Ozonolysis trioxolane synthesis

The ozonolysis of alkenes has been comprehensively covered in several excellent reviews (see Section 4.16.1) and will therefore not be discussed in detail here. It is pertinent, given the importance of 1,2,4-trioxolane synthesis, to highlight the key points of the ozonolysis reaction mechanism and several other developments. 

The transformation of tetrasubstituted ethylenes into 1,2,4-trioxolanes may also be achieved if the ozonolysis is carried out in the presence of a foreign carbonyl compound as described in Section 4.33.3.4. With formaldehyde as added carbonyl compound, 3,3-disubstituted derivatives are obtained, whereas in the presence of excess ketone (e.g. by using the latter as solvent), the ozonolysis gives rise to tetrasubstituted 1,2,4-trioxolanes which are difficult to prepare by other methods. Reactions (163) -> (164) and (165) -> (166) provide two examples of this versatile 1,2,4-trioxolane synthesis. Unlike the parent system (2), alkyl- and/or aryl-substituted 1,2,4-trioxolanes generally are stable, non-explosive compounds. Mixtures of crossed ozonides (cf. Section 4.33.3.1.1) or of cis and trans isomers can be separated by thin layer, column or gas chromatography. The cis isomers of symmetrical 3,5-disubstituted 1,2,4-trioxolanes are meso forms, whereas the corresponding trans isomers represent racemates which in some cases have been resolved into their optical... 

The formation of 1,2,3-trioxolanes from an alkene and ozone is the first step in the ozonolysis reaction, which is widely used in synthesis to convert alkenes to aldehydes or carboxylic acids. No instances of double bond migration during ozonolysis are known (since the first step is a cyclo-... 

The final synthetic analogues we consider are the trioxolanes prepared by Vennerstrom and coworkers. These are prepared by a very efficient co-ozonolysis procedure from oxime 90 and a carbonyl compound 91 (Scheme 37A). This provides the 1,2,4-trioxolane in yields of greater than 50%. Further studies on 4-substituted cyclohexanones (e.g. 92) revealed that this reaction proceeds with very good cisitrans selectivity to produce the ester 93, which was derivatized to produce a clinical candidate OZ 277 (6) as shown. The chemistry for the synthesis of this compound has been scaled up beyond 30 kg (Scheme 37B). 

In the decade since the publication of CHEC-II(1996) <1996CHEC-II(4)581>, two outstanding developments have taken place in the field of 1,2,4-trioxolanes (1) isolation of many stable 1,2,4-trioxolanes (secondary ozonides), and their facile synthesis by alternative methods to ozonation (2) most significantly, technological advances in the industrial synthesis of 1,2,4-trioxolanes by co-ozonolysis for preparing on an industrial scale the first fully synthetic antimalarial medicines. Earlier work has been excellently summarized <1984CHEC(6)851>. 

---