoretical insights on potential-dependent oxidation behaviors and antioxidant strategies of MXenes

Significant efforts have been devoted to investigating the oxidation of MXenes in various environments. However, the underlying mechanism of MXene oxidation and its dependence on the electrode potential remain poorly understood. Here we show the oxidation behavior of MXenes under the working conditions of electrochemical processes in terms of kinetics and thermodynamics by using constant-potential ab initio simulations. The theoretical results indicate that the potential effects can be attributed to the nucleophilic attack of water molecules on metal atoms, similar to that taking place in the Oxygen Evolution Reaction. Building upon these findings, we deduced the oxidation potential of the common MXenes, and proposed antioxidant strategies for MXene. Finally, we demonstrated that MBenes, the boron analogs of MXenes, may undergo a similar nucleophilic attack in water and inferred that molecule-induced Walden inversion is widely present in material reconstructions. This work contributes to a fundamental understanding MXene stability at the atomic level, and promotes the transition in materials discovery from trial-and-error synthesis to rational design.

Unconventional Pathways in Nitrogen-Centered SN2 Reactions: From Roundabout to Hydride Transfer.

The mechanisms and dynamics of bimolecular nucleophilic substitution (SN2) reactions are complex and influenced by the nature of the central atom. In this study, we explore SN2 at a nitrogen center (SN2@N) by investigating the reaction of chloramine (NH2Cl) with methoxide ion (CH3O-) using ab initio classical trajectory simulations at the MP2(fc)/aug-cc-pVDZ level of theory. We observe that, in addition to the expected SN2 product formation (CH3ONH2 + Cl-), a high-energy proton-transfer pathway leading to CH3OH and NHCl- dominates, with near-quantitative agreement between simulations and experimental data. Notably, we identify a novel hydride-transfer pathway yielding NH3, H2CO, and Cl-, revealing alternative reactivity channels previously uncharacterized in nitrogen-centered SN2 reactions. Mechanistic analysis uncovers unconventional roaming-mediated and roundabout pathways alongside the traditional direct rebound and indirect mechanisms. Additionally, an umbrella inversion of the NH2 group resulting in retention of configuration in the CH3ONH2 product was observed in a fraction of trajectories.

Unveiling the GT114 family: Structural characterization of A075L, a glycosyltransferase from Paramecium bursaria chlorella virus-1 (PBCV-1).

Protein A075L is a β-xylosyltransferase that participates in producing the core of the N-glycans found in VP54, the major viral capsid protein of Paramecium bursaria chlorella virus-1 (PBCV-1). In this study, we present an X-ray crystallographic analysis of the apo form of A075L, along with its complexes with the sugar donor and with a trisaccharide acceptor. The protein structure shows a typical GT-B folding, with two Rossmann-like fold domains, in which the acceptor substrate binds to the N-terminal region, and the nucleotide-sugar donor binds to the C-terminal region. We propose that the catalytic mechanism follows a direct displacement SN2-like reaction, where Asp73 serves as a catalytic base that deprotonates the incoming nucleophile of the acceptor, facilitating direct displacement of the UDP with the inversion of the anomeric configuration of the acceptor without metal ion dependence, while the interactions with side chains of Arg158 and Arg208 stabilize the developing negative charge. Using isothermal titration calorimetry, nuclear magnetic resonance spectroscopy, high-performance liquid chromatography, and molecular dynamics simulations, the catalytic activity and specificity of this enzyme have been unraveled.

Nickel-Catalyzed Direct Fluorosulfonylation of Vinyl Bromides and Benzyl Bromides for Sulfonyl Fluorides.

An efficient nickel-catalyzed direct fluorosulfonylation of vinyl bromides and benzyl bromides under mild reaction conditions has been developed for sulfonyl fluorides utilizing Na2S2O4 and NFSI as the sulfur dioxide and fluorine sources, respectively. This reaction system tolerates organic bromide compounds, such as β-styryl bromides, alkyl vinyl bromides, and benzyl bromides, to achieve corresponding sulfonyl fluorides in moderate to good yields, with convenient operation, mild conditions, broad substrate scope, good functional group compatibility, and excellent retention of configuration to vinyl bromides.

Efficient quantum mechanical minimum free energy path calculation by combining path integral hybrid Monte Carlo and climbing image nudged elastic band methods, and its application to the addition reaction of hydrogen isocyanide to formaldehyde.

