Q6(a). Hydroxyl-directed epoxidation: mCPBA versus V(acac)₂/TBHP

Introduction. An allylic OH can steer an epoxidising agent to its own face of the C=C (directed epoxidation). How strongly it steers depends on the reagent and on whether the OH is pseudo-axial or pseudo-equatorial in the half-chair of the cyclohexene.

Scheme: mCPBA (left): syn major + anti minor. V(acac)₂/TBHP (right): syn only. Syn = epoxide O on the same face as OH (and trans to tert-butyl). Each product is racemic.

Conformation of the substrate

1. The bulky tert-butyl group at C-4 must be pseudo-equatorial; it locks the half-chair.
2. OH (C-1) and tert-butyl (C-4) are trans: in this half-chair the OH is also pseudo-equatorial.
3. The C=C (C-2, C-3) lies between them. Its face syn to OH is the face anti to tert-butyl.

V(acac)₂/TBHP: one product

1. Vanadium exchanges a ligand for the allylic alkoxide and binds ᵗBuOO⁻; the peroxide oxygen is held on the metal next to the C=C.
2. O is delivered intramolecularly to the face of the alkene that carries the OH: syn epoxide only.
3. The O–V link is a covalent tether (metal alkoxide), far firmer than a hydrogen bond, and the metal can reach the face of the C=C syn to OH from this pseudo-equatorial OH as well (delivery is most effective of all with a pseudo-axial OH). The tert-butyl group sits on the opposite face and does not oppose it.
4. Product: (1R*,2R*,3S*,4S*)-4-tert-butyl-2,3-epoxycyclohexan-1-ol, the epoxide cis to OH, a single diastereomer (racemic).

mCPBA: two isomers

1. The peracid is directed only by an O–H…O hydrogen bond from the allylic OH to the peracid (Henbest): a weak, transient contact, not a bond to the reagent.
2. Undirected attack on the other face competes, so the H-bond steering is only partial.
3. Both faces are therefore attacked: the syn (cis) epoxide (still the major product, as the tert-butyl hinders the other face) and the anti (trans) epoxide, a mixture of two diastereomers.

Conclusion. V(acac)₂/TBHP coordinates the alkoxide and the peroxide and delivers O to the OH face: one product, the syn (cis) epoxy alcohol. mCPBA is steered only by a weak hydrogen bond: syn + anti epoxy alcohols.

Application. Vanadium- and titanium-catalysed directed epoxidations are used in terpene and steroid synthesis; the Sharpless asymmetric epoxidation (Ti(OⁱPr)₄, diethyl tartrate, TBHP) extends the idea to enantioselective epoxidation of allylic alcohols.