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Journal of organic chemistry 87, pp. 2985–2996. Abstract: DBU-promoted Michael addition/cyclization/aromatization of nitroethane and alpha-alkenoyl ketene dithioacetals.

A Michael addition makes a bond at the beta carbon of a conjugated electrophile through conjugate addition. An enamine can supply a carbon nucleophile; subsequent hydrolysis restores its original carbonyl group.

A is a fused five-/six-membered bicyclic diketone containing sulfur. To specify its structure unambiguously, retain the cyclohexanone numbering C1=O, C2 and C3 for the original alkene. Add the five-membered ringThe original C1 ketone remains, and the former methyl-ester carbonyl becomes the second ketone. The product is drawn in the first panel below.

methoxide first deprotonates the thiol. The soft thiolate attacks the beta carbon C3 in a Michael addition, shifting the enone electrons onto oxygen. The resulting enolate is nucleophilic at C2. It then attacks its tethered ester carbonyl intramolecularly, forming a five-membered ring through a tetrahedral intermediate. Collapse expels methoxide. proton transfers and work-up give the neutral bicyclic beta-diketone.

The initial 1,4 addition followed by intramolecular Claisen acylation explains the regiochemistry: it connects C3 to sulfur and C2 to the ester carbonyl, giving a favorable five-membered closure. Addition to the original ketone would not give this same enolate-and-ester arrangement. The net loss of methanol from the combined starting materials gives the observed ${\mathrm{C}}_8{\mathrm{H}}_{10}{\mathrm{O}}_2\mathrm{S}$ formula.

Label the enamine carbon bonded to nitrogen C1 and its alkene partner C2; C6 is the other carbon next to C1. B is the C-alkylated iminium ion bromide. Its new substituent at C2 is $-\mathrm{C}{\mathrm{H}}_2-\mathrm{C}(\mathrm{C}{\mathrm{O}}_2\mathrm{Et})=\mathrm{C}{\mathrm{H}}_2$, while C1 is double-bonded to the pyrrolidine nitrogen, which bears positive charge. bromide is the counterion, accounting for Br in the empirical formula without requiring a retained C–Br bond.

The C2 end of the enamine attacks the bromomethyl carbon by $S_{\mathrm{N}}2$ displacement. Simultaneously, donation of the nitrogen lone pair creates the C1=N bond. This is ordinary enamine C-alkylation, not N-alkylation.

proton transfer removes an alpha proton at C6, converting the iminium ion into the enamine regioisomer C1=C6. That enamine attacks the terminal $\mathrm{C}{\mathrm{H}}_2$ of the tethered acrylate in an intramolecular Michael addition. nitrogen donation restores the iminium ion, and protonation of the ester enolate completes the sequence.

The new bridge is $C2-\mathrm{C}{\mathrm{H}}_2-\mathrm{CH}(\mathrm{C}{\mathrm{O}}_2\mathrm{Et})-\mathrm{C}{\mathrm{H}}_2-C6$. Together with the original ring and its C1 bridge this produces the bicyclo$[\mathrm{3.3.1}]$nonane iminium ion skeleton in C. It retains the pyrrolidine group and the ester; hydrolysis to a ketone is not part of the displayed reaction. The second panel of the original annulation figure shows the chemical atom connectivity and distinguishes ionic bromide in B from a covalent bromine substituent.

Number the cyclopentenone carbonyl carbon $C_1$, its alkene carbons $C_2$ and $C_3$ with OR at $C_3$, and its saturated carbons $C_4$ and $C_5$. The ester alkene has alpha carbon $X$, bearing Me and CO2Et, and beta carbon $Y$, bearing the protected carbon substituent. lithium diisopropylamide generates the ordinary ketone enolate at the saturated alpha carbon $C_5$. The acetonide is retained.

