Bridgehead enolates, reactivity

Formation of the antiaromatic enolate 11 from the low acidity ketone 10 " is evidently unfavourable compared with its acyclic variant 17. Attempts at isolating a stable enol derivative of 10, such as its silyl enol ether, have proved unsuccessful ". Treatment of benzocyclobutanone (10) with LiTMP in THE at —78°C, followed by the addition of trimethylsilyl chloride (MesSiCl), gave the corresponding C-silylated benzocyclobutanone 18 (equation 3) ". The non-aromatic C-lithiated ketone 20 appears to be more preferred than its related 0-lithiated enolate 11. Unlike traditional lithium enolates, this particular lithium enolate reacts in situwilh its parent compound, benzocyclobutanone (10), to give the diketone 19 (equation 3). In comparison, bridgehead enolates have also been shown to be similarly reactive ... 

Evidently, these or closely related intermediates are accessible and reactive, since the synthesis was successfully achieved as outlined in Scheme 13.28. In addition to the key cationic cyclization in Step D, interesting transformations were carried out in Step E, where a bridgehead tertiary alcohol was reductively removed, and in Step F, where a methylene group, which was eventually reintroduced, had to be removed. The endocyclic double bond, which is strained because of its bridgehead location, was isomerized to the exocyclic position and then cleaved with Ru04/I04. The enolate of the ketone was then used to introduce the C(12) methyl group in Steps F-3 and F-4. 

Interesting heteroatom-substituted derivatives such as 67 have also been synthesized via the reaction of bis enol ether 66 with thiol-containing dicarbonyl electrophiles, Eq. 54 [81]. Compound 68 bearing a bridgehead silyl substituent was produced from the reaction of 65 with a ketoacylsilane [82], Subsequent decarboxylation and desilylation of 68 generates 69, Eq. 55. The overall sequence represents a method to obtain the product of a formal inversion of the usual reactivity of 65 with ketoaldehydes. Extensive studies failed to reverse the observed regio selectivity. 

The high diastereoselectivily of this triple tandem reaction can be explained by the mechanism depicted in Scheme 3.1.5. At first glance, the thermal oxy-Cope rearrangement of 99 leads to enol 100, which tautomerizes in situ to produce the ketone 101. This ketone can adopt two chair-Uke conformations at the transition state, W and X. A close examination of the transition state Z reveals a psuedo-1,3-diaxial O-allyl-ring methylene interaction. Therefore, this favors the transition state W over X as the reactive conformer to provide the enol 102. Einally, the Claisen rearrangement proceeds anti to the bridgehead alcohol at C5 to afford the desired bicycUc product 103. 

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