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Lactone

A lactone is a cyclic ester derived from the intramolecular reaction of a hydroxy carboxylic acid, where the hydroxyl group reacts with the carboxylic acid group to form a ring containing the ester linkage, eliminating water in the process.^[1] These compounds are characterized by their ring structure, in which the ester functional group is integrated into the cycle, typically involving 4 to over 20 atoms, though smaller rings like β-lactones (four-membered) are less stable and larger macrolactones are common in natural products.^[2] Lactones exhibit diverse physical properties, including low volatility and characteristic odors, and are named according to the position of the hydroxy group relative to the carboxylic acid, such as γ-lactones for five-membered rings and δ-lactones for six-membered rings, which are the most prevalent due to favorable ring strain and stability.^[3] Lactones occur widely in nature, contributing to the flavors and aromas of fruits, dairy products, and essential oils, where they impart fruity, coconut-like, or peachy notes through their volatile structures.^[4] In biology, many natural lactones, such as sesquiterpene lactones and macrocyclic variants, exhibit potent bioactivities including antibacterial, antiviral, anti-inflammatory, antifungal, and antitumor effects, often serving as plant defense compounds or prodrugs in pharmaceuticals like statins, which are lactone forms that hydrolyze to active hydroxy acids in vivo.^[5] Synthetic lactones, meanwhile, play key roles in polymer chemistry; for instance, ε-caprolactone undergoes ring-opening polymerization to produce polycaprolactone, a biodegradable polyester used in tissue engineering, drug delivery systems, and medical implants due to its biocompatibility and mechanical properties.^[6] Beyond these applications, lactones are valuable synthetic intermediates in organic chemistry, enabling the construction of complex molecules through hydrolysis, reduction, or ring-opening reactions, and their thermodynamic properties—such as enthalpies of formation and hydrolysis—have been extensively studied to understand strain energies in rings from C4 to C13.^[7] Commercially, they find use in fragrances, food additives, and agrochemicals, underscoring their versatility across industries while highlighting the need for careful handling of certain types due to potential skin sensitization or phototoxicity.^[8]

Fundamentals

Structure and Properties

Lactones are cyclic esters formed by the intramolecular esterification of hydroxycarboxylic acids, where the hydroxyl group reacts with the carboxylic acid group to eliminate water and form a closed ring structure.^[9] This cyclization typically occurs when the hydroxy and carboxy groups are positioned to form rings of 3 to 7 members, with the general connectivity involving an ester linkage (-O-C(=O)-) integrated into the cyclic framework.^[4] The molecular structure of lactones varies by ring size, influencing their stability and reactivity. For instance, γ-lactones, which feature a five-membered ring, have the general formula represented as a cycle with the sequence -O-C(=O)-CH_2-CH_2-CH_2-, where the oxygen bridges the carbonyl carbon and the γ-carbon.^[10] Ring strain plays a critical role: α-lactones (3-membered rings) and β-lactones (4-membered rings) exhibit high strain energies, approximately 85-87 kJ/mol greater for α- than β-lactones and around 22.8 kcal/mol for β-lactones, rendering them reactive transients rarely isolated under standard conditions.^[11]^[12] In contrast, γ-lactones (5-membered) and δ-lactones (6-membered) possess lower ring strain, making them thermodynamically stable and common in natural and synthetic contexts.^[4] Physically, lactones are typically colorless liquids or solids with boiling points elevated relative to analogous acyclic esters due to their cyclic nature; for example, γ-butyrolactone (a γ-lactone) boils at 204°C and is miscible with water and most organic solvents.^[13] Similarly, δ-valerolactone (a δ-lactone) exhibits a boiling point of 230 °C and good solubility in polar solvents.^[14] In infrared (IR) spectroscopy, the carbonyl (C=O) stretching frequency serves as a diagnostic feature, appearing at higher wavenumbers for smaller rings due to strain-induced s-character increase in the carbonyl carbon: approximately 1730-1750 cm⁻¹ for δ-lactones and up to 1770 cm⁻¹ for γ-lactones.^[15] Chemically, lactones display hydrolytic sensitivity that correlates inversely with ring size and directly with strain; smaller α- and β-lactones undergo rapid hydrolysis under mild conditions due to the energetic favorability of strain relief, while γ- and δ-lactones require harsher acidic or basic environments for ring opening.^[16] This reactivity stems from the strained ester bond, which facilitates nucleophilic attack at the carbonyl carbon, ultimately yielding the parent hydroxycarboxylic acid.^[17]

