Late-stage Functionalization Research Articles

A Covalent Triazine Framework for Photocatalytic Anti-Markovnikov Hydrofunctionalizations.

Porous materials-based heterogeneous photocatalysts, performing selective organic transformations, are increasing the applicability of photocatalytic reactions due to their ability to merge traditional photocatalysis with structured pores densely decorated with catalytic moiety for efficient mass and charge transfer, as well as added recyclability. We herein disclose a porous crystalline covalent triazine framework (CTF)-based heterogeneous photocatalyst that exhibits excellent photoredox properties for different hydrofunctionalization reactions such as hydrocarboxylations, hydroamination and hydroazidations. The high oxidizing property of this CTF enables the activation of styrenes, followed by regioselective C-N and C-O bond formation at ambient conditions. A change in the physicochemical and optoelectronic properties of the CTF, upon protonation during catalysis, lies at the basis of its photocatalytic properties. This allows us to obtain hydrocarboxylations, hydroamination, and hydroazidations from a myriad of electron-donating and -withdrawing aromatic and aliphatic substrates. This catalytic approach is further extended to late-stage functionalization of bio-active molecules. Finally, detailed characterizations of the CTF and further mechanistic investigations provides mechanistic insights in these reactions.

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis.

With the resurgence of electrosynthesis in organic chemistry, there is a significant increase in the number of routes available for late-stage functionalization (LSF) of drugs. Electrosynthetic methods, which obviate the need for hazardous chemical oxidants or reductants, offer unprecedented control of reactions through the continuous variation of the applied potential and the possibility of combination with photochemical processes. This capability is a substantial advantage for performing electrochemical or photoelectrochemical LSF. Ultimately, these protocols are poised to become a vital component of the medicinal chemist's toolkit. In this review, we discuss electrochemical protocols that have been demonstrated to be applicable for the LSF of pharmaceutical drugs, their derivatives, and natural substrates. We present and analyze representative examples to illustrate the potential of electrochemistry or photoelectrochemistry for the LSF of valuable molecular scaffolds.

Transition-Metal-Free Late-Stage Decarboxylative gem-Difluoroallylation of Primary Alkyl Acids.

A transition-metal-free late-stage decarboxylative gem-difluoroallylation of carboxylic acids with α-trifluoromethyl alkenes has been described by the use of organo-photoredox catalysis. Both primary alkyl and heteroaryl acids were readily incorporated. This approach merits feedstock materials, mild reaction conditions, and wide functionality tolerance. The synthetic utility of this approach has been highlighted by the late-stage functionalization of a variety of acid-containing natural products and drug molecules.

Metal and Photocatalyst-Free Amide Synthesis via Decarbonylative Condensation of Alkynes and Photoexcited Nitroarenes.

Depending on the intrinsic photoactivity of nitroarenes, we herein developed a practical Brønsted acid-catalyzed decarbonylative amide synthesis from alkynes and photoexcited nitroarenes without any metal or photocatalyst. This method exhibited compatibility with water and air, broad substrate applicability, marvelous functional group tolerance, and wide applications in scale-up synthesis, late-stage functionalization, and total synthesis. Mechanism studies and DFT calculations supported that a 1,3,2-dioxazole intermediate was involved, and gaseous carbon monoxide was the only byproduct during amide construction.

Photocatalytic furan-to-pyrrole conversion.

The identity of a heteroatom within an aromatic ring influences the chemical properties of that heterocyclic compound. Systematically evaluating the effect of a single atom, however, poses synthetic challenges, primarily as a result of thermodynamic mismatches in atomic exchange processes. We present a photocatalytic strategy that swaps an oxygen atom of furan with a nitrogen group, directly converting the furan into a pyrrole analog in a single intermolecular reaction. High compatibility was observed with various furan derivatives and nitrogen nucleophiles commonly used in drug discovery, and the late-stage functionalization furnished otherwise difficult-to-access pyrroles from naturally occurring furans of high molecular complexity. Mechanistic analysis suggested that polarity inversion through single electron transfer initiates the redox-neutral atom exchange processes at room temperature.

