Butenolide anions

Organolithium con imds also react with acetals or oithoesters in the presence of BF3-OEt2. Dialkoxymethylations of lithium enolates with triethyl orthoformate are carried out by adding BF3-OEt2 to the mixture (equation 45). Prior mixture of an enolate and the Lewis acid results in a drastic decrease of the product yield. Lithium enolates are generated from silyl enol ethers and MeLi, and C—C bond formation proceeds legiospecifically with respect to the enolates. The condensation is applicable to a fully substituted enolate. Butenolide anions add to acetals or orthoesters pretreated with BF3-OEt2 at the C-S position (equation 46). ... 

Subsequent to our use of butenolide anions in aldol reactions to construct sidechains of steroids, two groups have reported a similar method for synthesis of brassinolide or its analogs. Kametani and co-workers employed the dianion of 3-isopropyltetronic acid which was reacted with a 20-keto steroid. The aldol product was dehydrated and the product hydrogenated to furnish the brassinolide sidechain (28,29). Zhou and Tian have used the reaction of a C-22 aldehyde derived from... 

Butenolide anions react with orthoesters that have been activated by BFa OEtj. The disubstituted butenolide (177) is prepared from (176) by conjugate addition followed by elimination (Scheme 99). ... 

It is well known that butenolide anions do not react with orthoesters, and that butenolides do not react with carbo-cations generated from acetals and orthoesters. However, by combining both reactive species, Pelter has successfully accomplished the synthesis of butenolides such as (67). Furthermore, this general strategy has been used in the synthesis of piperolide and fadyenolide intermediates. 

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. 

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 carbonyl anion equivalent is generated from 1 equiv (1 m in THF, —78 <"C) of piperonal dithiomethyl acetal by treatment with 1 equiv of BuLi. After stirring for 40 min at —78 °C, 1 equiv (1 M in TIIF) of the butenolide is slowly added over a period of 30 min. The resulting white suspension is stirred for 3 h at — 78 °C whereupon 1 equiv (1 M in THF) of the 3,4,5-trimethoxybenzyl bromide is rapidly added followed immediately by 1 equiv of TMEDA. The temperature of the mixture is raised to — 20 °C and stirring continued for 10 to 12 h. Standard workup gives the adduct 24 as an amorphous yellow solid crude yield 99% d.r. (trans/cis) >99 <1. 

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). 

Racemic yatein 43 was obtained by Michael addition of the anion of piperonaldehyde dithiomethyl acetal to 5/7-furan-2-one (butenolide), followed by trapping of the resulting enolate with 3,4,5-trimethoxybenzyl bromide (see section 3.2.2). This process gave 43 with the desired trans stereochemistry at the butyrolactone. Oxidative coupling of the two... 

By treatment with NaH, bicyclic furoisoxazolidines 192 failed to give the expected 3-alkyl-substituted 2-amino-butenolides 193, but instead afforded the 3-amino-2(577)-furanones 195 with conservation of the lactone ring and fragmentation of the isoxazolidine nucleus. In this case, the initially formed anion evolved to 194 with formation of an endocyclic double bond and elimination of formaldehyde (Scbeme 45). The two-step process - intramolecular 1,3-dipolar cycloaddition and NaH treatment of the furo[3,4-( ]isoxazolidine adducts - was applied to the synthesis of enantiopure 3-alkylamino-5-methyl-2(5/7)furanones <2002JOC4380>. 

Methoxy(phenylthio)methane and methoxy(phenylsulfonyl)methane are useful formyl anion equivalents for one-carbon homologation. For instance, addition of methoxy(phenylthio)methyllithium to ketones, followed by rearrangement of the adduct, provides a new method for the preparation of a-(phe-nylthio) aldehydes (equation 39). The reanangement is stereospecilic. This method has been used for the total synthesis of annelated furans such as (-)-)-euryfiiran, butenolides such as isodenninin and con-fertifolin and spirocyclic tetrahydiofurans and butenolides. ... 

Butenolides. These species are P-acylvinyl anion equivalents. Their reaction with carbonyl compounds, with subsequent treatment with TFAA and DBU, affords butenolides. A synthesis of rosefuran is based on this process. 

The newest techniques employ silylation. Even the anions of saturated butenolides afford the enol ester on reaction with chlorotrimethylsilane91 applied to a butenolide the method readily supplies a 2-silyloxyfuran. Such ethers are even more easily procured by allowing a butenolide to react with chlorotrimethylsilane in the presence of triethylamine and zinc chloride but for reasons that remain unclear, acetonitrile is the only satisfactory solvent.92 A typical transformation of 2-trimethylsilyloxyfuran is shown in Scheme 19. 

The aldehyde was then used in an aldol reaction with the anion from 3-isopropylbut-2-enolide. [The lactone was prepared in the following way bromination of 3-methyl-2-butanone under kinetic conditions (-15 °C) afforded the 1-bromo derivative. The bromine was displaced by acetate on refluxing a solution in acetone with anhydrous KOAc. Reaction of the resulting keto-acetate with the anion from triethylphosphonoacetate afforded the desired butenolide in 55% yield.] The anion was generated in tetrahydrofuran from the butenolide and lithium diisopropylamide and was cooled to -78 °C before addition of the aldehyde. The temperature was maintained below -70 °C for 5h and the reaction was quenched with ammonium chloride at this temperature. Under these conditions (kinetic) the 22R23R intermediate (3) was obtained in 65% yield (26). 

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