Article
Chemistry, Multidisciplinary
Gonzalo de Gonzalo, Caroline E. Paul
Summary: This review discusses recent advances in the application of alcohol dehydrogenases in cascade reactions, collaborating with other enzyme classes, chemocatalysts, or organocatalysts to obtain high value-added products such as chiral diols and amino alcohols. The review also looks towards future developments in chemoenzymatic and organoenzymatic cascades.
CURRENT OPINION IN GREEN AND SUSTAINABLE CHEMISTRY
(2021)
Article
Chemistry, Physical
Patricia Rodriguez-Salamanca, Gonzalo de Gonzalo, Jose A. Carmona, Joaquin Lopez-Serrano, Javier Iglesias-Siguenza, Rosario Fernandez, Jose M. Lassaletta, Valentin Hornillos
Summary: This article describes a highly enantioselective biocatalytic dynamic kinetic resolution (DKR) for configurationally labile N-arylindole aldehydes. The DKR is achieved through atroposelective bioreduction of the carbonyl group using commercial ketoreductases (KREDs), resulting in axially chiral N-arylindole aminoalcohols with excellent conversions and optical purities. The strategy relies on the racemization of the stereogenic axis facilitated by a transient Lewis pair interaction between NMe2 and the aldehyde groups. This protocol offers a broad substrate scope under mild conditions.
Review
Chemistry, Multidisciplinary
Lucy A. Harwood, Luet L. Wong, Jeremy Robertson
Summary: Kinetic resolution using biocatalysis is an excellent complementary technique to traditional asymmetric catalysis, producing valuable oxygenated structures for synthetic route development. Enzymes catalyzing the insertion of an oxygen atom into the substrate, such as the Baeyer-Villiger rearrangement, epoxidation, and hydroxylation, play a key role in oxidative kinetic resolution. These key enantiomer-enriched intermediates have important applications in natural product synthesis.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Physical
Naara Oliveira Santana Froes, Uchchhal Bandyopadhyay, Jonatas Martins Negreiro, Thiago de Sousa Fonseca, Fatima Miranda Nunes, Marcos Carlos de Mattos, Geancarlo Zanatta, Joao Victor de Melo Pereira, Celina de Jesus Guimaraes, Claudia do O. Pessoa, Bruno Poti e Silva, Eric Manoury, Maria Conceicao Ferreira Oliveira
Summary: This work reports the lipase mediated kinetic resolution of (±)-1, resulting in the formation of enantiopure (Rp)-1 and enantioenriched (Sp)-2. The lipase from Thermomyces lanuginosus was found to exhibit high enantioselectivity towards the acetylation of (Sp)-1, leading to the preferential formation of (Sp)-2. Both (Rp)-1 and (Sp)-2 showed low cytotoxicity and no selectivity against the tested cell lines.
MOLECULAR CATALYSIS
(2023)
Article
Chemistry, Physical
Jacob S. DeHovitz, Todd K. Hyster
Summary: Isomerizations are chemical processes that transform a compound into a different structure while maintaining the same chemical formula. The recent resurgence of photochemistry has led to an increased focus on using radicals and diradicals as key intermediates for isomerization. Understanding the mechanisms behind these approaches can help streamline chemical synthesis.
Article
Chemistry, Multidisciplinary
Kazuma Takahara, Yuki Horino, Koki Wada, Hiromu Sakata, Yukinari Sunatsuki, Masaaki Kojima, Takayoshi Suzuki
Summary: In this study, the crystal structures and crystallization behaviors of a series of heterotrinuclear Zn/ Ln/ Zn complexes were investigated. Homochiral structures were observed, and various types of spontaneous resolution were found, including the exclusive formation of left-handed Δ-conglomerates in the Tb-III complex, which is termed absolute spontaneous resolution.
