One-pot Cascades Research Articles

One-Pot Multienzyme Cascades for Stereodivergent Synthesis of Tetrahydroquinolines.

The tetrahydroquinoline (THQ) framework is commonly found in natural products and pharmaceutically relevant molecules. Apart from the use of transition metal catalysts and chiral phosphoric acids, the chiral 2-substituted 1,2,3,4-THQs are synthesized using amine oxidase biocatalysts. However, the use of imine reductases (IREDs) in their asymmetric synthesis remained unexplored. In the current work, IREDs are employed in telescopic multienzyme cascades to catalyze the intramolecular reductive amination leading to chiral 2-alkyl and 2-aryl substituted-1,2,3,4-tetrahydroquinolines starting from inexpensive nitroalkenones. The cascades containing NtDBR (an ene reductase), NfsB (a nitro reductase) with either Na2S2O4 or V2O5, various IREDs, and glucose dehydrogenase (for NADPH regeneration) are used to synthesize a broad range of (R)/(S)-2-alkyl-substituted (THQs) (26 examples) with high yield (up to 93%) and excellent ee (up to 99%) in one-pot. The method further facilitates the one-pot biocatalytic synthesis of chiral 2-aryl substituted THQs (26 examples) from amino chalcones. Lastly, the asymmetric synthesis of several (R)- and (S)-THQ based intermediates of Hancock alkaloids showed the practical application of the newly developed biocatalytic cascades.

One-pot chemo- and photo-enzymatic linear cascade processes.

The combination of chemo- and photocatalyses with biocatalysis, which couples the flexible reactivity of the photo- and chemocatalysts with the highly selective and environmentally friendly nature of enzymes in one-pot linear cascades, represents a powerful tool in organic synthesis. However, the combination of photo-, chemo- and biocatalysts in one-pot is challenging because the optimal operating conditions of the involved catalyst types may be rather different, and the different stabilities of catalysts and their mutual deactivation are additional problems often encountered in one-pot cascade processes. This review explores a large number of transformations and approaches adopted for combining enzymes and chemo- and photocatalytic processes in a successful way to achieve valuable chemicals and valorisation of biomass. Moreover, the strategies for solving incompatibility issues in chemo-enzymatic reactions are analysed, introducing recent examples of the application of non-conventional solvents, enzyme-metal hybrid catalysts, and spatial compartmentalization strategies to implement chemo-enzymatic cascade processes.

Synthesis of a sacubitril precursor via the construction of one-pot chemoenzymatic cascades

A key precursor of sacubitril was synthesized with excellent diastereoselectivity via the construction of three one-pot enzymatic cascades.

Nature stays natural: two novel chemo-enzymatic one-pot cascades for the synthesis of fragrance and flavor aldehydes.

Novel synthetic strategies for the production of high-value chemicals based on the 12 principles of green chemistry are highly desired. Herein, we present a proof of concept for two novel chemo-enzymatic one-pot cascades allowing for the production of valuable fragrance and flavor aldehydes. We utilized renewable phenylpropenes, such as eugenol from cloves or estragole from estragon, as starting materials. For the first strategy, Pd-catalyzed isomerization of the allylic double bond and subsequent enzyme-mediated (aromatic dioxygenase, ADO) alkene cleavage were performed to obtain the desired aldehydes. In the second route, the double bond was oxidized to the corresponding ketone via a copper-free Wacker oxidation protocol followed by enzymatic Baeyer-Villiger oxidation (phenylacetone monooxygenase from Thermobifida fusca), esterase-mediated (esterase from Pseudomonas fluorescens, PfeI) hydrolysis and subsequent oxidation of the primary alcohol (alcohol dehydrogenase from Pseudomonas putida, AlkJ) to the respective aldehyde products. Eight different phenylpropene derivatives were subjected to these reaction sequences, allowing for the synthesis of seven aldehydes in up to 55% yield after 4 reaction steps (86% for each step).

Where Chemocatalysis Meets Biocatalysis: In Water.

