Halogenated butyrolactones from the biomass-derived synthon levoglucosenone

• Johannes Puschnig,
• Martyn Jevric and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2025, 21, 2297–2301, doi:10.3762/bjoc.21.175

• Baeyer–Villiger oxidation affording the fluorinated, chlorinated, and brominated dideoxyribonolactones. Keywords: butyrolactone; cyrene; fluorine; halogenation; levoglucosenone; Introduction The γ-butyrolactone ring is a privileged scaffold found in natural products and can be used as a valuable

• dichloro-magnesium enolates to protected ᴅ-glyceraldehyde [11]. In 1988, Hertel et al. from the Lilly laboratories published the first synthesis of the clinically important anticancer agent gemcitabine, using an intermediate γ-butyrolactone constructed using protected ᴅ-glyceraldehyde and ethyl

• chiral halogenated lactones, which could be useful in the enantioselective synthesis of valuable drug precursors. The syntheses feature the use of readily available and cheap starting materials, and we have also demonstrated some of these transformations on a gram scale. Halogen-containing butyrolactone

C2 to C6 biobased carbonyl platforms for fine chemistry

• Jingjing Jiang,
• Muhammad Noman Haider Tariq,
• Florence Popowycz,
• Yanlong Gu and
• Yves Queneau

Beilstein J. Org. Chem. 2025, 21, 2103–2172, doi:10.3762/bjoc.21.165

• , with high selectivity towards HFO (83%) and high conversion of furfural (70%) (Scheme 32). Yuan et al. [112] reported the synthesis of γ-butyrolactone (GBL) by the hydrodeoxygenation of HFO prepared by photocatalytic conversion of furfural. HFO is converted to GBL by two pathways: the first one is

• formation of gem-bis-4,4-(5-methyl-2-furyl)-2-butenoic acid in 13% yield (Scheme 42, path d) [131]. Industrial chemicals with four carbon structures like pyrrolidines, 1,4-butanediol, maleic acid, and butyrolactone are often petroleum-based. However, developing sustainable biomass-derived routes for these

• moderate temperatures (100–150 °C), could be selectively converted into valuable C4 products with remarkable yields: maleic acid and γ-butyrolactone were both obtained in 93% yield, while 1,4-butanediol, tetrahydrofuran, and 2-pyrrolidone were produced in 60%, 64%, and 67% yields, respectively (Scheme 43a

Oxetanes: formation, reactivity and total syntheses of natural products

• Peter Gabko,
• Martin Kalník and
• Maroš Bella

Beilstein J. Org. Chem. 2025, 21, 1324–1373, doi:10.3762/bjoc.21.101

• ) [78]. Initially, racemic 2-bromo-γ-butyrolactone (114) was contracted by ethanolic KOH into oxetanecarboxylic acid, which was then esterified and the enantiomeric ethyl esters were resolved by an enzymatic hydrolysis. Finally, the enantioenriched ester 115 was successfully employed in several multi

Hypervalent iodine-mediated intramolecular alkene halocyclisation

• Charu Bansal,
• Oliver Ruggles,
• Albert C. Rowett and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 3113–3133, doi:10.3762/bjoc.20.258

• fluoride forms the product. In 2017, Kitamura and co-workers reported the synthesis of fluorinated tetrahydrofurans 25 and butyrolactone 27 (Scheme 15) [33]. Unsaturated alcohols 23 and 3-butenoic acid (24) were competent starting materials, using PhI(OPiv)2 as an oxidant and pyridine·HF as a source of

• fluoride. Unsaturated alcohols gave moderate yields of racemic fluorinated tetrahydrofurans 26. Moderate yields were also reported for the fluorocyclisation of 3-butenoic acid (24) to form the fluorinated butyrolactone 28. The preparation of fluorinated oxazolines was reported in 2018 by Gilmour and co

