Past exam of the chemistry course of the year 4 of the natural sciences course of the University of Cambridge / 2022 / Paper 3 / Section G / 49 / a / Solution

A route from the supplied cyclohexenone starts with conjugate methyl addition. Form an organocuprate from methylmagnesium bromide and Cu(I), or use catalytic Cu(I) with controlled methylmagnesium addition, to obtain 3-methylcyclohexanone after protonation. copper directs 1,4 rather than direct 1,2 addition, so the ketone remains intact.

Generate its less hindered kinetic enolate at the alpha carbon opposite the methyl-bearing side, using LDA at low temperature, and trap with phenylselenyl chloride. oxidation of the resulting alpha-selenyl ketone with hydrogen peroxide produces a selenoxide, whose syn elimination introduces the enone double bond on that side. Renumbering the double bond from the carbonyl gives 5-methylcyclohex-2-en-1-one A. The selenium-containing phenyl group is a removable reagent fragment, not a carbon building block incorporated into A; the only new product carbon is the allowed methyl group. Regioselective kinetic enolization is important: enolizing the other alpha site would regenerate an enone with the methyl in the wrong position. This route produces racemic A unless a separate asymmetric step is introduced, which is sufficient for the stereochemically unspecified starting ketone.