January 21, 2025
Mild [3 + 3] Annulation of (Trifluoromethyl)alkenes with Thioureas Enabled by Chemoselective Defluorinative Amination: Synthesis of 6-Fluoro-3,4-dihydropyrimidine-2(1H)-thiones
Rongbin Peng - and
Chuanle Zhu *
The chemoselective defluorinative [3 + 3] annulation of (trifluoromethyl)alkenes with thioureas is reported. This protocol affords various attractive 6-fluoro-3,4-dihydropyrimidine-2(1H)-thiones in high yields, features transition-metal free, mild conditions, efficient, is operationally simple and gram-scalable, tolerates diverse useful functional groups.
Photoredox-Catalyzed Three-Component Sulfonaminoalkynylation of Alkenes via a Radial/Polar Crossover
Lixian Shen - ,
Jie Liu - ,
Xue Peng - ,
Zhengwen Lei *- ,
Zhen Wang *- , and
Yao-Fu Zeng *
We report a photoredox-catalyzed three-component sulfonaminoalkynylation of alkenes with N-aminopyridine salts and potassium alkynyltrifluoroborate salts. This aminoalkylation reaction underwent a radial/polar crossover mechanism, which was distinguished from the previous reports. A variety of β-alkynylated sulfonamides were obtained in moderate to excellent yields. The versatility of this method was further evidenced by its successful application in modifying biological molecules in advanced stages of development.
Enantiodivergent Synthesis of Both (R)- and (S)-Heteroaryl Aldols by Rationally Engineered Aldolases
Karishma Naik - ,
Kodru Jeevani - ,
Krishnendu Bar - , and
Thangavelu Saravanan *
Aldolases, especially 2-deoxyribose-5-phosphate aldolase (DERA) enzymes, have been widely employed to access key chiral precursors for various active pharmaceutical ingredients (APIs). This has been enabled by expanding their substrate scope toward non-natural acceptors and donors via protein engineering. In this study, we endeavored to broaden the acceptor substrate scope of DERA from Geobacillus sp. (DERAGeo) toward the heteroaryl aldehydes through a rational protein engineering approach. We successfully performed iterative saturation mutagenesis of DERAGeo, resulting in two enantiocomplementary variants, viz., (R)-selective DERAGeo-S185G and (S)-selective DERAGeo-T12I/S185A, with enhanced catalytic efficiencies and enantioselectivities. Remarkably, the natural enantioselectivity of DERAGeo was reversed by a single mutation (S185G). The synthetic applicability of the mutants was demonstrated by conducting aldol reactions on a semipreparative scale, from which both (R)- and (S)-enantiomers of heteroaryl aldols were isolated with high yields (up to 99%) and excellent enantiopurities (up to 99:1 e.r.).
Salvicsite A-C: Three Seco-Norabietane Diterpenoids Including an Unusual Tetracyclic Skeleton from Salvia castanea Diels f. tomentosa Stib
Lian-Yu Tang - ,
Liu-Nian-Qiu Wang - ,
Man-Rui Ao - ,
Zi-Feng Guo - ,
Jing-Ming Jia - , and
An-Hua Wang *
Three seco-norabietane diterpenoids, salvicsites A–C (1–3), along with two known compounds, were isolated from the roots and rhizomes of Salvia castanea Diels f. tomentosa Stib. Salvicsite A (1) represents an unprecedented structural combination, featuring an eight-membered α-methyl-α,β-unsaturated lactone ring and a five-membered α,β-unsaturated lactone ring, based on a 6/6/5/8 ring system. Their structures were elucidated through comprehensive spectroscopic analyses, X-ray crystallography, and quantum chemical calculations. Putative biosynthetic pathways of 1–3 were proposed, with compound 5 being the plausible biogenetic precursor. The AChE inhibition assay demonstrated that salvicsite A (1) exhibited a notable inhibitory effect against AChE, with an IC50 value of 9.56 ± 1.05 μM. Enzymatic kinetic studies indicated that salvicsite A (1) acted as a mixed-type inhibitor, and its binding mode was explored through molecular docking. The results of the cytotoxic activity demonstrated that only compound 5 exhibited inhibitory activity.
January 20, 2025
Cu(II)-Catalyzed Annulative Sulfonylimination of α-Carbonyl-γ-alkynyl Sulfoxonium Ylides through Sulfoxonium Ylide Elimination for Access to (Z)-1H-Isochromenes
Peng Zhou *- ,
Hao-Ze Wu - ,
Qiuyun Li - ,
Wen-Juan Hao - ,
Man-Su Tu *- , and
Bo Jiang *
1H-Isochromene scaffolds are ubiquitous in natural products and significant bioactive molecules. Although several methods for these molecular syntheses have been developed, reports on the efficient construction of iminated isochromenes are still rather limited. Herein, we report a new Cu(II)-catalyzed annulation and sulfonylimination cascade of α-carbonyl-γ-alkynyl sulfoxonium ylides with sulfamides, enabling direct C–C σ-bond elimination to furnish iminated (Z)-1H-isochromenes in 51–97% yields. During the reaction process, the sulfoxonium ylide unit as a traceless eliminative group is the key to successful sulfonylimination, which enables Cu(II)-catalyzed N–H insertion and subsequent acetic acid-mediated C–C σ-bond elimination.
Visible-Light-Induced Insertion of Siloxycarbene into Amide N–H Bonds: Synthesis of Carbinolamides from Acylsilanes and Amides
Praveen Dharavath - ,
Raju Vaggu - ,
Rajesh Manda - ,
René Grée - , and
Saibal Das *
The insertion of carbene into secondary amide N–H bonds remains underexplored in organic synthesis. In this work, we discovered the visible-light-induced insertion of siloxycarbene into amide N–H bonds. This metal-free, facile reaction proceeds with atom economy under mild conditions with a broad range of secondary N–H amides, including benzanilide, acetanilide, oxindole, isatin, quinolinone, and maleimide, affording stable N- and O-acetals in excellent isolated yields. In addition, the chemoselective insertion reveals the robustness of this chemical transformation.
