437 results on '"Wolfgang Holzer"'
Search Results
52. Chemoselective reduction of isothiocyanates to thioformamides mediated by the Schwartz reagent
- Author
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Raffaele Senatore, Wolfgang Holzer, Vittorio Pace, Karen de la Vega-Hernández, Margherita Miele, and Ernst Urban
- Subjects
chemistry.chemical_classification ,010405 organic chemistry ,Alkene ,Hydride ,Organic Chemistry ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Electrophile ,Nitro ,Chemical groups ,Azide ,Physical and Theoretical Chemistry ,Chemoselectivity ,Schwartz reagent - Abstract
Thioformamides are easily prepared - under full chemocontrol - through the partial reduction of isothiocyanates with the in situ generated Schwartz reagent. The high electrophilicity of the starting materials enables the straightforward addition of the hydride ion, thus constituting a reliable and high-yielding method for obtaining variously functionalized thioformamides. Sensitive chemical groups to the reduction conditions such as nitro, ester, alkene, azo, azide and keto groups do not interfere with the chemoselectivity of the process. Moreover, the stereochemical information embodied in the starting material is fully retained in the final products. The synthetic potential of the selected thioformamide template is also briefly discussed.
- Published
- 2019
53. Taking advantage of lithium monohalocarbenoid intrinsic α-elimination in 2-MeTHF: controlled epoxide ring-opening
- Author
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Laura, Ielo, Margherita, Miele, Veronica, Pillari, Raffaele, Senatore, Salvatore, Mirabile, Rosaria, Gitto, Wolfgang, Holzer, Andrés R, Alcántara, and Vittorio, Pace
- Abstract
The intrinsic degradative α-elimination of Li carbenoids somehow complicates their use in synthesis as C1-synthons. Nevertheless, we herein report how boosting such an α-elimination is a straightforward strategy for accomplishing controlled ring-opening of epoxides to furnish the corresponding β-halohydrins. Crucial for the development of the method is the use of the eco-friendly solvent 2-MeTHF, which forces the degradation of the incipient monohalolithium, due to the very limited stabilizing effect of this solvent on the chemical integrity of the carbenoid. With this approach, high yields of the targeted compounds are consistently obtained under very high regiocontrol and, despite the basic nature of the reagents, no racemization of enantiopure materials is observed.
- Published
- 2021
54. A 13C chemical shifts study of iodopyrazoles: experimental results and relativistic and non-relativistic calculations
- Author
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Wolfgang Holzer, José Elguero, Dionisia Sanz, Ibon Alkorta, Rosa M. Claramunt, Ministerio de Ciencia, Innovación y Universidades (España), and Comunidad de Madrid
- Subjects
Work (thermodynamics) ,Desmotropy ,010405 organic chemistry ,Chemistry ,Chemical shift ,Solid-state ,15N chemical shifts ,mDKS/B3LYP/VTZ ,010402 general chemistry ,Condensed Matter Physics ,01 natural sciences ,Tautomer ,0104 chemical sciences ,ZORA ,nr-GIAO ,Physical and Theoretical Chemistry ,Atomic physics ,mDKS/B3LYP/VDZ ,Tautomerism - Abstract
This work reports the C chemical shifts of 49 iodopyrazoles and the N chemical shifts of 6 iodopyrazoles, most of them from the literature but a number of significant cases from the present work. Most experimental data were from solution studies but some of them correspond to the solid state (CPMAS). The calculations include non-relativistic calculations (nr-GIAO) and relativistic ones (ZORA, mDKS/B3LYP/VDZ and mDKS/B3LYP/VTZ). In the case of NH-pyrazoles, problems of tautomerism and desmotropy arise that have been also studied. The manuscript is dedicated to develop some equations containing corrections for heavy atoms to predict C and N chemical shifts., Ministerio de Ciencia, Innovación y Universidades (Project PGC2018-094644-B-C2) and Dirección General de Investigación e Innovación de la Comunidad de Madrid (PS2018/EMT-4329 AIRTEC-CM).
- Published
- 2021
55. Pseudo-Dipeptide Bearing α,α-Difluoromethyl Ketone Moiety as Electrophilic Warhead with Activity against Coronaviruses
- Author
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Antonio Rescifina, Maria Teresa Sciortino, Giorgio Gribaudo, Nicola Micale, Andrea Citarella, Anna Piperno, Vittorio Pace, Barbara Mognetti, Wolfgang Holzer, and Davide Gentile
- Subjects
Ketone ,SARS-CoV-2 Mpro ,Coronavirus M Proteins ,coronavirus ,medicine.disease_cause ,Virus Replication ,01 natural sciences ,lcsh:Chemistry ,chemistry.chemical_compound ,Coronavirus 229E, Human ,Moiety ,hCoV-229E ,Cytotoxicity ,lcsh:QH301-705.5 ,Spectroscopy ,Coronavirus ,chemistry.chemical_classification ,pro ,cysteine proteases ,difluoromethyl ketone ,virus diseases ,General Medicine ,Dipeptides ,Ketones ,Computer Science Applications ,Molecular Docking Simulation ,Thermodynamics ,Human ,Stereochemistry ,Molecular Dynamics Simulation ,010402 general chemistry ,Coronavirus 229E ,Antiviral Agents ,Catalysis ,Article ,Cell Line ,Inorganic Chemistry ,Viral Matrix Proteins ,Cysteine proteases ,Difluoromethyl ketone ,HCoV-229E ,SARS-CoV-2 M ,medicine ,Humans ,Physical and Theoretical Chemistry ,Binding site ,Molecular Biology ,Dipeptide ,Binding Sites ,010405 organic chemistry ,SARS-CoV-2 ,Organic Chemistry ,COVID-19 ,Settore CHIM/06 - Chimica Organica ,Settore CHIM/08 - Chimica Farmaceutica ,0104 chemical sciences ,chemistry ,lcsh:Biology (General) ,lcsh:QD1-999 ,Cell culture ,Docking (molecular) ,A549 Cells - Abstract
The synthesis of α-fluorinated methyl ketones has always been challenging. New methods based on the homologation chemistry via nucleophilic halocarbenoid transfer, carried out recently in our labs, allowed us to design and synthesize a target-directed dipeptidyl α,α-difluoromethyl ketone (DFMK) 8 as a potential antiviral agent with activity against human coronaviruses. The ability of the newly synthesized compound to inhibit viral replication was evaluated by a viral cytopathic effect (CPE)-based assay performed on MCR5 cells infected with one of the four human coronaviruses associated with respiratory distress, i.e., hCoV-229E, showing antiproliferative activity in the micromolar range (EC50 = 12.9 ± 1.22 µM), with a very low cytotoxicity profile (CC50 = 170 ± 3.79 µM, 307 ± 11.63 µM, and 174 ± 7.6 µM for A549, human embryonic lung fibroblasts (HELFs), and MRC5 cells, respectively). Docking and molecular dynamics simulations studies indicated that 8 efficaciously binds to the intended target hCoV-229E main protease (Mpro). Moreover, due to the high similarity between hCoV-229E Mpro and SARS-CoV-2 Mpro, we also performed the in silico analysis towards the second target, which showed results comparable to those obtained for hCoV-229E Mpro and promising in terms of energy of binding and docking pose.
- Published
- 2021
56. Taking advantage of lithium monohalocarbenoid intrinsic α-elimination in 2-MeTHF: controlled epoxide ring-opening en route to halohydrins
- Author
-
Veronica Pillari, Laura Ielo, Andrés R. Alcántara, Rosaria Gitto, Wolfgang Holzer, Raffaele Senatore, Margherita Miele, Salvatore Mirabile, and Vittorio Pace
- Subjects
Organic Chemistry ,Epoxide ,chemistry.chemical_element ,Ring (chemistry) ,Biochemistry ,Combinatorial chemistry ,Solvent ,chemistry.chemical_compound ,Enantiopure drug ,chemistry ,Reagent ,Lithium ,Physical and Theoretical Chemistry ,Carbenoid ,Racemization - Abstract
The intrinsic degradative α-elimination of Li carbenoids somehow complicates their use in synthesis as C1-synthons. Nevertheless, we herein report how boosting such an α-elimination is a straightforward strategy for accomplishing controlled ring-opening of epoxides to furnish the corresponding β-halohydrins. Crucial for the development of the method is the use of the eco-friendly solvent 2-MeTHF, which forces the degradation of the incipient monohalolithium, due to the very limited stabilizing effect of this solvent on the chemical integrity of the carbenoid. With this approach, high yields of the targeted compounds are consistently obtained under very high regiocontrol and, despite the basic nature of the reagents, no racemization of enantiopure materials is observed.
