MXPA00010133A - Production of furanones - Google Patents

Abstract

The present invention relates to the side chain functionalisation of fimbrolides (halogenated 3-alkyl-5-methylene-2(5H)-furanones) and their synthetic analogues, that yields fimbrolides substituted with a halogen, an oxygen or a nitrogen functionality in the alkyl chain, especially fimbrolide alcohols, carboxylate and sulfinate and sulfonate esters, ethers, aldehydes, ketones, acids, amides, nitro derivatives, hydrophobic, hydrophilic and fluorophilic alkyl derivatives and polymers.

Description

PRODUCTION OF FURANONAS Field of the Invention, ft. The present invention relates to the function of the chain fimbrolides (3-alkyl-5-methylene-2 (5H) -furanones halogenated) and their synthetic analogues, which produce fimbrolides substituted with a halogen, an oxygen function or a nitrogen function in the alkyl chain, especially alcohols of fimbrolide, carboxylate and sulfinate and sulfonate esters, ethers, • 10 aldehydes, ketones, acids, amides, nitro derivatives, and polymers.

Background of the Invention It is known that a variety of fimbrolides that possess antifungal and antimicrobial properties can be isolated from the red seaweed Delisea fimbriata, Delisea elegans and Delisea pulchra. The very few reported syntheses of functionalized fimbrolides use (E) -β-bromo-β-lithioacrylate or 3-formyl-β-methylfuran or allenes as starting materials. These syntheses are unnecessarily long, tedious and provide very fimbrolide casualties. The inventors of the present invention have recently reported the preparation of a range of fimbrolides having chain lengths of different sizes (Manny and associates (1997) Tetrahedron 53: 15813-15826, the description of which is incorporated in the present invention as reference. ).

Prior to the present invention, it had not been appreciated that the side chains of the fimbrolides could be directly functionalized allowing a variety of functionalized halogen or oxygen fimbrolides. We have discovered that the 5 fimbrolides behave similarly to allylic or benzylic compounds in their reactivity, and consequently they are receptive for free radical functionalization. The derived halogen compounds can be converted into alcohols or esters directly from the halogen derivatives, or into ketones, esters / amides, alcohols or other halides indirectly from corresponding alcohols or esters. The fimbrolides substituted with an appropriate group in the alkyl chain have the ability to produce polymers through said group, either directly or through copolymerization with suitable monomers. This is The preparation of these halides, alcohols, esters, ethers, amines, amides, and nitro compounds, ketones, oligomers and polymers based on fimbrolides, which form the main aspect of the present invention. The fimbrolides prepared according to the present The invention includes not only synthetic versions of the two fimbrolides that arise naturally, but also other functionalized fimbrolides that we consider to be novel compounds. The compounds synthesized according to the present invention may be in accordance with formula (I): 5 ro wherein R6 is H, OH, alkyl, alkoxy, oxoalkyl, alkenyl, aryl or arylalkyl, whether substituted or unsubstituted, straight chain or branched chain, hydrophobic, hydrophilic or fluorophilic; R2 and R3 are, independently or both, H or halogen; Rg is halogen; Z is independently selected from the group R6, halogen, OOH, OC (0) R6, = O, amine, azide, thiol, Re, mercaptoalkyl, alkenyloxy, mercaptoalkenyl, aryloxy, mercaptoaryl, arylalkyl, mercaptoarylalkyl, SC (0) R6, OS (0) R6, OS (0) 2R6, NHC (0) R6 = NR4 or NHR4; and R 4 is OH, alkyl, alkoxy, poly (ethylene glycol), alkenyl, aryl or arylalkyl. The compounds according to Formula (I), apart from those in which R1 = propyl, R2 = Br, R3 = H, Rg = Br and Z is OC (0) CH3 or OH, are considered new and are part of the present invention. In the structural formula provided in the present invention, a particular geometry does not take place unless it is specifically manifested. For example, the formulas are intended to cover both the Z-isomers and the E-isomers.

Summary of the Invention • In a first aspect, the present invention provides a method for forming a fimbrolide derivative, the method including the reaction of a fimbrolide with a halogenating agent and / or an oxygenation agent to form compounds with the formula ( the): Wherein R-i is hydrogen, alkyl, alkoxy, oxoalkyl, alkenyl, aryl or arylalkyl, whether substituted or unsubstituted, straight chain or branched chain, hydrophobic, hydrophilic or fluorophilic; X is a halogen (X = F, Cl, Br or I), OH, OOH, OC (0) R? or 20 = 0); R2 and R3 are, independently or both, hydrogen or halogen; and Rg is halogen. The fimbrolide used in the method can be a fimbrolide 25 having the formula: wherein Ri, R2, R3 and R9 are as defined above. Preferably, the halogenating agent is selected from N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, bromine, cupric bromine, and phenyltrimethylammonium perbromo. However, it will be appreciated that other halogenating agents would also be suitable for the present invention. Preferably, the oxygenation agent is selected from lead tetraacetate, Rose Bengal / oxygen gas, peroxide hydrogen / vanadium pentoxide, selenium dioxide, and 3-chloroperoxybenzoic acid. However, it will be appreciated that other oxygenation agents may also be suitable for the present invention. The reaction conditions are selected to be appropriate to the nature of the reaction that is taking place. Preferably, the reaction conditions, when a halogenating agent is used, are for example carbon tetrachloride or chloroform or dichloromethane / with or without light / reflux, tetrahydrofuran / room temperature.

Preferably, the reaction conditions, when an oxygenation agent is used, are acetic acid or acetic acid mixed with a solvent / reflux, pyridine / room temperature, acetone / 30 ° C, dioxane / reflux, and dichloromethane / temperature • ambient. The inventors of the present invention have discovered that the preferred bromination conditions are N-bromosuccinimide in the presence of catalytic amounts of benzoyl peroxide in carbon tetrachloride and light / reflux. The light source can be • For any suitable source, for example, the inventors of the present invention have discovered that a 250W sun lamp is very suitable. In a second aspect, the present invention consists of a fimbrolide derivative having the formula (la), where Ri is Hydrogen, alkyl, alkoxy, oxoalkyl, alkenyl, aryl or arylalkyl, whether substituted or unsubstituted, straight chain or branched chain, hydrophobic, hydrophilic or fluorophilic; X is a halogen (X • = Cl, Br or I) or oxygen (X = OH, OOH, 00 (0 ^ or = 0); R2, R3 are, independently or both, hydrogen or halogen and; Rg is Halogen, with the provision that the following two derivatives are excluded Ri = propyl, X = OH, R2 = Br, R3 = H; and R-i = propyl, X = OC (O) CH3, R2 = Br, R3 = H). In a third aspect, the present invention consists of a method for forming a fimbrolide derivative, including the method The displacement and / or functionalization of the halogen or oxygen substituent in the side chain of fimbrolide, treating with a nucleophile or an electrophile to form compounds with the formula (II): wherein R-i is hydrogen, alkyl, alkoxy, oxoalkyl, alkenyl, aryl or arylalkyl, whether substituted or unsubstituted, of straight chain or branched chain, hydrophobic, hydrophilic or fluorophilic; R2 and R3 are, independently or both, hydrogen or halogen; Rg is halogen; and R4 is selected from the group of halogen, amine, azide, hydroxyl, thiol, or any alkyl, alkoxy, mercaptoalkyl, f alkenyloxy, mercaptoalkenyl, aryloxy, mercaptoaryl, arylalkyloxy, mercaptoarylalkyl, OCYO J RL SC (0) R? , OS (O) RI, OS (0) 2RI, NHC (O) R? , OC (0) N H R? , o = O, hydrophobic, hydrophilic or fluorophilic. The fimbrolide treated in the method of the third aspect can be a compound of the formula: wherein R-i, R2, R3 and R9 are as defined above and R7 is halogen (F, Cl, Br or I), OH, OOH, OC (0) R? o = 0); Preferably the nucleophile is selected from metal halides, water, organic metal carboxylates, organic alcohols, dimethyl sulfoxide, and organonitriles. However, it will be appreciated that other nucleophiles may also be suitable for the present invention. Preferably the electrophile is selected from acids organic, isocyanates, carboxylic or sulfonic acid halides or acylating or active sulfinylating agents, such as imidazoles , carbonyl f, carboxylic anhydrides, carboxylic acids activated for carbodiimide, sulfonyl halides, and sulfonic anhydrides and diethylaminosulfur trifluoride. However, it will be appreciated that Other electrophiles will be suitable for the present invention. The reaction conditions of the method of the third aspect are selected to be appropriate to the nature of the reaction that is taking place. Suitable reaction conditions, when a nucleophile is used, are acetone or dioxane / room temperature or reflux, water / dioxane or acetone or tetrahydrofuran / reflux, metal acetates / organic acids / pure or high boiling / reflux solvents, alcohols organic / reflux, dimethyl sulfoxide / room temperature, and organonitriles / 5 silver acid / triflate catalyst / reflux. The reaction conditions, when using an electrophile, are organic / pure acids and / or solvent / acid / reflux catalyst, organic acid halides or anhydrides or isocyanates / base catalyst / solvent / room temperature, and diethylaminosulfide trifluoride / dichloromethane / low temperature. In a fourth aspect, the present invention consists of a fimbrolide derivative having the formula (II), wherein Ri is hydrogen, alkyl, alkoxy, oxoalkyl, alkenyl, aryl or arylalkyl, whether substituted or unsubstituted, straight chain or branched chain, hydrophobic, hydrophilic or fluorophilic; R2 and R3 are, independently or both, hydrogen or halogen; Rg is halogen, and R4 is selected from the group of halogen, amine, azide, hydroxyl, thiol, or any alkyl, alkoxy, mercaptoalkyl, alkenyloxy, mercaptoalkenyl, aryloxy, mercaptoaryl, arylalkyloxy, or mercaptoarylalkyl, OC (O) R? , SC (O) R? , OS (0) R? , OS (O) 2R? , N HCIOJRL OC (0) N H RI, or = O, hydrophobic, hydrophilic or fluorophilic, with the proviso that the following two derivatives are excluded R1 = propyl, X = OH, R2 = Br, R3 = H; 2. R1 = propyl, X = OC (O) CH3, R2 = Br, R3 = H.

