Alkylidene-y-lactones

The cyclofunctionalization of 4-alkynoic and 5-alkynoic acids generates y-alkylidene-y-lactones and 5-alkylidene-S-lactones, respectively (equation 76 and Table 22). The initial products from the reactions catalyzed by mercury or silver salts undergo protiodemetallation under the reaction conditions. The vi-nylpalladium intermediates undergo either protiodemetallation or coupling with an added allyl halide. The palladium(II)-catalyzed cyclization of 3-alkynoic acids proceeds by 5-endo closure to give 3-buten-4-olides (Table 22, entry 2).50 190... 

Several other transannular lactonizations and reductions have been reported to proceed in high overall yields. Also other acid derivatives, such as amides and esters, cyclize to form lactones. Alkynoic acids have been lactonized to y-alkylidene-y-lactones in good yield, e.g. the conversion of (31) to (32 equation 29). Unfortunately the vinyl selenide product can isomerize from ( ) to (Z) in a secondary process. Analogous lactam formation is also known. Unsaturated amides, when cyclized with benzenese-lenenyl halides, produce good yields of lactams or iminolactones depending upon the alkene utilized. The amide (33) cyclizes to the iminolactone (34), producing a mixture of stereoisomers (65 35 Scheme 5). The amide (35) is cyclized to lactam (36) in moderate yield. 

Reaction with alkylidene-y-lactones. Hoye and Caruso have prepared the reagent by reaction of diphenyl diselenide with sodium sand (Alfa) in THF at 80° in a resealable sealed tube. The reaction is complete after 3 hours. Potassium selenophenolate can be prepared in the same way. The two reagents seem to be comparable... 

This type of alkynol ether hydrocyanation gives rise to a new stereospecific route to a-alkyli-dene y-lactones. Acidic hydrolysis and cyclization of some of the products obtained, as above, give a-alkylidene-y-lactones in 65-83% yield with the double-bond geometry predetermined via stereoselective hydrocyanation2T... 

Aldol reaction between a ketone and an aldehyde can be controlled by prior conversion of the ketone into the ethyloxalyl derivative before reaction with the aldehyde. The keto-lactone so formed is decomposed to an alkene moiety with base. This method is particularly well suited to the formation of a-alkylidene-cyclo-alkanones (ring size >6) and a-alkylidene-y-lactones (Scheme 73). ... 

A similar synthesis of (Z)-a-alkylidene-y-lactones from alkenyl iodides was reported by Luo et al. In a related procedure,the presence of an acetyl group a to the hydroxyl group of the iodide led to the formation of a,/S-unsaturated butenolides. The presumed intermediate a-methylene lactone probably undergoes isomerization to the more stable butenolide under the reaction conditions, as shown in Scheme 8. 

A wide variety of o-haloaryl ketones phio] (Schemes 8 and 9) and (Z)-/S-halo-a,/3-unsaturated ketones (Schemes 10 and 11) undergo carbonylative 5-O-exo cyclization to give predominantly (Z)-y-alkylidene-y-lactones. In cases where the a-carbon center is substituted, the ZIE ratio of the cxo-alkylidene group is generally high (>50). If it is unsubstituted, the ZIE ratio is generally < 10. ... 

Marinez V J C, Yoshida M, Gottlieb O R 1979 Six groups of cu-ethyl-, cu-ethenyl- and co-ethynyl-cr-alkylidene-y-lactones (1). Tetrahedron Lett 1021-1024... 

Occurrence, Biosynthesis, and Biological Activities 149 Table 4.1 Major categories of natural a-alkylidene-y-lactones. 

Nonterpenoid a-alkylidene-y-lactones 3.1. y-Lactones with lignan skeleton... 

Scheme 4.4 Organometallic reagents in the synthesis of a-alkylidene-y-lactones and lactams 26.

Optically active allylboronates bearing chiral auxiliary located at the boron atom found widespread applications in asymmetric synthesis. Enantiomerically enriched a-alkylidene-y-lactones and lactams can also be synthesized following such a synthetic approach. VUlieras et al. (41, 45] demonstrated the potential of chiral allylboronates derived from 2-phenyl-2,3-bomanediol, ephedrine, or norephedrine for this purpose. Chiral allylboronates 46a,b were obtained in a sequence of reactions involving transformation of achiral precursors 32 into the corresponding boronic acids 44 followed by their esterification with enantiomerically pure diol or 1,2-aminoalcohol 45 (Scheme 4.10). In the case of methyl-substituted derivatives 32b (R = Me), initial composition of E- and Z-isomers was transferred to the target allylboronates 46b. Importantly, the isomeric mixture was separated by means of the column chromatography. 

In 2001, Ballini and coworkers [46] demonstrated that convenient method for the preparation of 2-methylene-4-nitroalkanoates 56 relies on a reaction between ethyl 2-(bromomethyl)acrylate 55a with selected nitroalkanes 51 (Scheme 4.14). Originally formed adducts 56 were transformed into target Y-substituted-a-alkylidene-y-lactones 50a in a sequence of reactions involving oxidation of the nitro group to carbonyl group by means ofa Nef reaction, subsequent reduction of4-03K>aIkanoates 57 obtained and acid-mediated cyclization of 4-hydroxyalkanoates. 

Scheme 4.22 Synthesis of a-alkylidene-y-lactones 89 via vinylalumination of epoxides 87.

Elimination Reaction in the Synthesis of or-Alkylidene-y-Lactones or y-Lactams... 

P-Elimination reaction constitutes one of the most important methods for the formation of carbon-carbon double bond. It can be successfully employed in the synthesis of a-alkylidene-y-lactones and y-lactams when correspondingly functionalized, saturated y-lactones or y-lactams 192 bearing a good leaving group in the I -position are available (Scheme 4.47). 

Oxidation of the C-2 carbon atom in the corresponding 3-alkylidenetetrahydro-furanones 204 constitutes another convenient method for the synthesis of a-alkylidene-Y-lactones 20aa (Scheme 4.50). 

Scheme 4.S0 Oxidative strategies for the preparation of a-alkylidene-y-lactones 20aa.

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