Furanone production

Determining costs of secondary metabolites is inherentiy difficult as a result of the variable responses, multiple physiological roles of the metabolites, as well as the different types of costs involved in the production of secondary metabolites (production, transport, storage, maintenance) (Strauss et al. 2002). Emerging studies are now taking more of these variables into consideration. For example, work with clonal populations of D. pulchra has estimated costs of furanone production in relation to chemical defense and phenotype by investigations of reproductive... 

Scheme 23.19 Furanone production schemes involving biocatalytic steps (italicised) (adapted from [270,271])...

The complex Ru(tpy)(bpy)02 [tpy = 2,2,2"-terpyridine, bpy = 2,2 -bypyridine] oxidizes organic substrates by hydride abstraction or oxo transfer. This complex, and its derivatives, cleave DNA by oxidation of the sugar at the V position and oxidation of guanine. Oxidation at the V position leads to the release of free bases and a furanone product. The kinetic parameters for the oxidation of D-ribose, 2-deoxy-D-ribose, and nucleotides by Ru(tpy)(bpy)02 were determined in phosphate buffer (pH 7). The increased reactivity of DNA as compared to RNA was rationalized on the basis of deactivation of the sugar oxidation product by the polar effect of the 2 -hydroxyl group.160... 

Although the complete mechanism of the reaction is uncertain at this time, we established the intermediacy of 8 by isolating it from a reaction which was worked up immediately after bromine addition. We showed that resubjecting 8 to acetic acid fails to afford any furanone product unless HBr is also reintroduced. This observation is consistent with the proposed rearrangement of 8 to 9 which should be catalyzed by strong acid and which produces an intermediate with a more stable enolic form. Nevertheless, the proposed subsequent series of intermediates represents only one of several possible sequences which could lead to the observed product. 

Photochemical reaction of 124 (Ar = Ph) using conventional photolysis was originally reported to give only a 27% yield of the furanone product, but photolysis in a continuous flow reactor in acetonitrile instead increased the yield to 97% (Eqn (4.74)). Since only the endo conformation of vinyl-ketene 125 can cycHze to the fiiranone this indicates either that only endo-125 is formed upon ring opening due to torquo-selective effects, or that any exo-125 reverts to the endo stereoisomer (Eqn (4.74)). 

Of these, the 2(5//)-furanones 2 are perhaps the compounds having the most interesting synthetic and biological importance. The synthesis and properties of compounds 2 have recently attracted much attention. The 2(5//)-furanone fragment is present in a wide variety of biologically active natural products (84MI1) moreover these furanones possess utility as valuable synthetic intermediates (86T3715). 

Owing to their frequent occurrence in natural products and their synthetic utility, 2(5//)-furanones are important synthetic targets and intermediates. In considering the methods for the preparation of these compounds, we will emphasize the recent developments in this area. 

It has been reported that concentrated H2SO4 (98%) promotes conversion of 3,5-dibromolevulinic acid 47 into 4-bromo-5-(bromomethylene)-2(5// )-furanones 48 (R = Br R = H) along with minor products, while similar treatment using 20% oleum gives the isomeric 5-(dibromomethylene)-2(5// )-furanone 49 (R = H R = Br) as the major product (63AJC165). Spectroscopic data and chemical structures were not provided for the minor substances, but the formation of the major product was explained on the basis of the enol-lactonization process followed by oxidation (63AJC165). 

When the translactonization reaction of 67 (R , R = Me, Et) was conducted in acetic acid (R" = Me) as a reaction solvent, at the boiling point, somewhat different results were obtained A mixture of products identified as the furanones 68 and the 4-benzoylamino-5-oxo-2,5-dihydrofuran-2-yl acetates 69 were obtained (Scheme 21) (97T1843). 

The different furanones 104 were tested for their potency as inhibitors of PGE2 production both in transfected Chinese hamster ovarian (CHO) cells expressing human COX-2 and in human whole blood. Compound 104r proved to be an orally active and selective COX-2 inhibitor that is devoid of the ulcerogenic effect at >100 times the dose for antiinflammatory, analgesic, and antipyretic effects (99BMC3187). 

Reduction of 3,5,5-tris-aryl-2(5// )-furanones 115 (R, R, R = aryl) with dimethyl sulfide-borane led to the formation of the 2,5-dihydrofurans 116 in high yields. However, in the case of 3,4-diaryl-2(5//)-furanones 115 (R, R = aryl R = H or r = H R, R = aryl), the reduction led to a complicated mixture of products of which only the diarylfurans 117 could be characterized (Scheme 36) (88S68). It was concluded that the smooth conversion of the tris-aryl-2(5//)-furanones to the corresponding furan derivatives with the dimethylsulfide-borane complex in high yields could be due to the presence of bulky aryl substituents which prevent addition reaction across the double bond (88S68). 