Molecular Fragmentation and Recombination for the Synthesis of GFP Chromophore Analogues
Hongxu Liu - ,
Harnimarta Deol - , and
Eric V. Anslyn *
Green fluorescent protein (GFP) chromophores are widely studied as fluorescent moieties for sensing and imaging applications. Herein, we present a straightforward synthetic strategy that involves the reaction of glycine amides with 1,3-diketones to form imidazolones through an unusual molecular fragmentation and recombination pathway. Mechanistic investigations, including crossover experiments, inspired a competing strategy that incorporates exogenous ketones into the products, yielding fluorescent GFP chromophore analogues. This method holds the potential for fluorescent labeling of glycine-terminated peptides.
January 17, 2025
Copper-Catalyzed 1,4-Alkylarylation of 1,3-Enynes with Ethers and Aryl Boronic Acids Enabled via C(sp3)–H Functionalization
Yunhe Lv *- ,
Weiya Pu - ,
Le Zhang - ,
Dandan Li - ,
Linjie He - ,
Linxia Dai - ,
Yaning Zhou - ,
Shuaike Zhao - ,
Fei Chen - , and
Jun-Long Zhan
Herein, we present a copper-catalyzed, three-component intermolecular 1,4-alkylarylation of 1,3-enynes with ethers and aryl boronic acids. This method, driven by α-C(sp3)–H functionalization of the oxygen atom in ethers, regioselectively produces various tetrasubstituted allenes from simple, readily available precursors. Key features include mild reaction conditions and a simple catalytic system.
Cascade Aza-Prins/Friedel–Crafts Reaction of Homocinnamyloxycarbamate and Aromatic Aldehydes Yielding Aromatic Ring-Annulated Hydrocyclopenta-1,2-oxazinane
Tinatina Junior Kindala - ,
Kazuhiko Takatori - , and
Shinji Nagumo *
The cascade aza-Prins/Friedel–Crafts reaction of homocinnamyloxycarbamate with electron-rich aromatic aldehydes has been successfully established. Most of the aromatic aldehydes react with the carbamate stereoselectively to generate cis-hydroindeno-1,2-oxazinanes. However, the cascade reactions of benzaldehydes bearing two methoxy groups at the meta-positions exhibit a unique stereochemical profile. Furthermore, the cascade reaction of benzaldehyde bearing three methoxy groups at the meta- and para-positions proceeds along with a skeletal rearrangement. Additionally, the aza-Prins/Ritter reaction of cinnamyloxycarbamate with various aldehydes was found during the development of the cascade reaction. In contrast to the cascade aza-Prins/Friedel–Crafts reaction, the aza-Prins/Ritter reaction gave trans-disubstituted isoxazolidines. These stereochemical profiles for both reactions were considered on the basis of several transition-state models.
Synthesis of Unprotected Racemic Tryptophan Derivatives Using Gramine via Nickel(II) Complex
Qiangqiang Chen - ,
Yazhou Li - ,
Zhekai Xiao - ,
Vadim A. Soloshonok - ,
Ramin Javahershenas - ,
Hong Liu *- , and
Jiang Wang *
A chemical method for the preparation of nonprotected tryptophan via nickel(II) complexes under simple operating conditions was established. The carefully designed nickel(II) glycinates are inexpensive and can be quantitatively recovered releasing the target tryptophans in high yield. The method has a wide range of synthesis generality, allowing the preparation of various substituted tryptophans. Furthermore, the scalability of this method bodes well for its synthetic use as a general approach to biologically interesting tailor-made tryptophans and related compounds.
Annulative Coupling of Sulfoxonium Ylides with Aldehydes and Naphthols or Coumarins: Easy Access to Fused Dihydrofurans
Rahul Kumar Saini - ,
Paran J. Borpatra - , and
Satyendra Kumar Pandey *
We present a novel, metal- and additive-free method for the robust synthesis of dihydrofuran-fused naphthalenes and coumarins. This approach utilizes the annulative coupling of sulfoxonium ylides with aldehydes, naphthols, or coumarins at ambient temperature. The method exhibits broad substrate compatibility, accommodating various functional groups on sulfoxonium ylides and naphthol or coumarin derivatives and resulting in good to high yields of the desired products. Additionally, we successfully scaled up the reactions, and the synthesized derivatives were further converted to other valuable bioactive molecules, validating the viability of our approach.
Multicomponent Synthesis of Alkyl BCP-Heteroaryls via Electron Donor–Acceptor Complex Photoactivation under Mild Conditions
Yanhe Li - ,
Jun Xu *- ,
Yuxin Wang - ,
Ruiyuan Xu - ,
Yuxuan Zhao - , and
Wanmei Li *
In the vanguard of sustainable chemistry, the pursuit of efficient pathways for the synthesis of alkyl bicyclo[1.1.1]pentane-heteroaryls has captured the attention of the scientific vanguard. We herein report a groundbreaking and eco-conscious multicomponent coupling reaction that paves the way for the alkylation and heteroarylation of [1.1.1]propellane, a process uniquely enabled by the photochemical prowess of an electron donor–acceptor (EDA) complex. This method is distinguished by its minimalist yet powerful approach: devoid of transition metals, additives, and photosensitizers. Its universality is further exemplified by the seamless compatibility of a broad spectrum of alkyl halides and heteroarenes under standardized conditions, heralding a new era of synthetic versatility. The method’s practicality is underscored by its capacity for late-stage modification of pharmaceuticals, offering a transformative tool for the enhancement of existing drug molecules. Moreover, the facile derivatization of the synthesized products underscores the method’s adaptability and potential for diverse applications. Our mechanistic studies have elucidated the underlying radical-relay pathway, pinpointing the pivotal role of the EDA complex in initiating the transformation. This discovery not only enriches our fundamental understanding of the reaction but also opens avenues for strategic optimization.