Chemoenzymatic catalysis, by definition, involves the merging of sequential reactions using both chemocatalysis and biocatalysis, typically in a single reaction vessel. A major challenge, the solution to which, however, is associated with numerous advantages, is to run such one-pot processes in water: the majority of enzyme-catalyzed processes take place in water as Nature's reaction medium, thus enabling a broad synthetic diversity when using water due to the option to use virtually all types of enzymes. Furthermore, water is cheap, abundantly available, and environmentally friendly, thus making it, in principle, an ideal reaction medium. On the other hand, most chemocatalysis is routinely performed today in organic solvents (which might deactivate enzymes), thus appearing to make it difficult to combine such reactions with biocatalysis toward one-pot cascades in water. Several creative approaches and solutions that enable such combinations of chemo- and biocatalysis in water to be realized and applied to synthetic problems are presented herein, reflecting the state-of-the-art in this blossoming field. Coverage has been sectioned into three parts, after introductory remarks: (1) Chapter 2 focuses on historical developments that initiated this area of research; (2) Chapter 3 describes key developments post-initial discoveries that have advanced this field; and (3) Chapter 4 highlights the latest achievements that provide attractive solutions to the main question of compatibility between biocatalysis (used predominantly in aqueous media) and chemocatalysis (that remains predominantly performed in organic solvents), both Chapters covering mainly literature from ca. 2018 to the present. Chapters 5 and 6 provide a brief overview as to where the field stands, the challenges that lie ahead, and ultimately, the prognosis looking toward the future of chemoenzymatic catalysis in organic synthesis.

Two-enzyme cascade catalyzed trideuteromethylative modification of natural products

Site-selective incorporation of the trideuterated “magic methyl” group may provide profound pharmacological benefits, which has been considered as an important tool for drug optimization and development in medicinal chemistry. S-adenosyl-L-methionine (SAM) usually acts as the methyl donor under the catalysis of SAM-dependent methyltransferases (MTs), which transfer a methyl group from SAM to substrates, and are widely reported for methylation in natural product biosynthesis. However, it is difficult to introduce other high-value functional groups to substrates in this way since SAM analogs are not easy to obtain in biological methods. Herein we report that trideuterated SAM can be obtained from S-adenosylhomocysterine (SAH) and trideuterated methyl iodide (CD3I) under the participation of halide methyltransferase (HMT). Subsequent one-pot cascades with different MTs achieved the regioselective trideuteromethylation of three natural products, which indicated that trideuterated SAM can be accepted as a co-substrate by C-, N-, O-specific MTs for enzyme-catalyzed trideuteromethylation of natural products.

Versatile and Facile One-Pot Biosynthesis for Amides and Carboxylic Acids in E. coli by Engineering Auxin Pathways of Plant Microbiomes

The development of enzymatic routes toward amide and carboxylic acid bond formation in bioactive molecular scaffolds using aqueous conditions is a major challenge for biopharmaceutical and fine chemical industrial sectors. We report biocatalytic and kinetic characterization of two indole-3-acetamide (IAM) pathway enzymes, tryptophan-2-monooxygenase (iaaM) and indole-3-acetamide hydrolase (iaaH), present in plant microbiomes that produce indole-3-acetic acid (IAA). In this pathway, tryptophan is converted to indole-3-acetamide by the monooxygenase activity of iaaM, followed by its hydrolysis to form carboxylic acid by iaaH enzyme. Since IAA or auxin is an essential natural plant hormone and an important synthon for fine chemicals, the developed monooxygenase-based bioconversion route has a wider scope compared to currently available synthetic and biocatalytic methods to produce synthetic auxins and a range of amides and carboxylic acids for agrochemical and pharmaceutical applications. To display this, one-pot multienzyme biosynthetic cascades for preparative-scale production of IAA derivatives were performed by incorporating tryptophan synthase and tryptophan halogenase enzymes. We also report the creation of an efficient de novo biosynthesis for IAA and its derivatives from glucose or indoles via a reconstructed IAM pathway in Escherichia coli.

Multienzyme One-Pot Cascades Incorporating Methyltransferases for the Strategic Diversification of Tetrahydroisoquinoline Alkaloids.

The tetrahydroisoquinoline (THIQ) ring system is present in a large variety of structurally diverse natural products exhibiting a wide range of biological activities. Routes to mimic the biosynthetic pathways to such alkaloids, by building cascade reactions in vitro, represents a successful strategy and can offer better stereoselectivities than traditional synthetic methods. S‐Adenosylmethionine (SAM)‐dependent methyltransferases are crucial in the biosynthesis and diversification of THIQs; however, their application is often limited in vitro by the high cost of SAM and low substrate scope. In this study, we describe the use of methyltransferases in vitro in multi‐enzyme cascades, including for the generation of SAM in situ. Up to seven enzymes were used for the regioselective diversification of natural and non‐natural THIQs on an enzymatic preparative scale. Regioselectivites of the methyltransferases were dependent on the group at C‐1 and presence of fluorine in the THIQs. An interesting dual activity was also discovered for the catechol methyltransferases used, which were found to be able to regioselectively methylate two different catechols in a single molecule.