- Published
- 2021
57. Direct and straightforward transfer of C1 functionalized synthons to phosphorous electrophiles for accessinggem-P-containing methanes
- Author
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Margherita Miele, Wolfgang Holzer, Vittorio Pace, Laura Ielo, Ernst Urban, and Saad Touqeer
- Subjects
Geminal ,Organic Chemistry ,Synthon ,Biochemistry ,Combinatorial chemistry ,chemistry.chemical_compound ,Nucleophile ,chemistry ,Electrophile ,Nucleophilic substitution ,Methyllithium ,Physical and Theoretical Chemistry ,Phosphine ,Carbanion - Abstract
The direct transfer of different α-substituted methyllithium reagents to chlorinated phosphorous electrophiles of diverse oxidation state (phosphates, phosphine oxides and phosphines) is proposed as an effective strategy to synthesize geminal P-containing methanes. The methodology relies on the efficient nucleophilic substitution conducted on the P-chlorine linkage. Uniformly high yields are observed regardless the specific nature of the carbanion employed: once established the conditions for generating the competent nucleophile (LiCH2Hal, LiCHHal2, LiCH2CN, LiCH2SeR etc.) the homologated compounds are obtained via a single operation. Some P-containing formal carbanions have been evaluated in transferring processes, including the carbonyl-difluoromethylation of the opioid agent Hydrocodone.
- Published
- 2021
58. Synthesis, Biological, and Computational Evaluation of Antagonistic, Chiral Hydrobenzoin Esters of Arecaidine Targeting mAChR M1
- Author
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Jonas Aronow, Marius Ozenil, Helmut Spreitzer, Verena Pichler, Wolfgang Wadsak, Chrysoula Vraka, Wolfgang Holzer, Daniela Piljak, and Marcus Hacker
- Subjects
0301 basic medicine ,Stereochemistry ,muscarinic ,In silico ,Pharmaceutical Science ,lcsh:Medicine ,lcsh:RS1-441 ,Article ,lcsh:Pharmacy and materia medica ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Discovery ,Muscarinic acetylcholine receptor ,Chemistry ,Chinese hamster ovary cell ,lcsh:R ,subtype selectivity ,Arecaidine ,Ligand (biochemistry) ,drug development ,Chiral column chromatography ,030104 developmental biology ,Membrane ,Cell culture ,Molecular Medicine ,030217 neurology & neurosurgery - Abstract
Muscarinic acetylcholine receptors (mAChRs) are a pivotal constituent of the central and peripheral nervous system. Yet, therapeutic and diagnostic applications thereof are hampered by the lack of subtype selective ligands. Within this work, we synthesized and chemically characterized three different stereoisomers of hydrobenzoin esters of arecaidine by NMR, HR-MS, chiral chromatography, and HPLC-logP. All compounds are structurally eligible for carbon-11 labeling and show appropriate stability in Dulbecco&rsquo, s phosphate-buffered saline (DPBS) and F12 cell culture medium. A competitive radioligand binding assay on Chinese hamster ovary cell membranes comprising the human mAChR subtypes M1-M5 showed the highest orthosteric binding affinity for subtype M1 and a strong influence of stereochemistry on binding affinity, which corresponds to in silico molecular docking experiments. Ki values toward M1 were determined as 99 ±, 19 nM, 800 ±, 200 nM, and 380 ±, 90 nM for the (R,R)-, (S,S)-, and racemic (R,S)-stereoisomer, respectively, highlighting the importance of stereochemical variations in mAChR ligand development. All three stereoisomers were shown to act as antagonists toward mAChR M1 using a Fluo-4 calcium efflux assay. With respect to future positron emission tomography (PET) tracer development, the (R,R)-isomer appears especially promising as a lead structure due to its highest subtype selectivity and lowest Ki value.
- Published
- 2020
59. Chemoselective Homologation-Deoxygenation Strategy Enabling the Direct Conversion of Carbonyls into (
- Author
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Margherita, Miele, Andrea, Citarella, Thierry, Langer, Ernst, Urban, Martin, Zehl, Wolfgang, Holzer, Laura, Ielo, and Vittorio, Pace
- Subjects
Letter - Abstract
The sequential installation of a carbenoid and a hydride into a carbonyl, furnishing halomethyl alkyl derivatives, is reported. Despite the employment of carbenoids as nucleophiles in reactions with carbon-centered electrophiles, sp3-type alkyl halides remain elusive materials for selective one-carbon homologations. Our tactic levers on using carbonyls as starting materials and enables uniformly high yields and chemocontrol. The tactic is flexible and is not limited to carbenoids. Also, diverse carbanion-like species can act as nucleophiles, thus making it of general applicability.
- Published
- 2020
60. Electrophilicity Scale of Activated Amides
- Author
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Laura, Ielo, Vittorio, Pace, Wolfgang, Holzer, Md Mahbubur, Rahman, Guangrong, Meng, Roman, Szostak, and Michal, Szostak
- Abstract
The structure and properties of amides are of tremendous interest in organic synthesis and biochemistry. Traditional amides are planar and the carbonyl group non-electrophilic due to n
- Published
- 2020
61. Chemoselective Homologation-Deoxygenation Strategy Enabling the Direct Conversion of Carbonyls into (n+1)-Halomethyl-Alkanes
- Author
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Vittorio Pace, Thierry Langer, Margherita Miele, Wolfgang Holzer, Andrea Citarella, Ernst Urban, Martin Zehl, and Laura Ielo
- Subjects
chemistry.chemical_classification ,010405 organic chemistry ,Chemistry ,Hydride ,Organic Chemistry ,Halide ,Settore CHIM/06 - Chimica Organica ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,0104 chemical sciences ,Nucleophile ,Electrophile ,Physical and Theoretical Chemistry ,Carbenoid ,Deoxygenation ,Alkyl - Abstract
The sequential installation of a carbenoid and a hydride into a carbonyl, furnishing halomethyl alkyl derivatives, is reported. Despite the employment of carbenoids as nucleophiles in reactions with carbon-centered electrophiles, sp3-type alkyl halides remain elusive materials for selective one-carbon homologations. Our tactic levers on using carbonyls as starting materials and enables uniformly high yields and chemocontrol. The tactic is flexible and is not limited to carbenoids. Also, diverse carbanion-like species can act as nucleophiles, thus making it of general applicability.
- Published
- 2020
62. Electrophilicity Scale of Activated Amides: 17O NMR and 15N NMR Chemical Shifts of Acyclic Twisted Amides in N−C(O) Cross-Coupling
- Author
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Laura Ielo, Roman Szostak, Guangrong Meng, Vittorio Pace, Wolfgang Holzer, Md. Mahbubur Rahman, and Michal Szostak
- Subjects
Steric effects ,Electronic tuning ,N-C(O) activation ,010405 organic chemistry ,Chemistry ,O NMR spectroscopy ,cross-coupling ,transition-metal catalysis ,twisted amides ,Chemical shift ,Organic Chemistry ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Medicinal chemistry ,Oxidative addition ,Catalysis ,0104 chemical sciences ,chemistry.chemical_compound ,Electrophile ,Peptide bond ,Organic synthesis ,Amide bonds - Abstract
The structure and properties of amides are of tremendous interest in organic synthesis and biochemistry. Traditional amides are planar and the carbonyl group non-electrophilic due to nN →π*C=O conjugation. In this study, we report electrophilicity scale by exploiting 17 O NMR and 15 N NMR chemical shifts of acyclic twisted and destabilized acyclic amides that have recently received major attention as precursors in N-C(O) cross-coupling by selective oxidative addition as well as precursors in electrophilic activation of N-C(O) bonds. Most crucially, we demonstrate that acyclic twisted amides feature electrophilicity of the carbonyl group that ranges between that of acid anhydrides and acid chlorides. Furthermore, a wide range of electrophilic amides is possible with gradually varying carbonyl electrophilicity by steric and electronic tuning of amide bond properties. Overall, the study quantifies for the first time that steric and electronic destabilization of the amide bond in common acyclic amides renders the amide bond as electrophilic as acid anhydrides and chlorides. These findings should have major implications on the fundamental properties of amide bonds.
- Published
- 2020
63. Straightforward chemoselective access to unsymmetrical dithioacetals through a thiosulfonate homologation-nucleophilic substitution sequence
- Author
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Wolfgang Holzer, Vittorio Pace, Veronica Pillari, Laura Ielo, and Natalie Gajic
- Subjects
Chemistry ,Substitution (logic) ,Metals and Alloys ,Sequence (biology) ,General Chemistry ,Direct Technique ,Combinatorial chemistry ,Catalysis ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,chemistry.chemical_compound ,Sulfonate ,Nucleophile ,Electrophile ,Materials Chemistry ,Ceramics and Composites ,Nucleophilic substitution - Abstract
A sequential C1-homologation-nucleophilic substitution tactic is presented for the preparation of rare unsymmetrical dithioacetals. The judicious selection of thiosulfonates as convenient sulfur electrophilic sources - upon the homologation event conducted on an intermediate α-halothioether - guarantees the release of the non-reactive sulfonate group, thus enabling the subsequent nucleophilic displacement with an external added thiol [(hetero)aromatic and/or aliphatic]. Uniform high yields and excellent chemocontrol were deduced during the extensive scope study, thus documenting the versatility of the direct technique for the preparation of these unique and manipulable materials.
