A-methylene-8-lactone

Aromatic a-methylene-8-lactones. A new approach to this system is outlined in equation (1). 

Silyloxycyclopropanecarboxylates are masked homoenolate equivalents which can also add to dimethyl(methylene)iminium salts. In one of several examples reported by Reissig and Lorey, methyl 2-f-butyl-2-(trimethylsilyloxy)cyclopropanecarboxylate and triflate salt (33) react to produce methylaminomethyl-y-oxo ester (64 Scheme 14). The reactive intermediate has not been precisely determined but is most likely a ring-opened enolate (63) or its silyl ketene acetal derivative. The reaction can also be performed using the chloride iminium salt (31) in the presence of TiCU, but the reproducibility is poor due to reduced solubility. The products of these reactions are convenient precursors to a-methylene-8-lactones and acrylic acid derivatives. 

The first enantioselective, organocatalytic approach for the synthesis of a-methylene-8-lactone (194) and 8-lactam (195), utilizing the Michael addition of the aliphatic aldehyde (193) to ethyl 2-(diethoxypho-sphoryl)acrylate (192), in the presence of the pirolidyne derivative (196) has been presented by Jorgensen and co-workers (Scheme 68). ... 

In 2004, Krishna and coworkers [59] reported that optically active a-methylene-y- and S-lactones can be obtained via intramolecular asymmetric Morita-Baylis-Hillman reaction starting from enantiomerically pure starting materials (Scheme 4.28). Diastereoselective cyclizations of chiral acrylates 103 and 105 were realized using DABCO as nucleophilic promoter. P,y-Disubstituted-a-methylene-y-lactone 104 and bicyclic a-methylene-8-lactone 106 with hydroxyl substituent in the 3-position were readily accessed following such strategy. 

Dialkoxyphosphoryl-5-oxoalkanoates 148 can also serve as precursors of a-diethoxyphosphoryl-S-lactones and, in a consequence, of a-methylene-8-lactones. Two most common approaches to these synthetic intermediates are depicted in Scheme 4.39. First one relies on the Michael addition of enohzable carbonyl compounds 67 to the 3-diethoxyphosphorylalk-2-enoates 147. Second strategy utilizes Michael addition ofphosphonoacetates 143 to the a,fS-unsaturated carbonyl compounds 149. Examples of both approaches will be discussed in the following paragraph. 

Such an approach for the synthesis of optically active a-methylene-8-lactones was further extended to include enamines derived from (J )- or (S)-dihydrocarvone and (R)- or (S)-l-phenylethylamine in the Michael addition step [71]. In such a manner, a synthesis of all four enantiomericaUy pure diastereoisomers of 7-isopropenyl-4a-methyl-3-methyleneoctahydrochromen-2-one was accomplished. Furthermore, the possibihty to control stereochemical outcome of the Michael addition step by employing chiral phosphinate auxihary in the starting dicyclohexylammonium acrylate was also demonstrated by KrawcTyk and coworkers [72]. 

Among various a-methylene-8-lactones, derivatives with the S-lactone ring fused with the aryl ring having a structure of 3,4-dihydrocoumarins occupy prominent position and received substantial attention in the past few years. In 2007, Krawczyk and coworkers [76] demonstrated that the 3,4-dihydrocoumarin framework can be accessed by a means of Michael-type Friedel-Crafts reaction between 3-aryl-2-diethoxyphosphorylacrylic acids 181 and electron-rich hydroxyarenes 182... 

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... 

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... 

However, 6,6-dimethyl-l-methylene-4,8-dioxaspiro[2.5]octane, an acetal of 2-methylenecyclo-propane, undergoes a thermally induced [3 + 2] cycloaddition with simple ketones to yield acetals of a-methylene-y-lactones. ... 

Nishitani, K., Nakamura, Y, Orii, R., Aral, C., and Yamakawa, K., Studies on the terpenoids and related alicyclic compounds. Part 43. Stereoselective intramolecular cyclization of P-alkoxycarbonyl-CO-formylallylsilanes into bicyclic a-methylene-y-lactones, Chem. Pharm. Bull., 41, 822, 1993. Kuroda, C., Ohnishi, Y, and Satoh, J.Y, Intramolecular cyclization of P-(aIkoxycarbonyl)allylsilane with conjugated ketone. A new entry to bicyclo[4.3.0]nonane. Tetrahedron Lett., 34, 2613, 1993. Kuroda, C., Inoue, S., Takemura, R., and Satoh, J.Y, Intramolecular cyclization of allylsilanes in the synthesis of guaian-8,12-olide. Stereoselective formation of trans- and cw-fused methylenelactones, 7. Chem. Soc., Perkin Trans. 1, 521, 1994. 

An interesting route to a-carboxy-8-lactones (81) and a-methylenelactones (80), based on hydrolysis of Knoevenagel products (79) of Meldrum s acid with cyclic aliphatic ketones (78), has been developed (Scheme 14). Reduction of 5-methylene derivatives of Meldrum s acid has been performed catalyti-caiiyi30 or by use of LAH. Imidoylation reaction of Meldrum s acid and subsequent solvolysis of the resulting (82) yields -enamino esters (83) in good yields.Flash vacuum pyrolysis of alkylidene derivatives of Meldrum s acid can be used to prepare methylene ketenes (84), a class of compounds difficult to prepare by conventional methods. By this procedure, methylene ketenes are obtained from aromatic aldehydes and ketones and from aliphatic ketones in only two steps. Intramolecular trapping of the methylene ketene obtained from the ketone (85) has been used successfully in the synthesis of the naphthol (86). ... 

Allylations. In reactions using allylsilane as nucleophiles TiCU is one of the most popular catalysts. It is now employed in allylating squaric acid derivatives, 8-phenylmenthyl pyruvate, and (V-acyliminium ions. A remarkable observation is that the four stereocenters of the products from l,8-bis(trimethylsilyl)-2,6-octadiene and two aldehyde molecules are generated with good control. The stereoselective intramolecular reaction is most suitable for the synthesis of bicyclic a-methylene-y-lactones. ... 

Reaction of the diazo compound with 5 resulted in 6. Lithium aluminum hydride reduction of the sodium enolate resulted in the acid-sensitive alcohol 7. Treatment of 7 with acid led to the ketal 8 and then to the furane 9. Reduction of the sodium enolate of 10 led to the a-diol 11, which had been converted previously into the a-methylene-y-lactone 12. 

Acid-promoted lactonization of y-hydroxy esters is an important way to construct lactones. For example, Scolastico and co-workers first reported the lactonization of MBH adducts 213 using 0.7 m HCl in ACOH-H2O, obtaining cx-methylene-p-hydroxy-5-butyrolactones 215a,b in moderate yields (Scheme 4.65). Trifluoroacetic acid, CSA and sulfuric acid were also used in such lactonizations. In an alternative method, ot-methylene-p-hydroxy-8-butyrolactone 215c was synthesized by the intramolecular MBH reaction in 62% yield (Scheme 4.66). A series of a-alkylidene-8-butyrolactones and multi-substituted a-methylene-8-butyrolactones have been synthesized from MBH adducts (Figure 4.2). 

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