Synthesis and Reactions of a 2(5H)‐Furanone Bearing Two Furyl Substituents

A 2(5H)‐furanone bearing two furyl rings was synthesized. The behavior of this furanone toward some nitrogen nucleophiles, namely, hydrazine hydrate, benzylamine, and ammonium acetate, was studied. The nitrile group at position‐3 of the furanone was utilized to construct thiazolidine ring by the action of thioglycollic acid. The acid hydrazide synthesized from the previous step was allowed to react with some carbonyl compounds, namely, acetonylacetone, acetylacetone, ethyl acetoacetate, ethyl cinnamate, diethylmalonate, phthalic anhydride, benzil, and 4‐methoxybenzaldehyde, to form pyrrole, pyrazole, and pyrazolopyridazine ring systems bearing two furyl groups. The structures of all the products obtained were illustrated from their analytical and spectral data.     

Assessing the Molecular Targets and Mode of Action of Furanone C-30 on Pseudomonas aeruginosa Quorum Sensing

Quorum sensing (QS), a sophisticated system of bacterial communication that depends on population density, is employed by many pathogenic bacteria to regulate virulence. In view of the current reality of antibiotic resistance, it is expected that interfering with QS can address bacterial pathogenicity without stimulating the incidence of resistance. Thus, harnessing QS inhibitors has been considered a promising approach to overriding bacterial infections and combating antibiotic resistance that has become a major threat to public healthcare around the globe. Pseudomonas aeruginosa is one of the most frequent multidrug-resistant bacteria that utilize QS to control virulence. Many natural compounds, including furanones, have demonstrated strong inhibitory effects on several pathogens via blocking or attenuating QS. While the natural furanones show no activity against P. aeruginosa, furanone C-30, a brominated derivative of natural furanone compounds, has been reported to be a potent inhibitor of the QS system of the notorious opportunistic pathogen. In the present study, we assess the molecular targets and mode of action of furanone C-30 on P. aeruginosa QS system. Our results suggest that furanone C-30 binds to LasR at the ligand-binding site but fails to establish interactions with the residues crucial for the protein’s productive conformational changes and folding, thus rendering the protein dysfunctional. We also show that furanone C-30 inhibits RhlR, independent of LasR, suggesting a complex mechanism for the agent beyond what is known to date.     

Studies directed towards the synthesis of schisanartane and related complex nortriterpenoids: construction of models of the peripheral ABC and FGH segments of rubrifloradilactone C

A conceptually unifying and flexible approach to the ABC and FGH segments of the nortriterpenoid rubrifloradilactone C, each embodying a furo[3,2-b]furanone moiety, from the appropriate Morita-Baylis-Hillman adducts is delineated.     

A general,flexible, ring closing metathesis (RCM) based strategy for accessing the fused furo[3,2-b]furanone moiety present in diverse bioactive natural products

A simple and straightforward methodology of general utility to construct sterically encumbered furo[3,2-b]furanone scaffolds present in a diverse range of bioactive natural products is delineated. The methodology emanates from readily available Morita–Baylis–Hillman adducts and employs sequential ring closing metathesis and oxy-Michael addition cascade as the key steps.     

Synthesis of angularly fused cyclopentanoids and analogous tricycles via photoinduced ketyl radical/radical anion fragmentation-cyclization reactions

Angular fused tricycles were synthesized through intramolecular tandem fragmentation-cyclization reactions by photochemically induced electron transfer (PET) of tricyclic α-cyclopropyl ketones with an unsaturated side chain at the position γ to the carbonyl group. The reactions resulted in regioselective cleavage of a β-cyclopropyl bond with formation of angular fused tricyclic ring systems via ketyl radical/radical anions as reactive intermediates. In general, triethylamine (TEA) was used as a strong reducing reagent in acetonitrile. The preferred regioselectivity of the cyclization step (exo vs endo) depending on the substitution pattern at the quaternary carbon center (Cβ′) of the tricyclic α-cyclopropyl ketones was investigated. In addition, we also checked a two-step pathway for the synthesis of angular dioxa-triquinanes including photolysis of an allyloxy-substituted cyclopenta[c]furanone derivative and subsequent β-cleavage of the resulted dioxa-[4.5.5.5]fenestrane under reductive PET conditions.     

Substituted benzaldehydes in the darzens condensation with alkyl dihaloacetates

The Darzens reaction of dihaloacetic acid esters with aromatic aldehydes produces either arylhaloglycidic or arylhalopyruvic esters depending on the nature of the substituent in the aromatic ring. Alkyl p-methoxyphenylchloropyruvates undergo spontaneous intermolecular cyclocondensation to form pyranone or furanone derivatives depending on the character of the alkyl fragment. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1402–1410, August, 2006.     