- Published
- 2020
64. The use of TBM process data as a normative basis of the contractual advance classification for TBM advances in hard rock
- Author
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Dietmar Bach, Wolfgang Leitner, Nedim Radoncic, and Wolfgang Holzer
- Subjects
Computer science ,021105 building & construction ,0211 other engineering and technologies ,Normative ,02 engineering and technology ,Geotechnical Engineering and Engineering Geology ,Construction engineering ,021101 geological & geomatics engineering ,Civil and Structural Engineering - Published
- 2018
65. Ring-closing metathesis as a key step to construct 2,6-dihydropyrano[2,3-c]pyrazole ring system
- Author
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Sonata Kriktolaitytė, Wolfgang Holzer, Aurimas Bieliauskas, and Algirdas ačkus
- Subjects
010405 organic chemistry ,Stereochemistry ,Chemistry ,wittig olefination ,Organic Chemistry ,Construct (python library) ,Pyrazole ,ring-closing metathesis ,010402 general chemistry ,Ring (chemistry) ,01 natural sciences ,0104 chemical sciences ,lcsh:QD241-441 ,chemistry.chemical_compound ,Ring-closing metathesis ,lcsh:Organic chemistry ,Key (cryptography) ,2,6-dihydropyrano[2,3-c]pyrazole ,1-phenylpyrazol-3-ol - Abstract
A simple and efficient synthetic route to the 2,6-dihydropyrano[2,3-c]pyrazole ring system was developed by employing ring-closing metathesis (RCM) as a key step. The required diene substrate for the RCM reaction was prepared by a three-step procedure starting form 1-phenyl-1H-pyrazol-3-ol. Treatment of the obtained 4-ethenyl-1-phenyl-3-[(prop-2-en-1-yl)oxy]-1H-pyrazole with Grubbs‘ first-generation catalyst afforded the target 2-phenyl-2,6-dihydropyrano[2,3-c]pyrazole. 2-(4-Fluorophenyl)- and 2-(4-bromophenyl)-2,6-dihydropyrano[2,3-c]pyrazole were synthesized by an analogous way. The structures of the obtained heterocyclic products were unequivocally confirmed by detailed 1H, 13C, 15N and 19F NMR spectroscopic experiments and HRMS measurements. The optical properties of 2-phenyl-2,6-dihydropyrano[2,3-c]pyrazole were studied by UV–Vis and fluorescence spectroscopy.
- Published
- 2018
66. One-pot synthesis of polycyclic heterocyclic compounds by condensation of 1-carbamoylmethyl-2,3,3-trimethyl-3H-indolium salts with pyridine-2, 3, and 4- and quinoline-4-carboxaldehydes
- Author
-
Aurimas Bieliauskas, Vytas Martynaitis, Virginė Amankavičienė, Neringa Kleizienė, Živilė Žukauskaitė, Algirdas Šačkus, and Wolfgang Holzer
- Subjects
010405 organic chemistry ,Organic Chemistry ,Quinoline ,One-pot synthesis ,Nuclear magnetic resonance spectroscopy ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Medicinal chemistry ,Chloride ,0104 chemical sciences ,Catalysis ,chemistry.chemical_compound ,Acetic acid ,chemistry ,Drug Discovery ,Pyridine ,medicine ,Piperidine ,medicine.drug - Abstract
A one-pot synthesis of new polycyclic heterocyclic compounds was carried out via the condensation of 1-carbamoylmethyl-2,3,3-trimethyl-3H-indolium chloride with pyridine- and quinolinecarboxaldehydes. The heating of the aforementioned 3H-indolium salts with 1 eq. of pyridine-2, 3, and 4- or quinoline-4-carboxaldehyde in ethanol in the presence of piperidine as a catalyst provided 9a-[2-(pyridyl)ethenyl]- or 9a-[2-(quinolyl)ethenyl]-9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-one derivatives as the main products. However, reaction outcome was dramatically different for the analogous reactions in acetic acid. In this case, the heating of the chloride with 2 eq. of pyridine-2-carboxaldehyde afforded derivatives of 9a-[3-(pyridin-2-yl)indolizin-2-yl]-9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-one as the major product, while the use of 2 eq. of pyridine-3 and 4- or quinoline-4-carboxaldehyde led to the formation 2-heteroaryl-1-heteroarylmethyl-9H-pyrrolo[1,2-a]indole-3-carboxamides. Plausible pathways for the cyclization reactions are discussed. The structural assignments were based on 1H, 13C and 15N NMR spectroscopy, HRMS and single-crystal X-ray diffraction data.
- Published
- 2018
67. An unusual thionyl chloride-promoted C−C bond formation to obtain 4,4'-bipyrazolones
- Author
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Algirdas Šačkus, Wolfgang Holzer, Vittorio Pace, Vytas Martynaitis, Gernot A. Eller, Gytė Vilkauskaitė, and Ashenafi Damtew Mamuye
- Subjects
Decarboxylation ,Crystal structure ,thionyl chloride ,Alkaline hydrolysis (body disposal) ,010402 general chemistry ,pyrazolones ,01 natural sciences ,Medicinal chemistry ,Full Research Paper ,X-ray structure analysis ,lcsh:QD241-441 ,chemistry.chemical_compound ,Thionyl chloride ,lcsh:Organic chemistry ,lcsh:Science ,13C ,15N) ,dimerization ,010405 organic chemistry ,Chemistry ,NMR (1H ,Organic Chemistry ,Bond formation ,0104 chemical sciences ,Pyrazolones ,lcsh:Q - Abstract
Dialkyl 5,5'-dioxo-4,4'-bipyrazole-4,4'-dicarboxylates are readily obtained by the reaction of 5-hydroxypyrazole-4-carboxylates in refluxing thionyl chloride. The obtained diesters can be transformed into the corresponding 4,4'-bipyrazoles via alkaline hydrolysis and subsequent decarboxylation. Detailed NMR spectroscopic investigations (1H, 13C, 15N) were undertaken with all products prepared. Moreover, the structure of a representative 5,5'-dioxo-4,4'-bipyrazole-4,4'-dicarboxylate was confirmed by X-ray crystal structure analysis.
- Published
- 2018
68. Merging lithium carbenoid homologation and enzymatic reduction: A combinative approach to the HIV-protease inhibitor Nelfinavir
- Author
-
Andrés R. Alcántara, Laura De Luca, Wolfgang Holzer, Laura Ielo, Laura Castoldi, Pilar Hoyos, Vittorio Pace, and María J. Hernáiz
- Subjects
Drug Synthesis ,Homologation ,Alcohol ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Homologation, Lithium carbenoids, Enzymatic reductions, Drug Synthesis, a-haloketones, Halohydrins, Selectivity, Halohydrins, Biochemistry, Drug Discovery3003, Pharmaceutical Science, Organic Chemistry ,a-haloketones ,chemistry.chemical_compound ,Amide ,Drug Discovery ,medicine ,HIV Protease Inhibitor ,Selectivity ,Selective reduction ,Carbenoid ,chemistry.chemical_classification ,010405 organic chemistry ,Organic Chemistry ,Lithium carbenoids ,Diastereomer ,Combinatorial chemistry ,0104 chemical sciences ,Enzymatic reductions ,Halohydrins ,Nelfinavir ,Enzyme ,chemistry ,medicine.drug - Abstract
An effective stereocontrolled synthesis of the HIV protease inhibitor Nelfinavir is reported. Two transformations were identified crucial for achieving success: the formation of a densely functionalized α-chloroketone via the homologation of a Weinreb amide with chloromethyllithium (LiCH2Cl), followed by its erythro selective reduction into the corresponding chiral chlorohydrin. A commercially available enzyme P2-C02 was particularly well suited for this purpose, affording the key alcohol (in an excellent 99% de), which was then smoothly converted into the active biologically active agent.
- Published
- 2018
69. Synthesis and NMR-Spectroscopic Investigations with 4-Chloroacyl-1-phenylpyrazolin-5-ones
- Author
-
Gernot A. Eller and Wolfgang Holzer
- Subjects
Calcium hydroxide ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Pyrazole ,010402 general chemistry ,01 natural sciences ,Chloride ,Tautomer ,Medicinal chemistry ,0104 chemical sciences ,chemistry.chemical_compound ,medicine ,Organic chemistry ,Moiety ,medicine.drug - Abstract
The synthesis of various 4-acylpyrazolones bearing in the acyl moiety either a terminal chloro-substituent or a terminal ortho-chlorophenyl group was achieved by reaction of 3-methyl-1-phenyl-2-pyrazolin-5-one (tautomer to 3-methyl-1-phenyl-1H-pyrazol-5-ol) with the corresponding acid chloride using calcium hydroxide / 1,4-dioxane. In one case (reaction with chlorobutanoyl chloride) a spontaneous cyclization occurred leading to the corresponding oxepino[2,3-c]pyrazole. Detailed NMR spectroscopic investigations with all prepared compounds were performed.
