title: Studies on the synthesis of (+/-)-stenine: a combined intramolecular [4 + 2]-cycloaddition/rearrangement cascade.
abstract: Several cyclic 2-(methylthio)-5-amidofurans containing tethered unsaturation were prepared via the reaction of dimethyl(methylthio)sulfonium tetrafluoroborate (DMSTF) with beta-alkoxy-gamma-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 degrees 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.
authors.affiliation: Department of Chemistry, Emory University, Atlanta, GA 30322, USA. chemap@emory.edu
authors.forename: Albert
authors.initials: A
authors.lastname: Padwa
authors.forename: John D
authors.initials: JD
authors.lastname: Ginn
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis*; D020650:Combinatorial Chemistry Techniques; D015394:Molecular Structure; D041901:Stemonaceae / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D000470:Alkaloids; C441784:stenine