Γ-butyrolactone Derivatives Research Articles

Structural Simplification of Podophyllotoxin: Discovery of γ-Butyrolactone Derivatives as Novel Antiviral Agents for Plant Protection.

Natural products are a valuable resource for the discovery of novel crop protection agents. A series of γ-butyrolactone derivatives, derived from the simplification of podophyllotoxin's structure, were synthesized and assessed for their efficacy against tobacco mosaic virus (TMV). Several derivatives exhibited notable antiviral properties, with compound 3g demonstrating the most potent in vivo anti-TMV activity. At 500 μg/mL, compound 3g achieved an inactivation effect of 87.8%, a protective effect of 71.7%, and a curative effect of 67.7%, surpassing the effectiveness of the commercial plant virucides ningnanmycin and ribavirin. Notably, the syn-diastereomer (syn-3g) exhibited superior antiviral activity compared to the anti-diastereomer (anti-3g). Mechanistic studies revealed that syn-3g could bind to the TMV coat protein and interfere with the self-assembly process of TMV particles. These findings indicate that compound 3g, with its simple chemical structure, could be a potential candidate for the development of novel antiviral agents for crop protection.

γ-Butyrolactone Derivatives of MSA-2 are STING Prodrugs.

STING agonists are potent enhancers of a pro-inflammatory response and, thus, potentially useful therapeutics. Unfortunately, many agonists developed to date require complex drug delivery formulations and often have poor water solubility, limiting their use for systemic administration. Here, we report the discovery and chemical characterization of lactones of MSA-2 as new STING prodrugs with enhanced properties. We show that these prodrugs form efficient inclusion complexes with tumor myeloid cell targeting cyclodextrin nanoparticles and propose a new mechanism of formation and hydrolysis.

Undescribed polyketides from endophytes associated with the critically endangered conifer Abies beshanzuensis

Four undescribed polyketides, beshanzones A (1) and B (2) as well as beshanhexanols A (3) and B (4), along with three known ones (5–7) were isolated from the rice fermentation of two endophytic fungi associated with the critically endangered Chinese endemic conifer Abies beshanzuensis. γ-Butyrolactone derivatives 1, 2, and 5 were isolated from Phomopsis sp. BSZ-AZ-2, an interesting strain that drawn our attention this time. The cyclohexanol derivatives 3, 4, 6, and 7 were obtained during a follow-up investigation on Penicillium commune BSZ-P-4-1. The chemical structures including absolute configurations of compounds 1–4 were determined by spectroscopic methods, Mo2(OAc)4 induced electronic circular dichroism (IECD), GIAO NMR calculations and DP4+ probability analyses. In particular, compound 2 contains a novel 5/5 bicyclic ring system, which might be biogenetically derived from the known compound 5 through hydrolysis followed by an Aldol reaction. All isolates were evaluated for their antimicrobial activities against a small panel of bacterial and fungal pathogens. Compounds 6 and 7 showed moderate inhibitory activities against Candida albicans, with MIC values of 16 and 32 μg/mL, respectively.

Palladium-Catalyzed Dehydrogenative Carbonylative Esterification of Allenoic Acids for the Synthesis of γ-Butyrolactone Derivatives.

A highly efficient dehydrogenative carbonylative esterification of allenoic acids using Pd-catalysis was developed, providing a novel approach to synthesizing esterified γ-butyrolactone derivatives with consistently good to excellent results demonstrated across over 50 examples. Additionally, we used a heterogeneous catalyst known as Pd-AmP-MCF and harnessed biomimetic-aerobic-oxidation conditions to facilitate the practical execution of this reaction. Furthermore, our detailed study of γ-butyrolactone products highlighted their potential in synthesizing bioactive compounds.

Asymmetric Retro-Claisen Reaction Catalyzed by Chiral Aza-Bisoxazoline–Zn(II) Complex: Enantioselective Synthesis of α-Arylated Ketones

An asymmetric retro-Claisen reaction of α-monosubstituted β-diketones and quinones (or quinone imine) has been developed under the catalysis of a chiral aza-bisoxazoline-Zn(II) complex. The reaction proceeds via a sequence of conjugate addition, arylation, hemiketal anion-initiated C-C bond cleavage, and enantioselective protonation of enolate to provide various functionalized α-arylated ketones bearing a tertiary stereogenic center with high enantioselectivities. Notably, biologically important benzofuran and γ-butyrolactone derivatives could be synthesized by application of the developed protocol.

