Article
Chemistry, Multidisciplinary
Ze-Shu Wang, Lu-Jing Zhu, Cui-Ting Li, Bin-Yang Liu, Xin Hong, Long-Wu Ye
Summary: In recent years, there has been significant attention on the asymmetric catalysis of ynamides, with most reactions focused on central chirality. However, the synthesis of axially chiral compounds from ynamides has been limited to noble-metal catalysis. This study presents a metal-free protocol for the construction of axially chiral N-heterocycles from ynamides using chiral Bronsted acid-catalyzed 5-endo-dig cyclization. The method allows for the practical and atom-economical synthesis of valuable N-arylindoles with excellent enantioselectivities, and the resulting axially chiral N-arylindole skeletons can be employed in asymmetric catalysis.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Multidisciplinary
Vasco Corti, Mathias Kirk Thaegersen, Valdemar Juel Enemaerke, Nomaan M. Rezayee, Casper L. Barlose, Karl Anker Jorgensen
Summary: The first atroposelective aminocatalytic methodology for the construction of C-N atropisomers is described. By directly coupling indole-2-carboxaldehydes to ortho-quinones, a new library of functionalized and enantioenriched C-N atropisomers was obtained using a designed and synthesized aminocatalyst. The synthetic utility of these atropisomers was demonstrated through various transformations.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
Article
Chemistry, Physical
Yin Xu, Gan-Lu Qian, Da-Qiu Cui, Peng-Cheng Qian, Chao-Yue Zhao, Xin Hong, Bo Zhou, Long-Wu Ye
Summary: Herein, a chiral Bronsted acid-catalyzed desymmetrization reaction of diynes is reported, providing a facile access to enantioenriched 1,3-diaminopropanol derivatives and γ-butyrolactones with high enantioselectivities. These products can be used as precursors for the synthesis of versatile N- and O-heterocycles, which are important structural cores of bioactive molecules. Control experiments and theoretical calculations are used to confirm the mechanism and elucidate the origin of enantioinduction.
Article
Chemistry, Multidisciplinary
Peng-Fei Chen, Bo Zhou, Peng Wu, Binju Wang, Long-Wu Ye
Summary: A novel Brønsted acid catalyzed intramolecular hydroalkoxylation/Claisen rearrangement is described for the synthesis of valuable spirolactams from readily available ynamides with good yields, diastereoselectivities, and broad substrate scope. An unexpected dearomatization of nonactivated arenes and heteroaromatic compounds occurs in this reaction. Furthermore, an asymmetric version of this reaction was achieved through efficient kinetic resolution by chiral phosphoric acid catalysis, with theoretical calculations showing a preference for the [3,3]-rearrangement over the [1,3]-rearrangement.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Organic
Timothy J. Paris, Chris Schwartz, Rachel Willand-Charnley
Summary: The successful synthesis and isolation of heteroaryl ketene acetals were achieved through intermolecular transfer of alkoxyl from electrophilic peroxides to lithiated benzofurans, indoles, and pyridines, showing enhanced reactivity towards electrophilic oxygen. The stability of the heteroaryl ketene acetals throughout purification techniques was superior, possibly due to increased aromaticity of the indole and pyridine structures. The reported products demonstrated resilience to workup and flash column chromatography procedures, overcoming typical issues associated with alkyl ketene acetal synthesis.
JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Jia-Bin Pan, Zhi-Chun Yang, Xuan-Ge Zhang, Mao-Lin Li, Qi-Lin Zhou
Summary: Here, we present a method for enantioselective phosphoric acid catalyzed amination of ketenes generated from α-aryl-α-diazoketones. Mechanistic studies elucidated the reaction pathway and explained how the catalyst expedited the transformation and controlled the enantioselectivity.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Zan Yang, Xun Zhang, Yu Jiang, Qiang Ma, Saihu Liao
Summary: The properties of poly(vinyl ether)s depend significantly on their tacticity, with considerable efforts focused on developing stereoselective cationic polymerization methods for isotactic PVEs. Current methods using metal-based Lewis acids have limitations on catalyst loading and monomer scope. A metal-free stereoselective cationic polymerization of vinyl ethers has been introduced using chiral confined Bronsted acids, offering advantages such as high efficiency, high stereoselectivity, and simplicity in operation.
