Site-selective Functionalization Research Articles

Site-Selective Functionalization of Outer Surface and Different Inner Spaces of Nanoscale Hierarchically Mesoporous MOFs for the Specific Detection of Cancer Cells

Site-Selective Functionalization of Outer Surface and Different Inner Spaces of Nanoscale Hierarchically Mesoporous MOFs for the Specific Detection of Cancer Cells

Nanoparticles that Distinguish Chemical and Supramolecular Contexts of Lysine for Single-Site Functionalization of Protein.

Lysine is one of the most abundant residues on the surface of proteins and its site-selective functionalization is extremely challenging. The existing methods of functionalization rely on differential reactivities of lysine on a protein, making it impossible to label less reactive lysines selectively. We here report polymeric nanoparticles that mimic enzymes involved in the posttranslational modifications of proteins that distinguish the chemical and supramolecular contexts of a lysine and deliver the labeling reagent precisely to its ε amino group. The nanoparticles are prepared through molecular imprinting of cross-linkable surfactant micelles, plus an in situ, on-micelle derivatization of the peptide template prior to the imprinting. The procedures encode the polymeric nanoparticles with all the supramolecular information needed for sequence identification and precise labeling, allowing single-site functionalization of a predetermined lysine on the target protein in a mixture.

Site-Selective Radical Aromatic C-H Functionalization of Alloxazine and Flavin through Ground-State Single Electron Transfer.

Flavins and their alloxazine isomers are key chemical scaffolds for bioinspired electron transfer strategies. Their properties can be fine-tuned by functional groups, which must be introduced at an early stage of the synthesis as their aromatic ring is inert towards post-functionalization. We show that the introduction of a remote metal-binding redox site on alloxazine and flavin activates their aromatic ring towards direct C-H functionalization. Mechanistic studies are consistent with a synthetic sequence involving ground-state single electron transfer (SET) with an electrophilic source followed by radical-radical coupling. This unprecedented reactivity opens new opportunities in molecular editing of flavins by direct aromatic post-functionalization and the utility of the method is demonstrated with the site-selective C6 functionalization of alloxazine and flavin with a CF3 group, Br or Cl, that can be further elaborated into OH and aryl for chemical diversification.

Mechanistic Approach Toward the C4-Selective Amination of Pyridines via Nucleophilic Substitution of Hydrogen.

The development of site-selective functionalization of N-heteroarenes is highly desirable in streamlined synthesis. In this context, direct amination of pyridines stands as an important synthetic methodology, with particular emphasis on accessing 4-aminopyridines, a versatile pharmacophore in medicinal chemistry. Herein, we report a reaction manifold for the C4-selective amination of pyridines by employing nucleophilic substitution of hydrogen (SNH). Through 4-pyridyl pyridinium salt intermediates, 4-aminopyridine products are obtained in reaction with aqueous ammonia without intermediate isolation. The notable regioselectivity was achieved by the electronic tuning of the external pyridine reagents along with the maximization of polarizability in the proton elimination stage. Further mechanistic investigations provided a guiding principle for the selective C-H pyridination of additional N-heteroarenes, presenting a strategic avenue for installation of diverse functional groups.

Palladium-Catalyzed C(sp2)–H Activation for Site-Selective Functionalization of Peptides

Palladium-Catalyzed C(sp2)–H Activation for Site-Selective Functionalization of Peptides

Selenium chemistry for spatio-selective peptide and protein functionalization.

The ability to construct a peptide or protein in a spatio-specific manner is of great interest for therapeutic and biochemical research. However, the various functional groups present in peptide sequences and the need to perform chemistry under mild and aqueous conditions make selective protein functionalization one of the greatest synthetic challenges. The fascinating paradox of selenium (Se) - being found in both toxic compounds and also harnessed by nature for essential biochemical processes - has inspired the recent exploration of selenium chemistry for site-selective functionalization of peptides and proteins. In this Review, we discuss such approaches, including metal-free and metal-catalysed transformations, as well as traceless chemical modifications. We report their advantages, limitations and applications, as well as future research avenues.

