Total Synthesis Highlights

The preparation of 2 began with the enantioselective Robinson annulation of the β-keto ester 4
with crotonaldehyde (5), mediated by the organocatalyst 6. In this protocol, originally developed
by Karl Anker Jørgensen, the single stereogenic center was established by conjugate addition,
presumably to the chiral iminium salt generated by the condensation of 5 with 6. Subsequent aldol
(or more likely Mannich) cyclization followed by elimination gave 7. Hydrolysis and
decarboxylation by heating with p-TsOH converted 7 to 1. This procedure was robust enough to
allow preparation of a ten gram batch of 1. This Jørgensen annulation is the current method of
choice for the enantioselective preparation of 2,5-dialkyl cyclohexenones.
Conjugate addition of the propargyl anion equivalent 8 to 1 proceeded with the expected > 95:5
axial diastereoselectivity, to give the silyl enol ether 9. Exposure of the derived iodide 10 to
catalytic [Ph 3 PAu]Cl and AgBF 4 induced smooth cyclization to the cis hydrindane 2.
Before constructing the nine-membered ring amine of fawcettimine (3), it was first necessary to
protect the ketone as the ketal. Pd-mediated coupling of the alkenyl iodide with the organoborane
derived from 11 then proceeded smoothly, as did the subsequent hydroboration of the terminal
alkene.
Neither the mesylate nor the tosylate derived from 12 could be induced to cyclize. In contrast,
intramolecular displacement of the iodide proceeded well, to give 13. Hydroboration followed by
oxidation then gave 15, which on deprotection cyclized to (+)-fawcettimine (3).