Diaportones A-C: Three New Metabolites From Endophytic Fungus Diaporthe foeniculina BZM-15.

Phytochemical investigation of Diaporthe foeniculina BZM-15 led to one new γ-butyrolactone derivative, diaportone A (1), one cyclopentenone derivative, diaportone B (3), and one monoterpene derivative, diaportone C (5), along with six known compounds (2, 4, and 6–9). Their structures as well as the absolute configurations were characterized by means of NMR, HRESIMS, and ECD spectroscopy and quantum chemistry calculation, respectively. Furthermore, all compounds were evaluated for their cytotoxic activity and antibacterial activity, and compounds 7 and 8 displayed significant antiproliferative effects on three human cancer cell lines (SF-268, MCF-7, and HepG2) with IC50 values ranging from 3.6 to 15.8 μM.

Microwave Radiation Applied to the Synthesis of -butyrolactone Derivatives

Many natural products with a broad spectrum of biological effects bear the g-butyrolactone ring. Given the difficulty in isolating large amounts of butyrolactones from natural sources, interest in synthesizing structural analogs of these compounds and in studying their biological properties has increased. In this review, we summarize the main synthetic methodologies to construct γ-butyrolactone derivatives by using multicomponent processes. DOI: http://dx.doi.org/10.17807/orbital.v13i4.1657

Advances, Challenges, and Opportunities of Poly(γ-butyrolactone)-Based Recyclable Polymers

The discovery and prosperous growth of synthetic polymers have presented both significant advantages and daunting challenges in the last century. To address the issues of environmental pollution and fossil consumption, recyclable, degradable, and/or biobased polymers have been given much attention in the polymer science community. This viewpoint focuses on the emerging fully chemical recyclable poly(γ-butyrolactone)-based polymers. The breakthrough from nonpolymerizable to efficient polymerization is highlighted by the benefits of the development of a series of catalysis for ring-opening polymerization of γ-butyrolactone. Subsequently, the design of γ-butyrolactone derivatives and synthesis of more recyclable polymers are summarized together with the discussions about the structure and property relationship. Finally, the remaining challenges and promising opportunities are suggested in order to provide insights into the further direction for sustainable polymers.

γ- and δ-lactones as fumarate esters analogues and their neuroprotective effects

The γ-butyrolactone and δ-valerolactone structural units are present in different natural products with significant pharmacological properties. Fumaric acid ester-based drugs are used for the treatment of psoriasis and, more recently, multiple sclerosis. We synthesized different γ-butyrolactone and δ-valerolactone derivatives where the fumarate moiety is forced into a lactone ring in search of strategies to maintain the anti-inflammatory activity of fumaric acid esters limiting the side effects and enhancing the bioavailability. The structures of all synthesized compounds obtained were identified on the basis of their spectral data. The toxicity profile as well as the neuroprotective properties of the synthesized derivatives were evaluated in human neuroblastoma SH-SY5Y cell line. All tested fumaric esters presented lower cytotoxicity and higher neuroprotective properties, in comparison to dimethyl fumarate. Pre-treatment of cells with at least seven compounds for 24 h lead to a significantly neuroprotection against H2O2-induced cell damage. Our results demonstrate that SH-SY5Y cells are suitable cellular model to evaluate the neuroprotective role of fumaric acid esters, and support further evaluation of BG-12 derivatives aimed at decreasing cytotoxicity and limiting the side effects for improvement of treatments for multiple sclerosis and psoriasis.

Chemical constituents from ethyl acetate soluble extraction of Litsea cubeba

Chemical investigation on the constituents of the ethyl acetate soluble extraction of Litsea cubeba has resulted in the isolation and structure elucidation of thirty compounds, including one sesquiterpene(1), four monoterpenes(2-5), two γ-butyrolactone derivatives(6 and 7), seven tyramine derivatives(8-14), fifteen aromatic compounds(15-29), and one pyrone derivative(30) via various chromatographic techniques and spectroscopic data analysis(MS, IR, 1 D and 2 D NMR). Compounds 1-7, 13 and 14 were obtained from the genus Litsea for the first time.