- Published
- 2017
70. Exploiting a 'Beast' in Carbenoid Chemistry: Development of a Straightforward Direct Nucleophilic Fluoromethylation Strategy
- Author
-
Giovanna Parisi, Wolfgang Holzer, Giuseppe Romanazzi, Serena Monticelli, Marco Colella, Leonardo Degennaro, Thierry Langer, Vittorio Pace, and Renzo Luisi
- Subjects
Reaction conditions ,flow chemistry ,010405 organic chemistry ,Chemistry ,chemistry.chemical_element ,fluoromethylation ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,Catalysis ,0104 chemical sciences ,Colloid and Surface Chemistry ,Nucleophile ,Electrophile ,fluoromethylation, flow chemistry ,Organic chemistry ,Lithium ,Carbenoid - Abstract
The first direct and straightforward nucleophilic fluoromethylation of organic compounds is reported. The tactic employs a “fleeting” lithium fluorocarbenoid (LiCH2F) generated from commercially available fluoroiodomethane. Precise reaction conditions were developed for the generation and synthetic exploitation of such a labile species. The versatility of the strategy is showcased in ca. 50 examples involving a plethora of electrophiles. Highly valuable chemicals such as fluoroalcohols, fluoroamines, and fluoromethylated oxygenated heterocycles could be prepared in very good yields through a single synthetic operation. The scalability of the reaction and its application to complex molecular architectures (e.g., steroids) are documented.
- Published
- 2017
71. Molecular dimensions and structural features of neutral polysaccharides from the seed mucilage of Hyptis suaveolens L
- Author
-
Wolfgang Holzer, Renate Loeppert, Andrea Čavarkapa, Werner Praznik, Helmut Viernstein, Frank M. Unger, and Monika Mueller
- Subjects
Magnetic Resonance Spectroscopy ,Oligosaccharides ,Galactans ,01 natural sciences ,Analytical Chemistry ,Mannans ,chemistry.chemical_compound ,0404 agricultural biotechnology ,Polysaccharides ,Hyptis suaveolens ,Mole ,Organic chemistry ,Tetrasaccharide ,Molecule ,Galactoglucomannan ,Glucans ,Molar mass ,Molecular Structure ,biology ,010405 organic chemistry ,Polysaccharides, Bacterial ,04 agricultural and veterinary sciences ,General Medicine ,Nuclear magnetic resonance spectroscopy ,biology.organism_classification ,040401 food science ,0104 chemical sciences ,Molecular Weight ,chemistry ,Mucilage ,Seeds ,Hyptis ,Food Science ,Nuclear chemistry - Abstract
The seed mucilage of Hyptis suaveolens L. includes acid - and neutral heteropolysaccharides in a ratio of about 1:1. The anionic charged fraction responsible for swelling and viscous behaviour possesses an average molar mass of Mw=350kg/mol, Mn=255kg/mol. The neutral polysaccharide fraction shows an average molar mass of Mw=47kg/mol and Mn=28kg/mol and is composed of d-Galp-, d-Glcp- and d-Manp residues in a molar ratio of about 3:2:1. The structural features present galactoglucan (30%) and galactoglucomannan (70%) with a high level of terminal β-linked d-Galp residues (18%). Structural details of galactoglucomannan are derived by combined enzymatic and chemical methods as well as NMR spectroscopy. Sequences of octa/nonasaccharide β-d-Glcp-(1→4)[β-d-Galp-(1→2)-α-d-Galp-(1→6)]-β-d-Manp-(1→4)-β-d-Glcp-(1→4)-β-d-Glcp-(1→4)[β-d-Galp-(1→2)-α-d-Galp-(1→6)]-β-d-Manp and lower mass tetrasaccharide repeating units β-d-Glcp-(1→4)[β-d-Galp-(1→2)-α-d-Galp-(1→6)]-β-d-Manp were found. The level of the prebiotic activity is related to the availability of β-linked d-Galp residues in the side chains of the molecules.
- Published
- 2017
72. A greener and efficient access to substituted four- and six-membered sulfur-bearing heterocycles
- Author
-
Pietro Mastrorilli, Alexander Roller, Giovanna Parisi, Vittorio Pace, Cosimo Altomare, Modesto de Candia, Leonardo Degennaro, Wolfgang Holzer, Claudia Carlucci, and Renzo Luisi
- Subjects
010405 organic chemistry ,Organic Chemistry ,Regioselectivity ,chemistry.chemical_element ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Sulfur ,Acceptor ,0104 chemical sciences ,Solvent ,Silanol ,chemistry.chemical_compound ,chemistry ,Computational chemistry ,Electrophile ,Lipophilicity ,Organic chemistry ,Surface modification ,Physical and Theoretical Chemistry ,CYCLIC SULFONES FUNCTIONALIZATION REGEIOSELECTIVITY - Abstract
The regioselective functionalization of four- and six-membered cyclic sulfones was investigated using a lithiation/electrophile trapping strategy. The protocol features an interesting eco-compatibility profile because of the use of 2-MeTHF as a solvent (more eco-friendly than other organic solvents) and n-hexyllithium as a lithiating agent safer than other alkyllithium compounds. Several derivatives were prepared with different stereochemistry and substitution patterns. A number of selected derivatives, spanning a range of 5 log P units, were characterized for their lipophilicity through RP-HPLC. A good linear correlation, with a slope close to 1.0, was observed between the experimentally determined RP-HPLC lipophilicity parameters (log k'w) and calculated log P (clog P) values, whereas a systematic difference in absolute values between the chromatographic parameters and in silico lipophilicity descriptors can be attributed mainly to silanophilic interactions between the H-bond acceptor SO2 group and free silanol groups on silica-based C18 columns, which results in increased retention times.
- Published
- 2017
73. Highly chemoselective difluoromethylative homologation of iso(thio)cyanates: expeditious access to unprecedented α,α-difluoro(thio)amides
- Author
-
Margherita Miele, Wolfgang Holzer, Vellaisamy Sridharan, Vittorio Pace, and Rosarita D'Orsi
- Subjects
chemistry.chemical_classification ,Nitrile ,010405 organic chemistry ,Metals and Alloys ,Thio ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,Catalysis ,0104 chemical sciences ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,chemistry.chemical_compound ,chemistry ,Nucleophile ,Reagent ,Isothiocyanate ,Electrophile ,Materials Chemistry ,Ceramics and Composites ,Nitro ,Thioamide - Abstract
The new motif – α,α-difluoromethyl thioamide – has been assembled starting from isothiocyanate (as thioamide precursor) and a formal difluoromethyl-carbanion generated from commercially available TMSCHF2. Upon proper activation of this reagent with potassium tert-amylate, the high-yielding transfer of the difluorinated nucleophile takes place under high chemocontrol. Various sensitive functionalities (e.g. ester, nitrile, nitro, azido groups) can be accommodated across the isothiocyanate core, thus allowing a wide scope. The methodology is highly flexible and adaptable to prepare analogous α,α-difluoromethyl oxoamides by conveniently using isocyanates as the electrophilic building-blocks.
- Published
- 2019
74. Direct and Chemoselective Synthesis of Tertiary Difluoroketones via Weinreb Amide Homologation with a CHF
- Author
-
Margherita, Miele, Andrea, Citarella, Nicola, Micale, Wolfgang, Holzer, and Vittorio, Pace
- Subjects
Hydrocarbons, Fluorinated ,Molecular Structure ,Stereoisomerism ,Ketones ,Amides ,Methane - Abstract
The homologation of Weinreb amides into difluoromethylketones with a formal nucleophilic CHF
- Published
- 2019
75. Direct and Chemoselective Synthesis of Tertiary Difluoroketones via Weinreb Amide Homologation with a CHF2-Carbene Equivalent
- Author
-
Wolfgang Holzer, Margherita Miele, Nicola Micale, Vittorio Pace, and Andrea Citarella
- Subjects
Potassium ,chemistry.chemical_element ,EFFICIENT ,010402 general chemistry ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,Nucleophile ,Transfer agent ,Amide ,KETONES ,CARBONYL-COMPOUNDS ,DIFLUOROMETHYLATION ,DIFLUOROALKYLATION ,FLUORINE ,ACCESS ,BOND ,Physical and Theoretical Chemistry ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Settore CHIM/06 - Chimica Organica ,Combinatorial chemistry ,0104 chemical sciences ,Carbene - Abstract
The homologation of Weinreb amides into difluoromethylketones with a formal nucleophilic CHF2 transfer agent is reported. Activating TMSCHF2 with potassium tert-amylate enables a convenient access ...
