Article
Chemistry, Organic
Chuan-Jin Hou, Alexander W. Schuppe, James Levi Knippel, Anton Z. Ni, Stephen L. Buchwald
Summary: A method for stereoselective hydroalkenylation of alkynes using enol triflates was reported in this study. The formation of Z,Z- or Z,E-1,3-dienes with excellent stereoselectivity and yield was achieved by leveraging an in situ-generated and geometrically pure vinyl-Cu(I) species. This approach allowed for the synthesis of highly substituted Z-dienes, including pentasubstituted 1,3-dienes, which are challenging to prepare using existing methods.
Article
Chemistry, Organic
Qi Zhang, Deb Kumar Das, Shuang Yang, Yao Fu, Xinqiang Fang
Summary: The mechanism of N-heterocyclic carbene-catalyzed umpolung of beta,gamma-unsaturated alpha-diketone was found to be more complicated than originally proposed, involving nucleophilic O-acylated homoenolate and electrophilic alpha,beta-unsaturated acyl azolium intermediates. Both DFT calculations and experimental studies confirmed the existence of these key intermediates, leading to a revised mechanism for product formation.
JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Chemistry, Inorganic & Nuclear
Ba L. Tran, Jeremy D. Erickson, Amy L. Speelman, R. Morris Bullock
Summary: The ability of Cu-H complexes to selectively insert unsaturated hydrocarbons has made them valuable catalysts. The formation of Cu allyl intermediates from 1,3-dienes and Cu hydrides is a promising strategy. However, there is limited research on the mechanistic studies and characterization of intermediates in Cu-H catalysis. This study explores the steric effects of NHC ligands on two key elementary steps of CuH-catalyzed carbonyl allylation and provides insights for a range of catalytic reactions.
INORGANIC CHEMISTRY
(2023)
Article
Chemistry, Organic
Vaibhav B. Patil, Sandip B. Jadhav, Jagadeesh Babu Nanubolu, Rambabu Chegondi
Summary: In this study, a CuH-catalyzed asymmetric desymmetrization reaction of prochiral cyclopentane-1,3-diones was reported. By using PMHS as a cost-effective hydride source, cyclic 3-hydroxy ketones with an all-carbon quaternary center could be synthesized with high diastereoselectivity. The reaction demonstrated excellent functional group tolerance, including reducible alkyne, alkene, and ester groups, and showed a broad substrate scope. The importance of chiral cyclic 3-hydroxy ketone building blocks was further demonstrated through the synthesis of (-)-estrone, the toxicodenane E core, and fused indoles.
Article
Chemistry, Organic
Xia Zhao, Wen-Yan Tong, Xiaotai Wang
Summary: This study investigates the detailed workings of copper-catalyzed hydroarylation of alkenes with polyfluoroarenes, focusing on C-F bond functionalization. The results show that the regioselectivity of the reaction is influenced by a combination of orbital and dispersion interactions induced by the aryl alkene substrate. The mechanistic insights obtained from this study can have significant implications for the development of new transition metal-catalyzed hydroarylation and C-F functionalization reactions.
ORGANIC CHEMISTRY FRONTIERS
(2023)
Article
Chemistry, Organic
Xia Zhao, Wen-Yan Tong, Xiaotai Wang
Summary: This study investigates the detailed mechanism of CuH-catalyzed hydroarylation of alkenes with polyfluoroarenes involving C-F bond functionalization. The research reveals that the regioselectivity is determined by a combination of orbital and dispersion interactions induced by the aryl alkene substrate. Additionally, the benzyl ligand facilitates a cupratropic shift, allowing for nucleophilic aromatic substitution. Noncovalent interactions play a crucial role in the regioselectivity of C-F bond cleavage.