In a fifth aspect, the present invention consists of a method for forming a fimbrolide derivative, the method including the reaction of a hydroxyl substituent on the side chain of fimbrolide with an oxidation agent to form a compound of • agreement with the formula (l l l): (m) wherein R2 and R3 are, independently or both, hydrogen or halogen; R5 is OH or the same as R-i; R9 is halogen; and R i is hydrogen, alkyl, alkoxy, oxoalkyl, alkenyl, aryl or arylalkyl, whether substituted or unsubstituted, straight chain or branched chain, hydrophobic, hydrophilic or fluorophilic; • The fimbrolide substituted by hydroxyl used in the method of the fifth aspect, can have the formula: where R5, R2 and 3 are as described above.

Preferably, the oxidizing agents are acidic chromium reactants in any form, either free or supported polymer (eg Jones reagent, pyridinium chlorochromate, pyridinium dichromate, chromium trioxide, etc.), dioxide • 5 manganese, potassium permanganate, selenium dioxide, ceric ammonium nitrate, ruthenium tetraoxide, and hot nitric acid. However, it will be appreciated that other oxidation agents can also be used for the present invention. The reaction condition, under which the method of the third aspect is carried out, can be any suitable condition. The reaction conditions preferably use Jones reagent / with or without phase / acetone / room temperature / room temperature, toluene / reflux, potassium permanganate / buffered / room temperature, dioxane / reflux, ceric ammonium nitrate / aqueous acetic acid / steam bath, carbon tetrachloride / reflux, and acetic acid / steam bath. However, it will be appreciated that other reaction conditions may also be used for the present invention. The inventors of the present invention have found that the use of Jones reagent in acetone / room temperature is particularly suitable. In a sixth aspect, the present invention consists of a fimbrolide derivative having the formula (11), wherein R-i is hydrogen, alkyl, alkoxy, oxoalkyl, alkenyl, aryl or arylalkyl, whether substituted or unsubstituted, straight chain or branched chain, hydrophobic, hydrophilic or fluorophilic; R2 and R3 are, independently or both, hydrogen or halogen; Rg is halogen; and R5 is OH or the same as R-i. The present invention also provides a method for forming oximes, mines, hydrazones and fimbrolide amines. Therefore, in a seventh aspect, the present consists of a method for forming an analogous fimbrolide derivative from a compound of the formula (11), the method including the reaction of an aldehyde or ketone substituent on the side chain of fimbrolide of the compound, with an amine derivative to form a compound with the formula (IV) or (V): wherein R-i is hydrogen, alkyl, alkoxy, oxoalkyl, alkenyl, aryl or arylalkyl, whether substituted or unsubstituted, straight chain or branched chain, hydrophobic, hydrophilic or fluorophilic; R2 and R3 are, independently or both, hydrogen or halogen; Rg is halogen; and R8 is OH, NHRi, NHC (X) NH2, N HC (X) N HR! (X = O, S, NRi) or any R ^ Preferably, the amine derivatives used are hydroxyl amine hydrochloride, alkyl and aryl hydrazines, amine • alkyl or aryl in the presence or absence of a reducing agent. However, it will be appreciated that other amine derivatives may also be used for the present invention. The reaction conditions used in the method of the seventh aspect can be any suitable conditions f 10 for the nature of the reaction carried out. For example, when an amine derivative is used, suitable conditions are ethanol or methanol / room temperature or reflux, toluene in the presence of a catalyst / room temperature or reflux and ethanol or methanol in the presence of sodium borohydride or cyanoborohydride. sodium / room temperature or reflux. In an eighth aspect, the present invention consists of a fimbrolide derivative having the formula (IV) and (V), wherein Ri is hydrogen, alkyl, alkoxy, oxoalkyl, alkenyl, aryl or arylalkyl, whether substituted or unsubstituted , straight chain or branched chain, hydrophobic, hydrophilic or fluorophilic; R2 and R3 are, independently or both, hydrogen or halogen, Rg is halogen and R8 is OH, NHR-,, NHC (X) N H2, NHC (X) NHR-, (X = 0, S, NR1) or any R- | . In a ninth aspect, the present invention provides an oligomer or polymer formed by oligomerization or polymerization of a compound according to the present, directly or with one or more other monomers. The one or more other monomers may be any suitable polymerizable copolymer, for example, acrylate ester such • 5 as alkyl, hydroxyalkyl, aminoalkyl, or substituted aryl, acrylates or methacrylates, crotonates, substituted or unsubstituted acrylonitriles, vinyl alcohols or acetates, and styrene. In a tenth aspect, the present invention consists in incorporating fimbrolides according to the first, third, fifth of 10 seventh aspects of the present invention, whether in surface covers or polymers, through the newly introduced function in the chain alkyl or in the alkyl chain by itself, through direct polymerization or copolymerization with suitable monomers. In an eleventh aspect, the present invention consists of a fimbrolide derivative produced by the method according to the first, third, fifth or seventh aspects of the present invention. In a twelfth aspect, the present invention consists of the use of a fimbrolide derivative according to the present invention.

The inventors of the present invention have discovered that many of the fimbrolide derivatives having the formula (I) have antimicrobial, antiseptic, microbacterial static and / or algae antigeneration properties. Therefore, the fimbrolide derivatives are suitable for use as agents antimicrobial and / or antigeneration of algae.

In a thirteenth aspect, the present invention provides a compound of the formula (VI): (SAW) wherein R2, R3, Rg and R-i (except when R1 is hydrogen) are as defined above. f 10 An example of a compound according to this form of the present invention is 4-Bromo-5- (bromomethylene) -3- (1-butenyl) -2 (5H) -furanone. The thirteenth aspect compound can be formed by dehydrating the hydroxyl substituent on the fimbrolide side chain. The dehydration can be catalyzed by H2SO4 in the presence of toluene. As used in the present invention in the • Claims: The term "halogen" means F, Cl, Br, or I. The term "alkyl" is taken to mean straight chain, branched chain cyclic alkyl or cycloalkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, and the like. Preferably, the alkyl group is from 1 to 25 carbon atoms. The alkyl group can be optionally substituted by one or more fluorine, chlorine, bromine, iodine, carboxyl, C 1 -C 4 alkoxycarbonyl, hydroxyl, carbonyl and aryl groups. The term "aryl" is taken to include phenyl, naphthyl or other aromatic abac benzenoid or any other aromatic heterocyclic nucleus containing N, O, S, P or chalcogen heteroatom such as pyridyl, pyrimidyl, indolyl or furanyl. The term "alkoxy", as used in the present invention in the claims, denotes straight or branched chain alkoxy, preferably containing from 1 to 25 carbon atoms. ^ 10 carbon and similar functional groups, such as polyethylene glycol (PEG) and cyclic ethers. The term "alkenyl" is taken to mean a straight chain, a branched chain or cycloalkyl groups having one or more double bonds. Preferably, the alkyl group is from 1 to 25 carbon atoms. The alkyl group can be optionally substituted by one or more halogen atoms, carbonyl, hydroxyl, carboxyl, C 1 -C 4 alkoxycarbonyl groups. The term "amine", as used in the present description in the claims, means any primary, secondary or tertiary basic nitrogen containing group or molecule, aromatic or non-aromatic. Throughout this specification, unless the context requires otherwise, the word "understand", or variations such as "comprises" or "comprising", shall be understood to mean implies the inclusion of an element, member or step manifested, or group of elements, members or step, but not the exclusion of any other element, member or step, or group of elements, members or steps. In order that the present invention may be understood more clearly, preferred forms will be described with reference to the examples and drawings that follow.

