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15 pages, 1793 KB

Open AccessArticle

Formation of Racemic Phases of Amino Acids by Liquid-Assisted Resonant Acoustic Mixing Monitored by Solid-State NMR Spectroscopy

by Leeroy Hendrickx, Calogero Quaranta, Emilian Fuchs, Maksim Plekhanov, Mirijam Zobel, Carsten Bolm and Thomas Wiegand

Molecules 2025, 30(18), 3745; https://doi.org/10.3390/molecules30183745 - 15 Sep 2025

Viewed by 296

Abstract

Mechanochemistry has become a fundamental method in various sciences including biology and chemistry. Despite its popularity, the mechanisms behind mechanochemically induced reactions are not very well understood. In previous work, we investigated molecular-recognition processes of molecules capable of forming racemic phases in ball [...] Read more.

Mechanochemistry has become a fundamental method in various sciences including biology and chemistry. Despite its popularity, the mechanisms behind mechanochemically induced reactions are not very well understood. In previous work, we investigated molecular-recognition processes of molecules capable of forming racemic phases in ball mill devices. Solid-state nuclear magnetic resonance (solid-state NMR) was used as the key technique to analyze such events. We now extended this study and focused on mechanochemically induced racemic-phase formations of two representative amino acids, alanine and serine, in a resonant acoustic mixer. The data reveal the importance of adding small amounts of solvents (here water) to facilitate the underlying solid-state molecular-recognition processes. The role of water therein is further studied by deuterium magic-angle spinning (MAS) NMR experiments, also revealing that resonant acoustic mixing (RAM) enables efficient hydrogen to deuterium exchange in enantiopure serine, paving the way to deuterate organic compounds in the RAM device. Full article

(This article belongs to the Special Issue NMR and MRI in Materials Analysis: Opportunities and Challenges)

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19 pages, 4361 KB

Open AccessArticle

Pinene-Based Chiral Bipyridine Ligands Drive Potent Antibacterial Activity in Rhenium(I) Complexes

by Justine Horner, Gozde Demirci, Aurelien Crochet, Aleksandar Pavic, Olimpia Mamula Steiner and Fabio Zobi

Molecules 2025, 30(15), 3183; https://doi.org/10.3390/molecules30153183 - 29 Jul 2025

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Abstract

Antimicrobial resistance (AMR) poses a critical global health threat by rendering existing antibiotics ineffective against infections, leading to increased mortality, prolonged illnesses, and higher healthcare costs. Developing new antibiotics is essential to combat resistant pathogens, safeguard modern medical procedures, and prevent a return [...] Read more.

Antimicrobial resistance (AMR) poses a critical global health threat by rendering existing antibiotics ineffective against infections, leading to increased mortality, prolonged illnesses, and higher healthcare costs. Developing new antibiotics is essential to combat resistant pathogens, safeguard modern medical procedures, and prevent a return to a pre-antibiotic era where common infections become untreatable. We report a series of chiral tricarbonyl rhenium(I) complexes incorporating enantiopure pinene-substituted bipyridine ligands (L#) of the general formula fac-[Re(CO)₃L#X] and fac-[Re(CO)₃L#Py]⁺ (where X = Cl or Br and Py = pyridine). These complexes were isolated as mixtures of two diastereomers, characterized by standard techniques, and evaluated for cytotoxic activity against methicillin-resistant and methicillin-sensitive Staphylococcus aureus (MRSA and MSSA). The results revealed notable antibacterial efficacy (MIC = 1.6 μM), reflected in high therapeutic indices (Ti > 10). In contrast, analogous complexes bearing non-chiral 2,2′-bipyridine ligands exhibited no activity, underscoring the critical role of chirality in modulating biological interactions at the molecular level. These findings highlight the potential of chiral Re(I) complexes as promising scaffolds for the development of more potent and selective antibacterial agents. Full article

(This article belongs to the Topic Metal Ions in Health and Diseases: Current Progress and Future Challenges)

