A comprehensive understanding of the mechanism of the biomimetic total synthesis of brevianamide A.

Recently, several studies on the chemical synthesis of brevianamide A (BA) were reported. In particular, a highly efficient and remarkably selective synthetic strategy was reported by Lawrence's group. However, a unified mechanistic understanding of these results is still lacking. We have carried out a DFT study and proposed a unified mechanism to understand these experimental results. Starting from intermediate 2, the most favorable reaction sequence is a fast tautomerization, followed by a σ-migration of the base moiety, and a final inverse-electron demanding Diels-Alder reaction, resulting in the formation of the BA product stereoselectively. This reaction mechanism can also be applied to understand the biosynthesis of BA that involves enzymatic catalysis.

Accurate Structure Prediction for Cyclic Peptides Containing Proline Residues with High-Temperature Molecular Dynamics.

Cyclic peptides (CPs) are emerging as promising drug candidates. Numerous natural CPs and their analogs are effective therapeutics against various diseases. Notably, many of them contain peptidyl cis-prolyl bonds. Due to the high rotational barrier of peptide bonds, conventional molecular dynamics simulations struggle to effectively sample the cis/trans-isomerization of peptide bonds. Previous studies have highlighted the high accuracy of the residue-specific force field (RSFF) and the high sampling efficiency of high-temperature molecular dynamics (high-T MD). Herein, we propose a protocol that combines high-T MD with RSFF2C and a recently developed reweighting method based on probability densities for accurate structure prediction of proline-containing CPs. Our method successfully predicted 19 out of 23 CPs with the backbone rmsd < 1.0 Å compared to X-ray structures. Furthermore, we performed high-T MD and density reweighting on the sunflower trypsin inhibitor (SFTI-1)/trypsin complex to demonstrate its applicability in studying CP-complexes containing cis-prolines. Our results show that the conformation of SFTI-1 in aqueous solution is consistent with its bound conformation, potentially facilitating its binding.

Cobalt-Catalyzed Enantioselective Reductive Arylation, Heteroarylation, and Alkenylation of Michael Acceptors via an Elementary Mechanism of 1,4-Addition.

Cobalt complexes with chiral quinox ligands effectively promote the enantioselective conjugate addition of enones using aryl, heteroaryl, and alkenyl halides and sulfonates. Additionally, a cobalt complex with a strongly donating diphosphine, BenzP*, successfully catalyzes the asymmetric reductive arylation and alkenylation of α,ß-unsaturated amides. Both catalytic systems show broad scopes and tolerance of sensitive functional groups. Both reactions can be scaled up with low loadings of cobalt catalysts. Experimental results and density functional theory (DFT) calculations suggest a new mechanism of elementary 1,4-addition of aryl cobalt(I) complexes.

Understanding the Nonlinear Hammett Relationship in Osmylation of Olefins with OsO4-Amine Ligands: Importance of Singlet-Diradical Character.

Although the concerted [3 + 2] mechanism of osmium-catalyzed asymmetric dihydroxylation has been generally accepted, the unusual nonlinear Hammett relationship induced by amine-type ligands remains unexplained. To understand this, we carried out a density functional theory (DFT) study for the osmylation of substituted styrenes by the following: OsO4, OsO4-pyridine, OsO4-4-cyanopyridine, OsO4-4-pyrrolidinopyridine, and OsO4-quinuclidine. Calculations using the M06 functional successfully reproduce the experimentally observed nonlinear relationships. The transition states exhibit considerable singlet-diradical character, which causes the nonlinear Hammett relationship. Regardless of the presence or absence of an amine-type ligand, an electron donation from styrene to OsO4 is observed, indicating no mechanistic change. Calculations indicate that the electronic interaction between the amine-type ligand and styrene also influences the reaction rate.

Catalytic glycosylation for minimally protected donors and acceptors.

Oligosaccharides have myriad functions throughout biological processes1,2. Chemical synthesis of these structurally complex molecules facilitates investigation of their functions. With a dense concentration of stereocentres and hydroxyl groups, oligosaccharide assembly through O-glycosylation requires simultaneous control of site, stereo- and chemoselectivities3,4. Chemists have traditionally relied on protecting group manipulations for this purpose5-8, adding considerable synthetic work. Here we report a glycosylation platform that enables selective coupling between unprotected or minimally protected donor and acceptor sugars, producing 1,2-cis-O-glycosides in a catalyst-controlled, site-selective manner. Radical-based activation9 of allyl glycosyl sulfones forms glycosyl bromides. A designed aminoboronic acid catalyst brings this reactive intermediate close to an acceptor through a network of non-covalent hydrogen bonding and reversible covalent B-O bonding interactions, allowing precise glycosyl transfer. The site of glycosylation can be switched with different aminoboronic acid catalysts by affecting their interaction modes with substrates. The method accommodates a wide range of sugar types, amenable to the preparation of naturally occurring sugar chains and pentasaccharides containing 11 free hydroxyls. Experimental and computational studies provide insights into the origin of selectivity outcomes.

