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)].
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.
Lewis Acid-Mediated Regioselective Hydrofunctionalization of Styrenes with Isatins and Heterocycles
Shengxiang Qin - ,
Yunshi Liao - ,
Qiang Ni - ,
Rihui Cao - ,
Albert S. C. Chan - , and
Liqin Qiu *
The ligand-free Lewis acid-mediated regioselective hydroamination and hydroarylation of styrenes have been successfully developed in the presence of isatins or heterocyclic aryl compounds such as benzothiophenes and benzofurans. The reactions tolerate a variety of functional groups and afford the corresponding products in moderate to good yields. Deuterium labeling experiments show that the functionalized hydrogen of styrenes was derived from the nitrogen–hydrogen of the substrates in the hydroamination. Preliminary mechanistic studies suggest that the reactions may be a radical or a carbocation process.
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 8, 2025
Combining Photochemical Oxyfunctionalization and Enzymatic Catalysis for the Synthesis of Chiral Pyrrolidines and Azepanes
Maria Logotheti - ,
Susanne Gehres - ,
Alexandre S. França - ,
Uwe T. Bornscheuer - ,
Rodrigo O. M. A. de Souza *- , and
Matthias Höhne *
This publication is Open Access under the license indicated. Learn More
Chiral heterocyclic alcohols and amines are frequently used building blocks in the synthesis of fine chemicals and pharmaceuticals. Herein, we report a one-pot photoenzymatic synthesis route for N-Boc-3-amino/hydroxy-pyrrolidine and N-Boc-4-amino/hydroxy-azepane with up to 90% conversions and >99% enantiomeric excess. The transformation combines a photochemical oxyfunctionalization favored for distal C–H positions with a stereoselective enzymatic transamination or carbonyl reduction step. Our study demonstrates a mild and operationally simple asymmetric synthesis workflow from easily available starting materials.
Cobalt(II)-Catalyzed Selective C2–H Heck Reaction of Native (N–H) Indoles Enabled by Salicylaldehyde Ligand
Jia-Wei Li - ,
Shuai Shi - ,
Xiao-Hong Chen - ,
Mao-Gui Huang - ,
Yong-Liang Ban - ,
Hui Zhang - , and
Yue-Jin Liu *
Direct functionalization of native (N–H) indoles via C–H activation remains a challenge. Herein, we report a salicylaldehyde-promoted cobalt-catalyzed selective C2–H Heck reaction of native (N–H) indoles with both active and unactivated olefins in the presence of free N–H bonds. A series of structurally diverse C2-alkenylated native (N–H) indoles including natural product and drug derivatives were prepared directly and effectively without additional preprotection and deprotection procedures.
Metal-Free Electrochemical Allylic C–H Aerobic Oxidation
Tong Shen - ,
Jianyou Zhao - ,
Xuanxuan Ren - ,
Zhong-Quan Liu *- , and
Shuai Liu *
A scalable and sustainable electrochemical protocol for allylic C–H aerobic oxidation has been developed, enabling the formation of enones without the use of stoichiometric toxic oxidants or metal catalysts and offering an environmentally benign alternative to traditional chemical oxidation techniques. The process has been successfully applied to selectively oxidize a series of natural products and drug molecules, underscoring its potential for widespread adoption in both academic and industrial contexts.
January 7, 2025
Modular Room Temperature Synthesis of Sulfoximidoyl Amidines Enabled by Pd-Catalyzed Cascade Aza-Claisen Rearrangement Strategy
Zhigang Huang - ,
Zhengyu Xu - ,
Tianming Huang - ,
Fang Xun - ,
Jianqiao Weng - ,
Li Wei - , and
Zhiyuan Chen *
Reported herein is a concise synthesis of sulfoximidoyl amidines enabled by a Pd-catalyzed cascade aza-Claisen rearrangement and nucleophilic reaction at room temperature. Free NH-sulfoximines and N-allylynamides were employed as the modular building blocks to produce the expected sulfoximine amidine derivatives in highly chemoselective models and in 100% atom efficiency. A broad range of functional groups were well tolerated under these gentle reaction conditions to give the desired products in generally good to excellent yields.