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13 pages, 1147 KB

Open AccessHypothesis

Possible Enantioseparation of Racemic Ribose on Chiral Surface Formed by Adsorption of Nucleobases

by Roman Bielski and Michal Tencer

Life 2025, 15(8), 1160; https://doi.org/10.3390/life15081160 - 23 Jul 2025

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Abstract

The paper proposes a putative prebiotic scenario leading to homochirality in the RNA world. In this scenario, racemic ribose, the only chiral moiety in RNA, was enantioseparated (in its pyranose form) on a chiral surface formed by the adsorption of (prochiral) nucleobases (NBs) [...] Read more.

The paper proposes a putative prebiotic scenario leading to homochirality in the RNA world. In this scenario, racemic ribose, the only chiral moiety in RNA, was enantioseparated (in its pyranose form) on a chiral surface formed by the adsorption of (prochiral) nucleobases (NBs) on a mineral or metal. Purine bases (adenine and guanine) are more likely candidates for this process than pyrimidine bases because they have more H-bond donors and acceptors. Another possible candidate surface for the enantioseparation of ribose would be formed by the adsorption of nucleobase pairs, e.g., guanine–cytosine (GC). Interactions of ribose molecules with hydrogen bond donors and acceptors of NBs or NB pairs (located on the surface) enforced the orientation of ribose molecules in two directions perpendicular to each other and parallel to the surface. Consequently, the energy of interactions of enantiomers of the sugar with the surface was not the same. Thus, a solvent moving along the surface caused the enantiomers of ribose to move with different rates, resulting in the enantioseparation of ribose in a chromatography-like process. The same process would also separate ribose from other monosaccharides in the mix. Hydrogen bonding between nucleobases was also pivotal in the formation of large homochiral domains on the surfaces. Full article

(This article belongs to the Special Issue Origin of Life in Chemically Complex Messy Environments: 2nd Edition)

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12 pages, 2771 KB

Open AccessArticle

A Supramolecular Extension of Mosher’s Method: Absolute Configuration Assignment of N-Amino Acid Derivatives via Bis-Thiourea Chiral Solvating Agent

by Virginia Rondinini, Federica Aiello, Federica Cefalì, Alessandra Recchimurzo, Gloria Uccello Barretta and Federica Balzano

Molecules 2025, 30(14), 2930; https://doi.org/10.3390/molecules30142930 - 11 Jul 2025

Viewed by 588

Abstract

The bis-thiourea chiral solvating agent (CSA) BTDA enables the NMR-based determination of absolute configuration in N-3,5-dinitrobenzoyl (DNB) amino acid derivatives without requiring covalent derivatization. A reliable trend of the sense of nonequivalence and absolute configuration is found in both ¹H and [...] Read more.

The bis-thiourea chiral solvating agent (CSA) BTDA enables the NMR-based determination of absolute configuration in N-3,5-dinitrobenzoyl (DNB) amino acid derivatives without requiring covalent derivatization. A reliable trend of the sense of nonequivalence and absolute configuration is found in both ¹H and ¹³C NMR spectra. A dual-enantiomer approach, using (R,R)- and (S,S)-BTDA, generates diastereomeric complexes with the enantiopure substrate, and distinct spatial arrangements are reflected in consistent and interpretable Δδ values. The observed chemical shift differences correlate reliably with the stereochemistry of the chiral center and are further supported by ROESY (Rotating-frame Overhauser Enhancement SpectroscopY) experiments and binding constants’ measurements, confirming the formation of stereoselective non-covalent complexes. This methodology extends the logic of Mosher’s analysis to solvating agents and remains effective even in samples containing single pure enantiomers of the amino acid derivative. The BTDA-based dual-CSA system thus represents a robust, non-derivatizing strategy for stereochemical assignment by NMR, combining operational simplicity with broad applicability to DNB derivatives of amino acids with free carboxyl function. Full article

(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition: 3rd Edition)

