One-Pot Synthesis of Polycyclic Nucleosides with Unusual Molecular Skeletons

Abstract

2Reaction of enamine sultone 1 with a 1:1 mixture of water and acetonitrile in the presence of acetic acid (pH=5-6) allowed its efficient transformation into the hemiaminal 3. Unexpectedly, 3 underwent an spontaneous intermolecular reaction with acetone to give the novel tetracyclic nucleosides 5 and 6.The unique tetracyclic structure of 5 and 6 prompted us to start a study to explain their formation. A transient iminium intermediate, as result of the condensation of 3 with acetone, has been observed using NMR and HPLC-ESI-MS experiments. Additionally, through catalytic hydrogenation we were able to trap some of the putative iminium/enamine intermediates as the corresponding amines. The electrophilic nature of the iminium intermediate seems to be the driving force for the attack of a second molecule of acetone and for the subsequent intramolecular cyclizations that takes place to afford 5 and 6. It seems that the hydroxyl group at the α-position of the pyrrolidine ring, present in 3, is also crucial for the formation of 5 and 6.The scope of the reaction was examined using simple aliphatic ketones (2-butanone, 3-pentanone), as well as the α,β−unsaturated ketone (methyl vinyl ketone). Our experimental results indicate that the nature of the ketone (R 1 COR 2 ) is critical for the attack of the NH of the pyrrolidine ring present in 3 and the subsequent cyclization. Different types of ketones can be attacked by the NH of the pyrrolidine ring present in 3, however only with acetone the attack and subsequent cyclization proceeds spontaneously.3