The carbon end of this enolate attacks ester beta carbon Y. Its pi system shifts through X onto the ester oxygen, forming the first new bond $C_5-Y$ and an ester enolate at X. That enolate now attacks the original cyclopentenone beta carbon $C_3$ intramolecularly, giving the second new bond $X-C_3$. The original enone electrons move onto its ketone oxygen, and protonation of the final ketone enolate completes the product. The OR substituent is retained at the new bridgehead; it need not leave in either Michael addition.

The atom map provides a useful structural check. Between bridgeheads $C_3$ and $C_5$, the three paths are $C_3-C_2-C_1-C_5$, $C_3-C_4-C_5$, and $C_3-X-Y-C_5$. Their numbers of internal atoms are 2, 1 and 2, establishing the norbornane skeleton. Both original carbonyls survive and both initial alkenes are consumed. The two successive conjugate additions give this atom map without requiring a concerted cycloaddition.

The new bridge is made by an intramolecular Michael addition. On the cyclohexanone side, the methyl-bearing fused alpha carbon is quaternary and cannot be deprotonated there. triethylamine can instead generate a small equilibrium population of the enolate at the other, methylene alpha carbon. Its carbon attacks the beta carbon of the enone in the seven-membered ring. The enone pi electrons move towards its carbonyl and then onto oxygen, creating the new bridge and a second enolate.

protonation of that enolate at the former methyl-substituted enone alpha carbon restores the left-hand ketone. The initial enone C=C has therefore become a saturated C–C bond while one new transannular C–C bond forms. Both ketones are retained, and the initial two-ring framework becomes a three-ring framework without changing the total index of hydrogen deficiency. The methyl originally at the fused quaternary centre does not migrate; the other methyl ends up on a protonated, formerly unsaturated carbon. A strong-base concentration large enough for quantitative enolate generation is unnecessary for a favourable intramolecular trapping reaction, and neither an aldol dehydration nor a methyl shift is needed.

The cyclohexanone enamine attacks the beta carbon of the cyclopentenone. Its nitrogen lone pair forms an iminium C=N bond as the enamine pi bond forms the new C–C bond; simultaneously the enone pi system shifts onto its oxygen. proton transfer converts the resulting cyclopentanone enolate back to the ketone.

A final iminium deprotonation regenerates an enamine, but the position of its double bond matters. Label the nitrogen-bearing cyclohexane carbon $h_1$, its initially nucleophilic neighbour $h_2$, and the other neighbour $h_6$. After addition, $h_2$ bears the cyclopentanone substituent. deprotonation at $h_6$ gives $h_1=h_6$, the less substituted, less hindered enamine drawn in A. Merely restoring the original $h_1=h_2$ bond would give a different regioisomer. Interconversion through the iminium ion permits this enamine regioisomerization under the reaction conditions. The methyl and mesylate substituents are spectators during this first Michael addition.

Pyrrolidine and 2-methylcyclohexanone first form an enamine, through carbonyl addition, carbinolamine formation, dehydration to an iminium ion, and alpha deprotonation. The less hindered enamine carbon is on the side opposite the methyl-bearing alpha carbon. It attacks the terminal beta carbon of methyl vinyl ketone, while the conjugated $\pi$ system shifts to oxygen. Protonation gives an alkylated iminium species; aqueous acid then hydrolyses it back to the ketone.

The result is a Michael addition product: the previously unsubstituted alpha carbon bears $-\mathrm{C}{\mathrm{H}}_2\mathrm{C}{\mathrm{H}}_2\mathrm{COC}{\mathrm{H}}_3$. In drawing the arrows, start the new C–C bond at the enamine carbon, not at nitrogen. The iminium bond is restored during addition and removed by hydrolysis. The sequence is an enamine-mediated conjugate addition, rather than direct addition to the methyl vinyl ketone carbonyl.

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 $(\mathrm{C}{\mathrm{H}}_2{)}_4\mathrm{NHBoc}$.

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 $\mathrm{BocNH}(\mathrm{C}{\mathrm{H}}_2{)}_4\mathrm{CHO}$. 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 $\mathrm{BocNH}(\mathrm{C}{\mathrm{H}}_2{)}_4\mathrm{CH}=\mathrm{CHCOMe}$.

