1,3-Dienes ozonolysis, ozone

The most common procedure is ozonolysis at -78 °C (P.S. Bailey, 1978) in methanol or methylene chloride in the presence of dimethyl sulfide or pyridine, which reduce the intermediate ozonides to aldehydes. Unsubstituted cydohexene derivatives give 1,6-dialdehydes, enol ethers or esters yield carboxylic acid derivatives. Oxygen-substituted C—C bonds in cyclohexene derivatives, which may also be obtained by Birch reduction of alkoxyarenes (see p. 103f.), are often more rapidly oxidized than non-substituted bonds (E.J. Corey, 1968 D G. Stork, 1968 A,B). Catechol derivatives may also be directly cleaved to afford conjugated hexa-dienedioic acid derivatives (R.B. Woodward, 1963). Highly regioselective cleavage of the more electron-rich double bond is achieved in the ozonization of dienes (W. KnOll, 1975). 

One approach to unnatural amino acids is to use a readily available amino acid, such as L-phenyl-alanine, as the starting material. The Birch reduction of L-phenylalanine (1) was carried out with lithium in ammonia, followed by acylation of the amino group to produce compound 2, which was further esterihed to produce the cyclohexa-l,4-dienyl-L-alanine derivative 3 (Scheme 11.1). The ozonolysis step of the reaction was carried out at -78°C in a dichloromethane solution presaturated with ozone to reduce the extent of oxidation of the diene 3 to produce 4. Cyclization was then carried out by the introduction of either hydroxylamine hydrochloride to produce the isoxazol-5-ylalanine derivative 5 or phenylhydrazine to give a 1 1 mixture of (l-phenylpyrazol-3-yl)alanine derivative 6 and the (l-phenylpyrazol-2-yl)alanine derivative 7.4,5... 

Ozonolysis as used below is the oxidation process involving addition of ozone to an alkene to form an ozonide intermediate which eventually leads to the final product. Beyond the initial reaction of ozone to form ozonides and other subsequent intermediates, it is important to recall that the reaction can be carried out under reductive and oxidative conditions. In a general sense, early use of ozonolysis in the oxidation of dienes and polyenes was as an aid for structural determination wherein partial oxidation was avoided. In further work both oxidative and reductive conditions have been applied . The use of such methods will be reviewed elsewhere in this book. Based on this analytical use it was often assumed that partial ozonolysis could only be carried out in conjugated dienes such as 1,3-cyclohexadiene, where the formation of the first ozonide inhibited reaction at the second double bond. Indeed, much of the more recent work in the ozonolysis of dienes has been on conjugated dienes such as 2,3-di-r-butyl-l,3-butadiene, 2,3-diphenyl-l,3-butadiene, cyclopentadiene and others. Polyethylene could be used as a support to allow ozonolysis for substrates that ordinarily failed, such as 2,3,4,5-tetramethyl-2,4-hexadiene, and allowed in addition isolation of the ozonide. Oxidation of nonconjugated substrates, such as 1,4-cyclohexadiene and 1,5,9-cyclododecatriene, gave only low yields of unsaturated dicarboxylic acids. In a recent specific example... 

Interestingly, addition of BF3 etherate to the ozonolysis of o-dimethoxybenzene derivatives results in increased yields of (Z,Z)-dienes (eq 27, compare to eq 20).In this case, it is thought that coordination of the Lewis acid to the diene reduces its electron density and suppresses further attack by ozone. Also, the fact that the BF3 is already coordinated to ether may limit its ability to coordinate to ozone and increase its electrophilic reactivity. 

Although the full significance of the reactions of ozone with diene rubbers was not to be appreciated until the mid-1940s its importance was recognized in part, by the early years of this century, with the ozonolysis techniques developed by Harries (see Chapters 1 and 2). Subsequently the reactions between olefins and ozone were studied by various workers and much of the experimental data obtained can be accounted for by a series of mechanisms proposed by Criegee (1951, 1954, 1955). The essential proposals are summarized below. 

Ozonolyses of various dienes containing an enol carbonate afford products in which the isolated double bonds rather than the enol ones are cleaved. Rate measurements for ozonolysis of a variety of cyclohexene derivatives indicate that the enol carbonate function has a very low reactivity towards ozone. NMR and computational data indicate that the enol carbonate is not particularly electron deficient in its double bond. It is therefore suggested that the retardation is instead caused by ozone association with the carbonate group. The steric and electronic effects of alkyl and aryl substituents on the rate of ozonation of cyclic hydrocarbons have been studied. ... 

Upon alkaline fusion of lupulone the following acids and ketones have been obtained, in addition to carbon dioxide acetic acid and 5-(3-methyl-2-butenyl)-2,10-dimethylundeca-2,9-dien-6-one 5-methyl-4-hexenoic acid and 3-(3-methyl-2-butenyl)-6-methyl-5-hepten-2-one 2-(3-methyl-2-butenyl)-5-methyl-4-hexenoic acid and 6-methyl-5-hepten-2-one (see also 14.4.). The position of the double bonds in these compounds has been confirmed by ozonolysis, whereby only acetone was isolated, The same result has been obtained by direct ozonization of lupulone (9,10). Consequently, lupulone is the enolized 2-(3-methylbutanoyl)-4,6,6-tris-(3-methyl-2-butenyl)-cyclohexane-1,3,5-trione (23, Fig. 77). The structure has been proved by synthesis (see 11.4.). 

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