Cross-Coupling of Carbonyl Derivatives and N-Arylamines Enabled by Visible Light for Easy Access to 1,2-Amino Alcohols
Yan Xu - ,
Haohuan Zhuang - ,
Yulin Song - ,
Weiqiong Shi - ,
Xu Chen - ,
Lixiang Zhang - ,
Xuan Huang *- , and
Junmin Zhang *
We disclosed a new strategy for the synthesis of 1,2-amino alcohols enabled by visible light without the requirement of a photocatalyst and metal. Under light irradiation at 400 nm, the reaction of carbonyl derivatives and N-arylamines proceeds via an electron-donor–acceptor (EDA) intermediate, obtaining diverse vicinal amino alcohols decorated with a two-electron-rich/-deficient aryl group.
Direct Synthesis of 2-Functionalized 3-Nitroindoles from Diazo(nitro)acetanilides
Qingchun Meng - ,
Xuan Ke - , and
Jiaxi Xu *
2-Hydroxyl/acetoxy-3-nitroindoles are directly and efficiently prepared in good to excellent yields from diazo(nitro)acetanilides under the catalysis of Cu(MeCN)4PF6 in DCM through an intramolecular aromatic C–H insertion or followed by acetylation. 2-Hydroxyl-3-nitroindoles can be further transformed to 3-halo-3-nitroindolin-2-ones and 3-alkanamidoindolin-2-ones readily. All of them are important synthetic building blocks for construction of indole derivatives.
Direct Stereoselective Synthesis of 2-Deoxyglycosides via Visible-Light-Induced Photoacid-Catalyzed Activation of Glycosyl o-[1-(p-MeO-Phenyl)vinyl]benzoates (PMPVBs) as Donors
Mahendra K. V. Rotta - ,
Sangay Moktan - ,
Priyanka Pradhan - , and
Pavan K. Kancharla *
The photoacid-catalyzed synthesis of 2-deoxy glycosides is presented using stable glycosyl o-[1-(p-MeO-Phenyl)vinyl]benzoate (PMPVB) donors and employing the eosin Y and diphenyl disulfide (PhSSPh) catalytic system in the presence of blue LED lights. The remote activation of the alkene functionality under the photoacid catalysis followed by a 5-exo-trig cyclization led to the generation of oxocarbenium ions that were trapped to provide the glycosylated products in excellent yields and decent selectivities under mild conditions. This method is also useful for the photoacid-catalyzed synthesis of p-methoxybenzyl-alkyl ethers.
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.
Base-Controlled Synthesis of Heteroatom-Embedded 9-Membered Cycloalkynes and 6-Membered Sultams through Copper-Catalyzed Cyclization
Haoyang Liu - ,
Hailiang Xing - ,
Peilan Yu - ,
Yanjie Wang - ,
Jia-Lei Yan - ,
Junyang Liu *- , and
Min Wang *
A facile copper-catalyzed, base-controlled cyclization reaction has been developed for the synthesis of 9-membered cycloalkyne and 6-membered heterocycle sultams under mild conditions. This protocol utilizes a copper-catalyzed intramolecular A3 (alkyne–aldehyde–amine) coupling reaction to efficiently synthesize 9-membered cycloalkyne sultams in yields up to 90%. Alternatively, by substituting NaHCO3 with DBU, the protocol achieves selective deprotection of the N-propargyl group, thereby facilitating the formation of 6-membered heterocyclic sultams, also in high yields.
