Review
Chemistry, Physical
Kai Wu, Junhai Huang, Lei Shao
Summary: The synthesis of chiral amines is important in the pharmaceutical industry. IRED, a promising biocatalyst, has been found to catalyze direct asymmetric reductive amination and conjugate reduction, producing valuable amine diastereomers. This review provides insights into the catalytic mechanisms of IREDs and highlights their potential for industrial applications.
Article
Chemistry, Applied
Damien Baud, Nadine Tappertzhofen, Thomas S. Moody, John M. Ward, Helen C. Hailes
Summary: Transaminase enzymes have great potential in the synthesis of drugs, and a chemoenzymatic approach for the synthesis of serotonin/melatonin receptor agonists has been developed. Starting from a prochiral ketone compound, both enantiomers of 8-methoxy-2-aminotetraline were obtained in high yields and enantiomeric excesses through stereoselective transamination. These compounds were further converted into either 8-methoxy-2-acetimidotetralines or 8-hydroxy-2-aminodipropyltetralines.
ADVANCED SYNTHESIS & CATALYSIS
(2022)
Article
Chemistry, Physical
Anshul Rajput, Tanaya Manna, Amit Mondal, Arijit De, Jhilik Mondal, Syed Masood Husain
Summary: Due to a lack of general asymmetric methodology, access to chiral substituted tetrahydro-1-, 2-, and 3-benzazepines remained limited. This study developed a general biocatalytic method using imine reductases (IREDs) for the synthesis of variously substituted chiral tetrahydro benzazepines. The reduction of seven-membered prochiral cyclic imines by selected IREDs resulted in preparative scale synthesis of chiral benzazepines with high enantiomeric excess and isolated yield.
Article
Chemistry, Multidisciplinary
Eve M. Carter, Esther Ambrose-Dempster, John M. Ward, Tom D. Sheppard, Helen C. Hailes
Summary: Mechanochemical reactions have emerged as a green synthetic method due to their rapidity and lower solvent usage compared to traditional approaches. This study describes the first mechanoenzymatic reactions using transaminases for amination of aldehydes and ketones, resulting in the production of amines with significantly less aqueous medium. The use of whole cells and shorter reaction times also led to high yields and stereoselectivities.
Article
Chemistry, Multidisciplinary
Amelia K. Gilio, Thomas W. Thorpe, Nicholas Turner, Gideon Grogan
Summary: The synthesis of chiral amines through the reductive amination reaction is a significant reaction in synthetic chemistry, with applications in pharmaceutical and bioactive molecule synthesis. While transition metal catalysis is commonly used, biocatalytic methods have gained interest due to their selectivity and sustainability. The discovery of imine reductase and reductive aminase enzymes has paved the way for an industrial approach to chiral amine production, enabling scale-up from laboratory to ton-scale reactions.
Article
Chemistry, Physical
Eve M. Carter, Fabiana Subrizi, John M. Ward, Tom D. Sheppard, Helen C. Hailes
Summary: Transaminase enzymes were used to directly react with hydrazones, forming amine products. The addition of an extra electrophile in the reaction mixture increased amine yields by sequestering hydrazine. Pyridoxal 5'-phosphate (PLP) and PEG-aldehydes were found to enhance amine yield, particularly in the amination of (S)-(-)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP) hydrazones for chiral beta-substituted amines.
Article
Chemistry, Multidisciplinary
Yu-Fei Ao, Shuxin Pei, Chao Xiang, Marian J. Menke, Lin Shen, Chenghai Sun, Mark Dorr, Stefan Born, Matthias Hohne, Uwe T. Bornscheuer
Summary: We created variants of ATA from Ruegeria sp. (3FCR) with improved catalytic activity and reversed stereoselectivity, and collected a high-quality dataset. We designed a modified one-hot code to describe the effects of substrates and residues within ATAs. Finally, we built a predictor for catalytic activity and stereoselectivity, and applied it for the data-driven design of optimized variants which showed improved activity. We also demonstrated that the model can predict the catalytic activity for ATA variants of another origin by retraining with additional data.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Immunology
Qiongqiong Zhou, Bingfang Yan, Wanying Sun, Qi Chen, Qiling Xiao, Yuncai Xiao, Xiliang Wang, Deshi Shi
Summary: The study demonstrated that carboxylesterases PLE1 and PLE6 can hydrolyze endocannabinoids 2-AG and AEA, leading to increased inflammatory response. Exogenous addition or transfection of PLE6 enhanced the expression and secretion of proinflammatory cytokines, while BNPP reduced inflammation triggered by LPS and inhibited the formation of AA and proinflammatory mediators. This innovative connection between PLE-endocannabinoid-inflammation highlights the critical roles of carboxylesterases in pathophysiological processes related to endocannabinoid metabolism.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Chemistry, Organic
Alina Nastke, Harald Groeger
Summary: A process concept for the asymmetric biocatalytic reduction of heterocyclic imines was studied, which utilizes a heterogenized aqueous phase containing enzymes and cofactors for the biotransformation in pure organic medium. The process simplifies the work-up steps and achieves high conversion, yield, and enantiomeric excess.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Organic
Tingting Liu, Zefei Xu, Jinhui Feng, Shanshan Yu, Min Wang, Peiyuan Yao, Qiaqing Wu, Dunming Zhu
Summary: Two enantiocomplementary imine reductases (IREDs) with high enantioselectivity were identified through screening and engineering, which allowed the synthesis of a series of 1-heteroaryl tetrahydroisoquinolines with high to excellent ee values and isolated yields, providing an effective method for constructing pharmaceutically important alkaloids, including the intermediate of kinase inhibitor TAK-981.
