Article
Chemistry, Multidisciplinary
Efrey A. Noten, Rory C. McAtee, Corey R. J. Stephenson
Summary: This research discloses an intramolecular reaction that utilizes a nitrogen radical to form a C-N bond and repurposes the nitrogen atom's activating group to form a C-C bond, enabling the efficient synthesis of arylethylamines. The protocol utilizes photoredox catalysis under mild conditions.
Article
Chemistry, Multidisciplinary
Christopher W. Lamartina, Cassandra A. Chartier, Sumin Lee, Neel H. Shah, Tomislav Rovis
Summary: Here, a modular peptide ligation methodology is reported, which uses Rh(III) catalysis to couple dioxazolones, arylboronic acids, and acrylamides to construct amide bonds in a diastereoselective manner under mild conditions. The method shows excellent functional group tolerance and a large substrate scope, allowing for the construction of unnatural amino acid residues. This methodology is demonstrated in the synthesis of diastereomeric proteasome inhibitor analogs and the ligation of oligopeptides to construct a polypeptide with an unnatural residue.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Multidisciplinary
Benjamin T. Jones, Javier Garcia-Carceles, Lewis Caiger, Ian R. Hazelden, Richard J. Lewis, Thomas Langer, John F. Bower
Summary: Intramolecular Pd(0)-catalyzed alkene 1,2-aminoarylation reactions were utilized to access structurally complex benzo- and spiro-fused N-polyheterocycles. The method involved using N-(pentathiorobenzoyloxy)carbamates as initiating motifs, showcasing aza-Heck-type alkene amino-palladation prior to C-H palladation of the aromatic component. This chemistry was demonstrated in the total synthesis of the complex alkaloid (+)-pileamartine A, leading to the reassignment of its absolute stereochemistry.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Chemistry, Organic
Wen-Jun Yue, Craig S. Day, Adrian J. Brenes Rucinski, Ruben Martin
Summary: We present a modular catalytic technique that simplifies the preparation of gem-difluoroalkanes from unactivated sp3 precursors. This method exhibits simplicity, generality, and site selectivity, allowing for the functionalization of advanced intermediates and olefin feedstocks. Our strategy involves a cooperative interplay of halogen- and hydrogen-atom transfer, providing a new entry point to difluorinated alkyl bioisosteres of interest in drug discovery.
Article
Chemistry, Physical
Amit Kumar Simlandy, Warabhorn Rodphon, Turki M. Alturaifi, Binh Khanh Mai, Hui-Qi Ni, John A. Gurak Jr, Peng Liu, Keary M. Engle
Summary: A redox-neutral catalytic coupling of nitroalkanes and unactivated alkenes is reported in this study, which proceeds by a directed carbopalladation mechanism. The combination of PdI2 as the precatalyst and HFIP solvent enables the reaction uniquely. Structurally complex nitroalkane products, including nitro-containing carbo- and heterocycles, can be prepared under convenient conditions without the use of toxic or corrosive reagents. The reaction mechanism is examined through deuterium labeling experiments and isolation of a catalytically relevant intermediate. Different catalytic activation modes are utilized to demonstrate orthogonal methods for site-selective functionalization of a polyfunctional nitroalkyl ketone. Density functional theory (DFT) calculations reveal that the carbopalladation transition state is stabilized by a Na·I interaction and H·I hydrogen bond with HFIP.
Article
Chemistry, Physical
Amit Kumar Simlandy, Warabhorn Rodphon, Turki M. Alturaifi, Binh Khanh Mai, Hui-Qi Ni, John A. Gurak, Peng Liu, Keary M. Engle
Summary: We report a redox-neutral catalytic coupling of nitroalkanes and unactivated alkenes that proceeds by a directed carbopalladation mechanism. The reaction is enabled by the combination of PdI2 as the precatalyst and HFIP solvent. Complex nitroalkane products, including nitro-containing carbo- and heterocycles, can be prepared under convenient conditions without the need for toxic or corrosive reagents.
