Lactone Function Research Articles

Use of Cleavable Coordinating Rings as Protective Groups in the Synthesis of a Rotaxane with an Axis that Incorporates More Chelating Groups Than Threaded Macrocycles

A new methodology allowing preparation of a linear "unsaturated" [3]rotaxane consisting of an axis incorporating more coordination sites than threaded rings was developed. It was based on the preliminary synthesis of a "saturated" [5]rotaxane consisting of a four-chelating site axis threaded through four macrocyclic components, two of them being cleavable rings incorporating a lactone function and the two others being "secure" non-cleavable rings. The stoppering reaction was based on click chemistry. Subsequently, cleavage and removal of the two lactone-containing macrocycles from the [5]rotaxane in basic medium afforded the desired "unsaturated" [3]rotaxane in quantitative yield.

Porphothionolactones: synthesis, structure, physical, and chemical properties of a chemodosimeter for hypochlorite

The conversion of the lactone functionality of porpholactones, porphyrin analogs in which a porphyrin β,β'-double bond was replaced by a lactone moiety, to a thionolactone functionality using Lawesson's reagent is described. The resulting novel thionolactones were spectroscopically characterized and their electronic structure defined using experimental (UV-vis, fluorescence, cyclic voltammetry) and theoretical methods (molecular modelling at the B3LYP/6-31G(d) level). The structures of two benchmark thionolactones were determined by single crystal X-ray diffractometry. The idealized planarity of the chromophores rationalize the bathochromically shifted optical spectra of the thionolactones when compared to the lactones on electronic grounds. The thionolactone moiety can be used as a synthetic handle in the preparation of oxazolochlorins using RANEY® nickel-induced hydrodesulfurization reactions. Importantly, the meso-pentafluorophenyl-based porphothionolactone fluoresces by at least a factor of 60 less compared to the corresponding lactone. The hypochlorite-selective conversion of the thionolactone to the lactone is the basis for the use of this thionolactone as a switch-on chemodosimeter for hypochlorite, a widely used disinfectant and molecule of biological significance in some inflammatory processes.

TG/DSC/FTIR characterization of linear geranyl diesters

The synthesis, thermal behavior, and characterization of the decomposition products of linear geranyl diesters: digeranyl succinate, digeranyl glutarate, digeranyl adipinate, and digeranyl sebacinate were presented. The linear geranyl diesters were prepared in direct esterification process of a molar stoichiometric ratio of geraniol and suitable acidic reagent in solvent-free medium at 130 °C using butylstannoic acid as a catalyst. Their structure was confirmed based on FTIR, 1H- and 13C-NMR spectra. It was proved that the use of tin catalyst allowed decreasing the reaction time and increasing the final conversion of substrates when compared to non-catalyzed process. It considerably simplifies the processing by reduction of the preparation cost and thus this new method of synthesis of aroma diesters may be attractive for practical applications. The thermal behavior of prepared compounds was studied by TG/DSC/FTIR coupled method. TG analysis showed that diesters are thermally stable up to temperatures above 200 °C. The DTG curves confirmed that these decomposition run as a single-stage process. The T max1 were in the range of 294.5–313.8 °C depending on the aliphatic chain length (–CH2–)n in the structure of aroma diesters, which was in accordance with DSC data. The analysis of the gases evolved during heating of diesters in inert atmosphere indicated on the asymmetrical disrupt of their bonds. The cleavage of ester bond and O-geranyl bond was expected. It resulted in production of the mixture of derivatives of geraniol (acyclic and alicyclic monoterpene hydrocarbons) like myrcene, ocimene, or limonene as main decomposition products. In addition, the formation of anhydride, lactone, or ketone functionalities among the degradation products clearly confirmed the proposed degradation path of studied diesters.

ChemInform Abstract: Special Features of Reaction of 2‐(5‐Methyl‐2‐phenyl‐2H‐1,2,3‐diazaphosphol‐4‐yl)‐4H‐benzo [d]‐1,3,2‐dioxaphosphorin‐4‐one with Diethyl Mesoxalate.

