The design of enzymes with complex active sites that mediate multistep reactions remains an outstanding challenge. With serine hydrolases as a model system, we combined the generative capabilities of RFdiffusion with an ensemble generation method for assessing active site preorganization to design enzymes starting from minimal active site descriptions. Experimental characterization revealed catalytic efficiencies (/) up to 2.
View Article and Find Full Text PDFThe development of new synthetic methodologies are instrumental for enabling the discovery of new medicines. Those methods that provide efficient access to structural alternatives for aromatic compounds (i.e.
View Article and Find Full Text PDFWhile it is well established that half-sandwich Ru(II) complexes possess metal-centered chirality, effective strategies to leverage their metal-centered chirality toward asymmetric synthesis have been challenging due to the configurational lability of the metal stereocenters. The metal-centered chirality is typically mediated by enantiopure ligands, which occupy a relatively narrow chemical space compared to their achiral counterparts. We demonstrate that achiral ligands can be used to access chiral-at-ruthenium half-sandwich complexes with exceptionally high configurational stability.
View Article and Find Full Text PDFWhile enantioenriched alcohols are highly significant in medicinal chemistry, total synthesis, and materials science, the stereoselective synthesis of tertiary alcohols with two adjacent stereocenters remains a formidable challenge. In this study, we present a dual catalysis approach utilizing photoredox and nickel catalysts to enable the unprecedented chemoselective functionalization of tertiary allylic C-H bonds in allyl ethers instead of cleaving the C-O bond. The resulting allyl-Ni intermediates can undergo coupling with various aldehydes, facilitating a novel enantioconvergent approach to access extensively functionalized homoallylic sec,tert-vicinal diols frameworks.
View Article and Find Full Text PDF-Aryl ketenimines have been established as highly reactive aza-dienophiles. Intermolecular cycloadditions are achieved upon heating in the presence of 2,5-bis(silyloxy)furans and proceed with high levels of peri-, regio-, chemo- and diastereo-selectivity. Spontaneous C-O cleavage yields oxygenated pyridone derivatives in a highly convergent and redox-neutral manner.
View Article and Find Full Text PDFElectron transfer (ET) is crucial in many chemical reactions, but its mechanism and role are hardly understood in nanobiotechnology due to the complexity of reaction species and pathways involved. By modulating and monitoring electron behavior at the single-molecule level, we can better understand the fundamental mechanisms and ways to control them for technological use. Here, we unravel a mechanism of single-electron catalysis under positively charged nanoconfinement.
View Article and Find Full Text PDFMetal-mediated cysteine -arylation is an emerging bioconjugation technique due to its high chemoselectivity, rapid kinetics, and aqueous compatibility. We have previously demonstrated that by altering the steric profile of the ligand and aryl groups of an Au(iii) oxidative addition complex, one can modulate the kinetics of the bimolecular coordination and induce rate constants up to 16 600 M s. To further enhance the rate of coordination, density functional theory (DFT) calculations were performed to investigate the steric properties of the ,-ligated Au(iii) oxidative addition complex as well as the thermodynamics of the -arylation reaction.
View Article and Find Full Text PDFConformational isomerism determines the performance of materials and the activity of biomolecules. However, a complete dynamic study of conformational isomerization is still a formidable challenge at the single-molecule level. In this work, we present real-time in situ electrical monitoring of the full rotation dynamics of a single aromatic chain covalently embedded in graphene electrodes with single-event resolution.
View Article and Find Full Text PDFGroup 13 aminoxy complexes of the form (L)E(TEMPO) (TEMPO = 2,2,6,6-tetramethylpiperidine 1-oxyl; L = THF (tetrahydrofuran) or Py (pyridine); E = Al, Ga, In) were prepared and structurally characterized. The complexes (THF)Ga(TEMPO) (1·THF) and (Py)In(TEMPO) (2·Py) are shown to heterolytically cleave H under mild conditions (3 atm, 20 °C, ≤ 1 h). 1·THF reacts reversibly with H to form a formal H-adduct that bears a Ga(iii) hydride site and a protonated TEMPO ligand with concomitant loss of THF, consistent with Ga(iii) and TEMPO functioning as Lewis acid and base, respectively.
View Article and Find Full Text PDFCarbon-hydrogen (C-H) bonds are the foundation of essentially every organic molecule, making them an ideal place to do chemical synthesis. The key challenge is achieving selectivity for one particular C(sp)-H bond. In recent years, metalloenzymes have been found to perform C(sp)-H bond functionalization.
