Of butenolides

About 75 ml. of ethanol is used for every gram of butenolide to be dissolved. Clarification of the solution with charcoal should be avoided because the butenolide tends to separate from solution during filtration and clogs the steam-jacketed funnel. The crystallized butenolide melts at 150-152°. 

The method described above may be used for the preparation of a wide variety of butenolides substituted in the arylidene ring with either electron-withdrawing or electron-releasing substituents. y-Lactones such as a-benzylidene-7-phenyl-A 1 -bu-tenolide are isoelectronic with azlactones, but have received much less attention. Like the azlactone ring, the butenolide ring may be opened readily by water, alcohols, or amines to form keto acids, keto esters, or keto amides.7 a,-Benzylidene-7-phenyl-A3,1 -butenolide is smoothly isomerized by aluminum chloride to 4-phenyl-2-naphthoic acid in 65-75% yield via intramolecular alkylation. 

Feringa-butenolide 114, in the presence of Dess-Martin periodinane reagent and 2,6-lutidine, gave the bis-ketone 115 which underwent intramolecular cycloaddition to afford endo-selectively the desired decalin-based lactone 116 (Equation 2.32) [114]. Double activation of butenolidic double bond strongly increases the reactivity of dienophile 115. 

In the synthesis of butenolides substituted in a position adjacent to the carbonyl, the bis(dimethylamino)phosphinyloxy group has been employed for the direction of an incoming electrophile (Scheme 8). ... 

Esters are commonly regarded as unreactive toward addition of alkyl radicals [120]. Recently, two studies have demonstrated that this may not be true. In the first, somewhat special, example, the addition of a benzylic radical to the carbonyl group of butenolides was observed during the preparation of potential novel /3-lactam antibiotics (Scheme 29) [118]. 

The hydrocarboxylation of suitably substituted hydroxyalkylacetylenes and alkenes has been widely used to prepare a variety of butenolides and butyrolactones (see Scheme 63101,102 and Refs. 8 and 10a for reviews of earlier literature) a closely related reaction is shown in Scheme 64.103,104... 

Catalytic hydrogenation (194) of butenolide 147, obtained from D-galac-tono-, D-glucono-, or D-mannono-1,4-lactones, afforded stereoselectively the 2,6-di-0-benzoyl-3,5-dideoxy-D,L-t/ira>hexo no-1,4-lactone 177. 

Numerous procedures for the preparation of butenolides have been developed. Font and coworkers (234-236) prepared the 5-O-substituted derivatives 223a-c of D-ribono-1,4-lactone. The cw-glycol system of223a reacted with ATjV-dimethylformamide dimethyl acetal and then with iodomethane to give the trimethylammonium methylidene intermediate 224. Pyrolysis of 224 gave the butenolide 225. 

Cyclic orthoformates are useful intermediates for the synthesis of butenolides (235). Treatment of D-ribonolactone, or its 5-0-substituted derivatives, with one molar equivalent of ethyl orthoformate gave diastereoisomeric... 

The double bond of butenolides undergoes stereoselective Michael addition of organometallic reagents, affording useful synthetic intermediates. Thus 1,4-addition of lithium dimethylcuprate to 231 gave 236 as a single isomer, which was employed (237) for the synthesis of the bromopentene derivative 237. 

The double bond of butenolides reacts under Diels-Alder conditions and the resulting chiral bicycles have served as precursors of prostacycline analogs and chrysanthemic acids (250,251). The butenolide 248 was obtained by the procedure described by Ireland et al. (237). A bicyclo[4.3.0] ring system (254) was prepared by Diels-Alder reaction of 248 with butadiene in the presence of aluminum trichloride. Reduction of 254 (LiBH4) yielded the... 

The pyrazoline derivative 260 was also the precursor for the synthesis (252) of the naturally occurring umbelactone. Reaction of butenolide 159c with diazomethane gave the pyrazoline 260, which was subjected to pyrolysis to give (—)-(5 )-umbelactone (261). As the natural umbelactone was described as being dextrorotatory, the synthesis of (+)-(R)-umbelactone from 159c was also performed. 

Cycloadditions (253) of butenolides with isoprene afforded a 1 1 mixture of Diels-Alder regioisomers. The selectivity is increased by the use of aluminum trichloride as catalyst. Although the butenolides studied did not react with furan, even in the presence of catalysts, they reacted smoothly with cyclopentadiene. For example, reaction of (—)-angelica lactone (159a) with... 

Pentalenolactone E methyl ester (46), an angularly fused sesquiterpene lactone, was first isolated and characterized by Cane and Rossi [38]. One approach to the synthesis of this material is illustrated in Scheme 5. Key to the successful implementation of the plan is the synthesis of butenolide 49, the electrochemi-cally promoted cyclization of 49 to the tricyclic y-lactone 48, ring opening of the latter to convert the linearly fused system to the angularly fused six-membered ring lactone 47, and functional group elaboration leading to the natural product 46 [36,37]. 