Silanediol-Bay-Bridge Rigidified Axially Chiral Perylene Bisimide
Oliver Nagler - ,
Rajeev K. Dubey - , and
Frank Würthner *
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Chiral organic molecules with a complementing π-structure are highly desired to obtain materials with good semiconducting properties and pronounced chirality effects in the visible region. Herein, we introduce a novel design strategy to achieve an axially chiral and rigid perylene bisimide (PBI) dye by attaching the chirality-inducing 2,2′-biphenoxy moiety at one side of the bay area and the rigidity-inducing di-tert-butylsilanediol bridge on the other side. This yielded a new bay-functionalized PBI derivative carrying the combination of a highly rigid and, simultaneously, an axially chiral perylene core. As a result, the derivative exhibits well-resolved absorption and emission spectra in the visible region, with a fluorescence quantum yield close to unity. Furthermore, the M- and P-enantiomers were found to be stable with a racemization barrier of 102 kJ mol–1 and, hence, could be successfully separated by chiral chromatography and studied by circular dichroism (CD) spectroscopy. This rigidified chiral-PBI could also be crystallized and analyzed by X-ray diffraction, showing the highest torsion angle of the perylene core with a value of up to 30.3° in the family of PBIs carrying the same di-tert-butylsilanediol bridge.
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.
π-Expanded and N-Doped Fluoranthenes
Franziska Spruner von Mertz - ,
Jonas Polkaehn - ,
Alexander Villinger - ,
Peter Ehlers - , and
Peter Langer *
Novel π-expanded and N-doped fluoranthenes were synthesized and thoroughly investigated. These eight unsubstituted compounds are obtained in a multistep synthesis with CH activation as the last key reaction step. The structures vary in their position of π-expansion on the fluoranthene scaffold and the location of the pyridinic nitrogen atom. This facilitates an in-depth investigation of the impact of such alterations in the fluoranthene structure on their overall properties. Accordingly, optical and electrochemical properties of these polyaromatic heterocycles were investigated, and DFT/TD-DFT and NICS calculations were performed. This paper entails a thorough study on b- and l,j-expanded and N-doped fluoranthenes.
Database Construction for the Virtual Screening of the Ruthenium-Catalyzed Hydrogenation of Ketones
Haruno Nakajima - ,
Chihaya Murata - ,
Naoki Noto *- , and
Susumu Saito *
During the recent development of machine-learning (ML) methods for organic synthesis, the value of “failed experiments” has increasingly been acknowledged. Accordingly, we have developed an exhaustive database comprising 300 entries of experimental data obtained by performing ruthenium-catalyzed hydrogenation reactions using 10 ketones as substrates and 30 phosphine ligands. After evaluating the predictive performance of ML models using the constructed database, we conducted a virtual screening of commercially available phosphine ligands. For the virtual screening, we utilized several models, such as histogram-based gradient boosting and Ridge regression, combined with the Mordred descriptors and MACCSKeys, respectively. The disclosed approach resulted in the identification of high-performance phosphine ligands, and the rationale behind the predictions in the virtual screening was analyzed using SHAP.
Diastereospecific Synthesis of Vicinally Substituted 2-Oxazolidinones via Oxidative Rearrangement of α,β-Unsaturated γ-Lactams
Anna Lidskog - ,
Yutang Li - ,
Arvind Kumar Gupta - ,
Abhishek Mishra - ,
Anders Sundin - , and
Kenneth Wärnmark *
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A diastereospecific synthesis of vicinally substituted 2-oxazolidinones from α,β-unsaturated lactams using m-chloroperoxybenzoic acid is reported. Several highly substituted 2-oxazolidinones were obtained in 19–46% yields in a one-pot reaction with complete control over the relative stereochemistry. The proposed reaction sequence consists of a Baeyer–Villiger oxidation, an epoxidation, and a concerted rearrangement. Experimental results and density functional theory calculations indicate that a CH2COOEt substituent at position 4 of the lactam is necessary for the diastereospecific rearrangement to take place.