Classification and Nomenclature

Lactones are classified primarily according to the size of the cyclic ester ring formed by intramolecular esterification of hydroxy carboxylic acids. The most common classification uses Greek letter prefixes to denote the position of the hydroxyl group relative to the carboxylic acid in the parent chain, which corresponds to specific ring sizes: α-lactones feature a three-membered ring, β-lactones a four-membered ring, γ-lactones a five-membered ring, δ-lactones a six-membered ring, and ε-lactones a seven-membered ring. Larger rings, typically those with more than twelve members, are designated as macrolactones and are often found in complex natural products. For smaller lactones, the Greek prefix system (α-, β-, γ-, etc.) remains widely used in both common and systematic nomenclature to indicate ring size and strain characteristics. In contrast, larger lactones are generally named using heterocyclic nomenclature, treating the ring as a substituted oxacycloalkane with the ester functionality incorporated. According to IUPAC recommendations, preferred names for lactones are derived by naming them as heterocyclic compounds with a carbonyl group, using suffixes such as "-one" for the lactone moiety. For example, γ-butyrolactone is systematically named oxolan-2-one, reflecting its five-membered ring with oxygen at position 1 and the carbonyl at position 2.^[18] This substitutive nomenclature prioritizes the heterocyclic parent structure and is applicable to both saturated and unsaturated variants.^[18] The term "lactone" was coined in 1844 by French chemist Théophile-Jules Pelouze, derived from "lactic acid" combined with the suffix "-one" to describe the cyclic ester obtained from its dehydration.^[6] In 1880, German chemist Wilhelm Rudolf Fittig broadened the term to encompass all cyclic esters of hydroxy acids, formalizing its general application.^[6] Lactones were first recognized as a distinct class of compounds in the early 19th century through isolation from natural products, such as coumarin from tonka beans in 1820, which exemplified the δ-lactone structure fused to a benzene ring.^[19] This period marked the initial structural elucidation of cyclic esters amid broader advances in organic chemistry from plant-derived substances.^[19]

Occurrence and Biological Significance

Natural Sources

Lactones are ubiquitous in nature, occurring across various organisms and contributing to diverse ecological and sensory roles. In plants, particularly those in the Asteraceae family, sesquiterpene lactones represent a major class of secondary metabolites, with over 5,000 distinct structures identified. These compounds are biosynthesized from farnesyl pyrophosphate and feature a characteristic α-methylene-γ-lactone moiety. A prominent example is artemisinin, a sesquiterpene lactone isolated from the leaves of sweet wormwood (Artemisia annua), used traditionally in herbal medicine.^[20]^[21]^[22] In animals and microorganisms, lactones appear in bioactive compounds essential for defense and metabolism. Macrolide antibiotics, such as erythromycin produced by the soil bacterium Saccharopolyspora erythraea, contain a large 14-membered macrocyclic lactone ring attached to deoxy sugars, enabling their antibacterial properties. Similarly, glucono-δ-lactone, a six-membered lactone derived from glucose oxidation, is naturally produced by fungi like Aspergillus niger through enzymatic fermentation and occurs in trace amounts in honey, fruit juices, and wine.^[23]^[24] Lactones also impart characteristic flavors to food and beverages, enhancing sensory appeal. For instance, γ-decalactone, a five-membered lactone, is a key aroma compound in peaches and strawberries, contributing peachy and fruity notes at concentrations up to several parts per million. In dairy products, δ-decalactone, its six-membered isomer, provides a creamy, coconut-like flavor to butter, where it forms via β-oxidation of hydroxy fatty acids during processing.^[25]^[26]^[27] Beyond these, lactones feature in other natural products with unique functions. Ascorbic acid (vitamin C), found in citrus fruits and leafy greens, is a furanoid lactone essential for human nutrition, biosynthesized in plants and most animals via the conversion of L-galactono-1,4-lactone. Nepetalactone, a bicyclic monoterpene lactone comprising up to 99% of catnip (Nepeta cataria) essential oil, acts as an insect repellent and feline attractant.^[28] The biosynthesis of lactones in secondary metabolism typically involves enzymatic lactonization, where hydroxyl groups react with carboxylic acids under catalysis by lipoxygenases, cytochrome P450s, or Baeyer-Villiger monooxygenases to form cyclic esters. This process, often part of terpenoid or polyketide pathways, enables the structural diversity observed in natural lactones.^[29]^[21]