Little has investigated monoactivated and doubly activated alkenes tethered to butenolide with respect to electroreductive cyclization [202]. The geminally activated systems 227 undergo cyclization to diastereomeric products 228 and 229 in an 1 1 mixture, whereas both the a,j8-unsaturated monoester and a,/ -unsaturated mononitrile fail to cyclize. Only saturation of the C-C double bond of butenolide is observed. The author explains these results by distinct reactivity and lifetime of the intermediate radical anions. The radical anions derived from the monoactivated olefins are less delocalized than those of 227 and therefore should be shorter lived and more reactive. In this case preferential saturation occurs. The radical anions derived from the doubly activated alkene 227 are comparatively long-lived and less basic and thus capable of attacking the C-C double bond of the butenolide moiety. A decrease in saturation, accompanied by a marked increase in cyclization, is observed. 

Examples are known of hydrocoupling between methyl acrylate and ketones in both protic and aprotic solvents. Reaction in acid solution is thought to involve reduction of the protonated ketoneto a radical, which adds to acrylate. In aprotic solvents, the ketone is more difficult to reduce and electron addition occurs on methyl acrylate. Modest yields of coupling product, dimethylbutanolide, are obtained from acetone and methyl acrylate in dimethylformamide [134]. Better results are obtained by reduction of methyl acrylate and an exces of the carbonyl compound in dimethyIformamide in the presence of chlorotrimethylsilane [135]. This process is useful for the synthesis of butenolides and some examples are given in Table 3.8. 

Anodic oxidation of fiirans in acetic acid leads to the 2,5-diacetoxy-2,5-dihydro-furan 58 [185, 186]which is readily converted to 2-acetoxyfiiran, This has proved a valuable intermediate for the synthesis of butenolides [187]. Reactions in moist acetonitrile yield the 2,5-dihydro-2,5-dihydroxyfurans which can be oxidised to the maleic anhydride 59 [188], Oxidation of furan-2-carboxylic acid in methanol and sulphuric acid is a route to the ester of a-ketoglutaric acid [189]. 

Scheme 48 Synthesis of butenolides fused to pento- or hexopyranoses and thiosugar analogs from furanos-3-nloses...

The Diels-Alder cycloadduct of furan and maleic anhydride has played a key role in a new synthesis of butenolides (79S607). Treatment of the cycloadduct (24) with methanol affords a half acid ester which is reacted in turn with an excess of a Grignard reagent to produce the lactone (25) on acidic work-up. On heating this lactone at 150-180 °C, thermal fragmentation takes place to yield the 4,4-dialkylbutenolide (26) in high overall yield (Scheme 5). 

If the halide and the hydroxy group are present in the same molecule, reaction (107) leads to the synthesis of lactones.484 With complex (102) as catalyst a series of butenolides were prepared in good yields from vinyl iodides (equation 110). Four- and six-membered ring lactones and a-methylene lactones were prepared. 5,486 The mechanism proposed was analogous to that of Scheme 37. This cyclization has been used in the synthesis of the natural product zearalenone.487 PdCl2 was the catalyst. 

The crossed intramolecular [2 + 2]-photocycloaddition of allenes to a, 3-unsat-urated y-lactones has been extensively studied by Hiemstra et al. in an approach to racemic solanoedepin A (87). The sensitized irradiation of butenolide 85 in a 9 1 mixture of benzene and acetone, for example, led selectively to the strained photocycloadduct 86 (Scheme 6.31) [89]. The facial diastereoselectivity is determined by the stereogenic center, to which the allene is attached. The carbon atom in exposition to the carbonyl carbon atom is attacked from its re face, forming a bond to the tertiary allene carbon atom, while the P-carbon atom is being connected to the internal allene carbon atom by a si face attack. The method allows facial diaster-eocontrol over three contiguous stereogenic centers in the bicyclo[2.1.1]heptane part of the natural product. 

The synthesis of triptolide (149) by Berchtold[49], provides many interesting information for organic chemists. An excellent method has been developed for the construction of butenolide ring. The periodate oxidation of o-hydroxymethylphenoles appears to be a convenient method for the stereospecific construction of the C-ring functionality in triptolide and related substances. 

In planning the synthesis of a series of carbapyranoses in their chiral non racemic format, Zanardi and co-workers [7d] utilized the seven-carbon lactone 149, in turn prepared by elaboration of butenolide 12 (vide supra, Scheme 3). 

The regioselective preference for the formation of the branched product can be reversed by an increase of steric hindrance, especially at the propargylic position. Preferential formation of the linear isomer was also observed with 4-hy-droxyalkynoates, allowing the synthesis of butenolides via cyclization [37] (Eq. 26). 

Double cyclizations to butenolides and furanes. Radicals can undergo intramolecular addition to triple bonds when separated by three carbons. This strategy can be used for synthesis of butenolides (equation 1) and -substituted furanes (equation II). Cyclization of vinyl bromides." Fused and bridged ring systems can be prepared... 

The epoxidation of butenolides is often difficult, because the reaction product easily isomerizes to the corresponding y-oxo acid. Treatment of butenolide 44 with an excess of sodium hypochlorite in pyridine at 0°C cleanly yielded epoxy acid 45. which on warming to 65 °C underwent ring closure to the diastereomerically pure epoxylactone 46. Compound 46 was converted to tfl-cerulenin. Similarly, butenolide 47 was epoxidized to epoxylactone 48, albeit in low yield. Epoxylactone 48 was converted into an aromatic analog of cerulenin92. 

Epoxidation of Butenolides with Sodium Hypochlorite Typical Procedure92 ... 

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