Article
Multidisciplinary Sciences
Leipeng Xie, Shenghao Wang, Lanlan Zhang, Lei Zhao, Chun Luo, Linping Mu, Xiuguang Wang, Chao Wang
Summary: The authors presented a method to add aryl and amino groups to alkenes regio- and diastereoselectively via nickel catalysis and a removable directing group. This method enables high levels of regio-, chemo- and diastereocontrol, and is compatible with broad substrate scope and high functional group tolerance. The utility of this method in site-selective modification of pharmaceutical agents has been demonstrated.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Multidisciplinary
Yuan Cai, Sagnik Chatterjee, Tobias Ritter
Summary: We present a photoinduced copper-catalyzed azidoarylation of alkenes at a late stage with arylthianthrenium salts, allowing access to highly functionalized acyclic (hetero)arylethylamine scaffolds that are otherwise difficult to access. A mechanistic study is consistent with a rac-BINAP-Cu-I-azide (2) as the photoactive catalytic species. We show the utility of the new method by the expedient synthesis of racemic melphalan in four steps through C-H functionalization.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Multidisciplinary
Daichi Okumatsu, Kensuke Kiyokawa, Linh Tran Bao Nguyen, Manabu Abe, Satoshi Minakata
Summary: The alkylamination of alkenes using pristine carboxylic acids was achieved by the photoexcitation of (diarylmethylene)amino benziodoxolones (DABXs), which serve as both an oxidant and an aminating reagent. The developed method is a simple photochemical reaction without the need for external photosensitizers and shows a broad substrate scope, enabling the facile synthesis of various structurally complex amines.
Article
Chemistry, Organic
Rahul K. Shukla, Atul K. Chaturvedi, Subir Pal, Chandra M. R. Volla
Summary: In this study, a Pd(II)-catalyzed regioselective hydrocarbofunctionalization of unactivated alkenes was demonstrated. The regioselectivity of the reaction was controlled by using a bidentate auxiliary and specific alkynes, leading to the formation of 1,6-dicarbonyl compounds through a cascade sequence.
Article
Chemistry, Physical
Rahul K. Shukla, Atul K. Chaturvedi, Chandra M. R. Volla
Summary: A Pd(II)-catalyzed directed, regio-controlled hydroheteroarylation of unactivated alkenes has been developed for the construction of gamma-heteroaryl-substituted carbonyl compounds. The methodology is operationally simple and compatible with a variety of nucleophiles to deliver structurally divergent heterocyclic skeletons. This approach also demonstrated synthetic utility in gram-scale synthesis, directing group removal, and late-stage modification of drugs and natural products.
Article
Chemistry, Multidisciplinary
Zhan Dong, Qiongyao Tang, Changyu Xu, Li Chen, Haiting Ji, Sitian Zhou, Liangliang Song, Liang-An Chen
Summary: Transition-metal catalyzed intermolecular 1,2-diarylation of electronically unactivated alkenes is a widely studied topic, but most examples are limited to terminal alkenes. Furthermore, the asymmetric 1,2-diarylation of unactivated alkenes remains unsolved and is challenging. In this study, a highly efficient directed nickel-catalyzed reductive 1,2-diarylation of unactivated internal alkenes with high diastereoselectivities is described. Moreover, enantioselective 1,2-diarylation of unactivated terminal and challenging internal alkenes is achieved with good to high enantioselectivities and high diastereoselectivities by generating a cationic Ni-catalyst through the addition of alkali metal fluoride.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Ruijie Mi, Zhiying Ding, Songjie Yu, Robert H. Crabtree, Xingwei Li
Summary: This study presents the design of N-protected O-allylhydroxyamines as bifunctional olefins for catalytic asymmetric carboamidation, resulting in the formation of chiral amino alcohols via C-H activation. The reaction pattern is dependent on the nature of the (hetero)arene reagent, with achiral (hetero)arenes giving centrally chiral beta-amino alcohols and axially prochiral or axially racemic heteroarenes yielding amino alcohols with both axial and central chirality. A nitrene-based reaction mechanism has been proposed based on experimental studies. The amino alcohol products show promising applications.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Multidisciplinary
Apurba Samanta, Shyamal Pramanik, Subhashis Mondal, Soumitra Maity
Summary: In this study, organic photoredox-catalyzed alkylamination of olefins was achieved by blocking the traditional photoredox-ATRA process with Zn(OAc)(2). Various carbon-centered radicals (alpha-alkylcarbonyl, benzyl, cyanomethyl) effectively participated in this strategy, leading to the formation of versatile carboamination products with high synthetic value.