Recent Advances in Photoinduced Modification of Amino Acids, Peptides, and Proteins.

The chemical modification of biopolymers like peptides and proteins is a key technology to access vaccines and pharmaceuticals. Similarly, the tunable derivatization of individual amino acids is important as they are key building blocks of biomolecules, bioactive natural products, synthetic polymers, and innovative materials. The high diversity of functional groups present in amino acid-based molecules represents a significant challenge for their selective derivatization Recently, visible light-mediated transformations have emerged as a powerful strategy for achieving chemoselective biomolecule modification. This technique offers numerous advantages over other methods, including a higher selectivity, mild reaction conditions and high functional-group tolerance. This review provides an overview of the most recent methods covering the photoinduced modification for single amino acids and site-selective functionalization in peptides and proteins under mild and even biocompatible conditions. Future challenges and perspectives are discussed beyond the diverse types of photocatalytic transformations that are currently available.

Divergent [2 + n] Heteroannulation of β-CF3-1,3-enynes with Alkyl Azides via Hydrogen Atom Transfer and Radical Substitution.

A copper-promoted divergent intermolecular [2 + n] heteroannulation of β-CF3-1,3-enynes with alkyl azides via alkyl radical-driven HAT and radical substitution (C-C bond formation) to form four- to ten-membered saturated N-heterocycles is developed. This method enables the aryl-induced or kinetically controlled site selective functionalization of the remote C(sp3)-H bonds at positions 2, 3, 4, 5, 6, 7, or 8 toward the nitrogen atom through triplet nitrene formation, radical addition across the C═C bond, HAT and radical substitution cascades, and features a broad substrate scope, excellent site selectivity, and facile late-stage derivatization of bioactive molecules. Initial deuterium-labeling and control experiments shed light on the reaction mechanism via nitrene formation and HAT.

Stereo- and Site-Selective Acylation in Carbohydrate Synthesis

AbstractCarbohydrates are synthetically challenging molecules with vital biological roles in all living systems. To better understand the biological functions of this fundamentally important class of molecules, novel methodologies are needed, including site-selective functionalization and glycosylation reactions. This account describes our efforts toward the development of novel methodologies for site-selective functionalization of carbohydrates and stereoselective glycosylation through various acylation reactions.

Iodoarene-directed photoredox β-C(sp3)-H arylation of 1-(o-iodoaryl)alkan-1-ones with cyanoarenes via halogen atom transfer and hydrogen atom transfer.

Site selective functionalization of inert remote C(sp3)-H bonds to increase molecular complexity offers vital potential for chemical synthesis and new drug development, thus it has been attracting ongoing research interest. In particular, typical β-C(sp3)-H arylation methods using chelation-assisted metal catalysis or metal-catalyzed oxidative/photochemical in situ generated allyl C(sp3)-H bond processes have been well developed. However, radical-mediated direct β-C(sp3)-H arylation of carbonyls remains elusive. Herein, we describe an iodoarene-directed photoredox β-C(sp3)-H arylation of 1-(o-iodoaryl)alkan-1-ones with cyanoarenes via halogen atom transfer (XAT) and hydrogen atom transfer (HAT). The method involves diethylaminoethyl radical-mediated generation of an aryl radical intermediate via XAT, then directed 1,5-HAT to form the remote alkyl radical intermediate and radical-radical coupling with cyanoarenes, and is applicable to a broad scope of unactivated remote C(sp3)-H bonds like β-C(sp3)-H bonds of o-iodoaryl-substituted alkanones and α-C(sp3)-H bonds of o-iodoarylamides. Experimental findings are supported by computational studies (DFT calculations), revealing that this method operates via a radical-relay stepwise mechanism involving multiple SET, XAT, 1,5-HAT and radical-radical coupling processes.

Sulfur-Directed α-C(sp3)-H Amidation of Pyrrolidines with Dioxazolones under Rhodium Catalysis.