- Published
- 2019
76. Modular and Chemoselective Strategy for the Direct Access to α-Fluoroepoxides and Aziridines via the Addition of Fluoroiodomethyllithium to Carbonyl-Like Compounds
- Author
-
Thierry Langer, Wolfgang Holzer, Arianna Tota, Veronica Pillari, Leonardo Degennaro, Renzo Luisi, Marco Colella, Serena Monticelli, and Vittorio Pace
- Subjects
chemistry.chemical_classification ,Ketone ,Lithium amide ,Nitrile ,010405 organic chemistry ,Organic Chemistry ,Sequence (biology) ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,0104 chemical sciences ,Highly sensitive ,chemistry.chemical_compound ,Deprotonation ,chemistry ,Physical and Theoretical Chemistry ,Chemoselectivity - Abstract
An expeditious, high-yielding synthesis of rare α-fluoroepoxides and α-fluoroaziridines through the addition of the unkown fluoroiodomethyllithium (LiCHIF)—formed via deprotonation the commercially available fluoroiodomethane with a lithium amide base—to carbonyl-like compounds is documented. The ring-closure reactions, leading to α-fluorinated three-membered heterocycles, rely on the diversely reactive C–I and C–F bonds. Excellent chemoselectivity was observed in the presence of highly sensitive functionalities—aldehyde, ketone, nitrile, alkene—which remained untouched during the homologation sequence.
- Published
- 2019
77. 17O NMR and 15N NMR chemical shifts of sterically-hindered amides: Ground-state destabilization in amide electrophilicity
- Author
-
Laura Ielo, Roman Szostak, Wolfgang Holzer, Guangrong Meng, Michal Szostak, Vittorio Pace, Mina Hanna, and Shicheng Shi
- Subjects
chemistry.chemical_classification ,Steric effects ,010405 organic chemistry ,Carboxylic acid ,Chemical shift ,Metals and Alloys ,General Chemistry ,Nuclear magnetic resonance spectroscopy ,010402 general chemistry ,01 natural sciences ,Catalysis ,0104 chemical sciences ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,chemistry.chemical_compound ,chemistry ,Computational chemistry ,Amide ,Electrophile ,Materials Chemistry ,Ceramics and Composites ,Electronic effect ,Peptide bond - Abstract
The structure and spectroscopic properties of the amide bond are a topic of fundamental interest in chemistry and biology. Herein, we report 17O NMR and 15N NMR spectroscopic data for four series of sterically-hindered acyclic amides. Despite the utility of 17O NMR and 15N NMR spectroscopy, these methods are severely underutilized in the experimental determination of electronic properties of the amide bond. The data demonstrate that a combined use of 17O NMR and 15N NMR serves as a powerful tool in assessing electronic effects of the amide bond substitution as a measure of electrophilicity of the amide bond. Notably, we demonstrate that steric destabilization of the amide bond results in electronically-activated amides that are comparable in terms of electrophilicity to acyl fluorides and carboxylic acid anhydrides.
- Published
- 2019
78. Design, Synthesis, and Pharmacological Evaluation of Novel beta 2/3 Subunit-Selective gamma-Aminobutyric Acid Type A (GABA(A)) Receptor Modulators
- Author
-
Christoph Schwarzer, Ernst Urban, Vittorio Pace, Steffen Hering, Thierry Langer, Stefan Boehm, Serena Monticelli, Thomas Seidel, Sophia Khom, Isabella Salzer, Marco Stadler, Wolfgang Holzer, and Denise Luger
- Subjects
0303 health sciences ,Chemistry ,GABAA receptor ,Voltage clamp ,Loreclezole ,Pharmacology ,Valerenic acid ,01 natural sciences ,Aminobutyric acid ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,In vivo ,Drug Discovery ,medicine ,Molecular Medicine ,Potency ,Receptor ,030304 developmental biology ,medicine.drug - Abstract
Subunit-selective modulation of γ-aminobutyric acid type A receptors (GABAAR) is considered to exert fewer side effects compared to unselective clinically used drugs. Here, the β2/3 subunit-selective GABAAR modulators valerenic acid (VA) and loreclezole (LOR) guided the synthesis of novel subunit-selective ligands with simplified structures. We studied their effects on GABAARs expressed in Xenopus laevis oocytes using two-microelectrode voltage clamp technique. Five compounds showed significantly more efficacious modulation of GABA-evoked currents than VA and LOR with retained potency and selectivity. Compound 18 [(E)-2–Cyano-3-(2,4-dichlorophenyl)but-2-enamide] induced the highest maximal modulation of GABA-induced chloride currents (Emax: 3114 ± 242%), while 12 [(Z)-3-(2,4-dichlorophenyl)but-2-enenitrile] displayed the highest potency (EC50: 13 ± 2 μM). Furthermore, in hippocampal neurons 12 facilitated phasic and tonic GABAergic inhibition, and in vivo studies revealed significantly more potent protect...
- Published
- 2019
79. Multinuclear NMR spectra and GIAO/DFT calculations of N-benzylazoles and N-benzylbenzazoles
- Author
-
Wolfgang Holzer, Laura Castoldi, M. Carmen Torralba, José Elguero, Dionisia Sanz, Viktoriya Kyselova, Ibon Alkorta, Rosa M. Claramunt, Agencia Estatal de Investigación (España), Comunidad de Madrid, and Ministerio de Ciencia, Innovación y Universidades (España)
- Subjects
Empirical equations ,010405 organic chemistry ,Chemistry ,Chemical shift ,Crystal structure ,010402 general chemistry ,Condensed Matter Physics ,X-ray crystal structure ,01 natural sciences ,GIAOcalculations ,0104 chemical sciences ,NMR spectra database ,Nitrogen-15NMR ,Atomic orbital ,Group (periodic table) ,ProtonNMR ,Physical chemistry ,Physical and Theoretical Chemistry ,N-benzylazoles ,Carbon-13NMR ,Monoclinic crystal system - Abstract
The H, C, and N chemical shifts of almost the whole series of N-benzyl azoles and benzazoles, with the exception of the unknown 1-benzyl-1H-pentazole (10) and the very unstable 2-benzyl-2H-isoindole (12), have been measured. In addition, the X-ray crystal structure of 1-benzyl-1H-indazole (14) was solved (monoclinic, space group P2 /n), its geometry being very close to that used for the calculations. The absolute chemical shieldings were calculated at the gauge-independent atomic orbital (GIAO)/Becke, 3-parameter, Lee-Yang-Parr (B3LYP)/6-311++G(d,p) level and then transformed with very robust empirical equations into chemical shifts of the three nuclei showing an excellent agreement with the 313 experimental values., This work was carried out with financial support from the Spanish Ministerio de Ciencia, Innovación y Universidades (Projects PGC2018-094644-B-C2 and RTI2018-097416-B-C21) and Dirección General de Investigación e Innovación de la Comunidad de Madrid (PS2018/EMT-4329 AIRTEC-CM). Thanks are also given to the CTI (CSIC) for their continued computational support.
- Published
- 2019
80. Telescoped, Divergent, Chemoselective C1 and C1-C1 Homologation of Imine Surrogates: Access to Quaternary Chloro- and Halomethyl-Trifluoromethyl Aziridines
- Author
-
Laura Ielo, Wolfgang Holzer, Thierry Langer, Saad Touqeer, Vittorio Pace, and Alexander Roller
- Subjects
Trifluoromethyl ,010405 organic chemistry ,Communication ,Imine ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,Catalysis ,Communications ,0104 chemical sciences ,Carbenoids ,chemistry.chemical_compound ,chemistry ,Nucleophile ,aziridines ,chemoselectivity ,lithium ,Electrophile ,homologation - Abstract
A conceptually novel, high‐yielding, mono‐ or bis‐homologation was realized with lithium halocarbenoids and enables the one‐step, fully chemocontrolled assembly of a new class of quaternary trifluoromethyl aziridines. Trifluoroacetimidoyl chlorides (TFAICs) act as convenient electrophilic platforms, enabling the addition of either one or two homologating elements by simply controlling the stoichiometry of the process. Mechanistic studies highlighted that the homologation event, carried out with two different carbenoids (LiCH2Cl and LiCH2F), leads to fluoromethyl analogues in which the first nucleophile is employed for constructing the cycle and the second for decorating the resulting molecular architecture.
- Published
- 2019
81. Telescoped, Divergent, Chemoselective C1 and C1‐C1 Homologation of Imines Surrogates: A Straightforward Access to Quaternary Chloro‐ and Halomethyl‐trifluoromethyl‐aziridines
- Author
-
Saad Touqeer, Laura Ielo, Wolfgang Holzer, Thierry Langer, Vittorio Pace, and Alexander Roller
- Subjects
chemistry.chemical_compound ,Trifluoromethyl ,chemistry ,General Medicine ,Medicinal chemistry - Published
- 2019
82. Sustainable Asymmetric Organolithium Chemistry: Enantio- and Chemoselective Acylations through Recycling of Solvent, Sparteine, and Weinreb 'Amine'
- Author
-
Alexander Roller, Thierry Langer, Serena Monticelli, Wolfgang Holzer, Vittorio Pace, and Berit Olofsson
- Subjects
General Chemical Engineering ,asymmetric chemistry ,Cyclopentyl methyl ether ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Acylation ,chemistry.chemical_compound ,medicine ,acylation ,Environmental Chemistry ,Organic chemistry ,General Materials Science ,Chemoselectivity ,Derivatization ,Green & Sustainable Science & Technology ,green solvents ,Full Paper ,Chemistry ,organolithium ,Sparteine ,Enantioselective synthesis ,Kemi ,Full Papers ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,Solvent ,General Energy ,chemoselectivity ,Chemical Sciences ,Amine gas treating ,0210 nano-technology ,medicine.drug - Abstract
The well‐established Hoppe–Beak chemistry, which involves enantioselective generation of organolithium compounds in the presence of (−)‐sparteine, was revisited and applied to unprecedented acylations with Weinreb amides to access highly enantioenriched α‐oxyketones and cyclic α‐aminoketones. Recycling of the sustainable solvent cyclopentyl methyl ether, sparteine, and the released Weinreb “amine” [HNMe(OMe)] was possible through a simple work‐up procedure that enabled full recovery of these precious materials. The methodology features a robust scope and flexibility, thus allowing the enantioselective preparation of scaffolds amenable of further derivatization.