January 16, 2025
Computational Insights into “Lone Pair–Lone Pair Interaction-Controlled” Isomerization in the Asymmetric Total Syntheses of (+)-3-(Z)-Laureatin and (+)-3-(Z)-Isolaureatin
Hyoungsu Kim - ,
Deukjoon Kim - , and
Jiyong Park *
Described herein is our computational study to rationalize the stereoselective epimerization of α,α’-cis-disubstituted oxolane and oxetane ketones 6 and 7 to the corresponding α,α’-trans ketones 8 and 9 reported in our previous total syntheses of (+)-3-(Z)-isolaureatin (1) and (+)-3-(Z)-laureatin (2). Density functional theory (DFT) calculations using appropriately truncated models revealed that the α,α’-trans ketones are more stable than the α,α’-cis ketones, in very good agreement with experimental results. The computational results showed that the isomer with a longer interatomic distance between the two ring oxygen atoms was lower in energy, which suggested the presence of repulsive interactions between those oxygen atoms. Support for these distance-dependent repulsive interactions came from the observation that the energy differences between the two isomers correlated with the solvent polarity. Most importantly, a larger interoxygen distance difference could be responsible for the enhanced stereoselectivity for epimerization of oxetane ketone 7 compared to oxolane ketone 6 [0.25 Å (trans only) vs 0.13 Å (trans/cis = 4:1)].
Synthesis of Nonplanar Push–Pull Chromophores with Various Heterocyclic Moieties via [2 + 2] Cycloaddition-Retroelectrocyclization Reaction
Xu Chen - and
Tsuyoshi Michinobu *
A series of 1,1,4,4-tetracyanobuta-1,3-diene (TCBD) derivatives with various heterocyclic moieties, including pyridine, carbazole, indole, and benzothiadiazole, was newly synthesized through a [2 + 2] cycloaddition-retroelectrocyclization reaction. Symmetric electron-rich 1,3-butadiynes with end-capped heterocyclic substituents were reacted with tetracyanoethylene (TCNE), yielding the target TCBD products in 60–80% yields under ambient or mild heating conditions. The thermal stability and optical and electrochemical properties of both 1,3-butadiyne precursors and the corresponding TCBD derivatives were investigated by using thermogravimetric analysis (TGA), UV–vis spectroscopy, and cyclic voltammetry (CV). The TCBD derivatives featured narrow bandgaps due to the intramolecular charge transfer interactions of push–pull chromophores. In addition, the optimized structures and frontier molecular orbitals with their energy levels were determined by density functional theory (DFT) calculations.
Visible-Light-Induced Synthesis of Esters via a Self-Propagating Radical Reaction
Zelin Zhao - ,
Wenping Li - ,
Qiujie Shan - ,
David J. Young - ,
Zhi-Gang Ren - , and
Hong-Xi Li *
We herein disclose a visible-light-induced synthesis of O-aryl esters through the cross-dehydrogenative coupling of aldehydes with phenols using BrCCl3, in which phenolate functions as both a substrate and a photosensitizer. This transition-metal- and photocatalyst-free visible-light-induced esterification is suitable for a wide range of substrates and gives moderate to excellent yields (up to 95%). Mechanistic studies provided evidence of a self-propagating radical reaction involving homolytic cleavage of the aldehydic C–H bond and the formation of acyl bromides. BrCCl3 serves as an oxidant and a hydrogen atom transfer (HAT) agent.
Synthesis of Enantiopure cis- and trans-Fused Octahydroisoindole-1-Phosphonic Acids from Octahydroisoindolones
Gaspar Maravilla-Moreno - ,
R. Israel Hernández-Benítez - ,
Mario Ordóñez *- , and
José Luis Viveros-Ceballos *
Phosphonic analogs of octahydroisoindole-1-carboxylic acids are bicyclic proline derivatives of interest in drug design and enzymatic mechanism studies. Here we report the stereoselective synthesis of the cis- and trans-fused octahydroisoindole system using oxazoloisoindolone lactam and 1,2-cyclohexanedicarboxylic anhydride as advanced chiral precursors, respectively, yielding enantiopure octahydroisoindolone intermediates with the desired stereochemistry at the ring junction. Finally, using these intermediates, the target (1R,3aR,7aS)- and (1R,3aR,7aR)-octahydroisoindole-1-phosphonic acids and their enantiomers were obtained with complete stereocontrol via highly diastereoselective addition of trimethyl phosphite to chiral N-acyliminium ions as the key step.
January 15, 2025
Metal- and Azide-Free Iodine-Promoted Aerobic Oxidative Cyclization to Trifluoromethylated Triazoles
Dengke Li *
A novel metal- and azide-free methodology for the synthesis of trifluoromethylated 1,2,3-triazoles from arylamines with a new 3-bromo-1,1,1-trifluoropropan-2-one derived tosylhydrazone has been developed under mild reaction conditions. The new α-bromo-trifluoromethylated tosylhydrazone reagent was operationally safe and bench-stable from low-cost and readily commercially available starting materials in the iodine-promoted aerobic oxidative cycloaddition reaction with arylamines, affording a variety of trifluoromethylated 1,2,3-triazoles in good to excellent yields.
HOMAc: A Parameterization of the Harmonic Oscillator Model of Aromaticity (HOMA) That Includes Antiaromaticity
Enrique M. Arpa *- ,
Sven Stafström - , and
Bo Durbeej *
This publication is Open Access under the license indicated. Learn More
The harmonic oscillator model of aromaticity (HOMA) offers a straightforward route to quantifying aromaticity that requires no other information than the bond lengths of the conjugated ring in question. Given that such information is often readily obtainable from quantum-chemical calculations, it is pertinent to improve this parametrized model as much as possible. Here, a new version of HOMA is presented where, atypically, the corresponding parameters are derived from the actual bond lengths of both aromatic and antiaromatic (rather than nonaromatic) reference compounds, as calculated with a high-level method. The resulting model, which we denote HOMAc, covers CC, CN, NN, and CO bonds and is tested at eight different levels of theory for 45 (single-ring, multi-ring, carbocyclic, N,O-heterocyclic) molecules across the aromatic–antiaromatic spectrum. Thereby, it is found that HOMAc provides a description of aromaticity and antiaromaticity in better accord with magnetic, energetic, and π-delocalization-based reference data than does the standard parametrization of HOMA. Altogether, the results highlight the possibility to realize more reliable geometry-based probing of (anti)aromaticity with the use of HOMAc and with substantial freedom in the choice of quantum-chemical method.
