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Special Issue "Chemoenzymatic Synthesis and Application"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Organic Chemistry".

Deadline for manuscript submissions: closed (15 October 2019).

Special Issue Editor

Dr. Paola Vitale
Website
Guest Editor
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "A. Moro", Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, I-70125 Bari, Italy
Interests: Asymmetric synthesis; Applied biocatalysis; Whole cells biocatalysis; Sustainable chemistry; Green chemistry; Synthesis of bioactive heterocycles; COX inhibitors; Isoxazoles, Isoxazolines; Heterocyclic chemistry
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Special Issue Information

Dear colleagues,

The chemo-enzymatic processes are very important in the field of applied catalysis.

They are multistep reaction sequences, where biocatalytic reactions are combined with other transformations, providing very efficient tools in preparative organic synthesis and materials chemistry. In biocatalytic reactions, the enzymes responsible for the cell metabolism are used by organic chemists to accomplish extremely selective and specific chemical transformations in milder conditions of pH and temperature, which are often difficult to achieve by conventional routes.

Biocatalytic processes have in fact received increasing attention among environmentally-friendly synthetic approaches, either for laboratory scale syntheses and for industrial productions, by avoiding some drawbacks of other synthetic approaches, such as high costs, the toxicity of reagents, harsh conditions, and side product formation. In many research programs of public and private research institutions, chemoenzymatic processes have been studied in the last decades for the synthesis of renewable molecules derived from biomass, for the preparation of new bio-based monomers/additives and new value-added features for polymers and materials.

Moreover, in chemo-enzymatic processes, the biocatalytic step can be an asymmetric reaction that allows the formation of new chemical bonds in a stereocontrolled manner, which is an important challenge in the preparation of strategic enantiopure building blocks for the pharmaceutical industry. Chirality in fact is extremely important for the safety and efficiency of drugs, because their biological effects strongly depend on the interaction with the receptors in different parts of the body. Chemo-enzymatic synthesis can be performed either by isolated enzymes that are sometimes more stable, specific and minimize byproduct formation, or by using whole cells (wild-type or recombinant biocatalysts) that have internal cofactor regeneration systems that work as a perfect cheap and green chemical factory. Miming the biochemical pathways in cells, some chemo-enzymatic processes can be performed by coupling sequential reactions catalyzed by different enzymatic consortia, where biotransformations can also be used for the regeneration of costly cofactors, or to enable thermodynamically unfavorable steps in cascade processes, without isolation of the intermediates, and often avoiding protective group chemistry.

This Special Issue will publish full original papers, review articles, and short communications focusing on novel chemo-enzymatic approaches (also enantioselective) as valuable processes for the preparation of fine chemicals, chiral building blocks, or highly functionalized molecules, even on a large scale. Sustainable methodologies from the combination of biocatalysis and different areas of (transition) metal-, organo-, photoredox-catalysis, also using unconventional environmentally-friendly reaction media are also of great interest.

Dr. Paola Vitale
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Biocatalysis
  • Chemoenzymatic synthesis
  • Bio-based molecules from biomasses
  • Sustainable chemistry
  • Environmentally-friendly synthesis
  • Active pharmaceutical ingredient (API) synthesis
  • Asymmetric catalysis
  • Metal catalysis
  • Organo-catalysis
  • Photoredox catalysis
  • Chiral building blocks
  • Unconventional reaction media

Published Papers (7 papers)

