Late-stage Functionalization Research Articles

Reusable Ni-immobilized MOF Catalyst for Dehydrogenation of N-heterocycles Under Milder Conditions.

Herein, we have demonstrated the design and synthesis of a novel Ni-immobilized MOF as heterogeneous catalyst for the dehydrogenation of N-heterocycles. A series of five and six-member N-heteroarenes bearing one or more heteroatoms were synthesized in up to 98% yield (> 33 examples). Late stage functionalization to the synthesis of b-glucuronides inhibitor, antimalarial drug quinine, and the nonsteroidal anti-inflammatory drug (NSAID) indomethacin were obtained under milder reactions conditions. A series of mechanistic studies revealed the detection of H2 and H2O2 during the progress of the reactions and suggested the involvement of enamine-imine intermediate species for sequential dehydrogenation. Detailed characterization of the fresh catalyst and reused catalyst were performed using SEM, TEM, BET, PXRD, and EDX elemental mappings. The catalyst could be recycled up to four-times without much loss in catalytic activities. In-situ formed defects, pore size enlargement and additional Lewis acid sites within catalyst nanocrystals assisted in attaining high activity and selectivity to N-heteroarenes.

Access to 2,3-Dihydropyridines Involving Cyano Transformation Relay through Gold Catalysis Assisted by a Lewis Acid.

A gold(I)-catalyzed cyclization of enynone-nitriles with amines to 2,3-DHPs assisted by La(OTf)3 has been developed. The compatibility with abundant nucleophiles, high functional group tolerance, rapid assembly of molecular complexity, and late-stage functionalization of bioactive substances make this approach attractive for the construction of 2,3-DHPs, which have rarely been synthesized in the literature. The reaction proceeds via cascade cyclization involving gold/Lewis acid cooperative activation of the alkene and the cyano moiety.

Synthesis and Evaluation of 9-epi-Koshidacin B as Selective Inhibitor of Histone Deacetylase 1.

A concise synthetic route to an epimer of the recently isolated biologically active cyclic tetrapeptide koshidacin B has been developed, which featured a late-stage functionalization of a macrocyclic scaffold through a cross metathesis reaction. The synthetic 9-epi-koshidacin B showed marginal differences in spectroscopic behavior with that of the natural product but exhibited conformational preferences similar to those reported for analogous substrate chlamydocin. Moreover, it exhibited a useful level of selective inhibition of biologically relevant enzyme histone deacetylase 1 with an IC50 value of 0.145 μM over two other isoforms. Docking studies indicate that the natural product as well as its 9-epimer binds very similarly to the active site of HDAC1 indicating little influence of the configuration of the C9-stereocenter.

Late-Stage Functionalization of Guanine-Based Nucleosides, Nucleotides, and Oligonucleotide: Synthesis and Derivatization of Tricyclic Nucleoside Analogues.

We report here the synthesis of tricyclic nucleoside analogues via acid-catalyzed cyclization of guanine with 1,1,3,3-tetramethoxypropane. The method enables the use of hydroxyl-unprotected antiviral drugs (acyclovir, ganciclovir, and penciclovir), guanosines, oligonucleotide, and triazole-linked nucleoside dimers as substrates. Nucleoside trimer and tetramer were synthesized by derivatization reactions.

Multicomponent Heterogeneous Semiconductor Photocatalytic Sulfinylsulfonylation of Alkenes with Alkyl Iodides and SO2.

A multicomponent heterogeneous semiconductor photocatalytic sulfinylsulfonylation of alkenes with alkyl iodides and SO2 was displayed under mild metal-free conditions by using boron carbonitride (BCN) as the alternative photocatalyst. This approach has resulted in the production of a wide range of structurally diverse sultine products in moderate to high yields, using readily available starting materials including alkyl iodides and olefins with broad functional group tolerance. The method is also suitable for the late-stage functionalization of complex bioactive molecules. A radical-polar crossover cyclization (RPCC) process was proposed based on mechanistic studies.

Phosphinothio(seleno)ation of alkynes/olefins and application on the late-stage functionalization of natural products

Non-metallic catalysis has been known as a remarkable development strategy for hydrofunctionalization of unsaturated hydrocarbons. Herein, we report a unique chemically active method of BF3·OEt2 promoted multi-component, highly regioselective, and chemoselective hydrothio(seleo)phosphonylation of unsaturated hydrocarbons, which exhibits high yield and good substrate universality. The reaction mechanism was further elucidated to be Markovnikov addition by controlling experiments, 31P and 19F NMR spectra tracking experiments, X-ray diffraction analysis, and DFT calculations. Furthermore, the gram-scale attempt and the application of the reaction on the derivatization of natural products have been successfully conducted, leading to the discovery of 3as with potential anti-Parkinson's disease (PD) activities at 1 μM. This streamlined and efficient methodology has established a new platform for non-metallic Lewis acids-promoted hydrofunctionalization of unsaturated hydrocarbons and its application on new drug research.

