Butenolides intermediates

New Au(III)-pyridine-2-carboxylate complexes were developed to catalyze the intramolecular reaction between furan and acetylene to form phenols <04AE(G)6545>. These pre-catalysts provide higher reaction conversion than AuClj. The Lewis acid catalyzed vinylogous Mukaiyama-Mannich addition of trimethylsilyloxyfuran to aldimines, that generates 6-amino-Y-butenolide intermediates, was applied to the synthesis of piperidines... 

Recently, the conversion of alkenes or non-activated internal alkynes into the corresponding carboxylic acids and/or butenolides has been achieved through carboxylation of titanacycle intermediates of type 73 with carbon dioxide (Scheme 27).78... 

One of the earliest and most important discoveries in metal-catalyzed asymmetric synthesis is Sharpless s Ti-catalyzed epoxidation of allylic alcohols. A mere mention of all the total syntheses that have used this technology would require a separate review article Here, we select Trost s masterful total synthesis of solamin (100, Scheme 14), for its beautiful and multiple use of Sharpless s asymmetric epoxidation.1161 Optically pure epoxy alcohol 95 is converted to both epoxy iodide 96 and diol 97 The latter two intermediates are then united to give 98, which is oxidized and converted to dihydrofuran 99 by a Ramberg-Backlund transformation. The Re catalyzed butenolide annulation that is used to afford the requisite unsaturated lactone only adds to the efficiency of this beautiful total synthesis. 

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 synthetic usefulness of reactions of lithiated methoxyallene 42 with suitable electrophiles was demonstrated by several syntheses of bioactive natural products or substructures thereof [52-58]. An interesting application was described by Fall et al. [52] after addition of alkyl iodide 55 to lithiated methoxyallene 42, deprotonation by tert-butyllithium and addition of carbon dioxide occurred at the terminal y-carbon and thus provided butenolide 57 after acidic workup. Desilylation of this intermediate with TBAF finally gave bicyclic oxepane derivative 58 in good overall yield (Scheme 8.14). 

Substituted propargylic alcohols were found to undergo direct carbonylation to the corresponding butenolides in 67-98% yield (Eq. 9.120) [86]. This reaction requires a catalytic amount of Pd2(dba)3-CHC13 (4%) and l,4-bis(diphenylphosphi-no)butane (8%) in CH2C12 under an atmosphere of CO (600 psi) and H2 (200 psi) at 95 °C for 36 h. The cyclocarbonylation reaction is believed to proceed via an allenyl-palladium intermediate, which is formed by initial insertion of Pd(0) into the C-O bond of the alkynol followed by rearrangement (Scheme 9.25). 

The reaction of an allene with an aryl- or vinylpalladium(II) species is a widely used way of forming a Jt-allyl complex. Subsequent nucleophilic attack on this intermediate gives the product and palladium(O) (Scheme 17.1). Oxidative addition of palladium ) to an aryl or vinyl halide closes the catalytic cycle that does not involve an overall oxidation. a-Allenyl acids 27, however, react with palladium(II) instead of with palladium(O) to afford cr-vinylpalladium(II) intermediates 28 (Scheme 17.12). These cr-complexes than react with either an allenyl ketone [11] or with another alle-nyl acid [12] to form 4-(3 -furanyl)butenolides 30 or -dibutenolides 32, respectively. 

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. 

Chiral butenolides are valuable synthons towards y-butyrolactone natural products [37] and have also been successfully applied to the synthesis of paraconic acids. The lactone 91, readily available from the hydroxyamide (rac)-90 by enzymatic resolution [38] followed by iodolactonization, proved to be an especially versatile key intermediate. Copper(I)-catalyzed cross coupling reactions with Grignard reagents allowed the direct introduction of alkyl side chains, as depicted in 92a and 92b (Scheme 13) [39, 40]. Further... 

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]. 

A pentopyranoside-fused butenolide is the key intermediate for the synthesis of the natural micotoxin patulin [226, 227]. Its synthesis involves Wittig olefination of a 3,4-di-O-protected arabinopyran-2-uloside, followed by protecting group removal and dehydration (Scheme 47). In other research, the glucopyranosid-2-uloside 190 was converted into the butenolide derivative 191 by aldol condensation with diethyl malonate and transesterification [228]. The latter was shown to be prone to autoxi-dation, leading to 192. Subsequent Michael addition with hydroxide ion, followed by decarboxylation, furnishes C-branched-chain sugar 193. 

