Enolisation Under thermodynamic control

The double bond in enone 18 sprouts from a ring and aldol disconnection does indeed simplify the problem considerably since the starting materials are an unenolisable aldehyde 20 and a cyclic enolisable ketone 19. There is only one place for enolisation in either molecule. The condensation between 19 and 20 with HC1 in MeC02H gives the enone 18 in 75% yield.4 The stereochemistry of the enone double bond is under thermodynamic control (chapter 4). 

The less reactive ketones can be persuaded to react with other, usually non-enolisable, carbonyl compounds as in the reaction of cyclohexanone 5 with diethyl carbonate to give the P-keto-ester 7. This reaction is really under thermodynamic control as the favourable equilibrium between the product 7 and its stable enolate 8 more than compensates for the unfavourable equilibrium between 5 and its unstable enolate 6. This stable enolate 8 is a specific enolate. 

Acid conditions ensure enolisation on the more substituted side (Chapter 20) and thermodynamic control gives the -isomer of (17)—the one we want. Eschenmoser found that oxidative cleavage of (16) under acidic conditions led to spontaneous lactone formation without the isolation of (15). 

Under more equilibrating conditions such as alkoxide bases in alcohol solution or amide bases in liquid ammonia, enolisation occurs to give the extended enolate 83 which is then alkylated in the a-position by alkyl halides. At first this seems the most difficult combination to achieve thermodynamic enolisation followed by kinetically controlled addition of an electrophile, but it is in fact a common result achieved with a variety of bases. Examples include the synthesis of pentethylcyclanone 100, an anti-tussive drug, by alkylation of the enone 103, the aldol dimer of cyclopentanone. Disconnection at the branchpoint to the available alkyl halide 102 X = Cl requires a-alkylation of the extended enolate 101 derived from the cyclopentanone aldol dimer27 103. This is easily achieved by sodium amide in toluene.28... 

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