Alkaloids ofNitraria sibirica. Structure of nitrabirine

Total Synthesis via Biomimetic Late-stage Heterocyclization, Assignment of the Relative Configuration and Biological Evalu-ation of the Nitraria Alkaloid (±)-Nitrabirine

“…Most of the simple Nitraria spiranic alkaloids including (+)-nitramine (1), (+)-isonitramine (2), ( ̶ )-sibirine (3) and ( ̶ )-sibirinine (4) have already been successfully targeted by racemic or enantioselective total syntheses, [9][10][11][12][13][14] which contributed to their structure elucidation enabling the X-ray diffraction of their single crystals finally revealing their stereo configurations. However, to the best of our knowledge, no synthesis of nitrabirine (5) or nitrabirine-N-oxide (6) has been reported so far, completely elucidating their stereochemistry.…”

“…The biosynthesis of nitrabirine (5) and nitrabirine-Noxide (6) was proposed in 2010 by Poupon and Gravel 1 based on the initial reduction of the pivotal, lysine-derived achiral intermediate 7 releasing intermediate 8, which is in equilibrium with its tautomer 9 as outlined in Scheme 1. A stereoselective spirocyclization of the enamine 9 might lead to the spirocyclic imine 10, which undergoes a late-stage heterocyclization with the glycine-derived α-aminoaldehyde 11 leading after final elimination of water and oxidation of the 8a' Position to the formation of nitrabirine (5). Scheme 1.…”

“…1 The simple Nitraria spiranic alkaloids include (+)-nitramine (1), (+)-isonitramine (2), ( ̶ )-sibirine (3), ( ̶ )-sibirinine (4), (±)-nitrabirine ( 5) and (±)-nitrabirine-N-oxide (6) (Figure 1), which have been isolated from two species of the Nitraria genus, namely Nitraria schoberi (for 1) 2 and Nitraria sibirica (for 2, 3, 4, 5, and 6). [1][2][3][4][5][6] Structurally, the simple Nitraria spiranic alkaloids comprise a 2-azaspiro [5.5]undecan-7-ol framework with a central chiral quaternary carbon centre. Additionally, aminal formation bridging the secondary amine in the 2-position with the hydroxy moiety in the 7-position leads to the tricyclic core of (-)sibirinine (4).…”

“…Additionally, aminal formation bridging the secondary amine in the 2-position with the hydroxy moiety in the 7-position leads to the tricyclic core of (-)sibirinine (4). The structures of nitrabirine (5) and nitrabirine-N-oxide (6) contain an additional annulated imidazole ring in their tricyclic tetrahydro-5'Hspiro[cyclohexane-1,8'-imidazo [1,2-a]pyridin]-2-ol skeleton (Figure 1).…”

Pyrroles and gem-Dihalocyclopropanes as Building Blocks for Alkaloid Synthesis

“…The equivalent intramolecular process is essentially equally effective as evidenced by the smooth conversion of the linked system 112 (Scheme 13) into the tricyclic product 113 (76%) that is obtained as a single isomer of, as yet, undetermined stereochemistry. Extensions of these sorts of procedures to substrates such as the pyrrole/gem-dibromocyclopropane conjugate 114 (Scheme 14) might be expected to deliver the spirocyclic product 115 that is reminiscent of the unusual natural product nitrabirine (116) [36]. Compound 115 also embodies key structural elements associated with the biologically significant lycopodium alkaloid serratine (117) [37].…”