Ozonolysis reactions ester

Scheme 12.19 illustrates some cases in which ozonolysis reactions have been used in the course of syntheses. Entries 1 to 4 are examples of use of ozonolysis to introduce carbonyl groups under reductive workup. Entries 5 and 6 involve oxidative workup and give dicarboxylic acid products. The reaction in Entry 7 is an example of direct generation of a methyl ester by methoxide trapping. 

The ozonolysis reaction, followed by reductive workup with sulfur dioxide, as described in Part A of the present procedure, illustrates a general method which has been developed for the preparation of acetals. Application of the procedure is illustrated by conversion of the following olefins in alcoholic solution to the corresponding acetals (1) l-chloro-4-(o-nitrophenyl)-2-butene to o-nitrophenylacetaldehyde dimethyl acetal in 84% yield (2) l,4-dibromo-2-butene tobromoacetaldehyde dimethyl acetal in 67% yield (3) 3-butenoic acid to malonaldehydic acid diethyl acetal ethyl ester in 61% yield (4) cyclopentadiene to malonaldehyde bis(diethyl acetal) in 48% yield and (5)... 

Ozone, while somewhat inconvenient to use, is way qiecific in its reactions with alkenes. It is widely employed for selective synthesis, for qualitative and quantitative analysis of unsaturated compounds, and for studying the position of double bonds in macromolecules. The nature of the products obtained from ozonolysis reactions is determitted by the way in which the reaction is carried out Different workup procedures (hydrolytic, reductive or oxidative) can be used to produce alcohols, aldehydes, ketones, carboxylic acids or esters. 

Phosphorus-containing compounds provide useful substrates for ozonolysis reactions as well and can provide several products depending on the reaction workup. Several biological uses exist for -amino-a-hydroxy phosphonic acid derivatives and they can be readily prepared by ozonolysis of Al-(ethoxycarbonyl)-/3-amino-Q -methylene phosphonic esters after reductive workup with sodium borohydride (eq 54). When the reaction mixture is treated with sodium hydroxide in MeOH, an anomalous ozonolysis reaction occurs and cleavage of the methylene as well as the carbon-phosphorus bond occurs to yield (V-(ethoxycarbonyl)-a-amino methyl carboxylic esters. 

When making methyl esters from carboxylic acids, diazomethane is generated first from diazald. Just as in the case of ozone in the ozonolysis reaction, the problem of determining oxidation states for atoms in different resonance structures of diazomethane is avoided since it is generated in situ. 

We have focused our attention on the solid phase synthesis of such compounds and described our results here. Alternative routes for the preparation of peptide aldehydes and side-chain protected peptide aldehydes in solid phase synthesis are described. Three new linkers that are stable tmder classical Fmoc or Boc strategies have been developed to obtain the peptide aldehyde from the solid support. One of these linkers was conceptualized on the basis of the Weinreb amide (49) and the other on the basis of phenolic esters (50). Both strategies required the reduction with hydrides of the peptide-linker-resin to release the peptidic aldehydic function. The use of these two different approaches was demonstrated by the synthesis of N-protected a-amino-aldehydes and peptide aldehydes, llie third approach used the ozonolysis reaction for the generation of the desired aldehyde. This concept requires a linker incorporating a double bond in the a-position of the asymmetric carbon of the C-terminal residue that will be cleaved by ozone to produce the carbonyl function. 

In an unusual application of the Wittig reaction, treatment of clavulanic acid derivatives and esters of penicillin V with methoxycarbonylmethylenetriphenylphosphorane afforded the corresponding exo-alkylideneazetidines. Thus penicillin V benzyl ester (104) gave (lOS) as a mixture of E and Z isomers. The /3-lactam could be regenerated by low-temperature ozonolysis (81CC929). 

Butylethylidene and 1-phenylethylidene ketals were prepared selectively from the C4-C6, 1,3-diol in glucose by an acid-catalyzed transketalization reaction [e.g., Me3CC(OMe)2CH3, TsOH/DMF, 24 h, 79% yield PhC(OMe)2Me, TsOH, DMF, 24 h, 90% yield, respectively]. They are cleaved by acidic hydrolysis AcOH, 20°, 90 min, 100% yield, and AcOH, 20°, 3 days, 100% yield, respectively. Ozonolysis of the /-butylmethylidene ketal affords hydroxy ester, albeit with poor regiocontrol, but a more sterically differentiated derivative may give better selectivity, as was observed with the ethylidene ketal. ... 

Alkoxyallenes have also been subjected to oxidative reaction conditions [46, 62, 74, 132-134]. Ozonolysis of the already mentioned a-hydroxy-substituted methoxyal-lenes 230 provided a syn-anti mixture of a-hydroxy esters 231 (Scheme 8.58) [62]. 

Similarly, treatment of a-tosylamino-substituted allene 83 provided the expected a-amino ester 232 in good yield [74], The analogous reaction could also be performed with methoxyallene-aziridine adduct 46, which furnished enantiomerically pure /3-amino acid 233 [46], Although the ozonolysis approach seems to constitute a versatile and flexible method for the construction of a-amino and a-hydroxy esters, only a few examples have been reported so far. 

Unsaturated acids may be split chemically at their double bonds. Permanganate-periodate oxidation has been used to produce the corresponding carboxylic acids, while an alternative technique of ozonolysis results in the formation of aldehydes and aldehyde esters. All these reaction products may be identified by GLC and the information used to determine the position of the double bond in the original fatty acid. 

Trioxolanes are key intermediates in the ozonolysis of alkenes (Section 4.16.8.2). This reaction is of considerable importance in synthetic chemistry where ozonide intermediates are often reduced (to aldehydes or alcohols) or oxidized (to carboxylic acids) in situ. Advantage has been taken of the stability of certain derivatives to investigate selective chemical reactions. An example of selective reduction is shown in Scheme 47 <91TL6454> with other uses of the 1,2,4-trioxolane ring as a masked aldehyde or ester referred to in Section 4.16.5.2.1. 

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). 

---