SCIENCE CHINA-CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Daniel Moser, Kalipada Jana, Christof Sparr
Summary: In this study, the feasibility of atroposelective P-III/P-V=O redox organocatalysis by the Staudinger-aza-Wittig reaction is described. The formation of isoquinoline heterocycles allows for the synthesis of a wide range of valuable atropisomers with high enantioselectivities. The reaction is catalyzed by a chiral phosphine catalyst, with stereocontrol achieved through a silane reductant and Bronsted acid co-catalysis. The products can be easily transformed into N-oxides, naphthol, and triaryl phosphine variants, providing access to diverse aromatic heterocycles with precise control over their configuration.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Applied
Jasper S. Moehler, Lena K. Beiersdoerfer, Brenno Masina, Philipp Wechsler, Helma Wennemers
Summary: N-heterocyclic moieties are commonly found in pharmaceuticals and agrochemicals, but pose a challenge for metalorganic and organocatalytic transformations. This study presents tripeptide catalysts for stereoselective conjugate addition reactions between N-heterocyclic substituted aldehydes and electrophiles, achieving high yields and selectivities.
ADVANCED SYNTHESIS & CATALYSIS
(2022)
Article
Chemistry, Organic
Kyu Ree Lee, Subin Ahn, Sang-gi Lee
Summary: The study presents a novel method for the synthesis of monocyclic nine-membered N,O-heterocycles through a synergistic palladium/rhodium dual catalytic cycloaddition of vinylpropylene carbonates with N-sulfonyl-1,2,3-triazoles. Furthermore, the resulting oxazonines can be transformed into cis-fused [4.3.0] bicyclic compounds via a transannular Alder-ene rearrangement.
Article
Chemistry, Applied
Romain Melot, Sandra Olivero, Veronique Michelet
Summary: A synthetic route for alkynylated saturated N-heterocycles was developed via a sequential combination of Shono oxidation and gold(I)-catalyzed alkynylation reaction. The electrochemical Shono oxidation enabled efficient access to various N,O-acetals through direct C-H bond functionalization of cyclic amines. The gold-catalyzed process allowed the introduction of aryl acetylene partners with different electron properties. Promising initial results on asymmetric version were obtained.
ADVANCED SYNTHESIS & CATALYSIS
(2023)
Article
Chemistry, Organic
Qiongya Li, Chunlan He, Jiahui Su, Ying Shao, Shengbiao Tang, Jiangtao Sun
Summary: We report a rhodium-catalyzed reaction that efficiently synthesizes pyridazine derivatives from N-acyl pyridazinones and diazoacetates under mild reaction conditions. This reaction likely proceeds through a carbene insertion into a C=O bond and an unprecedented 1,4-N to-O acyl rearrangement reaction.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Avene C. Colgan, Rupert S. J. Proctor, David C. Gibson, Padon Chuentragool, Antti S. K. Lahdenpera, Kristaps Ermanis, Robert J. Phipps
Summary: This study reports a significant advancement in the catalytic enantioselective Minisci reaction, allowing the use of α-hydroxy radical coupling partners to obtain valuable enantioenriched secondary alcohol products. The approach is highly regioselective as well as highly enantioselective.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Physical
Laura E. English, Matthew D. Jones, David J. Liptrot
Summary: An N-heterocyclic phosphine (NHP) has been investigated as a catalyst for transesterification reactions of commercial polymer samples, displaying high degradation activity towards poly(lactic acid) with methanol. However, attempts to depolymerise other polymers were unsuccessful, and NHP was found to form a new active catalyst under transesterification conditions.
