= Solution
There are three largely independent constructions: \b[a substituted Robinson-annulation core, a protected vicinal diol, and the <ester> acyl fragment]. Disconnect the <ester> first to an allylic <alcohol> on the bicyclic ring and the acid $\mathrm{HO_2CCH(Et)CH(Me)_2}$. Disconnect the <benzylidene acetal> to a side chain $\mathrm{-CH_2CH(OH)CH_2OH}$ and <benzaldehyde>. Reversing 1,2-reduction of the allylic <alcohol> gives the corresponding bicyclic enone; its six-membered enone ring is a Robinson disconnection back to a suitably alpha-substituted cyclohexanone and methyl vinyl <ketone>.
An efficient way to protect the side chain before annulation is to prepare \b[4-(bromomethyl)-2-phenyl-1,3-dioxolane] from $\mathrm{BrCH_2CH(OH)CH_2OH}$ and <benzaldehyde> with mild acid and water removal. The desired five-membered <acetal> protects the adjacent hydroxyl groups, while its external primary <bromide> remains an alkylating site. Alpha alkylation of the indicated cyclohexanone with this <bromide> gives a ring bearing $\mathrm{-CH_2CH(O-)CH_2O-}$ in the benzylidene-protected form. There is no need to expose the eventual ring enone to a nonselective late dihydroxylation.
Generate the <enolate> at the \b[other, less substituted alpha position] of the cyclohexanone and add methyl vinyl <ketone>. Hydrolysis of an enamine-mediated Michael variant or direct <enolate> trapping gives the appropriate 1,5-dicarbonyl. Intramolecular <aldol condensation> closes a six-membered ring onto the original cyclohexanone <carbonyl>. Dehydration gives the fused bicyclic enone, with the protected three-carbon side chain on the adjacent <carbon> of the original ring. Regioselecting the initial <Michael addition> is essential: reaction at the side-chain-bearing alpha site would place that substituent at the wrong fusion position.
Reduce the new enone <carbonyl> \b[by 1,2-addition], for example <sodium borohydride> with cerium(III) <chloride> under Luche-type conditions, to retain the displayed ring C=C bond and produce the allylic <alcohol>. The <benzylidene acetal> should be maintained through these neutral/basic operations. The target has no wedge/dash assignments, so a constitutional solution does not require a claim of a unique fused-ring/<alcohol> <diastereomer>; isolate the required constitutional annulation product.
For the acyl branch, form the <enolate> of the indicated \b[<methyl butanoate>], add acetone, then dehydrate the beta-hydroxy <ester>:
$$
\mathrm{MeO_2CCH_2Et\longrightarrow MeO_2CCH(Et)C(OH)Me_2
\longrightarrow MeO_2CC(Et)=CMe_2}.
$$
Hydrogenate this isolated alkene before coupling it to the bicyclic substrate, giving $\mathrm{MeO_2CCH(Et)CHMe_2}$. <saponification> gives $\mathrm{HO_2CCH(Et)CHMe_2}$; activate it as its acid <chloride> or use a mild ester-coupling reagent, then acylate the bicyclic allylic <alcohol>. Performing the <hydrogenation> on the separate acyl branch avoids reducing the target ring alkene. Strong acid should be avoided during the final esterification because the benzylidene group is acid-labile.
The <carbon> audit is particularly useful: the fused rings contain six carbons from cyclohexanone plus four from methyl vinyl <ketone>; the side chain has three carbons from the protected bromodiol; the benzylidene unit supplies its <acetal> <carbon> and <phenyl group>. In the acyl fragment, the four butanoate acyl carbons plus three acetone carbons give seven; the starting <ester> methoxy <carbon> is lost during hydrolysis.
\Image[/past-exam-of-the-chemistry-course-of-the-year-3-of-the-natural-sciences-course-of-the-university-of-cambridge/2022/paper-1-q11-first-route.png]
{title=Original modular disconnections separating protected side-chain installation, regioselected Robinson annulation and synthesis of the seven-carbon acyl group}
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