Cooperative Catalysis in Stereoselective O- and N-Glycosylations with Glycosyl Trichloroacetimidates Mediated by Singly Protonated Phenanthrolinium Salt and Trichloroacetamide.

The development of small-molecule catalysts that can effectively activate both reacting partners simultaneously represents a pivotal pursuit in advancing the field of stereoselective glycosylation reactions. We report herein the development of the singly protonated form of readily available phenanthroline as an effective cooperative catalyst that facilitates the coupling of a wide variety of aliphatic alcohols, phenols, and aromatic amines with α-glycosyl trichloroacetimidate donors. The glycosylation reaction likely proceeds via an SN2-like mechanism, generating β-selective glycoside products. The developed protocol provides access to O- and N-glycosides in good yields with excellent levels of β-selectivity and enables late-stage functionalization of O- and N-glycosides via cross-coupling reactions. Importantly, this method exhibits excellent β-selectivity that is unattainable through a C2-O-acyl neighboring group participation strategy, especially in the case of glycosyl donors already containing a C2 heteroatom or sugar unit. Kinetic studies demonstrate that the byproduct trichloroacetamide group plays a previously undiscovered pivotal role in influencing the reactivity and selectivity of the reaction. A proposed mechanism involving simultaneous activation of the glycosyl donor and acceptor by the singly protonated phenanthrolinium salt catalyst with the assistance of the trichloroacetamide group is supported by kinetic analysis and preliminary computational studies. This cooperative catalysis process involves four consecutive hydrogen bond interactions. The first interaction occurs between the carbonyl oxygen of the trichloroacetamide group and the hydroxyl group of alcohol nucleophile (C═O···HO). The second involves the trichloroacetamide-NH2 forming a hydrogen bond with the nitrogen atom of the phenanthroline (NH···N). The third involves the donor trichloroacetimidate (═NH) engaging in a hydrogen bond interaction with the phenanthrolinium-NH (NH···N═H). Lastly, the protonated trichloroacetimidate-NH2 forms a hydrogen bond with the fluorine atom of the tetrafluoroborate ion.

Photoredox-Catalyzed Regioselective 1,3-Alkoxypyridylation of gem-Difluorocyclopropanes.

Difluoromethylene and pyridine cores are very important structural units in medicinal chemistry. Herein, we report the development of photoredox-catalyzed ring-opening and 1,3-alkoxypyridylation of gem-difluorinated cyclopropanes using 4-cyanopyrines and alcohols, employing cyclopropane radical cations as the key intermediate. The reaction exhibits high regioselectivity under mild conditions and can also be practiced on gram-scale synthesis, telescoped reaction, and late-stage functionalization of biological molecules.

Ru(II)-Catalyzed Redox-Neutral C-H Olefination and Tandem Cyclization with Vinyl Sulfones: Leveraging Sulfinate Anion as a Leaving Group for the Synthesis of 3-Methyleneisoindolin-1-ones.

We developed a Ru(II)-catalyzed redox-neutral C-H olefination of N-methoxybenzamides with vinyl sulfones. The reaction is operationally simple and conducted at ambient temperature and does not require silver additives or external oxidants, making it suitable for late-stage functionalization. Notably, we leveraged the leaving group ability of sulfinate anion to synthesize 3-methyleneisoindolin-1-ones through a tandem C-H olefination/cyclization/elimination sequence at ambient temperature. Moreover, we successfully demonstrated the synthetic versatility of 3-methyleneisoindolin-1-one for the construction of an isoindolobenzazepine core.

Advances in Pyridine C-H Functionalizations: Beyond C2 Selectivity.