CRYSTAL GROWTH & DESIGN
(2023)
Article
Chemistry, Organic
Lucas Lima Zanin, Thiago Kelvin Brito Matos, Andrei Leitao, Javier Ellena, Andre Luiz Meleiro Porto
Summary: The study presented a chemo-enzymatic strategy to prepare enantiomerically enriched hydroxy-DHPM compounds, and demonstrated through experiments that this method can provide products with high enantiomeric excess values.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2022)
Review
Biotechnology & Applied Microbiology
Chenming Huang, Junling Liu, Jiali Fang, Xian Jia, Zhendong Zheng, Song You, Bin Qin
Summary: This review discusses the advances in the research area of KRED-catalyzed asymmetric synthesis for biomanufacturing of chiral chemicals with at least two chiral centers through the kinetic resolution (KR) approach and the dynamic kinetic resolution (DKR) approach.
FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Sarah Bierbaumer, Luca Schmermund, Alexander List, Christoph K. Winkler, Silvia M. Glueck, Wolfgang Kroutil
Summary: In this study, a concurrent biocatalytic reduction and photocatalytic oxidation process was demonstrated. By coupling the enantioselective biocatalytic sulfoxide reduction and light-dependent sulfoxidation, a cyclic deracemization process for nonracemic sulfoxides was achieved with excellent conversions and optical purity.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Physical
Yongkai Pan, Donglei Wang, Yunrong Chen, DeKun Zhang, Wei Liu, Xiaoyu Yang
Summary: The kinetic resolution of alpha-tertiary propargylic amines was successfully achieved through asymmetric remote aminations of anilines with azodicarboxylates enabled by chiral phosphoric acid catalysis. A broad range of substituents at the alpha-position were well tolerated, with high kinetic resolution performances. Additionally, excellent stereoselectivity was demonstrated for alpha-tertiary amines bearing an alpha-CN group under the same reaction conditions. The successful transformations of the chiral amination products and the recovered propargylic amines showcased the power of this method in asymmetric synthesis of alpha-tertiary amines and their derivatives.
Review
Chemistry, Applied
Li-Cheng Yang, Heping Deng, Hans Renata
Summary: This article summarizes the chemoenzymatic and biocatalytic methodologies for DKR developed in the past decade, highlighting their applications in the preparation of active pharmaceutical ingredients and emerging paradigms.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2022)
Article
Chemistry, Physical
Lei Wan, Rachel S. Heath, Clare F. Megarity, Adam J. Sills, Ryan A. Herold, Nicholas J. Turner, Fraser A. Armstrong
Summary: The ability to drive and observe rapid enzyme catalysis in both directions is achieved by immobilizing cascade components within electrode nanopores and coupling reactions to fast, quasi-reversible NADP(+)/ NADPH electrochemistry. By using two electrodes in sequence, each containing an enantioselective alcohol dehydrogenase for one halfcycle, efficient one-pot de-racemizers can be achieved.
Review
Chemistry, Organic
Helene Pellissier
Summary: Organocatalytic dynamic kinetic resolution (DKR) has emerged as a promising field in the past two decades, allowing efficient separation of chiral compounds. This review aims to provide an update on organocatalytic DKRs since 2016.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Physical
Fang-Rui Zhang, Nan-Wei Wan, Jin-Mei Ma, Bao-Dong Cui, Wen-Yong Han, Yong-Zheng Chen
Summary: An efficient enzymatic process has been developed for the synthesis of valuable compounds through catalytic kinetic resolution, demonstrating synthetic utility and scalability.
Article
Multidisciplinary Sciences
Lin-Xin Ruan, Bo Sun, Jia-Ming Liu, Shi-Liang Shi
Summary: Despite the importance of enantioenriched tertiary alcohols bearing two contiguous stereocenters, their efficient synthesis has remained a challenge. In this study, we report a platform for their preparation using nickel-catalyzed addition of organoboronates to racemic ketones, achieving high levels of diastereo- and enantioselectivity.
Article
Chemistry, Multidisciplinary
Johannes Buchler, Eimear Hegarty, Kirsten Schroer, Radka Snajdrova, Nicholas J. J. Turner, Olivier Loiseleur, Rebecca Buller, Camille Le Chapelain
Summary: Novartis AG and Syngenta AG collaborated with the Competence Center for Biocatalysis (CCBIO) to develop a sustainable approach to late-stage halogenation using machine-learning guided protein engineering. They successfully evolved versatile catalysts capable of selectively chlorinating complex molecules, demonstrating the synthetic usefulness of such a strategy.
