Unsubstituted Lactones

Unsubstituted 3-alkyl- or 3-aryl-isoxazoles undergo ring cleavage reactions under more vigorous conditions. In these substrates the deprotonation of the H-5 proton is concurrent with fission of the N—O and C(3)—-C(4) bonds, giving a nitrile and an ethynolate anion. The latter is usually hydrolyzed on work-up to a carboxylic acid, but can be trapped at low temperature. As shown by Scheme 33, such reactions could provide useful syntheses of ketenes and /3-lactones (79LA219). 

The addition of dibutylcupratc to the a-substituted /1-formyl esters 1 preferentially affords, via chelation control, the cw-disubstituted y-lactone 241. These results are in agreement with those found with a-unsubstituted /1-esters39-41 (vide supra), assuming a seven-membered chelate as transition state of the addition reaction. The diastercosclectivity is somewhat lower with esters 1 as the stereogenic center is one carbon atom further removed from the reaction center and therefore the steric influence of the substituent R1 is less pronounced. 

Five-membered unsubstituted lactone, y-butyrolactone (y-BL), is not polymerized by conventional chemical catalysts. However, oligomer formation from y-BL was observed by using PPL or Pseudomonas sp. lipase as catalyst. Enzymatic polymerization of six-membered lactones, 8-VL and l,4-dioxan-2-one, was reported. 8-VL was polymerized by various lipases of different origins. The molecular weight of the enzymatically obtained polymer was relatively low (less than 2000). 

Five-membered unsubstituted lactone, y-butyrolactone, is not polymerized by conventional chemical catalysts. On the other hand, oligomer formation from y-butyrolactone was observed by using PPL or Pseudomonas sp. lipase as catalyst [23,69]. 

It should be noted that codimerization was achieved from diphenyl cyclopropenone and unsubstituted cyclopropenone (2JS)197. Phenyl hydroxy cyclopropenone, which appears to be an associated dimer in (dioxane) solution52, formed a dimeric pulviniv acid lactone 260 on treatment with thionyl chloride51, probably via oxidative rearrangement of a dimer 259 ... 

Ouhadi T, Hamitou R, Jerome R, Teyssie P (1976) Soluble bimetallic p-oxoalkoxides. 8. Structure and kinetic behavior of the catalytic species in unsubstituted lactone ring-opening polymerization. Macromolecules 9 927-931... 

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). 

Dondoni et al. prepared a 1-hydroxyethylene peptide using a thiazole-aldehyde synthesis starting from an amino acid.[38] The aldehyde is converted into an alkanoate by Wittig alkenation and reduction of the double bond (Scheme 18). Then, removal of the tert-bu-tyldimethylsilyl group gives the unsubstituted lactone. In the last step, the lactone is alkylated using the method reported by Kleinman and co-workers. 20 ... 

Methylpyridazin-3 (2H)-one 1-oxides unsubstituted at position 6 afford photochemi-cally a mixture of the corresponding 6-hydroxypyridazin-3(2H)-one, lactone (46) and isomaleimide (47). 4-Methylcinnoline 1-oxide gives a mixture of the methyl substituted benzofuran (48), the indazole (49) and the indole (50), while 4-methylcinnoline 2-oxide gives a mixture of the deoxygenated starting compound, benzisoxazole (51) and o-aminoacetophenone (Scheme 16). 

The similar scheme starting from 4-methylpyridine was used in 1909 by Loffler and Stitzel60 for the synthesis of unsubstituted quinuclidine. These authors could not isolate the pure compound, which was first obtained 11 years later by Meisenheimer,22 who also described a transformation of 4-methylquinoline into benzo quinuclidine. Later, the intramolecular alkylation of 4-(j3-haloalkyl)-piperidines was used for other syntheses of quinuclidine61 and its derivatives. 2- and 4-methylquinuclidines (12),23,62,63 and (13)2S, dibenzoquinuclidine (14),20 3-hydroxymethyl-3-methylquinuclidine (15),36,37,64 and 3-carboxymethyl-3-hydroxymethylquinuclidine lactone (16),65 were prepared by this method. 

Since the trimethylglucose has been shown to form a 6-lactone, characterized by its rapid mutarotation in aqueous solution,161-163 and to give rise when methylated and hydrolyzed to 2,3,4,6-tetramethyl-D-gluco-pyranose,189 it follows that C5 is unsubstituted. While it is clear that the third methoxyl group must be present on C6, little direct evidence is available to support this view. The syntheses of the trimethylglucose from methyl 2,3-anhydro-/3-D-mannopyranoside (known to condense with benzaldehyde and therefore to carry free hydroxyl groups on C4 and C6)168 and also from 3-benzyl-D-glucose162 leave, however, no doubt that C6 is methylated. 

Phenyl 2,5-di-0-acetyl-/8-D-glucofuranosidurono-7-lactone was decomposed by sodium methoxide to give the corresponding methyl 0-D-gluco-furanosidurono-y-lactone38 (poorly characterized), which indicates that even phenyl-unsubstituted phenyl glycosiduronic acids can react with alkoxides under very mild conditions. 

If the electrophilic end of the alkene is unsubstituted, it is particularly prone to conjugate additions. Examples include exo-methylene lactones 63, ketones 64 and vinyl ketones 65 that are often used... 

It has been reported that reaction of n. 3-unsatu rated carboxylic acids with bis(collidine)bromine(l) hexafluorophos-phate leads to the formation of 2-oxetanones in moderate yields (Equation 33) <1999JOC81>. As with the related reaction of cinnamyl alcohols (discussed in Section 2.05.9.1), this 4- electrophilic intermediate. The cyclization reaction was diastereospecific single (E)- or (Z)-isomers were reacted to give single stereoisomeric products. Lactonization was favored by substrates that were /3-dialkyl-substituted, or ct-alkyl/aryl-, /3-aryl-substituted on the C-C double bond. ct-Monoalkyl/aryl, /3-unsubstituted substrates gave either polymeric products or exclusive vinyl bromide formation. 

Propynyl alcohols have been converted into (Z)-a-(alkoxycarbonyl)methylene /3-lactones by dialkoxycarbonylation in alcoholic media, under a carbon monoxide-air (3 1) atmosphere, using a PdVKI catalyst (Equation 37) <1997J(P1)147>. The (Z)-stereochemistry of the products was attributed to the syn nature of the carbon monoxide insertion. Substitution at the ct-alkyl position was essential to generate the lactone products in good yields. When the propynyl alcohols were cr-alkyl-unsubstituted, no /3-lactone formation was observed instead, a maleic diester and its cyclic isomer were the predominant products. Where substrates were mono-a-alkyl-substituted, yields of the /3-lactone were low, unless the alkyl group was sufficiently sterically bulky. 

---