- Published
- 2018
83. The Use of the Comins-Meyers Amide in Synthetic Chemistry: an Overview
- Author
-
Serena, Monticelli, Giovanna, Parisi, Marta, Rui, Karen, de la Vega-Hernández, Irene, Murgia, Raffaele, Senatore, Wolfgang, Holzer, Ernst, Urban, Thierry, Langer, and Vittorio, Pace
- Subjects
Biological Products ,Molecular Structure ,Chemistry Techniques, Synthetic ,Amides - Abstract
Formylation reactions are fundamental operations in synthetic chemistry allowing the incorporation into a given structure formyl groups amenable to further deiivatization. Conceptually, the introduction of such groups through the reaction between an electrophilic donor and a nucleophilic acceptor (i.e. organometallic reagent) constitutes a reliable technique with widespread applications. In this Highlight, we summarize the effectiveness of the so called Comnins-Meyers amide - [2-(N-methyl-N-formylamino]pyridine - in such a chemistry with vistas to the synthesis of natural products and biologically active substrates.
- Published
- 2018
84. Synthesis of stable α-fluoromethyl putative carbanions via a chemoselective reduction-monofluoromethylation sequence of diselenides under sustainable conditions
- Author
-
Wolfgang Holzer, Monika Malik, Vittorio Pace, Raffaele Senatore, and Ernst Urban
- Subjects
Chemistry ,Organic Chemistry ,Organoselenium ,Organometallics ,Sequence (biology) ,Fluorine ,Biochemistry ,Environmentally friendly ,Combinatorial chemistry ,C1 synthons ,Solvent ,Diselenide ,Yield (chemistry) ,Drug Discovery ,Green solvents ,Carbanion - Abstract
α-Fluoromethyl selenoethers were prepared through a sequential one-pot diselenide reduction-fluoromethylation with the fluorinated, highly manipulable C1 source ICH2F. The reaction benefited from the employment of the environmentally friendly solvent MeTHF (2-methyltetrahydrofuran) which enabled to maximize the efficiency of both steps of the technique. A series of variously functionalized analogues – featuring a remarkable degree of stability imparted by selenium - could be chemoselectively accessed in high yield and purity through an intuitive and experimentally simple protocol.
- Published
- 2021
85. Straightforward and direct access to β-seleno- amines and sulfonylamides via the controlled addition of phenylselenomethyllithium (LiCH2SePh) to imines
- Author
-
Wolfgang Holzer, Vittorio Pace, Raffaele Senatore, Simona Collina, Roberta Listro, Saad Touqeer, and Monika Malik
- Subjects
Nucleophile ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Drug Discovery ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,0104 chemical sciences ,Carbanion - Abstract
The transfer of a α-methyl phenylseleno carbanion to variously functionalized N-aryl and N-sulfonyl imines is reported. The fast selenium-lithium exchange conducted on a diselenoacetal with n-BuLi enables the generation of the attacking homologative nucleophile under chemoselective conditions preserving concomitant potentially sensitive functionalities to the lithiating conditions. Uniformly high yields were observed, thus establishing a valuable and conceptually simple approach to the title compounds.
- Published
- 2020
86. Lithium Halomethylcarbenoids: Preparation and Use in the Homologation of Carbon Electrophiles
- Author
-
Wolfgang Holzer, Vittorio Pace, and Norbert De Kimpe
- Subjects
Nucleophilic addition ,010405 organic chemistry ,Chemistry ,General Chemical Engineering ,chemistry.chemical_element ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,chemistry.chemical_compound ,Reagent ,Electrophile ,Materials Chemistry ,Organic chemistry ,Organic synthesis ,Lithium ,Microreactor ,Carbenoid ,Carbanion - Abstract
alpha-Halomethyllithium carbenoids are useful homologating reagents which - reacting under proper reaction conditions as carbanions - enable the installation via nucleophilic addition of a reactive halomethyl fragment onto a preformed carbon-heteroatom bond. The pronounced thermolability represented - since seminal studies by Kobrich - the Achilles' heel of these reagents: the use of Barbier-type methodologies (i.e., the electrophile should be present in the reaction mixture prior to the formation of the carbenoid) was pivotal in order to suppress decomposition through -elimination processes. Nowadays, the use of low temperatures (-78 degrees C) guarantees reliable procedures and, significantly, the employment of microreactor technologies allows external trapping to be performed even at higher temperatures as reported by Luisi. We will discuss the -halomethyllithium-mediated homologations of a series of carbon electrophiles such as carbonyl compounds, imines, esters, Weinreb amides, and isocyanates.
- Published
- 2016
87. Chemoselective Addition of Halomethyllithiums to Functionalized Isatins:A Straightforward Access to Spiro‐Epoxyoxindoles
- Author
-
Wolfgang Holzer, Thierry Langer, Vittorio Pace, Ashenafi Damtew Mamuye, and Laura Castoldi
- Subjects
chemistry.chemical_classification ,010405 organic chemistry ,Grignard reaction ,Alkyne ,chemistry.chemical_element ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Copper ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Intramolecular force ,Alkoxide ,Electrophile ,Organic chemistry ,Chemoselectivity - Abstract
An efficient, chemoselective approach to spiro-epoxyoxindoles via the addition of chloromethyllithium followed by ring-closure of the intermediate alkoxide is reported. Chemoselectivity is fully preserved in the presence of different electrophilic sites. The synthetic potential of selected spiro-epoxyindoles has been exploited in the copper(I)-catalyzed intramolecular oxyarylation of an alkyne and in the formation of N,N-dimethylisoindigo via the addition of dihalocarbenoids.
- Published
- 2016
88. A Robust, Eco‐Friendly Access to Secondary Thioamides through the Addition of Organolithium Reagents to Isothiocyanates in Cyclopentyl Methyl Ether (CPME)
- Author
-
Wolfgang Holzer, Alexander Roller, Sandra Safranek, Laura Castoldi, Thierry Langer, Vittorio Pace, and Serena Monticelli
- Subjects
Reaction conditions ,Nucleophilic addition ,Organic Chemistry ,One-pot synthesis ,Cyclopentyl methyl ether ,General Chemistry ,Environmentally friendly ,Combinatorial chemistry ,Catalysis ,chemistry.chemical_compound ,Enantiopure drug ,chemistry ,Reagent ,Organic chemistry - Abstract
The nucleophilic addition of widely available and variously functionalized organolithium reagents to isothiocyanates represents a straightforward, high-yielding, one-pot method to access secondary thioamides. The simple reaction conditions required and the broad scope (>50 cases examples) makes it a robust and reliable method to access both simple and complex thioamides, including enantiopure ones. Noxious and unpleasant-smelling sulfurating agents, usually employed in the literature established methods, are avoided during the whole synthetic procedure thus, rendering the protocol highly attractive, also for sustainability aspects.
- Published
- 2015
89. Enhanced arecoline derivatives as muscarinic acetylcholine receptor M1 ligands for potential application as PET radiotracers
- Author
-
Marius Ozenil, Markus Mitterhauser, Chrysoula Vraka, Wolfgang Holzer, Helmut Spreitzer, Wolfgang Wadsak, Verena Pichler, Katharina Pacher, Marcus Hacker, Theresa Balber, and Alexander Roller
- Subjects
Magnetic Resonance Spectroscopy ,Arecoline ,CHO Cells ,Pharmacology ,Ligands ,01 natural sciences ,Mice ,Radioligand Assay ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Cricetulus ,In vivo ,Drug Discovery ,Muscarinic acetylcholine receptor ,medicine ,Animals ,Humans ,030304 developmental biology ,0303 health sciences ,Nonspecific binding ,010405 organic chemistry ,Receptor, Muscarinic M1 ,Organic Chemistry ,Brain ,General Medicine ,Muscarinic acetylcholine receptor M1 ,Arecaidine ,Acetylcholinesterase ,0104 chemical sciences ,Molecular Docking Simulation ,Molecular Weight ,chemistry ,Positron-Emission Tomography ,Lipophilicity ,Microsomes, Liver ,Radiopharmaceuticals ,medicine.drug - Abstract
Supported by their involvement in many neurodegenerative disorders, muscarinic acetylcholine receptors (mAChRs) are an interesting target for PET imaging. Nevertheless, no radiotracer is established in clinical routine. Within this work we aim to develop novel PET tracers based on the structure of arecoline. Fifteen novel arecoline derivatives were synthesized, characterized and tested for their affinity to the mAChRs M1-M5 and the conceivable off-target acetylcholinesterase. Five arecoline derivatives and arecoline were labeled with carbon-11 in good yields. Arecaidine diphenylmethyl ester (3b), arecaidine bis(4-fluorophenyl)methyl ester (3c) and arecaidine (4-bromophenyl)(4-fluorophenyl)methyl ester (3e) showed a tremendous gain in mAChR affinity compared to arecoline and a pronounced subtype selectivity for M1. Metabolic stability and serum protein binding of [11C]3b and [11C]3c were in line with properties of established brain tracers. Nonspecific binding of [11C]3c was prevalent in kinetic and endpoint experiment on living cells as well as in autoradiography on native mouse brain sections, which motivates us to decrease the lipophilicity of this substance class prior to in vivo experiments.