January 5, 2025
Energy Transfer (EnT)-Mediated Stereoselective Aryl-Heterofunctionalization of Unactivated Alkynes via Radical Rearrangement
Xin-Chao Meng - ,
Tian-Xiong Pan - ,
Feng Yang - ,
Hai-Xi Zhu - ,
Yu-Wen Huang - ,
Bo-Rong Leng *- ,
De-Cai Wang *- , and
Yi-Long Zhu *
In this study, we present a novel catalyst-free energy transfer mediated radical rearrangement strategy for the aryl-heterofunctionalization of unactivated alkynes, leading to the synthesis of polyfunctional olefins with exceptional stereoselectivity. This innovative approach, driven by visible light, exemplifies green chemistry principles by eliminating the reliance on transition metals, external oxidants, and photocatalysts. The broad applicability of our method is demonstrated through the successful synthesis of a diverse array of compounds, including vinyl sulfones, vinyl selenides, and vinyl sulfides. Preliminary mechanistic insights suggest an energy transfer mechanism, highlighting the efficiency and selectivity of this novel strategy.
January 4, 2025
TEMPO-Mediated Direct C(sp2)–H Alkoxylation/Aryloxylation of 1,4-Quinones
Amol B. Gadekar - ,
Dhananjay S. Nipate - ,
Krishnan Rangan - , and
Anil Kumar *
A convenient and efficient transition-metal-free method has been developed for the C(sp2)–H alkoxylation/aryloxylation of 1,4-quinones by direct cross-dehydrogenative coupling with readily available alcohols and phenols in the presence of TEMPO under simple and mild conditions. The method allowed the installation of a wide range of alkoxy/aryloxy groups, exhibited high functional group tolerance, showed a broad substrate scope, afforded good to excellent yields of products in a simple one-pot operation, and could be performed on a gram scale. Mechanistic investigation indicated the involvement of the radical pathway.
Electrochemical Three-Component C–H Functionalization of Indoles with Sodium Bisulfite and Alcohols to Access Indole-Containing Sulfonate Esters
Wei Zhou - ,
Peng Chen - ,
Xiao-Qing Xie - ,
Yanli Wu - ,
Haixin Ding - ,
Ruchun Yang - ,
Xian-Rong Song - ,
Mu-Jia Luo *- , and
Qiang Xiao *
Herein, an efficient electrochemical three-component C–H functionalization of indoles with sodium bisulfite and alcohols is described, providing a sustainable and convenient synthetic route for the construction of structurally valuable indole-containing sulfonate esters in moderate to good yields. This protocol proceeds in an undivided cell without any metal catalysts or oxidants, features a broad substrate scope, and has an excellent functional group tolerance. Preliminary mechanistic studies suggest that a radical–radical pathway may be involved in this three-component reaction system.
Xanthine Nucleosides with Pyrazolo[3,4-d]pyrimidine Skeleton: Functionalization with Halogen Atoms, Clickable Side Chains, Pyrene, and iEDDA Cycloadducts, and Impact of Ionic Forms on Photophysical Properties
Dasharath Kondhare - ,
Simone Budow-Busse - ,
Constantin Daniliuc - , and
Peter Leonard *
Xanthine nucleosides play a significant role in the expansion of the four-letter genetic code. Herein, 7-functionalized 8-aza-7-deazaxanthine ribo- and 2′-deoxyribonucleosides are described. 2-Amino-6-alkoxy nucleosides were converted to halogenated 8-aza-7-deazaxanthine nucleosides by deamination followed by hydroxy/alkoxy substitution. 8-Aza-7-deaza-7-iodo-2′-deoxyxanthosine served as an intermediate in Suzuki–Miyaura, Sonogashira, and Stille reactions. Alkynyl and vinyl side chains as well as fluorescent tags were introduced. Pyrene conjugates were derived by copper(I)-catalyzed cycloaddition. Inverse-electron-demand Diels–Alder reaction of 8-aza-7-deaza-7-vinyl-2′-deoxyxanthosine with 3,6-dipyridyl-tetrazine proceeded with a second-order rate constant of 0.042 L M–1 s–1. X-ray analysis of 8-aza-7-deaza-7-vinyl-2′-deoxyxanthosine displayed two conformers with a syn conformation. Crystal packing is stabilized by xanthine base pairs. UV spectroscopy confirmed the sensitivity of 7-functionalized 8-aza-7-deazaxanthine nucleosides to pH changes. Halogen and alkynyl substituents decrease pK values, and vinyl, pyrene, or benzofuran leads to an increase. Fluorescence measurements of 8-aza-7-deaza-7-benzofuran-2′-deoxyxanthosine disclosed solvatochromism and enhanced fluorescence when the pH or the viscosity of the solvent is increased. Nucleoside pyrene conjugates connected by a linear linker displayed monomer emission, and two pyrene residues connected by a dendritic linker exhibited excimer emission. According to their fluorescence properties and sensitivity to pH changes, the functionalized 8-aza-7-deazaxanthine nucleosides expand the class of nucleosides applicable to fluorescence detection for diagnostic and therapeutic purposes.