• , iodoetherification of 2,2-diphenyl-4-penten-1-carboxylic acid (47') and 2,2-diphenyl-4-penten-1-ol (47) was reported by Liu and Li in 2014 (Scheme 26) [30]. The authors reported using PhI(OAc)2 and KI in the synthesis of iodonated γ-butyrolactone 83 and iodomethyltetrahydrofuran 82 in excellent yields (Scheme 44

Transition-metal-free decarbonylation–oxidation of 3-arylbenzofuran-2(3H)-ones: access to 2-hydroxybenzophenones

• Bhaskar B. Dhotare,
• Seema V. Kanojia,
• Chahna K. Sakhiya,
• Amey Wadawale and
• Dibakar Goswami

Beilstein J. Org. Chem. 2024, 20, 2655–2667, doi:10.3762/bjoc.20.223

• lactones are limited. Both photochemical decarboxylation methods reported for α,γ-butyrolactone [16] and γ-butyrolactones [17] yielded the products in very poor to moderate yields (Figure 2a and 2b). Recently, a transition-metal-free decarboxylation of α,β-unsaturated aromatic lactones was reported for the

Chiral bifunctional sulfide-catalyzed enantioselective bromolactonizations of α- and β-substituted 5-hexenoic acids

• Sao Sumida,
• Ken Okuno,
• Taiki Mori,
• Yasuaki Furuya and
• Seiji Shirakawa

Beilstein J. Org. Chem. 2024, 20, 1794–1799, doi:10.3762/bjoc.20.158

• -substituted 4-pentenoic acids without additional substituents on the carbon–carbon double bond (Scheme 1c) [26][27]. Chiral α-substituted γ-butyrolactone products as important building blocks for pharmaceutical development were obtained in a highly enantioselective manner in our catalytic system using

Tetrabutylammonium iodide-catalyzed oxidative α-azidation of β-ketocarbonyl compounds using sodium azide

• Christopher Mairhofer,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1510–1517, doi:10.3762/bjoc.20.135

• straightforwardly. Furthermore, this procedure was also successfully extended to γ-butyrolactone-based products 7. Unfortunately, this methodology came to its limits when using tetralone-based β-ketoesters like compound 8, which resulted in a complex product mixture, or the acylic β-ketoester 9, which did not show

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

• sesquiterpene with a unique framework. Indeed, this natural compound has a rare [6.3.0] carbocyclic backbone with a bridging butyrolactone, and possesses five cis stereocenters [39][40]. This compound, in a racemic version, has been studied by Krafft, Cheung and Abboud (Scheme 13) [39]. The initial strategy

• displays a similar backbone as asteriscanolide (2), with an α,β-unsaturated ketone on the eight-membered ring, fused with a γ-butyrolactone and a cyclopentane, onto which a cyclopropane is also grafted [48]. The total synthesis of (±)-naupliolide (97) reported by Ito et al. constituted another example of

A two-phase bromination process using tetraalkylammonium hydroxide for the practical synthesis of α-bromolactones from lactones

• Yuki Yamamoto,
• Akihiro Tabuchi,
• Kazumi Hosono,
• Takanori Ochi,
• Kento Yamazaki,
• Shintaro Kodama,
• Akihiro Nomoto and
• Akiya Ogawa

Beilstein J. Org. Chem. 2021, 17, 2906–2914, doi:10.3762/bjoc.17.198

• polymerization (ATRP) reactions and functional polymer synthesis [29][30][31][32][33][34]. Although α-bromo-γ-butyrolactone, which is a five-membered lactone, is easily accessible from the five-membered lactone by some bromination methods [35][36], the bromination method for the six-membered lactone, δ

• begin by first discussing the properties and stabilities of industrially important five- and six-membered lactones. γ-Butyrolactone and its α-brominated derivative are both stable at room temperature; α-bromo-γ-butyrolactone is readily synthesized by brominating the five-membered lactone under basic

• 2). 2a was obtained in 89% yield when this protocol was used on a 31 mmol scale (Table 1, entry 3). γ-Butyrolactone (1b) and ε-caprolactone (1c) were also converted into the corresponding dibromocarboxylic acids 2b and 2c in yields of 76% and 70%, respectively (Table 1, entries 4 and 5). Since we

