Total synthesis of the akuammiline alkaloid (+/-)-vincorine.

The first total synthesis of the akuammiline alkaloid (+/-)-vincorine (6) has been accomplished in about 1% overall yield in 31 steps. A concise assembly of the core 1,2-disubstituted 1,2,3,4-tetrahydro-4a,9a-iminoethanocarbazole (1), a distinctive feature of akuammiline and strychnos alkaloids, was developed via a three-step one-pot cascade reaction consisting of copper-catalyzed intramolecular cyclopropanation, ring-opening, and ring closure. The construction of the last seven-membered E-ring in a rigid two-ring moiety (31, 45 to 47) through Heck coupling, Michael addition, pi-allyl/Heck or pi-allyl/Stille coupling failed, leading us to seek an alternative method. After successful addition of an acetate side chain on C15 of the cyclohexenyl ring (D-ring) in Boc-protected 35b by a Johnson-Claisen rearrangement and multistep modification of the functionality in the rearrangement product 33a, the E-ring formation was then realized for providing pentacyclic lactam 32 through intramolecular condensation of the acid group on the D-ring and the amine group on the C-ring with Mukaiyama's reagent. An E-ethylidenyl group on the E-ring was stereoselectively added to afford lactam 56a through a two-step reaction of 32 consisting of aldol addition with acetaldehyde and cis-elimination of the resulting hydroxyl group. Final elaboration of 56a, including opening of the seven-membered E-ring, selective reduction of the alpha,beta-unsaturated ester, and reclosure of the seven-membered E-ring completed the total synthesis of 6.