Biological Roles

Lactones play diverse roles in plant defense mechanisms, particularly sesquiterpene lactones, which serve as allelochemicals to deter herbivores and pathogens. These compounds, prevalent in the Asteraceae family, exhibit potent anti-herbivory activity by disrupting insect development, reproduction, and feeding behavior, thereby enhancing plant survival in herbivore-rich environments.^[30] For instance, sesquiterpene lactones like costunolide and parthenolide inhibit microbial growth by alkylating sulfhydryl groups in enzymes and disrupting pathogen cell walls, contributing to allelopathic effects that suppress competing plants and invading microbes.^[31] This defensive function is evolutionarily significant, as evidenced by the stereochemical variations in lactone ring junctions that modulate resistance levels against specific herbivores.^[32] In microbial interactions, γ- and δ-lactones demonstrate broad antimicrobial activity, primarily by disrupting bacterial cell membranes and inhibiting essential biosynthetic pathways. These smaller ring lactones interact with phospholipids in the membrane, increasing permeability and leading to leakage of cellular contents, which compromises bacterial viability.^[33] A notable example is patulin, a γ-lactone mycotoxin produced by Penicillium species, which exhibits antibacterial properties against Gram-positive and Gram-negative bacteria, historically utilized in the 1960s for treating infections due to its ability to inhibit microbial proliferation.^[34] Such activities highlight lactones' ecological role in fungal-bacterial competition within natural environments. Sesquiterpene lactones also mediate anti-inflammatory and cytotoxic effects in biological systems through targeted inhibition of the NF-κB signaling pathway, a key regulator of immune responses. Compounds like helenalin directly alkylate the p65 subunit of NF-κB via Michael addition at the α-methylene-γ-lactone moiety, preventing DNA binding and transcriptional activation without affecting IκB degradation or nuclear translocation.^[35] This selective inhibition reduces pro-inflammatory cytokine production, as demonstrated in various cell types stimulated by TNF-α or other inducers, underscoring the lactones' potential in modulating inflammation. Similarly, parthenolide exhibits comparable NF-κB suppression, contributing to cytotoxic effects against aberrant cells by halting survival signaling.^[36] Beyond defense, lactones function in interspecies signaling, exemplified by nepetalactone, a monoterpene lactone from catnip (Nepeta cataria), which acts as a potent attractant for domestic cats by mimicking feline pheromones and eliciting euphoric behaviors in responsive individuals.^[37] In insects, various lactones serve as pheromones to coordinate social and reproductive activities; for example, unsaturated γ-lactones like buibuilactone function as sex attractants in scarab beetles, while macrocyclic lactones regulate queen-worker interactions in primitively eusocial wasps by suppressing ovarian development in subordinates.^[38]^[39] These signaling roles facilitate chemical communication essential for species-specific behaviors. In human physiology, endogenous lactones arise from fatty acid metabolism, particularly through the lactonization of hydroxy fatty acids during β-oxidation processes. Enzymes such as serum paraoxonase 1 (PON1) catalyze the formation of lactones from substrates like 4-hydroxydocosahexaenoic acid (4-HDoHE), an oxidation product of docosahexaenoic acid, accounting for a significant portion of plasma lactonizing activity under calcium-dependent conditions.^[40] These metabolites influence lipid homeostasis and may modulate inflammatory responses, linking lactone formation to broader metabolic regulation in health and disease.^[41]

Synthesis

Classical Methods

One of the most traditional approaches to lactone synthesis is the acid-catalyzed lactonization of hydroxy acids, where the hydroxyl group intramolecularly attacks the protonated carboxylic acid, leading to dehydration and ring closure. This method, established in the late 19th and early 20th centuries, is particularly favorable for forming γ- and δ-lactones due to the stability of five- and six-membered rings, with reaction rates increasing dramatically for smaller rings compared to larger ones. For instance, γ-hydroxybutyric acid undergoes cyclization in the presence of concentrated sulfuric acid or hydrochloric acid to yield γ-butyrolactone in high yields, often under heating to drive off water. The general reaction can be represented as:

\text{R-CH(OH)-(CH}_2)_n\text{-COOH} \xrightarrow{\text{H}^+} \text{lactone + H}_2\text{O}

where n = 2 for γ-lactones and n = 3 for δ-lactones.^[42]^[43] Halolactonization represents another classical route, involving the electrophilic addition of halogens such as iodine or bromine to unsaturated carboxylic acids, followed by intramolecular nucleophilic attack by the carboxylate to form the lactone ring. First described by Bougault in 1904, this method typically proceeds under mild conditions in aqueous or organic media, providing regioselective access to γ- and δ-halo-lactones with the halogen adding anti to the double bond. A representative example is the iodolactonization of 4-pentenoic acid with iodine in aqueous sodium bicarbonate, yielding 5-iodomethyl-dihydrofuran-2(3H)-one as the γ-lactone product. This approach has been widely employed in natural product synthesis, such as Corey's iodolactonization step in prostaglandin intermediates during the 1960s and 1970s.^[43]^[44] Lactones can also be prepared from diols via oxidation methods or from esters through transesterification. Oxidation of 1,4-diols to γ-lactones, for example, was classically achieved using chromic acid or ruthenium tetroxide, selectively oxidizing the primary alcohol to a carboxylic acid that then cyclizes with the secondary alcohol. A notable pre-1960 method involves the treatment of 1,4-butanediol with chromic acid in sulfuric acid, affording γ-butyrolactone in moderate yields after distillation. Transesterification routes, often base- or acid-catalyzed, enable lactone formation from hydroxy esters by exchange with a lower alcohol, facilitating ring closure under equilibrium conditions; this was commonly used for macrolactones in the mid-20th century, such as the conversion of linear ω-hydroxy esters to large-ring lactones via potassium carbonate in methanol.^[45]^[46] The Baeyer-Villiger oxidation of cyclic ketones to lactones, discovered in 1899, remains a cornerstone classical technique, employing peracids to insert an oxygen atom adjacent to the carbonyl, with migratory aptitude determining regioselectivity (tertiary > secondary > primary alkyl groups). Industrially, this method converts cyclohexanone to ε-caprolactone using peracetic acid or m-chloroperbenzoic acid (mCPBA) in yields exceeding 90%, serving as a key step in nylon-6 production precursors. The reaction's mechanism involves nucleophilic addition of the peracid to the ketone, followed by concerted migration and elimination.^[47]^[48]