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14 pages, 2002 KB

Open AccessArticle

Synthesis and Application of a New Cyclic Phosphoric Acid in Enantioselective Three-Component Mannich Reactions

by Giovanni Ghigo, Alessio Robiolio Bose and Stefano Dughera

Molecules 2025, 30(14), 2928; https://doi.org/10.3390/molecules30142928 - 10 Jul 2025

Viewed by 538

Abstract

A novel point-chiral six-membered cyclic phosphoric acid was synthesized starting from an enantiopure precursor via a concise three-step route. Its catalytic performance was evaluated in enantioselective three-component Mannich reactions. Under optimized conditions, the catalyst provided good yields and satisfactory enantiomeric excesses (up to [...] Read more.

A novel point-chiral six-membered cyclic phosphoric acid was synthesized starting from an enantiopure precursor via a concise three-step route. Its catalytic performance was evaluated in enantioselective three-component Mannich reactions. Under optimized conditions, the catalyst provided good yields and satisfactory enantiomeric excesses (up to 89%). The basic mechanism of the catalysis was also studied by the DFT method. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Organic Chemistry)

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10 pages, 1355 KB

Open AccessArticle

Alternative HPLC-DAD Direct-Phase Approach to Measurement of Enantiopurity of Lactic Acid Derivatives

by Maria Montrone, Cosimo Cardellicchio and Maria Annunziata M. Capozzi

Appl. Sci. 2025, 15(12), 6433; https://doi.org/10.3390/app15126433 - 7 Jun 2025

Viewed by 997

Abstract

Lactic acid (LA) is a natural organic acid that can be used in a wide variety of industries. Recently, the production of lactic acid by fermentation protocols has gained relevance. However, these biotechnological processes often encounter challenges in the production of enantiopure D- [...] Read more.

Lactic acid (LA) is a natural organic acid that can be used in a wide variety of industries. Recently, the production of lactic acid by fermentation protocols has gained relevance. However, these biotechnological processes often encounter challenges in the production of enantiopure D- or L-lactic acid. Thus, the measurement and control of the enantiopurity of lactic acid and its derivatives is a crucial step in these productions, especially when monomers have to be used to synthesize polymers, such as polylactic acid (PLA). In the present work, we propose a measurement of the enantiopurity of lactic acid mixtures with HPLC-DAD by using direct-phase conditions, which are mild, and a large set of different employable chiral columns. To this end, we report the synthesis of two new LA derivatives (2-nitrobenzyl 2-hydroxypropanoate and 2,4-dinitrobenzyl 2-hydroxypropanoate) and benzyl 2-hydroxypropanoate, with a selective and non-racemizing chemical functionalization. Then, three commercially available HPLC direct-phase chiral columns are tested to achieve a method for measuring the enantiomeric purity of lactic acid derivatives. The 2-nitrobenzyl lactate was chosen as the best lactic acid derivative and the Chiralpak IA column was chosen as the most effective chiral column to achieve a new and efficient protocol (Rs = 3.57 and α = 1.13) for the measurement of the enantiopurity of lactic acid. Full article

(This article belongs to the Section Chemical and Molecular Sciences)

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15 pages, 1680 KB

Open AccessArticle

The Missing Structures of Pasteur’s Aspartates

by Damian J. C. Kersten and Martin Lutz

Crystals 2025, 15(6), 521; https://doi.org/10.3390/cryst15060521 - 29 May 2025

Viewed by 556

Abstract

In his crystallographic research on chiral separation, Louis Pasteur reported the crystals of the sodium salts of enantiopure and racemic aspartic acid. Their atomic structure remained unknown to this day. In the present article, the two crystal structures are reported. The X-ray diffraction [...] Read more.