Site-selective functionalization of saturated N-heterocycles such as pyrrolidines is a central topic in organic synthesis and drug discovery. We herein report the sulfur-assisted rhodium(III)-catalyzed sp3 C-H amidation of pyrrolidines with dioxazolones as amidating agents. The amenability of the thioamide directing group is elucidated by a series of control experiments.

Chemical Engineering of Artificial Transcription Factors by Orthogonal Palladium(II)-Mediated S-Arylation Reactions.

Site-selective functionalization strategies are in high demand to prepare well-defined homogeneous proteins for basic research and biomedical applications. In this regard, cysteine-based reactions have enabled a broad set of transformations to produce modified proteins for various applications. However, these approaches were mainly employed to modify a single reactive site with a specific transformation. Achieving site selectivity or multiple transformations, essential for preparing complex biomolecules, remains challenging. Herein we demonstrate the power of combining palladium(II)-mediated C-S bond formation and C-S bond cleavage reactions to selectively edit desired cysteine sites in complex and uniquely modified proteins. We developed an orthogonal palladium(II) strategy for rapid and effective diversification of multiple cysteine sites (3-6 residues) with various transformations. Importantly, we employed our approach to prepare 10 complex analogues, including modified, stapled, and multimeric proteins on a milligram scale. Furthermore, we also synthesized a focused library of stabilized artificial transcription factors that displayed enhanced stability and potent DNA binding activity. Our approach enables rapid and effective protein editing and opens new avenues to engineer new biomolecules for fundamental research and therapeutic applications.

Recent Advances in C–H Functionalization of Pyrenes

In recent years, transition metal-catalyzed C–H activation and site-selective functionalization have been considered to be valuable synthetic tactics to functionalize organic compounds containing multiple C–H bonds. Pyrene is one of the privileged and notorious polycyclic aromatic hydrocarbons. Pyrene and its derivatives have found applications in various branches of chemical sciences, including organic chemistry, chemical biology, supramolecular sciences, and material sciences. Given the importance of pyrene derivatives, several classical methods, including the C–H functionalization method, have been developed for synthesizing modified pyrene scaffolds. This review attempts to cover the recent developments in the area pertaining to the modification of the pyrene motif through the C–H activation process and the functionalization of C–H bonds present in the pyrene motif, leading to functionalized pyrenes.

Electrochemical Modification of Polypeptides at Selenocysteine.

Mild strategies for the selective modification of peptides and proteins are in demand for applications in therapeutic peptide and protein discovery, and in the study of fundamental biomolecular processes. Herein, we describe the development of an electrochemical selenoetherification (e-SE) platform for the efficient site-selective functionalization of polypeptides. This methodology utilizes the unique reactivity of the 21st amino acid, selenocysteine, to effect formation of valuable bioconjugates through stable selenoether linkages under mild electrochemical conditions. The power of e-SE is highlighted through late-stage C-terminal modification of the FDA-approved cancer drug leuprolide and assembly of a library of anti-HER2 affibody conjugates bearing complex cargoes. Following assembly by e-SE, the utility of functionalized affibodies for in vitro imaging and targeting of HER2 positive breast and lung cancer cell lines is also demonstrated.

Dimethyl Sulfoxide/Visible-Light Comediated Chemoselective C–S Bond Formation Between Tryptophans and Thiophenols Enables Site-Selective Functionalization of Peptides

Dimethyl Sulfoxide/Visible-Light Comediated Chemoselective C–S Bond Formation Between Tryptophans and Thiophenols Enables Site-Selective Functionalization of Peptides

Spatial Precision Tailoring the Catalytic Activity of Graphene Monolayers for Designing Janus Swimmers.

