Methylenebutyrolactones

Bz(MeOCI )CH], making this one of the few brief methods available for the preparation of such enantiomers. However, one drawback with this method is the final rather harsh acidic hydrolysis step which would certainly remove a wide variety of protecting groups, for example. 

A solution to this is to use the corresponding esters (391) which condense equally well with aldehydes using BF as catalyst  

The possibilities for asymmetric synthesis with this system have yet to be examined. (5, y-Disubstituted as well as monosubstituted lactones (390) can also be obtained via related condensations of bromomethyl 

A different approach to a-methylenebutyrolactones is a further development of the chemistry of 2-silyloxycyclopropane carboxylates (393), which, when treated with the trifluoromethanesulphonate analogue of Eschenmoser s salt and a Lewis acid (TMSOTf), are converted into 8-amino-esters (394) and thence lactones (395) following borohydride reduction and elimination.33 Overall yields are reasonable for this multi-step approach. A carbanion based approach to monosubstituted lactones. (390) begins by metallation and regio-selective condensation of ketene dithioacetal (396) with an aldehyde. 

An efficient new method for the dehydration of a-hydroxymethyl butyrolactones (398) to give the corresponding a-methylene derivatives 

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- 

Still and Schneider have described a total synthesis of ( )-frullanolide (82) in which the lactone ring is constructed by an enolate Claisen rearrangement of the type developed by Ireland s group, followed by iodolactonization, viz. (83) - (84). 

The reaction of malonate enolates with cyclohexane epoxides leads to mixtures of the two possible lactones (87) and (88), convertible into the corresponding a-methylene-lactones by now relatively standard procedures. In a similar vein, the bis-spirolactone (90) can be obtained from epoxide (89). Spirolactones can also be prepared from cyclic ketones by condensation with ethyl a-bromomethylacrylate in the presence of zinc, and cyclization of the adduct in cold, dilute acid.  

Reagents i, Li ii, PBr3 iii, NaH iv, Toluene-p-sulphonyl-S-methylcarbazate v, HgCl2, HgO vi, HzSeOs 

Valerolactones.—Baldwin and Reiss have provided another example of the general rules of ring closure, by studying the cyclization of hydroxy-ester (98) the cycliza-tion leads to the lactone (99) by a 6-exo-trig process rather than to the ether (97) which would arise by a disfavoured 6-endo-trig mechanism. 

Chiral lactones (336) have been prepared in high optical yields using bromomethylacrylate as the electrophile in condensations with chiral sulphoxides similar optical yields of lactones (336) can also be obtained from condensations between aldehydes and chiral 2-(stannylmethyl)propenamides [cf. (335) Bu Sn in place of Me Si amide]. Deconjugative alkylation of 

A novel synthesis of (+)-avenaciolide (341) centres on the stereospecific elaboration of the anti-ester (339) by an enolate Claisen rearrangement of the corresponding ( Z)-allylic glycolate and a highly stereoselective selenolactonization of the derived 

The synthesis of higher homologues, the a-al)tylidene-butyrolactones (344), continues to attract interest. A new route proceeds by hydrocyanation of 3-hydroxyalkyne 

A deconjugative alkylation procedure has been used to contruct 

The /3-amino-ester (151) has been used as an acrylate anion equivalent which is alkylated and after elimination gives an unsaturated ester (152) subsequent D. G. Schmidt and H. Zimmer, Synth. Commun., 1981,11, 385. 

Transition-metal-promoted carbonylation reactions continue to provide interesting new routes to a-methylene lactones. The /runs -vinyl bromide (156) reacts with Ni(CO)4 to give the c -fused lactone (157) in 95% yield. By contrast, the reaction of the frans -acetylenic alcohol (158) with carbon monoxide and PdCl2 leads to the frans-fused lactone corresponding to (157). The ether (159) has been oxidized with CrOs-pyridine to the corresponding lactone, which was obtained as a mixture of isomers in modest yield.  

A total synthesis of racemic eriolanin is reported in which a-methylenation of a butyrolactone is carried out in the final stages. The use of the ubiquitous Brederick s reagent [Bu OCH(NMe2)2] for this same purpose appears in a synthesis of racemic aromatin. Another interesting point about the route is 

The use of iodolactonization in the synthesis of 5-lactones is demonstrated in routes to a prostaglandin endoperoxide analogue, and to the antibiotic malyngolide. The latter compound (164) has also been prepared as a mixture of C-2 epimers by lactonization of the epoxide (163). Stereoselective sul-phenyl-lactonization plays an important role in a synthesis of octahy-droleukotrienes, and cyclization of the cyclopropyl acid (165) leads to the lactone (166). A spirocyclic dilactone has been prepared and undergoes 

Coombs, Y. Guindon, J. Rokach, D. Ethier, and R. Hall, Tetrahedron Lett., 1981, 22,4933. 

