title: A one-pot bicycloannulation method for the synthesis of tetrahydroisoquinoline systems.
abstract: A highly effective method for the synthesis of the core indolo[2,3-alpha]quinolizidine skeleton found in yohimbine is described. The reaction of N-monosubstituted thioamides with bromoalkenoyl chlorides furnishes thioisomünchnones as transient 1,3-dipoles that undergo ready intramolecular cycloaddition across the tethered pi-bond to give thio-bicycloannulated products in a one-pot operation. The stereochemical outcome of the intramolecular reaction is the consequence of an endo cycloaddition of the neighboring pi-bond across the transient thioisomünchnone dipole. A major limitation of the method is that when a hydrogen is present in the alpha-position of the thioamide the initially formed thio-N-acyliminium ion undergoes proton loss to produce a S,N-ketene acetal at a faster rate than dipole formation. Treatment of tetrahydro-beta-carboline-1-thione with 2-bromooct-7-enoyl chloride followed by reductive removal of sulfur from the cycloadduct resulted in the formation of (+/-)-alloyohimbanone. Attempts to cycloadd the thioisomünchnone dipole across several nucleophilic pi-bonds failed, and instead, products derived from cyclization of the pi-bond onto the initially formed thio-N-acyliminium ion were formed. The resulting N,S-ketals were further converted into several tetrahydroisoquinoline alkaloids in good yield.
authors.affiliation: Department of Chemistry, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: A
authors.initials: A
authors.lastname: Padwa
authors.forename: L S
authors.initials: LS
authors.lastname: Beall
authors.forename: T M
authors.initials: TM
authors.lastname: Heidelbaugh
authors.forename: B
authors.initials: B
authors.lastname: Liu
authors.forename: S M
authors.initials: SM
authors.lastname: Sheehan
mesh_terms: D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis*; D007546:Isoquinolines / Q000138:chemical synthesis*; D011807:Quinolizines / Q000138:chemical synthesis*; D013057:Spectrum Analysis
chemical_list: D001643:Bridged Bicyclo Compounds; D007546:Isoquinolines; D011807:Quinolizines