The pyridine core is a crucial component in numerous FDA-approved drugs and Environmental Protection Agency (EPA) regulated agrochemicals. It also plays a significant role in ligands for transition metals, alkaloids, catalysts, and various organic materials with diverse properties, making it one of the most important structural frameworks. However, despite its significance, direct and selective functionalization of pyridine is still relatively underdeveloped due to its electron-deficient nature and the strong coordinating ability of nitrogen. Among the variety of synthetic transformation, direct functionalization of C-H bond is straightforward and atom economical approach and it's advantageous for late-stage functionalization of pyridine containing drugs. In recent years, innovative strategies for regioselective C-H functionalization of pyridines and azines have emerged, offering numerous benefits such as high regioselectivity, mild conditions, and enabling transformations that were challenging with traditional methods. This review emphasizes the latest advancements in meta and para-C-H functionalization of pyridines through various approaches, including pyridine phosphonium salts, photocatalytic methods, temporary de-aromatization, Minisci-type reactions, and transition metal-catalyzed C-H activation techniques. We discuss the advantages and limitations of these current methods and aim to inspire further progress in this significant field.

Chemoenzymatic Synthesis of the Cyclopiane Family of Diterpenoid Natural Products.

A three-stage chemoenzymatic synthesis of the cyclopiane family and related diterpenes is reported. Deoxyconidiogenol with a 6/5/5/5-fused tetracyclic cyclopiane skeleton was first produced by an engineered E. coli host harboring the corresponding terpene cyclase PchDS. Ten cyclopiane diterpenes were synthesized by late-stage functionalization of rings A, B and D of the cyclopiane skeleton through direct redox operations, directed C-H activation, and enzymatic hydroxylation, respectively. Skeletal diversification was achieved by taking advantage of the selective 1,2-alkyl migration of a cyclopiane cation generated chemically or enzymatically. Three cyclopiane-related skeletons, including the spiro 5/5/5/5-tetracyclic skeleton of spiroviolene, the angular 5/6/5/5-fused ring system of phomopsene, and the new linear 5/6/5/5-fused tetracyclic ring system of amycolatene, were produced either by chemical skeletal transformation from the cyclopiane skeleton, or by terpene cyclases discovered by genome mining.

Scalable deoxygenative alkynylation of alcohols via flow photochemistry

Internal alkynes are often contained in bioactive pharmaceuticals and crucial intermediates in material sciences, yet their production methods are often limited and challenging, necessitating the development of more efficient and versatile synthetic routes. Here we report a method of deoxygenative alkynylation of alcohols via flow photochemistry. Formation of N-heterocyclic carbene-alcohol adducts undergoes oxidation by a photocatalyst, generating alkyl radicals. These radicals are subsequently trapped by an alkynylation agent, yielding the desired alkyne. Compared to batch reactions, the strategy using flow photochemistry is practical and efficient to complete the reaction in relatively short time with good yields. A wide range of functional groups were tolerated. The broad application of this method for alkyne synthesis in industry settings is anticipated, supported by the potential in late-stage functionalization of biomolecules and gram-scale synthesis.

NADH Analogues Enable Metal- and Light-Free Decarboxylative Functionalization.

Here we report a metal- and light-free decarboxylative functionalization approach enabled by reduced nicotinamide adenine dinucleotide (NADH) analogues. The efficient and operationally simple approach, conducted in 5 minutes from in-situ preparation of aryliodine (III) dicarboxylates under open-air and ambient conditions, enables diverse bond formation and exhibits a broad substrate scope of over 70 examples. Late-stage functionalization of drug molecules and natural products further demonstrates the synthetic utility of this method. Combined experimental and computational studies elucidate the mechanistic pathway. These transformations streamline the synthesis of sp3 carbon-enriched compounds, adding a new dimension to classical decarboxylative reactions.

Pd-Catalyzed Decarbonylative Suzuki-Miyaura Cross-Coupling of Pyramidalized N-Mesyl Amides by a Tandem N-C(O)/C-C Bond Activation.

The Suzuki-Miyaura biaryl cross-coupling is the pivotal technology for carbon-carbon coupling in pharmaceutical, polymer, and agrochemical fields. A long-standing challenge has been the development of efficient precursors for the decarbonylative cross-coupling of amide bonds. Herein, we report a highly chemoselective palladium-catalyzed Suzuki-Miyaura cross-coupling of N-mesyl amides for the synthesis of biaryls by a tandem N-C(O)/C-C bond activation with high selectivity for decarbonylative cleavage. The results demonstrate the first example of a decarbonylative coupling (-CO) of amide bonds activated by an atom-economic, low-cost, and benign N-pyramidalized mesyl group (>30 examples). The reaction shows high generality and functional group tolerance and can be applied in late-stage functionalization of pharmaceuticals. Notably, N-mesyl amides are significantly more reactive than other classes of amides in the decarbonylative Suzuki cross-coupling manifold. Density functional theory (DFT) studies demonstrate considerably lower barrier for rate-limiting transmetalation using N-mesyl amides. The study establishes N-mesyl amides as versatile precursors for Suzuki-Miyaura cross-coupling to afford valuable biaryls and opens the door to deploy N-mesyl amides in challenging cross-couplings of amides by decarbonylation.