Poly(4-hydroxybutyric acid) derivatives with rapid self-degradation <italic>via</italic> intramolecular cyclization under physiological conditions

Biodegradable aliphatic polyesters have been widely used in biomedical fields owing to their good biocompatibility. One big challenge is to precisely modulate their degradation rate and degradation products under physiological conditions. In this work, we designed and synthesized two types of poly(4-hydroxybutyric acid) derivatives that can quickly depolymerize via intramolecular cyclization into corresponding γ-butyrolactone derivatives under physiological conditions. The polymers were synthesized by the Passerini multicomponent polymerization of OEG-NC and ethyl ( E )-4-oxo-but-2-enoate, followed by hydrogenation. Nuclear magnetic resonance (NMR) and gel permeation chromatography (GPC) were used to follow the degradation of these polyesters under physiological conditions (pD 7.4 buffer solution, 37 °C). It was demonstrated that the molar mass of the polyester gradually decreased with time together with the increase of the amount of corresponding γ-butyrolactone derivatives as the only degradation product. After 1 d, 85% of the polyester was degraded. When the pH of the buffer was decreased to 6.8 or a mixture of buffer and acetone was used as the degradation media, the degradation was slowed down, but γ-butyrolactone derivatives are still the only degradation products, implying that increase of the medium polarity and pH can accelerate the degradation. Three small model molecules that mimic the polymer repeating unit, end group, and degradation product were synthesized and their hydrolysis were investigated under identical conditions. Based on these results, we confirm that under physiological conditions, no random degradation via hydrolysis of the polyester backbone occurred. The degradation mechanism was thus elucidated. The first step is the fast head-to-tail depolymerization of the polyester via intramolecular cyclization, forming γ-butyrolactone derivatives as the only products. Then, slow hydrolysis of γ-butyrolactone derivatives into 4-hydroxy butyrate occurred. This type of polyester is the first reported depolymerizable polyester with simple structure under physiological conditions. Our current efforts are end-capping these polymers with various stimuli-responsive functional groups to develop new self-immolative polymers that can be used in biomedical fields as drug carriers.

Antibacterial and NF-κB Inhibitory Lumazine Peptides, Aspochalasin, γ-Butyrolactone Derivatives, and Cyclic Peptides from a Hawaiian Aspergillus flavipes.

Five new lumazine peptides (1-5), a new aspochalasin derivative (6), and a new γ-butyrolactone derivative (7), together with seven known compounds (8-14), were isolated from a Hawaiian fungal strain, Aspergillus flavipes FS888. Compound 1 is an uncommon natural product containing an isocyano group. The structures of the new compounds 1-7 were elucidated by NMR spectroscopy, HRESIMS, chemical derivatization, and ECD analysis. Compounds 12-14 showed significant antibacterial activity against S. aureus when in combination with disulfiram. Additionally, compounds 9 and 13 showed NF-κB inhibitory activity with IC50 values of 3.1 ± 1.0 and 10.3 ± 2.0 μM, respectively.

Stereoconvergent Conjugate Addition of Arylboronic Acids to α-Angelica Lactone Derivatives: Synthesis of Stereochemically Complex γ-Butyrolactones.

Catalyzed stereoconvergent 1,4-additions to unsaturated carbonyls are rare but of high potential value. This letter details the development of enantioselective arylation reactions of boronic acids and β,γ-butenolides. These reactions are catalyzed by commercially available hydroxy[(S)-BINAP]-rhodium(I) dimer to afford stereochemically complex γ-butyrolactone derivatives. The reaction products provide functionality amenable to further manipulation and can lead to products with up to three contiguous stereocenters. The reaction proceeds under a dynamic kinetic resolution manifold by isomerizing the achiral starting material into an interconverting mixture of enantiomeric conjugate acceptors, followed by catalyst-controlled, enantiomer-selective 1,4-addition. Base-promoted racemization of the intermediate α,β-butenolide is possible due to the high kinetic and thermodynamic acidity of the γ-proton.

Colletolides A and B, two new γ-butyrolactone derivatives from the endophytic fungus Colletotrichum gloeosporioides

Two new γ-butyrolactone derivatives, colletolides A and B (1 and 2), together with three known compounds, sclerone (3), 3-methyleneisoindolinon (4) and indole-3-acetamide (5), were isolated from the culture of the endophytic fungus Colletotrichum gloeosporioides B12, which resides in the medicinal plant Illigera rhodantha Hance. Their structures were characterized by a combination of HR-ESI-MS, NMR and ECD spectra. Compounds 1 and 2 showed moderate antibacterial activity against Xanthomonas oryzae pv. oryzae, X. oryzae pv. oryzicola and Ralstonia solanacearum with the same MIC values of 128 μg/mL.

