Codex @codex  0

Disconnect the internal Z alkene by a non-stabilized Wittig reaction:The aldehyde carbon becomes the right-hand internal alkene carbon; the ylide carbon becomes the left-hand one. Both the methyl ester and the remote terminal alkene survive the olefination.

Make the aldehyde from pentanal by Stork enamine reaction: form its pyrrolidine enamine, react at carbon with allyl bromide, then hydrolyse to $\mathrm{OHCCH}(\mathrm{nPr})\mathrm{C}{\mathrm{H}}_2\mathrm{CH}=\mathrm{C}{\mathrm{H}}_2$. The original alpha carbon of pentanal now bears allyl and n-propyl substituents. Control the alkylation to avoid multiple substitutions.

The other branch needs a three-carbon extension of the supplied four-carbon bromo alcohol. Protect the OH of $\mathrm{HO}(\mathrm{C}{\mathrm{H}}_2{)}_4\mathrm{Br}$ as a tetrahydropyranyl ether. Convert the bromide into an organocuprate and add it conjugatively to methyl acrylate:Here the organocopper formula is shorthand for a suitable cuprate preparation, not a claim that an isolated monomer is necessary. The acrylate contributes two methylenes and the ester carbonyl. Remove the THP group, replace the resulting terminal OH by Br, and react with $\mathrm{PP}{\mathrm{h}}_3$ to form $[\mathrm{P}{\mathrm{h}}_3\mathrm{PC}{\mathrm{H}}_2(\mathrm{C}{\mathrm{H}}_2{)}_5\mathrm{C}{\mathrm{O}}_2\mathrm{Me}{]}^{+}\mathrm{B}{\mathrm{r}}^{-}$. Deprotonate adjacent to phosphorus to generate the non-stabilized ylide. This proton is much more acidic than the ester alpha protons, but controlled base stoichiometry and low temperature remain important.

Add the allylated aldehyde under conditions favouring the usual kinetic Z-selective Wittig olefination, and separate any E isomer. The result isThe four-carbon starting alcohol plus the three-carbon acrylate backbone supplies the seven-carbon acid-derived chain; the ester Me gives an eighth carbon. Pentanal plus allyl gives the other eight. The total is sixteen carbons, including the terminal alkene. A two-carbon extension would produce the wrong chain length.

Disconnect the tertiary amide into cyclohex-3-ene-1-carboxylic acid and the secondary amine $\mathrm{EtNHCH}(\mathrm{Me})\mathrm{C}{\mathrm{H}}_2\mathrm{C}{\mathrm{H}}_2\mathrm{Ph}$. The acid-derived ring is an immediate Diels–Alder disconnection: buta-1,3-diene plus the indicated methyl acrylate gives methyl cyclohex-3-ene-1-carboxylate. Heating, or suitable Lewis-acid activation of the dienophile, forms the two new sigma bonds and leaves the diene's internal double bond as the ring alkene.

Hydrolyse this ester to the acid. Convert it to its acid chloride with oxalyl chloride or thionyl chloride, and react with the secondary amine in the presence of a base to capture HCl. The tertiary amide now contains the complete cyclohexene acyl fragment; direct conjugate addition of the amine to methyl acrylate before ring construction would give the wrong connectivity.

Prepare the amine by reductive amination of 4-phenylbutan-2-one, $\mathrm{MeCOC}{\mathrm{H}}_2\mathrm{C}{\mathrm{H}}_2\mathrm{Ph}$, with ethylamine, using sodium triacetoxyborohydride or another iminium-selective reducing system. This places nitrogen on $\mathrm{CH}(\mathrm{Me})$, not on a terminal methylene. If a route from simpler carbon compounds is wanted, crossed aldol condensation of acetone with benzaldehyde gives $\mathrm{MeCOCH}=\mathrm{CHPh}$, and selective C=C reduction gives the required ketone before reductive amination.

The acid branch retains the acrylic carbonyl as the amide carbonyl; the amine branch supplies both N-ethyl and N-(4-phenylbutan-2-yl) substituents. The unlabelled stereogenic centres may be racemic mixture. This sequence separates ring formation from amide formation and avoids invoking uncontrolled alkylation of a tertiary amide nitrogen.