Modern Methods

Recent advances in lactone synthesis from 2020 to 2025 have emphasized catalytic strategies that enhance efficiency, selectivity, and sustainability, often building on classical routes by incorporating transition metals, radicals, and biocatalysts to access complex structures with minimal steps. These methods prioritize atom economy and stereocontrol, enabling the preparation of γ-, δ-, and β-lactones with diverse substituents for applications in materials and pharmaceuticals. Transition metal catalysis has seen notable progress in direct C-H functionalization approaches. A palladium-catalyzed tandem β-C(sp³)–H olefination/lactonization strategy enables the one-step synthesis of γ-alkylidene lactones from carboxylic acids and olefins, proceeding via molecular stitching under mild conditions with high regioselectivity and broad substrate scope, including aryl and alkyl variants.^[49] This method achieves yields up to 90% and demonstrates compatibility with functional groups, marking a significant improvement in efficiency over multi-step classical processes. Radical-mediated processes have emerged as powerful tools for carbonylation reactions. In a divergent radical tandem carbonylation of multi-substituted homoallylic alcohols, amines tune the selectivity to favor γ-lactones or 1,4-diones, utilizing visible-light photoredox catalysis with CO as the carbonyl source. The protocol delivers γ-lactones in yields ranging from 60% to 85% across a variety of substrates, including tertiary alcohols, and proceeds via an alkyl radical intermediate for precise control over product divergence.^[50] Enzymatic synthesis offers a biocatalytic alternative with exceptional stereoselectivity. Engineered cytochrome P411 variants, evolved from serine-ligated P450 scaffolds, catalyze intramolecular carbene C-H insertions into benzylic or allylic positions of diazo precursors, assembling diverse lactone rings including five-membered γ-lactones, six-membered δ-lactones, and seven-membered ε-lactones.^[51] For instance, variant P411-LAS-5247 achieves up to 5600 total turnovers and >99% enantiomeric excess for γ-lactones, while further evolved enzymes like P411-LAS-5264 overcome ring strain barriers to form larger rings, extending to fused, bridged, and spiro scaffolds from simple starting materials. Enantioselective organocatalysis has advanced the incorporation of fluorinated motifs. An N-heterocyclic carbene (NHC)-catalyzed δ-lactonization of olefins with cinnamaldehydes, coupled to trifluoromethylation via radical relay cross-coupling using Togni's reagent, generates chiral δ-lactones with β- and γ-stereocenters in moderate to high yields (up to 82%) and enantioselectivities (>95% ee).^[52] Computational analysis reveals hydrogen-bonding in the radical intermediate as key to asymmetric induction, providing a scalable route to fluorinated δ-lactones. For β-lactones, ring-expansion carbonylation (REC) of epoxides has benefited from improved catalyst designs shifting toward heterogeneous systems. Bimetallic catalysts combining Lewis acids with cobaltate anions, such as immobilized [bpy-CTF-Al(OTf)₂]⁺[Co(CO)₄]⁻ on porous polymers, enable selective REC under mild conditions (50°C, 60 bar CO), achieving >99% conversion and 90% selectivity for propylene oxide to β-butyrolactone.^[53] These recyclable systems match homogeneous performance while addressing scalability, as exemplified by Co(CO)₄ in Cr-MIL-101 frameworks yielding site time yields of 34 h⁻¹. The REC process can be represented as:

\text{Epoxide} + \ce{CO} \xrightarrow{\text{catalyst}} \beta\text{-lactone}

This reaction proceeds via nucleophilic attack by cobalt on the epoxide, followed by CO insertion and ring expansion, highlighting the atom-economical nature of modern β-lactone synthesis.

