Y -Butyrolactone, formation

Ring closure resulting from attack of a heteroatom on a carboxyl group or its equivalent is merely a case of intramolecular esterification or amide formation. The y-butyrolactones or pyrrolidones obtained from such reactions are usually regarded as the province of aliphatic chemistry, so only a few examples are offered by way of illustration in Scheme 15. 

The mechanism of this reaction has been studied by several groups [133,174-177]. The consensus is that interaction of ester with the phenolic resole leads to a quinone methide at relatively low temperature. The quinone methide then reacts rapidly leading to cure. Scheme 11 shows the mechanism that we believe is operative. This mechanism is also supported by the work of Lemon, Murray, and Conner. It is challenged by Pizzi et al. Murray has made the most complete study available in the literature [133]. Ester accelerators include cyclic esters (such as y-butyrolactone and propylene carbonate), aliphatic esters (especially methyl formate and triacetin), aromatic esters (phthalates) and phenolic-resin esters [178]. Carbamates give analogous results but may raise toxicity concerns not usually seen with esters. 

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). 

Homoenolate Reactivity The ability to generate homoenolates from enals and its application to the preparation of y-butyrolactones 30, through reaction with an aldehyde or aryl trifluoromethyl ketone, was reported independently by Glorius [8], and Bode and Burstein [9] (Scheme 12.4). A sterically demanding NHC catalyst is required to promote reactivity at the d terminus and to prevent competitive benzoin dimerisation. Nair and co-workers have reported a similar spiro-y-lactone formation reaction using cyclic 1,2-diones, including cyclohexane-1,2-dione and substituted isatin derivatives [10]. 

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]. 

A variety of functionalities, tether lengths, and alkene substitution patterns were tolerated (Equation (35)).52,53 Of particular significance is the synthesis of a-methylene-y-butyrolactone 55, as only Zhang had reported successfully using Alder-ene chemistry to gain access to this novel system (see Section 10.12.4.3). The reaction was sensitive to the length of the tether, since there was a marked decrease in yield for the formation of the six- and seven-membered carbocycles (53 and 54, respectively) compared to the five-membered case 52. 

Zhang68 has applied the cyclization of esters to the formation of a-methylene-y-butyrolactones, thus offering a novel and enantioselective entry to these substructures. The importance of this unsaturated lactone is evidenced by its ubiquitous presence in nearly a third of all naturally occurring secondary metabolites. The Alder-ene reaction has been applied to a formal total synthesis of (+)-pilocarpine, a leading therapeutic reagent for the treatment of narrow and wide glaucoma. Zhang intersected Btichi s synthetic intermediate (i )-181 (Scheme 47) in only two steps with a 99% ee and a 91% overall yield. In comparison, Biichi synthesized (i )-181 in five steps with a 92% ee and a 20% overall yield. 

The original preparation of y-crotonolactone by Lespieau involved a five-step sequence from epichlorohydrin and sodium cyanide. A recent detailed study of this procedure reported an overall yield of 25% for the lactone. Glattfeld used a shorter route from glycerol chlorohydrin and sodium cyanide hydrolysis and distillation of the intermediate dihydroxy acid yielded y-cro-tonolactone in 23% yield and -hydroxy-y-butyrolactone in 28% yield. The formation of y-crotonolactone in 15% yield has also been reported from pyrolysis of 2,5-diacetoxy-2,5-dihydrofuran at 480-500 . ... 

The formation of a-bromo-y-butyrolactone has been reported in 70% yield by uncatalyzed reaction of bromine at 160-170°, as well as by the catalyzed procedure used here. ... 

Lu, H., Wang, J., Zhao, Y., Xuan, X., and Zhuo, K. Excess molar volumes and viscosities for binary rtrixtrrres of y-butyrolactone with methyl formate, ethyl formate, methyl acetate, ethyl acetate, and acetonitrile at 298.15 K,J. Chem. Eng. Data, 46(3) 631-634, 2001. 

Homoenolates generated catalytically with NHCs can also be employed for C-C and C-N bond formation. Bode and Glorias have independently accomplished the diastereoselective synthesis of y-butyrolactones by annulation of enals and aldehydes [121, 122]. Bode and co-workers envisioned that increasing the steric bulk of the acyl anion equivalent would allow reactivity at the homoenolate position. While trying to suppress the competing benzoin and enal dimerization the authors comment on the steric importance of the catalyst. Thiazolium pre-catalyst 173 proved unsuccessful at inducing annulation. A-mesityl substituted imidazolium salt 200 was found to provide up to 87% yield and moderate diastereoselectivities (Scheme 34). 

Scheme 35 Proposed mechanism of NHC catalyzed formation of y-butyrolactone...

Antibiotic production and morphological differentiation (formation of aerial mycelium and sporulation) in Streptomyces species and in some other actinomycetes is regulated by small signaling molecules called y-butyrolactones or butanolids. These quorum-sensing signals bind to... 

Tab. 8.1 summarizes the various substrates that were subjected to the rhodium-catalyzed reaction using a Rh-dppb catalyst system. Only ds-alkenes were cycloisomerized under these conditions, because the trans-alkenes simply did not react. Moreover, the formation of the y-butyrolactone (Tab. 8.1, entry 8) is significant, because the corresponding palladium-, ruthenium-, and titanium-catalyzed Alder-ene versions of this reaction have not been reported. In each of the precursors shown in Tab. 8.1 (excluding entry 7), a methyl group is attached to the alkene. This leads to cycloisomerization products possessing a terminal alkene, thus avoiding any stereochemical issues. Also,... 

As an application of maleate formation, the carbonylation of silylated 3-butyn-l-ol affords the y-butyrolactone 539[482], Oxidative carbonylation is possible via mercuration of alkynes and subsequent transmetallation with Pd(II) under a CO atmosphere. For example, chloromercuration of propargyl alcohol and treatment with PdCI2 (1 equiv.) under 1 atm of CO in THF produced the / -chlorobutenolide 540 in 96% yield[483]. Dimethyl phenylmale-ate is obtained by the reaction of phenylacetylene, CO, PdCl2, and HgCl2 in MeOH[484,485],... 

The effects of added salts are shown in Fig. 8. Sodium chloride has a small positive effect on the hydrolysis rate, and sodium chloride and sodium perchlorate have a similar, rather larger, effect on the rate of lactone formation. This is the expected result, for many salts increase the protonating power of the medium as measured by Hammett s acidity function116, and thus assist acid-catalyzed reactions. Sodium perchlorate, unusually, has a small negative effect on the hydrolysis rate. Qualitatively similar results have been found by Bunton et al,56, who studied the effects of added salts on the acid-catalyzed hydrolysis of ethyl acetate. Added lithium and sodium chloride assist the Aac2 hydrolysis of ethyl acetate, but the perchlorates have essentially no effect. In each case the effect is a little more positive than for y-butyrolactone hydrolysis, and, in particular, chloride anions appear to assist Aac2 hydrolysis more effectively than do the perchlorates. 

Two types of esterification reaction that can be studied with water as solvent are lactone formation, in which the alcohol is part of the same molecule as the acid, and the lsO-exchange reaction of carboxylic acids, which makes it possible to examine A-2 reactions of carboxylic acids under the conditions used for ester hydrolysis. Work in both these fields confirms the similarities between ester hydrolysis and formation. The hydrolysis and formation of y-butyrolactone have already been discussed (p. 109). We deal here with the lsO-exchange reactions of carboxylic acids. 

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