Article
Chemistry, Multidisciplinary
Xin Gao, Joshua R. Turek-Herman, Young Joo Choi, Ryan D. Cohen, Todd K. Hyster
Summary: This study demonstrates that engineered flavin-dependent 'ene'-reductases (EREDs) can catalyze radical additions into oximes with high stereoselectivity to prepare alpha-tertiary amines, which are common in pharmaceutical molecules. Two evolved EREDs were competent catalysts for this transformation, and mechanistic studies revealed the role of oximes in the enzyme templated charge-transfer complex. The products can be further derivatized for the synthesis of various motifs, showcasing the versatility of ERED photoenzymatic catalysis in organic synthesis.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Chemistry, Physical
Sophie G. Bender, Todd K. Hyster
Summary: This research presents a photoenzymatic reaction for the reductive coupling of electron-deficient heterocycles with alkenes, resulting in the generation of a gamma-stereocenter with high enantioselectivity. It expands the substrate capabilities of ene-reductases in chemical synthesis.
Article
Chemistry, Organic
Tingting Liu, Zefei Xu, Jinhui Feng, Shanshan Yu, Min Wang, Peiyuan Yao, Qiaqing Wu, Dunming Zhu
Summary: Two highly enantioselective enantiocomplementary imine reductases (IREDs) were discovered through screening and enzyme engineering, which exhibited catalytic activity towards the reduction of 1-heteroaryl dihydroisoquinolines. By utilizing (R)-IR141-L172M/Y267F and (S)-IR40, a series of different 1-heteroaryl tetrahydroisoquinolines were efficiently synthesized with excellent enantioselectivity (82 to >99% ee) and high isolated yields (80 to 94%), providing an effective method for constructing pharmaceutically important alkaloids, including the intermediate of kinase inhibitor TAK-981.
Article
Biochemistry & Molecular Biology
Agnieszka Wojtkielewicz, Urszula Kielczewska, Aneta Baj, Jacek W. Morzycki
Summary: The study elaborated a five-step transformation of a spiroketal side chain of tigogenin into an indolizidine system present in solanidane alkaloids. The key intermediate in the synthesis, spiroimine 3, was readily obtained from tigogenin by oxidation and amination. Subsequent mild reduction and mesylation resulted in the formation of different products depending on reaction conditions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Physical
Netgie Laguerre, Paul S. Riehl, Daniel G. Oblinsky, Megan A. Emmanuel, Michael J. Black, Gregory D. Scholes, Todd K. Hyster
Summary: This study presents a novel photoenzymatic allylation method for the synthesis of cyclic lactams with high enantioselectivity. The termination of the reaction via the cleavage of the silyl group to generate a silyl radical represents a distinct mechanism compared to traditional radical allylations, demonstrating the potential of EREDs.
Article
Chemistry, Physical
Willem B. Breukelaar, Nakia Polidori, Amit Singh, Bastian Daniel, Silvia M. Guleck, Karl Gruber, Wolfgang Kroutil
Summary: The biocatalytic reduction of oxime moiety to amine group has recently been discovered, but the reaction pathway remained unclear. Through studying crystal structures, molecular dynamics simulations, and investigating biocatalytic cascades and intermediates, evidence suggests that the reaction proceeds via an imine intermediate rather than a hydroxylamine intermediate. The imine is further reduced by the ene-reductase to produce the amine product. A non-canonical tyrosine residue contributes to the catalytic activity by protonating the hydroxyl group of the oxime in the first reduction step.
Article
Chemistry, Applied
Philipp Petermeier, Christoph Kohlfuerst, Ana Torvisco, Roland C. C. Fischer, Alejandro Mata, Doris Dallinger, C. Oliver Kappe, Joerg H. H. Schrittwieser, Wolfgang Kroutil
Summary: Substituted piperidine rings are efficiently prepared with multiple stereocentres using multi-enzymatic and chemo-enzymatic methods from achiral diketoester precursors. Highly enantioselective transamination and diastereoselective reduction processes enable the synthesis of optically pure piperidines. This approach offers a more streamlined and efficient route for the synthesis of trisubstituted piperidines with potential applications in drug discovery.