Selective Functionalization of Alkenes and Alkynes by Dinuclear Manganese Catalysts.

ConspectusAlkenes and alkynes are fundamental building blocks in organic synthesis due to their commercial availability, bench-stability, and easy preparation. Selective functionalization of alkenes and alkynes is a crucial step for the synthesis of value-added compounds. Precise control over these reactions allows efficient construction of complex molecules with new functionalities. In recent decades, second- and third-row precious transition metal catalysts (palladium, platinum, rhodium, ruthenium) have been pivotal in the development of metal-catalyzed synthetic methodology. These metals exhibit excellent catalytic activity and selectivity, enabling efficient synthesis of functionalized organic molecules. However, recovery and reuse of precious metals have long been a challenge in this field. In recent years, exploration of earth-abundant metal-catalyzed organic reactions has interested both academic and industrial researchers. The development of such catalytic systems offers a promising approach to overcome the limitations of precious metal catalysts. For example, manganese is the third most naturally abundant transition metal with minimal toxicity and excellent biocompatibility. It exhibits good catalytic activity in several organic reactions, including C-H bond functionalization, selective reduction, and radical reactions. This Account outlines our recent progress in dinuclear manganese catalysis for selective functionalization of alkenes and alkynes. We have established the elementary manganese(I)-catalysis in transmetalation with R-B(OH)2. This finding has enabled us to apply the catalyst for the selective 1,2-difunctionalization of structurally diverse alkenes and alkynes. Mechanistic studies suggest a double manganese center synergistic activation model, as superior to Mn(CO)5Br in some cases. In addition, we have developed a ligand-tuned metalloradical strategy of dinuclear manganese catalysts (Mn2(CO)10), bridging the gap between the organometallics and radical chemistry, highlighting the unique radical functionalization of alkenes. Interestingly, using the same starting materials, different ligands can deliver completely different products. Meanwhile, a cooperative catalysis strategy involving manganese and other catalysts (e.g., cobalt, iminium) has also been developed and is briefly discussed. For manganese/iminium synergistic catalysis, a new mechanism for migratory insertion and demetalization-isomerization in synergistic HOMO-LUMO activation was disclosed. This strategy expands the application of low-valent manganese catalysts for enantioselective C-C bond-forming reactions. New reaction discovery is outpacing mechanism studies for dinuclear manganese catalysis, and future studies with time-resolved spectroscopy will improve understanding of the mechanism. Based on these intriguing findings, the precise functionalization of alkenes and alkynes by dinuclear manganese catalysts will expedite a novel activation model to enable late-stage functionalization of complex molecules.

Alcohols as Alkyl Electrophiles for Deoxygenative Heck Reaction Enabled by Excited State Pd Catalysis.

Here, we present a general method for the photoinduced Pd-catalyzed deoxygenative Heck reaction of vinyl arenes with ortho-iodophenyl-thionocarbonate derived from alcohols. Mechanistic studies reveal that the deoxygenation involves a 5-endo-trig cyclization and fragmentation process, with radical addition identified as the rate-determining step in this transformation. This one-pot procedure demonstrates excellent selectivity for less hindered hydroxyl groups in diols, facilitating late-stage functionalization of complex molecules and scalability to gram-scale synthesis. The protocol highlights significant synthetic potential and can be extended to the cascade 1,1-difunctionalization of isocyanides and the intermolecular radical cascade cyclization of N-arylacrylamides.

CF3S-N bond formation under mild conditions. Easy access to trifluoromethanesulfenamides with a versatile reagent

Trifluoromethanesulfenamides (CF3SN-molecules) are interesting products for further applications. In particular, the presence of the CF3SN group can contribute to increase their lipophilicity. The better way to obtain such products is the direct trifluoromethylthiolation of the corresponding amines. Herein, an efficient method under mild conditions (room temperature, iodide catalysis) is described to obtain the expected trifluoromethanesulfenamides in a late-stage functionalization. This method is based on the use of the reagent BB23 (N-tosyl, N-methyltrifluoromethanesulfenamide), demonstrating the high versatility and polyvalence of this reagent in organofluorine chemistry. Some bioactive elaborated compounds were successfully functionalized.