Chemical Reactivity

Ring-Opening Reactions

Ring-opening reactions of lactones primarily involve nucleophilic acyl substitution at the carbonyl group, leading to cleavage of the ester bond and formation of hydroxy acids or related derivatives.^[54] This process is facilitated by the inherent strain in smaller lactone rings, such as β- and γ-lactones, which undergo ring opening more rapidly than larger, less strained rings like δ- or ε-lactones due to relief of angular and torsional strain upon opening. Hydrolysis represents the most common ring-opening pathway, yielding ω-hydroxy carboxylic acids. In base-catalyzed hydrolysis, hydroxide ion acts as a nucleophile, attacking the carbonyl carbon to form a tetrahedral intermediate; subsequent expulsion of the alkoxide ion and proton transfer results in the carboxylate salt of the hydroxy acid.^[55] This mechanism is generally faster than acid-catalyzed hydrolysis for lactones, as the basic conditions enhance nucleophilic attack without protonating the leaving group prematurely.^[55] Acid-catalyzed hydrolysis, conversely, begins with protonation of the carbonyl oxygen, increasing its electrophilicity; water then adds to form a protonated tetrahedral intermediate, followed by proton transfers and elimination of the alcohol leaving group to afford the neutral hydroxy acid.^[16] The general reaction can be represented as:

\text{Lactone} + \ce{H2O} \xrightarrow{\ce{OH- or H+}} \ce{HO-(CH2)_n-COOH}

where n corresponds to the ring size minus two carbons.^[54] Aminolysis involves nucleophilic attack by an amine on the lactone carbonyl, forming a tetrahedral intermediate that collapses to expel the alkoxide and yield an amide with a pendant hydroxyl group.^[56] This reaction is particularly useful in amide bond formation, such as in peptide synthesis, where primary or secondary amines react under mild conditions, often catalyzed by bases like sodium 2-ethylhexanoate to deprotonate the ammonium salt and facilitate nucleophilic addition.^[57] The rate of aminolysis also increases with ring strain, mirroring hydrolysis trends, and proceeds via a similar nucleophilic acyl substitution mechanism without requiring harsh conditions for unstrained γ- or δ-lactones.^[56] A representative example is the hydrolysis of γ-butyrolactone, a five-membered ring lactone, which readily undergoes base-catalyzed ring opening in aqueous sodium hydroxide to produce 4-hydroxybutanoic acid in high yield.^[54] This transformation highlights the practical utility of lactone ring opening in organic synthesis, where control over reaction conditions allows selective cleavage without affecting other functional groups.^[16]

Reduction and Functionalization

Lactones can be fully reduced to the corresponding diols using strong reducing agents such as lithium aluminum hydride (LiAlH4), which cleaves the ester linkage and reduces the carbonyl group to an alcohol. This transformation is particularly useful for preparing aliphatic diols from cyclic esters. For instance, treatment of γ-butyrolactone with excess LiAlH4 in refluxing tetrahydrofuran yields 1,4-butanediol in high yield.^[58] Catalytic hydrogenation provides an alternative method for reducing lactones to diols, often under milder conditions and with high selectivity. In the hydrogenation of γ-butyrolactone over CuCo/TiO2 bimetallic catalysts, a 95% yield of 1,4-butanediol is achieved at a Cu:Co ratio of 1:9, with the reaction proceeding via stepwise hydrogenolysis of the C-O bond.^[59] The general reaction for full reduction can be represented as:

\text{Lactone} + \text{LiAlH}_4 \rightarrow \text{diol}

Selective reduction of the carbonyl group in lactones to form lactols (cyclic hemiacetals) is possible using milder reagents like sodium borohydride (NaBH4), avoiding cleavage of the ring. This approach is especially effective for sugar lactones, where NaBH4 in aqueous or alcoholic media reduces the lactone to the corresponding aldose lactol with minimal over-reduction.^[60] For α-hydroxy lactones, such as those in ginkgolides, NaBH4 selectively affords lactols in good yields due to the enhanced reactivity of the carbonyl.^[61] Diisobutylaluminum hydride (DIBAL-H) offers another selective reduction pathway, typically converting lactones to lactols at low temperatures, such as -78 °C in dichloromethane. This method is widely employed in total synthesis; for example, reduction of pentolactones with DIBAL-H provides the desired lactols in good yields prior to further transformations. Under controlled conditions, DIBAL-H can also yield aldehydes from lactone ring-opening, though lactol formation predominates for smaller rings.^[62] Functionalization of lactones often targets the α-position or conjugated systems to introduce new substituents without disrupting the ring. For α,β-unsaturated lactones, conjugate (Michael) additions enable stereoselective installation of alkyl groups. Copper-catalyzed asymmetric conjugate addition of alkylzirconium reagents, generated in situ from alkenes and Schwartz's reagent, to 6- and 7-membered α,β-unsaturated lactones proceeds at room temperature with up to 93% enantiomeric excess, as demonstrated in the formal synthesis of mitsugashiwalactone.^[63] This modification enhances the utility of lactones in cross-coupling reactions.