ADVANCED SYNTHESIS & CATALYSIS
(2023)
Article
Chemistry, Applied
P. Petermeier, C. Kohlfuerst, A. Torvisco, R. C. Fischer, A. Mata, D. Dallinger, C. O. Kappe, J. H. Schrittwieser, W. Kroutil
ADVANCED SYNTHESIS & CATALYSIS
(2023)
Article
Chemistry, Applied
Mathias Pickl, Markus Ebner, Samantha Gittings, Pere Clapes, Wolfgang Kroutil
Summary: Although optical pure amino alcohols are highly demanded, their synthesis remains challenging due to the requirement of elaborate protection strategies. This study presents a multi-enzymatic methodology that allows the synthesis of enantioenriched 1,3-amino alcohols from commodity chemicals. By utilizing a Type I aldolase and enzymatic transamination, both diastereomers of the 1,3-amino alcohol motif were accessible, resulting in the desired amino alcohols with high enantioselectivity.
ADVANCED SYNTHESIS & CATALYSIS
(2023)
Article
Biochemistry & Molecular Biology
Sarah A. Berger, Christopher Grimm, Jonathan Nyenhuis, Stefan E. Payer, Isabel Oroz-Guinea, Joerg H. Schrittwieser, Wolfgang Kroutil
Summary: Mass spectrometry-based high-throughput screening methods combine the advantages of photometric or fluorometric assays and analytical chromatography. However, their limited use is due to the requirement of specialised and expensive hardware. We demonstrate that a common platform, single-quadrupole HPLC-MS, can be used for rapid analysis of diverse biotransformations by flow-injection mass spectrometry (FIA-MS), providing validated activity and selectivity information with a one-minute analytical run time per sample. Our results establish FIA-MS as a versatile and reliable alternative to traditional methods for screening enzymatic reactions.
Review
Chemistry, Physical
Veronique Alphand, Willem J. H. van Berkel, Valentina Jurkas, Selin Kara, Robert Kourist, Wolfgang Kroutil, Francesco Mascia, Marc M. Nowaczyk, Caroline E. Paul, Sandy Schmidt, Jelena Spasic, Paula Tamagnini, Christoph K. Winkler
Summary: The recent increase of interest in photocatalysis has expanded to biocatalysis and led to a surge in the development of light-dependent enzyme-mediated or enzyme-coupled processes. Reviewing the progress in photobiocatalysis, we suggest categorizing it into different disciplines and providing guidelines for reporting research results and performing photobiocatalytic reactions. Overall, we believe that this field enhances the diversity of biocatalytic reactions and harnesses the selectivity of enzymes in photocatalysis. We anticipate that the ongoing enthusiasm for light-dependent enzymatic processes will uncover new photobiocatalytic mechanisms, complementing biocatalysis with novel bond-forming reactions and innovative strategies for utilizing light as a sustainable energy source.
Article
Chemistry, Organic
Beata Zdun, Tamara Reiter, Wolfgang Kroutil, Pawel Borowiecki
Summary: We developed chemoenzymatic routes using low-cost starting materials and enzyme preparations to synthesize tenofovir. The key step involved stereoselective reduction or kinetic resolution using alcohol dehydrogenase or lipase as biocatalysts. By employing immobilized lipase in a mixture of vinyl acetate and toluene, the desired (R)-ester was obtained with high yield and optical purity. Alternatively, reduction of a ketone using lyophilized E. coli cells containing recombinant alcohol dehydrogenase resulted in excellent conversion and yield of the corresponding (R)-alcohol. The enzymatic strategy could be applied in the synthesis of tenofovir prodrug derivatives.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Correction
Chemistry, Physical
Stefan Simic, Migle Jakstaite, Wilhelm T. S. Huck, Christoph K. Winkler, Wolfgang Kroutil
Article
Chemistry, Multidisciplinary
Christopher Grimm, Simona Pompei, Kristina Egger, Michael Fuchs, Wolfgang Kroutil
Summary: Lignin-derived aryl methyl ethers have potential as carbon sources in chemistry. An alternative method for their demethylation is through cobalamin-dependent enzymes, which require a methyltransferase and a carrier protein. Fusion proteins, connecting the methyltransferase with the corrinoid-binding protein, showed better performance than separate proteins, enabling a simpler protocol for demethylation. The fusion enzyme has promising applications in diversifying natural products and valorizing lignin.
Article
Chemistry, Physical
Willem B. Breukelaar, Nakia Polidori, Amit Singh, Bastian Daniel, Silvia M. Glueck, Karl Gruber, Wolfgang Kroutil
Summary: The biocatalytic reduction of oxime to amine has been observed in ene-reductases transforming alpha-oximo beta-keto esters. Through structural analysis, molecular dynamics simulations, biocatalytic cascades, and investigation of possible intermediates, it has been determined that the reaction proceeds via an imine intermediate and not through a hydroxylamine intermediate. A non-canonical tyrosine residue in ene-reductase OPR3 was found to play a role in protonating the hydroxyl group of the oxime in the first reduction step.
Article
Chemistry, Multidisciplinary
Emmanuel Cigan, Jakob Pletz, Sarah A. Berger, Bettina Hierzberger, Michael Grilec-Zlamal, Alexander Steiner, Isabel Oroz-Guinea, Wolfgang Kroutil
Summary: This study demonstrates an efficient access to the morphinan scaffold using a combination of organic synthesis and enzymatic reactions. The synthesis of a medicinally important compound class, promorphinans, was achieved by minimizing protecting group techniques and utilizing biocatalysis.