The nucleus of the one-time widely prescribed prescribed COX-2 inhibitor, rofecoxib, better known by its trade name Vioxx , actually comprises a butenolide rather than a classical heterocycle. The drug was withdrawn from the market at full flood due to an unexpectedly high incidence of adverse cardiovascular side effects. The compound is included at this point to emphasize the breadth of the SAR for COX-2 anti-inflammatory agents. Reaction of phenylacetic acid (35-1) with ethyl bro-moacetate in the presence of triethylamine leads to the formation of the ester (35-2). Treatment of that intermediate with a strong base generates a carbanion at the benzyhc position in an intramolecular reaction, this attacks the terminal ester carbonyl to yield the butenolide (35-3). Reaction of that compound with triflic anhydride converts the... 

Finally, the outstanding functional group tolerance of the Stille reaction was exploited to prepare a series of alkylidenebutenolids. y-(Dibromomethylene)butenolide (6.42.) was sequentially coupled with phenyltributylstannane and styryltributylstannane to result in the selective exchange of the two bromine atoms. In the first intermediate it is always the Z-olefin that is formed.62... 

PCC will oxidize 2-hydroxymethyl-5-bromofuran derivatives (90) to -y-hydroxy-butenolides (91) (79TL1507). This simple, high yield procedure thus provides an important route to these synthetically useful intermediates (equation 2). 

Methoxy-2-furylcarbinols (367) were converted into a 3 1 mixture of 4-ylidene-butenolides (369) and 4-oxo-2-enoic acid methyl esters (370) by zinc chloride catalysis. The carbonium ion (368) is the key intermediate, the stability of which made the conversion very fast, providing high yields (Scheme 99) (80T3071). 

Chiral Rh(II) oxazolidinones Rh2(BNOX)4 and Rh2(IPOX)4 (25a,b) were not as effective as Rh2(MEPY)4 for enantioselective intramolecular cyclopropanation, even though the steric bulk of their chiral ligand attachments (COOMe versus i-Pr or CH2Ph) are similar. Significantly lower yields and lower enantioselectivides resulted from dinitrogen extrusion from prenyl diazoacetate catalyzed by either Rh2(4.S -lPOX)4 or Rh2(4S-BNOX)4. This difference, and those associated with butenolide formation [91], can be attributed to the ability of the carboxylate substituents to stabilize the carbocation form of the intermediate metal carbene (3b), thus limiting the Rh2(MEPY)4-catalyzed reaction to concerted carbene addition onto both carbon atoms of the C-C double bond. 

Thus, 1.7-octadiene (79), which was subjected to monohydroboration followed by asymmetric dihydroxylation of the remaining double bond to give triol 80 with approximately 80% ee. Further transformations then afforded the desired butenolide 81. Double asymmetric dihydroxylation of diene 83 and subsequent protection gave hydroxy lactone 84 [98], which was then converted into acetylenic bis(hydroxy)bistetrahydrofuran 82 as the required intermediate for the (+)-asimicin synthesis. Mitsunobu inversion at C-24 gave rise to the diastereomeric (+)-bullatacin precursor. 

Tandem Passerini/Knoevenagel reactions were also performed by employing 2-nitrophenylacetic acid as the acid component to give the butenolides 65 that were reduced to the intermediate amines 66, which immediately cyclized to give indoles 67 in very high yields via a ring-switching process (Scheme 2.24) [52],... 

The aldol (23) on treatment with benzenesulphonyl chloride yields the oxetanone ((3-lactone) (24) which is an intermediate in the synthesis of the butenolides (25) (95SC479). Aliphatic terminal alkynes or arylalkynes react with nitrones in the presence of a copper based catalyst system to give 1,3,4-trisubstituted [3-lactones (95JOC4999). 

The [2 + 2]-photocycloaddition chemistry of a,(3-unsaturated lactones has been widely explored. The factors governing regio- and simple diastereoselectivity are similar to what has been discussed in enone photochemistry (substrate class Al, Section 6.2). The HT product is the predominant product in the reaction with electron-rich alkenes [84]. A stereogenic center in the y-position of ot,P-unsaturated y-lactones (butenolides) can serve as a valuable control element to achieve facial diastereoselectivity [85, 86]. The selectivity is most pronounced if the lactone is substituted in the a- and/or P-position. The readily available chiral 2(5H)-furanones 79 and 82 have been successfully employed in natural product total syntheses (Scheme 6.30). In both cases, the intermediate photocycloaddition product with 1,2-dichloroethylene was reductively converted into a cyclobutene. In the first reaction sequence, the two-step procedure resulted diastereoselectively (d.r. = 88/12) in product 80, which was separated from the minor diastereoisomer (9%). Direct excitation (Hg lamp, quartz) in acetonitrile solution was superior to sensitized irradiation (Hg lamp, Pyrex) in acetone, the former providing the photocycloaddition products in 89% yield, the latter in only 45%. Cyclobutene 80 was further converted into the monoterpenoid pheromone (+)-lineatin (81) [87]. In the second reaction... 

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