Article
Chemistry, Organic
Chao-Jiu Long, Hong-Ping Pu, Yan-Hong He, Zhi Guan
Summary: A novel method for achieving enantioselective alpha-alkylation of secondary acyclic amines with ketones through the combination of photocatalysis and the catalytic promiscuity of lipase is described. Various beta-amino ketones were synthesized from secondary acyclic amines with good yields (up to 89%) and moderate enantio- and diastereoselectivities (up to 89 : 11 er and 93 : 7 dr) under mild conditions without oxidants and cofactors. This method exhibits wide substrate scope, excellent functional group tolerance, and simple operation.
ORGANIC CHEMISTRY FRONTIERS
(2023)
Article
Multidisciplinary Sciences
Marie L. J. Wong, Alistair J. Sterling, James J. Mousseau, Fernanda Duarte, Edward A. Anderson
Summary: Bicyclo[1.1.1]pentanes (BCPs) are essential in contemporary drug design, yet methods to access BCPs with adjacent stereocenters are limited. This study presents a photo- and organocatalyzed asymmetric addition of simple aldehydes to [1.1.1]propellane to generate enantioenriched alpha-chiral BCPs.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Organic
Shuichi Nakamura, Masato Kibe, Tsunayoshi Takehara, Takeyuki Suzuki
Summary: The first enantioselective reaction of alpha-isocyanoacetonitriles was established using cinchona alkaloid amide-Cu(II) catalysts, resulting in imidazolines with tetrasubstituted stereogenic carbon centers. The reaction exhibited high diastereo- and enantioselectivities, which were explained by control experiments and density functional theory calculations. The conversion of the products into chiral compounds demonstrated the potential application of alpha-isocyanoacetonitriles in asymmetric and organic syntheses.
Article
Chemistry, Multidisciplinary
Jun-Jie Tian, Ning Liu, Qi-Fei Liu, Wei Sun, Xiao-Chen Wang
Summary: This study reports the successful direct asymmetric vinylogous Mannich reactions of acyclic alpha, beta-unsaturated ketones using chiral bicyclic bisborane catalysts. The strong Lewis acidity and steric bulk of the bisborane catalysts played crucial roles in achieving high yields and selectivities.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Chemistry, Multidisciplinary
Xiao Rui Wen, Wen Qing Zhu, Cai Lin Zhang, Hong Li, Jin Zhang, Min Ge Yang, Yong Li Kou, Yu Xia Liu, Yang Li
Summary: Amide compounds are important in various fields like biomedical chemistry, materials science, and life science. The synthesis of alpha-CF3 amides, especially compounds with 3-(trifluoromethyl)-1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepine-2-one, has been a challenge due to their tensile properties and instability of the rings. However, by using a palladium-catalyzed carbonylation reaction, we have successfully synthesized alpha-CF3 acrylamide. By controlling the ligands, we can obtain different amide compounds with good substrate adaptability and functional group tolerance.
Article
Chemistry, Organic
Chao-Jiu Long, Hong-Ping Pu, Yan-Hong He, Zhi Guan
Summary: A new method for the direct enantioselective α-alkylation of secondary acyclic amines with simple ketones is described, using a combination of photocatalysis and the catalytic promiscuity of lipase. Various β-amino ketones were synthesized in good yields of up to 89%, with moderate enantio- and diastereoselectivities (up to 89:11 er and 93:7 dr) under mild, oxidant- and cofactor-free conditions. This novel protocol exhibits wide substrate scope, excellent functional group tolerance, and simple operation characteristics.
ORGANIC CHEMISTRY FRONTIERS
(2023)
Article
Chemistry, Physical
Nuria Martin, Francisco G. Cirujano
Summary: The direct synthesis of amides from carboxylic acids and amines is of great importance in fine chemistry, drug synthesis, and protein construction in living organisms. The use of heterogeneous catalysts is preferred due to their advantages in terms of easy isolation, recovery, and recycling. This article reviews the most relevant reported heterogeneous catalysts for direct amide bond formation, focusing on their physicochemical properties, catalytic performance, and understanding of the reaction mechanism. The types of active sites incorporated on the solid catalyst surface, their interplay with the support material, and key properties such as surface area and pore size are thoroughly discussed.
