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Incoming links: Sodium borohydride
Past exam of the chemistry B course of the University of Cambridge 2023 Paper 1 B4 b ii Solution 2026-10-20
Write the reacting terminus as , where includes the pre-existing stereocentres and the intact substituent. ozone undergoes 1,3-dipolar cycloaddition across the terminal alkene to give a molozonide. In a resonance description of ozone as , the alkene pi pair bonds to one terminal oxygen while the other terminal oxygen forms the second C–O bond and the ozone pi bond shifts onto its central oxygen. Cleavage of this unstable primary ozonide produces a carbonyl compound and a carbonyl oxide, which recombine to form the secondary ozonide. Reductive workup breaks the peroxide bonds and gives the carbonyl fragments and formaldehyde.
Excess sodium borohydride also reduces the newly formed aldehyde: hydride attacks its carbonyl carbon, shifting the pi electrons onto oxygen, and the final acidic workup protonates the alkoxide. Thus the retained chain becomes . The terminal alkene carbon becomes formaldehyde and can be reduced to methanol; it is no longer part of the main product. This accounts for the one-carbon shortening of the retained skeleton.
The original amide carbonyl is present in both H and I and is not reduced under the ordinary borohydride workup. The existing stereocenters and benzyl ether are retained. Stopping the mechanism at an aldehyde, or deleting the amide C=O when reading the smaller printed scheme, would give the wrong product. The new terminal alcohol carbon is CH2 and therefore adds no stereocenter.
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.
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. 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”.
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.
One valid asymmetric route uses N-Boc-(R)-proline as a chiral starting material. Convert its acid to the Weinreb amide with N,O-dimethylhydroxylamine and a coupling reagent such as EDC, then add phenylmagnesium bromide at low temperature. chelation of the magnesium tetrahedral intermediate prevents a second addition; aqueous workup releases the phenyl ketone. Reduce it with sodium borohydride, separate the resulting alcohol diastereomers, and retain the one with configuration at both pyrrolidine C2 and the benzylic carbinol. This is an asymmetric synthesis through a pre-existing enantiopure centre, even though the final reduction need not be perfectly diastereoselective. If the other protected alcohol is isolated, Mitsunobu esterification with a carboxylic acid followed by ester hydrolysis inverts just the carbinol centre. Keeping nitrogen Boc-protected during that inversion avoids neighbouring-amine participation. Mild Boc removal followed by reductive benzylation with benzaldehyde and sodium triacetoxyborohydride gives D, the amino alcohol. Use conditions that avoid epimerizing the amino ketone.
For ring expansion, activate D's alcohol with methanesulfonyl chloride and a tertiary amine base. Its own tertiary nitrogen attacks the benzylic carbon from the back, displacing mesylate with inversion and making a fused aziridinium ion. Acetate, supplied as a soluble acetate salt, attacks the original pyrrolidine C2 from the opposite face and breaks the old C2–N bond. The new N–benzylic-C bond is retained, incorporating that side-chain carbon into the six-membered ring. Inversion at the two successively attacked carbons gives the cis acetate/phenyl piperidine E in the displayed orientation. Attack at the benzylic carbon instead would simply open the three-membered ion back to a five-membered-ring derivative; specifying the attacked carbon is the crucial regiochemical step.