Protoverbine, the Parent Member of a Class of Macrocyclic Spermine Alkaloids

The 17-membered macrocyclic spermine alkaloids protoverbine ((8S)-8-phenyl-1,5,9,13-tetraazacycloheptadecan-6-one, 1) and its N(9),N(13)-methylene-bridged derivative protomethine ((2S)-2-phenyl-1,5,9,14-tetraazabicyclo[12.3.1]octadecan-4-one, 2) were isolated from Verbascum pseudonobile Stoj. et Stef. (Scrophulariaceae) and characterized. The synthesis of their racemates is described. The possible role of (S)-protoverbine (1) and (S)-protomethine (2) as precursors in the biogenesis of the whole class of N(1),N(9)- and/or N(13)-substituted alkaloids, the groups of verbamethine ((S)-3a – f), verbacine ((S)-4a – f), incasine B′/verdoline ((S)-5a – f), verbamedine ((S)-6a – f), and verbascenine ((S)-7a – f), is discussed.