Neighboring-Group Participation by a Less Electron-Donating, Participating C-2-Ester Ensures Higher 1,2-trans Stereoselectivity in Nucleophilic Substitution Reactions of Furanosyl Acetals
Yuge Chun - ,
Wouter A. Remmerswaal - ,
Jeroen D. C. Codée *- , and
K. A. Woerpel *
This publication is Open Access under the license indicated. Learn More
Nucleophilic substitution reactions of C-2-acyloxy furanosyl acetals can be highly diastereoselective. We here show that the presence of a less electron-donating p-nitrobenzoyloxy group at C-2 of a furanosyl acetal can be of use to control the 1,2-trans stereoselectivity of acetal substitution reactions with higher stereoselectivity than the analogue with the more electron-donating benzoyloxy group, just as what was observed in the pyranosyl system. Computational results support a reaction manifold involving both open oxocarbenium ions and cis-dioxolenium ions to provide the 1,2-cis and 1,2-trans products. Participation by the less electron-donating C-2-(p-nitrobenzoyloxy) group forms a less stabilized cis-dioxolenium ion that reacts with the incoming nucleophile more readily to provide 1,2-trans products. The relative stability of the furanosyl cis-dioxolenium ion versus the open oxocarbenium ion is much higher than the pyranosyl system as a result of the lower energy penalty for forming the cis-fused [5,5]-bicyclic dioxolenium ion.
Enantiospecific Synthesis of Tetrahydroindolizines from Spiro-cyclopropanecarboxylated Sugars
M V Kamala Lakshmi - ,
Intzar Ali - , and
Ramu Sridhar Perali *
A facile two-step enantiospecific synthesis of 5,6,7,8-tetrahydroindolizine scaffolds has been developed via TMSOTf-promoted [3 + 2] cycloaddition between carbohydrate-derived spirocyclic donor–acceptor cyclopropanecarboxlates and alkyl/aryl nitriles followed by an intramolecular Mitsunobu reaction of the resulting chiral 2/5-(4-hydroxybutyl)pyrrole derivatives.
Rh(III)-Catalyzed [4 + 2] Annulation and Dehydrogenative Annulation of N-Chloroimines with Maleimides
Hanxiao Xu - ,
Zhixin Wang - ,
Xuanzhen Han - , and
Jin Zhu *
We herein report a Rh(III)-catalyzed C–H bond coupling of N-chloroimines with maleimides, in which the [4 + 2] annulation and dehydrogenative annulation processes can be selectively achieved by simply adjusting the reaction conditions. This protocol is compatible with various functional groups, shows exquisite selectivity, and presents a concise synthetic procedure to respective products in moderate to good yields. With all these merits, this strategy may be applicable in the construction of related azaheterocyclic skeletons.
January 14, 2025
Dual Photoredox and Copper-Catalyzed Asymmetric Remote C(sp3)–H Alkylation of Hydroxamic Acid Derivatives with Glycine Derivatives
Jian Chen - ,
Pingping Ruan - ,
Hongying Fan - ,
Xue Zhang - ,
Shiyun He - ,
Jinyu Hou - ,
Meiling Ye - ,
Yuanyuan Li - ,
Guanghui Lv *- , and
Yong Wu *
Dual photoredox and copper-catalyzed remote asymmetric C(sp)3–H alkylation of hydroxamic acid derivatives with glycine derivatives via a 1,5-hydrogen transfer (1,5-HAT) process has been realized. The reaction was characterized by redox-neutral and mild conditions, good yields, excellent enantioselectivity, and broad substrate scope. This protocol provides a straightforward and efficient strategy to prepare highly valuable enantioenriched noncanonical α-amino acids. Moreover, the potential synthetic value of this reaction was demonstrated in late-stage asymmetric alkylation of dipeptides with a high diastereomeric ratio.
Synthesis and Structure of Methylated Acetylenic Nitriles
Dirk Hollenwäger *- ,
Daniela Staudacher - ,
Niklas Kölbl - ,
Dominik Leitz - ,
Valentin Bockmair - , and
Andreas J. Kornath
Cyanoacetylene and dicyanoacetylene react in the ternary methylation system CH3F/SbF5/SO2 under the formation of its corresponding N-monomethylated and N,N′-dimethylated species, respectively. Additionally, in the case of dicyanoacetylene, an N,N′-dimethylated HF-addition product was obtained. The salts were characterized by low-temperature vibrational spectroscopy. In the case of [C4H4N][SbF6], [C5H3N2][SbF6]·SO2, and [C6H8N2F2][SbF6]2, single-crystal X-ray structures are reported. Surprisingly, all of the obtained salts are room-temperature stable. The experimental data are discussed, together with quantum chemical calculations at the M06-2X/aug-cc-pVTZ level of theory.
Bis(dialkylaminethiocarbonyl)disulfides Act as Electron Acceptors for EDA Complexes for the Synthesis of Dithiocarbamate Derivatives under Visible Light
Hong Yang - ,
Yuanyuan Cheng - ,
Haibo Zhu - ,
Gaowen Ren - ,
Dongliang Zhang - ,
Zhanggao Le - , and
Zongbo Xie *
This study proposes a green and efficient atom- and step-economical method for converting hazardous CS2 to dithiocarbamate derivatives under visible light irradiation and catalyst-free conditions. By the construction of novel C–S and C–N bonds, a series of β-dicarbonyl compounds and amines are incorporated into the products. Under light, CS2 and amine first form bis(dialkylaminethiocarbonyl)disulfides, which then react with K2CO3-activated β-dicarbonyl compounds to form electron donor–acceptor (EDA) complexes and subsequently generate the target products. This study confirms for the first time that bis(dialkylaminethiocarbonyl)disulfides can act as electron acceptors to form an EDA complex with β-dicarbonyl compounds, which are then coupled to form the target product under light.
