Ion Hydration Enables Generality in Asymmetric Catalysis: Desymmetrization to P-Stereogenic Triarylphosphine Derivatives.

Asymmetric synthesis relies on seamless transmission of stereochemical information from a chiral reagent/catalyst to a prochiral substrate. The disruption by substrates' structural changes presents a hurdle in innovating generality-oriented asymmetric catalysis. Here, we report a strategy for substrate adaptability by exploiting a fundamental physicochemical phenomenon-ion hydration, in developing remote desymmetrization to access P-stereogenic triarylphosphine oxides and sulfides.

Metallaphotocatalytic triple couplings for modular synthesis of elaborate N-trifluoroalkyl anilines.

The integration of trifluoromethyl groups and three-dimensional quaternary carbon moieties into organic molecules has emerged as a prominent strategy in medicinal chemistry to augment drug efficacy. Although trifluoromethyl (hetero)aromatic amines and derivatives are prevalent frameworks in pharmaceuticals, the development of trifluoromethyl-embedded, intricately structured alkyl amine scaffolds for medicinal research remains a significant challenge. Herein, we present a metallaphotoredox multicomponent amination strategy employing 3,3,3-trifluoropropene, nitroarenes, tertiary alkylamines, and carboxylic acids.

One-Pot Telescoping -Transfer and Trifluoromethylation for the Synthesis of 2-CFS-Imidazoles with -Oxides as Convenient Precursors.

Readily available 2-unsubstituted imidazole -oxides were examined as starting materials for the preparation of fully substituted 1,4,5-aryl/alkyl 2-trifluoromethylsulfanyl-imidazoles. Whereas activation of the -oxide function followed by attempted nucleophilic addition of the SCF was in vain, the alternative approach involving "sulfur transfer reaction" and subsequent electrophilic trifluoromethylation with Togni reagent provided target products in high yield via a one-pot procedure. The structure of representative enantiomerically pure imidazol-2-yl trifluoromethyl sulfide was confirmed by X-ray analysis.

Modular alkene synthesis from carboxylic acids, alcohols and alkanes via integrated photocatalysis.

Alkenes serve as versatile building blocks in diverse organic transformations. Despite notable advancements in olefination methods, a general strategy for the direct conversion of carboxylic acids, alcohols and alkanes into alkenes remains a formidable challenge owing to their inherent reactivity disparities. Here we demonstrate an integrated photochemical strategy that facilitates a one-pot conversion of these fundamental building blocks into alkenes through a sequential C(sp)-C(sp) bond formation-fragmentation process, utilizing an easily accessible and recyclable phenyl vinyl ketone as the 'olefination reagent'.

The Synthesis and Properties of Spirophenanthrene.

Motivated by the success of 9,9'-spirobifluorene () in optoelectronic materials, we synthesized a novel spiro compound, spirophenanthrene (). Incorporating a phenanthrene unit as the core, we aimed to leverage the π-conjugation of to surpass the limitations of . Experimental and theoretical studies revealed significant advantages over , including red-shifted wavelengths, tunable LUMO energy levels, and enhanced thermal stability.

Computation-Guided Discovery of Diazole Monosubstituted Tetrazines as Optimal Bioorthogonal Tools.

Monosubstituted tetrazines are important bioorthogonal reactive tools due to their rapid ligation with -cyclooctene. However, their application is limited by the reactivity-stability paradox in biological environments. In this study, we demonstrated that steric effects are crucial in resolving this paradox through theoretical methods and developed a simple synthetic route to validate our computational findings, leading to the discovery of 1,3-azole-4-yl and 1,2-azole-3-yl monosubstituted tetrazines as superior bioorthogonal tools.

Selective Chiral Interactions between Hydrophilic/Hydrophobic Amino Acids and Growing Gypsum Crystals.

In nature, selective interactions between chiral amino acids and crystals are important for the formation of chiral biominerals and provide insight into the mysterious origin of homochirality. Here, we show that chiral amino acids with different hydrophilicities/hydrophobicities exhibit different chiral selectivity preferences in the dynamically growing gypsum [001] steps. Hydrophilic amino acids show a chiral selectivity preference for their d-isomers, whereas hydrophobic amino acids prefer their l-isomers.

Chemoenzymatic Synthesis of Fluorinated Mycocyclosin Enabled by the Engineered Cytochrome P450-Catalyzed Biaryl Coupling Reaction.

Installing fluorine atoms onto natural products holds great promise for the generation of fluorinated molecules with improved or novel pharmacological properties. The enzymatic oxidative carbon-carbon coupling reaction represents a straightforward strategy for synthesizing biaryl architectures, but the exploration of this method for producing fluorine-substituted derivatives of natural products remains elusive. Here, in this study, we report the protein engineering of cytochrome P450 from (CYP121) for the construction of a series of new-to-nature fluorine-substituted Mycocyclosin derivatives.

