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Incoming links: Lithium aluminium hydride
Sodium borohydride is chemoselective for the ketone; lithium aluminium hydride reduces both the ketone and the lactam. In an amide, donation of the N lone pair into the carbonyl system reduces the carbonyl carbon's electrophilicity. It is therefore substantially less susceptible to the milder hydride donor.
Lithium aluminium hydride supplies more strongly reducing hydride equivalents, and the strong affinity of aluminium for oxygen assists removal of the amide oxygen through the iminium pathway. This difference explains both the unchanged lactam carbonyl in B and the absence of that oxygen in C. Both reactions are interpreted after the usual protonating workup.
B is 4-hydroxy-1-methylpyrrolidin-2-one; C is 1-methylpyrrolidin-3-ol. Their ring connectivities are shown below. Each ring remains five membered; the attached N-methyl group is retained.
For B, a B–H bond of sodium borohydride supplies a hydride equivalent to the ketone carbonyl carbon, and the carbonyl pair moves to oxygen. This gives an alkoxide, whose protonation during the reaction or workup gives the secondary alcohol. The lactam carbonyl remains. Converting one to adds two H atoms and gives .
For C, lithium aluminium hydride reduces that ketone in the same net way and also reduces the lactam. Coordination of the amide oxygen to aluminium assists hydride attack at its carbonyl carbon, giving a tetrahedral intermediate. The N lone pair then forms a C=N bond while the C–O bond breaks to an aluminium-bound oxygen group. A resulting iminium ion accepts a second hydride at carbon, yielding the cyclic tertiary amine. Aqueous workup protonates the ketone-derived alkoxide.
The lactam conversion replaces by ; its oxygen is removed rather than retained as another alcohol. Together with ketone reduction, the net change is , giving . No stereochemistry is specified: the new alcohol stereocentre is formed as a racemic mixture in an achiral environment.
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.
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.
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.
methyl fluorosulfonate alkylates the tertiary isoxazolidine nitrogen, giving a quaternary N-methyl ammonium salt; the methyl remains attached to nitrogen in F. hydride from lithium aluminium hydride then cleaves the N–O bond, releasing the corresponding oxygen as an aluminium-bound alkoxide while restoring neutral tertiary amine nitrogen. Aqueous workup protonates the alkoxide to give the alcohol.
Thus the C–O bond made in the cycloaddition survives as the alcohol-bearing C–O bond, and the formaldehyde-derived methylene survives as the extra carbon between nitrogen and the carbon framework. The N–O bond is the one removed. N-methylation followed by reductive N–O cleavage gives the bridged amino alcohol F without requiring cleavage of its newly formed C–C bond or hydrogenation of a nonexistent residual alkene.