A-methylene-y-lactone

Epoxynitrone (742) can be transformed to a positively charged heterodiene (743) using CF3S03SiMe3 or CF3S03Si(Bu )Me2 as electrophilic reagents (79HCA205). The diene adds to isolated double bonds to afford oxazines such as (744) via an inverse electron demand Diels-Alder pathway. Subsequent addition of cyanide to the iminium salt leads to a stable derivative (745) which can be converted through its mesylate (746) to an a-methylene y-lactone (747) on base treatment followed by acid hydrolysis (Scheme 171). 

Chiral a-methylene-y-lactones.1 (R)-( + )-Alkyl p-tolyl sulfoxides (2), readily obtainable in almost quantitative yield from (l),2 on lithiation (LiTMP) and reaction with lithium a-bromomethylacrylate (3) are converted into a-methylene-y-sulfinyl carboxylic acids (4), which can be separated by chromatography or crystallization. Reduction of optically pure 4 provides y-tolylthio acids [(S)-5], which on methylation and treatment with potassium f-butoxide are converted into (4R)-a-methylene-y-lactones (6), with inversion of chirality. 

In certain other systems, there is compelling evidence for the insertion into a metal-caiboxylate complex (equation 37). For example, in the synthesis of a-methylene-y-lactones from alkynic alcohols,70,71 no double bond rearrangement to a butenolide occurs, a reaction shown to take place in the presence of transition metal hydrides. The source of the vinyl proton (deuterium) on the a-methylene group is indeed the alcohol function. Finally, palladium carboxylate complexes containing alkynic (equation 40) or vinyl tails (equation 41) can be isolated and the corresponding insertion reaction can be observed. 

Methylene homologation, with zinc carbenoids, 9, 127 a-Methylene-y-lactone, via carbonylation, 11, 549 Methylenes... 

Monocarbonylation of 3-butyn-l-ol (27) in the presence of thiourea as an additive gives a-methylene-y-lactone (28), a structure widely distributed in certain natural products [22], A derivative of vemolepine 30 is prepared from 29 by this method [23]. Carbonylation of the rigid system of 2-exo-ethynyl-7-5y -norbomanol (31) with PdCl2 in the presence of thiourea at 50 °C afforded the a-methylene-d-lactone 32 in 47% yield [24]. 

Yields are high (70-80%) except in the case of sterically hindered ketones (f-BuCOCH3). In all cases, the branched versus linear alcohol ratio is at least 95 5. a-methylen-y-lactones are prepared from ethyl 2-(bromomethyl)acrylate and carbonyl compounds using the same procedure (Protocol 4) with yields depending on the steric environment of the carbonyl compound.11... 

Sesquiterpenes containing either a methylene-y-lactone or a cyclopentenone moiety can react with thiol groups to form a covalent linkage. If the thiol group is on a key enzyme, interaction with artemisinin could inactivate the enzyme, disrupting metabolism. Cysteine is a good antidote for artemisinin as a phytotoxin, but there is no evidence that it is due to a direct interaction of the two molecules.15... 

Sesquiterpene lactones are typical secondary metabolites of many members of the Asteraceae, the composite family (45, 46). The lactone moiety in these compounds is usually present as an a -methylene-y-lactone function with the lactone bridge joining carbon atoms 12 and 6 or 12 and 8 on the sesquiterpene skeleton (see Figure... 

The adducts (4) can be converted into a-methylene-y-lactones (7) by the method used earlier by Eschenmoser (5, 111) for related adducts. 

R. Csuk, A. Fiirstner, H. Sterk, and H, Weidmann, Synthesis of carbohydrate derived a-methylene-y-lactones by diastereoselective, low temperature Reformatsky-type reactions, J. Carbohydr. Chem. 5 459 (1986). 

All of the compounds isolated from T. cinerariaefolium have inhibited root growth of Chinese cabbage seedlings [32]. This physiological activity seems to be attributed to the sesquiterpenoids with an a-methylene-y-lactone ring system. 

Giese showed that an anomeric radical, obtained by reaction of acetobromoglucose 225 with tributyltin hydride, adds to sugar-derived a-methylene-y-lactones such as 226 with good yields and high a stereoselectivity [103] (O Scheme 47). 

Another traditional medicine from Iceland, a lichen (Cetaria islandica), is used to treat gastrointestinal ailments and has also been shown to have anti-HP activity [88]. Protolichesterinic acid. Fig. 8, an aliphatic a-methylene-y-lactone, was... 

Further studies on the synthesis of psuedoguaianolides cf. Vol. 6, p. 90) have resulted in the total synthesis of the cytotoxic compounds ( )-damsin (447) (Scheme 43) and ( )-confertin (449) (Scheme 44). The realization that many sesqui-terpenoids containing a-methylene-y-lactone rings display important biological activity (cf. pp. 88 and 96) has prompted the development of several procedures... 

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