We propose an efficient algorithm for a minimum free energy path calculation based on the path integral hybrid Monte Carlo (PIHMC) method by combining the climbing image-nudged elastic band (CI-NEB) and the thermodynamic integration (TI) methods. Here, the CI-NEB and the TI methods are used to find a transition state along the reaction path and evaluate the free energy path, respectively. Our algorithm is applied to the Walden inversion reaction of the hydronium ions (H3O+). The numerical results show that the computational effort by our algorithm is significantly reduced compared to that of the previously proposed algorithm combining PIHMC without losing accuracy. We also demonstrate the importance of temperature and isotope effects on the addition reaction of hydrogen isocyanide to formaldehyde. In this reaction, the nuclear quantum effect causes the structural change at the TS and decreases the energy barrier.

On the Origin of Enantioselectivity in Chiral Zeolite Asymmetric Catalyst GTM-3: Host-Guest Transfer of Chirality.

Knowledge of how extra-large-pore chiral zeolite asymmetric catalysts based on the -ITV framework imprint their chirality during a catalytic reaction is crucial in order to spread the scope for the catalytic enantioselective production of chiral compounds of interest. In this work, we have carried out a combined experimental and computational study on the catalytic activity of antipode GTM-3 catalysts during the ring-opening of trans-stilbene oxide with 1-butanol. Identification of the enantiomers of all the chiral species unraveled a surprising catalytic behavior: these chiral catalysts promote the transformation of one enantiomer of trans-stilbene oxide in the corresponding unlike product (with inversion of configuration of the attacked C) via an SN2 mechanism, and at the same time, the transformation of the other enantiomer of trans-stilbene oxide via an SN1-like mechanism into the like (with retention of configuration) and secondary products (diphenylacetaldehyde via Meinwald rearrangement and derived products). A computational study based on DFT + D methods suggested a potential explanation for this catalytic behavior, associated with a different orientation of trans-stilbene oxide enantiomers bound on the Ge(T7) positions in d4r units, which is stabilized by the development of intraframework H-bonds between the interrupted T7OH adjacent positions characteristic of this framework. Calculations suggest that each enantiomer of trans-stilbene oxide follows a different reaction pathway, one favoring the SN2 route by addition of butanol from the opposite side to form unlike-products, while the different orientation of the antipode enantiomer disfavors such SN2 route mainly by steric repulsions and at the same time favors the reaction toward the SN1 mechanism to give like- and secondary-products. Our study suggests that the strong enantioselectivity of GTM-3 catalysts for this reaction is associated with the particular orientation adopted by the chiral reactants within the chiral nanospace provided by the -ITV framework, similarly to what occurs with enzymes, and such preferential orientation is directly controlled by the asymmetric cavities where the reaction takes place, by the particular features of the Ge active sites in adjacent interrupted positions and by the presence of several framework OH groups in the nearby nanospace that interact with guest species. The experimental observations and the reaction mechanism proposed suggest that GTM-3 catalysts prepared from the (1S,2S) enantiomer of the N,N-ethyl-methyl-pseudoephedrinium organic agent should be enriched in the P4332 enantiomorphic space group of the -ITV framework and GTM-3 prepared from the (1R,2R) enantiomer in the antipode P4132. Interestingly, resolution of the absolute configuration of GTM-3 materials from 3D-electron diffraction data has been accomplished and confirms such an assignment, giving an average 82% enantio-enrichment in the corresponding chiral polymorph. Structure-solution of the location of the chiral structure-directing agents indicates that the transfer of chirality from the molecular component to the zeolite polymorph is governed by the development of strong H-bonds between the molecular hydroxyl group and the interrupted T(7)OH framework positions.

A Convenient Synthesis of Short α-/β-Mixed Peptides as Potential α-Amylase Inhibitors.