Synthesis of Sulfonated Peptides Using a Trifluoromethyltoluene-Protected Amino Acid
Ashley E. DeYong - ,
Kaicheng Li - , and
Elliot L. Chaikof *
A scalable, seven step synthesis is reported for a trifluoromethyl toluene protected sulfonated phenylalanine building block whose utility was demonstrated in the synthesis of four CXCR4-derived sulfonopeptides. When compared to a conventional trichloroethyl protected building block, overall yield was improved by up to 4-fold. We believe this building block will prove to be of significant value for the synthesis of a variety of peptide targets containing phenylalanine sulfonate, a bioisostere of tyrosine sulfate, enabling orthogonal protection strategies and improving synthetic efficiency and yield.
Visible-Light-Induced C(sp3)-H Activation for Minisci Alkylation of Pyrimidines Using CHCl3 as Radical Source and Oxidant
Jiatian Zhuo - ,
Jinshan Liu - ,
Min Zhou - ,
Lin Ma - , and
Min Zhang *
A highly efficient Minisci reaction of pyrimidines with alkyl radical generated from visible-light-induced activation of simple C(sp3)-H feedstocks such as (cyclo)alkanes, ethers, alcohols, esters, and amides is reported. A mechanistic study revealed that alkyl radical was generated via hydrogen atom transfer (HAT) of C(sp3)-H with dichloromethyl radical (·CHCl2), which was generated by photoreduction of chloroform.
Visible-Light-Mediated Cascade 1,4-Hydrogen Atom Transfer versus Dearomative Spirocyclization of N-Benzylacrylamides: Divergent Access to Functionalized γ-Ketoamides and 2-Azaspiro[4.5]decanes
Chandra Shekhar Nishad - ,
Ashish Kumar - ,
Kamaldeep Kaur - , and
Biplab Banerjee *
Visible-light-driven metal- and photocatalyst-free cascade 1,4-HAT and dearomative spirocyclization of N-benzylacrylamides are described for sustainable synthesis of a variety of pharmaceutically important γ-ketoamides and 2-Azaspiro[4.5]decanes in one pot in good to excellent yields. Readily accessible and nontoxic materials, expensive Ir or Ru photocatalyst-free mild conditions, excellent functional group tolerance, operational simplicity, and scalability enhance the practical value of this protocol. Mechanistic studies reveal that acyl radicals generated from α-oxocarboxylic acids trigger the rare 1,4-HAT and dearomative spirocyclization. The synthetic potential of this environmentally benign method is further showcased by late-stage functionalization of drug molecules, amino acid, and peptides.
Manganese(III)-Mediated Selective Cascade Phosphorylation-Cyclization of Tertiary Enamides for the Synthesis of Multi-Substituted 3-Phosphorylpyridines
Xin-Ming Xu *- ,
Sen Chen - ,
Qian Liu - ,
Xinyue Cao - ,
Zhongyuan Zhao - ,
Jinchun Chen *- ,
Yuhang Yao - ,
Chan Yang - , and
Kai Sun *
A novel regioselective manganese(III)-mediated radical cascade cyclization of N-propargyl enamides with various H-phosphine oxides, H-phosphinates and H-phosphonates was developed. Mechanistic studies show that the reaction is mainly composed of the selective addition of phosphonyl radical to C≡C bond and the intramolecular 6-endo-trig cyclization of vinyl radical. Utilizing this protocol, we successfully synthesized a diverse range of 3-phosphorylpyridines in high efficiency with good functional group compatibility and simple operation.
January 13, 2025
Silver-Catalyzed Cascade Radical Isonitrile Insertion/Defluorinative Cyclization: Direct Synthesis of 4-CF2H-2-Phosphinoyl-quinolines
Xuehua Zhang - ,
Ping Wang - ,
Yubo Jiang - ,
Baomin Yang - , and
Tiebo Xiao *
A novel silver-catalyzed cascade radical isonitrile insertion and defluorinative cyclization have been developed to synthesize CF2H- and phosphinoyl-containing quinolines from ortho-isocyanyl α-trifluoromethylstyrenes. The reaction proceeded under redox-neutral conditions and allowed the construction of a highly attractive quinoline ring system, with the simultaneous formation of the CF2H group and introduction of various phosphinoyl groups in a single transformation, showing operational simplicity, a wide substrate scope, good tolerance for functional groups, and remarkable atom-/stepeconomy. Mechanistic studies indicated that the reaction is likely to involve the participation of P-centered radicals and key carbanion intermediates.
Visible-Light-Induced Glycosylation/Annulation of 2-Isocyanobiaryls and Glycosyl NHP Esters to Access Nonclassical Heteroaryl C-Glycosides
Guanghui Lv - ,
Yangyang Wang - ,
Penghua Zhang - ,
Yafei Zhu - ,
Mi Wang - ,
Zhaohui Ma - ,
Cuimei Zhang - ,
Jian Chen - ,
Li Guo *- , and
Yong Wu *
A photoredox-promoted cascade glycosylation/cyclization reaction of 2-isocyanobiaryls and glycosyl NHP esters was established for the synthesis of nonclassical heteroaryl C-glycosides. This methodology is characterized by an exceedingly simple reaction system, high diastereoselectivity, and good functional group tolerance. In contrast to traditional strategies, this innovative approach circumvents the need for high temperature, transition metal, and photocatalyst, offering an environmentally friendly and efficient protocol.