ORGANIC CHEMISTRY FRONTIERS
(2023)
Article
Chemistry, Multidisciplinary
Hye Won Moon, Feng Wang, Kalishankar Bhattacharyya, Oriol Planas, Markus Leutzsch, Nils Noethling, Alexander A. Auer, Josep Cornella
Summary: This research investigates the transfer hydrogenation of azoarenes catalyzed by bismuth through experimental and computational studies. The role of protic and hydridic hydrogens in the reaction is identified through kinetic analysis and reactivity studies using p-trifluoromethylphenol and pinacolborane. The possibility of bismuth-ligand cooperativity is also assessed.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Organic
Lingfei Hu, Han Gao, Yanlei Hu, Yan-Bo Wu, Xiangying Lv, Gang Lu
Summary: The factors controlling the regioselectivity in alkene hydrocupration were investigated computationally using energy decomposition analysis. It was found that the Markovnikov-selective hydrocupration with electronically activated mono-substituted olefins is mainly influenced by destabilizing Pauli repulsion due to the electron delocalization effect. On the other hand, the anti-Markovnikov-selective hydrocupration with 1,1-dialkyl-substituted terminal olefins is dominated by repulsive electrostatic interactions caused by the unequal pi electron distribution induced by alkyl substituents.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Organic
Jia-Yin Wang, Guigen Li, Wen-Juan Hao, Bo Jiang
Summary: A new asymmetric catalytic conjugate reduction method has been established for synthesizing enantioenriched cyclobuta[a]-naphthalen-4(2H)-ones using copper-bisphosphine complexes as catalysts, providing excellent regio- and enantioselectivities. This protocol is tolerant to a broad scope of substrates, exhibits high compatibility with various substituents, and offers excellent stereoselectivity.
Article
Chemistry, Multidisciplinary
Ya-Qian Zhang, Xue-Yu Han, Yue Wu, Peng-Jia Qi, Qing Zhang, Qing-Wei Zhang
Summary: In this study, a highly regio- and enantioselective hydrophosphinylation reaction of secondary phosphine oxides and enynes was achieved through Ni catalysis. A new mechanism was discovered through kinetic studies and DFT calculations. The alkene moiety played a vital role in the reactivity, regio-, and enantioselectivity.
Article
Chemistry, Multidisciplinary
Sergio Cuesta-Galisteo, Johannes Schorgenhumer, Xiaofeng Wei, Estibaliz Merino, Cristina Nevado
Summary: This study presents a nickel-catalyzed asymmetric reductive hydroarylation method for synthesizing enantioenriched alpha-arylbenzamides. By using a BIm ligand, diethoxymethylsilane, and aryl halides, aryl groups can be selectively introduced to the internal position of the olefin, creating a new stereogenic center alpha to the N atom with neutral reagents and mild reaction conditions. This provides a straightforward route to pharmacologically relevant motifs found in anticancer drugs, SARS-CoV PLpro inhibitors, and KCNQ channel openers.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Review
Chemistry, Multidisciplinary
Anna Roglans, Anna Pla-Quintana, Miquel Sola
Summary: The review in this article covers the mechanistic aspects of the transition-metal-catalyzed [2 + 2 + 2] cycloaddition reaction involving various unsaturated substrates with metals such as Co, Ni, Ru, Rh, Ir, Pd, etc. It provides an overview from the early studies to the present day, focusing on the key mechanistic aspects that influence reactivity and selectivity, comparing different unsaturated substrates and transition metals used.
Article
Chemistry, Organic
Amanda A. Barboza, Attilio Chiavegatti Neto, Isac G. Rosset, Guilherme A. M. Jardim, Marco A. B. Ferreira
Summary: In this study, a new synthesis method for 3-carbonyltrisubstituted furans through Pd-catalyzed oxidative cycloisomerization reactions was reported. The use of molecular oxygen as the sole oxidant provides good functional tolerance and mild reaction conditions, while avoiding the need for stoichiometric amounts of oxidants and strong acid additives. Deep investigation of intermediates and transition states of the reaction mechanism was performed, providing a detailed mechanistical profile.
JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Zi-Lu Wang, Qi Li, Meng-Wei Yang, Zhao-Xin Song, Zhen-Yu Xiao, Wei-Wei Ma, Jin-Bo Zhao, Yun-He Xu
Summary: A copper-catalyzed ligand-controlled selective 1,2- and 1,4-hydrosilylation of 1,3-enynes was reported, which achieved enantiomerically enriched propargyl- and 1,2-allenylsilane products in high yields and excellent enantioselectivities. The reaction showed broad substrate scope and excellent regioselectivities, with mechanistic studies revealing the importance of allenylcopper as the reactive intermediate and the role of ligand in controlling the regioselectivity switch. The high enantiocontrol in the 1,4-hydrosilylation was also explained by DLPNO-CCSD(T) calculations.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Multidisciplinary
Ebbin Joseph, Rafael D. Hernandez, Jon A. Tunge
Summary: Sustainable catalysis: The development of a cobalt-catalyzed decarboxylative allylation of nitrophenyl alkanes, nitroalkanes, and ketones is accomplished. The protocol offers the regioselective synthesis of various allylated products with broad functional group tolerance. Mechanistic studies revealed an unusual activation of Co(II)-salts using new organoreductants.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Chemistry, Applied
Liam Byrne, Christian Skold, Per-Ola Norrby, Rachel H. Munday, Andrew R. Turner, Peter D. Smith
Summary: The development of biaryl 2,5-diphenylphospholanes as a new class of C-2-symmetric, monodentate ligands for asymmetric Suzuki-Miyaura (ASM) reactions has led to the successful preparation of a range of atropisomeric biaryl and heterobiaryl products with good to excellent levels of enantioselectivity. DFT studies indicate that the formation of a constraining ligand pocket and coordination of one of the biaryl methoxy groups to the metal center in the optimized ligands are crucial for restricting conformational freedom in the bond-forming step.
ADVANCED SYNTHESIS & CATALYSIS
(2021)
Article
Chemistry, Multidisciplinary
Anna Lidskog, Sami Dawaigher, Carlos Solano Arribas, Anna Ryberg, Jacob Jensen, Karl Erik Bergquist, Anders Sundin, Per-Ola Norrby, Kenneth Warnmark
Summary: In this study, a model system involving a bis(18-crown-6) Troger's base receptor and 4-substituted hepta-1,7-diyl bisammonium salt ligands was used to investigate interactions between non-polar peptides side chains and a protein's aromatic cavity. Experimental results showed a preference for an all-anti conformation of the heptane chain in most ligands, with the substituent located inside or partially inside the aromatic cavity when bound to the receptor. Computational analysis revealed that molecular mechanics (MM) methods outperformed density functional theory (DFT) methods in estimating free binding energies.
CHEMISTRY-A EUROPEAN JOURNAL
(2021)
Article
Chemistry, Organic
Jessica Wahlers, Michael Maloney, Farbod Salahi, Anthony R. Rosales, Paul Helquist, Per-Ola Norrby, Olaf Wiest
Summary: This study developed and applied a TSFF method to predict the stereoselectivity of aryl boronic acids conjugate addition to enones, achieving good results through automated screening and validation. Detailed error analysis and identification of structural origins for outliers were conducted. The results showed that the majority of virtual screening outcomes were in line with expectations.
JOURNAL OF ORGANIC CHEMISTRY
(2021)
Review
Chemistry, Multidisciplinary
Kjell Jorner, Anna Tomberg, Christoph Bauer, Christian Skold, Per-Ola Norrby
Summary: The introduction of more data in chemical reactivity models reduces the dependence on mechanistic hypotheses, as 'big data' applications potentially learn them implicitly through data training. These models can predict reaction barriers, lab-relevant properties, and calculations with a quantum-mechanical component are preferred for quantitative predictions of reactivity. Big data applications tend to be more qualitative but can be broadly applied to different kinds of reactions.
NATURE REVIEWS CHEMISTRY
(2021)
Correction
Chemistry, Multidisciplinary
Kjell Jorner, Anna Tomberg, Christoph Bauer, Christian Skold, Per-Ola Norrby
NATURE REVIEWS CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Jessica Wahlers, Jessica Margalef, Eric Hansen, Armita Bayesteh, Paul Helquist, Montserrat Dieguez, Oscar Pamies, Olaf Wiest, Per-Ola Norrby
Summary: The transition state force field (TSFF) derived by the quantum-guided molecular mechanics (Q2MM) method can be used to rapidly screen ligand/substrate combinations, revealing multiple cases of computationally predicted major enantiomer differing from the experimentally observed one in literature reactions.
