In spite of the concise nature of this synthetic sequence, the poor selectivity again observed in the reduction of the initially formed dienamine cycloadduct prompted us to consider the alternative intermolecular asymmetric cycloaddition strategy. We identified 4-bromo-TDO 14d (as used in the synthesis of 15p, Fig. ) as a potential candidate for this route, since its bromine substituent would protect the corresponding thiophene from unwanted dimerisation during oxidation and could also likely be removed under mild conditions later in the synthesis. We were pleased to find that the intermolecular cycloaddition of N-Boc tryptamine 17 with 14d (used directly from oxidation of thiophene 18) afforded a single diastereomer of dihydrocarbazole 19. In situ addition of trifluoroacetic acid effected Boc deprotection and triggered cyclisation of the tryptamine sidechain onto the dienoyl motif, giving a single diastereomer of the pyrrolidine product 20 in 57% yield (from 18) after a basic workup. We found that the allylic bromide resident in 20 could then be selectively cleaved by hydrogenolysis without reduction of the adjacent alkene; attachment of the vinyl iodide sidechain 10 smoothly afforded 16, thus intercepting the intramolecular cycloaddition route, but now with perfect control of stereochemistry at the three contiguous stereocentres within the tetracycle. To complete the asymmetric synthesis of akuammicine, the camphorsultam amide underwent methanolysis to the corresponding ester (-)-12 (67%), with the camphorsultam moiety recovered in high yield. Heck cyclisation of (-)-12 proceeded in 75% yield to afford (-)-akuammicine. This synthesis proceeded in six steps in the longest linear sequence (LLS) by the intramolecular cycloaddition route (or just four steps from tryptamine, 14% overall yield), or in seven steps LLS via the intermolecular variant (20% overall yield). Four additional natural products (lagumicine, alstolucines B and F, and echitamidine) were synthesised from akuammicine using an established years, and has been employed by chemists as a chiral resolving agent since Fischer's seminal report in 1899 ; its catechol derivative has been exploited as a chiral ligand in asymmetric catalysis . The challenge for any synthesis of brucine relates to the highly electron-rich nature of the indoline ring, which confers sensitivity towards oxidation and electrophilic degradation. To implement the TDO cascade approach to brucine, we first needed to synthesise N-PMB-5,6-dimethoxytryptamine 27. Due to the aforementioned instability of electron-rich aromatics, precedents for the synthesis of highly oxidised tryptamines are not well documented, but after extensive investigation we found that 27 could be accessed using a Larock indole synthesis between iodoaniline 28 and alkyne 29, which afforded 27 in good yield (61% over two steps). The successful progression of 27 towards brucine via the intramolecular cascade required only minor modifications to the route employed for strychnine: alkylation of 27 with sidechain 24 proceeded uneventfully (92%), but due to the reduced stability of the 5,6-dimethoxyindole, the intramolecular TDO cascade with 14a required a lower reaction temperature (60 °C) with a correspondingly longer reaction time in order to prevent decomposition, affording product 30 after reduction of the dienamine (30% yield from 27, 1.3:1 dr).