Water-Soluble Aromatic Nanobelt with Unique Cellular Internalization.

A water-soluble aromatic nanobelt was synthesized, and its cellular uptake behavior in HeLa cells was investigated. The late-stage functionalization of the parent methylene-bridged [6]cycloparaphenylene ([6]MCPP) provided an easily accessible alkyne-functionalized nanobelt in a single reaction step. The alkyne-substituted [6]MCPP was subjected to Cu-catalyzed azide-alkyne cycloaddition by using a dye-attached azide to obtain a water-soluble aromatic nanobelt. Cell-imaging experiments on the synthesized nanobelt in HeLa cells revealed stop-and-go cellular uptake dynamics. Similar experiments with control molecules and theoretical studies indicated that the unique dynamics of the nanobelt was derived from the belt-shaped structure.

Organic Photoredox-Catalyzed Site-Selective Alkylation of Glycine Derivatives and Peptides via Infrequent 1,2-Hydrogen Atom Transfer of Amidyl Radicals.

Herein, we disclose a visible-light-driven photoredox-catalyzed protocol for site-selective alkylation of glycine derivatives via 1,2-hydrogen atom transfer, which is distinguished by metal free and mild conditions, high chemoselectivity, and good functional group compatibility. This protocol provides a unique approach for synthesizing valuable α,β-diamino acid derivatives. Furthermore, the potential synthetic merit of this transformation is proven by a scale-up reaction and late-stage functionalization of peptides.

Synthesis of chiral sulfilimines by organocatalytic enantioselective sulfur alkylation of sulfenamides.

Sulfilimines are versatile synthetic intermediates and important moieties in bioactive molecules. However, their applications in drug discovery are underexplored, and efficient asymmetric synthetic methods are highly desirable. Here, we report a transition metal-free pentanidium-catalyzed sulfur alkylation of sulfenamides with exclusive chemoselectivity over nitrogen and high enantioselectivity. The reaction conditions were mild, and a wide range of enantioenriched aryl and alkyl sulfilimines were obtained. The synthetic utility and practicability of this robust protocol were further demonstrated through gram-scale reactions and late-stage functionalization of drugs.

Unveiling Alternate Electrode Electrolysis in Electro-Photochemical and Electro-Organic Syntheses.

Electro-photochemical organic synthesis is a rapidly growing field. Recently, technological advancement has contributed significantly to improve electro- and photolytic organic transformations in terms of energy efficiency and productivity. Herein, we have introduced alternating electrode electrolysis|alternate electrode electrolysis (AEE), a new technique in electrosynthesis which in combination with blue LED demonstrated an interesting three-component reaction with aryl diazoesters, 1,4-quinones, and acetone to synthesize ketal-functionalized 1,4-quinones. The AEE setup consists of two pairs of cathode-anode compared to the conventional setup of one pair. Each pair would be polarized or in a resting stage with a preset interval of choice. This would maintain a continuous potential resulting in maximum current and would facilitate the mass transport, thereby increasing the overall efficiency of the reaction. AEE offers the efficient utilization of photochemically generated carbenes. We extended AEE applications in paired photoelectrolysis reactions for the late-stage functionalization of bioactive molecules and pharmaceutical agents. As an application of AEE in electrosynthesis (without light), we demonstrated the efficient hydroxylation of fluorinated benzene and the reduction of benzonitrile to benzyl amine. The amalgamation of AEE with blue LED contributes to sustainability, and we believe that it holds great promise in the field of electro-photochemical organic synthesis.

HFIP-Mediated, Highly Chemo-, Regio-, and Stereoselective Hydrofunctionalizations of Ynamides: Access to Stereodefined Alkenes Bearing Drugs and Natural Products.