In his crystallographic research on chiral separation, Louis Pasteur reported the crystals of the sodium salts of enantiopure and racemic aspartic acid. Their atomic structure remained unknown to this day. In the present article, the two crystal structures are reported. The X-ray diffraction of both crystals was severely affected by twinning. Their crystal packing is very similar and can be described as a three-dimensional coordination network. A decomposition of the structures into layers helps to explain the twinning as stacking faults. In the enantiopure crystal, the layers are parallel to

(0, 1, 0)

and in the racemic crystal parallel to

(0, 0, 1)

. The sum formula of the two crystal structures is identical, representing the monohydrate of the monosodium aspartate. Full article

(This article belongs to the Section Organic Crystalline Materials)

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14 pages, 1652 KB

Open AccessArticle

The Enzymatic Synthesis of Perdeuterated D- and L-Lactic Acid-d₄ and Polymerization of Their Lactides to Polylactic Acid

by Anna E. Leung, Andreas Raba, Klaus Beckerle, Jürgen Allgaier and Hanna P. Wacklin-Knecht

Bioengineering 2025, 12(6), 575; https://doi.org/10.3390/bioengineering12060575 - 27 May 2025

Cited by 1 | Viewed by 1152

Abstract

We report the synthesis of highly enantiopure perdeuterated poly-L-lactic acid and poly-D-lactic acid polymers with well-defined molecular weight by polymerization of perdeuterated lactides. Enantiopure D- and L-lactic acid-d₄ monomers were synthesized from sodium pyruvate-d₃ using D- and L-lactate dehydrogenase [...] Read more.

We report the synthesis of highly enantiopure perdeuterated poly-L-lactic acid and poly-D-lactic acid polymers with well-defined molecular weight by polymerization of perdeuterated lactides. Enantiopure D- and L-lactic acid-d₄ monomers were synthesized from sodium pyruvate-d₃ using D- and L-lactate dehydrogenase enzymes (D-LDH and L-LDH) as biocatalysts. The reduced form of the co-enzyme nicotinamide adenine dinucleotide-d₁ (NADH-d₁) was generated in situ from the oxidized form nicotinamide adenine dinucleotide (NAD⁺) by formate dehydrogenase (FDH)-catalyzed oxidation of sodium formate-d₁ to carbon dioxide with concerted reduction of NAD⁺ to NADH-d₁. For the conversion of the perdeuterated lactic acid monomers to the corresponding lactide dimers, we developed a process for generating these compounds in the high purity needed for the final anionic ring-opening polymerization step. This method enabled the generation of a range of perdeuterated polylactic acid polymers that are highly suitable for the characterization of polymer structure and dynamics using neutron scattering, infrared and nuclear magnetic resonance spectroscopy methods that are sensitive to deuterium. Furthermore, these deuterium-labeled polymers are well-suited to the study of the biodegradation of PLA-based plastics. Full article

(This article belongs to the Special Issue Design and Synthesis of Functional Deuterated Biomaterials)

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21 pages, 2130 KB

Open AccessArticle

A Straightforward Approach Towards Phosphadecalones by Microwave-Assisted Diels–Alder Reaction

by Elżbieta Łastawiecka, Anna E. Kozioł and K. Michał Pietrusiewicz

Molecules 2025, 30(11), 2338; https://doi.org/10.3390/molecules30112338 - 27 May 2025

Viewed by 637

Abstract

A stereoselective and scalable strategy for the synthesis of phosphorus-containing bicyclic and tricyclic compounds from 1-phenylphosphin-2-en-4-one 1-oxide is presented. This activated dienophile, available in both racemic and enantiopure forms, undergoes smooth [4+2] cycloadditions with acyclic and cyclic dienes, affording products with excellent yields [...] Read more.

