P-lactone,

Lactones whose rings are three or four membered (a lactones and p lactones) are very reactive making their isolation difficult Special methods are normally required for the laboratory synthesis of small ring lactones as well as those that contain rings larger than SIX membered... 

P-Hydroxy acids lose water, especially in the presence of an acid catalyst, to give a,P-unsaturated acids, and frequendy P,y-unsaturated acids. P-Hydroxy acids do not form lactones readily because of the difficulty of four-membered ring formation. The simplest P-lactone, P-propiolactone, can be made from ketene and formaldehyde in the presence of methyl borate but not from P-hydroxypropionic acid. P-Propiolactone [57-57-8] is a usehil intermediate for organic synthesis but caution should be exercised when handling this lactone because it is a known carcinogen. 

DimeriZa.tlon. A special case of the [2 + 2] cyclo additions is the dimerization of ketenes. Of the six possible isomeric stmctures, only the 1,3-cyclobutanediones and the 2-oxetanones (P-lactones) are usually formed. Ketene itself gives predominandy (80—90%) the lactone dimer, 4-methylene-2-oxetanone (3), called diketene [674-82-8], approximately 5% is converted to the symmetrical dimer, 1,3-cyclobutanedione [15506-53-3] (4) which undergoes enol-acetylation to so-called triketene [38425-52-4] (5) (44). 

Another principal use of ketene is in the production of sorbic acid [110-44-1] (80,81). In this process, which requires an acidic or manganese(II) catalyst, ketene adds to crotonaldehyde [123-73-9] (8) with subsequent conversion of the P-lactone and the polyester to sorbic acid (qv) (9). 

Dimeric aldoketenes and ketoketenes of P-lactone stmcture show a chemical behavior which is not much different to that of diketene. Thus nucleophiles add ia similar fashion to give derivatives of 3-ketoacids which are mono- or dialkylated at C-2 (aldo- and ketoketene dimers, respectively), but the reaction can often be slower than with the parent compound and, ia case of long-chain or bulky substituents, may not proceed at all. Other reactions can proceed differendy than those with diketene. For an overview of important reactions of aldoketene and ketoketene dimers see Reference 122. 

Very Htde is known about the toxicology of other dimeric ketenes. For the dimeric dimethylketene there is equivocal evidence of tumors resulting from massive exposure in rats reported for the P-lactone form (3,3-dimethyl-4-isopropyhdene-2-oxetanone), whereas the symmetric form (2,2,4,4 tetramethylcyclobutane-l,3-dione) induces tumors in mice after lengthy skin appHcations. 

The first synthesis of sorbic acid was from crotonaldehyde [4170-30-3] and malonic acid [141-82-2] in pyridine in 32% yield (2,17,18)- The yield can be improved with the use of malonic acid salts (19). One of the first commercial methods involved the reaction of ketene and crotonaldehyde in the presence of boron trifluoride in ether at 0°C (20,21). A P-lactone (4) forms and then reacts with acid, giving a 70% yield. 

Just as fflnides are more stable than esters, lactfflns are more stable than lactones. Thus, although p-lactones are rare (Section 19.15), p-lactfflns are fflnong the best known products of the phaiinaceutical industry. The penicillin and cephalosporin antibiotics, which are so useful in treating bacterial infections, are p-lactfflns and are customarily refeired to as (3-lactam antibiotics. 

Vinyloxiranes can also be converted into P-lactones (Scheme 9.30) [133, 134], Opening of 66 with Fe2(CO)9 resulted in the (7t-allyl)tricarbonyliron derivative 67 in good yield, together with a minor diastereomer (not shown). Oxidative cleavage of 67 then gave 3-lactone 68, which was used as a key intermediate in the preparation of the cholesterol biosynthesis inhibitor 1233A. 

Asymmetric alcoholyses catalyzed by lipases have been employed for the resolution of lactones with high enantioselectivity. The racemic P-lactone (oxetan-2-one) illustrated in Figure 6.21 was resolved by a lipase-catalyzed alcoholysis to give the corresponding (2S,3 S)-hydroxy benzyl ester and the remaining (3R,4R)-lactone [68]. Tropic acid lactone was resolved by a similar procedure [69]. These reactions are promoted by releasing the strain in the four-membered ring. 