Brief Description of the Drawings Figure 1 shows the structure of Delisea pulchra furanones and synthetic analogues and derivatives tested in the acorn settlement trial. Figure 2 shows the effect of furan? > RAS 2, 281, 2223, 2425, 26, 27, and 28 on the settlement of acornic larva larvae, as measured by the settlement expressed as a percentage of control. Figure 3 shows the growth curves of Staphylococcus aureus against different furanones. Figure 4 shows the growth curves of Staphylococcus aureus against compounds 33/34 and 45. Figures 5-5I show the structural formulas of other specific examples of compounds according to the present invention.

Detailed Description of the Invention Ways to Carry Out the Present Invention DETAILS OF THE EXPERIMENT Production of Fimbrolida ^ General. The melting points are not corrected. The microanalyses were carried out by Dr. H. P. Pham of the University of the New Microanalytical Laboratory of South Wales (REVISECT DRAFTING). 1 H NMR spectra were obtained in CDCI3 on a Bruker AC300F spectrometer (300 MHz) or a Bruker DMX500 (500 MHz). 13C NMR were obtained in the same solvent in a 10 Bruker AC300F spectrometer (75.5 MHz) or a Bruker DMX500 (125.8 MHz). The chemical changes in the scale d referenced internally for the solvent peaks were measured: CDCI3 (d 7.26, d 77.04). The ultraviolet spectra were measured in a Hitachi U-3200 spectrophotometer and referred to solutions in absolute MeOH. The infrared spectra were recorded on a Perkin-Elmer 298 spectrophotometer or a Perkin-Elmer 580B spectrophotometer, and referred to paraffin mulls. The electron impact mass spectra were recorded on a VG Quattro mass spectrometer with an ionization voltage of 70eV and at a source temperature of 20 ions of 200 ° C. The FAB spectra were recorded on an AutoSpecQ mass spectrometer. Column chromatography was carried out using Merck 60H silica gel (Art. 7736), while preparation thin layer chromatography was carried out on 2 mm plates using Merck silica gel 6OGF254 (Art. 7730). 25 RESULTS Fimbrolida Production The following are examples of a number of produced fimbrolides. EXAMPLE 1 • 4-Bromo-5- (bromomethylene) - and 5- (dibromomethylene) -3- (1-bromoethyl) -2 (5H) -furanone N-bromosuccinimide (17.3 g, 0.097 mol) was added to a solution of 4-Bromo-5- (bromomethylene) - and / or 5- (dibromomethylene) -3-ethyl-2 (3H) -furanone (22.6 g, 0.08 mol) in carbon tetrachloride • 10 (500 mL), which contains benzoyl peroxide (0.25 g). The mixture was irradiated with a 250 W lamp and refluxed in a bath of oil for 18 hours. After cooling the mixture to room temperature, it was filtered and the precipitate was washed with carbon tetrachloride (50 mL). The filtrate was evaporated under Reduced pressure and the crude product was purified by silica gel chromatogy using dichloromethane / light petroleum (2: 3) as the eluent, to yield the bromine compounds (22. g, 76%) in the form of a mixture. : 1 . 4-Bromo-5- (bromomethylene) -3- (1-bromoethyl) -2 (5H) -furanone A pale yellow solid, m.p. 79 ° C. vmax 2850, 1750, 1630, 1580, 1440, 1360, 1270, 1 180, 1065, 1000, 970, 940, 1080, 755 cm "1. ? max 306 nm (e 10826). 1 H n .m.r. d (CDCl 3) 2.06, cl, J 7.2 Hz, (H2 ') 3; . 00, q, J 7.2 Hz, H 1 '; 6.45, s, 5-CHBr. 13C n.m.r. d (CDCI3): 22.3, C2 '; 35.7, C 1 '; 94.3, 5-CHBr; 130.5, C4; 133.7, C; 149.5, C5; 165.8, C2. Mass spectrum: m / z 364 (M (8 Br 3), 2%); 362 (M (81 Br2, 79 Br), 8); 360 (M (81Br 79Br2), 8); 358 (M (79Br3), 2); 283 (85); 281 (100); 279 (85); 202 (12); 200 (12); 173 (18); 158 (35); 156 (35); 145 (38); 143 (42); 133 (28); 121 (26). 5- (Dibromomethylene) -3- (1-bromoethyl) -2 (5H) -furanone • A white solid m.p. 119 ° C. vmax 2900, 1720, 1590, 1450, 1370, 1250, 1170, 1080, 1060, 1000, 960, 840, 770, 720 crtT1. ? max 319 nm (e 12225). 1H n.m.r. d (CDCl 3): 1.99, t, J 7.2 Hz, (H2 ') 3; 4.87, q, J 7.2 Hz, H1 '; 7.56, s, H4. 13C n.m.r. d (CDCl 3): 23.9, C2 '; 36.0, C1"; 82.8, (5-CBr2); 134.7, C4; 138.2, C3; 149., C5; 165.5, C2.