Photocatalyzed Cascade Hydrogen Atom Transfers for Assembly of Multi-Substituted α-SCF and α-SCFH Cyclopentanones.

A photocatalyzed formal (3+2) cycloaddition has been developed to construct original polysubstituted α-SCF cyclopentanones in a regio- and diastereoselective manner. This building block approach leverages trifluoromethylthio alkynes and branched/linear aldehydes, as readily available reaction partners, in consecutive hydrogen atom transfers and C-C bond formations. Difluoromethylthio alkynes are also compatible substrates.

Computational insights into the binding modes, keto-enol tautomerization and stereo-electronically controlled decarboxylation of oxaloacetate in the active site of macrophomate synthase.

Oxaloacetic acid (OAA) is a β-ketocarboxylic acid, which plays an important role as an intermediate in some metabolic pathways, including the tricarboxylic acid cycle, gluconeogenesis and fatty acid biosynthesis. Animal studies have indicated that supplementing oxaloacetic acid shows an increase of lifespan and other substantial health benefits including mitochondrial DNA protection, and protection of retinal, neural and pancreatic tissues. Most of the chemical transformations of OAA in the metabolic pathways have been extensively studied; however, the understanding of decarboxylation of OAA at the atomic level is relatively lacking.

Electron Donor-Acceptor Complex Enabled Radical Cyclization of α-Diazodifluoroethyl Sulfonium Salt with Unactivated Alkynes.

An α-diazodifluoroethane sulfonium reagent was developed in this study to undergo [3 + 2] radical cyclization with unactivated alkynes to give the corresponding 3-difluoromethyl pyrazoles under blue light irradiation conditions. The key to the success of this transformation lies in the formation of an electron donor-acceptor (EDA) complex between an electron-deficient α-diazo sulfonium salt and an electron-rich triaryl amine. This study circumvents a major substrate scope limitation in polar cycloaddition reactions of existent diazodifluoroethane reagents.

Programmable synthesis of difluorinated hydrocarbons from alkenes through a photocatalytic linchpin strategy.

The introduction of difluoromethylene moieties into organic molecules has garnered significant attention due to their profound influence on the physicochemical and biological properties of compounds. Nonetheless, the existing approaches for accessing difluoroalkanes from readily available feedstock chemicals remain limited. In this study, we present an efficient and modular protocol for the synthesis of difluorinated compounds from alkenes, employing the readily accessible reagent, ClCFSONa, as a versatile "difluoromethylene" linchpin.

Copper-Catalyzed Regio- and Enantioselective Hydroboration of Difluoroalkyl-Substituted Internal Alkenes.

Catalytic asymmetric hydroboration of fluoroalkyl-substituted alkenes is a straightforward approach to access chiral small molecules possessing both fluorine and boron atoms. However, enantioselective hydroboration of fluoroalkyl-substituted alkenes without fluorine elimination has been a long-standing challenge in this field. Herein, a copper-catalyzed hydroboration of difluoroalkyl-substituted internal alkenes with high levels of regio- and enantioselectivities is reported.

Synthesis of di/trifluoromethyl cyclopropane-dicarbonitriles [2+1] annulation of fluoro-based diazoethanes with (alkylidene)malononitriles.

Herein, we describe a [2+1] annulation reaction of di/trifluorodiazoethane with (alkylidene)malononitriles. This protocol offers a streamlined synthesis of a wide range of stereospecific and densely functionalized difluoromethyl and trifluoromethyl cyclopropane-1,1-dicarbonitriles. Further functional group interconversions or skeletal elaborations afford structurally distinct cyclopropyl variants.

Selective Chiral Recognition between Amino Acids and Growing Gypsum Crystals.

In nature, selective chiral interactions between biomolecules and minerals provide insight into the mysterious origin of homochirality. Here, we show growing gypsum crystals in a nonequilibrium state can recognize chiral enantiomers of amino acids. The chiral selection for amino acids with different functional groups by growing minerals are distinct.

Constructing Photoactivatable Protein with Genetically Encoded Photocaged Glutamic Acid.

Genetically replacing an essential residue with the corresponding photocaged analogues via genetic code expansion (GCE) constitutes a useful and unique strategy to directly and effectively generate photoactivatable proteins. However, the application of this strategy is severely hampered by the limited number of encoded photocaged proteinogenic amino acids. Herein, we report the genetic incorporation of photocaged glutamic acid analogues in E.

One-Pot Synthesis of 1-Aryl-3-trifluoromethylpyrazoles Using Nitrile Imines and Mercaptoacetaldehyde As a Surrogate of Acetylene.