CATALYSIS COMMUNICATIONS
(2022)
Article
Chemistry, Organic
Yuzhu Xu, Yanfeng Dang
Summary: DFT computational investigations were conducted on the mechanism of enantioselective Cu/Pd-catalyzed allylation of an alpha-CF3 amide. The results revealed that a kinetically favored chiral Cu(I)-enolate species can react with racemic pi-allyl-Pd(II) species to deliver a stereocenter with stereoconvergence. The study also provided insight into the versatile modes of stereoinduction and the selective capture of pi-allyl-palladium(II) intermediates.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Review
Chemistry, Physical
Chenlong Zhang, Weipeng Hu, James P. Morken
Summary: In recent years, a-boryl organometallic reagents have become popular as versatile nucleophiles in asymmetric synthesis, enabling chemo- and stereoselective coupling reactions to produce enantioenriched boronic esters. This allows for efficient construction of complex structures with high functional group compatibility. Efforts have been focused on preparing enantiomerically enriched a-boryl organometallic reagents and developing stereoselective reactions of related racemic materials.
Article
Chemistry, Multidisciplinary
Hirotsugu Suzuki, Sora Kondo, Koichiro Yamada, Takanori Matsuda
Summary: A novel copper-catalyzed diastereo- and enantioselective reductive Mannich-type reaction was developed in this study, providing a direct and scalable synthetic method for enantioenriched beta(2,3,3)-amino acids with vicinal stereogenic centers. The protocol shows excellent synthetic utility and scalability.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Review
Chemistry, Organic
Koji Hirano
Summary: This review focuses on the importance of organofluorine compounds in pharmaceuticals and agrochemicals, with particular emphasis on the challenges and recent advances in the catalytic enantioselective synthesis of sp(3) carbon-based alkyl-CF3-containing molecules.
SYNTHESIS-STUTTGART
(2022)
Article
Chemistry, Applied
Ruslan A. Kovalevsky, Konstantin V. Vasechkin, Alexander S. Kucherenko, Sergei G. Zlotin
Summary: A direct enantioselective synthesis of 2-substituted chromen-4-ones with an amino group at the α-stereogenic center of the heterocycle has been developed. This method is based on Mannich-type asymmetric addition of 3-hydroxychromen-4-one and its analogues to N-protected imines in the presence of the alkaloid dihydrocuprein. α-Stereogenic chromenone amino derivatives were obtained in yields of 81-95% with up to 98% ee. The chiral adducts were then transformed into various enantiomerically enriched chromen-4-one functional derivatives.
ADVANCED SYNTHESIS & CATALYSIS
(2023)
Article
Chemistry, Multidisciplinary
Naoki Yasukawa, Shuichi Nakamura
Summary: Catalytic enantioselective synthesis methodologies have been actively explored and developed to access valuable compounds such as unnatural alpha-amino acids. Asymmetric addition to ketimine-type electrophiles has been recognized as a powerful strategy, although it was limited a few decades ago. This feature article comprehensively overviews the research field and highlights the significant progress made, focusing on the chiral catalyst system and transition state as key parameters for such reactions.
CHEMICAL COMMUNICATIONS
(2023)
Article
Chemistry, Multidisciplinary
Mingying Shi, Qi Zhang, Jiali Gao, Xueling Mi, Sanzhong Luo
Summary: In this study, a novel alkylthio reagent based on the MMTD fragment was introduced for direct alkylsulfenylation of ketones and aldehydes. By combining with chiral primary aminocatalysis, this protocol allows for facile access to diverse alpha-alkylthio quaternary carbon centers with good stereoselectivities.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Organic
Yuta Kondo, Yoshinobu Hirazawa, Tetsuya Kadota, Koki Yamada, Kazuhiro Morisaki, Hiroyuki Morimoto, Takashi Ohshima
Summary: A one-pot catalytic synthesis method for alpha-tetrasubstituted amino acid derivatives via in situ generation of N-unsubstituted ketimines is reported. This approach avoids the need for isolating unstable ketimines, resulting in higher yields and streamlining the synthesis process of highly congested alpha-amino acid derivatives.
Article
Chemistry, Multidisciplinary
Amelia Brasnett, Inga Pfeffer, Lennart Brewitz, Rasheduzzaman Chowdhury, Yu Nakashima, Anthony Tumber, Michael A. McDonough, Christopher J. Schofield
Summary: The study on human AspH variants reveals insights into its catalytic mechanism, with implications for the functional assignment of 2OG oxygenases and the design of non-protein biomimetic catalysts. The crystal structures show the metal-ligation by only a single protein histidine ligand, indicating a unique approach in Fe-II binding compared to the typical triad of residues. Both H725A and H679A AspH variants exhibit substantial catalytic activity, highlighting their potential applications.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Multidisciplinary Sciences
Martin A. Redhead, C. David Owen, Lennart Brewitz, Amelia H. Collette, Petra Lukacik, Claire Strain-Damerell, Sean W. Robinson, Patrick M. Collins, Philipp Schaefer, Mark Swindells, Chris J. Radoux, Iva Navratilova Hopkins, Daren Fearon, Alice Douangamath, Frank von Delft, Tika R. Malla, Laura Vangeel, Thomas Vercruysse, Jan Thibaut, Pieter Leyssen, Tu-Trinh Nguyen, Mitchell Hull, Anthony Tumber, David J. Hallett, Christopher J. Schofield, David I. Stuart, Andrew L. Hopkins, Martin A. Walsh
Summary: Effective agents to treat coronavirus infection are urgently needed to tackle COVID-19 and prepare for future outbreaks. Target identification, such as the main protease (M-pro) and papain-like protease (PLpro), is essential for protecting against future outbreaks. The discovery of non-antiviral therapeutic agents, including SDZ 224015 and Tarloxotinib, provides promising candidates for clinical evaluation in addressing COVID-19.