Polymerization

Lactones undergo ring-opening polymerization (ROP) to form aliphatic polyesters, a process widely employed for synthesizing biodegradable polymers. This chain-growth polymerization involves the nucleophilic attack on the carbonyl carbon of the lactone ring, leading to ring opening and propagation. The mechanisms of ROP for lactones can be cationic, anionic, or coordination-insertion, depending on the initiator and catalyst used.^[64] In cationic ROP, electrophilic initiators like Lewis acids activate the monomer, while anionic ROP employs nucleophilic initiators such as alkoxides or carbanions to deprotonate or directly attack the ring. Coordination-insertion mechanisms, often involving metal catalysts, proceed through coordination of the lactone to the metal center followed by insertion into the metal-alkoxide bond.^[65] A prominent example is the ROP of ε-caprolactone, a seven-membered lactone, which yields polycaprolactone (PCL), a semicrystalline polyester with a repeating unit of [-O-(CH₂)₅-C(=O)-]ₙ. This polymerization is typically conducted under coordination-insertion conditions and results in polymers with tunable molecular weights. Similarly, ROP of L-lactide, a six-membered dilactone derived from lactic acid, produces polylactic acid (PLA), an isotactic polyester valued for its stereoregularity and mechanical properties. The general reaction for ε-caprolactone ROP can be represented as:

n \ \ce{(CH2)5CO2} \rightarrow \ce{[-O-(CH2)5-C(=O)-]_n}

Stannous octoate, Sn(Oct)₂, serves as a benchmark catalyst for industrial-scale ROP of lactones like ε-caprolactone and lactide, offering high efficiency and control over polymerization at temperatures around 100–180°C.^[66] This catalyst operates via a coordination-insertion pathway, often with alcohol co-initiators to regulate chain length.^[67] The resulting polyesters, such as PCL and PLA, exhibit biodegradability through hydrolytic or enzymatic cleavage of ester bonds, making them suitable for biomedical applications including drug delivery systems and tissue scaffolds. Their degradation products are typically non-toxic and biocompatible, enabling controlled resorption in vivo.^[68]

Applications

Flavors and Fragrances

Lactones are key contributors to the sensory profiles in flavors and fragrances, imparting desirable fruity, creamy, and coconut-like aromas that enhance food, beverages, and perfumes. Among these, γ-nonalactone (also known as aldehyde C-18) delivers a sweet, coconut-peach character, making it a staple in formulations mimicking tropical fruits and dairy products.^[69] Similarly, δ-decalactone provides a rich, buttery, and creamy note with peachy undertones, often used to evoke natural dairy and stone fruit essences.^[70] Massoia lactone, or δ-2-decenolactone, stands out for its potent, diffusive coconut aroma, which is integral to recreating the scent of coconut in essential oils and flavor blends.^[71] These compounds' volatility and intensity allow them to define the top and heart notes in fragrances while providing depth in flavor systems. Both natural and synthetic sources supply these lactones for commercial use, with biotechnological methods gaining prominence for sustainable production. Naturally, they arise in dairy products, peaches, apricots, and coconut-derived oils through microbial or enzymatic processes during fermentation or ripening.^[72] Synthetic routes, including chemical cyclization of hydroxy acids, dominate traditional manufacturing, but fermentation-based biotechnology offers an eco-friendly alternative by engineering yeasts or fungi to convert abundant fatty acids into flavor lactones.^[73] For example, oleaginous yeasts like Yarrowia lipolytica have been optimized to produce γ- and δ-lactones via β-oxidation and lactonization pathways, yielding high-purity compounds suitable for food-grade applications.^[74] This approach not only reduces reliance on petrochemical feedstocks but also mirrors natural biosynthesis, enhancing authenticity in end products.^[75] In practical formulations, lactones are incorporated at low concentrations, typically in the range of 100 to 2,500 parts per million (ppm), to achieve impactful sensory effects without overpowering other notes.^[76] For instance, δ-decalactone at 100–200 ppm bolsters creamy profiles in cheese and butter flavors, while γ-nonalactone at around 1,000–1,500 ppm drives coconut and peach accords in fruit beverages and confections.^[69] Their stability is a key advantage; γ- and δ-lactones resist hydrolysis under neutral pH and moderate temperatures common in flavor emulsions and perfume bases, ensuring consistent aroma release over time.^[75] This durability supports their versatility in heat-processed foods like baked goods and dairy, as well as in long-lasting fragrance compositions.^[77] Overall, these properties make lactones indispensable for crafting authentic, appealing sensory experiences in consumer products.