Copper-Catalyzed Radical Cascade Cyclization of N-Substituted Indole-3-Aldehydes with Aryl Alkenes: Access to Pyrrolo[1,2-a]indole Scaffolds
Weibo Cheng - ,
Junzheng Sun - ,
Changji Liu - ,
Yidong Zhong *- ,
Chengcai Xia *- , and
Wenjing Yang *
Herein, we report a Cu-DTBP-catalyzed [3 + 2] cycloaddition reaction between 1-(2-oxo-2-phenylethyl)-1H-indole-3-aldehyde and arylalkene, using DMF as the solvent. Under relatively mild reaction conditions, a series of indole compounds were synthesized in moderate yields (up to 73%). This protocol features good functional group tolerance and high atom economy. In addition, we synthesized a total of 20 target compounds, providing a reliable and straightforward method to obtain structurally diverse pyrrolo[1,2-a]indole derivatives.
January 12, 2025
Water-Compatible Staudinger–Diels–Alder Ligation
Masaru Tanioka *- ,
Shohei Kanayama - ,
Fumino Kitamura - ,
Akinari Takano - ,
Yukiko Ikeda - ,
Aki Kohyama - ,
Tsuyoshi Yamada - , and
Yuji Matsuya *
The development of bioorthogonal reactions is expected to propel further advances in chemical biology. In this study, we demonstrate Staudinger–Diels–Alder (SDA) ligation as a candidate for a new bioorthogonal reaction. This reaction ligates two molecules via strong C–C bonds at room temperature. We found that the aryl substituent of azide-benzocyclobutene (azide-BCB) had a strong influence on the molecule’s tolerance to water. In particular, Cl-substituted azide-BCBs generated the ligated product in high yield, even in the presence of water. Mechanistic investigations using DFT methods revealed that hydrophobic electron-withdrawing substituents suppressed the side reactions of SDA ligation.
Continuous-Flow Ritter Reaction for Sustainable Amide Synthesis Using a Recyclable m-Phenolsulfonic Acid-Formaldehyde Resin Catalyst
Eman Soliman - ,
Heeyoel Baek - ,
Nobuyuki Mase - , and
Yoichi M. A. Yamada *
Herein, a rapid and efficient continuous-flow synthesis of amides is described. The Ritter reaction, catalyzed by a reusable solid acid catalyst composed of m-phenolsulfonic acid-formaldehyde resin (PAFR II), was used to convert nitriles and alcohols to amides in up to 90% yield. The continuous-flow system facilitates short reaction times and maintains activity for several weeks. This method is scalable, environmentally sustainable, and enables catalyst recycling.
PIII/PV═O Redox Catalysis Mediated Thioesterification of Carboxylic Acids with Disulfides under Air Conditions
Gang Sun - ,
Yi-Feng Zhao - ,
Yi-Han Yu - ,
Xiaoan Wen - ,
Haoliang Yuan - ,
Hongbin Sun *- , and
Qing-Long Xu *
An efficient organophosphorus-catalyzed thiocarbonylation reaction of disulfides with carboxylic acids under air conditions was described. Various functional groups on carboxylic acids and disulfides can be tolerated under the present reaction conditions, affording thioesters in good to excellent yields. This method exhibited excellent chemoselectivity and can be applied for the late-stage functionalization of drug molecules containing a carboxylic acid group.
January 10, 2025
Transient Directing Group-Assisted Palladium-Catalyzed C4-Alkynylation of Indoles
Shuqi Guo - ,
Huanfeng Jiang - ,
Shaorong Yang - , and
Wanqing Wu *
Pd-catalyzed C4-selective alkynylation of indoles was established by employing glycine as a transient directing group. This reaction exhibits high regioselectivity with the tolerance of a wide scope of functional groups to afford diverse alkynylated indoles in moderate to good yields. Moreover, the readily accessible scale-up synthesis and further decorations to achieve multifunctionalized indoles demonstrate the synthetic potential of this protocol.
Oxo-Sulfonylation of 1,7-Enynes via a Multicomponent Oxidative Radical Polar Crossover Approach
Pooja Yadav - ,
Prasun Sinha - , and
Purushothaman Gopinath *
Diastereoselective synthesis of trans-3,4-difunctionalized tetrahydroquinoline and chromane derivatives via the oxo-sulfonylation of 1,7-enynes is demonstrated. The reaction involves a three-component oxidative radical polar crossover (ORPC) approach wherein a vinyl carbocation intermediate undergoes nucleophilic substitution to afford the corresponding keto functional group. Deprotection of the N-Ts group, gram-scale synthesis, and other synthetic applications were illustrated. Control experiments and mechanistic studies show that water acts as the nucleophile in this reaction.
Copper-Catalyzed Domino Annulation of Isoselenocyanates: A Pathway to Structurally Diverse N, Se-Bis-Heterocyclic, and Fused Heterocyclic Compounds
Hai-Yang Wang - ,
Yi-Ling Fang - ,
Ying-Chun Wang *- , and
Yan He *
A copper-catalyzed domino addition/cyclization reaction was developed to synthesize novel benzoselenazole-linked 1,2,3-triazole and tetracyclic fused 12H-benzo[4,5]selenazole[2,3-b]quinazolin-12-one derivatives from isoselenocyanates. This domino reaction efficiently constructed multiple new chemical bonds in a single step, forming either four (one C–Se and three C–N) or three (one C–Se and two C–N) bonds. The reaction offers several key advantages, including mild conditions, broad substrate compatibility, and straightforward and safe operation. It presents a new method for synthesizing N, Se-containing polycyclic compounds, which have potential interest in medicinal chemistry. Notably, some of the synthesized compounds exhibited anticancer activity with IC50 values below 20 μmol L–1 against T24 human bladder cancer cells.
Diels–Alder Reactions of Boron-Substituted Furans with N-Phenylmaleimide: Strategies for Tuning the Reactivity and Selectivity
Federico Dezotti - ,
Noelia S. Medrán - , and
Silvina C. Pellegrinet *
The Diels–Alder reactions of boron-substituted furans with N-phenylmaleimide have been investigated experimentally and computationally. In contrast to previous results with maleic anhydride, in this case potassium 3-furanyltrifluoroborate and the analogue at C-2 reacted efficiently, giving the [4 + 2] cycloadducts at room temperature with high yields. The exo diastereoisomer was obtained exclusively for the latter, while its C-3 counterpart showed variable endo/exo diastereoselectivities. Many strategies have been devised to improve the reactivity and selectivity of 3-boryl furans.