The formation of the tran -aziridine 281 as the major product of the conjugated addition of benzylamine to the furanone 280 was rationalized in terms of selective facial protonation of the initially formed enol 284 (Scheme 75) (00TL3061). 

In any form of analysis it is important to determine the integrity of the system and confirm that artefacts are not produced as a by-product of the analytical procedure. This is particularly important in enantiomeric analysis, where problems such as the degradation of lactone and furanon species in transfer lines has been reported (40). As chromatography unions, injectors, splitters, etc. become more stable and greater degrees of deactivation are possible, problems of this kind will hopefully be reduced. Some species, however, such as methyl butenol generated from natural emissions, still remain a problem, undergoing dehydration to yield isoprene on some GC columns. 

In contrast to 2-cyclopentenone, 4-to7-butoxy-3-cyclopentenone gives mixtures of a-1,2- and y-1,4-adducts at — 70°C. Warmer reaction temperatures (0°C) give mainly the syn-y- 1,4-ad-duct, although in poor yield (43%). Addition of HMPA gives mixtures of a- and y-1,4-adducts plus 1,2-adducts. 2(5//)-Furanone gives mixtures of a- and y-1,4-addition products at — 70 C7. 

Efficient methods for the production of tetrahydro-5-oxo-3-furanalkanoates use chiral lactones based on 2(5//)-furanones as Michael acceptors110-114 (see Section 1.5.2.4.1.2.5.). For... 

The use of enantiomerically pure (R)-5-menthyloxy-2(5.//)-furanone results in lactone enolates, after the initial Michael addition, which can be quenched diastereoselectively trans with respect to the /J-substituent. With aldehydes as electrophiles adducts with four new stereogenic centers arc formed with full stereocontrol and the products are enantiomerically pure. Various optically active lactones, and after hydrolysis, amino acids and hydroxy acids can be synthesized in this way317. 

An analogous reaction has been carried out using malononitrile and different products derived by a Cross-Aldol reaction of acetone (Scheme 32). The cyclic furanimide 91 was then reacted under microwave irradiation in the presence of NaOEt with a second molecule of malononitrile to give the furanone 92 [66]. The NLO chromophore 93 was prepared using this procedure. 

Rapid reactions of linalool with OH radicals, NO3 radicals, and ozone in which the major products were acetone and 5-ethenyldihydro-5-methyl-2(3//)-furanone (Shu et al. 1997). 

The isoquinolinium ylide 241 reacts with allyl alcohol in a [3+2] cycloaddition to give the tetracyclic product 242 (Equation 32) the primary cycloaddition product spontaneously undergoes an intramolecular transesterification to give the isolated furanone. Similarly, reaction of such ylides with vinylene carbonate gives the tetracycles 243 (Equation 33) <1988BCJ2513>. 

A palladium catalyst is used in the transformation of a siloxyfuran to a phenyl substituted furanone <00JCS(P1)3350>. Similar products, furan-2(5//)-one derivatives, are afforded through the reaction of tetra-n-butylammonium fluoride with the corresponding substituted 2-siloxyfuran <00S1878>, as well as the oxidation of 3,4-disubstituted furans by singlet oxygen . 

Benzoylation of D-g/ycero-D-gw/o-heptono-1,4-lactone with an excess of benzoyl chloride and pyridine afforded the hept-2-enono-1,4-lactone as the main product (198). The di- and triunsaturated compounds were isolated in very low yield from the mother liquors (199). Higher yields of the di- and triunsaturated derivatives 153 and 154 were obtained when the /5-elimination reaction was performed with triethylamine on the previously synthesized per-O-benzoyl D-g/ycero-D-gw/o-heptono-1,4-lactone. Employing 10% triethylamine in chloroform, the lactone 153 was obtained as an E, Z dias-tereomeric mixture in 9 11 ratio as determined by H n.m.r. When 20% triethylamine was used, the furanone 154 was obtained in 59% yield (200). Its structure was assigned, on the basis of H and 13C n.m.r. spectra, as 3 -benzoyloxy - (5Z)-[(Z)-3 - benzoyloxy - 2 - propenyliden] -2(5 H)- furanone. The stereochemistry of the exocyclic double bonds was established (201) by nuclear Overhauser effect spectroscopy (NOESY). 

Rasmussen TB, Manefield M, Andersen JB, Eberl L, Anthoni U, Christophersen C, Steinberg P, Kjellberg S, Givskov M (2000) How Delisea pulchra furanones affect quorum sensing and swarming motility in Serratia liquefaciens MG1. Microbiology 146 3237-3244 Rosemeyer H (2004) The chemodiversity of purine as a constituent of natural products. Chem Biodiversity 1 361 101... 

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