- Published
- 2020
90. Design, Synthesis, and Pharmacological Evaluation of Novel β2/3 Subunit-Selective γ-Aminobutyric Acid Type A (GABA
- Author
-
Marco, Stadler, Serena, Monticelli, Thomas, Seidel, Denise, Luger, Isabella, Salzer, Stefan, Boehm, Wolfgang, Holzer, Christoph, Schwarzer, Ernst, Urban, Sophia, Khom, Thierry, Langer, Vittorio, Pace, and Steffen, Hering
- Subjects
Patch-Clamp Techniques ,Oocysts ,Triazoles ,Receptors, GABA-A ,Amides ,Hippocampus ,Protein Subunits ,Structure-Activity Relationship ,Xenopus laevis ,Indenes ,Seizures ,Drug Design ,Animals ,Pentylenetetrazole ,Anticonvulsants ,Female ,Sesquiterpenes - Abstract
Subunit-selective modulation of γ-aminobutyric acid type A receptors (GABA
- Published
- 2018
91. Homologation of halostannanes with carbenoids: a convenient and straightforward one-step access to α-functionalized organotin reagents
- Author
-
Saad Touqeer, Vittorio Pace, Laura Castoldi, Wolfgang Holzer, and Thierry Langer
- Subjects
Tandem ,010405 organic chemistry ,Metals and Alloys ,One-Step ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,Catalysis ,0104 chemical sciences ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,chemistry.chemical_compound ,chemistry ,Nucleophile ,Reagent ,Halogen ,Electrophile ,Materials Chemistry ,Ceramics and Composites ,Methyllithium - Abstract
A direct, single synthetic homologative transformation of halostannanes into mono- or di-substituted methyl analogues is documented. Critical for the success of the operation is the excellent nucleophilicity of carbenoid-like methyllithium reagents (LiCHXY, X, Y = halogen, OR, and CN): by simply individuating the reagents’ substitution pattern, the desired functionalized fragment is delivered to the electrophile. The wide scope of the protocol is evidenced also in the case of analogous halogermanium compounds. The tandem homologation–quenching with nucleophiles and the use of α-chloroallyllithium is also discussed.
- Published
- 2018
92. Expeditious and Chemoselective Synthesis of α-Aryl and α-Alkyl Selenomethylketones via Homologation Chemistry
- Author
-
Wolfgang Holzer, Raffaele Senatore, Laura Ielo, Laura Castoldi, and Vittorio Pace
- Subjects
chemistry.chemical_classification ,010405 organic chemistry ,Aryl ,Organic Chemistry ,chemistry.chemical_element ,010402 general chemistry ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Organic chemistry ,Lithium ,Physical and Theoretical Chemistry ,Racemization ,Selenium ,Alkyl ,Carbanion - Abstract
Diselenoacetals, previously considered byproducts in homologation tactics en route to α-selenoketones, are herein found to be excellent starting materials for this purpose. The easy selenium/lithium exchange they undergo affords seleno carbanions which are smoothly added to Weinreb amides to chemoselectively prepare α-aryl- and α-alkyl seleno methylketones through a single chemical operation. No racemization events are observed in the presence of optically pure starting materials.
- Published
- 2018
93. α-Arylamino Diazoketones: Diazomethane-Loading Controlled Synthesis, Spectroscopic Investigations, and Structural X-ray Analysis
- Author
-
Laura Castoldi, Laura Ielo, Alexander Roller, Gerald Giester, Vittorio Pace, and Wolfgang Holzer
- Subjects
Primary (chemistry) ,010405 organic chemistry ,Chemistry ,Diazomethane ,Organic Chemistry ,Alkylation ,010402 general chemistry ,01 natural sciences ,Scavenger (chemistry) ,0104 chemical sciences ,chemistry.chemical_compound ,Nucleophile ,Polymer chemistry ,Diazo ,X ray analysis - Abstract
Primary and secondary α-halomethyl diazoketones generated via Arndt–Eistert chemistry with minimum loading of diazomethane efficiently alkylate aromatic amines in the presence of calcium oxide to furnish the corresponding α-arylamino diazoketones under full chemocontrol. Such a simple inorganic acid scavenger fully neutralizes the hydrohalic acid formed during the nucleophilic displacement which otherwise would immediately react to produce the corresponding α-haloketone. The methodology can be further exploited in analogous acylation-type processes on secondary arylamino diazoketones. In depth spectroscopic (1H, 13C, and 15N NMR ) and crystallographic analyses document interesting structural features of these previously unknown diazo derivatives.
- Published
- 2018
94. Synthesis and anti-mitotic activity of 2,4- or 2,6-disubstituted- and 2,4,6-trisubstituted-2H-pyrazolo[4,3-c]pyridines
- Author
-
Vaida Milišiūnaitė, Eva Řezníčková, Veronika Malínková, Wolfgang Holzer, Vladimír Kryštof, Eglė Arbačiauskienė, Radek Jorda, Asta Žukauskaitė, and Algirdas Šačkus
- Subjects
Programmed cell death ,Stereochemistry ,Pyridines ,Mitosis ,Antineoplastic Agents ,Antimitotic Agents ,010402 general chemistry ,01 natural sciences ,Histone H3 ,Structure-Activity Relationship ,Drug Discovery ,Humans ,Fragmentation (cell biology) ,Cytotoxicity ,Cell Proliferation ,Pharmacology ,Cell Death ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,General Medicine ,Cell Cycle Checkpoints ,0104 chemical sciences ,Apoptosis ,Cell culture ,MCF-7 Cells ,Phosphorylation ,Drug Screening Assays, Antitumor ,K562 Cells - Abstract
An efficient synthetic route for the synthesis of 2H-pyrazolo[4,3-c]pyridines, primarily varying by the substituents at the 2-, 4- and 6-positions, is described here. A Sonogashira-type cross-coupling reaction was employed to yield 3-alkynyl-1H-pyrazole-4-carbaldehydes, ethanones and propanones from the corresponding 1H-pyrazol-3-yl trifluoromethanesulfonates. Subsequent treatment of the coupling products with dry ammonia afforded a versatile library of 2H-pyrazolo[4,3-c]pyridines, which were then evaluated for their cytotoxicity against K562 and MCF-7 cancer cell lines. The most potent of these compounds displayed low micromolar GI50 values in both cell lines. Active compounds induced dose-dependent cell-cycle arrest in mitosis, as shown by flow cytometric analysis of DNA content and phosphorylation of histone H3 at serine-10. Moreover, biochemical assays revealed increased activities of caspases-3/7 in treated cells, specific fragmentation of PARP-1, and phosphorylation of Bcl-2, collectively confirming apoptosis as the mechanism of cell death.
- Published
- 2017
95. Metal-Free Intramolecular Alkyne-Azide Cycloaddition To Construct the Pyrazolo[4,3-f][1,2,3]triazolo[5,1-c][1,4]oxazepine Ring System
- Author
-
Algirdas Šačkus, Eglė Arbačiauskienė, Wolfgang Holzer, and Vaida Laukaitytė
- Subjects
chemistry.chemical_classification ,chemistry.chemical_compound ,chemistry ,Metal free ,Stereochemistry ,Intramolecular force ,Organic Chemistry ,Alkyne ,Oxazepine ,Azide ,Physical and Theoretical Chemistry ,Ring (chemistry) ,Cycloaddition - Abstract
A simple and efficient synthetic route to a new pyrazolo[4,3-f][1,2,3]triazolo[5,1-c][1,4]oxazepine ring system has been developed by employing a metal-free, intramolecular alkyne-azide cycloaddition reaction as the key step. The structures of the obtained heterocyclic products were unequivocally confirmed by detailed 1H, 13C, and 15N NMR spectroscopic experiments and single-crystal X-ray diffraction analysis.
