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Incoming links: Ester enolate
Disconnect the amide into 2-propylhexanoic acid and N-methyl-2-(4-hexylphenyl)ethylamine. This keeps the nitrogen substituents distinct: one is Me and the other is the two-carbon aryl side chain. The acid's alpha carbon must bear both n-butyl and n-propyl groups.
For the acid fragment, esterify the supplied hexanoic acid, form its ester enolate with LDA, and alkylate with 1-iodopropane:hydrolysis gives 2-propylhexanoic acid; conversion with gives the acyl chloride for the final coupling. Limit the alkylating reagent and isolate the monoalkylated ester to avoid overalkylation.
For the aryl fragment, use another portion of hexanoic acid to make hexanoyl chloride. A Friedel-Crafts acylation of bromobenzene with this reagent and gives ortho and para products; isolate the para bromoaryl ketone. A Wolff-Kishner reduction converts into without deliberately hydrogenolyzing the aryl bromide. Acylation followed by carbonyl reduction installs an unrearranged n-hexyl group; direct Friedel–Crafts alkylation is a less reliable way to do that.
Convert the retained aryl bromide into its grignard reagent, open ethylene oxide, and work up to obtain . Oxidize the primary alcohol to under conditions that stop at the aldehyde, then perform reductive amination with methylamine and sodium triacetoxyborohydride. Excess methylamine helps favour the desired secondary amine over further alkylation. Finally acylate that secondary amine with the isolated acyl chloride, using a separate base to capture HCl.
The final amide has an N-methyl group, the para n-hexyl phenethyl group, and the required n-butyl/n-propyl acyl branching. The carbon check is in the acyl fragment plus in the amine fragment, giving overall. No absolute stereochemistry is specified at the acid alpha carbon.
This is an Ireland–Claisen rearrangement. Number the ester carbonyl carbon , its enolizable carbon , and the three allylic ring carbons , starting at the carbon bearing the ester oxygen.
lithium hexamethyldisilazide removes an proton and trimethylsilyl chloride traps the oxygen of the resulting ester enolate, giving a silyl ketene acetal. Heating permits a six-electron, [3,3]-sigmatropic rearrangement through the arrayThe electron-pair movements are , , and . Acidic work-up cleaves the silyl ester to the carboxylic acid. The benzyl ether remains a protecting group; it is not the migrating bond.
The suprafacial reaction transfers the starting allylic stereochemistry to , where the new side chain is delivered from the original oxygen face. In the product's printed orientation, the new C–C bond is behind the ring and the C methyl group is toward the viewer. At that ring star, the Cahn-Ingold-Prelog priority rules orders the groups as side chain, alkenyl ring direction, saturated ring direction, methyl, giving .
The second star is . Its priorities are carboxyl, substituted ring carbon, , H. A chair-like transition state normally places the bulky side chain pseudoequatorial. However, its absolute configuration also depends on the E/Z geometry of the trapped silyl ketene acetal: opposite geometries give opposite configurations at this star under the same suprafacial ring transfer. The printed conditions do not state solvent or the ketene-acetal geometry. Thus the secure assignment is the ring-star configuration and conditional -star stereochemistry, rather than an unqualified absolute assignment to both stars. Drawing the assumed ketene-acetal geometry and its chair is necessary before selecting one epimer.