Studies on the Synthesis of (±)-Stenine: A Combined Intramolecular [4 + 2]-Cycloaddition/Rearrangement Cascade

Several cyclic 2-(methylthio)-5-amidofurans containing tethered unsaturation were prepared via
the reaction of dimethyl(methylthio)sulfonium tetrafluoroborate (DMSTF) with β-alkoxy-γ-dithiane
lactams. Thermolysis of these furans resulted in an intramolecular Diels−Alder reaction (IMDAF).
The resulting oxa-bridge cycloadducts underwent a subsequent 1,2-methylthio shift to form tricyclic
lactams in high yield. Furan 9, annealed to an azepine ring, underwent the IMDAF reaction at or
below room temperature. Conformational effects imposed by the placement of a carbonyl group
within the tether, combined with a rotational bias about the C(2)−N bond, enhances the rate of
the IMDAF reaction of the seven-ring system so that it occurs readily at 25 °C. The feasibility of
using the cascade sequence in the context of a total synthesis of the Stemona alkaloid (±)-stenine
was explored. The eventual synthesis of (±)-stenine was carried out by an intramolecular Diels−Alder reaction of a 2-amido-5-methylthio-substituted furan containing a trans-pent-3-enoic acid
methyl ester side chain in order to create the desired azepinoindole skeleton. This was followed by
a series of reductions to set the syn-anti stereochemical relationship at the incipient ring fusion
sites present in stenine. All six stereocenters at the azepinoindole core were derived in high
stereoselectivity from the functionality present in the rearranged cycloadduct 10. Compound 10
was converted to stenine in 11 additional steps via a sequence that features a Crabtree's-catalyst
directed hydrogenation, iodolactonization, and a Keck allylation.