Synthesis of Substituted Pyridazin-3-ones, 1,2-Oxazin-3-ones,and Furopyrimidines from (Arylmethylidene)furan-2(3<Emphasis Type="Italic">H</Emphasis>)-ones

Reactions of 5-substituted 3-(arylmethylidene)furan-2(3H)-ones with hydrazine hydrate, hydroxylamine, and guanidine involved opening of the furanone ring. Their hydrazinolysis under mild conditions afforded acyclic 4-oxoalkanoic acid hydrazides which underwent heterocyclization to substituted pyridazinones in boiling ethanol. The presence of an alkyl substituent in the 5-position of the initial furanone favored heterocyclization with the formation of pyrazolidinone derivatives. The reactions of 3-(arylmethylidene)furan-2(3H)-ones with hydroxylamine and guanidine also produced new six-membered heterocycles, 2H-1,2-oxazin-3(4H)-ones and 4,6-disubstituted 3,4-dihydrofuro[2,3-d]pyrimidin-2-amines, respectively.     

The chemistry of the highly reactive 2,6‐bis(bromomethyl)‐4‐pyrone

Under basic conditions 2,6‐bis(bromomethyl)‐4‐pyrone 8 reacts with tetraethylene glycol to yield the unexpected macrocycle 9 , which is related to the antibiotic Kjellmanianone 10 . We propose that this ring transformation proceeds via the cyclopropyl intermediate d (Scheme 2), which undergoes a ring opening reaction comparable to the Favorskii rearrangement. Also, 8 reacts with methanol/sodium methoxide to yield the 3(2H)‐furanone derivative 11 , the formation of which is suggested to proceed via the intermediate k with a carbenium‐oxonium‐ion subunit (Scheme 3). The structure of the 3(2H)‐furanone derivative was confirmed by X‐ray analysis.     

Exploratory studies toward the synthesis of the peroxylactone unit of plakortolides

Our efforts in construction the 1,2-dioxane ring of plakortolides through two approaches are described. The first one involved as a key step an acid catalyzed 6-endo ring closure of β-hydroperoxy trans-epoxides directed by a vinyl group adjacent to the epoxide function. By this route, an advanced intermediate of plakortolides was obtained in six steps and 35% overall yield. The second approach featured a 1,2-dioxane ring forming by a double opening of bis-epoxides by ethereal hydrogen peroxide. This reaction did not proceed in the expected sense and exclusive formation of hydroperoxy tetrahydropyran derivatives was observed via a tandem oxacyclization–hydroperoxidation sequence.     

A biomimetic synthesis of the indolo[3,2-j]phenanthridine alkaloid, calothrixin B

A biomimetic approach to calothrixin B via a hypothetical metabolite, 6-formylindolo[2,3-a]carbazole, is described. The construction of a suitable indolo[2,3-a]carbazole ring system was carried out using an allene-mediated electrocyclic reaction involving two [b]-bonds of indoles as the key step.     

A general and efficient method for the synthesis of benzo-(iso)quinoline derivatives

A new, short and efficient synthesis of substituted benzo-(iso)quinoline derivatives is reported. The methodology is based on a Suzuki or Negishi cross-coupling followed by a cyclization reaction induced by t-BuOK in DMF to form the central ring. This approach allowed the synthesis of all four benzo-(iso)quinoline isomers and the substitution of each ring of the benzo-(iso)quinoline core.     

(E)‐6‐Methoxy‐3‐(α‐methoxybenzyl­idene)benzo[b]furan‐2(3H)‐one at 173 K

The title compound, C₁₇H₁₄O₄, is an unprecedented new synthetic isoaurone‐type enol ether that has the E configuration. The planar furanone ring is fused to a methoxy­benzene ring system, with an interplanar angle of 175.7 (1)°. Due to this ring fusion, the six‐membered ring has a significant amount of ring strain, as shown by the internal ring angle range of 115.8 (1)–124.7 (1)°, whereas the vinylic phenyl ring has internal angles between 119.7 (1) and 120.2 (1)°. The mol­ecules form infinite hydrogen‐bonding layers along the b direction of the form C—H?O, where the keto O atom acts as a bifurcated acceptor. These layers are connected along the c direction by another hydrogen bond with a methoxy H atom as donor. In addition to this connection, the layers are stacked via centres of symmetry by a pair of symmetry‐related benzo­furan­one ring systems.     

Radical cyclizations of acylsilanes in the synthesis of (+)-swainsonine and formal synthesis of (−)-epiquinamide

Radical cyclization of acylsilane is an useful synthetic methodology. To demonstrate the versatility of this method using the cyclization as a key step, polyhydroxylated indolizidine (+)-swainsonine was synthesized through two different bond connection approaches to construct the bicyclic skeleton. In the first approach, we used 2,3-isopropylidene-d-ribono-1,4-lactone (20) as a chiral building block to form the indolizidine skeleton through a 1,6-cyclization. In the second approach, (S)-(+)-5-oxo-2-tetrahydrofurancarboxylic acid (23) was used to construct the same ring system through a 1,5-cyclization. Starting from acid 23, we also synthesized exo-1-hydroxyquinolizidin-4-one (56), which was a synthetic intermediate in the synthesis of polyhydroxylated quinolizidine (−)-epiquinamide.     