- Published
- 2015
96. Synthesis of pyrazolo[4′,3′:3,4]pyrido[1,2-a]benzimidazoles and related new ring systems by tandem cyclisation of vic-alkynylpyrazole-4-carbaldehydes with (het)aryl-1,2-diamines and investigation of their optical properties
- Author
-
Wolfgang Holzer, Eglė Arbačiauskienė, Algirdas Šačkus, Vaida Milišiūnaitė, Aurimas Bieliauskas, and Gytė Vilkauskaitė
- Subjects
Benzimidazole ,Tandem ,Chemistry ,Aryl ,Organic Chemistry ,Ring (chemistry) ,Biochemistry ,Medicinal chemistry ,Fluorescence spectroscopy ,Catalysis ,chemistry.chemical_compound ,Diamine ,Drug Discovery ,Spectroscopy - Abstract
The synthesis of 2H- and 3H-pyrazolo[4′,3′:3,4]pyrido[1,2-a]benzimidazole derivatives from 3-alkynyl- or 5-alkynylpyrazole-4-carbaldehydes and benzene-1,2-diamines was carried out using copper-free tandem cyclisation. When 2,3-diaminopyridine was used as the diamine component in this type of tandem cyclisation, 3H-pyrazolo[4,3-c]imidazo[1,2-a:5,4-b′]dipyridine derivatives were obtained. Copper catalysis and microwave activation were required for the reaction of 5-alkynylpyrazole-4-carbaldehydes and 1,8-naphthalenediamine, affording the corresponding 13,13a-dihydro-3H-pyrazolo[4′,3′:3,4]pyrido[1,2-a]perimidines. The structure assignments were based on data from 1H, 13C and 15N spectroscopy and single-crystal X-ray diffraction analyses. The optical properties of the obtained new heterocyclic derivatives were studied by UV–vis and fluorescence spectroscopy.
- Published
- 2015
97. Synthesis and in Silico Evaluation of Novel Compounds for PET-Based Investigations of the Norepinephrine Transporter
- Author
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Amir Seddik, Gerhard F. Ecker, Wolfgang Holzer, Wolfgang Wadsak, Karem Shanab, Andreas Jurik, Christina Rami-Mark, Helmut Spreitzer, Catharina Neudorfer, and Markus Mitterhauser
- Subjects
Stereochemistry ,In silico ,Pharmaceutical Science ,Ligands ,Article ,Analytical Chemistry ,lcsh:QD241-441 ,Norepinephrine (medication) ,chemistry.chemical_compound ,lcsh:Organic chemistry ,Drug Discovery ,medicine ,Humans ,ADHD ,Computer Simulation ,Physical and Theoretical Chemistry ,Norepinephrine Plasma Membrane Transport Proteins ,FAPPI ,biology ,Methylamine ,Organic Chemistry ,BAT ,Transporter ,Reference Standards ,Ligand (biochemistry) ,NET ,cocaine dependence ,PET ,Monoamine neurotransmitter ,Norepinephrine transporter ,Biochemistry ,chemistry ,Chemistry (miscellaneous) ,Positron-Emission Tomography ,biology.protein ,Molecular Medicine ,Radiopharmaceuticals ,Sequence Alignment ,medicine.drug - Abstract
Since the norepinephrine transporter (NET) is involved in a variety of diseases, the investigation of underlying dysregulation-mechanisms of the norepinephrine (NE) system is of major interest. Based on the previously described highly potent and selective NET ligand 1-(3-(methylamino)-1-phenylpropyl)-3-phenyl-1,3-dihydro-2H-benzimidaz- ol-2-one (Me@APPI), this paper aims at the development of several fluorinated methylamine-based analogs of this compound. The newly synthesized compounds were computationally evaluated for their interactions with the monoamine transporters and represent reference compounds for PET-based investigation of the NET.
- Published
- 2015
98. From the discussion at the Tunnel Day 2010 to VIP 2 / Von der Diskussion am Tunneltag 2010 bis zum VIP 2
- Author
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Wolfgang Holzer and Walter Purer
- Subjects
Engineering ,business.industry ,Operations management ,Geotechnical Engineering and Engineering Geology ,business ,Humanities ,Civil and Structural Engineering - Abstract
The discussion “NATM – quo vadis” at the 7th Austrian Tunnel Day 2010 made quite clear that questions apart from tunnelling technology, especially questions about cooperation between project partners, represent the bottleneck holding back the successful implementation of infrastructure projects. Contracts with excessively low prices were identified as the essential cause of problems with cooperation between project partners. This consideration led to the forming of the VIP working group of the ITA Austria. The VIP tendering model should change precisely the process that was recognised as essential in the discussion at the Tunnel Day 2010. At the same time, however, it was clear that the cybernetic networking of all construction processes also had to be considered. The award itself is thus no isolated process but only a part of a mosaic of improved cooperation in construction. The following considerations have therefore been included in the VIP: – The close integration with all other processes requires cybernetic modelling. – Construction is not a purely technical but rather a techno-social process. – The quality of collaboration is essential for the overall success of a construction project. – The award criteria must be aimed at the optimisation of the completed structure. – Due to the complexity of infrastructure projects, tendering as a negotiation procedure is mostly more suitable than an open/non-open procedure. Die Diskussion “NOT – quo vadis” hat am 7. Osterreichischen Tunneltag 2010 hat eindrucksvoll vor Augen gefuhrt, dass nicht tunnelbautechnischen Fragestellungen, sondern Probleme der Kooperation der Projektbeteiligten den Engpass fur erfolgreiche Projektabwicklung im Infrastrukturbau darstellt. Fur die Kooperation der Projektbeteiligten wurde das Bauen mit zu niedrigen Preisen als masgebender Problemverursacher erkannt. Aus dieser Einschatzung hat sich die Arbeitsgruppe VIP der ITA-Austria gebildet. Mit dem Vergabemodell VIP sollte genau jener Prozess verandert werden, der aus der Diskussion des Tunneltags 2010 als masgebend erkannt wurde. Zugleich war aber auch klar, dass die kybernetische Vernetzung aller Prozesse des Bauens mit berucksichtigt werden mussen. Die Vergabe selbst ist daher kein isolierter Prozess, sondern nur ein Mosaikstein fur verbesserte Kooperation am Bau. Die folgenden Uberlegungen sind daher in die Erarbeitung des VIP eingeflossen: – Die enge Vernetzung mit allen anderen Prozessen erfordert eine kybernetische Modellierung. – Das Bauen ist kein rein technischer, sondern ein techno-sozialer Prozess. – Die Qualitat der Zusammenarbeit ist fur den Gesamterfolg eines Bauprojekts masgebend. – Die Kriterien fur die Vergabe mussen auf ein Optimum des fertigen Bauwerks ausgerichtet sein. – Aufgrund der Komplexitat von Infrastrukturprojekten ist die Vergabe im Verhandlungsverfahren gegenuber einem offenen/nicht offenen Verfahren meist besser geeignet.
- Published
- 2014
99. Efficient Access to All-Carbon Quaternary and Tertiary α-Functionalized Homoallyl-type Aldehydes from Ketones
- Author
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Laura Castoldi, Thierry Langer, Marta Rui, Wolfgang Holzer, Vittorio Pace, and Eugenia Mazzeo
- Subjects
chemistry.chemical_classification ,010405 organic chemistry ,chemistry.chemical_element ,General Medicine ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Aldehyde ,Catalysis ,Vinyl oxirane ,0104 chemical sciences ,chemistry ,Organic chemistry ,Chemoselectivity ,Carbenoid ,Carbon ,Isomerization - Abstract
β,γ-Unsaturated aldehydes with all-carbon quaternary or tertiary α-centers were rapidly assembled from ketones through a unique synthetic operation consisting of 1) C1 homologation, 2) Lewis acid mediated epoxide–aldehyde isomerization, and 3) electrophilic trapping. The synthetic equivalence of a vinyl oxirane and a β,γ-unsaturated aldehyde is the key concept of this previously undisclosed tactic. Mechanistic studies and labeling experiments suggest that an aldehyde enolate is a crucial intermediate. The homologating carbenoid formation plays a critical role in determining the chemoselectivity.
- Published
- 2017
100. Evidence and isolation of tetrahedral intermediates formed upon the addition of lithium carbenoids to Weinreb amides and N-acylpyrroles
- Author
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Thierry Langer, Laura Castoldi, Wolfgang Holzer, and Vittorio Pace
- Subjects
010405 organic chemistry ,Chemistry ,Metals and Alloys ,chemistry.chemical_element ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Catalysis ,0104 chemical sciences ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,chemistry.chemical_compound ,Materials Chemistry ,Ceramics and Composites ,Tetrahedron ,Imidazole ,Organic chemistry ,Reactivity (chemistry) ,Lithium - Abstract
The tetrahedral intermediates generated upon the addition of halolithium carbenoids (LiCH2X and LiCHXY) to Weinreb amides have been intercepted and fully characterized as O-TMS heminals. The commercially available N-trimethylsilyl imidazole is the ideal trapping agent whose employment, combined with a straightforward neutral Alox chromatographic purification, enables the isolation of such labile species. The procedure could be advantageously extended also for obtaining O-TMS heminals from N-acylpyrroles. These intermediates manifest interesting reactivity including as precursors of more complex carbenoids.
- Published
- 2017
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