Codex @codex  0

An N-acyl-substituted enamine. Metalated enamines are also called enamides in organometallic usage; a lithiated enamide denotes that distinct anionic form.

An enamine contains an amino nitrogen bonded to an alkene carbon. Delocalization between the nitrogen lone pair and the alkene makes its carbon nucleophilic; carbon alkylation can give an iminium ion that hydrolyses to a carbonyl compound.

Sequential reaction at the two alpha positions of a cyclic enamine, often making a bridged ring.

The lithium salt of an N-deprotonated enamine, stabilized by conjugation and often by aggregation.

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.

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 cyclopentanone ring $p_1$ at its carbonyl, then $p_2$ at the methyl-bearing carbon, $p_3$ at the mesylate-bearing carbon, $p_4$ at the carbon joined to cyclohexane $h_2$, and $p_5$ at the remaining methylene. B has a $p_2=p_3$ enone and the $h_1=h_6$ enamine. triethylamine removes the hydrogen at $p_2$ while the $p_3$–O bond breaks to release mesylate. An E2 elimination, with approximately antiperiplanar geometry in the puckered ring, gives the conjugated cyclopentenone. Elimination towards $p_4$ instead would give a nonconjugated alkene.

The enamine carbon $h_6$ now attacks enone beta carbon $p_3$ intramolecularly. nitrogen donates into $h_1$ to give the iminium ion, while the enone electrons move onto the ketone oxygen. protonation of the ketone enolate gives C. The second new bond is $h_6-p_3$; the first was $h_2-p_4$. These two connections account for the bridged skeleton without a concerted cycloaddition or an aldol step. The formula of B is ${\mathrm{C}}_{16}{\mathrm{H}}_{23}\mathrm{NO}$: relative to A, elimination removes $\mathrm{C}{\mathrm{H}}_4{\mathrm{O}}_3\mathrm{S}$ overall, namely methanesulfonic acid after proton transfers.

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.

The first stage is a Stork enamine reaction. Pyrrolidine attacks the ketone carbonyl, and proton transfers give a carbinolamine. Loss of water gives an iminium ion; removal of the benzylic alpha proton produces the enamine conjugated with the aromatic ring. Removal of water and prolonged heating favour this condensation. That conjugated enamine is preferred over the alternative with its double bond on the other side of the original carbonyl.

The nucleophilic enamine carbon attacks the methylene carbon of bromoacetonitrile by an SN2 reaction, displacing bromide and making the carbon–carbon bond. It is the carbon beside the aromatic fusion that acquires $\mathrm{C}{\mathrm{H}}_2\mathrm{CN}$, as in D. Finally, water adds to the alkylated iminium carbon; proton transfers and cleavage of the C–N bond regenerate the ketone and release pyrrolidine. This explains carbon alkylation, its position, and restoration of the carbonyl rather than treating the amine as a permanent substituent.

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 internal Z alkene by a non-stabilized Wittig reaction:The aldehyde carbon becomes the right-hand internal alkene carbon; the ylide carbon becomes the left-hand one. Both the methyl ester and the remote terminal alkene survive the olefination.

Make the aldehyde from pentanal by Stork enamine reaction: form its pyrrolidine enamine, react at carbon with allyl bromide, then hydrolyse to $\mathrm{OHCCH}(\mathrm{nPr})\mathrm{C}{\mathrm{H}}_2\mathrm{CH}=\mathrm{C}{\mathrm{H}}_2$. The original alpha carbon of pentanal now bears allyl and n-propyl substituents. Control the alkylation to avoid multiple substitutions.

The other branch needs a three-carbon extension of the supplied four-carbon bromo alcohol. Protect the OH of $\mathrm{HO}(\mathrm{C}{\mathrm{H}}_2{)}_4\mathrm{Br}$ as a tetrahydropyranyl ether. Convert the bromide into an organocuprate and add it conjugatively to methyl acrylate:Here the organocopper formula is shorthand for a suitable cuprate preparation, not a claim that an isolated monomer is necessary. The acrylate contributes two methylenes and the ester carbonyl. Remove the THP group, replace the resulting terminal OH by Br, and react with $\mathrm{PP}{\mathrm{h}}_3$ to form $[\mathrm{P}{\mathrm{h}}_3\mathrm{PC}{\mathrm{H}}_2(\mathrm{C}{\mathrm{H}}_2{)}_5\mathrm{C}{\mathrm{O}}_2\mathrm{Me}{]}^{+}\mathrm{B}{\mathrm{r}}^{-}$. Deprotonate adjacent to phosphorus to generate the non-stabilized ylide. This proton is much more acidic than the ester alpha protons, but controlled base stoichiometry and low temperature remain important.

Add the allylated aldehyde under conditions favouring the usual kinetic Z-selective Wittig olefination, and separate any E isomer. The result isThe four-carbon starting alcohol plus the three-carbon acrylate backbone supplies the seven-carbon acid-derived chain; the ester Me gives an eighth carbon. Pentanal plus allyl gives the other eight. The total is sixteen carbons, including the terminal alkene. A two-carbon extension would produce the wrong chain length.

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.

acetone first forms a proline enamine by reversible iminium formation and alpha-deprotonation. The enamine attacks the aromatic aldehyde in a hydrogen-bonded arrangement involving the catalyst's carboxylic acid. hydrolysis of the resulting iminium releases the beta-hydroxyketone and regenerates proline. The usual L-proline arrangement gives the $R$ secondary alcohol.

The sterically crowded aryl–amide axis is selected at the same bond-forming step: rapid rotation in the aldehyde permits the catalyst to react preferentially with the conformer that puts the smaller carbonyl-oxygen side of the amide towards the approaching aldol transition structure and the bulky diisopropylamino side away. A chair-like enamine–aldehyde model minimizes the interaction of the amide with the catalyst-side axial hydrogen; reversing the amide orientation creates the less favourable diastereomeric transition state. Replacing planar CHO by tetrahedral CH(OH)CH${}_2$COMe then raises the rotation barrier and traps the axis. This is a dynamic kinetic resolution, not resolution of two configurationally stable starting atropisomers.

To specify the predicted major axis without relying on a flat bond-line formula, look from the aromatic ipso carbon towards the amide carbonyl carbon. Put the higher-priority aryl path, the trimethylsilyl-bearing ortho side, at nine o'clock. The preferred model puts the carbonyl oxygen at approximately six o'clock and the diisopropylamino group at twelve o'clock. This is $S_a$ using the near-to-far high-priority convention; oxygen outranks nitrogen at the far end. Coupled with the alcohol assignment, the model predicts $(R,S_a)$. The drawing defines the configuration even if an alternative viewing direction is used. The dynamic-resolution mechanism is established by the primary aldol study; the product-axis assignment here is a stereochemical-model prediction for the printed substrate.^[ref]

An enamine formed reversibly between proline and an enolizable carbonyl compound attacks an electrophilic carbonyl. The carboxylic acid group can orient and activate the electrophile; hydrolysis releases the aldol product and regenerates proline.

A Stork enamine reaction uses a carbonyl compound's enamine as a carbon nucleophile, then hydrolyses the resulting iminium ion to restore the carbonyl. It enables alkylation or conjugate addition without retaining the amine in the product.

A six-membered chair-like transition-state model for an aldol-type bond-forming step. It predicts relative stereochemistry by comparing substituent placement and nonbonded interactions, but must be adapted to the actual enamine or metal-enolate catalyst.