Over the last decades, the increased incidence of metabolic disorders, such as type two diabetes and obesity, has motivated researchers to investigate new enzyme inhibitors. Inhibition of the α-amylase enzyme is one therapeutic approach in lowering glucose levels in the blood to manage diabetes mellitus. The objective of this study was to synthesize short α-/β-mixed peptides in the solution phase. The Boc-protected α-L-leucine was converted to β-analogue by using Arndt-Eistert synthesis with the advantage of no racemization and retention of configuration. Three novel short peptides were successfully synthesized: N(Boc)-Gly-β-Leu-OCH3(14), N(Boc)-O(Bz)α-Ser-β-Leu-OCH3(16), and N(Boc)-O(Bz)-α-Tyr-α-Gly-β-Leu-OCH3(17), characterized by FTIR and 1H NMR analysis. The synthesized peptide 16 showed highest inhibitory activity (45.22%) followed by peptide 14 (18.51%) and peptide 17 (17.05%), respectively. Intriguingly, peptide 16 showed higher inhibition on α-amylase compared with other α-/β-mixed peptides.

Molecular Mechanism of Double-Displacement Retaining β-Kdo Glycosyltransferase WbbB.

Glycosyltransferases (GTs) are pivotal enzymes involved in glycosidic bond synthesis, which can lead to either retention or inversion of the glycosyl moiety's anomeric configuration. However, the catalytic mechanism for retaining GTs remains a subject of controversy. In this study, we employ MD and QM/MM metadynamics to investigate the double-displacement catalytic mechanism of the retaining β-Kdo transferase WbbB. Our findings demonstrate that the nucleophile Asp232 initiates the reaction by attacking the sugar ring containing a carboxylate at the anomeric position, forming a covalent adduct. Subsequently, the adduct undergoes a rotational rearrangement, ensuring proper orientation of the anomeric carbon for the acceptor substrate. In the second step, Glu158 acts as the catalytic base to abstract the proton of the acceptor substrate to complete the transglycosylation reaction. Notably, His265 does not function as the anticipated catalytic acid; instead, it stabilizes the phosphate group through H-bonding interactions. Our simulations support the double-displacement mechanism implicated from the crystallographic studies of WbbB. This mechanism deviates from the common SNi-type and retaining glycoside hydrolase mechanisms, thereby expanding our understanding of GT catalytic mechanisms.

Stereoinvertive SN1 Through Neighboring Group Participation.

Neighboring group participation, the assistance of non-conjugated electrons to a reaction center, is a fundamental phenomenon in chemistry. In the framework of nucleophilic substitution reactions, neighboring group participation is known to cause rate acceleration, first order kinetics (SN1), and retention of configuration. The latter phenomenon is a result of double inversion: the first one when the neighboring group displaces the leaving group, and the second when a nucleophile substitutes the neighboring group. This powerful control of stereoretention has been widely used in organic synthesis for more than a century. However, neighboring group participation may also lead to inversion of configuration, a phenomenon which is often overlooked. Herein, we review this unique mode of stereoinversion, dividing the relevant reactions into three classes with the aim to introduce a fresh perspective on the different modes of stereoinversion via neighboring group participation as well as the factors that control this stereochemical outcome.

Stereoinvertive SN1 Through Neighboring Group Participation

AbstractNeighboring group participation, the assistance of non‐conjugated electrons to a reaction center, is a fundamental phenomenon in chemistry. In the framework of nucleophilic substitution reactions, neighboring group participation is known to cause rate acceleration, first order kinetics (SN1), and retention of configuration. The latter phenomenon is a result of double inversion: the first one when the neighboring group displaces the leaving group, and the second when a nucleophile substitutes the neighboring group. This powerful control of stereoretention has been widely used in organic synthesis for more than a century. However, neighboring group participation may also lead to inversion of configuration, a phenomenon which is often overlooked. Herein, we review this unique mode of stereoinversion, dividing the relevant reactions into three classes with the aim to introduce a fresh perspective on the different modes of stereoinversion via neighboring group participation as well as the factors that control this stereochemical outcome.

Chemical Synthesis of a Densely Functionalized Aminodisaccharide from Fusobacterium nucleatum ATCC 23726 O-Antigen.

Fusobacterium nucleatum, a colorectal-cancer-associated oncomicrobe, can trigger or accelerate numerous pathologies. We report the first synthesis of a conjugation-ready disaccharide containing six amino groups from F. nucleatum ATCC 23726 O-antigen. Rare 2,3-diamido-d-glucuronic acid amide and 2-acetamido-4-amino-d-fucose were synthesized from d-glucosamine through configuration inversion, nucleophilic substitution, C6 oxidation, and C6 deoxygenation. A judicious choice of protecting groups and reaction conditions enabled the selective installation of N-acetyl, N-propanoyl, N-formyl, and carboxamido groups.