Mass spectrum: m / z 364 (M (81Br3), 9%); 362 (M (81Br2, 79Br), 18); 360 (M (81Br 79Br2), 18); 358 (M (79Br3), 9); 283 (78); 281 (100); 279 (78); 227 (8); 225 (12); 223 (8); 202 (22); 200 (32); 174 (18); 172 (44); 146 (42); 145 (50); 144 (50); 143 (60). EXAMPLE 2 3- (1-Bromobutyl) -5- (dibromomethylene) -2 (5H) -furanone The procedure described for 4-bromo-5-w (bromomethylene) - and 5- (dibromomethylene) -3- ( 1-bromoethyl) -2 (5H) -furanone, to treat 3-butyl-5- (dibromomethylene) -2 (5H) -furanone (4.95 g, 16 mmol) with N-bromosuccinimide (3.83 g, 22 mmol) in carbon tetrachloride (70 mL), to provide after chromatogy the bromobutyl furanone in the form of a yellow solid (5.48 g, 88%). m.p. 55 ° C. vmax 3087, 2924, 2854, 1778, 1463, 1377, 967, 832 cm-1. ? max 314.2 nm (e 281 15). 1 H NMR d: 0.99, t, 3H, H-4 '; 1.50 m, 2 H, H-3 '; 2.10 m, 2H, H-2 '; 4.72 t, 1 H, H-1"; 7. 54 s, 1 H, H4. Mass spectrum: m / z 392 (M + 1 (81 Br3); 389 (M + 1 (81 Br, 79Br2); 386 (M + 1 (79Br3); 31 1; 309; 307; 269; 267 (100 %); 265. EXAMPLE 3 4-Bromo-5- (bromomethylene) - and 5- (dibromomethylene) -3- (1-acetoxybutyl) -2 (5H) -furanone A solution of 4 was refluxed for 18 hours. -bromo-5- (bromomethylene) - and / or 5- (dibromomethylene) -3- (1-bromobutyl) -2 (5H) -furanone (3.00 g, 7.7 mmol) in glacial acetic acid (160 mL) containing acetate Sodium (1.20 g, 15 mmol) The mixture was concentrated to approximately 20 mL and neutralized with an excess saturated sodium carbonate solution.The residual oil was extracted with ether (3 x 100 mL), washed with brine. Drying over sodium sulfate and evaporating The crude product was chromatoged on silica gel using dichloromethane / light petroleum (11) as the eluent to produce the acetoxybutylfuranones (0.96 g, 34%) in the form of a 4: 1 mixture. 4-Bromo-5- (bromomethylene) -3- (1-acetoxybutyl) -2 (5H) -furanone A pale yellow oil vmax 2940, 1775, 1740, 1640, 1600, 1450, 1420, 1370, 1220, 1 100, 1020, 985, 760, 730 cm'1. ? max 295 nm (e 6265). 1 H n.m.r. d (CDCl3) 0.93, t, J 7.2 Hz, (H4 ') 3; 1.35, m, (H3 ') 2; 1.84, m, (H2 ') 2; 2.07, s, COCH3; 5.50, bt, J 7.2 Hz, H 1 '; 6.37, s, 5-CH Br. 13C n .m.r. d (CDCl 3): 13.5, C4 '; 18.5, COCH3; 20.6, C3 '; 33.7, C2 '; 68.2, C1 '; 93.5, 5-CHBr; 130.2, C4; 1 31 .4, C3; 149.7, C5; 164.2, C2; 170.2, CO. Mass spectrum: m / z 370, (M (81 Br2), < 5%); 368 (M (81 Br, 79 Br), < 5); 366, (M (79Br2), < 5); 327 (18); 325 (26); 323 (18); 289 (22); 287 (22); 285 (14); 283 (28); 281 (14); 247 (12); 245 (12); 229 (14); 227 (14); 149 (28). 5- (Dibromomethylene) -3- (1-acetoxybutyl) -2 (5H) -furanone f A pale yellow solid m.p. 76 ° C. vmax 2880, 1760, 1735, 1445, 1370, 1225, 1170, 1100, 1030, 950, 840, 765, 7320 cm'1. ? max 314 nm (e 8900). 1H n.m.r. d (CDCl3) 0.94, t, J 7.2 Hz, (H4 ') 3; 1.36, m, (H3 ') 2; 1.84, m, (H2 ') 2; 2.12, s, COCH3; 5.59, bt, J 6.2 Hz, H1 '; 7.39, bs, H4.13C n.m.r. d (CDCl 3): 13.6, C4 '; 18.3, COCH3; 20.9, C3 '; 34.8, C2 '; 68.3, C1 '; 81.6, 5-CBr2; 135.0, C4; 136.1, C3; 149.3, C5; • 10 166.1, C2; 169.9, CO. Mass spectrum: m / z 370, (M (81Br2), 28%); 368 (M (81 Br, 79 Br), 54); 366, (M (79Br2), 28); 328 (20); 327 (18); 326 (36); 325 (28); 324 (20); 323 (18); 289 (16); 287 (16); 247 (16); 245 (16); 229 (12); 227 (12); 198 (10). EXAMPLE 4 5- (Dibromomethylene) -3- (1-acetoxyethyl) -2 (5H) -furanone The described procedure was used for 4-bromo-5- (bromomethylene) -3- (1-acetoxybutyl) -2 (5H) ) -furanone to treat 5- (dibromomethylene) -3- (1-bromoethyl) -2 (5H) -furanone (2.80 g, 7.7 mmol), with sodium acetate (1.20 g, 15 mmol) in glacial acetic acid (160 20 mL), to provide after chromatography the acetoxyethyl furanone in the form of a white solid (0.88 g, 34%) mp 124 ° C. vmax 2880, 1750, 1610, 1445, 1365, 1230, 1170, 1080, 1030, 990, 960, 930, 835, 760, 715 cm'1. ? max 313 nm (e 31296). 1H n.m.r. d (CDCl 3) 1.53, d, J 6.2 Hz, (H2 ') 3; 2.13, s, COCH3; 5.66, m, 1H, H1 '; 7. 43, bs, H4. 13C n.m.r. d (CDCl 3): 18.9, CH 3; 20.9, C2 '; 53.4, C1 '81.7, 5-CHBr; 134.6, C4; 136.7, C3; 149.2, C5; 166.0, C2; 169.6, CO Mass spectrum: m / z 342, (M (81Br2), < 5%); 340 (M (81Br, 79Br), 6) 338, (M (79Br2), < 5); 300 (30); 299 (26); 298 (62); 297 (44); 296 (32) • 5 295 (22); 281 (22); 279 (18); 261 (34); 259 (37); 219 (68); 217 (70) 201 (32); 200 (31); 199 (34); 174 (20); 172 (30); 170 (14); 157 (22) 145 (28); 143 (24). EXAMPLE 5 5- (Dibromomethylene) -3- (1-thioacetoxyethyl) -2 (5H) -fu? Anone ^ 10 A solution of 5- (dibromomethylene) -3- (1-bromoethyl) was refluxed for 12 hours. -2 (5H) -furanone (3.00 g, 7.7 mmol) in glacial acetic acid (160 mL) containing potassium thioacetate (1.20 g, 15 mmol). The mixture was concentrated to approximately 20 mL and neutralized with a solution of saturated sodium carbonate in excess. The residual oil was extracted with ether (3 x 100 mL), washed with brine, dried over sodium sulfate and evaporated. The crude product was chromatographed on silica gel, using dichloromethane / light petroleum (1: 1) as the eluent, to yield the thioacetoxyethylphuranones (0.96 g, 34%) in the form of a yellow oil. vmax 3200, 2910, 2850, 1780, 1730, 1690, 1600, 1450, 1420, 1380, 1350, 1270, 1170, 1105, 1010, 960, 880, 850, 810, 770 cm "1.? max 297 nm (e. 6664) .1H NMR d: 1.61 (d, 3H, J 7.2 Hz, H-2 '), 2.52 (s, 3H, SCOCH3), 4.49 (q, 1H, J 7.2 Hz, H-1'), 7.44 ( s, 1H, H4) Mass spectrum: m / z 358 (M (81Br2)), 356 (M (81 Br, 79Br)); 354 (M (79Br2)); 316, 314, 312, 283, 281 , 279, 277, 275, 235, 233, 200, 172, 153, 143. EXAMPLE 6 4-Bromo-5- (bromomethylene) -3- (1 -acetamidobutyl)) - 2 (5H) -furanone Trimethylsilyl trifluoromethanesulfonate was added (0.1 mL), with stirring to a cooled solution of 4-bromo-5- (bromomethylene) -3- (1-hydroxybutyl) - 2 (5H) -furanone (0.12 g, 0.37 mmol) in acetonitrile (10 mL) at a temperature of 5 ° C. After the reaction mixture was stirred for 1 hour at room temperature, it was quenched with water (20 mL) and extracted with ether (3 x 40 mL) .The combined ether extracts were washed with brine, dried over sodium sulphate and evaporated to produce the amide in the form of a light brown oil (0.1 g, 74%). Recrystallization of the crude product from dichloromethane / light petroleum afforded the pure amide in the form of a yellow powder, m.p. 153-55 ° C 1 H n.m.r. d (CDCl3) 0.93, t, J 7.2 Hz, (H4 ') 3; 1 .24-1 .40, m, (H3 ') 2; 1 .66-1 .77, m, (H2 ') 2; 1.98, s, M HCOCH3; 5.02, q, 7.9 Hz, H 1 '; 6.25, bd, J 8.7 Hz, N H; 6.38, s, 5-C HBr. 13C n.m.r. d (CDCl 3): 13.5, C4 '; 19.0, C3 '; 23.1, N HCOCH3; 35.2, C2 '; 45.7, C1 '; 93.6, 5-CHBr; 130.9, C4; 131 .9, C3; 149.6, C5; 165.3, C2; 169.6, N HCO. Mass spectrum: m / z 369, (M (81 Br2), < 5%); 367 (M (81 Br, 79 Br), < 5); 365, (M (79Br2), < 5); 362 (5); 364 (5); 326 (18); 324 (30); 322 (18); 284 (28); 282 (53); 280 (30). EXAMPLE 7 5- (Dibromomethylene) -3- (1-hydroxyethyl) -2 (5H) -furanone A solution of 5- (dibromomethylene) -3- (1-bromoethyl) was refluxed in an oil bath for 3 hours. -2 (5H) -furanone (18.0 g, 0.05 mol) in a mixture of dioxane (200 mL) and sulfuric acid (3M, 35 mL). After cooling the mixture to room temperature, • 5 was diluted with water (300 mL) and extracted with dichloromethane (3 x 200 mL). The combined dichloromethane extracts were washed with water, dried and evaporated. The crude product was purified by silica gel chromatography, using dichloromethane / light petroleum (1: 1) as an eluent to produce the f-10-hydroxyethyl furanone (9.6 g, 62%) in the form of a white solid. vmax 3300, 2870, 1750, 1595, 1440, 1370, 1250, 1170, 1030, 985, 955, 835, 770, 720 cm "1.? max 311 nm (e 5832). 1 H nmr d (CDCl 3) 1.50, d. , J 7.2 Hz, (H2 ') 3, 4.72, m, 1H, H1', 7.49, bs, H4, 13C nmr d (CDCl3): 21.8, C2 ', 63.4, C1', 81.3, 5-CHBr, 133.7 , C4; 140.3, C3; 149.5, C5; 167.3, C2. Mass spectrum: m / z 300, (M + 1 (81Br2), 18%); 298 (M + 1 (81 Br, 79 Br), 36); 296, (M + 1 (79Br2), 18); 285 (22); 283 (41); 281 (28); 257 • (78); 255 (100); 253 (78); 219 (15); 217 (15); 201 (22); 200 (34); 199 (36); 174 (24); 172 (38); 170 (18); 147 (21); 145 (28); 119 (38); 117 (38). EXAMPLE 8 5- (Dibromomethylene) -3- (1-hydroxybutyl) -2 (5H) -furanone The described procedure was used for 5- (dibromomethylene) -3- (1-hydroxyethyl) -2 (5H) -furanone for Treat 3 - (1-acetoxybutyl) -5- (dibromomethylene) -2 (5H) -furanone (0.70 g, 1.9 mmol) with acid Sulfuric acid (3 M, 5 mL) in dioxane (30 mL) to provide after chromatography the hydroxybutyl furanone in the form of a yellow oil (0.42 g, 68%). vmax 3441, 2960, 2931, 2873, 1779, 1615, 1267, 1 174, 1020, 965, 848 cm "1.? max 303.6 nm (e 1 161).