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Research

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Open AccessArticle
Stereoselective Bioreduction of α-diazo-β-keto Esters
Molecules 2020, 25(4), 931; https://doi.org/10.3390/molecules25040931 - 19 Feb 2020
Abstract
Diazo compounds are versatile reagents in chemical synthesis and biology due to the tunable reactivity of the diazo functionality and its compatibility with living systems. Much effort has been made in recent years to explore their accessibility and synthetic potential; however, their preparation [...] Read more.
Diazo compounds are versatile reagents in chemical synthesis and biology due to the tunable reactivity of the diazo functionality and its compatibility with living systems. Much effort has been made in recent years to explore their accessibility and synthetic potential; however, their preparation through stereoselective enzymatic asymmetric synthesis has been scarcely reported in the literature. Alcohol dehydrogenases (ADHs, also called ketoreductases, KREDs) are powerful redox enzymes able to reduce carbonyl compounds in a highly stereoselective manner. Herein, we have developed the synthesis and subsequent bioreduction of nine α-diazo-β-keto esters to give optically active α-diazo-β-hydroxy esters with potential applications as chiral building blocks in chemical synthesis. Therefore, the syntheses of prochiral α-diazo-β-keto esters bearing different substitution patterns at the adjacent position of the ketone group (N3CH2, ClCH2, BrCH2, CH3OCH2, NCSCH2, CH3, and Ph) and in the alkoxy portion of the ester functionality (Me, Et, and Bn), were carried out through the diazo transfer reaction to the corresponding β-keto esters in good to excellent yields (81–96%). After performing the chemical reduction of α-diazo-β-keto esters with sodium borohydride and developing robust analytical conditions to monitor the biotransformations, their bioreductions were exhaustively studied using in-house made Escherichia coli overexpressed and commercially available KREDs. Remarkably, the corresponding α-diazo-β-hydroxy esters were obtained in moderate to excellent conversions (60 to >99%) and high selectivities (85 to >99% ee) after 24 h at 30 °C. The best biotransformations in terms of conversion and enantiomeric excess were successfully scaled up to give the expected chiral alcohols with almost the same activity and selectivity values observed in the enzyme screening experiments. Full article
(This article belongs to the Special Issue Chemoenzymatic Synthesis and Application)
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Open AccessArticle
Plant-Mediated Enantioselective Transformation of Indan-1-one and Indan-1-ol. Part 2
Molecules 2019, 24(23), 4342; https://doi.org/10.3390/molecules24234342 - 27 Nov 2019
Cited by 1
Abstract
The main purpose of this publication was to obtain the S-enantiomer of indan-1-ol with high enantiomeric excess and satisfactory yield. In our research, we used carrot callus cultures (Daucus carota L.), whereby the enzymatic system reduced indan-1-one and oxidized indan-1-ol. During [...] Read more.
The main purpose of this publication was to obtain the S-enantiomer of indan-1-ol with high enantiomeric excess and satisfactory yield. In our research, we used carrot callus cultures (Daucus carota L.), whereby the enzymatic system reduced indan-1-one and oxidized indan-1-ol. During the reaction of reduction, after five days, we received over 50% conversion, with the enantiomeric excess of the formed S-alcohol above 99%. In turn, during the oxidation of racemic indan-1-ol after 15 days, 36.7% of alcohol with an enantiomeric excess 57.4% S(+) remained in the reaction mixture. In addition, our research confirmed that the reactions of reduction and oxidation are competing reactions during the transformation of indan-1-ol and indan-1-one in carrot callus cultures. Full article
(This article belongs to the Special Issue Chemoenzymatic Synthesis and Application)
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Open AccessArticle
Polyamidoamide Dendrimers and Cross-Linking Agents for Stabilized Bioenzymatic Resistant Metal-Free Bovine Collagen
Molecules 2019, 24(19), 3611; https://doi.org/10.3390/molecules24193611 - 07 Oct 2019
Cited by 1
Abstract
The work reports the use of polyamidoamine dendrimers (PAMAM) and a cross-linking agent, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide/N-hydroxysuccinimide (EDC/NHS) or 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM), for the thermal stabilization of dermal bovine collagen. The efficiency of EDC/NHS/PAMAM and DMTMM/PAMAM in the cross-linking of collagen is correlated to [...] Read more.
The work reports the use of polyamidoamine dendrimers (PAMAM) and a cross-linking agent, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide/N-hydroxysuccinimide (EDC/NHS) or 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM), for the thermal stabilization of dermal bovine collagen. The efficiency of EDC/NHS/PAMAM and DMTMM/PAMAM in the cross-linking of collagen is correlated to the increase of the collagen shrinkage temperature (Ts), measured by differential scanning calorimetry (DSC). An alternative enzymatic protocol was adopted to measure the degradability of EDC/NHS/PAMAM tanned hides; these data are correlated to the thermal stability values measured by DSC. In the presence of PAMAMs, EDC/NHS provides very high stabilization of bovine dermal collagen, giving Ts of up to 95 °C, while DMTMM achieves lower stabilization. Preliminary tanning tests carried out in best reaction conditions show that EDC/NHS/PAMAM could be an interesting, environmentally-sustainable tanning system which is completely free of metals, formaldehyde, and phenols. Two new unreported dendrimeric species were synthesized and employed. Full article