Synthesis and in vitro evaluation of taxol oxetane ring D precursors

A series of potential taxoid substrates was prepared in radiolabeled form to probe in vitro for the oxirane formation step and subsequent ring expansion step to the oxetane (ring D) presumably involved in the biosynthesis of the anticancer agent Taxol. None of the taxoid test substrates underwent transformation in cell-free systems from Taxus suggesting that these surrogates bore substitution patterns inappropriate for recognition or catalysis by the target enzymes, or that taxoid oxiranes and oxetanes arise by independent biosynthetic pathways.     

Stereoselective Triplet‐Sensitised Radical Reactions of Furanone Derivatives

The stereo‐ and regioselectivity of triplet‐sensitised radical reactions of furanone derivatives have been investigated. Furanones 7 a , b were excited to the ³ππ* state by triplet energy transfer from acetone. Intramolecular hydrogen abstraction then occurred such that hydrogen was transferred from the tetrahydropyran to the β position of the furanone moiety. Radical combination of the tetrahydropyranyl and the oxoallyl radicals led to the final products 8 a , b . In the intramolecular reaction, overall, a pyranyl group adds to the α position of the furanone. The effect of conformation was first investigated with compounds 9 a , b carrying an additional substituent on the tether between the furanone and pyranyl moiety. Further information on the effect of conformation and the relative configuration at the pyranyl anomeric centre and the furanone moiety was obtained from the transformations of the glucose derivatives 12 , 14 , 17 and 18 . Radical abstraction occurred at the anomeric centre and at the 5′‐position of the glucosyl moiety. Computational studies of the hydrogen‐abstraction step were carried out with model structures. The activation barriers of this step for different stereoisomers and the abstraction at the anomeric centre and at the 6‘‐position of the tetrahydropyranyl moiety were calculated. The results of this investigation are in accordance with experimental observations. Furthermore, they reveal that the reactivity and regioselectivity are mainly determined in the hydrogen‐abstraction step. Intramolecular hydrogen abstraction (almost simultaneous electron and proton transfer) in ³ππ* excited furanones only takes place under restricted structural conditions in a limited number of conformations that are defined by the relative configuration of the substrates. It is observed that in the biradical intermediate, back‐hydrogen transfer occurs leading to the starting compound. In the case of glucose derivatives, this reaction led to epimerisation at the anomeric centre.     

Synthesis of the C12-C24 fragment of peloruside A by silyl-tethered diastereomer-discriminating RCM

The C12-C24 fragment of peloruside A has been synthesized using, as a key step, a silyl-tethered ring closing metathesis reaction to form the C16-C17 (Z)-alkene. The metathesis reaction discriminates between diastereoisomers of the starting material. A diphenylsilyl bis-ether provides simultaneous protection for the C15 and C24 hydroxyl groups, and is expected to lead to high 1,5-anti selectivity in subsequent aldol reactions of the methyl ketone, allowing for a convergent stereoselective synthesis of peloruside A.     

Ti(III)-induced radical cyclization. A stereoselective entry to the perhydrobenzo[e]indene unit of new protein farnesyltransferase inhibitors, andrastins A-D

An efficient approach for the synthesis of a fully functionalized perhydrobenzo[e]indene, the BCD ring system of andrastins A-D, is described. The synthesis commences from (±)-Wieland-Miescher ketone and features a Ti(III)-induced radical cyclization as the central step.     

An approach for the enantioselective synthesis of biologically active furanones from a Morita-Baylis-Hillman adduct

Herein, we disclose an approach for the asymmetric synthesis of both enantiomers of an anti-inflammatory furanone. The approach is based on the utilization of a Morita-Baylis-Hillman adduct as starting material and has as key step a selective epoxide-opening/benzylic oxidation mediated by Palladium (II). This sequence afforded an advanced intermediate, which was used to accomplish the total synthesis. Experimental evidences allowed us to suggest a mechanistic proposal for the oxidation Palladium(II)-mediated.     

2-(对烷氧基苯甲酸酯基或对烷氧基苯丙烯酸酯基)-5-氧-2,5-二氢呋喃化合物的合成与液晶性质研究

Two series of p-alkoxybenzoates Ia-If and p-alkoxycinnamates IIa-IIf, each species beating one terminal furanone, have been synthesized and characterized by IR, ^13C NMR, ^1H NMR, MS spectra and elemental analysis. The mesogenic properties of both series of furanones have been studied by polarizing optical microscopy and differential scanning calorimetry （DSC）. The relationship between structures and mesogenic properties was discussed. The results show that the increased alkoxy chain length （C7-C12） and the bridging groups between the benzene ring and the furanone ring affected the mesomorphic properties greatly, and the two series of furanones might display monotropic or enantiotropic nematic （N） or semetic C （SmC） mesophases and different mesomorpic phase temperature ranges corresponding to different carbon chain length.     

General approach to 6-tosyl-2,3,4,5-tetrahydro-1H-1,3-diazepin-2-ones via nucleophile-mediated ring expansion of tetrahydropyrimidines

A general six-step approach to 6-tosyl-2,3,4,5-tetrahydro-1H-1,3-diazepin-2-ones has been developed. The key step involves a ring expansion reaction of 4-mesyloxymethyl- or 4-tosyloxymethyl-5-tosyl-1,2,3,4-tetrahydropyrimidin-2-one mediated by nucleophilic reagents.