Graphene monolayers have interesting applications in many fields due to their intrinsic physicochemical properties, especially when they can be postmodified with high precision. Herein, we describe the highly site-selective functionalization of freestanding graphene monolayers with platinum (Pt) clusters by bipolar electrochemistry. The deposition of such metal spots leads to catalytically active hybrid two-dimensional (2D) nanomaterials. Their catalytic functionality is illustrated by the spatially controlled decomposition of hydrogen peroxide, inducing motion at the water/air interface due to oxygen bubble evolution. A series of such 2D Janus structures with Pt deposition at predefined positions (corners and edges) is studied with respect to the generation of autonomous motion. The type and speed of motion can be fine-tuned by controlling the deposition time and location of the Pt clusters. These proof-of-principle experiments indicate that this type of hybrid 2D object opens up interesting perspectives in terms of applications, such as environmental detection or remediation.

Tributyl(1-((dimethylamino)(dimethyliminio)methyl)-1,4-dihydropyridin-4-yl)phosphonium Ditrifluoromethanesulfonate

Site-selective functionalization of pyridines is a crucial tool for the synthesis of diverse pharmaceuticals and materials. We introduced diiminium pyridine adducts as highly convenient and potent Lewis acids. We report that tributylphosphine selectively adds to the 4-position of pyridine in tetramethyldiiminium pyridine ditrifluoromethanesulfonate, resulting in the formation of the title compound. This finding represents an advancement towards the utilization of diiminium units as organic reagents or catalysts for pyridine functionalization. We also employ computational models to determine fluoride and hydride ion affinities, Fukui function f+(r), molecular electrostatic potential, and pKa values, providing valuable insights for future investigations in this area.

Hybrid Machine Learning Approach to Predict the Site Selectivity of Iridium-Catalyzed Arene Borylation.

The borylation of aryl and heteroaryl C-H bonds is valuable for the site-selective functionalization of C-H bonds in complex molecules. Iridium catalysts ligated by bipyridine ligands catalyze the borylation of the C-H bond that is most acidic and least sterically hindered in an arene, but predicting the site of borylation in molecules containing multiple arenes is difficult. To address this challenge, we report a hybrid computational model that predicts the Site of Borylation (SoBo) in complex molecules. The SoBo model combines density functional theory, semiempirical quantum mechanics, cheminformatics, linear regression, and machine learning to predict site selectivity and to extrapolate these predictions to new chemical space. Experimental validation of SoBo showed that the model predicts the major site of borylation of pharmaceutical intermediates with higher accuracy than prior machine-learning models or human experts, demonstrating that SoBo will be useful to guide experiments for the borylation of specific C(sp2)-H bonds during pharmaceutical development.

Site-Selective Modification of Peptides via Late-Stage Pd-Catalyzed Tandem Reaction of Phenylalanine with Benzoquinone.

An efficient and straightforward approach for site-selective functionalization of phenylalanine and phenylalanine-containing peptide via a Pd-catalyzed tandem reaction has been developed. The robust method underwent dual C-H activation, including C-C coupling with benzoquinone and intramolecular C-N cyclization, providing a feasible and rapid synthetic route to incorporate 4-benzoquinone-indoline fragments into peptides.

Direct Access to meta‐Alkylated N‐Arylazolium Salts via Ruthenium Catalyzed Electronically Controlled Site Selective Functionalization: Scope and Mechanistic Aspect

AbstractEffective access to azolium salts with varying stereoelectronic properties has always fascinated the organometallic chemists. Herein, we described a Ru(II)‐catalyzed one‐step access to diverse meta‐alkylated N‐aryl (benz)imidazolium salts (>40 examples) via σ‐bond activation strategy starting from the readily available azolium salts using alkyl bromide. Notably, the present method is compatible with a wide range of azolium salts and secondary/tertiary alkyl bromides, including the biologically relevant motifs. Various control experiments along with the DFT calculation established the reaction pathway of orthometalated Ru(II)‐NHC complex (6) formation followed by the generation of a Ru(III)‐intermediate, which controls the observed meta‐selectivity, via single electron transfer. Crucially, detailed insight of the reaction mechanism helped to comprehend why some substrates are challenging for this methodology.