(This article belongs to the Special Issue Chemoenzymatic Synthesis and Application)
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Open AccessArticle
Efficient Chemo-Enzymatic Transformation of Animal Biomass Waste for Eco-Friendly Leather Production
Molecules 2019, 24(16), 2979; https://doi.org/10.3390/molecules24162979 - 16 Aug 2019
Cited by 4
Abstract
Enzymatically processed animal biomass derived from treated bovine hides (wet blue scraps) is herein used as building block for the synthesis of a novel biopolymer. An enzymatic hydrolysis process allows to produce water-soluble lower molecular weight proteins (Bio-A), which are then reacted with [...] Read more.
Enzymatically processed animal biomass derived from treated bovine hides (wet blue scraps) is herein used as building block for the synthesis of a novel biopolymer. An enzymatic hydrolysis process allows to produce water-soluble lower molecular weight proteins (Bio-A), which are then reacted with glycerol and maleic anhydride (MA) in order to obtain a new intermediate (Bio-IA). With Bio-IA in hand, co-polymerization in the presence of acrylic acid is then carried out. Hydrolysed biomass, intermediates and the final biopolymer (Bio-Ac) have been characterized by means of NMR, FTIR and GPC analysis. Bio-Ac shows good performance when used as retanning agent to produce leather. Physical and mechanical properties of the leather treated with Bio-Ac have been compared with acrylic resin retanned leather, showing similar performance. The reported protocol represents an environmental-friendly interesting alternative to traditional petrochemical based retanning agents, commonly used by the leather industry. Full article
(This article belongs to the Special Issue Chemoenzymatic Synthesis and Application)
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Open AccessArticle
Asymmetric Whole-Cell Bio-Reductions of (R)-Carvone Using Optimized Ene Reductases
Molecules 2019, 24(14), 2550; https://doi.org/10.3390/molecules24142550 - 12 Jul 2019
Cited by 1
Abstract
(2R,5R)-dihydrocarvone is an industrially applied building block that can be synthesized by site-selective and stereo-selective C=C bond bio-reduction of (R)-carvone. Escherichia coli (E. coli) cells overexpressing an ene reductase from Nostoc sp. PCC7120 (NostocER1) in [...] Read more.
(2R,5R)-dihydrocarvone is an industrially applied building block that can be synthesized by site-selective and stereo-selective C=C bond bio-reduction of (R)-carvone. Escherichia coli (E. coli) cells overexpressing an ene reductase from Nostoc sp. PCC7120 (NostocER1) in combination with a cosubstrate regeneration system proved to be very effective biocatalysts for this reaction. However, the industrial applicability of biocatalysts is strongly linked to the catalysts’ activity. Since the cell-internal NADH concentrations are around 20-fold higher than the NADPH concentrations, we produced E. coli cells where the NADPH-preferring NostocER1 was exchanged with three different NADH-accepting NostocER1 mutants. These E. coli whole-cell biocatalysts were used in batch operated stirred-tank reactors on a 0.7 l-scale for the reduction of 300 mM (R)-carvone. 287 mM (2R,5R)-dihydrocarvone were formed within 5 h with a diasteromeric excess of 95.4% and a yield of 95.6%. Thus, the whole-cell biocatalysts were strongly improved by using NADH-accepting enzymes, resulting in an up to 2.1-fold increased initial product formation rate leading to a 1.8-fold increased space-time yield when compared to literature. Full article
(This article belongs to the Special Issue Chemoenzymatic Synthesis and Application)
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Open AccessArticle
Exploring Castellaniella defragrans Linalool (De)hydratase-Isomerase for Enzymatic Hydration of Alkenes
Molecules 2019, 24(11), 2092; https://doi.org/10.3390/molecules24112092 - 01 Jun 2019
Abstract
Acyclic monoterpenes constitute a large and highly abundant class of secondary plant metabolites and are, therefore, attractive low-cost raw materials for the chemical industry. To date, numerous biocatalysts for their transformation are known, giving access to highly sought-after monoterpenoids. In view of the [...] Read more.
Acyclic monoterpenes constitute a large and highly abundant class of secondary plant metabolites and are, therefore, attractive low-cost raw materials for the chemical industry. To date, numerous biocatalysts for their transformation are known, giving access to highly sought-after monoterpenoids. In view of the high selectivity associated with many of these reactions, the demand for enzymes generating commercially important target molecules is unabated. Here, linalool (de)hydratase-isomerase (Ldi, EC 4.2.1.127) from Castellaniella defragrans was examined for the regio- and stereoselective hydration of the acyclic monoterpene β-myrcene to (S)-(+)-linalool. Expression of the native enzyme in Escherichia coli allowed for identification of bottlenecks limiting enzyme activity, which were investigated by mutating selected residues implied in enzyme assembly and function. Combining these analyses with the recently published 3D structures of Ldi highlighted the precisely coordinated reduction–oxidation state of two cysteine pairs in correct oligomeric assembly and the catalytic mechanism, respectively. Subcellular targeting studies upon fusion of Ldi to different signal sequences revealed the significance of periplasmic localization of the mature enzyme in the heterologous expression host. This study provides biochemical and mechanistic insight into the hydration of β-myrcene, a nonfunctionalized terpene, and emphasizes its potential for access to scarcely available but commercially interesting tertiary alcohols. Full article
(This article belongs to the Special Issue Chemoenzymatic Synthesis and Application)
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Review