AbstractThe reaction proceeds with excellent regioselectivity by ring expansion at the lactone functionality to give a dioxaphosphepinedione derivative (III).

Enantioselective Total Synthesis of Marine Diterpenoid Clavulactone

The key steps in the synthesis of clavulactone are formation of an enantiopure cyclopentane precursor by epoxide rearrangement and intramolecular carbonyl-ene reaction, construction of the 3,4-dihydro-2H-pyran ring by intermolecular hetero-Diels-Alder reaction, closure of the eleven-membered ring, and finally generation of the lactone functionality by chemoselective allylic C(sp(3))-H oxidation.

Design and Synthetic Investigation towardgem-difluoromethylenated Fostriecin Analogue

Fostriecin is a promising leading anticancer compound. The α,β-unsaturated lactone in Fostriecin is believed to be the critical pharmacophore, which can covalently bind to the Cys269 residue of the PP2A subunit via a Michael 1,4-conjugate addition. We reasoned that the introduction of strong electron-withdrawing gem-difluoromethylene to replace the methylene group at the γ position of the lactone ring would lead to fostriecin analogue 4 with enhanced enzymatic binding affinity. Ac- cordingly, the synthesis of fostriecin analogue 4 was investigated. The skeleton of target molecule 4 was established conver- gently from fragments a, b and c via an magnesium mediated chelation-controlled addition and Stille coupling using Pd(CH3CN)Cl2 as catalyst. The key steps of synthesizing fragment a included the coupling between alkenyl iodide 8 and ethyl bromodifluoroacetate in the presence of copper powder and the establishment of C-5 stereocenter via lipase AK cata- lyzed kinetic resolution. The construction of C-11 and C-9 stereocenters in fragment b were realized by the lipase AK cata- lyzed kinetic resolution and CBS asymmetric reduction of α,β-unsaturated ketone 23 (BH3•PhNEt2 as reductive agent), re- spectively. The connection of fragments a and b proceeded through the magnesium mediated chelation-controlled addition procedures: fragment a (vinyl stannane) was firstly converted to vinyl lithium reagent 27 by the treatment of BuLi (1.05 equiv.) at -78 ℃, then the i-PrMgCl (2.0 equiv.) solution in THF was added dropwise to produce the critical magne- sium-ate complex intermediate A, finally the addition of fragment b solution in THF to the magnesium-ate complex A gave the coupled product 29. The Stille coupling of fragment c with vinyl iodide 39 prepared from 29 in the presence of Pd(CH3CN)Cl2 gave target molecule skeleton 40 in 85% yield. Finally, the protected fostriecin analogue 42 was successfully synthesized by a longest linear steps of 18 steps in 1.28% overall yield. However, the deprotection of compound 42 failed to give the target molecular 4. This could be caused by the instability of the fluorinated lactone in which the strong electron- withdrawing gem-difluoromethylene group enhanced the polarization of the lactone function. Keywords Fostriecin; difluoromethylene; α,β-unsaturated δ-lactone; enzymatic kinetic resolution; 1,5-oxidative cycliza- tion; hydrolysis of fluorinated lactone

In Vitro Antibacterial Activity of Sphaeropsidins and Chemical Derivatives toward Xanthomonas oryzae pv. oryzae, the Causal Agent of Rice Bacterial Blight

Sphaeropsidin A, the main phytotoxin produced by Diplodia cupressi, as well as the two natural analogues sphaeropsidins B and C and 14 derivatives obtained by chemical modifications were assayed for antibacterial activity against Xanthomonas oryzae pv. oryzae, Pseudomonas fuscovaginae, and Burkholderia glumae, the causal agents of severe bacterial rice diseases. The results showed a strong and specific activity of sphaeropsidin A against X. oryzae pv. oryzae, while no activity was observed against the other two pathogens. The results of structure-activity relationship studies showed that structural features important to impart this antibacterial activity are the presence of the C-7 carbonyl group and the hemiketalic lactone functionality. The C-13 vinyl group, the double bond of ring C, and/or the tertiary C-9 hydroxy group, as well as the pimarane arrangement of the tricylic carbon skeleton, were also important for the antibacterial activity. These findings may be useful in designing novel compounds for practical applications in agriculture.