A stereoselective and scalable strategy for the synthesis of phosphorus-containing bicyclic and tricyclic compounds from 1-phenylphosphin-2-en-4-one 1-oxide is presented. This activated dienophile, available in both racemic and enantiopure forms, undergoes smooth [4+2] cycloadditions with acyclic and cyclic dienes, affording products with excellent yields and controlled stereochemistry. Notably, the cis/trans-fusion of the cycloadducts (phosphadecalones and phosphahexahydrochrysene) can be selectively controlled by fine-tuning the conditions of microwave-assisted cycloaddition reaction. The influence of temperature, time, and steric effects on cis/trans and endo/exo selectivity was examined in detail. The molecular structure, including the absolute configuration, of eight products has been determined by X-ray crystallography. These analyses further established the endo-selective nature of the cycloaddition, favoring the P=O face of the dienophile. Post-cycloaddition transformations of selected P-stereogenic phosphadecalone, such as isomerization, reduction and deoxygenation, demonstrate the synthetic versatility of the resulting products. Full article

(This article belongs to the Special Issue Synthetic Studies Aimed at Heterocyclic Organic Compounds, 2nd Edition)

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9 pages, 2051 KB

Open AccessArticle

Beyond L-Proline: Investigation into the Catalytic Properties of Other Natural Amino Acids in an Organocatalytic Warfarin Synthesis

by Anna I. Wurz, Arhemy Franco-Gonzalez, Naomi R. Benson, Hope L. Jankowski, Sierra N. Carr, Ketan Chamakura, Lizbeth Chirinos, Sydney P. Coll, Kayla F. Ivory, Trinity J. Lamb, Shaya LeBauer, Grace L. McPherson, Thanh Nguyen, Jeimy Nolasco Guevara, Lily N. Parsad, Phuong Pham, Emma G. Piner, Kaci Richardson, Abdelhadi Bendjellal, Chelsea McRae and Robert M. Hughes Show full author list Hide full author list

Chemistry 2025, 7(2), 59; https://doi.org/10.3390/chemistry7020059 - 4 Apr 2025

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Abstract

Proline is considered the model organocatalytic amino acid. However, other naturally occurring amino acids remain a potent and perhaps overlooked source of organocatalytic potential. In this work, we investigated the capacity of various natural amino acids to promote enantioselectivity in a synthesis of [...] Read more.

Proline is considered the model organocatalytic amino acid. However, other naturally occurring amino acids remain a potent and perhaps overlooked source of organocatalytic potential. In this work, we investigated the capacity of various natural amino acids to promote enantioselectivity in a synthesis of warfarin. We have identified L- and d-arginine as enantioselective catalysts for this reaction and have developed a recrystallization method to isolate the enantiomers of warfarin with high enantiopurity. In addition, we used methylated derivatives of arginine to provide insight into the reaction mechanism. Full article

(This article belongs to the Topic Towards the Sustainable Synthesis of Biologically Active Molecules in Green Solvents)

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12 pages, 2563 KB

Open AccessFeature PaperArticle

Study on the Immobilization of a Transaminase Biocatalyst for the Synthesis of Sitagliptin

by Chiara Rosati, Oreste Piccolo and Antonella Petri

Catalysts 2025, 15(4), 326; https://doi.org/10.3390/catal15040326 - 28 Mar 2025

Cited by 1 | Viewed by 1992

Abstract

Sitagliptin, an important anti-diabetic drug, can be obtained using transaminase (TA) enzymes, which are known to be promising biocatalysts for the production of highly enantiopure amines under mild reaction conditions. In an industrial context, the use of immobilized enzymes can provide several advantages, [...] Read more.

Sitagliptin, an important anti-diabetic drug, can be obtained using transaminase (TA) enzymes, which are known to be promising biocatalysts for the production of highly enantiopure amines under mild reaction conditions. In an industrial context, the use of immobilized enzymes can provide several advantages, such as the improved stability of the biocatalyst and easy product recovery. In this study, a new commercially available transaminase enzyme to produce sitagliptin was immobilized on inorganic and organic supports using two different approaches: adsorption and covalent bond formation. Among the inorganic media, non-functionalized silica gel was chosen for its stability and competitive cost. A range of commercially available resins with different functionalities have also been selected for their characteristics that can meet industrial standards. The immobilized biocatalysts were first tested in the transamination of acetophenone as a model substrate, which obtains, in most cases, higher conversions with respect to soluble enzymes. The best results in the enantioselective synthesis of sitagliptin were achieved with the sample immobilized on the epoxy- and octadecyl-functionalized methacrylic resin, which allowed the complete conversion of the corresponding ketone and high enantioselectivity (>99% ee). Moreover, the recycling of the supported enzyme could be performed in a continuous flow system without loss of activity for five consecutive runs. Full article