CHEMICAL COMMUNICATIONS
(2022)
Article
Chemistry, Organic
Yi Yang, Hui Wang, Zehua Sun, Xinjin Li, Fenggang Sun, Qing Liu, Lizhi Zhang, Liping Xu, Hui Liu
Summary: A palladium-catalyzed multi-component regiodivergent arylamination/aryloxygenation of allenamide has been reported. The choice of base plays a critical role in determining the chemoselectivity and regioselectivity of the reaction. Additionally, the reaction can lead to the formation of alkenes with excellent Z configuration, which is controlled by the steric hindrance of coordinated palladium intermediates.
ORGANIC CHEMISTRY FRONTIERS
(2022)
Article
Chemistry, Multidisciplinary
Zhonglin Liu, Lucas J. Oxtoby, Juntao Sun, Zi-Qi Li, Nana Kim, Geraint H. M. Davies, Keary M. Engle
Summary: The site-selective palladium-catalyzed three-component coupling of unactivated alkenyl carbonyl compounds, aryl- or alkenylboronic acids, and N-fluorobenzenesulfonimide is described in this study. Regioselectivity is enhanced by tuning the steric environment on the bidentate directing auxiliary, facilitating challenging C(sp(3))-F reductive elimination from a Pd-IV intermediate to afford 1,2-carbofluorination products in moderate to good yields.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Van T. Tran, Nana Kim, Camille Z. Rubel, Xiangyu Wu, Taeho Kang, Tanner C. Jankins, Zi-Qi Li, Matthew V. Joannou, Sloan Ayers, Milan Gembicky, Jake Bailey, Emily J. Sturgell, Brittany B. Sanchez, Jason S. Chen, Song Lin, Martin D. Eastgate, Steven R. Wisniewski, Keary M. Engle
Summary: A flurry of recent research has focused on utilizing nickel catalysis in organic synthesis. This report presents ten different bench-stable, 18-electron, formally zero-valent nickel-olefin complexes that serve as competent pre-catalysts in various reactions. Characterization and analysis shed light on the structure, bonding, and properties of these complexes, while their application in nickel-catalyzed reactions highlights the complementary nature of the different pre-catalysts within this toolkit.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Ruihan Wang, Yidong Wang, Ruiqi Ding, Parker B. Staub, Christopher Z. Zhao, Peng Liu, Yi-Ming Wang
Summary: A newly-developed cationic cyclopentadienyliron dicarbonyl complex enables the conversion of propylene to its allylic C-C bond coupling products under catalytic conditions. This approach is also applicable to the allylic functionalization of simple alpha-olefins with distinctive branched selectivity. Experimental and computational studies reveal the allylic deprotonation of the metal-coordinated alkene as the turnover-limiting step and provide insights into the multifaceted roles of the newly designed ligand in promoting allylic C-H functionalization with enhanced reactivity and stereoselectivity.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Tobias Koengeter, Can Qin, Binh Khanh Mai, Qinghe Liu, Yucheng Mu, Peng Liu, Amir H. Hoveyda
Summary: This paper presents a stereoretentive strategy for catalytic cross-metathesis reaction between tri-, Z- or E-di, or monosubstituted olefins and Z- or E-2-bromo-2-butene, leading to the formation of various trisubstituted alkenyl bromides. The method is applicable for the generation of products containing polar moieties or sterically hindered alkenes.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Multidisciplinary
Amit Kumar Simlandy, Turki M. Alturaifi, Johny M. Nguyen, Lucas J. Oxtoby, Quynh Nguyen Wong, Jason S. Chen, Peng Liu, Keary M. Engle
Summary: We report a transient directing group (TDG) strategy for site-selective palladium-catalyzed reductive Heck-type hydroalkenylation and hydroalkynylation of alkenylaldehydes using alkenyl and alkynyl bromides. This strategy allows for the construction of a stereocenter at the delta-position with respect to the aldehyde. Computational studies reveal the beneficial roles of rigid TDGs, such as L-tert-leucine, in promoting TDG binding and inducing high levels of enantioselectivity in alkene insertion.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Carla Calvo-Tusell, Zhen Liu, Kai Chen, Frances H. Arnold, Marc Garcia-Borras
Summary: We successfully engineered P411 enzymes for enantiodivergent enzymatic carbene N-H insertions through computational modeling and molecular simulations. By introducing a new H-bond anchoring point, we could control the accessible conformations of the lactone-carbene intermediate and direct the reactive carbene for an enantioselective N-nucleophilic attack. With site-saturation mutagenesis and screening, we reversed the stereoselectivity of previously engineered S-selective P411 enzymes. The resulting variant, L5_FL-B3, displayed broad substrate scope, high yields (>99%), high efficiency (up to 12,300 TTN), and good enantiocontrol (up to 7:93 er).