Article
Chemistry, Multidisciplinary
Kosuke Yamamoto, Masami Kuriyama, Osamu Onomura
Summary: The development of facile synthetic methods for stereodefined aliphatic cyclic amines is crucial in organic chemistry, given their presence in natural products and biologically active compounds. N-Acyl cyclic N,O-acetals, prepared by electrochemical oxidation, serve as versatile precursors for such synthesis. Efforts have been made to develop strategies for diastereo- and/or enantioselective synthesis of cyclic amines using these electrochemically prepared precursors, along with investigations into chirality memory and halogen cation-mediated synthesis of nitrogen-containing heterocycles.
Article
Cardiac & Cardiovascular Systems
Dmytro O. Kryshtal, Daniel J. Blackwell, Christian L. Egly, Abigail N. Smith, Suzanne M. Batiste, Jeffrey N. Johnston, Derek R. Laver, Bjorn C. Knollmann
Summary: The main mechanism of antiarrhythmic action of flecainide is likely through inhibition of RyR2-mediated arrhythmogenic Ca release, rather than solely through sodium channel block. Experimental results in cardiomyocytes and mouse models have both confirmed this.
CIRCULATION RESEARCH
(2021)
Correction
Chemistry, Multidisciplinary
Suzanne M. Batiste, Jeffrey N. Johnston
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Chemistry, Organic
Thomas J. Struble, Ivor Smajlagic, Hayden Foy, Travis Dudding, Jeffrey N. Johnston
Summary: A pair of chiral bis(amidine) [BAM] proton complexes have been developed as catalysts for highly diastereo- and enantioselective direct aza-Henry reactions, leading to alpha-alkyl-substituted alpha,beta-diamino esters. Computational analysis supports distinct models for selectivity, with the more hindered binding cavity of the C-1-symmetric ligand favoring a pre-syn arrangement. Factors driving unusual high syn-diastereoselection include favorable dispersion forces from the anthracenyl substituent of the C-1-symmetric ligand.
JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Jade A. Bing, Nathan D. Schley, Jeffrey N. Johnston
Summary: This research presents a comparative analysis of non-fluorinated and alpha-fluoro nitroalkanes in their additions to azomethines, revealing an unusual crossover and reversal in diastereoselection.
Article
Chemistry, Medicinal
Jeffrey N. Johnston, Abigail N. Smith, Daniel J. Blackwell, Bjorn C. Knollmann
Summary: Hit-to-lead studies utilize various strategies to optimize binding to a target of interest, with ring size identified as a critical independent variable that can significantly impact potency.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Cardiac & Cardiovascular Systems
Chantal J. M. van Opbergen, Navratan Bagwan, Svetlana R. Maurya, Joon-Chul Kim, Abigail N. Smith, Daniel J. Blackwell, Jeffrey N. Johnston, Bjorn C. Knollmann, Marina Cerrone, Alicia Lundby, Mario Delmar
Summary: This study reveals the relationship between exercise, catecholaminergic stimulation, Ca-i(2+) homeostasis, and arrhythmogenesis in PKP2-deficient hearts. Training disrupts Ca-i(2+) homeostasis in PKP2cKO hearts, leading to proarrhythmogenic changes facilitated by intracellular beta-adrenergic receptors and hyperphosphorylation of phospholamban. The findings suggest potential treatments for arrhythmogenic right ventricular cardiomyopathy and highlight the importance of PKP2 and phospholamban in arrhythmogenesis.
