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Incoming links: Kinetic enolate
Enolate regioselectivity 2026-10-20
Preference for forming or reacting one enolate of a carbonyl compound with more than one alpha site. A less substituted kinetic enolate and an equilibrated more substituted enolate can give different carbon skeletons.
Open the lactone formally at its acyl–oxygen bond, then replace the resulting secondary alcohol by its ketone precursor. With , the useful sequence of retrosynthetic intermediates isDisconnect the last compound as a Michael addition product of the methyl-side enolate of and ethyl methacrylate:The substituted carbon of the methacrylate becomes the methyl-bearing carbon alpha to the lactone carbonyl. The ketone carbon becomes the oxygen-bearing ring carbon. This checks the six-membered ring connectivity.
The required branched methyl ketone itself comes from butan-2-one by ethyl-side aldol addition to acetone, followed by dehydration and selective hydrogenation:Choose and isolate the aldol regioisomer shown. For the subsequent Michael step, use a bulky base at low temperature to favour its less hindered methyl-side kinetic enolate. Reduce the resulting ketone selectively with while retaining the ester, hydrolyse the ester, then acidify and promote intramolecular esterification with water removal. The hydroxy acid closes to the required six-membered lactone. There is no specified stereochemical relationship to enforce, but a stereochemically pure target would require an additional selectivity or resolution step.
Both side chains have the order ring–, and both printed double bonds have the Z geometry. The two carbon side chains are cis to one another; equivalently the labelled ring H and ring Me are cis on the opposite face. A useful common late precursor therefore has two cis ring– substituents, which can undergo two Z-selective ethylidene Wittig reactions.
Use the starting 2-methylcyclohex-2-en-1-one in a reductive alpha-alkylation. Conjugate reduction under dissolving-metal/enolate-trapping conditions, followed by a primary electrophile , installs a protected two-carbon alcohol side chain at the original methyl-bearing alpha carbon. This gives 2-methyl-2-(2-siloxyethyl)cyclohexanone. The carbon at that position is now quaternary, with its original methyl retained. Alternatively, reduce the enone to 2-methylcyclohexanone and deliberately form/select its more substituted enolate before alkylation; its opposite kinetic enolate would give the wrong regioisomer.
Convert the remaining ring ketone to an exocyclic enoate by Horner–Wadsworth–Emmons olefination with a phosphonoacetate:Hydrogenate this sole alkene to give ring– at that carbon. Select the diastereomer with this substituent cis to the pre-existing protected hydroxyethyl side chain, so the newly installed ring H is cis to ring Me. Less hindered-face hydrogenation can assist this relationship, but the route should include separation/verification of the desired cis product rather than assert complete stereoselectivity without data.
Reduce the ester with lithium aluminium hydride to ring– and remove the TBS group from the other side chain. Both appendages are now two-carbon primary alcohols. Oxidize them to aldehydes under non-overoxidizing conditions, for example Dess–Martin oxidation, obtaining the cis dialdehyde with two ring– groups. Treat with excess salt-controlled, nonstabilized ethylidenetriphenylphosphorane under conditions favouring kinetic Z olefination; isolate the Z,Z product. Each aldehyde carbon becomes the inner vinylic carbon of its crotyl group, while the ylide supplies .
This order postpones both stereodefined alkenes until after hydrogenation, so they are not accidentally saturated. It also avoids assuming that a crotyl grignard reagent adds without allylic transposition or that direct alcohol deoxygenation fixes the required ring stereochemistry. An achiral synthesis gives a racemic mixture pair with the specified relative configuration.
Let . The useful disconnections are benzoate formation, carbonyl reduction and thiol conjugate addition:The sulfur-bearing carbon is the enone beta carbon, so this is a Michael disconnection, not attack of thiophenol on the alcohol-derived central carbon. Reduce the saturated ketone with sodium borohydride after installing SPh, then benzoylate the alcohol with benzoyl chloride and pyridine or a tertiary amine.
Disconnect the enone to and formaldehyde. Kinetic deprotonation on the methyl side of the hindered unsymmetrical ketone, trapping with formaldehyde, and dehydration gives . This order leaves the substituted side unchanged. An alpha-methylenation/Mannich-base-elimination variant is an equivalent way of installing the terminal enone.
Finally, disconnects by alpha alkylation to butan-2-one and 1-iodopropane. Use the more substituted, ethyl-side enolate of butan-2-one for this step, rather than its usual methyl-side kinetic enolate; an equilibrated/regioisomerically selected enolate or enol derivative is required, and the desired monoalkylated ketone should be isolated. Three carbons from propyl iodide and one from formaldehyde increase the original four-carbon ketone to the required eight-carbon alcohol/thioether skeleton. Choosing ethyl iodide here would leave the target short by one carbon.
This is a constitutional synthesis: the target drawing specifies no configuration at either newly formed stereogenic site, so no unproved stereoselective reduction or alkylation is needed. Regioisomeric enolate alkylation and competing overalkylation are the practical selectivity issues to control, rather than something that follows from writing “base”.
A route from the supplied cyclohexenone starts with conjugate methyl addition. Form an organocuprate from methylmagnesium bromide and Cu(I), or use catalytic Cu(I) with controlled methylmagnesium addition, to obtain 3-methylcyclohexanone after protonation. copper directs 1,4 rather than direct 1,2 addition, so the ketone remains intact.
Generate its less hindered kinetic enolate at the alpha carbon opposite the methyl-bearing side, using LDA at low temperature, and trap with phenylselenyl chloride. oxidation of the resulting alpha-selenyl ketone with hydrogen peroxide produces a selenoxide, whose syn elimination introduces the enone double bond on that side. Renumbering the double bond from the carbonyl gives 5-methylcyclohex-2-en-1-one A. The selenium-containing phenyl group is a removable reagent fragment, not a carbon building block incorporated into A; the only new product carbon is the allowed methyl group. Regioselective kinetic enolization is important: enolizing the other alpha site would regenerate an enone with the methyl in the wrong position. This route produces racemic A unless a separate asymmetric step is introduced, which is sufficient for the stereochemically unspecified starting ketone.