Addition of butenolide

Takei utilized a furan as the synthetic equivalent of a 1,4 dicarbonyl compound in his synthesis of pyrenophorin as described in Scheme 4.6. ° Thus butenolide 28, obtained by Michael addition of butenolide 27 to methyl vinyl ketone, was silylated to provide the silyloxyfuran. Treatment with lead tetraacetate followed by aqueous hydrolysis gave 29 in 55% yield. Protection of the ketones as dimethyl ketals followed by selective removal of the C-7 ketal and reduction gave seco acid 30. Dimerization and hydrolysis gave a mixture of 9 and 18 (17% from 29). 

Scheme 24 y-Selective addition of butenolides catalyzed by bifunctional organocatalyst... 

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]. 

Rauter s group exploited the synthesis of sugar derived bicyclic butenolides ( e.g. 140, Fig. 44),60 which possess cytotoxic and antitumor activities. The key structural feature of such compounds consists of the presence of the a,(3-unsaturated lactone, which allows them to act as Michael acceptors for the addition of enzymes nucleophiles. 

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. 

A total synthesis of (35, 4/ )-(+)-eldanolide (246), a sex attractant pheromone, has been reported (243). Compound 246 was synthesized by two different routes, both involving the butenolide 245 as the key precursor. The higher-yielding sequence is described here. Treatment of the tosylate acetal 242 with methanolic sodium methoxide led, as previously described by Hoffman and Ladner (244), to the epoxide 243. Addition of lithium diiso-butenylcuprate to 243 afforded 244, which after successive hydrolysis of the isopropylidene group, treatment with triethyl orthoformate, and pyrolysis,... 

Such dideoxynucleosides as CNT (306) and the potent anti-HIV drug ddC (307) have been obtained (280), respectively, from the butenolide 248 and from its saturated analogue. Thus, conjugate addition of cyanide to 248, followed by reduction of the lactone group, acetylation of HO-1, and coupling with silylated thymine, afforded, after deprotection, compound 306. 

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). 

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. 

As a furllier example of the addition of electron rich heteroaromatics to electron deficient alkenes, MacMillan has shown that y-butenolides can be prepared in one-step by the addition of silyloxyfurans (45) to a,p-unsaturated aldehydes (Scheme 19) [88]. Reactions were tolerant to substitution at the 4- and 5-positions of the furan... 

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. 

Scheme 6.32 y-Butenolides obtained from diastereoselective aldol addition of 2-trimethylsilyloxyfuran to aldehydes catalyzed by urea 32. 

Michael addition of a dithiane anion 20, generated from the dithiane 19 with butyllithium, to the butenolide 21 creates the enolate 22 which has been efficiently alkylated in situ by 3,4,5-trimethoxybenzyl chloride to give 24 (mp 146-146.5 °C) in 65% overall yield. Protona-tion of 22 furnished the Michael adduct 23, which again can be deprotonated16 with LDA at — 78 °C to give 22 and alkylated (trimethoxybenzyl chloride, THF, HMPA, 3 h at — 78 °C, 18 h at 20 °C) to yield 24. Both variants are equally completely diastereoselective giving rise to the trans- product. 

The conjugate addition of aryl dithiane anions to 2-butenolide has been examined as a route to ( )-podorhizol and ( )-isopodophyllotoxone (78JOC985). The dithiane of piperonal (802) was deprotonated and reacted with 2-butenolide to give the lactone anion which was trapped in turn with 3,4,5-trimethoxybenzaldehyde to afford a mixture of the threo and erythro aldol products (803). Desulfurization of the erythro dithiane with Raney nickel gave ( )-podorhizol (804 Scheme 188). 

Few examples exist for the conjugate addition of ester enolates to a,(3-unsaturated esters typically the incipient enolate undergoes decomposition and secondary reactions. The first examples, described by Schlessinger,144 are the addition of /-butyl lithioacetate and /-butyl a-lithio-a-(methylthio)propionate to butenolide (176 Scheme 69). Similarly, Normant reported that cyclopropanes are obtained from a-ha-loesters (177) and ethyl acrylate or acrylonitrile.145... 