Enantioselective Total Synthesis of Aplyviolene

The enantioselective total synthesis of the rearranged spongian diterpene aplyviolene has been completed in 14 steps from the known hydroazulenone 8. The key junction of the hydrocarbon and oxygenated fragments to form the critical C8 quaternary carbon stereocenter and set the stage for elaborating the delicate bicyclic lactone functionality was accomplished in high yield and exquisite stereoselectivity by Michael addition of an enantioenriched hydroazulenone enolate to an enantiopure α-bromocyclopentenone.

A Simple Synthesis of D-Galactono-1,4-Lactone and Key Building Blocks for the Preparation of Galactofuranosides

The oxidation of D-galactose by Br2 to yield D-galactono-1,4-lactone was developed and applied to the preparation of key building blocks for the synthesis of galactofuranosides. Three D-galactono-1,4-lactone derivatives protected as acetates, TBDMS ether, or acetonide were directly obtained in two steps on multigram scale with only one purification step. A mild deacetylation methodology afforded pure D-galactono-1,4-lactone and a new reduction of the lactone functionality using K-selectride was also optimized.

As many as six tandem reactions in one step! Unprecedented formation of highly functionalized benzothiophenes

A novel reaction pathway involving 1,3-diketones and 2,2'-dithiodibenzoylchloride that gives access to benzothiophenes with spiroketal, lactone, carbonyl, hydroxyl and carboxylic acid functionalities is discussed.

(R)-3,4,5-Trideoxy-5,6-didehydro-1,2-O-(2,2,2-trichloroethylidene)-α-D-glucofuranose-6,3-carbolactone: a new derivative of α-chloralose

The title compound [systematic name: (R)-2-trichloro­methyl-3a,3b,7a,8a-tetra­hydro-5H-pyrano[2′,3′:4,5]furano[2,3-d][1,3]dioxol-5-one], C9H7Cl3O5, a triyclic system that contains a central α-d-furan­ose ring cis-fused with a dioxolane ring as well as a δ-lactone ring, exhibits a twisted conformation. The CCl3 group has an axial orientation. The furan­ose ring approximates an envelope conformation due to the α,β-unsaturated lactone functionality. The asymmetric unit contains two independent mol­ecules with almost identical geometries.

Synthesis and Antibacterial Activity of Highly Oxygenated 1,8-Cineole Derivatives

Seventeen mono-, di- and trifunctionalized 1,8-cineole derivatives carrying OH, OAc, keto and lactone functions at C-5, C-8 and C-9 were synthesized from 1,8-cineole with fair to excellent yields. The antibacterial activity of these synthetic compounds against Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Staphylococcus aureus using the agar dilution method was examined. Lactones 1,3-dimethyl-2-oxabicyclo[2.2.2]octan-8- endo-acetyloxy-5→9-olide (15) and 1,3-dimethyl-2-oxabicyclo[2.2.2]octan-8- endo-ol-5→9-olide (16) showed the highest antibacterial activity against all the three Gram negative bacteria assayed. A structure-activity relationship (SAR) study on the oxygenated 1,8-cineole derivatives has allowed a model to be proposed for the recognition of the minimal structural requirements for the antimicrobial effect.

Chemical Instability Determines the Biological Action of the Artemisinins

Artemisinin is a sesquiterpene compound of plant origin. It has a low molecular weight, and it contains five oxygen atoms, two in a lactone function, one is part of a seven membered ring system and two forms a peroxide function bridging over the seven-membered ring. It is a highly energetic molecule prone to lose its activity if circumstances permit. Reduction of its lactone function into dihydroartemisinin makes derivatization easy. Esterification and ether formation contribute to stability. Dihydroartemisinin exists preferably in a beta epimeric format but flip-flops with the alpha epimer. Solvation effects play a role. In doing so, open forms are created and they contribute to the instability, both of the peroxide and of the seven-membered ring. Artemisinins constitute a remarkable class of compounds which display instability both biologically and chemically due to the presence of various functional groups. Activity ranges from a wonderful action against a series of parasites, in particular malaria and schistosomiasis, to bacteria, fungi and selected viruses. The latest developments indicate a potential use in adjuvant cancer chemotherapy. The built-in chemical instability, necessary for biological action, causes serious pharmaceutical problems and only a restricted number of derivatives are useful. Problems are accelerated under tropical conditions and the basic active drug dihydroartemisinin cannot be used as such since it is prone to accelerated breakdown into a series of inactive products. The pitfalls of chemical instability and pharmaceutical stability are discussed in relation to the current uses of the drugs.

