Reactions lactone formation

An additional example of lactone hydrolysis includes the API lovastatin (9). In addition to lactone cleavage reactions, lactone formation can also occur as in the case of the API cephalosporin cefuroxime sodium (Fig. 4) (10). 

Lactone formation by hypoiodite functionalization, 251 Lead tetraacetate, 147, 150 Lead tetraacetate reactions, 207, 239, 240, 281... 

With nonracemic chiral diazoacetates the insertion process occurs with evident match/mismatch characteristics. This has been demonstrated in reactions of optically pure 2-methylcyclohexyl diazoacetates (Eq. 9) [85] and in carbon-hydrogen insertion reactions of steroidal diazoacetates (Eq. 10) [86], as well as with the synthesis of pyrrolizidines 36 and 37 [84]. The mechanistic preference for formation of a /J-lactone in Eq. 10 over insertion into the 4-position is not clear,but there are other examples of /J-lactone formation [87]. In these and related examples, selectivities in match/mismatch examples are high, and future investigations are anticipated to show even greater applicability. 

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]. 

Nair and co-workers have demonstrated NHC-catalysed formation of spirocyclic diketones 173 from a,P-unsaturated aldehydes 174 and snbstitnted dibenzylidine-cyclopentanones 175. Where chalcones and dibenzylidene cyclohexanones give only cyclopentene products (as a result of P-lactone formation then decarboxylation), cyclopentanones 175 give only the spirocychc diketone prodncts 173 [73]. Of particular note is the formation of an all-carbon quaternary centre and the excellent level of diastereoselectivity observed in the reaction. An asymmetric variant of this reaction has been demonstrated by Bode using chiral imidazolium salt 176, obtaining the desymmetrised product with good diastereo- and enantioselectivity, though in modest yield (Scheme 12.38) [74],... 

Application of the carbonylation reaction to halides with appropriately placed hydroxy groups leads to lactone formation. In this case the acylpalladium intermediate is trapped intramolecularly. 

Other mechanisms of ketone oxidation are also known and will be discussed in Chapter 8. Peracid, which is formed from aldehyde, oxidizes ketones with lactone formation (Bayer-Villiger reaction). 

Few relevant data are available. Both equilibrium and rate constants have been measured for very few reaction series in solution, but comparisons are possible for lactone and thiolactone formation, and for a few anhydrideforming reactions (Tables 4 and 5). For lactone formation (Table 4) the EM for the rate process is of the same order of magnitude as that derived from the equilibrium constant data, and in some cases actually exceeds it (though only in one case by an amount clearly greater than the estimated uncertainty which is nominally a factor of 4 for these ratios). Lactonization generally involves rate-limiting breakdown of the tetrahedral intermediate, and the transition state is expected to be late and thus close in structure to the conjugate acid of the lactone. 

Non-redox reactions where water is formed as a product are reactions of dehydration. Such reactions can occur between two substrate molecules, or they can involve two functional groups in a single substrate, either creating a new bond (e.g., lactone formation), or transforming a single into a double bond. In xenobiotic metabolism, dehydration is usually in dynamic equilibrium with hydrolysis or hydration and is of relatively modest significance (Chapt. 11). 

As indicated by the conversion of 70 to 71, the electroreductive cyclization reaction provides as excellent method for the assembly of the bicyclo[3.2.1]oc-tane ring system. Several additional examples are portrayed in the following equations. In general, the use of an unsaturated nitrile rather than the corresponding ester is preferred, as this precludes lactone formation, and therefore... 

In subsequent work, Corey appUed BLA-type cationic oxazaborolidines to several other reactions, including [3 -i- 2] cycloaddition, cyanosilylation, Michael addition, and P-lactone formation. 

Related to case is reduction of the monoester (l/ ,25)-2-methoxycarbonyl-4-oxo-l-cy-clopentanecarboxylate (see p401) followed by lactone formation to give 36 and oxidation to the known bicyclic dione 3757. Configurational assignment rests on the fact that the ester group in 35 is reduced under the reaction conditions whereas the free acid is not. Thus, reliability in correlations of this type rests on a sufficient difference in reactivity of the two functional groups under the selected conditions. 