Late-stage-functionalization of anti-depressant molecule buspirone.

Buspirone, a well-established anxiolytic agent, has gained attention for its potential role as an antidepressant, primarily due to its unique pharmacological profile and the ability to modulate serotonin receptors effectively. Late-stage functionalization is considered as a pivotal strategy in drug synthesis that enhances the therapeutic efficacy of existing molecules. This review summarizes various late-stage functionalization techniques applicable to Buspirone, including photocatalyzed, metal-catalyzed, and enzyme-catalyzed reactions.

Cobalt-Catalyzed Highly α-Stereoselective Glycosylation of Glycals.

Following the satisfactory catalytic performance of cobalt in the C-glycosylation of glycals, further study of cobalt's application values was performed under mild conditions, leading to a range of highly α-stereoselective 2,3-unsaturated O-, S-, and N-glycosides. The synthetic potential of the developed protocol was underscored by the late-stage functionalization of pharmaceutically relevant molecules including the canagliflozin derivative (a potential candidate for treating type 2 diabetes and alleviating pathological aging). Furthermore, control experiments were conducted to elucidate a reasonable mechanism and rule out the pathway involving the configuration conversion between α- and β-anomers.

Feedstock chemical dichloromethane as the C1 source for the chemoselective multicomponent synthesis of valuable 1,4,2-dioxazoles

The development of mild and practical strategies to produce value-added fine chemicals directly from inexpensive and readily available commodity chemicals is actively pursued by chemists. However, the application of feedstock chemical dichloromethane (DCM) as the C1 source in organic synthesis is still in its infancy. Herein, we describe a multicomponent strategy for the chemoselective synthesis of valuable 1,4,2-dioxazoles by using DCM as a C1 source. Critical to the success of this process is tuning of the type of nucleophiles to inhibit the easily-occurring side reactions. This approach features mild and simple conditions, excellent chemoselectivity, metal free, and broad substrate scope covering different types of nucleophiles. Furthermore, its synthetic utility is further demonstrated by the preparation of deuterated 1,4,2-dioxazoles, the late-stage functionalization of complex molecules and large-scale synthesis. Preliminary mechanistic studies indicate the dual roles of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as both a proton scavenger and a nucleophilic catalyst. This work provides not only a platform for DCM application, but also an excellent complementary strategy to the established 1,4,2-dioxazoles synthesis.

Stabilized Carbon Radical-Mediated Assembly of Arylthianthrenium Salts, Alkenes and Amino Acid/Peptide Derivatives.

Efficiently assembling amino acids and peptides with bioactive molecules facilitates the modular and streamlined synthesis of a diverse library of peptide-related compounds. Particularly notable is their application in pharmaceutical development, leveraging site-selective late-stage functionalization. Here, a visible light-induced three-component reaction involving arylthianthrenium salts, amino acid/peptide derivatives, and alkenes are introduced. This approach utilizes captodatively-stabilized carbon radicals to enable radical-radical C─C coupling, effectively constructing complex bioactive molecules. This method offers a promising alternative route for modular synthesis of peptide-derived bio-relevant compounds.

Late-Stage Functionalization for the Introduction of Sulfilimines into Peptides

Late-Stage Functionalization for the Introduction of Sulfilimines into Peptides

Recent Advances in C-O Bond Cleavage of Aryl, Vinyl, and Benzylic Ethers.

Transition metal-catalyzed cross-coupling with aryl halides has revolutionized the way of diversifying aromatic compounds. Aryl ethers are attractive alternatives to aromatic halides as coupling partners considering the accessibility and potential environmental benefits. The last two decades have witnessed a striking success in the field of C-O bond activation of aryl ethers, including the construction of C-C bond and C-X bond, as well as reductive deoxygenation. Here, we present a comprehensive review of C-O bond activation in the context of aryl, vinyl, and benzylic ethers. This review elaborates on the current state-of-the-art methods, categorized by different catalytic systems, including transition metal catalysis, photoredox catalysis, and other innovative approaches. The newly developed methods allow C-O bond activation under mild conditions with exceptional functional group tolerance, potentially enabling the late-stage functionalization of pharmaceuticals. The limitations and future perspectives of the methods are also presented.