Now add the enolate of a second acetone molecule in a Michael addition. With $R=(\mathrm{C}{\mathrm{H}}_2{)}_4\mathrm{NHBoc}$, 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 $\mathrm{P}{\mathrm{h}}_3\mathrm{P}=\mathrm{C}{\mathrm{H}}_2$. 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.

Open the lactone formally at its acyl–oxygen bond, then replace the resulting secondary alcohol by its ketone precursor. With $R=\mathrm{CH}(\mathrm{Me})\mathrm{CH}(\mathrm{Me}{)}_2$, the useful sequence of retrosynthetic intermediates isDisconnect the last compound as a Michael addition product of the methyl-side enolate of $\mathrm{RCOC}{\mathrm{H}}_3$ 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 $\mathrm{NaB}{\mathrm{H}}_4$ 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 $\mathrm{H}{\mathrm{O}}_2\mathrm{CCH}(\mathrm{Et})\mathrm{CH}(\mathrm{Me}{)}_2$. Disconnect the benzylidene acetal to a side chain $-\mathrm{C}{\mathrm{H}}_2\mathrm{CH}(\mathrm{OH})\mathrm{C}{\mathrm{H}}_2\mathrm{OH}$ 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 $\mathrm{BrC}{\mathrm{H}}_2\mathrm{CH}(\mathrm{OH})\mathrm{C}{\mathrm{H}}_2\mathrm{OH}$ 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 $-\mathrm{C}{\mathrm{H}}_2\mathrm{CH}(\mathrm{O}-)\mathrm{C}{\mathrm{H}}_2\mathrm{O}-$ 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 $\mathrm{Me}{\mathrm{O}}_2\mathrm{CCH}(\mathrm{Et})\mathrm{CHM}{\mathrm{e}}_2$. saponification gives $\mathrm{H}{\mathrm{O}}_2\mathrm{CCH}(\mathrm{Et})\mathrm{CHM}{\mathrm{e}}_2$; 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.

Use the nitro group as a masked carbonyl and a carbon nucleophile. The most informative disconnection reverses the six-membered aldol annulation. Before that closure, the cyclopentanone beta carbon bearsThe carbon carrying $\mathrm{N}{\mathrm{O}}_2$ will become the lower carbonyl of the final six-membered ring by a Nef reaction. It comes from the specified nitromethane. The remote methyl ketone supplies the upper methyl-substituted alkene carbon after aldol condensation.

First, use a mild base to generate a nitromethane-derived nitronate and add it conjugatively to the indicated cyclopent-2-en-1-one. Protonation gives 3-(nitromethyl)cyclopentanone. Deprotonate its nitromethyl group and perform a second Michael addition to methyl vinyl ketone, giving $\mathrm{cyclopentanone}-!C3-\mathrm{CH}(\mathrm{N}{\mathrm{O}}_2)\mathrm{C}{\mathrm{H}}_2\mathrm{C}{\mathrm{H}}_2\mathrm{COC}{\mathrm{H}}_3$. The nitro-stabilized carbon is appreciably more acidic than a simple ketone alpha carbon, permitting selective nitronate formation; control the acceptor stoichiometry to avoid a further Michael alkylation of the remaining nitro-bearing H.

Form the enolate/enamine at the cyclopentanone carbon between its carbonyl and the side-chain-bearing carbon. Intramolecular attack on the remote methyl ketone closes a six-membered ring; the two shared atoms are the original enone alpha and beta carbons. Hydrolysis if required and dehydration create the alkene between the original alpha carbon and the newly formed tertiary carbinol carbon. That carbinol carbon retains its methyl substituent, placing the methyl exactly as required. The original cyclopentanone carbonyl remains the carbonyl of the five-membered ring.