Probability Density Reweighting of High-Temperature Molecular Dynamics.

Molecular dynamics (MD) simulation is a popular method for elucidating the structures and functions of biomolecules. However, exploring the conformational space, especially for large systems with slow transitions, often requires enhanced sampling methods. Although conducting MD at high temperatures provides a straightforward approach, resulting conformational ensembles diverge significantly from those at low temperatures. To address this discrepancy, we propose a novel probability density-based reweighting (PDR) method. PDR exhibits robust performance across four distinct systems, including a miniprotein, a cyclic peptide, a protein loop, and a protein-peptide complex. It accurately restores the conformational distributions at high temperatures to those at low temperatures. Additionally, we apply PDR to reweight previously studied high-T MD simulations of 12 protein-peptide complexes, enabling a comprehensive investigation of the conformational space of protein-peptide complexes.

Structure-Based Rational and General Strategy for Stabilizing Single-Chain T-Cell Receptors to Enhance Affinity.

The T-cell receptor (TCR) is a crucial molecule in cellular immunity. The single-chain T-cell receptor (scTCR) is a potential format in TCR therapeutics because it eliminates the possibility of αß-TCR mispairing. However, its poor stability and solubility impede the in vitro study and manufacturing of therapeutic applications. In this study, some conserved structural motifs are identified in variable domains regardless of germlines and species. Theoretical analysis helps to identify those unfavored factors and leads to a general strategy for stabilizing scTCRs by substituting residues at exact IMGT positions with beneficial propensities on the consensus sequence of germlines. Several representative scTCRs are displayed to achieve stability optimization and retain comparable binding affinities with the corresponding αß-TCRs in the range of µM to pM. These results demonstrate that our strategies for scTCR engineering are capable of providing the affinity-enhanced and specificity-retained format, which are of great value in facilitating the development of TCR-related therapeutics.

Mechanistic Insights into Sc(III)-Catalyzed Asymmetric Homologation of Ketones with Diazo Compounds: How Trans Influence Assists in Controlling Stereochemistry.

Asymmetric one-carbon homologation or ring expansion of ketones with formal insertion of carbene intermediate, is a challenging but useful strategy to construct a complex skeleton. Sc(III) and chiral ligands have been employed in this regard. However, due to flexible conformations and a variety of stereo models, the origin of stereochemistry remains ambiguous. Density functional theory (DFT) calculations were carried out to explore the interactions that control the stereoselectivity of a Sc(III)-catalyzed asymmetric homologation. The trans influence of counterions was found to affect the coordination mode of ketone to Sc(III), and consequently affect the stereoselectivity.

Mild Stereoselective Synthesis of Densely Substituted [3]Dendralenes via Ru-Catalyzed Intermolecular Dimerization of 1,1-Disubstituted Allenes.

Described here is a mild and stereoselective protocol for the synthesis of [3]dendralenes via the intermolecular dimerization of allenes. With the proper choice of a ruthenium catalyst, a range of unactivated 1,1-disubstituted allenes, without prefunctionalization in the allylic position, reacted efficiently to provide rapid access to densely substituted [3]dendralenes. An intermolecular C-C bond and three different types of C═C double bonds (di-, tri-, and tetrasubstituted) embedded in an acyclic structure were constructed with good to high E/Z stereocontrol. This is in contrast to the known catalytic protocols that focus on allenes with prefunctionalization at the allylic position and/or monosubstituted allenes, which would proceed by a different mechanism or require less stereocontrol. The silyl-substituted dendralene products are precursors of other useful dendralene molecules. Density functional theory (DFT) studies and control experiments supported a mechanism involving oxidative cyclometalation, ß-H elimination (the rate-determining step), and reductive elimination.

New Insights into the Cooperativity and Dynamics of Dimeric Enzymes.

A survey of protein databases indicates that the majority of enzymes exist in oligomeric forms, with about half of those found in the UniProt database being homodimeric. Understanding why many enzymes are in their dimeric form is imperative. Recent developments in experimental and computational techniques have allowed for a deeper comprehension of the cooperative interactions between the subunits of dimeric enzymes. This review aims to succinctly summarize these recent advancements by providing an overview of experimental and theoretical methods, as well as an understanding of cooperativity in substrate binding and the molecular mechanisms of cooperative catalysis within homodimeric enzymes. Focus is set upon the beneficial effects of dimerization and cooperative catalysis. These advancements not only provide essential case studies and theoretical support for comprehending dimeric enzyme catalysis but also serve as a foundation for designing highly efficient catalysts, such as dimeric organic catalysts. Moreover, these developments have significant implications for drug design, as exemplified by Paxlovid, which was designed for the homodimeric main protease of SARS-CoV-2.