Polymers and Materials

Lactones serve as key monomers in the synthesis of biodegradable polylactones, such as poly(lactic acid) (PLA) and poly(ε-caprolactone) (PCL), which are widely employed in plastics, coatings, and sustainable materials. PLA is primarily produced through the ring-opening polymerization (ROP) of lactide, a cyclic dimer of lactic acid, enabling the creation of high-molecular-weight polymers suitable for rigid applications like food packaging films and containers.^[78] Similarly, PCL is synthesized via ROP of ε-caprolactone, yielding flexible polymers used in hot-melt adhesives and coatings due to their low melting point and compatibility with other materials.^[79] These polylactones exhibit desirable properties that make them viable alternatives to petroleum-based plastics. PLA demonstrates good mechanical strength, with tensile strengths typically ranging from 50-70 MPa, and thermal stability up to its glass transition temperature of about 60°C, allowing for processing in standard extrusion and injection molding equipment.^[80] PCL, in contrast, offers superior flexibility and elongation at break exceeding 300%, complemented by biodegradability under composting conditions where it hydrolyzes into non-toxic byproducts.^[81] Both polymers are inherently biodegradable, with degradation rates influenced by environmental factors like moisture and microbial activity, typically completing within 6-24 months in industrial composting facilities.^[82] Industrial production of these materials emphasizes efficient ROP processes to achieve scalability. For PCL, ROP of ε-caprolactone is conducted using catalysts like stannous octoate, facilitating bulk polymerization at temperatures around 100-150°C to produce resins for adhesives and thermoplastic polyurethane blends.^[79] PLA production similarly relies on ROP of lactide in the presence of metal catalysts, with major manufacturers optimizing for high purity to ensure consistent material performance in packaging. Recycling aspects include mechanical reprocessing for PLA, where multiple extrusion cycles can retain significant mechanical properties though with gradual degradation, and chemical recycling via depolymerization back to lactide for closed-loop production.^[83] The adoption of bio-based lactone polymers significantly mitigates environmental impact by reducing reliance on fossil fuels and curbing plastic waste accumulation. PLA and PCL contribute to a circular economy, with their biodegradability preventing long-term persistence in landfills and oceans, potentially lowering global plastic pollution through substitution of conventional packaging materials.^[84] This shift supports sustainability goals, as life-cycle assessments indicate a 50-70% reduction in carbon footprint compared to polyethylene for equivalent applications.^[78]

Pharmaceuticals and Medicine

Lactones serve as key structural components in several active pharmaceutical ingredients, particularly in cardiovascular and antimicrobial therapies. Spironolactone, a synthetic steroid featuring a γ-lactone ring, acts as a potassium-sparing diuretic and competitive antagonist of aldosterone by binding to mineralocorticoid receptors, thereby promoting sodium and water excretion while conserving potassium.^[85]^[86] Macrolide antibiotics, such as erythromycin, incorporate a large macrocyclic lactone ring—typically 14- to 16-membered—attached to sugar moieties, enabling them to inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and exhibiting broad-spectrum activity against respiratory and skin infections.^[87]^[88] In oncology, sesquiterpene lactones have emerged as promising anticancer agents due to their ability to modulate multiple signaling pathways. Parthenolide, a naturally occurring sesquiterpene lactone from feverfew (Tanacetum parthenium), inhibits tumor growth by suppressing NF-κB activation, inducing apoptosis, and targeting cancer stem cells in various malignancies, including renal cell carcinoma and non-small cell lung cancer.^[89]^[90] These compounds often exert cytotoxicity through alkylation of cysteine residues in key proteins, highlighting their potential as adjuncts in combination therapies.^[91] Lactones also play a critical role in drug delivery systems, where biodegradable polyesters derived from lactide monomers enable controlled release. Poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulate therapeutics, degrading hydrolytically to release drugs at targeted sites, such as in cancer treatment or localized pain management, with tunable degradation rates based on polymer composition and molecular weight.^[92]^[93] This biocompatibility and sustained release profile have led to FDA-approved formulations for vaccines and chemotherapeutics.^[94] Recent advancements underscore the expanding therapeutic scope of lactones. A 2025 study in RSC Advances reviewed sesquiterpene lactones for their antiviral potential, demonstrating inhibitory effects against viruses like SARS-CoV-2 through disruption of viral replication via NF-κB modulation and direct binding to viral proteins.^[95] Similarly, β-lactones exhibit potent antimicrobial activity; for instance, certain β-lactone derivatives target serine hydrolases in Mycobacterium tuberculosis, blocking mycomembrane biosynthesis and offering leads for combating antibiotic-resistant strains.^[96]^[97] Despite these benefits, lactone-based pharmaceuticals face challenges related to chemical stability, particularly hydrolysis of the lactone ring in aqueous formulations. The lactone moiety in drugs like camptothecins or spironolactone can undergo pH-dependent ring-opening to form less active carboxylate species, necessitating strategies such as liposomal encapsulation or pH adjustment to maintain the bioactive lactone form during storage and administration.^[98]^[99] This instability can reduce efficacy and requires careful formulation design to ensure therapeutic reliability.^[100]

