Knoevenagel alkenylation

Retrosynthetic disconnection of hexahydrocannabinol 1 following the path of an intramolecular hetero DiELS-Alder reaction leads to the o-quinonemethide 2 as an electron-deficient hetero-1,3-diene 2 arises from a Knoevenagel alkenylation of citronellal 3 with the carbanion resulting from deprotonation of the CH-acidic methylene group of the keto tautomer 4 of 5-pentylresorcinol known as olivetol. 

The 5-keto acid 11 is supposed to be formed by hydroboration and oxidation of the terminal CC double bond in 12, feasible by allylation of the enone 13. Enone 13, once again, originates from an intramolecular Knoevenagel alkenylation of the a,5-diketone 14 prepared by addition of ethylmagnesium halide to the enol lactone 15 of the 5-keto acid 16. Preceding this keto acid, the allyl compound 17 is formed by nucleophilic opening of the cyclopropane ring with hydride and mefliylation in a position of the carbonyl in the cyclopropyl ketone 18. 

A number of new methods for the homologation of esters have been reported. Methyl bis(ethylthio)acetate, derived from dichloroacetate and the sodium salt of ethanethiol, can be smoothly alkylated under standard conditions to the corresponding a-alkyl (or alkenyl) derivatives, in excellent yield. The use of DBU as base to effect high yield dialkylations of Knoevenagel type substrates with alkyl bromides has been described. Directed additions of a-substituted ester enolates to cyclohexenone can be achieved by careful control of temperature. Conjugate addition of diphenylmethide to acrylate esters has been achieved after much trial and error substituted acrylates lead to the best yields. 

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