We disclose a sustainable and versatile synthetic strategy for the highly chemo-, regio-, and stereoselective hydrofunctionalizations of ynamides, through its activation by a solvent, HFIP, to access a wide variety of stereodefined ketene N,N, N,O, N,S, and N,Se acetals in high yield at room temperature. The reaction proceeded through the formation of the reactive keteniminium ion intermediate, formed via protonation at the β-carbon of ynamide by HFIP, followed by an attack of a nucleophile (syn-addition) at the α-carbon. When ynamides are treated with only HFIP at room temperature, the HFIP addition products of ynamides are formed in a 100% atom-economic fashion; however, in the presence of a stronger N-/O-/S-/Se-based nucleophile, the corresponding syn-hydroheterofunctionalized products are formed. Notably, HFIP played multiple roles, such as a reagent, in particular, a Brønsted acid, nucleophile, as well as solvent. Interestingly, HFIP is found to be unique for this transformation. Notably, this strategy is utilized for the late-stage functionalization of several marketed drugs and natural products, and it also enables the connection of two different drugs or a drug and a natural product through chemical bonds. Significantly, HFIP was recovered after the reaction and reused for consecutive reactions.

Molecular Editing of Toluene by Sequential meta-C-H/Benzylic C-N Deaminative Functionalizations.

An approach to synthesizing structurally diverse toluene derivatives via sequential meta-C-H and benzylic C-N deaminative functionalization was developed by using a recyclable bifunctional directing template. The functionalized Katritzky salt intermediates are shown to be engaged in a wide range of carbon-carbon and carbon-heteroatom bond formation reactions. The synthetic utility of the strategy was demonstrated by late-stage functionalization of toloxatone.

Redox-Active α-Amino-CF3 Reagents: Developing and Applications in Ni-Catalyzed Reductive Cross-Coupling.

α-Amino-CF3 compounds are widely employed in bio- and pharmaceutical chemistry for improved stability and bioactivities. Traditional methods often face challenges with functional group tolerance and lack a general approach for late-stage functionalization. Herein, we report a new type of redox-active α-amino-CF3 reagents, easily prepared from trifluoro acetaldehyde hydrates. These α-amino-CF3 reagents can serve as versatile building blocks for coupling with alkynyl bromides, aryl bromides, and enol triflates under nickel catalysis.

C3 Selective Hydroxylation of Pyridines via Photochemical Valence Isomerization of Pyridine N-Oxides.

The C-H hydroxylation of the pyridine C3 position is a highly desirable transformation but remains a great challenge due to the inherent electronic properties of this heterocycle core which bring difficulties in chemical reactivity and regioselectivity. Herein we present an efficient method for formal C3 selective hydroxylation of pyridines via photochemical valence isomerization of pyridine N-oxides. This metal-free transformation features operational simplicity and compatibility with a diverse array of functional groups, and the resulting hydroxylated products are amenable to further elaboration to synthetically useful building blocks. The synthetic utility of this strategy is further demonstrated in the effective late-stage functionalization of pyridine-containing medicinally relevant molecules and versatile derivatizations of 3-pyridinols.

Motor Cortical Neuronal Hyperexcitability Associated with α-Synuclein Aggregation.

Dysfunction of the cerebral cortex is thought to underlie motor and cognitive impairments in Parkinson disease (PD). While cortical function is known to be suppressed by abnormal basal ganglia output following dopaminergic degeneration, it remains to be determined how the deposition of Lewy pathology disrupts cortical circuit integrity and function. Moreover, it is also unknown whether cortical Lewy pathology and midbrain dopaminergic degeneration interact to disrupt cortical function in late-stage. To begin to address these questions, we injected α-synuclein (αSyn) preformed fibrils (PFFs) into the dorsolateral striatum of mice to seed αSyn pathology in the cortical cortex and induce degeneration of midbrain dopaminergic neurons. Using this model system, we reported that αSyn aggregates accumulate in the motor cortex in a layer- and cell-subtype-specific pattern. Particularly, intratelencephalic neurons (ITNs) showed earlier accumulation and greater extent of αSyn aggregates relative to corticospinal neurons (CSNs). Moreover, we demonstrated that the intrinsic excitability and inputs resistance of αSyn aggregates-bearing ITNs in the secondary motor cortex (M2) are increased, along with a noticeable shrinkage of cell bodies and loss of dendritic spines. Last, neither the intrinsic excitability of CSNs nor their thalamocortical input was altered by a partial striatal dopamine depletion associated with αSyn pathology. Our results documented motor cortical neuronal hyperexcitability associated with αSyn aggregation and provided a novel mechanistic understanding of cortical circuit dysfunction in PD.