HELVETICA CHIMICA ACTA
(2023)
Article
Chemistry, Multidisciplinary
Fei-Fei Chen, Xue-Feng He, Xin-Xin Zhu, Zhi Zhang, Xin-Yuan Shen, Qi Chen, Jian-He Xu, Nicholas J. Turner, Gao-Wei Zheng
Summary: The direct synthesis of a wide range of sterically demanding secondary amines using imine reductases has been achieved, enabling the production of important pharmaceutical ingredients and intermediates.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Organic
Christian Ascaso-Alegre, Juan Mangas-Sanchez
Summary: Cascade processes are a valuable approach for efficient synthesis by avoiding the isolation of reaction intermediates and achieving higher molecular complexity. In this study, we developed a novel method to synthesise chiral 1,4-nitro alcohols using a sequential cascade reaction, involving asymmetric C-C bond formation catalyzed by a chiral thiourea and bioreduction as crucial steps.
Article
Chemistry, Physical
Amelia K. Gilio, Thomas W. Thorpe, Alex Heyam, Mark R. Petchey, Balazs Pogranyi, Scott P. France, Roger M. Howard, Michael J. Karmilowicz, Russell Lewis, Nicholas Turner, Gideon Grogan
Summary: Imine reductases (IREDs) can catalyze the reduction of cyclic imines and the coupling of ketones and amines to form secondary amine products. The larger amines used in the coupling reactions were likely recruited from solution for enzyme reduction. Mutant IR77-A208N showed improved activity for amine product formation.
Article
Chemistry, Physical
Christian Schnepel, Laura Rodriguez Perez, Yuqi Yu, Antonio Angelastro, Rachel S. Heath, Max Lubberink, Francesco Falcioni, Keith Mulholland, Martin A. Hayes, Nicholas J. Turner, Sabine L. Flitsch
Summary: The activation of carboxylic acids to thioesters, especially Coenzyme A-based ones, is important but challenging. A generic thioester recycling enzyme, CARsr-A, was developed to catalyze the conversion of carboxylic acids to thioesters. This recycling system can regenerate thioesters for various acyl-S-Coenzyme A-dependent enzymes and enable the formation of diverse amides and non-native acylation reactions.
Article
Chemistry, Physical
Ashleigh J. Burke, Thomas M. Lister, James R. Marshall, Murray J. B. Brown, Richard Lloyd, Anthony P. Green, Nicholas J. Turner
Summary: Reductive aminases (RedAms) have shown potential in catalyzing coupling reactions between primary amines and aldehydes/ketones, leading to the synthesis of chiral secondary amines. However, the synthesis of tertiary amines, especially from coupling ketones with secondary amines, has been challenging. In this study, we demonstrated that RedAms, specifically RedAm-361 engineered through directed evolution, can selectively catalyze reductive aminations of cyclic secondary amines with carbonyl partners, including dynamic kinetic resolutions and enantioselective aminations. These biotransformations provide access to important structural motifs found in active pharmaceutical ingredients and other bioactive molecules. The discovery and engineering of RedAms have significant implications for the development of industrial biocatalysts in the production of key pharmaceutical intermediates.
Article
Chemistry, Multidisciplinary
Jack J. Sangster, Rebecca E. Ruscoe, Sebastian C. Cosgrove, Juan Mangas-Sanchez, Nicholas J. Turner
Summary: We present a one-pot chemoenzymatic process that combines monoamine oxidase (MAO-N)-catalyzed oxidation with metal-catalyzed allylboration and biocatalytic deracemization to efficiently synthesize enantioenriched C(1)-allylated tetrahydroisoquinolines. This cascade reaction is simple to operate, with all components added at the beginning of the reaction, and provides high yields and good to high enantiomeric excess of allylic amine derivatives, which can serve as important building blocks for further elaboration.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Physical
Haoyue Xiang, Salvatore Ferla, Carmine Varricchio, Andrea Brancale, Nicola L. Brown, Gary W. Black, Nicholas J. Turner, Daniele Castagnolo
Summary: Two enzymatic strategies were developed to oxidize 1,2,3,4-tetrahydroquinolines (THQs) and N-cyclopropyl-N-alkylanilines into quinolines and 2-quinolones, respectively. Whole cells and monoamine oxidase (MAO-N) enzymes were used for the biotransformation of THQs, while horseradish peroxidase (HRP)-catalyzed annulation/aromatization reaction followed by Fe-mediated oxidation was employed for the conversion of N-cyclopropyl-N-alkylanilines into 2-quinolone compounds.
