Eight new indole alkaloids (1-8) belonging to the rhazinilam-leuconolam-leuconoxine group, in addition to 52 other alkaloids, were isolated from the stem-bark extract of Leuconotis griffithii, viz., nor-rhazinicine (1), 5,21-dihydrorhazinilam-N-oxide (2), 3,14-dehydroleuconolam (3), and leuconodines A-E (4-8). The structures of these alkaloids were determined using NMR and MS analyses and in some instances confirmed by X-ray diffraction analyses. Alkaloids 1, 5, and 7 showed only moderate to weak cytotoxicity toward KB cells (IC50 12-18 μg/mL), while 8 showed moderate activity in reversing MDR in vincristine-resistant KB cells.
Several transformations of the seco Aspidosperma alkaloid leuconolam were carried out. The based-induced reaction resulted in cyclization to yield two epimers, the major product corresponding to the optical antipode of a (+)-meloscine derivative. The structures and relative configuration of the products were confirmed by X-ray diffraction analysis. Reaction of leuconolam and epi-leuconolam with various acids, molecular bromine, and hydrogen gave results that indicated that the structure of the alkaloid, previously assigned as epi-leuconolam, was incorrect. This was confirmed by an X-ray diffraction analysis, which revealed that epi-leuconolam is in fact 6,7-dehydroleuconoxine. Short partial syntheses of the diazaspiro indole alkaloid leuconoxine and the new leuconoxine-type alkaloids leuconodines A and F were carried out.
Two new indole alkaloids characterized by previously unencountered natural product skeletons, viz., criofolinine (1), incorporating a pyrroloazepine motif within a pentacyclic ring system, and vernavosine (2, isolated as its ethyl ether derivative 3, which on hydrolysis regenerated the putative precursor alkaloid 2), incorporating a pyridopyrimidine moiety embedded within a pentacyclic carbon framework, were isolated from a Malayan Tabernaemontana species. The structures and absolute configuration of these alkaloids were determined on the basis of NMR and MS analysis and confirmed by X-ray diffraction analysis.
The synthesis of a pentacyclic indole compound corresponding to the core structure of the misassigned indole alkaloid, tronoharine (1), is presented. The key reactions were a formal [3 + 3] cycloaddition of an indol-2-yl carbinol with an azadiene for the construction of the 6/5/6/6 tetracyclic system containing an all-carbon quaternary center and an intramolecular substitution reaction of an amine and a triflate for the creation of the bridged azepine ring. In addition, some other interesting transformations discovered during the synthetic studies are also discussed.