Although silylformylation of 3-butyn-I-ol 84 gives normal product 85 preferentially in the absence of EtsN, an appreciable amount (38%) of 7-lactone 86 is formed concomitantly." Protection of the hydroxy group in 84 leads to selective silylformylation of the acetylenic moiety as shown in Scheme 3. Hydrolysis of the silyl ether in 88 gives 85 as a single product. 4-Pentyn-I-ol 89 reacts with Mc2PhSiH under CO pressure to give a mixture of silylformylation product 90 (20%) and (5-lactone 91 (38%) after a short reaction time (0.5 h) (Equation (16)). The unusual lactone formation is not observed in the reaction of 5-hexyn-l-ol 92 in the presence of EtsN (Equation (17)). ... 

Intramolecular nucleophilic displacements, such as those in lactone formation, have faster reaction rates than intermolecular S,42 reactions because the latter require two species to collide. The neighboring participant is said to furnish anchimeric assistance. 

As in 0-52 hydrazides and hydroxamic acids can be prepared from carboxylic esters, with hydrazine and hydroxylamine, respectively. Both hydrazine and hydroxylamine react more rapidly than ammonia or primary amines (the alpha effect, p. 351). Imidates RC(=NH)OR give amidines RC(=NH)NH2. Lactones, when treated with ammonia or primary amines, give lactams. Lactams are also produced from y- and 8-amino esters in an internal example of this reaction. Isopropenyl formate is a useful compound for the formylation of primary and secondary amines,897... 

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. 

Nazarov and co-workers148 observed lactone formation-also in lb reaction r 2,3-di-e7Kfo-cnrboxybicycIo 2,2.V)hept-5-ouo with per-ucotic acid (Eq. 44). 

When the catalytic reaction of 6-hydroxymellein synthase is carried out in the absence of NADPH or with monomeric enzyme, keto-reduction of the carbonyl group of the triketomethylene chain does not take place, and the synthase liberates triacetic acid lactone instead of 6-hydroxymellein [64, 71]. However, the efficiencies of product formation are markedly lower than for the normal reaction. Two mechanisms could account for the low efficiency of triacetic acid lactone formation observed in the monomeric and the NADPH-depleted dimeric forms of 6-hydroxymellein synthase. These are 1) Reduced affinity of the cosubstrates acetyl-CoA and/or malonyl-CoA for the enzyme protein with the incomplete reaction centers 2) Reduced rate of reaction of acyl-CoA condensation and/or product liberation. To examine these possibilities, kinetic parameters of the two triacetic acid lactone-forming reactions were compared with those of the normal reaction which produces 6-hydroxymellein. The Km value of 6-hydroxymellein synthase for acetyl-CoA in the normal reaction was estimated to be 22 pM, while in both the NADPH-depleted dimer and the monomer reactions the affinity of 6-hydroxymellein synthase protein for acetyl-CoA was markedly lower at 284 and 318 pM respectively. By contrast the Km values for malonyl-CoA in the normal and the two abnormal reactions were essentially the same (40 - 43 pM), indicating that the affinity of 6-hydroxymellein... 

Methyl Cinnamate. Using lower temperature and pressure than those used by Falbe (5) (to avoid lactone formation) the selectivity of the reaction toward aldehydes and hydrogenated products was comparable with his. 

In the presence of a strong acid as catalyst, alkenoic acids will add internally to furnish a valuable route to lactones (Scheme 4).460 Regardless of the position of the double bond in the chain, the product obtained is always the y- and/or 8-lactone due to acid-catalyzed double bond migration to a position favorable for ring closure.461 The choice of catalyst and the reaction temperature are important in minimizing the amount of cycloalkenone side product that usually accompanies lactone formation.462... 

Cyclizations of (3,7-un saturated acids form -lactones (4-exo cyclization) when the reactions are conducted under conditions of kinetic control.1 - The most common procedure for (3-lactone formation, developed by Barnett, involves halolactonization in a two-phase system using an aqueous solution of the carboxylate salt of the substrate with the halogen (Br2 or I2) added in an organic solvent.18 Cyclization with bis(, ym-collidine)iodine(I) perchlorate provides a higher yield than the Barnett procedure in cases where cyclization is not favored by geminal a-substitution (Table 2, entries 1 and 2).14 Iodo- and bromo-... 

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