Cobalt-Catalyzed Enantioselective Cross-Electrophile Couplings: Stereoselective Syntheses of 5-7-Membered Azacycles.

Cobalt complexes of chiral pyrox ligands catalyzed enantioselective reductive couplings of nonconjugated iododienes with aryl iodides or alkenyl bromides. The reaction enabled stereoselective syntheses of 5-7-membered azacycles carrying quaternary stereocenters. Mechanistically, cross-electrophile selectivity originated from selective coupling of alkylcobalt(I) complexes generated after cyclization with aryl iodides.

Propeptide-Mediated Allosteric Regulation of Xylanase Xyl-1: An Integrated Experimental and Computational Analysis.

Most GH11 family endo-ß-1,4-xylanases contain a propeptide region linked to the N-terminal region. The mechanistic basis of this region harboring key regulation information for enzyme function, however, remains poorly understood. We reported an investigation on the allosteric regulation mechanism of the propeptide based on biochemical characterization, molecular dynamics simulations, and evolutionary analysis. We discovered that the mutant of truncated propeptide shows a remarkably increased thermal stability (melting temperature increased by 11.5 °C) and catalytic efficiency (1.7-fold kcat/Km value of wild type). Molecular dynamics simulations reveal that long-range fluctuations in the propeptide lead to a conformational perturbation in the catalytic pocket and the thumb region. The probability of sampling the active conformation during the glycosylation step is reduced (i.e., catalytic efficiency). In-depth sequence analysis indicates that the propeptide has a strong plasticity and degeneration trend, and propeptide truncation experiments of the homologous enzyme XynB validated the feasibility of the truncation strategy. This work reveals the role of GH11 family propeptides in functional regulation and provides a straightforward and practical method to increase the robustness of GH11 family xylanases.

Direct Amination of α-Triaryl Alcohols via Vanadium Catalysis.

α-Triaryl amines have been used as pharmaceuticals and pharmaceutical intermediates for antifungal and anticancer applications. Current methods to synthesize such compounds require at least two steps, and no direct amination of tertiary alcohols has been reported. Herein, we disclose efficient catalytic conditions for the direct amination of α-triaryl alcohols to access α-triaryl amines. VO(OiPr)3, a commercially available reagent, has been identified as an effective catalyst for the direct amination of several α-triaryl alcohols. This process is scalable, as demonstrated by a gram-scale synthesis, and the reaction still works at as low as a 0.01 mol % catalyst loading with the turnover number reaching 3900. Moreover, commercial pharmaceuticals including clotrimazole and flutrimazole have been successfully prepared rapidly and efficiently using this newly developed method.

Nickel-Catalyzed Enantioselective Reductive Arylation and Heteroarylation of Aldimines via an Elementary 1,4-Addition.

Nickel catalysts of chiral pyrox ligands promoted enantioselective reductive arylation and heteroarylation of aldimines, using directly (hetero)aryl halides and sulfonates. The catalytic arylation can also be conducted with crude aldimines generated from condensation of aldehydes and azaaryl amines. Mechanistically, density functional theory (DFT) calculations and experiments pointed to an elementary step of 1,4-addition of aryl nickel(I) complexes to N-azaaryl aldimines.

Inverse Electron-Demanding Diels-Alder Reactions in the Chemical Synthesis of Prenylated Indole Alkaloids Containing a Bicycle[2.2.2]diazaoctane Moiety: A Theoretical Study.

The Diels-Alder reaction is believed to be a key step in the biosynthesis of prenylated indole alkaloids containing a bicycle[2.2.2]diazaoctane moiety. Many chemical syntheses of bicyclic structures by Diels-Alder reactions have been reported, but the reaction mechanism remains underexplored. We have carried out DFT calculations on both acid- and base-promoted Diels-Alder reactions in these syntheses and reveal that the reactions occur through an inverse-electron demand mechanism. We hope that the new mechanism is helpful for the mechanistic understanding of the biosynthesis of this class of important natural products.

Enantioselective anti-Dihalogenation of Electron-Deficient Olefin: A Triplet Halo-Radical Pylon Intermediate.

The textbook alkene halogenation reaction establishes straightforward access to vicinal dihaloalkanes. However, a robust catalytic method for dihalogenizing electron-deficient olefins in an enantioselective manner is still under development, and its mechanism remains controversial. Herein, we disclose efficient regio-, anti-diastereo-, and enantioselective dibromination, bromochlorination, and dichlorination reactions of enones catalyzed by a chiral N,N'-dioxide/Yb(OTf)3 complex. With the combination of electrophilic halogen and halide salts as halogenating agents, an array of homo- and heterodihalogenated derivatives is achieved in moderate to good enantioselectivities. Moreover, DFT calculations reveal that a novel triplet halo-radical pylon intermediate is probable in accounting for the exclusive regio- and anti-diastereoselectivity.