Synthesis of (±)-9-[ c-4, t-5-bis(hydroxymethyl)cyclopent-2-en- r-1-yl]-9 H-adenine (BCA) derivatives branched at the 4′-position based on intramolecular S H2′ cyclization

Synthesis of 4′-branched BCA analogues ( 5) was carried out. Stereospecific construction of the cis-disposed 4′-carbon-substituents and 5′-hydroxymethyl group was secured by employing the bicyclo[3.3.0]lactone 16 as a key intermediate, which was prepared by radical-mediated intramolecular S H2′ cyclization of the phenylselenomethyl ester 15. After manipulation of the double bond of 16, bis(Boc)adenine was introduced based on the Mitsunobu reaction of the allyl alcohol 24. Transformation of the lactone function of 27 allowed preparation of the 4′-hydroxymethyl ( 31), the 4′-vinyl ( 32), the 4′-cyano ( 34), and the 4′-ethynyl ( 35) derivatives. Anti-HIV and anti-HCV activities of the free nucleosides 36– 38 were also examined.

Useful approach to access germanicanes from betulin

A new semisynthetic access to germanicane-type triterpenes was achieved from betulin, a natural triterpene of the lupane family. The Wagner–Meerwein rearrangement of acetylated betulinic acid allowed the formation of the typical ring E of germanicanes and a lactone function. Several germanicane derivatives can be obtained via the lactone ring-opening such as 19β-machaerocerol and 19β-machaeroceric acid. The cytotoxicity of some compounds was evaluated against two cancerous cell lines.

Oligomerization of levoglucosan by Fenton chemistry in proxies of biomass burning aerosols

Reactions of levoglucosan with \( OH^{ \bullet } \) produced from Fenton chemistry were studied in solution serving as a proxy for biomass burning aerosols. Two modes of oligomerization (≤2000 u) were observed for reaction times between 1 and 7 days using matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF-MS) and laser desorption ionization time-of-flight mass spectrometry (LDI-TOF-MS). Single-mass unit continuum mass distributions with dominant −2 u patterns were measured and superimposed by a +176/+162 u oligomer series. This latter oligomer pattern was attributed to a Criegee rearrangement (+14 u) of levoglucosan, initiated by \( OH^{ \bullet } \), forming a lactone (176 u). The acid-catalyzed reaction of any ROH from levoglucosan (+162 u) forms an ester through transesterification of the lactone functionality, whereupon propagation forms polyesters. Proposed products and chemical mechanisms are suggested as sources and precursors of humic-like substances (HULIS), which are known to possess a large saccharic component and are possibly formed from biomass burning aerosols (Andreae, Global Biomass Burning, MIT Press, Cambridge, Massachusetts, 3–21, 1991).

Versatile and Practical Macrocyclic Reagent with Multiple Hydrogen-Bonding Sites for Chiral Discrimination in NMR