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Another approach is the Michael addition to ethyl (3-nitroacrylate, as shown in Eq. 7.123, which has been used in the synthesis of a-methylenebutyrolactone, a moiety characteristic of many sesquiterpenes. ... 

The intermolecular C-C bond formation mediated by (TMSlsSiH has been the subject of several synthetically useful investigations. The effect of the bulky (TMSfsSiH can be appreciated in the example of jS- or -substituted a-methylenebutyrolactones with -BuI (Reaction 65). The formation of a,P- or a,y-disubstituted lactones was obtained in good yields and diastereoselectivity, when one of the substituents is a phenyl ring. 

Figure 6.2. Michael-type reaction between an a-methylenebutyrolactone group and a sul-phydryl-group-containing compound.

Enol lactones with a halogen at the vinylic position have been synthesized as potential mechanism-based inactivators of serine hydrolyases <81JA5459). 5-Hexynoic acids (181) can be cyclized with mercury(II) ion catalysis to y-methylenebutyrolactones (182) (Scheme 41). Cyclization of the 6-bromo and 6-chloro analogues leads stereospecifically to the (Z)-haloenol lactones (trans addition) but is quite slow. Cyclization of unsubstituted or 6-methyl or 6-trimethylsilyl substituted 5-hexynoic acids is more rapid but alkene isomerization occurs during the reaction. Direct halolactonization of the 5-hexynoic acids with bromine or iodine in a two-phase system with phase transfer catalysis was successful in the preparation of various 5-halomethylene- or 5-haloethylidene-2-phenylbutyrolactones and 6-bromo-and iodo-methylenevalerolactones (Scheme 42). 

The reactions of ft- or /-phenyl substituted a-methylenebutyrolactones with Bui in the presence of (TMS SiH afforded a.ft- or a,/-disubstituted lactones in good yield and with high diastereoselectivity (equation 33)85. With ft- or /-alkyl substituted substrates the same reaction was found to be less selective. 

Cycloalkanone enamines react with ethyl / -nitroacrylate to form adducts which yield y-lactones on treatment with sodium borohydride. Base-induced elimination of the elements of nitrous acid gives oe-methylenebutyrolactones 23 (equation 16)35. 

The generation of exocyclic double braids by rDA cycloreversion is usefrd for the synthesis of unsaturated lactones, which are an important part of many natural products. The a-methylenebutyrolactone tuli-... 

Acidic Fragmentation in the Course of a Clever Synthesis of o-Methylenebutyrolactones... 

This very useful reaction resulted from a failed attempt to introduce a new protected methyl vinyl ketone equivalent for the all important Robinson annul-lation reaction. This failure turned out to be quite rewarding, for it allowed for a fast, simple, mild, and high yielding construction of a-alkylidene ketones, esters, and nitriles, as well as /3-methylenebutyrolactones, a family of compounds with several representatives among the tumor growth inhibitors. The method, unfortunately, has its own limitations, which will be discussed after exposing probable mechanisms. 

The remaining bond rupture would afford a relatively more stable carb-anion on the butyrolactone ring of VII, a fundamentally acidic position widely employed in organic synthesis. The freed pair of electrons would then proceed to force the extrusion of an oxalic acid residue yielding the desired a-methylenebutyrolactone. The concerted addition-elimination process from VI to II is also a feasible alternative. 

Tyrosine phosphorylation of three MAPK subgroups (ERKl, ERK2 and P38) stimulated by LPS was inhibited by 28 in a dose dependent manner. It has been proposed that tyrosine kinase inhibition may occur through conjugation between the a-methylenebutyrolactone in parthenolide and the -SH group of target proteins [85]. 

An alternative synthesis of a-methyiene ketones and esters is provided by enolate alkylation using benzyl bromomethyl sulfide followed by oxidative elimination (Scheme 10). The addition of sodium thiophenoxide to a-methylenebutyrolactones has been recommended for protection of the sensitive double bond, which can be regenerated by oxidative elimination. ... 

Loeffler, A., Pratt, R. D., Pucknat, J., Gelbart, G., Dreiding, A. S. Preparation of a-methylenebutyrolactones by the Reformatskii reaction synthesis of protolichesterinic acid. Chimia 1969, 23, 413-416. 

Hay AJB, Hamburger M, Hostettmann K, Hoult JRS. Toxic inhibition of smooth muscle contractility by plant-derived sesquiterpenes caused by their chemically reactive a -methylenebutyrolactone functions. Br J Pharmacol 1994 112 9-12. 

Another example of iCCT comes from polymerization of a-methylenebutyrolactone (MBL).428 CCT from the radical derived from this monomer leads to the unsaturated lactone shown in eq 52. 

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