Synthesis of Quillaic Acid through Sustainable C-H Bond Activations.

To meet the demand for quillaic acid, a multigram synthesis of quillaic acid was accomplished in 14 steps, starting from oleanolic acid, leading to an overall yield of 3.4%. Key features include C-H activation at C-16 and C-23. Through Pd-catalyzed C-H acetoxylation, the oxidation at C-23 was observed as the major product, as opposed to at C-24. A copper-mediated C-H hydroxylation using O2 successfully afforded the single isomer, 16β-ol triterpenoid, followed by configuration inversion to the desired 16α-ol compound. In summary, with steps optimized and conducted on a multigram scale, quillaic acid could be feasibly acquired through C-H activation with inexpensive copper catalysts, promoting a more sustainable approach.

Editing Tetrasubstituted Carbon: Dual C-O Bond Functionalization of Tertiary Alcohols Enabled by Palladium-Based Dyotropic Rearrangement.

Many elegant asymmetric syntheses of enantioenriched tertiary alcohols have been developed, and both the transition metal-catalyzed and the radical-based peripheral functionalization of tertiary alcohols have attracted intensive research interest in recent years. However, directly editing tetrasubstituted carbons remains challenging. Herein, we report a Pd-catalyzed migratory fluoroarylation reaction that converts tertiary alcohols to α-fluorinated tertiary alkyl ethers in good to excellent yields. An unprecedented 1,2-aryl/PdIV dyotropic rearrangement along the C-O bond, integrated in a PdII-catalyzed domino process, is key to the dual functionalization of both the hydroxyl group and the tetrasubstituted carbon. This reaction, which is compatible with a broad range of functional groups, generates a tertiary alkyl fluoride and an alkyl-aryl ether functional group with inversion of the absolute configuration at the tetrasubstituted stereocenter.

Exploitation of Mechanistic Product Selectivity for the Two‐Step Synthesis of Optically Active Bio‐Derived Cyclic Carbonates Incorporating Amino Acids

AbstractThe synthesis of bio‐derived cyclic carbonates is attracting a lot of attention as the incorporation of bio‐derived functionality into these compounds provides the opportunity to prepare previously unknown structures, whilst also improving their sustainability profiles. This study presents a facile preparation of diastereomerically pure bio‐derived cyclic carbonates displaying a range of optical rotation values. These compounds are obtained from glycidol, amino acids and CO2 in a facile two‐step approach. Initially, the diastereomerically pure amino acid functionalised epoxides are prepared through a robust Steglich esterification of enantiopure glycidol (R or S) and an amino acid (D or L). Thereafter, in a second step, cycloaddition of the epoxide with CO2 results in the retention of the initial stereochemistry of the epoxide, furnishing novel diastereomerically pure and optically active cyclic carbonate products. A DFT study has explained the basis of this observed retention of configuration for these compounds. Further, results from this DFT study also provide new mechanistic information concerning a co‐catalyst‐free cycloaddition reaction starting from glycidol when using the gallium‐catalyst, which is found to operate through metal‐ligand cooperativity.

Unusual N[sbnd]H/O[sbnd]H Activation Mechanism for Au-Catalyzed N,O-Functionalization of 1,4-diyn-3-ols with N-hydroxyanilines

Au-catalyzed N,O-functionalization of 1,4-diyn-3-ols with N-hydroxyanilines provides a short and efficient approach to construct versatile pyrrole frameworks. Using DFT calculations, we systematically investigated the detailed mechanisms involved in this reaction. It was found that, the commonly asserted NH/OH activation mechanism was unfavoured due to a high energy barrier. The main reason was believed to be associated with the inversion of configuration on the sp3-hybrid C atom (generated after the H(N)-shift) which results in significant energy consumption for the subsequent H(O)-shift. Therefore, here we present a unique “1,4-elimination/1,4-syn-protodeauration” catalytic mechanism, in which (i) the charge delocalization on the carbon cation is conductive to the stability of the 1,4-elimination TS; (ii) the high exergonicity of the 1,4-elimination decreases the potential energy surface of the subsequent reaction; and (iii) the sp2-C site ensures energy-efficient retention of configuration during the 1,4-syn-protodeauration, in contrast to the energy-consuming inversion of configuration during the classical anti-protodeauration.

The Retaining Pse5Ac7Ac Pseudaminyltransferase KpsS1 Defines a Previously Unreported glycosyltransferase family (GT118).

