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Joined 2026-09-21 Message
Incoming links: Ylide
2,3-sigmatropic rearrangement 2026-10-20
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.
The left ring system is spiro, and the right-hand substituent is , not OMe directly attached to the cyclohexene ring. Let denote the right cyclohexenyl group bearing that methoxyethyl substituent cis to its linker. The connection to the left alkene carbon is . These observations suggest two Diels–Alder constructions. A left-hand dienehas the original cyclopentane carbon as one terminal diene atom; cycloaddition with an ethylene equivalent gives the spiro six-membered ring. Its residual double bond is between the two internal diene atoms, putting the linker on the required alkene carbon.
Build and its four-carbon alcohol appendage first. Protect the OH group of the indicated 4-Bromobutan-1-ol, for example as a THP ether. Convert the primary bromide to its grignard reagent and formylate with DMF, giving . olefination with an allylidenetriphenylphosphorane, , supplies a conjugated diene ; select the required diene geometry rather than assume a single E/Z outcome.
Cycloaddition with methyl vinyl ketone produces a cyclohexene with a protected four-carbon alcohol chain at one saturated ring carbon and an acetyl group at its adjacent ring carbon. Choose and isolate the adjacent-substituent cis regioisomer, matching the two dashed substituent bonds in the target. Endo preference and diene geometry can aid the selection, but an unsymmetrical diene is not guaranteed to give a unique regioisomer. Reduce the acetyl ketone to , then methylate that alcohol with sodium hydride/methyl iodide while the chain-end OH is protected. Remove the THP group under mild acid conditions to reveal , preserving the secondary methyl ether and the ring alkene.
Oxidize this primary alcohol to . Add vinylmagnesium bromide to give , then oxidize the allylic alcohol to the enone . This carbonyl carbon is the original alcohol-end carbon of 4-bromobutanol; after olefination it will be the linker-bearing carbon of the left ring alkene.
In the other branch, reduce the specified cyclopentanone to cyclopentanol, convert to bromocyclopentane, and react with triphenylphosphine to obtain the cyclopentylphosphonium salt. Deprotonation gives the cyclopentylidene phosphorane, whose ylidic carbon is part of the five-membered ring. Wittig olefination of the just-prepared enone gives the substituted diene displayed above. This carbonyl–ylide pairing keeps the ring carbon terminal in the diene and avoids accidentally constructing a fused ring instead of a spiro ring.
Finally, cycloadd an ethylene equivalent. Ethylene itself requires suitably forcing/high-pressure conditions; a more reactive alternative is phenyl vinyl sulfone, followed by reductive removal of the sulfone substituent using a method compatible with the methyl ether and retained C=C bonds. The latter installs the same two otherwise unsubstituted saturated carbons. Control or separate any additional cycloaddition isomers, and retain the previously selected cis configuration on .
The carbon count provides a strong check: cyclopentanone supplies five, bromobutanol four, DMF formylation one, the first allylidene ylide three, methyl vinyl ketone four, O-methylation one, vinylmagnesium two, and the final ethylene equivalent two, totalling 22 target carbons. Three original bromobutanol carbons form the linker; its fourth becomes the substituted carbon of the spiro ring's alkene. The proposal is a multistep constitutional/relative-stereochemical route with explicit regioisomer and diastereomer selection, not an unsupported claim of a single quantitative cycloaddition product.
First the tertiary amine attacks the primary allylic bromide carbon by SN2 reaction, giving the quaternary ammonium salt. The less hindered nitrogen face is favored by the pre-existing fused-ring stereochemistry.
DBU removes the proton at the carbon alpha to both the ammonium nitrogen and the ester carbonyl. The resulting ammonium ylide undergoes a concerted 2,3-sigmatropic rearrangement: the N–CH(allyl) bond breaks, a bond forms between the ylide carbon and the aryl-bearing terminal allyl carbon, and the double bond moves to give . Nitrogen becomes neutral again. An ordinary alkyl substitution would attach the wrong end of the allyl unit.
An envelope-like five-membered transition structure keeps Ar outside the crowded bicyclic framework. With the pre-existing OMe dash and ring-junction geometry fixed, place the newly installed side chain on the solid-wedge face at the former ylide carbon and choose the benzylic configuration that places Ar outward, as in the displayed intermediate. This is diastereoselective, suprafacial allyl transfer.
Finally methanesulfonic acid protonates the methyl acetal. Methanol leaves to give an oxocarbenium/iminium-stabilized electrophilic centre, which is attacked intramolecularly by the electron-rich arene at its available ortho position. Deprotonation restores aromaticity and closes the bridge. The terminal isopropenyl group survives; it is not the bond consumed in this final Intramolecular Friedel-Crafts reaction. The constrained tether selects the displayed bridged diastereomer.
Phosphorus ylide 2026-10-20
A ylide with adjacent phosphorus-positive and carbon-negative descriptions, often represented by a phosphorane form. Its carbon can be coupled to a carbonyl carbon in Wittig olefination.
Ylide 2026-10-20
Z-selective Wittig olefination 2026-10-20
Conditions favouring a Z alkene in a Wittig reaction, often using a nonstabilized ylide under kinetic, salt-controlled conditions. Isolation or verification is still required when complete stereoselectivity is not established.