Esters vinyl, ozonolysis

The Diels-Alder reaction of 3-methoxyfuran with octyl vinyl ketone took place at room temperature in quantitative yield to afford exclusively the endo cycloadduct (27) (81CC221). Reduction of the carbonyl group with lithium tri-r-butoxyaluminum hydride produced a single alcohol (28). Ozonolysis of the double bond followed by Jones oxidation yielded the lactone ester (29). Hydrolysis of the ester and lead tetraacetate oxidation gave the lactone acetate. This was converted by further hydrolysis and Jones oxidation to the bis-lactone (30), a known intermediate in the synthesis of ( )-isoavenaciolide (Scheme 6). 

An a,/3-unsaturated ester with a bornane skeleton 161 having a vinyl group reacts on ozonolysis in CH2CI2 at —78 °C at the more reactive vinylic double bond but not at the conjugated double bond. Subsequent treatment with dimethyl sulfide affords the aldehyde-ester 162 in 84% yield, leaving the ozonide 163 in 8% yield (Equation 12) <2001RJ01102>. 

Dimethylcyclohexenone was treated with vinyl magnesium bromide in the presence of cuprous bromide to afford a ketone 2. After protection of the carbonyl group with ethylene acetal, hydroboration, oxidation, and methylation with diazomethane yielded a methyl ester 6. The methyl ester 6 was treated with LDA/allyl bromide to give 7, followed by ozonolysis to afford an aldehyde 8. 

A typical example of an application of ozonolysis in synthesis is the cleavage of the alkene unit in 351 to give aldehyde 352, with loss of formaldehyde, a part of Smith s synthesis of (+)-thiazinotrienomycin In this case, the reductive workup used triphenylphosphine. Ozonolysis of 353 gave aldehyde 354, an intermediate in Corey s synthesis of the Cecropia Moth Juvenile hormone, via a reductive workup with DMS. Note that the electron rich vinyl ether moiety reacted in preference to the simple alkene moiety. The ozonolysis product of the methyl vinyl ether was a methyl ester. This method is particularly useful for the preparation of protected acids. In general, electron rich alkenes are oxidized faster than electron-poor alkenes. 

Having streamlined the synthesis of acyl chloride 54, the indirect preparation of methyl enol ester 51a was addressed. As previously discussed, attempts to synthesize 53a from formyl Meldrum s acid 58 had proven unsuccessful. However, Cossy and coworkers have reported the preparation of 53a via the ozonolysis of alkene 82 and subsequent use of the crude aldehyde in the total synthesis of octalactin. Thus, methyl vinyl acetate (82) was subjected to ozonolysis at —78 °C, followed by a reductive quench to provide formyl acetate 53a (Scheme 24). The crude methyl formyl acetate was acylated with acyl chloride 54, using the previously optimized conditions, to afford methyl enol ester 51a in 74% yield over two steps. This modification to the synthesis removes a further two reactions from the sequence with a formal synthesis of (—)-7-deoxyloganin (24) now achieved in 10 steps, a length more in keeping with the complexity of this target. 

During the initial studies on the chemistry of the suifenic acid functionality, Shelton and Davis (1967) observed that t-butylsulfenic acid (103) underwent conjugate addition to a propiolic ester to produce the vinyl sulfoxide (104). Similarly, the azetidinone suifenic acid (105), thermally generated from penicillin sulfoxide (106), was also found to undergo a conjugate addition with dimethyl acetylenedicarboxylate to yield a mixture of epimeric sulfoxides 107 and 108 (Barton et al., 1973 1974). This isomeric mixture could be reduced to the single sulfide (109). The double bond was isomerized to the a,p-unsaturated compound 110 which on progressive ozonolysis first produced the thiooxalate (111) and then the oxamide (112). 

In 2007, Steinfeldt et al. [34] utilized a falling film microreactor by IMM (www.imm-mainz.de) for studying the ozonolysis of acetic 1-vinyl-hexyl ester (63) in dichloromethane as a solvent. In order to determine the influence of reaction parameters (e.g., temperature, ozone partial pressure, and reactant concentration) on the product distribution, no reductive or oxidative treatment was applied. The reaction was studied in a temperature range from —50 to 0°C. Based on the obtained results, the mechanism shown in Figure 6.32 was suggested. 

Figure 632 Suggested reaction mechanism for the ozonolysis of 1-acetic 1-vinyl-hexyl ester (63) in CH2CI2. (Reproduced from Ref [34] with permission of the American Chemical Society.)...

The projected free radical cyclization proceeded as planned to give 172. Ozonolysis of the vinyl group, oxidation of the resulting aldehyde to an acid, and alkylation with diazomethane provided projected intermediate 162. Reduction of the lactone provided 173. Treatment of 173 with 6-methoxytryptamine and pivalic acid then provided a nearly equal mixture of lactams 174 (isoreserpine stereochemistry at Cg) and 175 (reserpine stereochemistry at C3). The correct C3 stereoisomer was moved forward to 176 (protection of the tertiary alcohol followed by reduction of the lactam). The silyl ethers were removed, the secondary ether was re-protected, and reaction with samarium iodide accomplished reduction of the a-hydroxy ester to provide 177. Removal of the TBS group and esterification of the alcohol completed the synthesis of reserpine. 

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