From Pseudocyclic to Macrocyclic Ionophores: Strategies toward the Synthesis of Cyclic Monensin Derivatives
Michał Sulik - ,
Robert Graniczny - ,
Jan Janczak - ,
Dagmara Kłopotowska - ,
Joanna Wietrzyk - , and
Adam Huczyński *
This publication is Open Access under the license indicated. Learn More
There has been a long search for a simple preparation of new cyclic analogues of ionophore antibiotics. We report a simple and general synthesis of three new cyclic derivatives of polyether ionophore, monensin A (MON). The application of the Huisgen 1,3-dipolar cycloaddition of azides and terminal alkynes to macrocyclization results in a concise, synthetic route to monensin lacton or lactam in only 4 steps. Additionally, macrolactamization by a simple amidation reaction using HATU, a commonly used conjugating agent, gives 72% yields and utilizes neither high dilution techniques nor template effects in the cyclization step. This in turn enables ready access to a range of unnatural MON analogues, showing the ability to form complexes with monovalent and divalent metal cations.
January 9, 2025
Impact of Adding N-hexylamine to Nickel Metallophotoredox C–N Coupling to Form Diarylamines
Haiyang Wang - ,
Fujun Li - ,
Wenbo Yang - ,
Yuchao Wang - ,
Alexander A. Miskevich - ,
Valery A. Loiko - ,
Lijing Zhang *- , and
Shengyang Tao *
The mechanistic understanding of how alkylamines impact Ni-metallophotoredox C–N coupling to form diarylamines remains unclear. In this study, 12-alkylamines were evaluated as additives to determine their effects on the synthesis of diarylamines in a flow photochemical system. Notably, n-hexylamine demonstrated the most significant promotional effect. Spectroscopic studies and experimental data reveal n-hexylamine substitutes DABCO as a Ni catalyst ligand, enhancing yields particularly in sterically hindered arylamines.
Four Alkaloids from Alstonia scholaris with Antitumor Activity via Disturbing Glutathione Homeostasis
Hao-Fei Yu - ,
Zhi Dai - ,
Lan-Chun Zhang - ,
Cai-Feng Ding - ,
Khalid-Hassan Mohamed - ,
Gui-Guang Cheng - ,
Xin Wei - ,
Ya-Ping Liu - ,
Rong-Ping Zhang *- , and
Xiao-Dong Luo *
Alstoschoquinolines A–D (1–4) representing three unprecedented scaffolds were isolated from the leaves of Alstonia scholaris through direct separation by LC/MS detection. 1 and 2 consisted of a 5/6/5-coupled quinoline architecture containing six consecutive chiral carbons, while 3 and 4 possessed a bridged ring featuring 6/6/6/6 and 6/6/8/6 skeletons, respectively. They might be derived from the corynantheine-type indole alkaloid via sequential oxidation and rearrangement. Compound 3 exhibited a significant inhibitory effect on colon carcinoma cells by disturbing glutathione circulation.
Merging Photoinduced Electron Transfer with Hydrogen Atom Transfer: Formal β-C(sp3)–H Pyridination of Carbonyls
Jian Li - ,
Jun Xu *- ,
Binbin Chen - ,
Qing Pang - ,
Jiabin Shen - ,
Kai Wang - , and
Pengfei Zhang *
In this study, a novel approach that combines photoinduced electron transfer (ET) with hydrogen atom transfer (HAT) has been introduced for the selective β-C(sp3)–H pyridination of carbonyl compounds. This method is notable for its absence of transition metals and its ability to function under benign reaction conditions, resulting in a range of pyridinated carbonyl derivatives with consistently moderate to good yields. The significance of this technique is further underscored by its potential for the late-stage functionalization of pharmaceutically significant molecules. Mechanistic investigations confirmed that the reaction proceeds via a radical-mediated pathway.
Visible Light-Induced Divergent Deoxygenation/Hydroxymethylation of Pyridine N-Oxides
Changhao Feng - ,
Hao Guo *- , and
Aishun Ding *
This study explores the deoxygenation of pyridine N-oxides and presents a one-step photoredox method for the direct synthesis of 2-hydroxymethylated pyridines from pyridine N-oxides. Mechanism studies elucidate the role of the catalyst and provide evidence of the possible electron transfer process and the formation of key radicals. A range of pyridine derivatives, particularly 2-hydroxymethyl-substituted pyridines, which may be difficult to obtain, can be synthesized in a single step.
Palladium-Catalyzed Tandem Reaction of β-Ketonitriles with Arylboronic Acids and Dimethyl Sulfoxide: Application to Multicomponent Synthesis of Poly-Substituted Pyridines
Ge Zeng - ,
Shiyan Wang - ,
Wantong Han - ,
Honggui Zhou - ,
Min Liu - ,
Yifei Li - ,
Miaochang Liu - ,
Jiuxi Chen *- , and
Renhao Li *
The Pd-catalyzed multicomponent tandem reaction of β-ketonitriles, arylboronic acids and DMSO was efficiently developed, enabling access to a variety of poly substituted pyridines. The protocol shows excellent chemoselectivity, generating nicotinonitriles or symmetrical tetrasubstituted pyridines under different conditions by tandem cyclization of enaminone intermediates with β-ketonitriles or enolates, respectively, and does not require extra ammonias. This method boasts notable advantages, such as the use of commercially available or easily prepared substrates, simple conditions, a broad substrate scope, and good functional group tolerance.
