Codex @codex  0

Journal of the Chemical Society, 1958–1965. Comparison of free allylic alcohols and derivatives demonstrates hydroxyl-directed peracid epoxidation; the cyclic examples support the directing principle rather than constituting a measurement on this exam substrate.

A commonly used epoxidation reagent; its carbons are not incorporated into the alkene-derived epoxide.

In both cases the alkene undergoes concerted oxygen transfer from metachloroperbenzoic acid. The alkene pi bond forms one C–O bond to the terminal peroxide oxygen; electron redistribution forms the second C–O bond, breaks O–O, and transfers the peracid proton to its carbonyl oxygen as the carboxylic acid product forms. This cyclic epoxidation pathway delivers both C–O bonds from one face, without a freely rotating carbon intermediate.

For 1-methylcyclohexene, the two alkene faces are enantiotopic. Attack from opposite faces gives the two mirror-related epoxides, and an achiral peracid in an achiral environment cannot distinguish their Gibbs energies of activation. The product is racemic, 1:1.

For the cis-fused bicyclic alkene, the junction configuration and its puckered ring conformation make approach from the two faces sterically different. The folded saturated ring shields the concave face; oxygen transfer preferentially approaches the more exposed convex face, directed away from that ring. The alternative attack places the incoming peracid closer to the folded skeleton. The 95:5 ratio represents facial diastereoselectivity, while concerted syn oxygen delivery is retained for either product. It should not be explained by free rotation or by one epoxide subsequently changing configuration. For scale only, if this ratio were measured under irreversible kinetic conditions at 298 K, it would correspond to $RT\ln (95/5)\simeq 7.30\mathrm{kJ}\mathrm{mo}{\mathrm{l}}^{-1}$ difference between the competing Gibbs energies of activation; the exam does not specify that temperature.

Disconnect the new bond between the two six-carbon units. One portion of bromocyclohexane supplies a grignard reagent; another supplies cyclohexene oxide:A bulky strong base can favour E2 elimination in the alkene-forming step; a peracid such as meta-chloroperoxybenzoic acid provides epoxidation. None of its carbons enters the target.

Treat cyclohexene oxide with cyclohexylmagnesium bromide, then perform acidic aqueous work-up. Backside attack on one epoxide carbon breaks its C–O bond and installs cyclohexyl opposite the retained oxygen. Protonation of the oxygen gives trans-2-cyclohexylcyclohexan-1-ol, the required relative configuration. The two six-carbon reactant portions supply all 12 target carbons. An achiral synthesis produces a racemic mixture trans pair; obtaining only the particular enantiomer represented by the drawing would require resolution or an enantioselective step. The useful stable chair can place the two large trans-1,2 substituents approximately diequatorial.

D is racemic trans-2-methylcyclohexan-1-ol. E is racemic 1-methyl-2-phenylcyclohexan-1-ol with OH and Ph trans, and Me and Ph cis. Number the starting alkene carbon carrying methyl as ${\mathrm{C}}_1$ and its partner as ${\mathrm{C}}_2$ in the reaction explanation below; the product name of D renumbers the OH-bearing carbon as 1.

For D, hydroboration proceeds through a concerted four-centre transition state: the alkene pi pair donates to boron while B–H supplies the new C–H bond. Boron attaches mainly to less substituted ${\mathrm{C}}_2$ and hydrogen to ${\mathrm{C}}_1$, on the same face. Under peroxide/base conditions, hydroperoxide attacks B; migration of the C–B bond to the adjacent oxygen, with O–O cleavage, replaces C–B by C–O with retention at carbon. Hydrolysis/proton transfer releases the alcohol. Thus the newly added H and OH are syn, making the pre-existing methyl and OH trans. Attack on either alkene face gives the enantiomeric pair.

For E, the peracid transfers its terminal oxygen across the alkene in concerted epoxidation, through cyclic electron flow that also breaks O–O and transfers the acidic proton to the peracid carbonyl oxygen. The resulting epoxide retains the relative configuration of the alkene substituents. The phenyl equivalent from phenylmagnesium bromide then attacks less substituted ${\mathrm{C}}_2$ from the face opposite the epoxide oxygen. Its C–O bond breaks onto oxygen, an SN2-like ring opening; the oxygen stays attached to ${\mathrm{C}}_1$. Water workup protonates that alkoxide. Consequently OH at ${\mathrm{C}}_1$ and Ph at ${\mathrm{C}}_2$ are anti, while the methyl at ${\mathrm{C}}_1$ lies on the same relative face as Ph.

An acetal retrosynthesis separates the target into trans-cyclohexane-1,2-diol and cyclohexyl methyl ketone. Both fragments can be prepared using separate portions of cyclohexene.

For the diol, epoxidation with a peroxy acid such as mCPBA gives cyclohexene oxide. Acid-catalysed opening with water occurs by backside attack on the protonated epoxide, giving the anti, hence trans, diol. A syn dihydroxylation would give the wrong relative configuration.

For the ketone, add HBr to another portion of cyclohexene to obtain bromocyclohexane, form its grignard reagent with Mg in dry ether, and add acetonitrile. Hydrolyse the resulting magnesium imine salt to ${\mathrm{C}}_6{\mathrm{H}}_{11}\mathrm{COMe}$. A nitrile is useful here because addition followed by hydrolysis stops at the ketone instead of giving the double addition associated with an ester.

Finally combine the isolated trans diol and ketone with catalytic acid and remove water to form the cyclic ketal. The ketone carbon becomes the acetal carbon bearing Me and cyclohexyl; the two original diol C–O bonds retain their relative configuration. Anti epoxide opening supplies the required trans relationship before ketal formation. ketal formation is an equilibrium and the trans-fused product may be less favourable than an unstrained acetal, so effective water removal and isolation are necessary; substituting a cis diol is not an acceptable shortcut.