NATURE COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
Taylor R. Quinn, Himani N. Patel, Kevin H. Koh, Brandon E. Haines, Per-Ola Norrby, Paul Helquist, Olaf Wiest
Summary: This paper introduces a method for generating surrogate potential energy functions that are faster to compute and as accurate as high-level electronic structure methods. By fitting transition state force fields to the Amber force field, it can be used for molecular dynamics studies of enzyme reactions.
Article
Chemistry, Multidisciplinary
Ester M. Di Tommaso, Per-Ola Norrby, Berit Olofsson
Summary: Vinylbenziodoxolones have been identified as efficient reagents for electrophilic vinylations under metal-free conditions. This paper presents the first mechanistic investigation of VBX vinylations, providing insights into the regio- and stereochemical outcome. The findings can be applied to predict the regioselectivity in vinylations of other nucleophile classes.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Organic
Jessica Wahlers, Anthony R. Rosales, Neil Berkel, Aaron Forbes, Paul Helquist, Per-Ola Norrby, Olaf Wiest
Summary: This study presents a MM3* force field for ferrocenyl ligands, which accurately predicts the stereochemical outcomes of aminations of Pd-allyl complexes. The force field was validated against DFT calculations and crystal structures, showing good accuracy and revealing the physical origin of deviations. The compatibility with previously developed force fields was also demonstrated.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Samuel Genheden, Per-Ola Norrby, Ola Engkvist
Summary: We present AiZynthTrain Python package that trains synthesis models in a robust, reproducible, and extensible way. It includes two pipelines for creating one-step retrosynthesis and RingBreaker models, which can be easily integrated into retrosynthesis software. By training on publicly available reaction data from USPTO, these are the first reproducible end-to-end retrosynthesis models. The pipeline demonstrates improved RingBreaker performance and robustness when trained on a more diverse proprietary dataset. This framework is expected to be expanded with other synthesis models in the future.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Editorial Material
Chemistry, Organic
Michael P. Maloney, Connor W. Coley, Samuel Genheden, Nessa Carson, Paul Helquist, Per-Ola Norrby, Olaf Wiest
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Editorial Material
Chemistry, Organic
Michael P. Maloney, Connor W. Coley, Samuel Genheden, Nessa Carson, Paul Helquist, Per-Ola Norrby, Olaf Wiest
Article
Chemistry, Multidisciplinary
Mandana Saebi, Bozhao Nan, John E. E. Herr, Jessica Wahlers, Zhichun Guo, Andrzej M. M. Zuranski, Thierry Kogej, Per-Ola Norrby, Abigail G. G. Doyle, Nitesh V. V. Chawla, Olaf Wiest
Summary: The lack of publicly available, large, and unbiased datasets poses a challenge for applying machine learning in synthetic chemistry. While data from electronic lab notebooks (ELNs) can potentially provide less biased large datasets, there is currently a lack of publicly available ELN datasets. This study presents the first real-world dataset from the ELNs of a pharmaceutical company, and explores its relationship with high-throughput experimentation datasets. The study shows that an attributed graph neural network performs well on high-throughput experimentation datasets for yield predictions, but fails to be predictive when trained on the ELN dataset. The implications of using ELN data for training ML-based models for yield predictions are discussed.
Article
Chemistry, Multidisciplinary
Taylor R. Quinn, Calvin N. Steussy, Brandon E. Haines, Jinping Lei, Wei Wang, Fu Kit Sheong, Cynthia Stauffacher, Xuhui Huang, Per-Ola Norrby, Paul Helquist, Olaf Wiest
Summary: Understanding enzymatic catalysis involves a detailed understanding of the complex interplay of structure and dynamics, which is challenging for both experimental and computational approaches. A novel approach using transition state force fields derived by quantum-guided molecular mechanics allows simulations at the microsecond timescale, enabling prediction of remote dynamic effects on enzyme activity. This approach has been validated experimentally, showing its potential in predicting remote allosteric residues.
Article
Chemistry, Multidisciplinary
Kjell Jorner, Tore Brinck, Per-Ola Norrby, David Buttar
Summary: The study introduces hybrid models combining traditional transition state modeling and machine learning to accurately predict reaction barriers, offering competitive accuracy in low-data scenarios.
