Methylene-butyrolactones

A general pathway to substituted a-methylene lactones (80) and bis-lactones (81) employs the carbanion (79) from itaconic acid. Although yields are often only moderate, the simplicity of the method and the availability of the starting materials 

A ready desulphurization of a-methylthio derivatives of esters and lactones has been developed which involves derivatization of the sulphur with ethyl trifluoro-methylsulphonylacetate followed by treatment with base. This leads to both endo-and exo-cycMc double bond formation (where possible) in approximately equal amounts, in the case of a-methylthio-butyrolactones. 

The reactions of the vinyl cuprates (86) with cyclic allylic epoxides and the subsequent conversions of the various [1,2] and [1,4] addition products to both cis-and trans fused a-methylene lactones has been reported in preliminary form. The methods seem to hold considerable promise even though mixtures of addition products are normally obtained. 

Greico has further applied the double oxidative elimination of selenium to form the two olefinic bonds in tuberiferine (88) at the same time. He also points out that an a-phenylseleno substituent on an a-methylbutyrolactone can survive a number of synthetic transformations, and thereby act as a protected form of the a-methylenebutyrolactone. Total syntheses of the related lactones ( )-confertin (89)105 and ( )-damsin (90) have been reported. Although the Minato-Horibe sequence for the introduction of the a-methylene group into a butyrolactone was successful in the latter case, it failed in the case of confertin and hence an alternative sequence was used involving condensation of the lactone with dimethyl carbonate, followed by enolate reduction and oxidation. 

A synthesis of the alkaloid gentiocrucine (96), the first example of a stable primary enamide, has been recordedbased upon a new route to 3-keto-8-valero-lactones. 

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Ethyl 3-nitroacrylate is an extremely reactive receptor in the Michael reaction. It has found use in the synthesis of the a-methylene-butyrolactone moiety3 characteristic of many sesquiterpenes, as shown... 

As early as 1950, feverfew was reported to cause contact dermatitis in at least one patient [62] and parthenolide was found to cause an allergic reaction in patients with the same condition [63]. Since then there have been many reports [64-68] of feverfew-induced allergic reactions, the condition being worst in the summer months coinciding with the flowering season of the plant. The a-methylene butyrolactone group was found to be a partial requirement for activity in contact dermatitis [69]. 

Cycloadditions to exocyclic C=C bonds have been carried out for ot-methylene-butyrolactones (254) (154,155), 4-methylenepyrazol-3-ones (255) (156), 4,5-dihy-dro-5-methylene-17/-pyrazoles (256) (157), 4,5-dihydroisoxazoles (257) (158),... 

Methylene butyrolactone has been used as a dipolarophile to synthesize, for the first time, ethyl-l-azabicyclo[2.2.1]hept-3-yl carboxylate using Achiwa s procedure. The synthetic pathway involves rearrangement of the spiropyrrolidine lactone resulting from the [l,3]dipolar addition.430... 

The silver-catalyzed synthesis of methylene butyrolactones has been known for a long time 39 the field was revived by Genet more recently.40 Scheme 12.21 shows that the silver(I) catalysis required 10 mol% of catalyst and 110°C, but then gave a very good yield of product. Scheme 12.22 displays the corresponding investigation of Genet and coworkers the different conditions and catalysts tested are shown in Table 12.15. 

METHYLENE ACETALS Dimethyl sulf-oxide-N-Bromosuccinimide. a-METHYLENE -BUTYROLACTONES Dibenzoyl peroxide. 1,2-Dibromoethane. METHYLENE CYCLOALKENES Dichlo-roketene. 

Some examples of more elaborate radical cyclizations accompanied by I-transfer are illustrated in Scheme 3. The cyclization of alkyl radicals onto propargyl esters has been demonstrated in synthesis of a-methylene butyrolactones [17]. This procedure uses thermolysis in the presence of benzoyl peroxide in order to induce initiation, and appears to progress in the absence of a distannane reagent. Attempts to carry out the cyclization under tin hydride conditions led to uncyclized, reduced substrate. A series of more complex radical cyclizations involving both I-transfer and unimolecular H-transfer have recently been reported. In these reactions, the radical initially formed by I-abstraction underwent 5>-exo cyclization to generate a vinyl radical. This radical, in turn, abstracted H from silicon in an intramolecular... 

The remarkable Michael-Michael-aldol ring closure sequence has been applied to spiro-lactone synthesis by using o-methylene-butyrolactone as the second Michael acceptor (Scheme 37). 33 The... 

The a-methylene-) -butyrolactone grouping is incorporated in a large number of sesquiterpenoids, many of which have significant biological activity. A number of routes have been devised for the synthesis of this moiety but recently an important contribution from Ourisson s laboratory has demonstrated that the more accessible a-methyl-y-lactones can be converted in two steps into the a-methylene analogues.This is achieved by reaction of the lactone (263 R = H) with triphenylmethyl-lithium and quenching the resultant enolate with 1,2-dibromoethane. Dehydrobromination of the derived bromide (263 R = Br) with diazabicyclononene gives exclusively the exocyclic methylene lactone (264). This method is only suitable for c/s-y-lactones since the trans-lactone yields exclusively the endocyclic isomer. To illustrate this method Ourisson et at. have converted dihydro-6-epi-santonin (265) into (- )-frullanolide (266). More recently the same authors have developed a method which is applicable to... 

Specific examples of the synthesis of natural products containing a-methylene-butyrolactone functions are to be found in the full reports from Danishefsky s group" and from Grieco s group " on the total synthesis of ( )-vernolepin (79) and its isomer, vernomenin Grieco et al. have also reported a synthesis of ( )-desoxyvernolepin " and demonstrated the use of the selenenation method for the introduction of an a-methylene substituent with a neat total synthesis of (+)-costunolide (80) from santonin," together with a general, stereochemically-... 

The polymerisation of naturally renewable methylene butyrolactones such as a-methylene-y-butyrolactone (yMBL) and y-methyl-a-methylene-y-butyr-olactone (yMMBL) could in a near future, be a powerful approach for... 

Finally, from Hellanthus tuberosus the sesquiterpene heliangine has been isolated, possessi an o6-methylene butyrolactone moiety. This lactone inhibits the elongation of Avena coleoptile sections and promotes root formation of Phaseolus cuttings (Eef. 1h - 19) ... 

The fact that the ft-methylene- -butyrolactone group is present in certain terpenoid antineoplastic agents has resulted in synthetic efforts directed at analogues derived from earbohydrates, such as (32) and (33). 3i... 

Dalla, V. and Pale, P. 1994. Silver-catalyzed heterocyclization First total synthesis of the naturally occurring cis 2-hexadecyl-3-hydroxy-4-methylene butyrolactone. Tetrahedron... 

Synonyms a-methylene butyrolactone Tuliposide A 4,5-dihydro-3-methylene-2(3H)-furanone 3-methylenedihydro-2(3H)-furanone dihydro-3-methylene-2(3H)-furanone Tulipaline A A... 

It is interesting to note that a naturally occurring antibiotic, methylene-butyrolactone (II) has been s)mthesized by carbonylating the acetylenic carbinol (I) (6) ... 

A number of methods describing improved syntheses of a-methylene-butyrolactones have been published. Magnesium methyl carbonate has been found to carboxylate butyrolactones (though not six-membered lactones) in high yield treatment of the acid (41) with aqueous formaldehyde and diethylamine, followed by separate treatment of the crude product with sodium acetate in acetic acid, gives the desired a-methylenebutyrolactone (42). An independently developed, complementary route involves thermal fragmentation of the salt (43), iodide ion functioning as a nucleophile for... 

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