(This article belongs to the Special Issue Recent Advances in Biocatalysis and Enzyme Engineering)

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13 pages, 1345 KB

Open AccessArticle

trans-α-Necrodyl Acetate: Minor Sex Pheromone Component of the Invasive Mealybug Delottococcus aberiae (De Lotto)

by Javier Marzo Bargues, Sandra Vacas, Ismael Navarro Fuertes, Daniel López-Puertollano, Jaime Primo, Antonio Abad-Somovilla and Vicente Navarro-Llopis

Insects 2025, 16(3), 318; https://doi.org/10.3390/insects16030318 - 19 Mar 2025

Viewed by 680

Abstract

Reported in Europe in the early 2000s, Delottococcus aberiae (De Lotto) (Hemiptera: Pseudococcidae) is an invasive mealybug pest that is causing severe damage to citrus production in eastern Spain. Once its main sex pheromone component was identified in a previous work as (4,5,5-trimethyl-3-methylenecyclopent-1-en-1-yl)methyl [...] Read more.

Reported in Europe in the early 2000s, Delottococcus aberiae (De Lotto) (Hemiptera: Pseudococcidae) is an invasive mealybug pest that is causing severe damage to citrus production in eastern Spain. Once its main sex pheromone component was identified in a previous work as (4,5,5-trimethyl-3-methylenecyclopent-1-en-1-yl)methyl acetate 1, the revision of virgin female effluvia is here reported to improve knowledge about the biology of D. aberiae. A new minor component has been identified in the volatile samples collected from virgin females as ((1R, 4R)-3,4,5,5-tetramethylcyclopent-2-en-1-yl)methyl acetate (trans-α-necrodyl acetate, (1R, 4R)-2), a compound also found in the essential oil of Lavandula stoechas subsp. luisieri. Bioassay testing of the activity of this compound showed that a synthetic sample of the racemate (±)-(trans)-2 was attractive to D. aberiae males both in the laboratory and field but with a lower attractant power than enantiopure (1R, 4R)-2 and (±)-(1). The 1:1 mixture of (1R, 4R)-2 and (±)-1 provided a slight additive effect. Further trials are needed to know the pest control potential of this minor compound but the possibility of obtaining this substance from a natural source could pose an important advantage to implement new methods for the sustainable control of D. aberiae. Full article

(This article belongs to the Special Issue Inter- and Intra-specific Interactions by Semiochemicals in Arthropods)

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17 pages, 8345 KB

Open AccessReview

Harnessing Alcohol Dehydrogenases in Organic Reaction Cascades: A Strategy for Enhanced Efficiency in Synthetic Organic Chemistry

by Heba Abuzenah, Muhammad Abdulrasheed, Auwal Eshi Sardauna, Bayan Al-Qataisheh and Musa M. Musa

Catalysts 2025, 15(3), 223; https://doi.org/10.3390/catal15030223 - 27 Feb 2025

Cited by 1 | Viewed by 1385

Abstract

Alcohol dehydrogenases (ADHs) are versatile enzymes that enable the reversible reduction of aldehydes and ketones to their corresponding alcohols. The exceptional chemo-, regio-, and stereoselectivity of ADHs position them as attractive catalysts for generating enantiopure alcohols, whether through deracemization of racemates or asymmetric [...] Read more.