• NMR d: 0.95 (t, 3H, H-4 '); 1.43 (m, 2H, H-3 '); 1.78 (m, 2H, H-2 '); 3.22 5 (s, 1 H, OH); 4.58 (d, 1 H, H-1 '); 7.52 (s, 1 H, H4). Mass spectrum: m / z 328 (M (81 Br2)); 326 (M (81 Br, 79 Br)); 324 (M (79Br2)); 299; 297; 285; 283 (100%); 281; 257; 255; 253; 247; 245; 203; 205; 175; 173. EXAMPLE 9 5- (Dibromomethylene) -3- (1-fluoroethyl) -2 (5H) -furanone • 10 A cooled solution of 5- (dibromomethylene) -3- (1-hydroxyethyl) was added dropwise with stirring. ) -2 (5H) -furanone (0.47 g, 1.6 mmol) in analytical grade dichloromethane (2 mL), to a solution of trifluoride (diethylamino) sulfide (1 mL) in dichloromethane (2 mL), and maintained in a cooling bath with ice dry / acetone. The progress of the reaction was monitored by thin layer chromatography. At the end of the reaction, the mixture was added dropwise to a conical vial containing water (100 mL). The product was extracted with dichloromethane (3 x 50 mL) and the organic layer was dried over anhydrous sodium sulfate. The crude product was chromatographed on a silica column using dichloromethane as the eluent. The Rf fraction of 0.90 in dichloromethane was collected and evaporated to yield the fluoro compound (0.47 g, 97%) in the form of a yellow solid m.p. 41 ° C. vmax 3096, 2924, 2854, 1790, 1754, 1609, 1463, 1376, 1264, 1 192, 1092, 990, 847, 771 cm'1. ? max 306.4 nm (e 4269). 1 H NMR d: 1.62 (m, 3H, H-2 '); 5.34, 5.52 (m, 1H, H-V (CHF)); 7.58 (s, 1H, 5-CHBr). 13C n.m.r. d (CDCl 3): 19.7 and 19.8, C2 '; 82.3, CBr2; 83.4 and 85.6, C1 '; 134.4, C4; 136.5 and 138.5, C3; 149.2, C5; 165.7, CO. Mass spectrum: m / z 302 (M (81Br2); 300 (M (81Br, 79Br); 298 (M (79Br2); 202; 200; 198; 175 (100%); 172; 170. EXAMPLE 10 5- (Dibromomethylene) -3- (1-fluorobutyl) -2 (5H) -furanone The procedure described for 5- (dibromomethylene) -3- (1-fluoroethyl) -2 (5H) -furanone was used to treat 5- (dibromomethylene) ) -3- (1-hydroxybutyl) -2 (5H) -furanone (0.24 g, 0.74 mmol) with trifluoride (diethylamino) sulfide (1.0 mL) in dichloromethane (3 mL), to provide after the chromatography the fluorobutyl furanone in the form of a pale yellow oil (0.23 g, 97%) vmax 3084, 2961, 2874, 1780, 1614, 1465, 1379, 1266, 1180, 1026, 966, 847, 784, 680 cm'1. 308.6 nm (e 24923) .1H NMR d: 0.95 (t, 3H, H-4 '); 1.52 (m, 2H, H-3'); 1.88 (m, 2H, H-2 '); 5.2, 5.4 (m, 1H, H-1 '(CHF)), 7.56 (s, 1H, 5-CHBr). 13C nmr d (CDCl 3): 13.5, C4'; 17.8, C3 '; 35.6 and 35.9, C2 '; 82.1, 5-CBr2; 86.5 and 88.8, C1 '; 134.8, C4; 135.7 and 135.7 and 136.0, C3; 149.3, C5; 165.7 and 165.8, CO. Mass spectrum: m / z 330 (M (81Br2); 328 (M (81Br, 79Br); 326 (M (79Br2); 288; 286; 284; 247 (100%); 207; 205. EXAMPLE 11 4- Bromo-5- (bromomethylene) -3- (1-butanoyloxybutyl)) -2 (5H) -furanone 4-bromo-5- (bromomethylene) -3- (1-hydroxybutyl) was refluxed together for 7 hours. -2 (5H) -furanone (4.75 g, 0.015 mol) and butanoyl chloride (7.8 mL, 0.075 mmol), and subsequently were cooled and poured into water (50 mL) and extracted with ether (3 x 30 mL). Combined ether extracts were washed consecutively with saturated sodium bicarbonate (2 x 50 mL) and • 5 brine (50 mL), dried over sodium sulphate and evaporated. The crude product was purified by silica gel chromatography using ether / light petroleum (1: 9) as the eluent, to give the butanoyloxybutyl furanone in the form of a pale yellow oil (3.60 g, 60%). vmax 2950, 1780, 1 730, 1635, 1600, f 10 1450, 1380, 1280, 1240, 1 165, 1060, 980, 840, 770 cm'1. ? max 289 nm (e 14900). 1 H n.m.r. d (CDCl 3) 0.91, t, J 7.4 Hz, OCOCH 2 CH 2 CH 3; 0.93, t, J 7.2 Hz, (H4 ') 3; 1.35, m, (H3 ') 2; 1.66, q, J 7.4 Hz, OCOCH2CH2CH3; 1.80-1.95, m, (H2 ') 2; 2.32, t, J 7.4 Hz, OCOCH2CH2CH3; 5.50. dd, J 6.4 Hz 8.0 Hz, H 1 '; 6.36, s, 5-CHBr. 15 13C n.m.r. d (CDCl 3): 13.4, OCOCH 2 CH 2 CH 3; 13.5, C4 '; 18.2, OCOCH2CH2CH3; 18.4, C3 '; 33.5, C2 '; 35.7, OCOCH2CH2CH3; 68.0, C1 '; 93.2, 5-CHBr; 130.6, C4; 132.4, C3; 149.6, C5; 165.9, C2; 172.7, CO. Mass spectrum: m / z 399, (M + 1 (81 Br2), < 5%); 397 (M + 1 (81 Br, 79 Br), < 5); 395, (M + 1 (79Br2), < 5); 327 (18); 325 (28); 323 (18); 317 20 (26); 315 (26); 31 1 (8); 309 (16); 307 (8); 283 (16); 281 (34); 279 (16); 267 (42); 265 (40); 247 (16); 245 (16); 223 (56); 221 (44). EXAMPLE 12 4-Bromo-5- (bromomethylene) -3- (1-octadecanoyloxybutyl)) - 2 (5H) -furanone They were stirred in an oil bath at a temperature of 1 10 ° C for 24 hours 4-bromo-5 - (bromomethylene) -3- (1-hydroxybutyl) - 2 (5H) -furanone (0.24 g, 0.7 mmol) and octadecanoyl chloride (0.3 mL, prepared from octadecanoic acid and thionyl chloride). The reaction mixture was diluted with ether (50 mL) and washed with water (3 x 20 mL) followed by brine (30 mL). The organic phase was dried over sodium sulphate and evaporated to produce a brown oil. The crude product was purified by silica gel chromatography, using dichloromethane as the eluent to produce the Octadecanoyloxybutyl furanone in the form of a dark brown oil (0.14 g, 32%). 1 H n.m.r. d (CDCl3) 0.87, t, J 7.2 Hz, OCO (CH2) 16Cj ± 3; 0.95, t, J 7.2 Hz, (H4 ') 3; 1.28, m, OCOCH2 (CH2)? SCH3; 1.35-1.45, m, (H3 ') 2; 1.58-1.60, m, OCOCH2CIH2; 1.75-2.05, m, (H2 ') 2; 2.34, t, J 7.2 Hz, OCOCH_2 (CH2)? 5CH3; 5.43, dd, J 6.2 Hz 7.7 Hz, H 1", 6.37, s, 5-CHBr, 13C nmr (dCd3): 13.5, OCO (CH2) 16CH3, 14.1, C4 ', 18.6, 22.7, 24.8 , 29.2, 29.3, 29.4, 29.6, 29.7, 31.9, 33.8, 33.9, CH2, 68.0, C1 ', 93.3, 5-CHBr, 130.7, C4, 131.3, C3, 149.8, C5, 163.7, C2; 173.1, CO. EXAMPLE 13 0 Method A 4-Bromo-5- (bromomethylene) -3- (1-acryloyloxybutyl) »2 (5H) -furanone The procedure described for 4-bromo-5- (bromomethylene) - 3- (1-butanoyloxybutyl)) - 2 (5H) -furanone to treat 4-bromo-5- (bromomethylene) -3- (1-hydroxybutyl)) - 2 (5H) -furanone (4.75 g, 5 0.015 mol) with acryloyl chloride (6.0 mL, 0.073 mol) The crude product was purified by silica gel chromatography, using ether / light petroleum (1: 9) as the eluent to produce the acryloyloxybutyl furanone in the form of a yellow oil ^ k pale (3.60 g, 60%) in the form of a white solid, vmax 3060, 2940, 2850, 1770, 1710, 1620, 1590, 1430, 1390, 1385, 1280, 1250, 1 160, 1095, 1030, 970, 835, 795, 760, 700 cm "1.? Max 293 nm (e 18170 ) 1 H n. Mr d (CDCI3) 0.91, t, J 7.4 Hz, ester CH3, 0.97, t, J 7.4 Hz, (H4 ') 3; 1 .38, m, (H3') 2; 1. 84-2.04, m, (H2 ') 2; 5.63, dd, J 6.7 Hz 8.2 Hz, H 1', 5.88, d, J 10.7 Hz, CH = CH2, 6.14, dd, J 10.7 Hz 16.3 • 10 Hz, CH = CH2; 6.39, s, 5-CHBr; 6.46, d, J 16.3 Hz, CH = CH2. 13C n.m.r. d (CDCl 3): 13.5, C4 '; 18.5, C3 '; 33.7, C2 '; 68.2, C1 '; 93.5, 5- CHBr; 127.5, CH = CH2; 130.4, C4; 131.5, CH = CH2; 132.1, C3; 149.8, C5; 163.7, C2; 165.2, CO. Mass spectrum: m / z 382, (M (81 Br2), < 5%); 380 (M (81 Br, 79 Br), < 5); 378, (M (79Br2), < 5); 327 (14); 325 (28); 323 (14); 301 (16); 299 (16); 283 (8); 281 (12); 279 (8); 269 (12); 267 (24); 265 (12); 229 (18); 227 (24); 225 (18); 223 (20); 203 (34); 201 (46); 175 (32); 173 (48); 147 (38); 145 (46); 143 (48). Method B Concentrated sulfuric acid (1 drop) was added to a solution from 4-bromo-5- (bromomethylene) -3- (1-hydroxybutyl)) - 2 (5H) -furanone (0.94 g, 3.0 mmol) and acrylic acid (2 mL) in benzene (5 mL). The mixture was refluxed for 4 hours, and then cooled to room temperature, poured into water (50 mL). The crude product was extracted with ether (2 x 50 mL), and the combined ether extract washed with a sodium carbonate solution. The extract was dried over anhydrous sodium sulfate, evaporated and chromatographed on a silica column using dichloromethane / light petroleum as the eluent, to produce the pure acryloyloxybutyl furanone if in the form of a brown oil (0.48 g, 42%). 5 EXAMPLE 14 4-Bromo-5- (bromomethylene) -3- (1-butanoyl) -2 (5H) -furanone To an ice-cooled solution of 4-Bromo-5- (bromomethylene) -3- (1 - hydroxybutyl) -2 (5H) -furanone (2.77 g, 8.5 mmol) in acetone (75 mL) was added dropwise with stirring the Jones reagent (12 mL), prepared by dissolving chromium trioxide (13.36 g) in sulfuric acid (11.2 mL) and water (38.5 mL). The mixture was stirred at room temperature for 1 hour, and the progress of the reaction was monitored by thin layer chromatography. At the end of the reaction, the mixture was poured into water (200 mL) and extracted with ether (3 x 100 mL). The combined ether extracts were washed with brine (100 mL), dried over sodium sulfate and evaporated to give the crude ketone. (2.23 g, 81%) in the form of a yellow solid. Recrystallization of the crude ketone from dichloromethane / hexane provided the pure ketone in the form of yellow plates, m.p. 83-84 ° C vmax 1700, 1680, 1630, 1540, 1310, 1000 cm'1. 1 H n .m.r. d (CDCl3) 0.97, t, J 7.2 Hz, (H4 ') 3; 1.70, m, (H3 ') 2; 2.93, t, J 7.2 Hz, (H2 ') 2; 6.74, s, 5-CHBr. 3C n .m .r. d (CDCl 3): 13.6, C4 '; 16.7, C3 '; 44.4, C2 '; 99.3, 5-CHBr; 125.7, C4; 138.1, C3; 150.4, C5; 163.5, CO; 194.1, C 1 '. Spectrum of mass: m / z 326, (M (81 Br2), < 5%); 324 (M (d1 Br, 79Br), 5); 320, (M (79Br2), < 5); 298 (10); 296 (22); 281 (16); 279 (8); 225 (4); 131 (14); 77 (32); 71 (52); 43 (100).

