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.
Department of Chemistry, University of Illinois at Chicago, 875 West Taylor Street, Chicago, Illinois 60607-7061, USA.
Joseph T
JT
Kim
Jason
J
Butt
Vladimir
V
Gevorgyan
D000470:Alkaloids / Q000138:chemical synthesis*; D002384:Catalysis; D003500:Cyclization; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis*; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010084:Oxidation-Reduction; D011743:Pyrimidines / Q000737:chemistry*; D013237:Stereoisomerism; D054836:Indolizidines
D000470:Alkaloids; D006575:Heterocyclic Compounds, 3-Ring; D011743:Pyrimidines; C475971:tetraponerine T6; D054836:Indolizidines