Article
Chemistry, Organic
Madelaine P. Thorpe, Abigail N. Smith, Michael S. Crocker, Jeffrey N. Johnston
Summary: The accessibility of bromonitromethane as a reagent for chemical synthesis has decreased recently, but this study presents a re-investigation and optimization of various preparations and the development of safe operating principles. This results in a reproducible procedure that offers a straightforward and sustainable way to obtain this critical reagent.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Michael S. Crocker, Zihang Deng, Jeffrey N. Johnston
Summary: Amide synthesis is widely used in drug development and peptide synthesis, but waste elimination in this process has had limited success. Umpolung amide synthesis has been developed as a method for enantioselective synthesis, but it cannot forge N-aryl amides. This study presents a direct synthesis method for N-aryl amides using a simple Bronsted base as a promoter, using alpha-fluoronitroalkanes and N-aryl hydroxyl amines.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Medicinal
Abigail N. Smith, Madelaine P. Thorpe, Daniel J. Blackwell, Suzanne M. Batiste, Corey R. Hopkins, Nathan D. Schley, Bjorn C. Knollmann, Jeffrey N. Johnston
Summary: The synthesis of N-Me and N-H analogues of ent-verticilide was described to enable a structure-activity relationship study based on cardiac ryanodine receptor (RyR2) calcium ion channel inhibition. The study found that a high degree of N-methyl amide content is critical for activity in the ent-verticilide series but not entirely so for the ent-verticilide B1 series.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Multidisciplinary
Ivor Smajlagic, Jeffrey N. Johnston, Travis Dudding
Summary: The fluorine atom has a strong and mysterious influence on chemical reactions, as evidenced by its recent discovery of causing diastereodivergence in an enantioselective aza-Henry reaction. This study comprehensively examined the cases of alpha-fluoro nitronate additions to aldimines, revealing the non-covalent interactions dictating anti-selectivity (alpha-aryl) versus syn-selectivity (alpha-alkyl) and the secondary orbital interaction between fluorine and the activated azomethine.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Chemistry, Organic
Jade A. Bing, Jeffrey N. Johnston
Summary: The synthesis of 7-membered carbocyclic fi-fluoro-amines is achieved by combining the enantioselective aza-Henry reaction of aliphatic N-Boc imines and ring-closing metathesis. Reductive denitration is used to obtain both diastereomers of the fi-fluoro amine carbocycle, each with high enantiomeric excess.
Article
Pharmacology & Pharmacy
Daniel J. Blackwell, Abigail N. Smith, Tri Do, Aaron Gochman, Jeffrey Schmeckpeper, Corey R. Hopkins, Wendell S. Akers, Jeffrey N. Johnston, Bjorn C. Knollmann
Summary: This study developed a bioassay to measure the concentrations of nat-verticilide and ent-verticilide in murine plasma and correlated plasma concentrations with antiarrhythmic efficacy. The results showed that ent-verticilide has favorable pharmacokinetic properties and reduces ventricular arrhythmias in the nanomolar range, warranting further drug development.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2023)
Article
Cardiac & Cardiovascular Systems
Kyungsoo Kim, Daniel J. Blackwell, Samantha L. Yuen, Madelaine P. Thorpe, Jeffrey N. Johnston, Razvan L. Cornea, Bjorn C. Knollmarnn
Summary: Atrial fibrillation (AF) is a common cardiac arrhythmia that increases the risk of stroke and morbidity. Variants on chromosome 4q25, near the PITX2 gene, have been identified as the strongest genetic risk factors for AF in humans. This study found that deficiency in Pitx2 leads to hyperactivation of the cardiac ryanodine receptor (RyR2), which is associated with increased susceptibility to AF. Treatment with the RyR2 inhibitor ent-verticilide reduces the incidence and duration of AF, suggesting that targeting hyperactive RyR2 may be a promising approach to treat atrial arrhythmias caused by Pitx2 deficiency.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Jenna L. Payne, Zihang Deng, Andrew L. Flach, Jeffrey N. Johnston
Summary: In recent years, enantioselective halolactonization reactions have grown rapidly, but most are only effective in forming smaller rings (6,5,4-membered). The formation of highly selective seven-membered epsilon-lactones is rare and has never been achieved without conformational bias. This study describes the first highly enantioselective 7-exo-trig iodolactonizations of conformationally unbiased epsilon-unsaturated carboxylic acids, using a combination of a bifunctional BAM catalyst, I-2, and I(iii) reagent (PhI(OAc)(2):PIDA).
Meeting Abstract
Biophysics
Jacob A. Schwarz, Daniel Blackwell, Abigail N. Smith, Robyn T. Rebbeck, Jeffrey N. Johnston, Bjorn C. Knollmann, Razvan L. Cornea
BIOPHYSICAL JOURNAL
(2022)
