title: A short diastereoselective synthesis of the putative alkaloid jamtine, using a tandem pummerer/mannich cyclization sequence.
abstract: Treatment of 2-phenylhex-5-enal with benzylamine followed by sequential reaction with ethylthioacetyl chloride and sodium periodate oxidation afforded a E/Z mixture of alpha-sulfinylamides. As anticipated from a 4pi-conrotatory mechanism, cyclization of each olefin afforded fused isoquinoline lactams as single diastereomers epimeric at the ethylthio position without any cross contamination. Some preliminary studies were directed toward the synthesis of mesembrine using a 3,4-dimethoxy aryl group. In this case, the Z-enamide prefers to undergo electrophilic aromatic substitution to give a substituted azepinone as the preferred product in 87% yield. In contrast, the E-enamide isomer provided the desired hydroindolone. The convergency and stereochemical control associated with the tandem Pummerer /Mannich cyclization make it particularly suited for the assembly of jamtine, a tetrahydroisoquinoline alkaloid reputed for its therapeutic properties. The key step in the synthesis involves a domino thionium/N-acyliminium ion cyclization to provide the tricyclic ring skeleton 27a as the major diastereomer. Deprotonation of 27a with NaH gave 28a, which contains the fully assembled skeleton of jamtine. Completion of the synthesis entailed installation of the double bond and reduction of the lactam. Oxidation of a synthetic sample of jamtine with MCPBA afforded the corresponding N-oxide, which does not match the spectral data reported in the literature for this alkaloid. Our synthetic efforts raise the possibility of a revision of the earlier assignment.
authors.affiliation: Department of Chemistry, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Padwa
authors.forename: M Diana
authors.initials: MD
authors.lastname: Danca
authors.forename: Kenneth I
authors.initials: KI
authors.lastname: Hardcastle
authors.forename: Michael S
authors.initials: MS
authors.lastname: McClure
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis*; D002384:Catalysis; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D003500:Cyclization; D007546:Isoquinolines / Q000138:chemical synthesis*; D008968:Molecular Conformation; D015394:Molecular Structure; D013237:Stereoisomerism
chemical_list: D000470:Alkaloids; D007546:Isoquinolines; C467072:jamtine