Alcohol dehydrogenases (ADHs) are versatile enzymes that enable the reversible reduction of aldehydes and ketones to their corresponding alcohols. The exceptional chemo-, regio-, and stereoselectivity of ADHs position them as attractive catalysts for generating enantiopure alcohols, whether through deracemization of racemates or asymmetric reduction of prochiral ketones. The emergence of robust ADHs capable of functioning effectively at elevated temperatures and in high concentrations of non-aqueous media has stimulated interest in integrating ADH-catalyzed asymmetric transformations with other chemical processes in a single pot, either in a stepwise mode or simultaneously. This review presents an overview of one-pot organic transformations that combine ADH-catalyzed asymmetric reductions with additional nonenzymatic chemical reactions, demonstrating the potential for enhanced efficiency and sustainability in synthetic organic chemistry. Full article

(This article belongs to the Special Issue Enzyme Catalysis and Enzyme Engineering)

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14 pages, 4067 KB

Open AccessArticle

Spherical Amides with C₃ Symmetry: Improved Synthetic Approach and Structural/Optical Analysis

by Daiki Koike, Hyuma Masu, Haruka Uno, Shoko Kikkawa, Hidemasa Hikawa and Isao Azumaya

Molecules 2025, 30(5), 1074; https://doi.org/10.3390/molecules30051074 - 26 Feb 2025

Viewed by 713

Abstract

A spherical amide with C₃ symmetry was synthesized by a one-step cyclization reaction using triphenylphosphine and hexachloroethane as coupling reagents. This method enabled synthesis of N-benzyl and N-allyl derivatives, which could not be obtained by the previously reported method. The [...] Read more.

A spherical amide with C₃ symmetry was synthesized by a one-step cyclization reaction using triphenylphosphine and hexachloroethane as coupling reagents. This method enabled synthesis of N-benzyl and N-allyl derivatives, which could not be obtained by the previously reported method. The optical resolution of each compound was measured, and their electronic circular dichroism spectra revealed that they were mirror images. The high structural symmetry resulted in a higher Δε (molar absorption difference against right or left circular polarization: ε_L − ε_R value compared to that of another structural isomer synthesized previously. The absolute structure of the enantiopure crystal of the N-benzyl derivative was determined using the Flack parameter obtained by X-ray crystallographic analysis. Full article

(This article belongs to the Section Organic Chemistry)

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23 pages, 970 KB

Open AccessArticle

Synthesis of Enantiostructured Triacylglycerol Prodrugs Constituting an Active Drug Located at Terminal sn-1 and sn-3 Positions of the Glycerol Backbone

by Lena Rós Jónsdottir and Gudmundur G. Haraldsson

Molecules 2025, 30(5), 991; https://doi.org/10.3390/molecules30050991 - 21 Feb 2025

Viewed by 751

Abstract

The current paper reports the asymmetric synthesis of a focused library of enantiostructured triacylglycerols (TAGs) constituting a potent drug of the NSAID type (ibuprofen or naproxen) along with a pure bioactive n-3 polyunsaturated fatty acid (PUFA) intended as a novel type of prodrug. [...] Read more.

The current paper reports the asymmetric synthesis of a focused library of enantiostructured triacylglycerols (TAGs) constituting a potent drug of the NSAID type (ibuprofen or naproxen) along with a pure bioactive n-3 polyunsaturated fatty acid (PUFA) intended as a novel type of prodrug. In this second category, a TAG prodrug of the terminal sn-1 or sn-3 position of the glycerol skeleton is acylated with a single saturated medium-chain fatty acid (C6, C8, C10, or C12), and another with the drug entity; the PUFA (EPA or DHA) is located in the sn-2 position. This was accomplished by a six-step chemoenzymatic approach, two of which were promoted by a lipase, starting from enantiopure (R)- and (S)-solketals. The highly regioselective immobilized Candida antarctica lipase (CAL-B) played a crucial role in the regiocontrol of the synthesis. The most challenging key step involved the incorporation of the drugs that were activated as oxime esters by the lipase exclusively in the terminal position of glycerol that is protected as a benzyl ether. All combinations, a total of 32 such prodrug TAGs, were prepared, isolated, and fully characterized, along with 24 acylglycerol intermediates, obtained in very-high-to-excellent yields in the majority of cases. Full article

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