Q4(a). Acid-catalysed Wagner–Meerwein aromatisation (duocarmycin B2 unit)

Introduction. The substrate is a reduced duocarmycin B2 derivative: its left-hand five-membered ring is an indoline with a quaternary C-2 (Me, CO₂Me, NH) and a secondary benzylic alcohol at C-3. In strong acid the alcohol ionises, a group on C-2 migrates to C-3 and the ring loses a proton to become an aromatic pyrrole (indole) ring. This dehydrative 1,2-shift is a Wagner–Meerwein rearrangement.

Scheme: Protonation of the C-3 OH and loss of water give a benzylic cation, stabilised by the electron-rich arene.

Scheme: The methoxycarbonyl group moves from C-2 to C-3; the cation at C-2 is an iminium ion; loss of the C-3 proton makes the pyrrole ring aromatic.

1. Ionisation. CH₃SO₃H protonates the C-3 hydroxyl; water leaves and gives a secondary benzylic cation at C-3, stabilised by the aromatic ring, which carries the donor N–R group (RDS).
2. 1,2-Shift. A group on the adjacent quaternary C-2 migrates with its bonding pair to C-3 (Wagner–Meerwein shift). The group that moves is the methoxycarbonyl group. The positive charge is now on C-2, next to the ring NH, so it is an iminium ion (C=N+H), much more stable than the benzylic cation.
3. Why CO₂Me and not Me migrates. Moving CO₂Me leaves the electron-donating CH₃ on the cationic C-2, where it stabilises the iminium ion; moving CH₃ would leave an electron-withdrawing ester on the carbon bearing the positive charge. An acyl group also migrates easily because its C=O π system helps bridge the two carbons in the transition state.
4. Aromatisation. Loss of the C-3 proton gives the aromatic pyrrole ring of an indole. This large gain in stability is the driving force: the reaction is irreversible.
5. Product A. The pyrrolo[3,2-e]indole with 2-methyl and 3-methoxycarbonyl groups on the new pyrrole ring; the CH₂Br, N–R and the 4-methylpiperazine carbamate are unchanged. C-2 and C-3 are no longer stereocentres. (This is the step that converts reduced duocarmycin B2 into the antitumour prodrug KW-2189.)

Why methanesulfonic acid

1. It is a strong acid (comparable with H₂SO₄), so it ionises a secondary alcohol at only 50°C.
2. Its conjugate base, mesylate, is non-nucleophilic: it does not trap the benzylic cation (HCl or HBr would give the benzylic halide) and does not displace bromide from the CH₂Br group.
3. It is non-oxidising and can be used anhydrous in dichloroethane; no water is present to hydrolyse the methyl ester or the carbamate, as aqueous mineral acids would.
4. 2.5 equivalents are needed because the basic N-methylpiperazine nitrogen (and partly the ring nitrogens) take up acid first; the excess acid catalyses the rearrangement.

Conclusion. A is the aromatic pyrrolo-indole carrying 2-CH₃ and 3-CO₂CH₃ (CH₂Br, N–R and the carbamate unchanged). It forms by a Wagner–Meerwein rearrangement (dehydration, 1,2-ester shift to an iminium ion, aromatisation). CH₃SO₃H is a strong, non-nucleophilic, non-oxidising acid that works in dry organic solvent.

Application. The duocarmycins and CC-1065 are DNA-alkylating antitumour agents; converting the unstable natural product into a stable aromatic seco form, as here, is how the clinical prodrug KW-2189 was made.