Cell surface sugar 5,7-diacetyl pseudaminic acid (Pse5Ac7Ac) is a bacterial analogue of the ubiquitous sialic acid, Neu5Ac, and contributes to the virulence of a number of multidrug resistant bacteria, including ESKAPE pathogens Pseudomonas aeruginosa, and Acinetobacter baumannii. Despite its discovery in the surface glycans of bacteria over thirty years ago, to date no glycosyltransferase enzymes (GTs) dedicated to the synthesis of a pseudaminic acid glycosidic linkage have been unequivocally characterised in vitro. Herein we demonstrate that A. baumannii KpsS1 is a dedicated pseudaminyltransferase enzyme (PseT) which constructs a Pse5Ac7Ac-α(2,6)-Glcp linkage, and proceeds with retention of anomeric configuration. We utilise this PseT activity in tandem with the biosynthetic enzymes required for CMP-Pse5Ac7Ac assembly, in a two-pot, seven enzyme synthesis of an α-linked Pse5Ac7Ac glycoside. Due to its unique activity and protein sequence, we also assign KpsS1 as the prototypical member of a previously unreported GT family (GT118).

The Retaining Pse5Ac7Ac Pseudaminyltransferase KpsS1 Defines a Previously Unreported glycosyltransferase family (GT118)

AbstractCell surface sugar 5,7‐diacetyl pseudaminic acid (Pse5Ac7Ac) is a bacterial analogue of the ubiquitous sialic acid, Neu5Ac, and contributes to the virulence of a number of multidrug resistant bacteria, including ESKAPE pathogens Pseudomonas aeruginosa, and Acinetobacter baumannii. Despite its discovery in the surface glycans of bacteria over thirty years ago, to date no glycosyltransferase enzymes (GTs) dedicated to the synthesis of a pseudaminic acid glycosidic linkage have been unequivocally characterised in vitro. Herein we demonstrate that A. baumannii KpsS1 is a dedicated pseudaminyltransferase enzyme (PseT) which constructs a Pse5Ac7Ac‐α(2,6)‐Glcp linkage, and proceeds with retention of anomeric configuration. We utilise this PseT activity in tandem with the biosynthetic enzymes required for CMP‐Pse5Ac7Ac assembly, in a two‐pot, seven enzyme synthesis of an α‐linked Pse5Ac7Ac glycoside. Due to its unique activity and protein sequence, we also assign KpsS1 as the prototypical member of a previously unreported GT family (GT118).

Enantioselective Intramolecular ortho Photocycloaddition Reactions of 2-Acetonaphthones.

2-Acetonaphthones, which bear an alkenyl group tethered to its C1 carbon atom via an oxygen atom, were found to undergo an enantioselective intramolecular ortho photocycloaddition reaction. A chiral oxazaborolidine Lewis acid leads to a bathochromic absorption shift of the substrate and enables an efficient enantioface differentiation. Visible light irradiation (λ=450 nm) triggers the reaction which is tolerant of various groups at almost any position except carbon atom C8 (16 examples, 53-99 % yield, 80-97 % ee). Consecutive reactions were explored including a sensitized rearrangement to tetrahydrobiphenylenes, which occurred with full retention of configuration. Evidence was collected that the catalytic photocycloaddition occurs via triplet intermediates, and the binding mode of the acetonaphthone to the chiral Lewis acid was elucidated by DFT calculations.

Enantioselective Intramolecular ortho Photocycloaddition Reactions of 2‐Acetonaphthones

Abstract2‐Acetonaphthones, which bear an alkenyl group tethered to its C1 carbon atom via an oxygen atom, were found to undergo an enantioselective intramolecular ortho photocycloaddition reaction. A chiral oxazaborolidine Lewis acid leads to a bathochromic absorption shift of the substrate and enables an efficient enantioface differentiation. Visible light irradiation (λ=450 nm) triggers the reaction which is tolerant of various groups at almost any position except carbon atom C8 (16 examples, 53–99 % yield, 80–97 % ee). Consecutive reactions were explored including a sensitized rearrangement to tetrahydrobiphenylenes, which occurred with full retention of configuration. Evidence was collected that the catalytic photocycloaddition occurs via triplet intermediates, and the binding mode of the acetonaphthone to the chiral Lewis acid was elucidated by DFT calculations.