January 3, 2025
Synthesis of N6-dA Damaged DNAs to Probe the Replication Ability of Human Translesion Polymerases
Siddharam Shivappa Bagale - ,
Priyanka U. Deshmukh - ,
Soumyadeep Mandal - ,
Harshada Malvi - ,
Kiran Kondabagil - , and
P. I. Pradeepkumar *
The DNA adducts formed by the alkenylbenzene natural products, safrole (SF) and methyleugenol (MEG) are primarily attributed to their reported carcinogenic properties. Herein, we report a concise strategy to access N6-Ac-SF/MEG-dA phosphoramidites, which were selectively incorporated into DNA oligonucleotides by solid-phase DNA synthesis. The replication studies using human polymerases hpolκ and hpolη showed that both polymerases replicate these adducts error-free, which indicates that these polymerases do not contribute to the adduct-induced mutagenicity.
Hydropersulfide (RSSH)-Mediated Hydrothiolation of Alkenes
Jeffrey Ash - ,
Kevin Curtis - ,
Shishir Bhowmik - ,
Samuel O. Odoh - , and
Jun Yong Kang *
A hydropersulfide-mediated hydrothiolation reaction of alkenes has been developed for C–S bond formation with Markovnikov selectivity. This new approach is a transition-metal-, additive-, and solvent-free reaction under mild conditions. The reaction is postulated to proceed by an ionic mechanism with the release of elemental sulfur based on our control experiments and density functional theory calculations.
Visible-Light-Catalyzed Fast Synthesis of 1,4-Benzoxazepine Derivatives from 2-Alkoxyarylaldehydes and N-Arylglycines
Sheng Huang - ,
Haibo Zhu - ,
AiXin Wang - ,
Guofang Jiang *- ,
Zhanggao Le - , and
Zongbo Xie *
A novel photocatalytic method for the synthesis of 1,4-benzoxazepine using 2-alkoxyarylaldehyde as an oxygen source and N-arylglycine as a nitrogen source has been reported. This method is mild, efficient, and fast, and the corresponding reaction can be completed within 2 h at room temperature under a nitrogen atmosphere and light-irradiation conditions. Mechanistic studies have confirmed that this scheme involves the decarboxylation cyclization of N-arylglycine and provides a convenient pathway for the preparation of various 2-alkyl-N-phenyl-substituted 1,4-benzoxazepine.
Palladium-Catalyzed Solvent-Controlled Divergent C2/C5 Site-Selective Alkynylation of Pyrrole Derivatives
Zeng Huang - ,
Chenjie Zhang - ,
Pengfei Zhou - ,
Cheng Wang - ,
Taoyuan Liang - ,
Shuangliang Zhao *- , and
Zhuan Zhang *
Among the known aromatic N-heterocycles, pyrroles are significant and versatile privileged components in pharmacologically relevant molecules. Herein, we demonstrate a protocol for the selective construction of alkynylated pyrroles in a diversity-oriented fashion through divergent C2/C5 site-selective alkynylation of pyrrole derivatives by employing a palladium catalyst with two different solvent systems. In the presence of 1,4-dioxane, the C2-alkynylation process via chelation-assisted palladation is favored. However, the use of a dimethylformamide/dimethyl sulfoxide (DMF/DMSO) solvent system could override the chelation effect of a weak ester-directing group, favoring the C5-alkynylation process via electrophilic palladation. Late-stage modification of biologically relevant scaffolds and further derivatization of the products highlighted the potential utility and importance of the solvent-controlled regiodivergence.