Visible-Light-Induced Imine Hydrogenation Catalyzed by Thioxanthone-TfOH Complex
Shijie Sun - ,
Jiahong Wang - ,
Hao Guo *- , and
Aishun Ding *
Amino compounds are important molecules, commonly found in nature and widely applied in industrial production. Recently, photocatalysis has been discovered as an efficient method to synthesize amino compounds by promoting imine hydrogenation. In this work, a strategy of imine hydrogenation catalyzed by 2e– consecutive photoinduced electron transfer (ConPET) process of thioxanthone-TfOH complex (9-HTXTF) was thoroughly investigated with its reaction conditions optimized, substrate scope examined, and reaction mechanism elucidated, which provides an efficient method for synthesizing amino compounds.
January 6, 2025
Ru(II)-Catalyzed ortho-Vinylation of Benzoic Acids in Water
Lalit Negi - ,
Aditi Soni - ,
Deepak Sharma - ,
Manisha Manisha - , and
Raj K. Joshi *
Herein, we report an efficient [Ru(η6-C6H6)Cl2]2 catalyzed oxidative C–H alkenylation of benzoic acid in the green solvent water. A regioselective olefination of benzoic acid with functionalized alkenes like styrene and acrylate was established at a very mild condition of 60 °C temperature and in an aqueous medium. In contrast to the cyclization of the carboxylic group, a selective ortho-olefination product of benzoic acid was observed with the acrylate. Moreover, a selective formation of mono-olefinated products were observed with activated olefins (acrylate), while mono and diolefinated products were recorded with unactivated olefins (styrene). In contrast to the reactivity of acrylates and styrenes, a fruitful development and formation of a novel five-member cyclic ring, i.e., the (Z)-3-ferrocenylideneisobenzofuran-1(3H)-one, was observed when vinylferrocene was considered as a coupling partner for the reaction.
Concerted or Stepwise? An Experimental and Computational Study to Reveal the Mechanistic Change as a Result of the Substituent Effects
Xiao Li *- and
Matthew P. Meyer
This study investigates the Cope elimination reaction, focusing on the mechanistic shift between concerted and stepwise pathways influenced by substituent effects. Experimental approaches, including kinetic isotope effects (KIEs) and linear free energy relationships (LFERs), alongside density functional theory (DFT) computations, were employed to explore the influence of substituents on the reaction kinetics and pathways. Our findings reveal temperature- and substituent-dependent partitioning between the concerted syn-β elimination and the stepwise E1cB mechanism, providing deeper insights into the mechanistic diversity of elimination reactions.
December 24, 2024
Iron-Assisted and Cu-Mediated Direct Aminocarbonylation of Nitroarene with Boronic Acid
Deepak Sharma - ,
Charu Sharma - ,
Sangeeta Kumari - , and
Raj K. Joshi *
Herein, we have established the formation of diaryl amide by aminocarbonylation of nitrobenzene with boronic acids. The method works in the catalytic presence of economical and commercially available CuI salt, which was significantly promoted by the Fe3Se2(CO)9 cluster. Mo(CO)6 serves as a source of CO, and it also acts as a reductant with a combination of iron cluster. Moreover, all the reaction worked under the ligand-free system and produced the desired diaryl amide in a significant time of 10 h. Water, a green solvent, was used as a source of hydrogen for the reduction of nitrobenzene to aniline. The method depicts a suitable functional group tolerance and produces a wide range of substrates in good to excellent amounts. To the best of our knowledge, this is the first report for the direct aminocarbonylation mediated by highly economical CuI. Moreover, water as a source of hydrogen for the reduction of nitroarene is always appreciated.
November 29, 2024
Advancements in Loop Cyclization Approaches for Enhanced Peptide Therapeutics for Targeting Protein–Protein Interactions
Lucia Lombardi *- ,
Luke A. Granger - ,
Robin J. Shattock - , and
Daryl R. Williams
This publication is Open Access under the license indicated. Learn More
Protein–protein interactions (PPIs) are pivotal in regulating cellular functions and life processes, making them promising therapeutic targets in modern medicine. Despite their potential, developing PPI inhibitors poses significant challenges due to their large and shallow interfaces that complicate ligand binding. This study focuses on mimicking peptide loops as a strategy for PPI inhibition, utilizing synthetic peptide loops for replicating critical binding regions. This work explores turn-inducing elements and highlights the importance of proline in promoting favorable conformations for lactamization, yielding high-purity cyclic peptides. Notably, our one-pot method offers enhanced versatility and represents a robust strategy for efficient and selective macrolactamization, expanding the scope of peptide synthesis methodologies. This approach, validated through the synthesis of AAV capsid-derived loops, offers a robust platform for developing peptide-based therapeutics and highlights the potential of peptide macrocycles in overcoming PPI drug discovery challenges and advancing the development of new therapeutics.
November 27, 2024
Visible-Light-Induced Divergent Oxygenation of Methylbenzene Utilizing Aryl Halides
Jianing Li - ,
Zongyi Yu - ,
Jingnan Zhao *- ,
Cunfei Ma - ,
Liyuan Duan - ,
Zunchao Liu - ,
Huinan Sun - ,
Guofeng Zhao - ,
Qilei Liu - , and
Qingwei Meng *
The selective oxidation of methylbenzene to value-added products is of indisputable importance in organic synthesis. Although photocatalytic oxidation reactions of toluene have achieved great success for the preparation of its oxidative products, such as carboxylic acids, benzaldehyde, and benzoate, there remains a lack of a unified photocatalytic system for the selective preparation of these oxidation products. Herein, we report a metal- and additive-free photocatalytic protocol enabled by aryl halides using O2 as a green oxidant for the selective synthesis of the above-mentioned three oxidation products by adjusting the reaction solvent. This strategy features many advantages, including environmentally friendly and mild reaction conditions, broad substrate applicability and functional group tolerance, and potential practical application for the synthesis of aromatic carboxylic drugs and polymer materials and degradation of polystyrene waste. The continuous-flow system was utilized for the oxidation of toluene, which resulted in a reduced reaction time and increased production efficiency. Detailed mechanistic investigation revealed that the hydrogen atom transfer process was facilitated by the bromine radical from aryl halides for further oxidation, and an electron donor–acceptor complex of methylbenzene and aryl halides may exist.