Controlling product selectivity with nanoparticle composition in tandem chemo-biocatalytic styrene oxidation

The combination of heterogeneous catalysis and biocatalysis into one-pot reaction cascades is a potential approach to integrate enzymatic transformations into existing chemical infrastructure.

Leloir Glycosyltransferases in Applied Biocatalysis: A Multidisciplinary Approach.

Enzymes are nature’s catalyst of choice for the highly selective and efficient coupling of carbohydrates. Enzymatic sugar coupling is a competitive technology for industrial glycosylation reactions, since chemical synthetic routes require extensive use of laborious protection group manipulations and often lack regio- and stereoselectivity. The application of Leloir glycosyltransferases has received considerable attention in recent years and offers excellent control over the reactivity and selectivity of glycosylation reactions with unprotected carbohydrates, paving the way for previously inaccessible synthetic routes. The development of nucleotide recycling cascades has allowed for the efficient production and reuse of nucleotide sugar donors in robust one-pot multi-enzyme glycosylation cascades. In this way, large glycans and glycoconjugates with complex stereochemistry can be constructed. With recent advances, LeLoir glycosyltransferases are close to being applied industrially in multi-enzyme, programmable cascade glycosylations.

Biocatalytic bis-C-alkylation of phenolics using one-pot cascades with promiscuous C-glycosyltransferase and prenyltransferase

Biocatalytic bis-C-alkylation of phenolics using one-pot cascades with promiscuous C-glycosyltransferase and prenyltransferase

Application of ω-Transaminases in the Pharmaceutical Industry

Chiral amines are valuable building blocks for the pharmaceutical industry. ω-TAms have emerged as an exciting option for their synthesis, offering a potential "green alternative" to overcome the drawbacks associated with conventional chemical methods. In this review, we explore the application of ω-TAms for pharmaceutical production. We discuss the diverse array of reactions available involving ω-TAms and process considerations of their use in both kinetic resolution and asymmetric synthesis. With the aid of specific drug intermediates and APIs, we chart the development of ω-TAms using protein engineering and their contribution to elegant one-pot cascades with other enzymes, including carbonyl reductases (CREDs), hydrolases and monoamine oxidases (MAOs), providing a comprehensive overview of their uses, beginning with initial applications through to the present day.

Chemo-biocatalytic one-pot two-step conversion of cyclic amine to lactam using whole cell monoamine oxidase

BACKGROUND Most biocatalysts currently involved in one-pot chemoenzymatic cascades are pure enzymes, while whole cells and crude enzyme extracts remain unexplored. This work aims to develop a chemo-biocatalytic one-pot two-step system involving whole cell monoamine oxidase (MAO, EC 1.4.3.4) coupled with a Cu-based oxidative system (CuI/H2O2) for the transformation of 1,2,3,4-tetrahydroisoquinoline (THIQ) to 3,4-dihydroisoquinolin-1(2H)-one (DHIO). RESULTS MAO-N variants D9 and D11 were tested as whole cell and crude lysate biocatalysts for biological oxidation. Whole Escherichia coli OverExpress C43(DE3) cells expressing MAO-N D9 showed the best performance (Vmax = 36.58 mmol L−1 h−1, KM = 8.124 mmol L−1, maximum specific productivity 89.3 μmol min−1 g−1DCW) and were employed in combination with CuI/H2O2 in a sequential one-pot two-step process. The biotransformation was scaled-up to the initial volume of 25 mL and after triple THIQ feeding, 48.2 mmol L−1 of the intermediate 3,4-dihydroisoquinoline (DHIQ) was obtained with a yield of 71.3%. Afterwards, chemical catalysts (1 mol% CuI and 10 eq. H2O2) were added to the biologically produced DHIQ, which was transformed to ∼30 mmol L−1 DHIO at 69.4% overall yield. CONCLUSION As MAO-N variants have wide substrate specificity, this work broadens the portfolio of one-pot chemoenzymatic processes employing whole cell biocatalysts, representing an alternative to using pure enzymes. © 2016 Society of Chemical Industry

Group 2 Catalysis for the Atom-Efficient Synthesis of Imidazolidine and Thiazolidine Derivatives.