Synthesis of Covalently Linked Furanone Polymer EXAMPLE 15 • 5 Preparation of furanone acrylate homopolymer The gas was extracted to a mixture of 4-bromo-5- (bromomethylene) - and 5- (dibromomethylene) -3- (1 -acyloiloxybutyl) -2 (5H) -furanone (0.36 g), AI BN (0.003 g) and toluene (0.75 mL), and subsequently heated to a temperature of 60 ° C for 24 hours. Hexane was added to the The mixture was mixed and the precipitated polymer was washed once with methanol. The final product was collected and dried to produce the polymer (0.04 g, conversion to 1 1%) of average mass 14284.

EXAMPLE 16 Preparation of Acrylate-Polymethyl Methacrylate Copolymer furanone The gas was extracted to a mixture of methyl methacrylate (3.0 fg), 4-bromo-5- (bromomethylene) - and 5- (dibromomethylene) -3- (1-acryloyloxybutyl) -2 (5H) -furanone ( 0.74 g) and AIBN (0.006 g), during V hour purging it with nitrogen gas and subsequently heating it to a temperature of 60 ° C for 24 hours. Hexane (50 mL) was added to the mixture and the precipitated polymer was washed once with methanol. The polymer was further purified by reprecipitation of chloroform and excess methanol. The final product was collected and dried to produce the polymer (1.74 g, conversion to 47%) of average mass 7578.

EXAMPLE 17 Preparation of furanone acrylate-polystyrene copolymer The gas was extracted into a mixture of styrene (1 5 g), 4-bromo-5- (bromomethylene) - and 5- (dibromomethylene) -3- (1-bromoethyl) ) -2 (5H) -furanone (0.16 g) and AI BN (0.023 g), for 1 hour purging with nitrogen gas and then heating to a temperature of 60 ° C for 3 hours. At the end of the polymerization, the mixture was poured into hexane and the precipitated polymer was washed twice with ether and dried under vacuum (0.1 mm Hg) at a temperature of 40 ° C for 24 hours., to produce the polymer (12.9 g, 85% conversion). An XPS analysis of the polymer powder in an aluminum foil confirmed the presence of bromine. EXAMPLE 18 Preparation of acrylate-poly (styrene / MEMA / MMA) polymer of furanone To a solution of styrene (5 g), MMA (5 g) and H EMA (5 g) in toluene (8 mL), added 4-Bromo-5- (bromomethylene) - and 5- (dibromometholene) -3- (1-bromoethyl) -2 (5H) -furanone (0.15 g) followed by dodecanetiol (2 mL) and AIBN (0.4 g) ). The gas was extracted into the mixture by means of two freeze-thaw cycles and subsequently heated to a temperature of 70 ° C for 24 hours. At the end of the polymerization, the mixture was treated with hexane and the precipitated polymer was washed with hexane and dried under vacuum (0.1 mm Hg) at room temperature for 24 hours, to yield the polymer (22.2 g, 87% conversion).

EXAMPLE 19 4-Bromo-5- (bromomethylene) -3- (1-butenyl) -2 (5H) -furanone Concentrated sulfuric acid (2 drops) was added to a solution of 4-bromo-5- (bromomethylene) - 3- (1-hydroxybutyl) -2 (5H) - • 5 furanone (2.0 g) in toluene (10 mL). The mixture was refluxed for 4 hours, and then cooled to room temperature, poured into water (50 mL). The crude product was extracted with ether (2 x 50 mL), and the combined ether extract was washed with a sodium carbonate solution. The extract was dried over Sodium sulfate, evaporated and chromatographed on a silica column using light petroleum as the eluent, to give pure 3 -) (1-1-butenyl) -furanone in the form of a light yellow oil (0.40 g). 1 Hnmr d (CCI3) 1 .10, t, J 7.2 Hz, (H4 ') 3; 2.26, q, J 7.2 Hz, (H3 ') 2; 6.20, d, CH = CH; 7.20, d, CH = CH; 6.24, s, 5-CH Br. 15 Fimbrolide Biological Activity MATERIALS AND METHODS • Inhibition of Cyprid Settlement The effects of synthetic furanones on acorn larva settlement were tested using acorn cyprids generation of cosmopolitan seaweed Balanus amphitrite Darwin. The furanone that arises in natural form 2, and the synthetically prepared compounds 281 (a 1: 1: 1 mixture of 2 &8 &1 synthesized), 2223 (a 1: 1 mixture of 22 &23 synthesized) , 2425 (a 1: 1 mixture of 24 &25 synthesized), 26, 27 and 28 (Figure 1), were compared for its effectiveness in deterring the acupressure of citrus. The compounds were dissolved in ethanol (99.7% + purity) in a concentration of from 180 μg.mL "1 to 1.8 μg.mL" 1. A 0.5 mL portion of each compound to be tested was added to treatment petri dishes (9 cm2 surface area), and only • 5 0.5 mL of ethanol was added to ethanol control plates. The dishes were dried on an agitator resulting in an extract cover in the treatment dishes with a concentration range from 10 μg.cm "2 to 100 ng.cm" 2 for each compound. Cipris larvae were obtained from laboratory cultures of a • 10 adult progene material from Balanus amphitrite. Naupliis of ß were collected. amphitrite and crawled over Skeletonema costatum until reaching the cyprid stage. Cipris larvae were filtered and maintained in seawater filtered at a temperature of 5 ° C for five days, before being used in the tests of settlement (Rittschof and associates, 1992). Settlement tests were carried out adding 25 • to 35 citrates to any of the treatment dishes, ethanol control dishes or untreated dishes, each containing 4 mL of sterilized filtered seawater (0.22 μm). All treatments and controls were tested in triplicate. The test dishes were incubated for 24 hours at a temperature of 28 ° C in a light-dark cycle h 15: 9 (Rittschof et al., 1992). After 24 hours, the test was terminated by the addition of three 40% formaldehyde drops and the non-settled larvae were filtered from the dish.

