A Short Diastereoselective Synthesis of the Putative Alkaloid Jamtine, Using a Tandem Pummerer/Mannich Cyclization Sequence

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 α-sulfinylamides. As
anticipated from a 4π-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.