SCIENTIFIC REPORTS
(2021)
Article
Chemistry, Medicinal
Lennart Brewitz, Jos J. A. G. Kamps, Petra Lukacik, Claire Strain-Damerell, Yilin Zhao, Anthony Tumber, Tika R. Malla, Allen M. Orville, Martin A. Walsh, Christopher J. Schofield
Summary: This study reports a mass spectrometry-based assay for monitoring the catalysis of SARS-CoV-2 papain-like protease (PLpro). The results show that the potencies of some reported PLpro inhibitors differ substantially from those obtained using fluorescence-based assays. Some M-pro inhibitors also show inhibitory effects on PLpro. The MS-based assay provides a useful tool for validating inhibitor potencies, especially for those operating by non-covalent mechanisms.
Article
Chemistry, Medicinal
Siegfried T. D. Thun-Hohenstein, Timothy F. Suits, Tika R. Malla, Anthony Tumber, Lennart Brewitz, Hani Choudhry, Eidarus Salah, Christopher J. Schofield
Summary: The study suggests that there is room for optimization of sulfur analogues for improved inhibition of M-pro mediated by ebselen/ebselen derivatives, particularly in terms of enhanced selectivity.
Article
Multidisciplinary Sciences
Yu Nakashima, Lennart Brewitz, Anthony Tumber, Eidarus Salah, Christopher J. Schofield
Summary: This study demonstrates that synthetic and naturally occurring 2OG derivatives can selectively modulate the activities of FIH and AspH, suggesting that these compounds may serve as a basis for developing 2OG oxygenase-targeting probes and drugs.
NATURE COMMUNICATIONS
(2021)
Article
Biology
Christopher J. Brereton, Liudi Yao, Elizabeth R. Davies, Yilu Zhou, Milica Vukmirovic, Joseph A. Bell, Siyuan Wang, Robert A. Ridley, Lareb S. N. Dean, Orestis G. Andriotis, Franco Conforti, Lennart Brewitz, Soran Mohammed, Timothy Wallis, Ali Tavassoli, Rob M. Ewing, Aiman Alzetani, Benjamin G. Marshall, Sophie Fletcher, Philipp J. Thurner, Aurelie Fabre, Naftali Kaminski, Luca Richeldi, Atul Bhaskar, Christopher J. Schofield, Matthew Loxham, Donna E. Davies, Yihua Wang, Mark G. Jones
Summary: This study provides evidence that the activation of the hypoxia-inducible factor (HIF) pathway is a critical regulator of pathogenetic collagen structure-function in fibrosis. Oxidative stress can drive the activation of pseudohypoxic HIF pathway, which alters collagen nanostructure and increases tissue stiffness.