The percentage of settlement of cyprids was later determined by counting settled and unsettled larvae. Statistical Analysis The data from the bioassays were analyzed • by variation analysis (ANOVA) followed by Tukey's multiple comparison test. The data were analyzed as percentages after the arcsine Ap transformations. RESULTS Ciprid Settlement Inhibition # 10 The settlement of the larva Cipris Balanus amphitrite was significantly inhibited by the compounds tested (Figure 2: Factor-two ANOVA [metabolite x concentration] followed by the Tukey test). All treatments completely inhibited settlement at the highest concentration (10 μg.cm "2). Ethanol controls were used in the analysis since ethanol had no significant effect on the settlement (ANOVA of • simple factor, P = 0.17). The synthetic furanone 2223 (Figure 1) was the most active metabolite (Figure 2). At a concentration of 1 μg.cm "2, 2223 completely inhibited the settlement and inhibited the settlement 80% compared to control at 500 ng.cm "2 The next most inhibiting compound was furanone 28 (Figure 1), which inhibited settlement completely by 5 μg.cm" 2 and inhibited settlement on 90 % in 1 μg.cm "2. A group of furanones, 2425, 26 and 27 completely inhibited the settling at 5 μg.cm" 2, but had no effect at 1 μg.cm "2. Furanone 2 and the synthetic analogue 281, a 1: 1: 1 mixture of 2, 8 and 1 (Figure 1), were the least effective compounds completely inhibiting settlement in the • μg.cm "2 .5 Inhibition of Staphylococcus aureus Staphylococcus aureus is a non-motile, facultatively anaerobic coccus gram-positive and is usually associated with the skin, skin glands, and mucous membranes of humans. the most important human staphylococcal pathogen and ^ 10 originates, for example, boils, abscesses and infections of the stomach (wound) .An experiment of selection of the different furanones against the growth of S. aureus was carried out in a BioRad Microplate reader 3550. Growth was measured as absorbency to 610 nm until 9 h. A complex growth medium, Nutrient Broth, was used, and the cells were developed at a temperature F of 37 ° C. Both the natural furanones (compounds 2, 3 and 4) and furanones synthesized (compounds 33/34 and 45) were used in the experiment in the concentration of 10 μg / mL. 20 The results showed that the furanones synthesized (33/34 and 45) inhibited the development of S. Aureus more effectively than natural furanones (Figure 3). The growth of the cells inoculated with 33/34 and 45, was completely inhibited during 9 hours compared to 2 hours for those inoculated with the natural compounds. However, all furanones inhibited the growth of S. aureus compared to the control. Additional experiments were carried out with the furanones synthesized 45 and 33/34 in the concentrations of • 5 10μg / mL and 5μg / mL. The cells were developed in flasks of lateral arms in an NB medium at a temperature of 37 ° C. The growth of the cells was measured at 610 nm for up to 48 hours. The results showed that compound 33/34 was more • 10 effective in inhibiting the growth of S. Aureus, compared to compound 45 (Figure 4), however, both compounds in both concentrations completely inhibited growth for 9 hours. The growth of the cells occurred after 9 hours with compound 45 in the concentration 5 μg / mL and after 15 hours in the concentration 10 μg / mL. Compound 33/34 in 5 μg / mL inhibited the growth for 15 hours and in the concentration 10 μg / mL the growth of S. Aureus was completely inhibited during 34 h. DISCUSSION 20 The derivation of furanones that arise naturally, resulted in an increase in the dissuasion of the acorn settlement. For example, manipulation of the length of the acyl side chain and function of the 1 'position of the acyl side chain of furanone resulted in a significant increase in the activity. This is clearly demonstrated in a comparison of the activity of furanones 2 and 2425. In 2425 a bromine was added at the 1 'position of the acyl chain resulting in an increase of five fold activity in the bioassay of the ^ 9 settlement (Figure 2). All synthesized furanones are Any of the new compounds that have not been previously reported in the literature or that are racemic mixtures of a naturally occurring furanone. The racemic analogues of naturally occurring compounds have the same activity as the optically pure form that arises in a manner '10 natural. Therefore, synthetic furanones, both analogs of naturally occurring compounds and new compounds, have comparable or better activity than the compounds from which their structure was derived, for example, furanone 2 vs 2425. It will be appreciated by the experts in art, which can be to make numerous variations and / or modifications to the present invention, as shown in the specific embodiments, without departing from the spirit or scope of the present invention, as widely described. The present modalities are, therefore, to be considered in all aspects as illustrative and not as restrictive.

Claims (26)