In the special case of 3-lactones, where small-angle strain is an important factor, alkyl-oxygen cleavage is observed (Bal2 mechanism, as in the similar case of hydrolysis of P-lactones, 10-10), and the product is not an amide but a P-amino acid ... 

Aldehydes, ketones, and quinones react with ketenes to give P-lactones, diphenylk-... 

This dimerization is so rapid that ketene does not form P-lactones with aldehydes or ketones, except at low temperatures. Other ketenes dimerize more slowly. In these cases the major dimerization product is not the P-lactone, but a cyclobutanedione (see 15-61). However, the proportion of ketene that dimerizes to p-lactone can be increased by the addition of catalysts such as triethylamine or triethyl phosphite. Ketene acetals R2C=C(OR )2 add to aldehydes and ketones in the presence of ZnCl2 to give the corresponding oxetanes. ... 

Decarboxylation of p-lactones (see 17-27) may be regarded as a degenerate example of this reaction. Unsymmetrical diacyl peroxides RCO—OO—COR lose two molecules of CO2 when photolyzed in the solid state to give the product RR. Electrolysis was also used, but yields were lower. This is an alternative to the Kolbe reaction (11-37). See also 17-29 and 17-40. 

C 3H,5N04 1148-11-4) see Angiotensinamide Captopril 7V-benzyloxycarbonyl-L-proline tert-butyl ester (C17H23NO4 16881-39-3) see Captopril 7V-benzyloxycarbonyl-L-serine (CiiHijNOj 7745-80-8) see Nelfinavir mesylate iV-benzyloxycarbonyl-L-serine-P-lactone (C Hi,N04 26054-60-4) see Nelfinavir mesylate 7V-benzyloxycarbonylsuccinimide... 

The dimerization of the parent ketene gives the P-lactone. One molecule of ketene reacts across the C=C bond as a donor and the other molecule reacts across the C=0 bond as an acceptor. This is similar to the concerted [2+2] cycloaddition reaction between bis(trifluoromethyl)ketene and ethyl vinyl ether to afford the oxetane (Scheme 26) [127], A lone pair on the carbonyl oxygen in the ketene molecule as a donor activates the C=C bond as the alkoxy group in vinyl ether. 

Dimerization of methylketene is catalyzed by an amine, trimethylsilylquinine, to give the P-lactone enantioselectively (Scheme 27) [129]. The catalyst amine attacks the ketene to form an ammonium enolate, an electron donating alkene. The donor is strong enough to react with a ketene across the C=0 bond. That is why the P-lactone is obtained instead of the 1,3-cyclobutandione, the uncatalyzed dimerization product of the monosubstituted ketene. 

An unexpected, one-step synthesis of a-chloro-P-lactones in 40-83% yield resulted when phenyl esters of a-chlorocarboxylic acids were treated under the conditions of the Darzens reaction with strong base in the presence of ketones or aldehydes <95AG(E)2028>. Previously, phenyl esters do not appear to have been used in this reaction. 

A porphinatoaluminum alkoxide is reported to be a superior initiator of c-caprolactone polymerization (44,45). A living polymer with a narrow molecular weight distribution (M /Mjj = 1.08) is ob-tmned under conditions of high conversion, in part because steric hindrance at the catalyst site reduces intra- and intermolecular transesterification. Treatment with alcohols does not quench the catalytic activity although methanol serves as a coinitiator in the presence of the aluminum species. The immortal nature of the system has been demonstrated by preparation of an AB block copolymer with ethylene oxide. The order of reactivity is e-lactone > p-lactone. 

FIGURE 2 Polymers that can be derived firom L-serine. (a) Poly-(serine ester) was obtained by ring opening polymerization of N-protected serine-p-lactones (19). (b) Poly(serine imine) has appar-... 

Making use of the same reaction principle, disubstituted ketenes 66 have been reacted with aldehydes 80 to form p-lactones 81 [100], with diazo-compounds 82 to form 1,2-diazetidin-3-ones 83 [101] and with nitroso-compounds 84 to form 1,2-oxazetidin-3-ones 85 as precursors of a-hydroxy carboxylic acids (Fig. 42) [102],... 

Wilson JE, Fu GC (2004) Asymmetric synthesis of highly substituted P-lactones by nucleophile-catalyzed [2 -t 2] cycloadditions of disubstituted ketenes with aldehydes. Angew Chem Int Ed 43 6358-6360... 

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