Past exam of the chemistry course of the year 4 of the natural sciences course of the University of Cambridge / 2022 / Paper 2 / Section F / 29

DBU removes the proton $\alpha$ to sulfonium, generating the propargyl-substituted sulfur ylide $\mathrm{M}{\mathrm{e}}_2{\mathrm{S}}^{+}-\mathrm{C}{\mathrm{H}}^{-}\mathrm{C}\equiv \mathrm{CMe}$. Its carbon attacks the enone $\beta$ carbon bearing indolyl, shifting the conjugated electrons into an enolate. The new intermediate has the carbon sequence ${\mathrm{O}}^{-}-\mathrm{C}(\mathrm{Ph})=\mathrm{C}(\mathrm{CN})-\mathrm{CH}(\mathrm{indolyl})-\mathrm{CH}(\mathrm{SM}{\mathrm{e}}_2^{+})(\mathrm{C}\equiv \mathrm{CMe})$.

Intramolecular attack by the enolate oxygen on the sulfonium-bearing carbon displaces dimethyl sulfide and closes a five-membered ring. This conjugate addition–O-alkylation sequence gives the dihydrofuran, retaining the C≡CMe substituent and placing the original carbonyl oxygen in the ring. Enolate carbon alkylation would instead give a cyclopropane; the observed oxygen-containing ring identifies the alternative closure. An approach and betaine conformation minimizing crowding between indolyl and alkynyl substituents, followed by stereoinverting displacement at the sulfonium carbon, rationalizes the depicted trans product. The result is racemic in the absence of an external chiral influence.

The first two operations invert the allylic hydroxyl group. Triphenylphosphine adds to the azodicarboxylate, generating the reagent pair that converts the alcohol into an alkoxyphosphonium leaving group. Benzoate displaces it with inversion at carbon, giving the inverted benzoate ester. Methoxide then cleaves that ester by nucleophilic acyl substitution, retaining the newly inverted carbon–oxygen stereochemistry because cleavage occurs at the acyl group, not by substitution at the stereogenic carbon.

The inverted allylic alcohol exchanges with the orthoacetate under acid catalysis. Ethanol loss produces an allyl ketene acetal, schematically $\mathrm{C}{\mathrm{H}}_2=\mathrm{C}(\mathrm{OEt})-\mathrm{O}-(\mathrm{allyl})$. A six-membered suprafacial Johnson-Claisen rearrangement breaks the allylic C–O bond, shifts the ring alkene by one position and forms the new bond from the original alkene terminus to the ketene-acetal CH${}_2$. The result is the $-\mathrm{C}{\mathrm{H}}_2\mathrm{C}{\mathrm{O}}_2\mathrm{Et}$ substituent at the carbon that was the remote end of the original double bond. A chair-like transition state placing the larger substituents away from axial crowding explains the stereochemical transfer; the inverted alcohol configuration selects the corresponding face.

Finally, TiCl${}_4$ activates the anomeric methoxy group and methoxide departure creates an oxocarbenium ion. Hydride transfer from triethylsilane replaces that methoxy substituent by hydrogen. The ring oxygen and pendant OTBS group remain intact. The sequence is inversion, stereospecific allylic rearrangement, then reductive removal of the anomeric methoxy group, rather than direct reduction or hydrolysis of the ester introduced by the Claisen step.

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]