View Article and Find Full Text PDFDue to the diverse chemical and physical properties of functional groups, mild and controllable ligation methods are often required to construct complex drugs and functional materials. To make diverse sets of products with tunable physicochemical properties, it is also useful to employ complimentary ligation methods that adopt the same starting materials. Here, we disclose the efficient and modular synthesis of amides or thioamides through the chemical ligation of acylsilanes with amines, simply by turning a light on or off.
View Article and Find Full Text PDFOxidant-free Au(I)/Au(III)-catalyzed cross-coupling has been recently enabled by the use of bidentate ,-ligands. To further develop these ,-ligands, computational studies were performed to understand their effects on the oxidative addition of aryl iodide electrophiles with Au(I). Using this mechanistic understanding, six new electron-rich ,-ligands were synthesized.
View Article and Find Full Text PDFThe mechanism of the dirhodium-catalyzed combined C-H functionalization/Cope rearrangement (CH/Cope) reaction discovered by the Davies group has been investigated with density functional theory (DFT) calculations and quasi-classical molecular dynamics (MD) simulations. Computations from the Davies group previously showed that there is a post-transition state bifurcation leading to a direct CH reaction and also to the CH/Cope product. While this work was in preparation, the Tantillo group and the Ess group independently reported quantum mechanical and molecular dynamics studies on the dirhodium-tetracarboxylate-catalyzed diazoester CH/Cope and CH insertion reactions with 1,3-cyclohexadiene and 1,4-cyclohexadiene, respectively.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
January 2025
Cyclobutanes are prominent structural components in natural products and drug molecules. With the advent of strain-release-driven synthesis, ring-opening reactions of bicyclo[1.1.
View Article and Find Full Text PDFOlefin metathesis, as a powerful metal-catalysed carbon-carbon bond-forming method, has achieved considerable progress in recent years. However, the complexity originating from multicomponent interactions has long impeded a complete mechanistic understanding of olefin metathesis, which hampers further optimization of the reaction. Here, we clarify both productive and hidden degenerate pathways of ring-closing metathesis by focusing on one individual catalyst, using a sensitive single-molecule electrical detection platform.
View Article and Find Full Text PDFThe π-bonds in unsaturated organic molecules are typically associated with having well-defined geometries that are conserved across diverse structural contexts. Nonetheless, these geometries can be distorted, leading to heightened reactivity of the π-bond. Although π-bond-containing compounds with bent geometries are well utilized in synthetic chemistry, the corresponding leveraging of π-bond-containing compounds that display twisting or pyramidalization remains underdeveloped.
View Article and Find Full Text PDFThe chemiluminescent light-emission pathway of phenoxy-1,2-dioxetane luminophores is increasingly attracting the scientific community's attention. Dioxetane probes that undergo rapid, flash-type chemiexcitation demonstrate higher detection sensitivity than those with a slower, glow-type chemiexcitation rate. This is primarily because the rapid flash-type produces a greater number of photons within a given time.
View Article and Find Full Text PDFHistone serotonylation has emerged as a key post-translational modification. WDR5 preferentially binds to serotonylated histone 3 (H3), and this binding event has been associated with tumorigenesis. Herein, we utilize genetic code expansion, structure-activity relationship studies, and computation to study an edge-face aromatic interaction between WDR5 Phe149 and serotonin on H3 that is key to this protein-protein interaction.
View Article and Find Full Text PDFNitriles are uncommon in nature and are typically constructed from oximes through the oxidative decarboxylation of amino acid substrates or from the derivatization of carboxylic acids. Here we report a third nitrile biosynthesis strategy featuring the cyanobacterial nitrile synthase AetD. During the biosynthesis of the eagle-killing neurotoxin, aetokthonotoxin, AetD transforms the 2-aminopropionate portion of 5,7-dibromo-L-tryptophan to a nitrile.
View Article and Find Full Text PDFEnzymes that proceed through multistep reaction mechanisms often utilize complex, polar active sites positioned with sub-angstrom precision to mediate distinct chemical steps, which makes their de novo construction extremely challenging. We sought to overcome this challenge using the classic catalytic triad and oxyanion hole of serine hydrolases as a model system. We used RFdiffusion to generate proteins housing catalytic sites of increasing complexity and varying geometry, and a newly developed ensemble generation method called ChemNet to assess active site geometry and preorganization at each step of the reaction.
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