Development of N-F fluorinating agents and their fluorinations: Historical perspective

• Teruo Umemoto,
• Yuhao Yang and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123

• observations are noted: N-Fluoro-2,6-bis(methoxymethyl)pyridinium triflate (5-4l) fluorinated the trimethylsilyl ether of γ-butyrolactone and 1-cyclohexenyl acetate in much higher yields than the N-fluoro-2,4,6-trimethyl salt 5-4j [32]. Thus, as seen in Scheme 13, 5-4l converted the Corey lactone 5-7 via its

Valorisation of plastic waste via metal-catalysed depolymerisation

• Francesca Liguori,
• Carmen Moreno-Marrodán and
• Pierluigi Barbaro

Beilstein J. Org. Chem. 2021, 17, 589–621, doi:10.3762/bjoc.17.53

Bifurcated synthesis of methylene-lactone- and methylene-lactam-fused spirolactams via electrophilic amide allylation of γ-phenylthio-functionalized γ-lactams

• Tetsuya Sengoku,
• Koki Makino,
• Ayumi Iijima,
• Toshiyasu Inuzuka and
• Hidemi Yoda

Beilstein J. Org. Chem. 2020, 16, 2769–2775, doi:10.3762/bjoc.16.227

• 501-1193, Japan 10.3762/bjoc.16.227 Abstract New synthetic methods for spirolactams bearing an α-methylene-γ-butyrolactone or its analogous methylene-lactam have been developed. The allylation of γ-phenylthio-functionalized γ-lactams with 2-(acetoxy)methyl acrylamides was accomplished by using 2.5

• -butyrolactone; spirolactams; Introduction α-Methylene-γ-butyrolactone is a pharmaceutically important motif which is found in a wide variety of bioactive molecules including natural products (Scheme 1a) [1][2][3]. For example, sesquiterpene lactones represented by parthenolide and helenalin have attracted

• reaction conditions and led to methylene-lactone-fused spirolactams 5a–h in excellent yields without exception (88–98% two-step yields). Thus, we established the bifurcated synthetic routes toward lactams spiro-fused to α-methylene-γ-butyrolactone or α-methylene-γ-butyrolactam by using 3-phenylthiolactams

Recent synthesis of thietanes

• Jiaxi Xu

Beilstein J. Org. Chem. 2020, 16, 1357–1410, doi:10.3762/bjoc.16.116

• -bis(hydroxymethyl)indolin-2-one (51) was reacted first with mesyl chloride and then treated with sodium sulfide to afford 6-bromospiro[indoline-3,3′-thietan]-2-one (53), which was further converted into the target inhibitor candidate 54 [42] (Scheme 12). 2-Methylene-γ-butyrolactone (55) as the initial

Visible-light-induced addition of carboxymethanide to styrene from monochloroacetic acid

• Kaj M. van Vliet,
• Nicole S. van Leeuwen,
• Albert M. Brouwer and
• Bas de Bruin

Beilstein J. Org. Chem. 2020, 16, 398–408, doi:10.3762/bjoc.16.38

• traditional reactivity of this compound. Here, we investigated the possibility of applying monochloroacetic acid as a substrate for photoredox catalysis with styrene to directly produce γ-phenyl-γ-butyrolactone. Instead of using nucleophilic substitution, we cleaved the carbon chlorine bond by single-electron

• reduction, creating a radical species. We observed that the reaction works best in nonpolar solvents. The reaction does not go to full conversion, but selectively forms γ-phenyl-γ-butyrolactone and 4-chloro-4-phenylbutanoic acid. Over time the catalyst precipitates from solution (perhaps in a decomposed

• acetonitrile. Indeed, the yield decreased with increasing amounts of acetonitrile. On the other hand, the selectivity for the formation of the lactone increased by adding more acetonitrile [46]. To evaluate if γ-phenyl-γ-butyrolactone (1) can be formed from 4-chloro-4-phenylbutanoic acid (3) in benzene we

