2 -Furanone derivatives

Wang etal, US Patent 6,667,330 (December 23, 2003) Galileo Pharmaceuticals, Inc. 

3-(lH-Benzimidazol-2-ylsulfanyl)-2-(lH-benzimidazol-2-yl-sulfanylmethyl)-4-hydroxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester 

A solution of 2-mercaptobenzimidazole (4.0 g) and 4 ml ethyl bromopyruvate dissolved in 40 ml ethyl alcohol and 50 ml acetone were mixed and stirred 16 hours at ambient temperature. Thereafter, 4.5 g pyruvate adduct was isolated, dissolved in CH2CI2, treated with aqueous NaHC03 until pH 7 obtained, and dimethylaminopyridine (0.7 g) added. The mixture was stirred, purified by chromatography using silica gel and CH2Cl2/ethyl alcohol, 1 1, and 500mg product isolated. and C-NMR data supplied. 

The mechanism for product formation entails an aldol condensation between the two tautomeric pyruvate derivatives and is illustrated and discussed by the author. 

3-Phenyl-4-(4(methylsulfonyl)phenyl)-2-(5H)-furanone derivatives of the current invention have also been prepared (1). 

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The reaction of the o-iodophenol 275 with an alkylallene affords the bcnzo-furan derivative 276[184], Similarly, the reactions of the 6-hydroxyallenes 277 and 279 with iodobenzene afford the tetrahydrofurans 278 and 280. Under a CO atmosphere, CO insertion takes place before the insertion of the allenyl bond, and a benzoyl group, rather than a phenyl group, attacks the allene carbon to give 280. Reaction of iodobenzene with 4,5-hexadienoic acid (281) affords the furanone derivative 282[185]. 

A frequently used transformation of a five-membered ring with one heteroatom to a pyrazol-3-one is that from furanone derivatives. 

In a similar manner, polymers with unsaturated chains or side chains can be converted to polyamines [66-69]. Conjugated diolefins usually undergo hydroformylation with low selectivities [70]. Mostly hydrogenation of at least one double bond occurs and mixtures of various saturated and unsaturated amines and diamines are obtained [71]. Similar to alkenes also alkynes may serve as unsaturated compounds in hydro aminomethylation reaction sequences. Although synthetically attractive, only a few investigations towards hydroformylation and hydroaminomethylation of alkynes in the presence of N-nuclcophilcs are known. Usually a preferred transformation to furanonic derivatives is observed under hydroformylation conditions [27]. 

With an ot, y-ketodiol, cyclization to produce a 3-furanone derivative is feasible, as is shown for the synthesis of ascofuranone (71) and geiparvarin (72) (Scheme 6.57) (286). The precursor for 71 was prepared by the cycloaddition of diene 66 to nitroalcohol 67. In this case, regioselective attack occurred only on the terminal double bond. Reductive cleavage-hydrolysis of the isoxazoline adduct 68 with Mo(CO)6 followed by acid-induced cyclization led to the furanone intermediate (286). A similar strategy was used for the synthesis of geiparvarin (72) (Scheme 6.58) (286). 

Furane derivatives were also prepared by the carbonylation of acetylene derivatives. Phenylacetylene was converted to the furanone derivative shown in 3.35. under reductive conditions, while in the presence of oxygen 2-phenylmaleic anhydride was isolated as the main product.43... 

Amongst furans are several compounds of great importance in fragrances and flavours. The rose owes some of its odour to a terpenoid furan, rosefuran, coffee some of its characteristics to furylmethanethiol and related compounds. Compounds like the 3-furanone derivative furaneol (10) are particularly interesting for their odours depend upon concentration— furaneol can seem to resemble pineapple, caramel, burnt toast etc. Furaneol is a dihydrofuran-3-one dihydrofuran-2-ones are obviously lactones and are usually dealt with as such. 

In presence of an alkene, furanone derivatives were obtained (equation 88).436 The hydrogen needed for the reaction was derived from the solvent, ethanol. [RhCl(CO)(PPh3)2] (71), [RhCl(PPh3)3] (23) and RhCl3-3H20 as well as binary carbonyls could all be used as catalysts. The mechanism shown in Scheme 28 was proposed. 

The aroma of DMHF is pineapple-like, and is not considered too detrimental. However, it can mask the fresh orange-like aroma at levels above 0.05 ppm. Shu et al. (41) noted that DMHF is a precursor of various flavor materials when reacted with amino acids at high temperatures. Many acyclic carbonyl and 3(2H)-furanone derivatives can be formed as primary and secondary degradation products during thermal degradation of DMHF (42). 

Step 1 analogues 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-dimethylamino-ethoxy) benzoyl]benzo[/3]thiophene, (I), and 2(5H)-furanone derivatives have been prepared and are described (1), (2), respectively. 

Cyclopropyl isocyanates react effectively with various nucleophilic reagents. Ammonia and amines yield urea derivatives, " alcohols and phenols afford carbama-tg5,i5 5,164,181,184,185 )V )y-dimethylhydrazine gives a semicarbazide derivative, whereas cyclo-propylammonium chlorides are obtained in refluxing hydrochloric acid. The yields are usually very good. When more highly functionalized nucleophiles are employed, such as the enolate from ethyl 4-chloro-3-oxobutanoate, more complex molecules can be obtained, e.g. the formation of furanone derivative 15. ... 

Baillie, T.A. et al., Mechanistic studies on the reversible metabolism of rofecoxib to 5-hydroxyrofecoxib in the rat Evidence for transient ring opening of a substituted 2-furanone derivative using stable isotope-labeling techniques, Drug Metab. Dispos., 29(12), 1614, 2001. 

Irradiation of the furanone derivative (77a) affords the two products (78) and (79) shown in Scheme 5. When the oxygen function at C-2 is not methylated (77b), irradiation yields the products (80, 81) (Scheme 6). In this case a different rearrangement mechanism is permitted as a result of the relative ease of opening of the furanone ring. The route to product (80) is thought to involve a Norrish Type II process of the carbonyl group with the proximate methoxy function. Subsequent rearrangement via the spiro intermediate (82) ultimately provides the product (80). In the first example (Scheme 5) the formation of (78) also involves... 

In 1995 we accomplished the total synthesis of (+)-eremantholide A (8). Our synthetic scheme was completely different from that of the Boeckman group. We selected our building block 2 as the starting material, and the retrosynthetic analysis is outlined in Scheme 6. At first, disconnection of two carbon-carbon bonds in 8 as depicted leads to two fragments, an A/B ring equivalent 55 and known disubstituted 3(2if)-furanone derivative 56. We planned the direct connection of intact 3(2if)-furanone 56 to 55 at a... 

These include rhazinilam (15.4.6) 494), which inhibits the disassembly of microtubules but has a different mechanism of action than taxol, laulimalide (15.4.7) and isolaulimalide (15.4.8) 496), WS9885B (15.4.9) 497), and polyisoprenylated benzophenones such as guttiferone E (15.4.10) 497). The naturally occurring 3(2H)-furanone derivative geiparvin has been found to counteract the microtubule-assembly effects of taxol, suggesting that it is a competitive inhibitor at the taxol-binding site of tubulin 498). 

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