Finally, form the secondary nitronate and carry out controlled acidic Nef hydrolysis to replace its $\mathrm{CH}(\mathrm{N}{\mathrm{O}}_2)$ unit by $\mathrm{C}=\mathrm{O}$. The resulting fused product contains the two required ketones. Carrying out the annulation before exposing this second ketone reduces competing enolate/aldol pathways that would be available in the corresponding triketone. The nitro intermediate's competing deprotonation means that the aldol step needs conditions designed to access the ring carbonyl enolate/enamine; simply treating every carbonyl position as equally reactive would not establish the route.

The carbon ledger is $5$ from cyclopentenone, $1$ from nitromethane and $4$ from methyl vinyl ketone, giving the nine-carbon fused skeleton plus its methyl substituent. A primary-nitro Nef reaction performed before the second carbon alkylation would instead give an aldehyde and would lose this useful protected-carbonyl construction.

Open the cyclic ester at its acyl–oxygen bond. The resulting delta-hydroxy acid isOxidation-state reversal at the benzylic alcohol gives $\mathrm{H}{\mathrm{O}}_2\mathrm{C}-\mathrm{CH}(\mathrm{nPr})-\mathrm{C}{\mathrm{H}}_2-\mathrm{CH}(\mathrm{iPr})-\mathrm{C}(=\mathrm{O})\mathrm{Ph}$. This identifies the key Michael disconnection between the central $\mathrm{C}{\mathrm{H}}_2$ and $\mathrm{CH}(\mathrm{iPr})$ 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 $\mathrm{PhCOC}{\mathrm{H}}_2\mathrm{iPr}$ further to the indicated acetophenone. Crossed aldol addition to acetone followed by dehydration gives $\mathrm{PhCOCH}=\mathrm{CM}{\mathrm{e}}_2$; selective conjugate reduction or controlled alkene hydrogenation then gives $\mathrm{PhCOC}{\mathrm{H}}_2\mathrm{CHM}{\mathrm{e}}_2$. 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, $\mathrm{Et}{\mathrm{O}}_2\mathrm{CC}{\mathrm{H}}_2\mathrm{nPr}$, 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–$\mathrm{CH}(\mathrm{nPr})$–$\mathrm{C}{\mathrm{H}}_2$–$\mathrm{CH}(\mathrm{iPr})$–$\mathrm{CH}(\mathrm{Ph})$–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.

The terminal alkene of D first undergoes Wacker oxidation, giving the side chain $\mathrm{Ar}-\mathrm{C}{\mathrm{H}}_2-\mathrm{C}{\mathrm{H}}_2-\mathrm{COC}{\mathrm{H}}_3$. Alkene coordination to Pd(II), water attack, proton transfers and beta-hydride elimination give the ketone. Copper and oxygen regenerate the active palladium oxidation state.

Base removes a proton from the terminal methyl of that ketone. Its enolate attacks the neighboring aromatic aldehyde intramolecularly, closing a six-membered ring. Dehydration gives a conjugated cyclohexadienone-type intermediate, and keto-enol tautomerism furnishes aromatic naphthol E. The retained methoxy and MOM-protected oxygen groups follow the original aromatic-carbon positions.

F is the O-allyl ether of E. Carbonate forms the naphthoxide and allyl bromide undergoes an SN2 reaction at its terminal carbon. Heating F then causes a [3,3]-Claisen rearrangement: the O–allyl bond breaks, the terminal allyl carbon bonds to the adjacent naphthalene C1, and the phenolic carbon temporarily becomes a ketone. Rearomatization gives G, with a free phenolic OH and a C1 allyl group. The C1 position gives the favored alpha-substituted naphthol and avoids the alternative less favorable annulation pattern.

The final step is a dearomative Michael addition, not a Nef conversion of the nitro group. Hydrogen bonding from the thiourea activates nitroethylene. The nucleophilic C1 resonance form of G attacks the terminal carbon of $\mathrm{C}{\mathrm{H}}_2=\mathrm{CHN}{\mathrm{O}}_2$, and proton transfer converts the nitronate to a 2-nitroethyl substituent. The phenolic carbon becomes a ketone.