Synthesis of 6H-Benzo[c]chromene Scaffolds: A Synthetic Strategy of Pd-Catalyzed Annulation Followed by Aerial Oxidation
Kangkana Chutia - ,
Priyanka Saikia - ,
Dhiraj Dutta - ,
Babulal Das - , and
Pranjal Gogoi *
A synthetic strategy of a palladium-catalyzed cascade annulation reaction followed by aerial oxidation was designed to construct 6H-benzo[c]chromene scaffolds. Various 6H-benzo[c]chromenes were synthesized under mild reaction conditions using easily accessible p-QMs and commercially available o-hydroxyarylboronic acids. One of the synthesized chromenes has been ambiguously confirmed by single-crystal XRD analysis. Interestingly, our synthesized 6H-benzo[c]chromenes could be easily transformed into valuable 6H-benzo[c]chromen-6-ones via aerial oxidation.
January 2, 2025
Copper-Catalyzed Oxidative Arylation and Hydroxylation of Indolin-2-ones for Direct Construction of Tetrasubstituted Carbon Centers
Tian-Yu Li - ,
Lin-Lin Xu - ,
Dan-Qing Wu - ,
Jia-Jun Liu - ,
Yin Yang - ,
Zhiwei Miao *- , and
Da-Zhen Xu *
This study introduces a novel methodology for the direct construction of tetrasubstituted centers, utilizing secondary C(sp3)–H and C(sp2)–H substrates, specifically indolin-2-ones and indoles, through an innovative oxidative cross-coupling reaction. Facilitated by a straightforward copper salt catalyst, this reaction proceeds efficiently at a mild temperature of 40 °C under operationally streamlined conditions. Emphasizing sustainability, this method is notably enhanced by employing air (molecular oxygen) as an eco-friendly oxidant. In this approach, air (molecular oxygen) not only serves as the terminal oxidant but also as the oxygen donor in the synthesis of oxygen-containing compounds.
Molecular Sensing of Chiral Carboxylic Acid Enantiomers Using CD Inductions in the Visible Light Region
Jeffrey S. S. K. Formen - ,
Eryn Nelson - , and
Christian Wolf *
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The reaction between a chiral carboxylic acid molecule and 1,1′-bis(diphenylphosphino)ferrocenepalladium dichloride in the presence of a mild base generates a chiroptically active metal complex displaying strong circular dichroism (CD) signals in the visible light region, a highly sought-after goal in the optical sensing realm. The molecular recognition process is complete within a few minutes and can be used for fast chiroptical determination of the enantiomeric composition and concentration of carboxylic acid samples. This method is operationally simple and broadly applicable to a large variety of structures including important drugs, natural products, amino acids, and hydroxy acids. All components needed are commercially available, and this optical sensing assay can be readily adapted by any laboratory interested in chirality analysis and high-throughput experimentation.
Highly Diastereoselective Access to Densely Functionalized Piperidine Cores of Influenza Endonuclease Inhibitors via a Metal-Free SN1 Approach
Yonglian Zhang *- ,
Chunrui Sun *- ,
Liangqin Guo - ,
Kake Zhao - ,
Frank Bennett - ,
Yu-hong Lam - ,
Qi Gao - ,
Kyle E. Ruhl - ,
Michael T. Pirnot - ,
Marion H. Emmert - ,
Kaspar Hollenstein - ,
Michael J. Eddins - ,
Hua-Poo Su - ,
Guangxin Shao - ,
Chaohui Song - ,
Michael Man-Chu Lo - ,
Feng Peng - ,
Ji Qi - ,
Brendan M. Crowley - ,
John A. McCauley - , and
Ian R. Price
A novel, highly diastereoselective, and metal-free synthesis of multisubstituted piperidines via an SN1 approach is reported in this study. The method allows for the preparation of highly functionalized compounds with exceptional diastereomeric selectivities and consistently reproducible yields. These compounds are of significant interest due to their remarkable biological activities toward influenza endonuclease.
