Highly diastereoselective approach toward (±)-tetraponerine T6 and analogues via the double cycloisomerization-reduction of bis-alkynylpyrimidines

A new, short, and efficient approach toward tricyclic alkaloids, involving the double cycloisomerization-reduction of bis-alkynylpyrimidines 3a-m, has been developed. The requisite bis-alkynylpyrimidines 3a-m were readily prepared via regioselective sequential Sonogashira coupling reactions of dibromopyrimidines 1. Bis-alkynylpyrimidines 3a-m were converted into the 5-6-5 tricyclic heteroaromatic cores 4a-m via the Cu(I)-assisted double cycloisomerization reaction. The reaction proceeded stepwise, which was confirmed by the isolation of the mono-pyrrolization intermediate 5. The structure of 5 was assigned by 2D NMR and by independent synthesis. Cycloisomerization of 5 under standard conditions afforded tricyclic 4g in 89% yield. The PtO₂-catalyzed hydrogenation of bis-pyrrolopyrimidines 4d, 4g, and 4i in acidic media afforded stable amidinium derivatives, 11a, 11b, and 11c. Further reduction of the latter with LiAlH₄ allowed for the highly diastereoselective total synthesis of (±)-tetraponerine T6 and its analogues.