Ir-Catalyzed Regioselective Dihydroboration of Thioalkynes toward Gem-Diboryl Thioethers.

While 1,1-diboryl (gem-diboryl) compounds are valuable synthetic building blocks, currently, related studies have mainly focused on those 1,1-diboryl alkanes without a hetero functional group in the α-position. gem-Diboryl compounds with an α-hetero substituent, though highly versatile, have been limitedly accessible and thus rarely utilized. Herein, we have developed the first α-dihydroboration of heteroalkynes leading to the efficient construction of gem-diboryl, hetero-, and tetra-substituted carbon centers. This straightforward, practical, mild, and atom-economic reaction is an attractive complement to the conventional multistep synthetic strategy relying on deprotonation of gem-diborylmethane by a strong base. Specifically, [Ir(cod)(OMe)]2 was found to be uniquely effective for this process of thioalkynes, leading to excellent α-regioselectivity when delivering the two boryl groups, which is remarkable in view of the many competitive paths including monohydroboration, 1,2-dihydroboration, dehydrodiboration, triboration, tetraboration, etc. Control experiments combined with DFT calculations suggested that this process involves two sequential hydroboration events. The second hydroboration requires a higher energy barrier due to severe steric repulsion in generating the highly congested α-sulfenyl gem-diboryl carbon center, a structural motif that was almost unknown before.

Selective Formal Carbene Insertion into Carbon-Boron Bonds of Diboronates by N-Trisylhydrazones.

Bisborylalkanes play important roles in organic synthesis as versatile bifunctional reagents. The two boron moieties in these compounds can be selectively converted into other functional groups through cross-coupling, oxidation or radical reactions. Thus, the development of efficient methods for synthesizing bisborylalkanes is highly demanded. Herein we report a new strategy to access bisborylalkanes through the reaction of N-trisylhydrazones with diboronate, in which the bis(boryl) methane is transformed into 1,2-bis(boronates) via formal carbene insertion. Since the N-trisylhydrazones can be readily derived from the corresponding aldehydes, this strategy represents a practical synthesis of 1,2-diboronates with broad substrate scope. Mechanistic studies reveal an unusual neighboring group effect of 1,1-bis(boronates), which accounts for the observed regioselectivity when unsymmetric 1,1-diboronates are applied.

Enantioselective Double Carbonylation Enabled by High-Valent Palladium Catalysis.

Palladium-catalyzed carbonylation reactions are efficient methods for synthesizing valuable molecules. However, realizing a carbonylation with excellent yield and chemo-, regio-, and enantioselectivities by classical low-valent palladium catalysis is highly challenging. Herein, we describe an enantioselective carbonylation reaction using a high-valent palladium catalysis strategy and employing a chiral sulfoxide phosphine (SOP) ligand. This double aminocarbonylation reaction begins with the formation of a carbamoylpalladium(II) species, which undergoes enantioselective oxidative addition with a cyclic diaryliodonium salt to generate a palladium(IV) intermediate, followed by a second CO insertion and reductive elimination. The mechanism has been illustrated with experimental and computational studies.

Breaking Conventional Site Selectivity in C-H Bond Activation: Selective sp3 versus sp2 Silylation by a Pincer-Based Pocket.

A deeply ingrained assumption in the conventional understanding and practice of organometallic chemistry is that an unactivated aliphatic C(sp3)-H bond is less reactive than an aromatic C(sp2)-H bond within the same molecule given that they are at positions unbiasedly accessible for activation. Herein, we demonstrate that a pincer-ligated iridium complex catalyzes intramolecular dehydrogenative silylation of the unactivated δ-C(sp3)-H (δ to the Si atom) with exclusive site selectivity over typically more reactive ortho δ-C(sp2)-H bonds. A variety of tertiary hydrosilanes undergo δ-C(sp3)-H silylation to form 5-membered silolanes, including chiral silolanes, which can undergo further oxidation to produce enantiopure ß-aryl-substituted 1,4-diols. Combined computational and experimental studies reveal that the silylation occurs via the Si-H addition to a 14-electron Ir(I) fragment to give an Ir(III) silyl hydride complex, which then activates the C(sp3)-H bond to form a 7-coordinate, 18-electron Ir(V) dihydride silyl intermediate, followed by sequential reductive elimination of H2 and silolane. The unprecedented site selectivity is governed by the distortion energy difference between the rate-determining δ-C(sp3)-H and δ-C(sp2)-H activation, although the activation at sp2 sites is much more favorable than sp3 sites by the interaction energy.