Bifunctional macrocycles 1-4 and diamide 5 were designed and synthesized. NMR studies demonstrated that, among them, receptor 1 functions as the best chiral solvating agent (shift reagent), which is effective for a wide range of chiral compounds having a carboxylic acid, oxazolidinone, carbonate, lactone, alcohol, sulfoxide, sulfoximine, sulfinamide, isocyanate, or epoxide functionality. The addition of only 5 mol % (69 microg, 0.15 mM) of 1 splits the enantiomeric signals of sulfoxide 13. The excellent performance of 1 as a chiral solvating agent, such as versatility, signal sharpness, high splitting ability, high sensitivity, wide detection window, and synthetic accessibility, is reported. NMR studies revealed that the principal binding site of 1 is the two amide NH groups of the lower segment and that the additional binding site is the pyridyl nitrogen. The V-shaped arrangement of the two 2,6-diacylaminopyridine moieties as constructed in 1 was found to be much more effective for binding a variety of compounds than the parallel alignment of the two binding motifs as constructed in 4. The NO2 group in 1 enhanced not only the binding ability but also the degree of enantioselectivity. Unexpectedly, the comparisons between 1 and 3 enabled us to find the importance of the relative orientation of the binaphthyl moiety; the orthogonal disposition of the binaphthyl moiety in 1 most effectively brings about the differential ring-current effect on the chiral guest molecule bound, which leads to the high degree of chiral discrimination in NMR.

Synthesis of a transition-state analog for the hydrolysis of the zearalenone lactone

The development of a catalytic antibody for the hydrolysis of the lactone functionality in zearalenone ( 1) is viewed as a potential solution to animal fertility problems associated with the estrogenic mycotoxin. A phosphonomacrolactone is proposed as a hapten for the generation of such antibodies. A suitably functionalized aryl phosphonic acid 4 was condensed with the racemic aliphatic fragment 5 via a Mitsunobu reaction. Macrocyclic formation was achieved via RCM to give advanced intermediate 23, a phosphonate analog of zearalenone, ready for deprotection and conjugation to a carrier protein.

Novel Stable Camptothecin Derivatives Replacing the E-Ring Lactone by a Ketone Function Are Potent Inhibitors of Topoisomerase I and Promising Antitumor Drugs

The E-ring lactone is the Achilles' heel of camptothecin derivatives: although it is considered necessary for the inhibition of the enzyme topoisomerase I (topo1), the opening of the lactone into a carboxylate abolishes the generation of topo1-mediated DNA breaks. S38809 is a novel camptothecin analog with a stable 5-membered E-ring ketone; therefore, it lacks the lactone function. DNA relaxation and cleavage assays revealed that S38809 functions as a typical topo1 poison by stimulating DNA cleavage at T downward arrow G sites. The activity was strongly dependent on the stereochemistry of the C-7 carbon atom that bears the hydroxy group. S38809 proved to be a potent cytotoxic agent, with a mean IC50 of 5.4 nM versus 11.6 nM for topotecan and 3.3 nM for SN38 (the active metabolite of irinotecan) on a panel of 31 human tumor cell lines. The cytotoxicity of S38809 and its ability to stabilize cleavable complexes was considerably reduced in camptothecin-resistant cells that express a mutated topo1, confirming that topo1 is its primary target. Cell death induced by topo1 poisoning requires the conversion of DNA single-strand breaks into double-strand breaks that can be detected by the formation of phosphorylated histone H2AX. In HCT116 cells, topotecan, SN38, and S38809 induced histone H2AX phosphorylation in S phase of the cell cycle, with S38809 being as potent as SN38 and 5-fold more potent than topotecan. In vivo, S38809 showed a marked antitumor activity against HCT116 xenografts. These findings open a new route for improving the pharmacological properties of camptothecin derivatives.

Aqueous Phosphoric Acid as a Mild Reagent for Deprotection of tert-Butyl Carbamates, Esters, and Ethers

Aqueous phosphoric acid (85 wt %) is an effective, environmentally benign reagent for the deprotection of tert-butyl carbamates, tert-butyl esters, and tert-butyl ethers. The reaction conditions are mild and offer good selectivity in the presence of other acid-sensitive groups, including CBZ carbamates, azetidine, benzyl and methyl esters, TBDMS, and methyl phenyl ethers. The mildness of the reaction is further demonstrated in the synthesis of clarithromycin derivative, in which a tert-butyl ester is removed in the presence of cyclic carbamate, lactone, ketal, acetate ester, and epimerizable methyl ketone functionalities. The reaction preserves the stereochemical integrity of the substrates. The reactions are high yielding, and the workup is convenient.