Asymmetric one-pot synthesis of five- and six-membered lactones via dynamic covalent kinetic resolution: Exploring the regio- and stereoselectivities of lipase

Cascade lipase-catalyzed lactonization has been applied to dynamic hemithioacetal formation, leading to efficient five- and six-membered lactone synthesis as well as chiral discrimination. Solvent-dependent regioselectivity was observed for the selective formation of 1,3-oxathiolan-5-one and γ-butyrolactone derivatives.

Dynamic kinetic resolution of bis-aryl succinic anhydrides: enantioselective synthesis of densely functionalised γ-butyrolactones.

The efficient Dynamic Kinetic Resolution (DKR) of disubstituted anhydrides has been shown to be possible for the first time. Using an ad hoc designed organocatalyst and an enantio- and diastereoselective cycloaddition process with aldehydes, stereochemically complex γ-butyrolactone derivatives can be obtained - with control over three contiguous stereocentres, one of which is all carbon quaternary.

Iridium-Catalyzed Enantioselective Allylic Substitution of Aliphatic Esters with Silyl Ketene Acetals as the Ester Enolates.

Enantioselective allylic substitution with enolates derived from aliphatic esters under mild conditions remains challenging. Herein we report iridium-catalyzed enantioselective allylation reactions of silyl ketene acetals, the silicon enolates of esters, to form products containing a quaternary carbon atom at the nucleophile moiety and a tertiary carbon atom at the electrophile moiety. Under relatively neutral conditions, the allylated aliphatic esters were obtained with excellent regioselectivity and enantioselectivity. These products were readily converted into primary alcohols, carboxylic acids, amides, isocyanates, and carbamates, as well as tetrahydrofuran and γ-butyrolactone derivatives, without erosion of enantiomeric purity.

Ring-opening polymerization of y-butyrolactone and its derivatives: A review

γ-Butyrolactone (γ-BL) derivatives are reviewed from the point of view of their ability to form polymers by ring-opening polymerization. The thermodynamic limitations for polymerization of γ-BL are discussed. Polymerizability of naturally available unsaturated and synthetic functional γ-BL derivatives enabling postfunctionalization of final polyesters is presented. Homopolymerization of γ-BL derivatives with significant effect of the substituent on the γ-BL ring strain is shown.

Synthesis of bicyclic γ-butyrolactone derivatives by rhodium catalyzed intramolecular C–H insertion of α-dizao α-phosphoryl cycloalkyl esters

Under the catalysis of Rh2(OAc)4, several readily prepared cycloalkyl α-diazo α-phosphoryl esters undergo a intramolecular C–H insertion reaction to afford the fused bicyclic α-phosphoryl-γ-butyrolactones in varying yields (10%–80%) and dr ratios (69:14:17 to >99:1). The experimental results reveal that the reactivity of the precursors and the diastereoselectivity of the cyclization are both influenced by the ring sizes of the cycloalkyl moieties. Moreover, most of the resulting products can be further elaborated into α,α-dialkyl γ-butyrolactones via a two-step alkylation/reductive alkylation sequence with the controlled installation of two alkyl groups to the lactones. In addition, application of Horner–Wadsworth–Emmons (HWE) olefination reaction to the insertion products allows an access to bicyclic α-alkylidene-γ-butyrolactone ring systems that occur ubiquitously in biologically active natural products and synthetic molecules.

Baeyer–Villiger monooxygenase-catalyzed desymmetrizations of cyclobutanones. Application to the synthesis of valuable spirolactones

A series of γ-butyrolactone derivatives, including some spiranic ones, was obtained through desymmetrization of the corresponding prochiral 3-substituted cyclobutanones via Baeyer–Villiger monooxygenase (BVMO)-catalyzed oxidation. After reaction optimization using several commercial enzymes, both antipodes of various lactones were synthesized in most cases with >90% conversion and >80% enantiomeric excess under mild reaction conditions. In some cases alcohol formation was also observed (up to 40% conversion) as an undesired side reaction due to the presence of alcohol dehydrogenases in these preparations. Selected transformations were achieved on a 100 mg scale showing the possibilities of these oxidative biocatalysts as a new source of highly interesting compounds.