In the course of a total synthesis of aphidicolin (107), the conjugate addition of the dienoiate (104) to the chiral butenolide derivative (105) serves as a key step. A 7.4 1 mixture of diasteieomeric products is obtained, from which the major isomer (106) can be isolated in pure form after recrystaliization (Scheme 41).121 The selectivity of this remarkable reaction, in which two quaternary stereogenic centers are simultaneously generated in a highly selective manner, can be explained by the assumption that the reactants approach each other in the chelate-mode indicated in (108). 

Fused ring 7-lactones may also be formed by cyclizations of l-cycloalkeneacetic acids under equilibrating conditions. Nicolaou obtained evidence for the presence of an unstable -lactone in the phenyl-selenolactonization of 1-cyclohexeneacetic acid, but rearrangement occured readily at room temperature to the more stable 7-lactone (equation 12).32 An example of a one-step conversion of a 2-methyl-1-cyclohexeneacetic acid to a fused butenolide by use of diphenyldiselenide and electrochemical oxidation has been reported.47 Recent studies by Rutledge showed that simultaneous addition of bromine and thallium carbonate to 1-cyclohexeneacetic acid gave the 7-lactone as the exclusive product (compare to Table 2) however, the mechanism of this reaction may differ from other cyclofunctionalizations.21... 

The chiral imidazolidinone 45 also catalyzes the Mukaiyama-Michael reaction between 2-silyloxy furans and a,/ -unsaturated aldehydes, affording enantiomeri-cally highly enriched y-butenolides (Scheme 4.18) [33]. For optimum catalytic performance, hydroxyl additives are necessary, and addition of 2 equiv. water proved best. 

Buu Hue, B.T., Dijkink, J., Kuiper, S.v., Schaik, S.v., Maarseveen, J.H., and Hiemstra, H. (2006) Synthesis of the tricyclic core of solanoeclepin a through intramolecular [2 + 2] photocyclo-addition of an allene butenolide. European Journal of Organic Chemistry, 127-137. 

Chiral rhodium(II) oxazolidinones 5-7 were not as effective as Rh2(MEPY)4 for enantioseleetive intramolecular cyclopropanation, even though the sterie bulk of their chiral ligand attachments (COOMe versus /-Pr or C Ph) are similar. Significantly lower yields and lower enantiomeric excesses resulted from the decomposition of 11 catalyzed by either Rh2(4S-IPOX)4, Rh2(4S-BNOX)4, or Rh2(4R-BNOX)4 (Table 3). In addition, butenolide 12, the product from carbenium ion addition of the rhodium-stabilized carbenoid to the double bond followed by 1,2-hydrogen migration and dissociation of RI12L4 (Scheme II), was of considerable importance in reactions performed with 5-7 but was only a minor constituent ( 1%) from reactions catalyzed by Rh2(5S-MEPY)4. This difference can be attributed to the ability of the carboxylate substituents to stabilize the earboeation form of the intermediate metal carbene. 

Hydroxymethylation of ketone (155) was followed by protection of the aliphatic hydroxy group (2-methoxypropyl ether) and addition of an a-benzyloxymethylene group at C-4. Acidic workup at the last stage of the reaction sequence produced (156). Its transformation to aldehyde (157) was carried out by successive treatment with methoxypropyl ether, acetic anhydride and pyridine, hydrochloric acid and methanol, and finally chromic acid, pyridine and hydrochloric acid. Dehydration of (157) led to the formation of (158) in 20% yield. Reagents other than the mentioned produced appreciable quantities of the cis A/B isomer. The butenolide (159) was finally synthesized by oxidation and hydrogenolysis. In order to complete the synthesis of triptolide it was necessary to introduce the... 

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