O2-Mediated Cu-Catalyzed Dehydrogenative Phenothiazination
Fang Xiao - ,
Xingben Wang - ,
Ben Ebel - ,
Iris M. Oppel - , and
Frederic W. Patureau *
In contrast to what one can be led to believe upon inspecting some of the recent literature, the dehydrogenative phenothiazination reaction does not require onerous technologies, complicated setups, or advanced catalysts in order to be mild and sustainable. We demonstrate this herein with a most facile, cost-effective, and sustainable Cu(II) catalyzed method, under 1 atm of O2 at room temperature in methanol, providing broad scope and high yields. These new results further set the dehydrogenative phenothiazination reaction among the green and practical coupling concepts of chemistry.
Mechanisms of Activating Agents to Form Organozinc Reagents from Zinc Metal: Lessons for Reaction Design
Martin Stang - ,
Erin M. Hanada - , and
Suzanne A. Blum *
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Activating agents enable the efficient preparation of organozinc complexes from zinc metal and organohalides, but their mechanisms had been obscured by the heterogeneous nature of these systems. Fluorescence microscopy, with the sensitivity to detect surface reaction intermediates, reveals distinct activating mechanisms of widely used activation strategies: trimethylsilyl chloride, LiCl, DMSO, and Rieke zinc powder. The resulting development of mechanistic models provides a better understanding of the oxidative-addition–solubilization sequence in organozinc reagent formation and contains lessons for methods development.
January 1, 2025
Total Syntheses of Indole Terpenoids (−)-Lyngbyatoxin, (−)-Teleocidin A2, and (−)-7-Geranylindolactam V
Jordan MacQueen - ,
Charles Wilber - ,
Syed Faiq - , and
Kelvin L. Billingsley *
A regiodivergent palladium-catalyzed Suzuki–Miyaura reaction has been successfully implemented to synthesize (−)-lyngbyatoxin, (−)-teleocidin A2, and (−)-7-geranylindolactam V. This ligand-controlled cross-coupling strategy allowed for the direct preparation of these natural products from a single advanced synthetic intermediate, providing the shortest reported route to each compound. Subsequent in vitro studies in cancer cell lines were conducted to explore the chemotherapeutic applications of these natural products.
December 31, 2024
Transamination of Zwitterionic Quinones with Polyamines: The Carbon Bridge Matters
Vlad Tarpa - ,
Jean-François Longevial - ,
Michel Giorgi - ,
Gabriel Canard - ,
Simon Pascal - ,
Denis Jacquemin *- , and
Olivier Siri *
The one-pot transamination reactions on a zwitterionic benzoquinonemonoimine yield either a quinoxaline derivative or bis-zwitterionic macrocycles, depending on the number of carbon atoms bridging primary polyamines. These latter products, featuring two confined donor cavities, are the result of a [2 + 2] condensation without the need for template effect or high dilution conditions.
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
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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.
November 21, 2024
Launching Graphene into 3D Space: Symmetry, Topology, and Strategies for Bottom-Up Synthesis of Schwarzites
Alexey V. Ignatchenko *
Schwarzites are hypothetical carbon allotropes in the form of a continuous negatively curved surface with three-dimensional periodicity. These materials of the future attract interest because of their anticipated large surface area per volume, high porosity, tunable electric conductivity, and excellent mechanical strength combined with light weight. A three-decade-long history attempting schwarzite synthesis from gas-phase carbon atoms went without success. Design of schwarzites is both a digital art and the science of placing tiles of sp2-carbon polygons on mathematically defined triply periodic minimal surfaces. The knowledge of how to connect polygons in sequence using the rules of symmetry unlocks paths for the bottom-up synthesis of schwarzites by organic chemistry methods. Schwarzite tiling by heptagons is systematically analyzed and classified by symmetry and topology. For the first time, complete plans for the bottom-up synthesis of many schwarzites are demonstrated. A trimer of heptagons is suggested as the key building block for most synthetic schemes.