A wide variety of functionalised imidazolidine-2-ones and -thiones, 2-imino-imidazolidines and thiazolidine-2-thiones have been synthesised under very mild reaction conditions by using simple and cost-effective alkaline earth bis(amide) precatalysts, [Ae{N(SiMe3 )2 }2 (THF)2 ] (Ae=Mg, Ca, Sr). The reactions ensue with 100 % atom efficiency as one-pot cascades from simple, commercially available terminal alkyne and heterocumulene reagents. The reactions take place through the initial assembly of propargylamidines, which are utilised in subsequent cyclisation reactions through addition of the isocyanate, isothiocyanate and, in one case, carbon disulfide reagents. This reactivity is deduced to take place through a well-defined sequence of heterocumulene hydroacetylenation and alkyne hydroamidation steps, which are all mediated at the alkaline earth centre. The rate and regioselectivity of the cyclisation reactions are, thus, found to be heavily dependent upon the identity of the catalytic alkaline earth centre employed. Similarly, the selectivity of the reactions was observed to be profoundly affected by stereoelectronic variations in the individual substrates, albeit by a similar Group 2-centred reaction mechanism in all cases studied.

One-pot triangular chemoenzymatic cascades for the syntheses of chiral alkaloids from dopamine

One-pot, one-substrate, triangular chemoenzymatic cascades featuring transaminase (TAm) and norcoclaurine synthase (NCS) enables the formation of (S)-benzylisoquinoline and (S)-tetrahydroprotoberberine alkaloids.

ChemInform Abstract: Rasta Resin—PPh3—NBniPr2 and Its Use in One‐Pot Wittig Reaction Cascades.

ChemInformVolume 43, Issue 23 Preparative Organic Chemistry ChemInform Abstract: Rasta Resin—PPh3—NBniPr2 and Its Use in One-Pot Wittig Reaction Cascades. Yan Teng, Yan Teng Dep. Chem., Univ. Hong Kong, Kowloon, Hong Kong, Peop. Rep. ChinaSearch for more papers by this authorJinni Lu, Jinni Lu Dep. Chem., Univ. Hong Kong, Kowloon, Hong Kong, Peop. Rep. ChinaSearch for more papers by this authorPatrick H. Toy, Patrick H. Toy Dep. Chem., Univ. Hong Kong, Kowloon, Hong Kong, Peop. Rep. ChinaSearch for more papers by this author Yan Teng, Yan Teng Dep. Chem., Univ. Hong Kong, Kowloon, Hong Kong, Peop. Rep. ChinaSearch for more papers by this authorJinni Lu, Jinni Lu Dep. Chem., Univ. Hong Kong, Kowloon, Hong Kong, Peop. Rep. ChinaSearch for more papers by this authorPatrick H. Toy, Patrick H. Toy Dep. Chem., Univ. Hong Kong, Kowloon, Hong Kong, Peop. Rep. ChinaSearch for more papers by this author First published: 10 May 2012 https://doi.org/10.1002/chin.201223047Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume43, Issue23June 5, 2012 RelatedInformation

Taming the Friedel–Crafts Reaction: Organocatalytic Approach to Optically Active 2,3‐Dihydrobenzofurans

Fine-tuning: Three types of optically active trans-2,3-disubstituted-2,3-dihydrobenzofurans having three contiguous stereogenic centers can be efficiently accessed by one-pot reaction cascades (see scheme; TMS = trimethylsilyl). High substitution diversity of the final products can be achieved from the same common precursors by fine-tuning of their reactivity through simple structural modifications.

One-pot reaction cascades catalyzed by base- and acid-functionalized mesoporous silica nanoparticles

Mesoporous silica nanoparticles (MSNs) containing base (primary amine) and sulfonic acid inside the MCM-41 type porous channels were successfully used as compatible catalysts for one-pot reaction cascades.

Application of Galactose Oxidase in Chemoenzymatic One-Pot Cascade Reactions Without Intermediate Recovery Steps

Various cascade routes starting from D-galactose derivatives—via 6-CH2OH oxidation catalyzed by galactose oxidase—are reported as one-pot procedures. The approach consists of combined bio- and chemocatalytic reactions as well as “spontaneous” chemical conversions. Workup is avoided by using compatible aqueous reaction conditions for all the consecutive reactions involved. A great benefit of this method is that D-galactose containing di-, tri- and oligosaccharides can be modified without the use of protecting groups and without any isolation and/or purification of intermediate products in these syntheses. The one-pot cascades, consisting of up to five consecutive transformations, gave rapid access to more than 40 uronic acid, amino sugar and deoxy sugar derivatives through enzymatic, homogeneous and heterogeneous catalytic conversions in water under mild conditions.