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Incoming links: Hydrogenation
Disconnect the N–cyclohexyl bond as a late reductive amination of a primary amine with cyclohexanone. Disconnect the exocyclic methylene as a Wittig methylenation of a substituted cyclohexanone. The useful ring precursor is 3-methyl-5-substituted cyclohex-2-en-1-one, accessible by a Robinson annulation. The pendant substituent throughout ring construction should be .
Start with nucleophilic substitution of the supplied bromo ester by cyanide:Reduce the nitrile selectively to the primary amine while retaining the ester, for example by controlled catalytic hydrogenation with Raney nickel in the presence of ammonia, and trap the amine promptly as its Boc carbamate. Avoid heating or concentrating the free amino ester, which can cyclize to a lactam. lithium aluminium hydride would be unsuitable at this stage because it also reduces the ester.
Partial reduction of the protected ester with DIBAL at low temperature gives . The carbon of the original nitrile is now the methylene nearest nitrogen; the original ester carbonyl is the aldehyde carbon. Condense this aldehyde with acetone and dehydrate to .
Now add the enolate of a second acetone molecule in a Michael addition. With , the resulting chain isIntramolecular aldol condensation gives 3-Me-5-R-cyclohex-2-en-1-one. The beta methyl derives from the carbonyl end attacked in the ring closure; the pendant aminoalkyl chain remains at C5. Hydrogenate the ring C=C selectively, retaining the ketone, then methylenate the ketone with preformed . Do the hydrogenation before installing the exocyclic methylene so that it is not hydrogenated away.
Remove Boc under brief mild conditions, checking for acid-induced exocyclic alkene isomerization. reductive amination of the resulting primary amine with cyclohexanone, followed by selective imine reduction, installs the secondary N-cyclohexyl group. Use controlled stoichiometry to suppress tertiary amine formation. The methyl and four-carbon aminoalkyl substituents occupy the required 1,3-related ring positions, with the exocyclic methylene at the former carbonyl. No ring stereochemistry is specified. The target contains eighteen carbons: six ring carbons, one ring methyl, one methylene, four in the linker, and six in the N-cyclohexyl group.
The key stereochemical disconnection is the cis-1,3-disubstituted cyclopentane, not a direct functionalization of two arbitrary cyclopentane positions. A Diels-Alder reaction of cyclopentadiene with nitroethylene fixes both ends of the new two-carbon bridge on the same face of the original five-membered ring.
Isolate the useful nitronorbornene adduct, convert its secondary nitro group to a ketone by a Nef reaction, and then hydrogenate the remaining ring alkene to norcamphor. Performing the nitro-to-ketone conversion before catalytic hydrogenation avoids simply reducing the nitro group to an amine.
Use a Baeyer-Villiger oxidation to insert oxygen between the carbonyl carbon and its adjacent bridgehead carbon. Bridgehead migration is favoured over migration of the competing methylene; isolate the required lactone regioisomer if necessary. This opens the way to a hydroxy cyclopentyl side chain without breaking the original five-carbon ring. In the resulting bridged lactone, one original cyclopentadiene terminus is bonded to O and the other bears the segment.
Reduce the lactone selectively with DIBAL to its lactol. Ring opening of that lactol gives the aldehyde equivalent cis-3-hydroxycyclopentyl-. The ring OH and the two-carbon aldehyde side chain are cis because their original attachments were the two ends of the Diels–Alder bridge; neither the migration nor lactol opening inverts those cyclopentane carbons.
Perform a Horner-Wadsworth-Emmons reaction on the lactol/aldehyde equilibrium using , where . Preform the phosphonate anion and allow for consumption of base by the lactol OH. Standard stabilized-phosphonate conditions favour the required E- unit. No further hydrogenation should follow it.
The required ester substituent can be prepared by reducing 4-methylpentan-2-one to 4-methylpentan-2-ol, esterifying with bromoacetic acid, and performing an Arbuzov reaction with triethyl phosphite to make the phosphonoacetate. No absolute configuration is indicated at that alcohol-derived centre.
Bridge-derived cis ring stereochemistry plus E-selective phosphonate olefination gives both specified relationships. Achiral cycloaddition and subsequent reagents give a racemic pair with this relative configuration; isolation of one absolute enantiomer would require resolution or an asymmetric variant. The acid fragment contains nine carbons: five from cyclopentadiene, two from nitroethylene and two from the phosphonoacetate. The ester alkyl group adds six, giving fifteen overall. The atom tracing in the original schematic in question 8 shows why oxygen insertion retains the five-membered ring rather than producing a six-membered carbocycle.
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.
There are three largely independent constructions: 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 . Disconnect the benzylidene acetal to a side chain 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 4-(bromomethyl)-2-phenyl-1,3-dioxolane from 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 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 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 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 methyl butanoate, add acetone, then dehydrate the beta-hydroxy ester:Hydrogenate this isolated alkene before coupling it to the bicyclic substrate, giving . saponification gives ; 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.
Original modular disconnections separating protected side-chain installation, regioselected Robinson annulation and synthesis of the seven-carbon acyl group
. Details. 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.
Open the cyclic ester at its acyl–oxygen bond. The resulting delta-hydroxy acid isOxidation-state reversal at the benzylic alcohol gives . This identifies the key Michael disconnection between the central and groups:The nucleophile is the enolate or enamine of the phenyl ketone. The electrophile's propyl substituent must be alpha to its ester carbonyl; using a beta-propyl acrylate would move the substituent to the wrong ring position.
Disconnect further to the indicated acetophenone. Crossed aldol addition to acetone followed by dehydration gives ; selective conjugate reduction or controlled alkene hydrogenation then gives . This avoids requiring an efficient SN2 alkylation with a secondary isopropyl halide. The alpha-propyl acrylate can be obtained by alpha-hydroxymethylation/dehydration of ethyl pentanoate, , using formaldehyde.
In the forward direction, perform the Michael coupling, reduce the phenyl ketone selectively with sodium borohydride while retaining the ordinary ester, hydrolyse the ester, and cyclize the delta-hydroxy acid by controlled acid-catalysed lactonization or an activated-acid coupling. The six-membered ring then has the order carbonyl–––––O. This atom order checks all three substituent positions. No relative configuration is specified, so the scheme does not imply a single diastereomer from the Michael addition or reduction.
C has a saturated backbone and pendant groups in its second block. Hydrogenation converts every backbone to ; lithium aluminium hydride then reduces each to . The resulting connectivity is .
Hydrogenation removes local double-bond rigidity and commonly lowers the segmental barrier to motion, favouring a lower glass transition temperature. Ester reduction changes polarity and side-group volume, while the new hydroxyl groups introduce hydrogen bonding, which can raise the hydroxyl-rich block's glass transition temperature and strengthen segregation. These competing effects preclude a numerical transition shift or an unconditional direction for both transitions from structure alone.
The repeat-unit formulae after both operations are and . Taking standard atomic masses,This is approximately 14.27 kg mol plus the net end-group mass. The termination chemistry is unspecified, so a more precise whole-chain mass is not determined; the methyl group lost during ester reduction must not remain in the second repeat's mass.
Raney nickel 2026-10-20
A porous nickel catalyst prepared by selective removal of aluminium from a nickel–aluminium alloy. It can catalyse hydrogenations; its use does not guarantee that every other reducible functional group will remain unchanged.