Methylene-y-lactones

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). 

A three-carbon unit can be introduced on ketosugars under Reformatsky conditions, as recently demonstrated by several groups [33,34], The analogous Dreiding-Schmidt procedure has also been applied in this case with successful double stereodifferentiation [35]. This is exemplified on ketone 18 which yields lactone 20 as a single isomer (see Scheme 10). The condensation on ketosugars of trimethylsilylacetate [36] or acrylate [33], in the presence of fluoride ion, has also been used with success for the synthesis of P-hydroxy acids or ra-methylene-y-lactones, respectively. 

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

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-y-lactones. Reaction of NaFp with a-bromopyruvate diethyl ketal results in the stable complex I, which on reaction with HPF is converted into the yellow crystalline, unstuhlc complex 2. The cation 2 serves an a-acrylic ester cation... 

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]. 

Based on these reactivities various derivatives of carbenes, such as the aminocarbene 238, are prepared by displacement of the OR group in 237 with amine via addition elimination, analogous to transesterification [74,75], As an example the carbanion 240, generated by deprotonation of 239, attacks ethylene oxide to give the lactone equivalent 241, which is further alkylated by chloromethyl methyl ether, again at the -position. Finally the oc-methylene-y-lactone 242 is obtained by oxidative demetallation with a Ce(TV) salt [76],... 

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. 

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