A synthetically useful approach for one-pot preparation of 1-aryl-3-trifluoromethylpyrazoles using in situ generated nitrile imines and mercaptoacetaldehyde applied as 1 equiv of acetylene is presented. This protocol comprises (3 + 3)-annulation of the mentioned reagents to form 5,6-dihydro-5-hydroxy-4-1,3,4-thiadiazine, followed by cascade dehydration/ring contraction reactions with -TsCl. In addition, representative nonfluorinated analogues functionalized with Ph, Ac, and COEt groups at the C(3)-position of the pyrazole ring were also prepared by the devised method.

Regioselective [3 + 2] cycloaddition of di/trifluoromethylated hydrazonoyl chlorides with fluorinated nitroalkenes: a facile access to 3-di/trifluoroalkyl-5-fluoropyrazoles.

Herein we describe the base-mediated [3 + 2] cycloaddition reaction of di/trifluoromethylated hydrazonoyl chlorides with fluorinated nitroalkenes. The reaction protocol provides a direct and facile strategy for the dual incorporation of a fluorine atom and fluoroalkyl group into pyrazole cores, thus allowing rapid access to a wide variety of densely functionalized 3-di/trifluoroalkyl-5-fluoropyrazoles in generally high yields with excellent regioselectivities. Furthermore, several drug-like 3-di/trifluoroalkyl-5-fluoropyrazoles have been synthesized, demonstrating potent inhibitory activities against cyclooxygenase 2 (COX-2).

Tetrazole Diversification of Amino Acids and Peptides via Silver-Catalyzed Intermolecular Cycloaddition with Aryldiazonium Salts.

Selective structural modification of amino acids and peptides is a central strategy in organic chemistry, chemical biology but also in pharmacology and material science. In this context, the formation of tetrazole rings, known to possess significant therapeutic properties, would expand the chemical space of unnatural amino acids but has received less attention. In this study, we demonstrated that the classic unimolecular Wolff rearrangement of α-amino acid-derived diazoketones could be replaced by a faster intermolecular cycloaddition reaction with aryldiazonium salts under identical practical conditions.

Highly Enantio- and Diastereoselective Hydrogenation of Cyclic Tetra-Substituted β-Enamido Phosphorus Derivatives.

Catalytic asymmetric hydrogenation of enamido phosphorus derivatives is one of the most efficient methods for the construction of chiral amino phosphorus products, among which the congested tetra-substituted substrates remains an unaddressed challenge. In this study, we utilize a commercially available Rh-Josiphos system for the efficient and stereoselective hydrogenation of a wide set of tetra-substituted cyclic β-enamido phosphonates/phosphine oxides, thus enabling access to chiral β-amino phosphorus compounds featuring two vicinal stereocenters. This protocol was broadly applicable to different ring systems possessing various phosphonate/phosphine oxide groups and further applied in the preparation of amino-phosphine ligands.

Photoinduced Defluorinative Branch-Selective Olefination of Multifluoro (Hetero)arenes.

We report a photoredox platform for constructing styrenyl polyfluoro (hetero)arenes with branch selectivity by taking advantage of sulfinate as both a radical-relay precursor and a sacrificial nucleofuge. This protocol merges photoredox catalysis with radical-radical coupling and an elimination process in a one-pot operation and features good functional group tolerance, mild conditions, and a facile method to access polyfluoro (hetero)aryl derivatives of natural products and drugs.

Rational enzyme design for enabling biocatalytic Baldwin cyclization and asymmetric synthesis of chiral heterocycles.

Chiral heterocyclic compounds are needed for important medicinal applications. We report an in silico strategy for the biocatalytic synthesis of chiral N- and O-heterocycles via Baldwin cyclization modes of hydroxy- and amino-substituted epoxides and oxetanes using the limonene epoxide hydrolase from Rhodococcus erythropolis. This enzyme normally catalyzes hydrolysis with formation of vicinal diols.

Amphiphilic Polyfluorinated Amino Ethers from Cyclic Sulfamidates.

Regioselective ring opening of cyclic sulfamidates was achieved by means of nucleophilic polyfluorinated alkoxides to access achiral and chiral β- and γ-OR amines and α-amino esters. Subsequent transformations provide free amines ready for incorporation into bioactive substances through amide bond formation or nucleophilic aromatic substitution.

Expanding the Scope of Genetically Encoded Lysine Post-Translational Modifications with Lactylation, β-Hydroxybutyrylation and Lipoylation.

Post-translational modifications (PTMs) occurring on lysine residues, especially diverse forms of acylations, have seen rapid growth over the past two decades. Among them, lactylation and β-hydroxybutyrylation of lysine side-chains are newly identified histone marks and their implications in physiology and diseases have aroused broad research interest. Meanwhile, lysine lipoylation is highly conserved in diverse organisms and well known for its pivotal role in central metabolic pathways.