1. R E I V I N D I C A C I O N S Having described the present invention, it is considered as a novelty and, therefore, property is claimed as 5 content in the following CLAIMS: A compound according to formula (I): wherein R6 is H, OH, alkyl, alkoxy, oxoalkyl, alkenyl, aryl or arylalkyl, whether substituted or unsubstituted, straight chain or branched chain, hydrophobic, hydrophilic or fluorophilic; R2 and R3 are, independently or both, H or halogen; Rg is halogen; Z is selected independently of the group Re, Halogen, OOH, OC (O) R6, = O, amine, azide, thiol, mercaptoalkyl, alkenyloxy, mercaptoalkenyl, aryloxy, mercaptoaryl, arylalkyloxy, mercaptoarylalkyl, SC (0) R6, OS (0) R6, OS (0) 2R6, NHC (0) R6 = NR4 or NHR4; and R4 is OH, alkyl, alkoxy, poly (ethylene glycol), alkenyl, aryl or arylalkyl, provided that: when Re is propyl, R2 is Br, R3 is H or Br and Rg is Br, then Z is different from H , OC (O) CH3 or OH; when Re is propyl, R2 is Br, R3 is H and Rg is I, then Z f is different from OC (0) CH3 or OH; 5 when Re is propyl, R2 is Br, R3 is H and Rg is Cl, then Z is different from OH; when Re is propyl, R2 is H, R3 and Rg are Br, then Z is different from H; and when Re is propyl, R2 is Br, Rg is Cl and Z is H, then R3 f 10 is different from Cl.
2. 2. A compound, as described in Claim 1, of formula (la): Wherein Ri is hydrogen, alkyl, alkoxy, oxoalkyl, alkenyl, aryl or arylalkyl, whether substituted or unsubstituted, straight chain or branched chain, hydrophobic, hydrophilic or fluorophilic; X is a halogen, OH, OOH, 00 (0 ^ or = 0; R2 and R3 are, independently or both, hydrogen or halogen; and Rg is halogen, provided that: when R-i is propyl, R2 is Br, R3 is H or Br and Rg is Br, • then X is different from OC (O) CH3 or OH; when R-i is propyl, R2 is Br, R3 is H and Rg is I, then X is different from OC (0) CH3 or OH; when R-i is propyl, R2 is Br, R3 is H, Rg is Cl, then X is different from OH. •
3. 3. A compound, as described in claim 1, of formula (I I): (II) Wherein R1 is hydrogen, alkyl, alkoxy, oxoalkyl, alkenyl, aryl or arylalkyl, substituted or unsubstituted, straight chain or branched chain, hydrophobic, hydrophilic or fluorophilic; R2 and R3 are, independently or both, hydrogen or halogen; Rg is halogen; and R4 is selected from the group of halogen, amine, azide, hydroxyl, thiol, or any alkyl, alkoxy, mercaptoalkyl, alkenyloxy, mercaptoalkenyl, aryloxy, mercaptoaryl, f-arylalkyloxy, mercaptoarylalkyl, OC (0) R ?, SC ( ) R? OS (O) R? 5 OS (0) 2R ?, NHCÍOJRL OC OJNHR !, o = O, hydrophobic, hydrophilic or fluorophilic, provided that: when R4 is propyl, R2 is Br, R3 is H or Br and R9 is Br, then R1 is different from H, OC (O) CH 3 or OH; when R4 is propyl, R2 is Br, R3 is H, Rg is I, then R1 is different from OC (O) CH3 or OH; when R4 is propyl, R2 is Br, R3 is H, Rg is Cl, then R-i is different from OH; when R4 is propyl, R2 is H, R3 and Rg are Br, then R1 is different from H; When R4 is propyl, R2 is Br, R3 and Rg are Cl, then R-i is different from H. •
4. 4. A compound, as described in Claim 1, of formula (III): Wherein R2 and R3 are, independently or both, hydrogen or halogen; Rs is OH or the same as R1; 99, Rg is halogen; and R1 is hydrogen, alkyl, alkoxy, oxoalkyl, alkenyl, aryl or arylalkyl, whether substituted or unsubstituted, straight chain or branched chain, hydrophobic, hydrophilic or fluorophilic.
5. 5. A compound, as described in Claim 1, f 10 of formula (IV) or (V): • wherein R-i is hydrogen, alkyl, alkoxy, oxoalkyl, alkenyl, aryl or arylalkyl, whether substituted or unsubstituted, straight chain or branched chain, hydrophobic, hydrophilic or 20 fluorophilic; R2 and R3 are, independently or both, hydrogen or halogen; Rg is halogen; and R8 is OH, N H R1, NHC (X) N H2, NHC (X) NH R-? (X = O, S, NR1) or 25 any R-i.
6. 6. A method for forming a fimbrolide derivative, wherein the method includes the reaction of a fimbrolide with a halogenating agent and / or an oxygenation agent to form compounds • with the formula (la): wherein R-i is hydrogen, alkyl, alkoxy, oxoalkyl, alkenyl, aryl or arylalkyl, whether substituted or unsubstituted, straight chain or branched chain, hydrophobic, hydrophilic or fluorophilic; X is a halogen (X = F, Cl, Br or I), OH, OOH, OC (O) R? or • = 0); R2 and R3 are, independently or both, hydrogen or halogen; and 20 Rg is halogen.
7. 7. A method, as described in Claim 6, further characterized in that the halogenating agent is selected from the group of N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, bromine, cupric bromine, and phenyltrimethylammonium perbromo.
8. 8. A method, as described in Claim 6, 5 further characterized in that the oxygenation agent is selected from the group of lead tetraacetate, Rosa de Bengal / oxygen gas, hydrogen peroxide / vanadium pentoxide, selenium dioxide, and 3-chloroperoxybenzoic acid.
9. 9. A method for forming a fimbrolide derivative, wherein the method includes the displacement and / or functionalization of the halogen or oxygen substituent on the fimbrolide side chain, by treating with a nucleophile or an electrophile to form compounds with the Formula (II): 15 wherein Ri is hydrogen, alkyl, alkoxy, oxoalkyl, alkenyl, aryl or arylalkyl, whether substituted or unsubstituted, straight chain or branched chain, hydrophobic, hydrophilic or 25 fluorophilic; R2 and R3 are, independently or both, hydrogen or halogen; Rg is halogen; and f. R4 is selected from the group of halogen, amine, azide, 5-hydroxyl, thiol, or any alkyl, alkoxy, mercaptoalkyl, alkenyloxy, mercaptoalkenyl, aryloxy, mercaptoaryl, arylalkyloxy, mercaptoarylalkyl, OC (0) R? , SC (0) R? , OS (O) R-? , OS (0) 2R? , N H CÍOJ RT, OC (O) NHR? , or = O, hydrophobic, hydrophilic or fluorophilic, provided that when R4 is propyl, R2 is Br, R3 and Rg are f 10 Cl, then R-i is different from H.
10. 10. A method, as described in Claim 9, further characterized in that the nucleophile is selected from metal halides, water, organic metal carboxylate, organic alcohols, dimethyl sulfoxide, and organonitrile / acid catalyst, and triflate silver. • eleven .
11. A method, as described in Claim 9, further characterized in that the electrophile is selected from acids Organic, isocyanates, acid halides or active acylating agents, such as carbonyl imidazoles or anhydrides (including activated hydrophilic PEG acids, PEG acid chlorides, PEG-oxycarbonylimidazoles and PEG-isocyanates) organic sulfonyl chlorides and diethylaminosulfide trifluoride. 25
12. 12. A method for forming a fimbrolide derivative, wherein the method includes the reaction of a hydroxyl substituent on the side chain of fimbrolide with an oxidation agent to form a compound according to the formula (11): wherein R2 and R3 are, independently or both, hydrogen or halogen; R5 is OH or the same as R1; Rg is halogen; and R-i is hydrogen, alkyl, alkoxy, oxoalkyl, alkenyl, aryl or arylalkyl, whether substituted or unsubstituted, straight chain or branched chain, hydrophobic, hydrophilic or fluorophilic.
13. 13. A method, as described in Claim 12, further characterized in that the oxidizing agents are selected from the group consisting of acid dichromate reagents in any form that can be free or supported polymer, chromium trioxide, manganese dioxide , potassium permanganate, selenium dioxide, ceric ammonium nitrate, ruthenium tetraoxide, and hot nitric acid.
14. 14. A method, as described in Claim 13, further characterized in that the acid dichromate agent is flp selected from the group consisting of Jones reagent, chlorochromate 5 pyridinium, pyridinium dichromate.
15. 15. A method for forming a fimbrolide analogue derived from a compound of the formula (11) Wherein R2 and R3 are, independently or both, hydrogen or halogen; > f R5 is OH or the same as R-i; Rg is halogen; and Ri is hydrogen, alkyl, alkoxy, oxoalkyl, alkenyl, aryl or arylalkyl, whether substituted or unsubstituted, straight chain or branched chain, hydrophobic, hydrophilic or fluorophilic, wherein the method includes the reaction of an aldehyde substituent or ketone in the fimbrolide side chain of the compound, with an amine derivative to form a compound with the formula 25 (IV) or (V): (IV) (V) wherein Ri is hydrogen, alkyl, alkoxy, oxoalkyl, alkenyl, aryl or arylalkyl, whether substituted or unsubstituted, straight chain or branched chain, hydrophobic, hydrophilic or fluorophilic; R2 and R3 are, independently or both, hydrogen or halogen; Rg is halogen; and R8 is OH, NHR1, N HC (X) NH2, NHC (X) NHR1 (X = O, S, NR-,) or any R-i.
16. 16. A method, as described in Claim 15, further characterized in that the amine derivative is selected from the group of hydroxyl amine hydrochloride, alkyl hydrazines and Aryl, alkyl or aryl amine optionally in the presence of a reducing agent.
17. 17. A fimbrolide derivative produced by the method, as described in any of the Claims 6 to
18. 18. An oligomer or polymer formed by oligomerization or polymerization of a fimbrolide compound of the formula: f wherein R is H, OH, alkyl, alkoxy, oxoalkyl, alkenyl, aryl or arylalkyl, whether substituted or unsubstituted, straight chain or branched chain, hydrophobic, hydrophilic or fluorophilic; R2 and R3 are, independently or both, H or halogen; R9 is halogen; Z is independently selected from the group Re, halogen, OOH, OC (O) R6, = O, amine, azide, thiol, mercaptoalkyl, f alkenyloxy, mercaptoalkenyl, aryloxy, mercaptoaryl, arylalkyl, mercaptoarylalkyl, SC (O) R6, OS (0) R6, OS (O) 2R6, NHC (0) R6 = NR4 or NHR4; and R4 is OH, alkyl, alkoxy, poly (ethylene glycol), alkenyl, aryl or arylalkyl, optionally with at least one other monomer.
19. 19. A polymer, as described in Claim 18, further characterized in that the polymer is a homopolymer of the fimbrolide compound of Claim 18.
20. 20. A polymer, as described in Claim 18, further characterized in that the polymer is a copolymer of at least one fimbrolide compound according to the claim 18, and at least one other polymerizable monomer. twenty-one .
21. The use of a compound, as described in any of Claims 1 to 5 or 17, in the form of an antimicrobial, antiseptic, static microbacterial agent and / or • 10 algae antigeneration.
22. 22. An antimicrobial, antiseptic and / or microbacterial static composition, further characterized in that it includes at least one compound, as described in any of the 15 Claims 1 to 5 or 17, or an oligomer or polymer, as described in any one of the Claims of 18 to • the 20.
23. 23. An algal antigen composition, which includes at least one compound, as described in any one of Claims 1 to 5 or 17, or an oligomer or polymer, as described in any one of the Claims of the 18 to the 20.
24. 24. A surface coating composition that incorporates at least one compound, as described in any one of Claims 1 to 5 or 17, or an oligomer or polymer, such and • as described in any of the Claims 18 through 20.
25. 25. A compound as described in formula (VI): (SAW) wherein Ri is alkyl, alkoxy, oxoalkyl, alkenyl, aryl or 15 arylalkyl, substituted or unsubstituted, straight chain or branched chain, hydrophobic, hydrophilic or fluorophilic; # R2 and R3 are, independently or both, hydrogen or halogen; and Rg is halogen.
26. 26. A compound as described in Claim 25, which is 4-Bromo-5- (bromomethylene) -3- (1-butenyl) -2 (5H) -furanone. SUMMARY The present invention relates to the functionalization of the f side chain of fimbrolides (3-alkyl-5-methylene-2 (5H) -halogenated furanones) and their synthetic analogs which produce fimbrolides Substituted with a halogen, or an oxygen function or a nitrogen function in the alkyl chain, especially fimbrolide, carboxylate and sulfinate alcohols and sulfonate esters, ethers, aldehydes, ketones, acids, amides, nitro derivatives, derivatives f 10 alkyl hydrophobic, hydrophilic and fluorophilic, and polymers. A & •