Past exam of the chemistry course of the year 4 of the natural sciences course of the University of Cambridge / 2022 / Paper 1 / 6

This is an Ireland–Claisen rearrangement. Number the ester carbonyl carbon $C_0$, its enolizable carbon $C_{\alpha }$, and the three allylic ring carbons $C_1-C_2=C_3$, starting at the carbon bearing the ester oxygen.

lithium hexamethyldisilazide removes an $\alpha$ proton and trimethylsilyl chloride traps the oxygen of the resulting ester enolate, giving a silyl ketene acetal. Heating permits a six-electron, [3,3]-sigmatropic rearrangement through the arrayThe electron-pair movements are $\pi (C_{\alpha }=C_0)\to C_0=O$, $\sigma (O-C_1)\to \pi (C_1=C_2)$, and $\pi (C_2=C_3)\to \sigma (C_3-C_{\alpha })$. Acidic work-up cleaves the silyl ester to the carboxylic acid. The benzyl ether remains a protecting group; it is not the migrating bond.

The suprafacial reaction transfers the starting allylic stereochemistry to $C_3$, where the new side chain is delivered from the original oxygen face. In the product's printed orientation, the new C${}_3$–C${}_{\alpha }$ bond is behind the ring and the C${}_3$ methyl group is toward the viewer. At that ring star, the Cahn-Ingold-Prelog priority rules orders the groups as side chain, alkenyl ring direction, saturated ring direction, methyl, giving $R$.

The second star is $C_{\alpha }$. Its priorities are carboxyl, substituted ring carbon, $\mathrm{C}{\mathrm{H}}_2\mathrm{C}{\mathrm{H}}_2\mathrm{OBn}$, H. A chair-like transition state normally places the bulky side chain pseudoequatorial. However, its absolute configuration also depends on the E/Z geometry of the trapped silyl ketene acetal: opposite geometries give opposite configurations at this star under the same suprafacial ring transfer. The printed conditions do not state solvent or the ketene-acetal geometry. Thus the secure assignment is the ring-star $R$ configuration and conditional $\alpha$-star stereochemistry, rather than an unqualified absolute assignment to both stars. Drawing the assumed ketene-acetal geometry and its chair is necessary before selecting one $\alpha$ epimer.

A is the kinetic, less-hindered-side silyl enol ether. Its double bond lies away from the methyl substituent. Forming B requires removal of a proton from the more hindered $\alpha$ position adjacent to the methyl-bearing carbon.

The base strengths alone do not determine the ratios. trimethylsilyl triflate is strongly electrophilic: oxygen silylation activates the ketone towards deprotonation, and irreversible trapping of the resulting silyl enol ether can make the product ratio reflect competing deprotonation rates. A weak amine therefore need not first produce a substantial equilibrium concentration of the free ketone enolate.

DBU is the strongest and comparatively accessible base, and distinguishes the two sites least strongly, giving the smallest A:B ratio. Triethylamine gives greater preference for the less-hindered site. The more sterically hindered diisopropylethylamine discriminates most strongly and gives the largest proportion of A. Its slightly higher conjugate-acid $p{K}_a$ than that of triethylamine does not reverse this trend, because steric accessibility and the coupled silylation/deprotonation mechanism matter alongside basicity. The data do not establish a simple thermodynamic enolate distribution.

The key sequence is deprotonation, anionic eight-pi electrocyclization, then elimination. Label the conjugated route from the lower cyclopentene to the right cyclopentene aswhere $C_3$ is the methylene joining the lower ring to the central alkene, and $C_4$ carries the $\mathrm{C}{\mathrm{H}}_2\mathrm{OC}(\mathrm{O})\mathrm{NM}{\mathrm{e}}_2$ substituent.

potassium hexamethyldisilazide removes a proton at $C_3$. The resulting anion is delocalized over the seven-carbon array: its six pi-bond electrons plus the lone pair make an eight-electron system. Thermal electrocyclic reaction is disrotatory for this $4n$ electron count. Joining $C_1$ and $C_7$ forms the seven-membered central ring and puts the remaining anionic character at $C_4$, with double bonds at $C_2=C_3$ and $C_5=C_6$.

That $C_4$ anion then forms $C_4=C{H}_2$, expelling the O-dimethylcarbamate group from the attached methylene. This E1cb elimination supplies the exocyclic methylene and explains why no oxygen remains in the depicted product. The disrotatory closure, with the cyclopentene ends folded to avoid unfavorable overlap, gives the trans relationship between the two lower fused-ring bonds shown by the wedge and dash. A simple [3,3] rearrangement would not create the required bond between the two remote cyclopentene termini.