A green, economical synthesis of β-ketonitriles and trifunctionalized building blocks from esters and lactones

• Daniel P. Pienaar,
• Kamogelo R. Butsi,
• Amanda L. Rousseau and
• Dean Brady

Beilstein J. Org. Chem. 2019, 15, 2930–2935, doi:10.3762/bjoc.15.287

• alkoxide anions. This reduces the occurrence of undesirable side-reactions, e.g., intermolecular aldol reaction, lactone/ketonitrile product dimerization and ring-opening polymerization. The application of this method to produce the analogous hemiketal 6 from γ-butyrolactone was not as efficient. Although

• the desired product 6 could indeed be isolated in 15% yield from γ-butyrolactone when the same reaction conditions were applied in THF, the use of 2MeTHF as solvent resulted in a complex mixture with only traces of the desired product, as revealed by crude product NMR spectroscopy. It is thought that

• be the uncyclized β-ketonitrile 7 (see Supporting Information File 1). This suggests that, in solution, the keto–hemiketal equilibrium for the butyrolactone product does not favor completely hemiketal 6, as was observed for the 6-membered cycle 5. The authors therefore propose that formation of the 6

Nanangenines: drimane sesquiterpenoids as the dominant metabolite cohort of a novel Australian fungus, Aspergillus nanangensis

• Heather J. Lacey,
• Cameron L. M. Gilchrist,
• Andrew Crombie,
• John A. Kalaitzis,
• Daniel Vuong,
• Peter J. Rutledge,
• Peter Turner,
• John I. Pitt,
• Ernest Lacey,
• Yit-Heng Chooi and
• Andrew M. Piggott

Beilstein J. Org. Chem. 2019, 15, 2631–2643, doi:10.3762/bjoc.15.256

• dehydrogenase could oxidise the alcohol (at C-11 or C-12) to an aldehyde. Depending on whether C-11 or C-12 formed an aldehyde, further oxidation of the aldehyde to a carboxylic acid and condensation with the γ-OH group would afford the butyrolactone ring in nanagenines A–E and isonanagenines B/D, respectively

Bipolenins K–N: New sesquiterpenoids from the fungal plant pathogen Bipolaris sorokiniana

• Chin-Soon Phan,
• Hang Li,
• Simon Kessler,
• Peter S. Solomon,
• Andrew M. Piggott and
• Yit-Heng Chooi

Beilstein J. Org. Chem. 2019, 15, 2020–2028, doi:10.3762/bjoc.15.198

• at the nerolidyl cation (Figure 5b) [28][29][30][31]. The biosynthesis of 1–8 and 10–11 are likely to be derived from sativene with a key oxidation at C-15 followed by a Baeyer–Villiger oxidation to break the C-14–C-15 bond (Figure 5c). Based on an isotope labelling study, the γ-butyrolactone moiety

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

• Iwona E. Głowacka,
• Aleksandra Trocha,
• Andrzej E. Wróblewski and
• Dorota G. Piotrowska

Beilstein J. Org. Chem. 2019, 15, 1722–1757, doi:10.3762/bjoc.15.168

• disease [99]. Synthesis of enantiomerically pure (3R,5S)-168 could be accomplished from the aziridine aldehyde (2S,1'R)-6 because the butyrolactone ring formation would proceed with inversion of configuration at C2 in the aziridine ring (Scheme 43) [100]. Thus, condensation of the aldehyde (2S,1'R)-6 with

High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine

• Eric Yu,
• Hari P. R. Mangunuru,
• Nakul S. Telang,
• Caleb J. Kong,
• Jenson Verghese,
• Stanley E. Gilliland III,
• Saeed Ahmad,
• Raymond N. Dominey and
• B. Frank Gupton

Beilstein J. Org. Chem. 2018, 14, 583–592, doi:10.3762/bjoc.14.45

• ]. With these issues in mind, we carried out a retrosynthetic analysis (Scheme 2) in which 10, an iodo analogue to the starting material 3, could be generated in a single step via a decarboxylative ring-opening of α-acetyl butyrolactone 8. The iodo analogue 10 could then be used without isolation to