Article
Chemistry, Physical
Yuqi Yu, Arnau Rue Casamajo, William Finnigan, Christian Schnepel, Rhys Barker, Charlotte Morrill, Rachel S. Heath, Leonardo De Maria, Nicholas J. Turner, Nigel S. Scrutton
Summary: Biocatalysis plays a crucial role in the discovery, development, and manufacturing of pharmaceuticals. A structure-based computational workflow called IREDFisher has been developed to prioritize protein sequences based on predicted activities, reducing the need for resource-intensive laboratory-based screening. IREDFisher successfully identified highly active imine reductases for various reactions, significantly reducing the number of samples that need to be tested in vitro. With a user-friendly web interface, IREDFisher enables rapid discovery of biocatalysts with minimal time and resource expenditure.
Article
Chemistry, Physical
Amelia K. Gilio, Thomas W. Thorpe, Alex Heyam, Mark R. Petchey, Balazs Pogranyi, Scott P. France, Roger M. Howard, Michael J. Karmilowicz, Russell Lewis, Nicholas Turner, Gideon Grogan
Summary: Imine reductases (IREDs) catalyze the reduction of cyclic imines and the coupling of ketones and amines, forming secondary amine products. IR77 enzyme was found to catalyze the coupling of larger bicyclic amines with cyclohexanone. Mutant IR77-A208N with improved activity for amine product formation was successfully synthesized using structure-guided mutagenesis.
Article
Chemistry, Multidisciplinary
Jack J. Sangster, Rebecca E. Ruscoe, Sebastian C. Cosgrove, Juan Mangas-Sanchez, Nicholas J. Turner
Summary: Here, we present a one-pot, chemoenzymatic process for synthesizing enantioenriched C(1)-allylated tetrahydroisoquinolines. This process involves the oxidation of monoamine oxidase (MAO-N) catalyst and the allylboration of a metal catalyst, followed by a biocatalytic deracemization, resulting in high yields and good to high enantiomeric excess of allylic amine derivatives. This cascade reaction is simple to operate, with all components added at the beginning of the reaction, and can produce key building blocks for further elaboration.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Physical
Amelia K. Gilio, Thomas W. Thorpe, Alex Heyam, Mark R. Petchey, Balazs Pogranyi, Scott P. France, Roger M. Howard, Michael J. Karmilowicz, Russell Lewis, Nicholas Turner, Gideon Grogan
Summary: Imine reductases (IREDs) can catalyze the reduction of cyclic imines and the coupling of ketones and amines to form secondary amine products. Previous studies mainly focused on using small hydrophobic amines, but for certain pharmaceutical targets, larger amines are required. In this study, the enzyme IR77 from Ensifer adhaerens was found to be a promising biocatalyst for the reductive amination of cyclohexanone with pyrrolidine. The mutant IR77-A208N showed improved activity for amine product formation, leading to isolated yields of up to 93% for the amination of cyclohexanone with larger amines.
Review
Chemistry, Multidisciplinary
Bo Yuan, Dameng Yang, Ge Qu, Nicholas J. Turner, Zhoutong Sun
Summary: This review summarizes the advancements in NAD(P)H-dependent amine dehydrogenases and imine reductases as biocatalysts for asymmetric reductive amination to produce optically active amines. These enzymes exhibit high activity and stereoselectivity, and can utilize a wide range of substrates. By discussing the evolutionary history, substrate scope, and applications of these enzymes, the review provides an outlook on emerging industrial biotechnologies for chiral amine production.
CHEMICAL SOCIETY REVIEWS
(2023)