H is the corresponding 1-allyl-1-(2-nitroethyl)naphthalen-2-one, retaining the methoxy and MOM substituents of G. The second ring now has a C2=O group and a C3=C4 bond, while the other ring remains aromatic. The reported ${}^{13}$C signal near $202$ ppm is consistent with that newly formed ketone. Related dearomative additions establish this reaction class.^[ref]

C1 is now an all-carbon quaternary stereocenter bearing both allyl and 2-nitroethyl groups. Both the drawn thiourea and the starting materials are achiral, so H is racemic. A chiral catalyst would be needed to select one absolute configuration.

A consistent proposed sequence is desilylation, five-membered hemiketal formation, retro hetero-Diels–Alder opening, intramolecular aldol addition and hemiacetal closure. The essential carbon rearrangement is loss of the original ketone–side-chain bond and formation of a bond between its two neighbouring carbons; it is not a simple Michael addition.

For an explicit atom map, label the starting six-membered ring $A-B=C-D-E-O_r-A$, with the ketone at $D$, methyl substituents at $A$ and $B$, the hydroxy group at $A$, and the side chain $E-X-T-\mathrm{Et}$. Here $X$ is the methylene and $T$ is the carbon bearing the protected alcohol. Let $O_D$ be the original ketone oxygen and $O_T$ the protected alcohol oxygen. These labels identify atoms, not new substituents.

First, Fluoride removes the silyl protecting group from $O_T$. The resulting alcohol attacks the protonated ketone at $D$, forming the five-membered hemiketal $D-E-X-T-O_T-D$. The original oxygen $O_D$ is now a hydroxy group; the original pyran ring remains intact at this stage.

Next, The original pyran ring can undergo a retro hetero-Diels-Alder reaction. The three electron-pair movements are $B=C\to C=D$, $D-E\to E=O_r$ and $O_r-A\to A=B$: break $D-E$ and $O_r-A$, and form the three indicated double bonds. The result is the tethered aldehyde/dienol esterThe temporary $D-O_T$ bond keeps both reacting ends within the same molecule. At $D$, both oxygen substituents remain attached, and the new $D-O_T$ tether prevents separation into independent fragments.

Then The $C=D$ enol attacks the tethered aldehyde at $E$. Formation of $C-E$, restoration of $D=O_D$, and proton transfer give the six-membered lactone ring $C-D-O_T-T-X-E-C$, with $E-O_{r}H$. This is an intramolecular aldol reaction, and it supplies the crucial new carbon–carbon bond without losing any carbon atom.

Finally, Keto-enol tautomerism at $A=B$ gives the methyl ketone at $A$ and introduces the hydrogen at $B$. The $E-O_{r}H$ alcohol then attacks that ketone, closing the five-membered hemiacetal ring $A-B-C-E-O_r-A$. The resulting fused rings have exactly the product's connectivity: $D$ is the lactone carbonyl, $O_T$ is its ring oxygen, and $O_r$ is the five-membered-ring oxygen.

The stereocentre at $T$ survives throughout this sequence. The configuration initially at $E$ is erased at the aldehyde stage, and those at $A$, $B$, $C$ and $E$ arise during the later cyclization and proton-transfer steps. A folded intramolecular aldol reaction followed by reversible hemiacetal formation is consistent with the drawn cis ring junction, but connectivity and orbital bookkeeping alone do not prove that it is the unique selected diastereomer. In particular, a claim of simple retention at $E$ would contradict this atom map.

A related pyranone-to-fused-lactone rearrangement under aqueous hydrogen fluoride is experimentally reported; that account also explicitly qualifies the relative stereochemistry as assigned on mechanistic grounds. The sequence above is a proposed explanation of the examination structure, rather than a mechanism claimed to have been experimentally established in that paper.^[ref]

A Robinson annulation combines a Michael addition with an intramolecular aldol reaction and dehydration. Tracking the atoms shows which carbonyl survives and which new bond closes the six-membered ring.