Article
Chemistry, Medicinal
Tika R. Malla, Lennart Brewitz, Dorian-Gabriel Muntean, Hiba Aslam, C. David Owen, Eidarus Salah, Anthony Tumber, Petra Lukacik, Claire Strain-Damerell, Halina Mikolajek, Martin A. Walsh, Christopher J. Schofield
Summary: This study describes the synthesis of penicillin derivatives and investigates their mechanism of inhibition on the SARS-CoV-2 main protease (M-pro) through mass spectrometric and crystallographic analyses. The results suggest that beta-lactams have potential as M-pro inhibitors by forming a stable acyl-enzyme complex through their reaction with the nucleophilic cysteine.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Lennart Brewitz, Bruce C. Onisko, Christopher J. Schofield
Summary: This study redefines the consensus sequence requirements for AspH-catalyzed EGFD hydroxylation and expands the range of hydroxylation catalyzed by AspH. The results show that fibulins are substrates for AspH and reveal the important role of AspH in cellular hydroxylation.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Xiao Liu, Raphael Reinbold, Shuang Liu, Ryan A. Herold, Patrick Rabe, Stephanie Duclos, Rahul B. Yadav, Martine I. Abboud, Sandrine Thieffine, Fraser A. Armstrong, Lennart Brewitz, Christopher J. Schofield
Summary: Variants of isocitrate dehydrogenase (IDH)1/2 alter cancer cell metabolism by reducing 2-oxoglutarate (2OG) to hydroxyglutarate. Synthetic derivatives of 2OG can serve as substrates and 2OG-competitive inhibitors for cancer-associated IDH1/2 variants, and some natural product derivatives are even more efficient substrates than 2OG. The study also suggests the potential of using IDH1/2 variants as biocatalysts and highlights the modulation of IDH1/2 variant activity and inhibition through active site binding.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Lennart Brewitz, Leo Dumjahn, Yilin Zhao, C. David Owen, Stephen M. Laidlaw, Tika R. Malla, Dung Nguyen, Petra Lukacik, Eidarus Salah, Adam D. Crawshaw, Anna J. Warren, Jose Trincao, Claire Strain-Damerell, Miles W. Carroll, Martin A. Walsh, Christopher J. Schofield
Summary: Nirmatrelvir is a nitrile-bearing small-molecule inhibitor that, in combination with ritonavir, is used to treat infections by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). It interrupts the viral life cycle by inhibiting the SARS-CoV-2 main protease (M-pro) which is essential for processing viral polyproteins into functional nonstructural proteins.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Lennart Brewitz, Yu Nakashima, Sonia K. Piasecka, Eidarus Salah, Sally C. Fletcher, Anthony Tumber, Thomas P. Corner, Tristan J. Kennedy, Giorgia Fiorini, Armin Thalhammer, Kirsten E. Christensen, Mathew L. Coleman, Christopher J. Schofield
Summary: Jumonji-C domain-containing protein 5 (JMJD5) is an important 2-oxoglutarate-dependent oxygenase that has various functions in development, circadian rhythm, and cancer. This study discovered potent JMJD5 inhibitors, which are 5-aminoalkyl-substituted derivatives of the broad-spectrum 2OG oxygenase inhibitor pyridine-2,4-dicarboxylic acid (2,4-PDCA). Crystallographic analyses showed that these inhibitors bind to JMJD5 in an induced fit manner, with the C5 substituent of 2,4-PDCA binding to the substrate-binding pocket of JMJD5. Cellular studies revealed that these lead compounds displayed similar phenotypes as clinically observed JMJD5 variants with reduced catalytic activity.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Anthony Tumber, Eidarus Salah, Lennart Brewitz, Thomas P. Corner, Christopher J. Schofield
Summary: Jumonji-C (JmjC) domain-containing protein 5 (JMJD5) is an oxygenase linked to circadian rhythm and cancer biology. Synthetic 2OG derivatives with cyclic carbon backbones are alternative cosubstrates of JMJD5, demonstrating structural similarity to factor inhibiting hypoxia-inducible transcription factor HIF-a (FIH). Broad-spectrum 2OG oxygenase inhibitors are also efficient JMJD5 inhibitors, while clinical inhibitors like roxadustat do not inhibit JMJD5. Solid phase extraction coupled to mass spectrometry assays will facilitate the development of selective JMJD5 inhibitors for cellular studies.
RSC CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
H. T. Henry Chan, Lennart Brewitz, Petra Lukacik, Claire Strain-Damerell, Martin A. Walsh, Christopher J. Schofield, Fernanda Duarte
Summary: This study investigates how SARS-CoV-2 PLpro binds viral polyprotein-derived oligopeptide substrates through molecular dynamics, docking, and quantum mechanics/molecular mechanics calculations. The results show that a proline located at the P2' position promotes catalysis.
RSC CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Lennart Brewitz, Yu Nakashima, Christopher J. Schofield
Summary: 2-oxoglutarate (2OG) is crucial in biological processes as a cosubstrate for 2OG oxygenases. Aspartate/asparagine-beta-hydroxylase (AspH), a human 2OG oxygenase, is upregulated in hypoxia and serves as a prognostic marker on cancer cells. Studies demonstrate that subtle chemical changes can significantly impact AspH activity.
Article
Chemistry, Multidisciplinary
Tika R. Malla, Anthony Tumber, Tobias John, Lennart Brewitz, Claire Strain-Damerell, C. David Owen, Petra Lukacik, H. T. Henry Chan, Pratheesh Maheswaran, Eidarus Salah, Fernanda Duarte, Haitao Yang, Zihe Rao, Martin A. Walsh, Christopher J. Schofield
Summary: The study presents a high-throughput M-pro assay and identifies beta-lactams, including penicillin esters, as potential inhibitors of M-pro. These findings suggest the potential of acylating agents for M-pro inhibition in anti-viral chemotherapy.
CHEMICAL COMMUNICATIONS
(2021)