Mannich base-connected syntheses mediated by ortho-quinone methides

• Petra Barta,
• Ferenc Fülöp and
• István Szatmári

Beilstein J. Org. Chem. 2018, 14, 560–575, doi:10.3762/bjoc.14.43

• -γ-butyrolactone in DMF at 130 °C [73]. This method could successfully be applied in the synthesis of the spiroketal core of rubromycins 22 and 23. One of the latest publications around the topic is published by Hayashi et al. in 2015 [74]. Starting from diarylmethylamines 24 and arylboroxines, they

Synthesis and metal binding properties of N-alkylcarboxyspiropyrans

• Alexis Perry and
• Christina J. Kousseff

Beilstein J. Org. Chem. 2017, 13, 1542–1550, doi:10.3762/bjoc.13.154

• alkylation conditions, intramolecular lactonisation of 4-bromobutyric acid to γ-butyrolactone (8) was more rapid than N-alkylation and no indolium product was observed (Scheme 4). Consequently, to obtain C4SP, we employed an optimised version of the three-step procedure of Natali et al. [3], wherein

Cyclodextrins tethered with oligolactides – green synthesis and structural assessment

• Cristian Peptu,
• Mihaela Balan-Porcarasu,
• Alena Šišková,
• Ľudovít Škultéty and
• Jaroslav Mosnáček

Beilstein J. Org. Chem. 2017, 13, 779–792, doi:10.3762/bjoc.13.77

• low content of oligoester components were first prepared by a totally green procedure by Harada and co-workers [17]. They succeeded to polymerize a series of cyclic esters including β-butyrolactone (BL), δ-valerolactone (VL) and ε-caprolactone (CL). A recent work published by Galia et al. [18] brings

• substituted unit appear as a small broadening of the peaks for the unsubstituted units. Similar compounds (CDs esterified with δ-valerolactone, β-butyrolactone and ε-caprolactone obtained by bulk polymerization) were reported by Harada et al. and were also analyzed by 13C NMR [17]. The structural assignment

New syntheses of (±)-tashiromine and (±)-epitashiromine via enaminone intermediates

• Darren L. Riley,
• Joseph P. Michael and
• Charles B. de Koning

Beilstein J. Org. Chem. 2016, 12, 2609–2613, doi:10.3762/bjoc.12.256

• -bromoacetonitrile. The preparation of 3 in three steps from commercially available 3-amino-1-propanol and γ-butyrolactone (4) and its subsequent transformation into the substituted enamines is shown in Scheme 1. As described previously [28], 3-amino-1-propanol was condensed with γ-butyrolactone (4) in a sealed

Cupreines and cupreidines: an established class of bifunctional cinchona organocatalysts

• Laura A. Bryant,
• Rossana Fanelli and
• Alexander J. A. Cobb

Beilstein J. Org. Chem. 2016, 12, 429–443, doi:10.3762/bjoc.12.46

• nitro functionality (Scheme 5). Similarly, Kesavan and co-workers reacted 3-O-Boc-oxindoles 23 with MBH carbonates 22 to generate a range of spirocyclic scaffolds containing α-exo-methylene-γ-butyrolactone 24 – again using β-ICPD (Scheme 6) [30]. Nazarov cyclization An asymmetric Nazarov cyclization has

Synthesis of Xenia diterpenoids and related metabolites isolated from marine organisms

• Tatjana Huber,
• Lara Weisheit and
• Thomas Magauer

Beilstein J. Org. Chem. 2015, 11, 2521–2539, doi:10.3762/bjoc.11.273

• ] either bear a similar seco-ring fragment, as observed for dictyodiol (24), or comprise a fused γ-butyrolactone moiety, as in dictyolactone (25, Figure 3). This review intends to provide a comprehensive overview of research covering xenicane diterpenoids and related natural products. In the following