Special Classes

Dilactones

Dilactones are organic compounds featuring two lactone rings within a single molecule, often conferring unique structural rigidity and reactivity compared to monolactones. These bicyclic systems can be classified into spiro-dilactones, where the two lactone rings share a single spiro carbon atom, and fused dilactones, where the rings share two adjacent atoms forming a common bond. Spiro-dilactones, such as leucodrin and leudrin derived from L-ascorbic acid, exhibit a compact, three-dimensional architecture that enhances their stability in physiological environments.^[101] Fused dilactones, exemplified by nonano-9-lactone fused to a δ-lactone ring synthesized from levoglucosenone adducts, provide extended conjugation and planarity, influencing their optical and thermal properties.^[102] Synthesis of dilactones typically involves the cyclization of dihydroxy diacids or related precursors through double lactonization processes. For instance, diastereoselective hydrogenation of dihydroxyadipic acid derivatives yields dilactones via sequential formation of γ- and δ-lactone rings under mild conditions, such as room temperature and atmospheric pressure using catalytic methods.^[103] In the case of spiro-dilactones related to ascorbic acid, organocatalytic 1,4-conjugate addition of L-ascorbic acid to α,β-unsaturated aldehydes, followed by intramolecular lactonization, affords compounds like leucodrin and leudrin in high diastereoselectivity.^[104] Fused dilactones can be accessed via oxidative cyclization of carbohydrate-derived diols, leveraging the inherent stereochemistry of the starting materials to control ring fusion.^[102] These methods often employ eco-friendly solvents like phosphate-citrate buffers (pH 5.0) to promote selectivity and yield, as demonstrated in the preparation of ascorbic acid lactone derivatives from 4-hydroxybenzyl alcohols.^[101] The properties of dilactones are markedly influenced by their bicyclic architecture, providing enhanced stability against hydrolysis and improved rigidity relative to acyclic or single-ring analogs. For example, terphenyl-bridged dilactones exhibit significantly amplified optical absorption and emission spectra due to their constrained crankshaft conformations, which restrict conformational flexibility.^[105] In natural products, chirality is a prominent feature, particularly in L-ascorbic acid-derived spiro-dilactones like dilaspirolactone aglycone isolated from Dicranopteris dichotoma, where the stereocenters at the spiro junction and side chains dictate biological specificity.^[101] This chirality contributes to their role in enantioselective processes, such as in antioxidant mechanisms. Representative examples include ascorbone, the oxidized form of dehydroascorbic acid, which incorporates dilactone motifs in its derivatives and serves as a scaffold for bioactive compounds with antioxidant applications. Ascorbic acid-based spiro-dilactones, such as those in leucodrin, demonstrate utility in cosmetics and medicine due to their free radical scavenging capabilities, mirroring the redox properties of vitamin C while offering greater structural persistence.^[101] Fused dilactones from sugar-derived precursors, like glucarodilactone derivatives, further highlight their potential in degradable materials, balancing stability in neutral conditions with controlled breakdown in basic environments for sustainable applications.^[106]

Macrocyclic Lactones

Macrocyclic lactones are a subclass of lactones featuring ring systems with more than 12 atoms, typically 14 to 20 members, which imparts unique structural flexibility and biological activity compared to smaller cyclic esters. These compounds are predominantly found in natural products derived from microbial sources, such as Streptomyces species, and include prominent examples like the avermectins, which possess a 16-membered macrocyclic lactone core fused to a disaccharide unit.^[107] Another key class is the macrolide antibiotics, exemplified by erythromycin, featuring a 14-membered aglycone lactone ring glycosylated with amino sugars.^[108] The synthesis of macrocyclic lactones is complicated by the entropic penalty associated with closing large rings, often leading to low yields from competing oligomerization. High-dilution techniques, where precursors are added slowly to reaction mixtures at concentrations below 0.01 M, favor intramolecular esterification or cross-coupling to form the macrocycle.^[109] Templating methods, such as coordination to transient metal complexes or hydrogen-bonding scaffolds, further assist by preorganizing the acyclic chain into a conformation conducive to cyclization, as demonstrated in the assembly of polyene macrolactones.^[110] Structurally, macrocyclic lactones adopt flexible, low-energy conformations that enable them to span extended binding pockets in target proteins, enhancing specificity and potency. In macrolide antibiotics, the lactone ring binds within the nascent peptide exit tunnel of the bacterial 50S ribosomal subunit, blocking translocation and inhibiting protein synthesis.^[107] Avermectins, conversely, exhibit antiparasitic activity by modulating ligand-gated ion channels in invertebrates through allosteric binding, causing hyperpolarization and paralysis without significant mammalian toxicity due to species-specific receptor differences.^[111] Recent advances in the total synthesis of complex macrolides have focused on modular and iterative strategies to address stereochemical complexity and scalability. For example, successive ring-expansion protocols using ylides or metathesis have enabled the construction of 14- to 18-membered lactones from smaller precursors, with applications in diversifying erythromycin analogs reported since 2021.^[112] Chemoenzymatic approaches, integrating polyketide synthases with synthetic fragments, have also facilitated the biosynthesis of macrolide variants, improving yields and enabling structure-activity studies as of 2023.^[113] These methods underscore a shift toward sustainable, high-efficiency routes for therapeutic development.

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Assessment of Avermectins-Induced Toxicity in Animals - MDPI
Mar 9, 2022 · Macrocyclic lactones, particularly the avermectins, have completely revolutionized the approaches aimed at control of parasites.Missing: rifamycin | Show results with:rifamycin