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, 14tetraazabicyclo[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 Β± f), verbacine ((S)-4a Β± f), incasine B'/ verdoline ((S)-5a Β± f), verbamedine ((S)-6a Β± f), and verbascenine ((S)-7a Β± f), is discussed.
Introduction. Β± The 17-membered macrocyclic spermine alkaloids (Γ)-(S)-verbacine (4a, Scheme 1), (Γ)-(S)-verballocine (4b), and their mono-and dimethoxy analogues (S)-4c Β± f have been isolated from the leaves of Verbascum pseudonobile Stoj. et Stef. (Scrophulariaceae) together with their N(9),N(13)-methylene-bridged derivatives ()-(S)-verbamethine (3a), ()-(S)-isoverbamethine (3b), and their MeO analogues (S)-3c Β± f [1 Β± 3]. In the same plant material were found also the N(13)formyl ((S)-6a Β± f) and N(13)-acetyl ((S)-7a Β± f) derivatives of (S)-4a Β± f, and the amidinium salts (S)-5a Β± f [4]. (S)-Verbascenine (7a), (S)-verballoscenine (7b), (S)verbacine (4a), and (S)-verballocine (4b) have been isolated also from V. phoeniceum L. [5] [6]. (S)-Isoverbamethine 3b (recently republished with the incorrect (R)configuration under the trivial name incasine C [7]), (S)-verballocine (4b), and the amidinium salts (S)-incasine B' (5a), and (S)-incasine B (5b) have been isolated also from Incavilea sinensis Lam. (Bignoniaceae) [7].
All of these 30 alkaloids are derived from the (S)-configured macrolactam 1 (Scheme 1). A similar precedent is already known, namely the closely related alkaloids (S)-buchnerine (9) (MeO derivative of 1) and its (S)-N(1)-[(Z)-4-methoxycinnamoyl] derivative 10 (dimethoxy derivative of (S)-verballocine, 4b), which have been isolated together from the leaves of Clerodendrum buchneri GΓrke (Verbenaceae) [8]. Therefore, it was likely that compound 1 is also present as natural product in the alkaloid extract from V. pseudonobile. The verification of this inference required a synthetically prepared sample of 1 as a reference compound for a more detailed investigation of the minor alkaloids from V. pseudonobile.
Results and Discussion. Β± The macrocyclic compound (AE)-1 has been synthesized in the course of the total synthesis of (AE)-verbacine (4a) and (AE)-verbascenine (7a) by Sbtemplate macrolactamization of the (AE)-amino ester 15 (Scheme 2) [9]. The starting (AE)-amino ester 15 was prepared by Michael addition of spermine (13) to ethyl