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Hui-Qi Ni, Malkanthi K. Karunananda, Tian Zeng, Shenghua Yang, Zhen Liu, K. N. Houk, Peng Liu, Keary M. Engle
Summary: Multistep organic synthesis allows the conversion of simple chemical feedstocks into more complex products with specific functions. This study introduces a novel approach to organic reactions that can generate multiple valuable products with different carbon skeletons in a single operation. Through a palladium-catalyzed reaction, a single alkene starting material can be converted into two structurally distinct products, demonstrating the potential for simultaneous access to diverse compounds. The findings of this study provide insights into the mechanistic details of this unique catalytic system and establish a new method for small-molecule library synthesis.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Multidisciplinary
Jingfeng Huo, Yue Fu, Melody J. Tang, Peng Liu, Guangbin Dong
Summary: In this research, the first nickel-catalyzed Catellani-type annulation of aryl triflates and chlorides was achieved to form various benzocyclobutene-fused norbornanes in high efficiency. Mechanistic studies revealed an unexpected outer-sphere concerted metalation/deprotonation pathway and the essential roles of the base and the triflate anion. Compared to palladium catalysis, the reaction showed a broad functional group tolerance and enhanced regioselectivity.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Applied
Paul J. Chirik, Keary M. Engle, Eric M. Simmons, Steven R. Wisniewski
Summary: Earth-abundant metal (EAM) catalysis has significant impact on the sustainability and cost improvement in the pharmaceutical industry. It replaces precious metals like palladium and utilizes the reactivity of first-row metals to enable more efficient routes to clinical candidates. This article describes the strategy for building these capabilities within the process group, including the development of a reaction screening platform, scalability demonstration, and increasing mechanism understanding.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2023)
Review
Chemistry, Organic
Taeho Kang, Omar Apolinar, Keary M. Engle
Summary: In this Review, the various strategies, mechanisms, and catalysts that have been applied to achieve enantioinduction in alkene 1,2-DCF are discussed.
SYNTHESIS-STUTTGART
(2023)
Article
Multidisciplinary Sciences
Lei Cheng, Dian Li, Binh Khanh Mai, Zhiyu Bo, Lida Cheng, Peng Liu, Yang Yang
Summary: The merger of photoredox catalysis and PLP biocatalysis enables the development of a new synthetic method for preparing valuable noncanonical amino acids, allowing controlled formation of chiral products.
Article
Chemistry, Organic
Yilin Cao, Zi-Qi Li, Keary M. Engle
Summary: A nickel-catalyzed heterocycle-directed 1,2-diarylation of alkenes with aryl iodide electrophiles and arylboronic acid neopentyl ester nucleophiles is reported, resulting in a series of 1,2,4-tri(hetero)aryl products under mild conditions. The transformation is enabled by a collection of azaheterocycle directing groups, giving moderate to excellent yields. The preparative utility of the method is demonstrated by a large-scale reaction.
TETRAHEDRON LETTERS
(2023)
Article
Chemistry, Physical
Wenzhen Fu, Natalia M. M. Neris, Yue Fu, Yunlong Zhao, Benjamin Krohn-Hansen, Peng Liu, Yang Yang
Summary: This study describes a metalloredox biocatalysis strategy to repurpose natural cytochromes P450 for catalysing asymmetric radical cyclization to arenes through an unnatural electron transfer mechanism. Directed evolution yielded a series of engineered P450 aromatic radical cyclases with complementary selectivities. The excellent tunability of this metalloenzyme family provides an exciting platform for utilizing free radical intermediates in asymmetric catalysis.
Article
Chemistry, Multidisciplinary
Yeongyu Hwang, Steven R. Wisniewski, Keary M. Engle
Summary: This study presents a ligand design approach for nickel-catalyzed three-component carboamidation, which is applicable to the synthesis of alkenyl amine derivatives. With this method, diverse nitrogen functionalities can be installed onto unactivated alkenes, leading to differentially substituted diamines.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