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Open AccessReview
Dihydrochalcones: Methods of Acquisition and Pharmacological Properties—A First Systematic Review
Molecules 2019, 24(24), 4468; https://doi.org/10.3390/molecules24244468 - 05 Dec 2019
Cited by 1
Abstract
Dihydrochalcones are a class of secondary metabolites, for which demand in biological and pharmacological applications is still growing. They posses several health-endorsing properties and, therefore, are promising candidates for further research and development. However, low content of dihydrochalcones in plants along with their [...] Read more.
Dihydrochalcones are a class of secondary metabolites, for which demand in biological and pharmacological applications is still growing. They posses several health-endorsing properties and, therefore, are promising candidates for further research and development. However, low content of dihydrochalcones in plants along with their low solubility and bioavailability restrict the development of these compounds as clinical therapeutics. Therefore, chemomicrobial and enzymatic modifications are required to expand their application. This review aims at analyzing and summarizing the methods of obtaining dihydrochalcones and of presenting their pharmacological actions that have been described in the literature to support potential future development of this group of compounds as novel therapeutic drugs. We have also performed an evaluation of the available literature on beneficial effects of dihydrochalcones with potent antioxidant activity and multifactorial pharmacological effects, including antidiabetic, antitumor, lipometabolism regulating, antioxidant, anti-inflammatory, antibacterial, antiviral, and immunomodulatory ones. In addition, we provide useful information on their properties, sources, and usefulness in medicinal chemistry. Full article
(This article belongs to the Special Issue Chemoenzymatic Synthesis and Application)
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