Perfect Partners: Biocatalytic Halogenation and Metal Catalysis for Protein Bioconjugation.

Flavin-dependent halogenases (FDHs) are the most extensively researched halogenases and show great potential for biotransformation applications. These enzymes use chloride, bromide, or iodide ions as halogen donors to catalyze the oxygen-dependent halogenation of electron-rich aryl moieties, requiring stochiometric amounts of FADH2 in the process. This makes FDH-catalyzed aryl halogenation a highly selective and environmentally friendly tool for the synthesis of aryl halides. The latter in turn serve as valuable intermediates for transition metal catalyzed cross coupling reactions for C-C bond formation. Previous research made extensive use of this approach to halogenate small molecules as building blocks for late-stage functionalization by transition-metal catalyzed cross-coupling reactions. Based on these results, several groups have managed to expand this research to protein targets over the past two years. Their work indicates an emerging methodology for bioconjugation using late-stage biocatalytic halogenation in conjunction with biorthogonal Suzuki-Miyaura cross-coupling. This strategy could present an attractive alternative to existing approaches due to the stability of the C-C bond bridging the generated biaryl moiety and the ease of late-stage enzymatic modification while maintaining excellent selectivity under mild conditions.

Base-Dependent Divergent Carbodifluoroalkylation and Halodifluoroalkylation of Alkenes under Visible-Light Irradiation.

Organic molecules containing a difluoroalkyl group are valuable and versatile chemicals because of their unique physicochemical and biological properties. Accordingly, the development of efficient and practical difluoroalkylation for the preparation of these compounds is important and attractive. Herein, we demonstrate photoredox-catalyzed and base-dependent selective carbodifluoroalkylation and halodifluoroalkylation of alkenes using readily available 2-(allyloxy)arylaldehydes [or 2-(allylamino)arylaldehydes] and XCF2COOEt (or BrCF2CONR1R2) as starting materials. The developed reaction enables convenient and accurate synthesis of difluoroalkylated chroman-4-ones and aldehydes and features broad substrate scope, mild conditions, and operational simplicity. Moreover, gram-scale product preparation and application of the title protocol in late-stage functionalization of pharmaceutical molecules are accomplished.

Potent and Selective Oxidatively Labile Ether-Based Prodrugs through Late-Stage Boronate Incorporation.

This manuscript describes a new strategy for prodrug synthesis in which a relatively inert ether group is introduced at an early stage in a synthetic sequence and functionalized in the final step to introduce a prodrug-activating group through a chemoselective process. Boryl allyloxy (BAO) ether groups are synthesized through several metal-mediated processes to form entities that are readily cleaved under oxidative conditions commonly found in cancer cells. The high cleavage propensity of the BAO group allows for ether cleavage, making these compounds substantially more hydrolytically stable in comparison to acyl-linked prodrugs while retaining the ability to release alcohols. We report the preparation of prodrug analogues of the natural products camptothecin and pederin from acetal precursors that serve as protecting groups in their synthetic sequences. The BAO acetal groups cleave in the presence of hydrogen peroxide to release the cytotoxic agents. The pederin-based prodrug shows dramatically greater cytotoxicity than negative controls and outstanding selectivity and potency toward cancer cell lines in comparison to non-cancerous cell lines. This late-stage functionalization approach to prodrug synthesis should be applicable to numerous systems that can be accessed through chemoselective processes.