Osmium tetroxide adds to the alkene through a concerted cyclic addition, giving a five-membered osmate ester with both C-O bonds on the same face. Hydrolysis releases the vicinal diol; NMO reoxidizes reduced osmium so that OsO can be catalytic.
The two new hydroxyl groups are therefore syn. For the drawn substrate, approach opposite the two existing solid-wedge substituents is less crowded: draw both new C-OH bonds dashed, while retaining the solid-wedge COBn and NHBoc bonds. The major diol is cis at its two new centres and anti to the pre-existing substituted face.
Syn delivery is the stereospecificity of cyclic osmylation; preference for one of the two diastereotopic alkene faces is substrate-controlled diastereoselectivity. Attack from the other face would still be syn but would give the minor diastereomer.
The hydroxylactam is a cyclic hemiaminal. Its alkoxide can open to the corresponding aldehyde/amidate, in its protonated representation. This exposes an aldehyde without reducing or replacing the lactam carbonyl.
The ketophosphonate anion attacks that aldehyde. Formation and collapse of the phosphorus-containing intermediate give the predominantly E enone and phosphate by Horner-Wadsworth-Emmons reaction. The amide nitrogen then closes by intramolecular aza-Michael addition at the enone beta carbon. Protonation of the ketone enolate gives the observed five-membered lactam with a substituent.
A folded, relatively unencumbered closure places OBn and the developing side chain in outward-facing positions; the expected major product has OBn and the C5 acetonyl substituent cis. With the OBn wedge retained, show the new C5–CHCOCH bond as a solid wedge. The closure is diastereoselective, while the original wavy hemiaminal centre is erased by aldehyde formation. This facial prediction rests on the preferred folded conformer rather than retention of either starting hemiaminal epimer.
This is a thermal Claisen rearrangement followed by intramolecular acetal exchange. Identify the six-atom array as the cyclopentenone enol-ether C=C–O–CH–C=C unit. In its concerted rearrangement:
- The O–CH bond breaks.
- A new C-C bond joins the other end of the cyclopentenone enol double bond to the cyclohexene carbon bearing CH(OEt).
- The former ether-bearing cyclopentene carbon becomes a ketone, and the cyclohexene double bond becomes the exocyclic methylene.
The intermediate is thus a substituted cyclopentane-1,3-dione, with the acetal tether now correctly placed for six-membered-ring closure. Its enol oxygen attacks the acetal carbon, replacing OEt and releasing ethanol. Enolization gives the conjugated cyclic enol ether drawn in the product; the second ethoxy group remains.
A chair-like Claisen rearrangement transition structure with the phenyl-bearing part of the cyclohexane directed outward avoids severe axial crowding. Suprafacial bond formation and the pre-existing configuration give the two indicated ring-junction hydrogens on opposite faces: the left H is a wedge and the right H a dash in the supplied orientation. Closure favors the acetal epimer with outward OEt, drawn as a wedge, while the original Ph remains dashed. This is substrate-controlled diastereoselection followed by conformationally selective acetal closure, rather than independent arbitrary assignment of three centres.
First the tertiary amine attacks the primary allylic bromide carbon by SN2 reaction, giving the quaternary ammonium salt. The less hindered nitrogen face is favored by the pre-existing fused-ring stereochemistry.
DBU removes the proton at the carbon alpha to both the ammonium nitrogen and the ester carbonyl. The resulting ammonium ylide undergoes a concerted 2,3-sigmatropic rearrangement: the N–CH(allyl) bond breaks, a bond forms between the ylide carbon and the aryl-bearing terminal allyl carbon, and the double bond moves to give . Nitrogen becomes neutral again. An ordinary alkyl substitution would attach the wrong end of the allyl unit.
An envelope-like five-membered transition structure keeps Ar outside the crowded bicyclic framework. With the pre-existing OMe dash and ring-junction geometry fixed, place the newly installed side chain on the solid-wedge face at the former ylide carbon and choose the benzylic configuration that places Ar outward, as in the displayed intermediate. This is diastereoselective, suprafacial allyl transfer.
Finally methanesulfonic acid protonates the methyl acetal. Methanol leaves to give an oxocarbenium/iminium-stabilized electrophilic centre, which is attacked intramolecularly by the electron-rich arene at its available ortho position. Deprotonation restores aromaticity and closes the bridge. The terminal isopropenyl group survives; it is not the bond consumed in this final Intramolecular Friedel-Crafts reaction. The constrained tether selects the displayed bridged diastereomer.
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