1.Leishmanicidal evaluation of tetrahydroprotoberberine and spirocyclic erythrina-alkaloids.
Callejon DR1, Riul TB2, Feitosa LG3, Guaratini T4, Silva DB5, Adhikari A6, Shrestha RL7, Marques LM8, Baruffi MD9, Lopes JL10, Lopes NP11. Molecules. 2014 May 5;19(5):5692-703. doi: 10.3390/molecules19055692.
Leishmaniasis is one of the World's most problematic diseases in developing countries. Traditional medicines to treat leishmaniasis have serious side effects, as well as significant parasite resistance problems. In this work, two alkaloids 1 and 2 were obtained from Corydalis govaniana Wall and seven alkaloids 3-9, were obtained from Erythrina verna. The structures of the compounds were confirmed by mass spectrometry and 1D- and 2D-NMR spectroscopy. The leishmanicidal activity of compounds 1-9 against Leishmania amazonensis was tested on promastigote forms and cytotoxicity against J774 (macrophage cell line) was assessed in vitro. Compound 1 showed potent activity (IC50 = 0.18 µg/mL), compared with the standard amphotericin B (IC50 = 0.20 µg/mL). The spirocyclic erythrina-alkaloids showed lower leishmanicidal activity than dibenzoquinolizine type alkaloids.
2.Intramolecular Redox-Mannich Reactions: Facile Access to the Tetrahydroprotoberberine Core.
Ma L1, Seidel D2. Chemistry. 2015 Sep 7;21(37):12908-13. doi: 10.1002/chem.201501667. Epub 2015 Jul 28.
Cyclic amines such as pyrrolidine undergo redox-annulations with 2-formylaryl malonates. Concurrent oxidative amine α-CH bond functionalization and reductive N-alkylation render this transformation redox-neutral. This redox-Mannich process provides regioisomers of classic Reinhoudt reaction products as an entry to the tetrahydroprotoberberine core, enabling the synthesis of (±)-thalictricavine and its epimer. An unusually mild amine-promoted dealkoxycarbonylation was discovered in the course of these studies.
3.Biocatalytic organic synthesis of optically pure (S)-scoulerine and berbine and benzylisoquinoline alkaloids.
Schrittwieser JH1, Resch V, Wallner S, Lienhart WD, Sattler JH, Resch J, Macheroux P, Kroutil W. J Org Chem. 2011 Aug 19;76(16):6703-14. doi: 10.1021/jo201056f. Epub 2011 Jul 19.
A chemoenzymatic approach for the asymmetric total synthesis of the title compounds is described that employs an enantioselective oxidative C-C bond formation catalyzed by berberine bridge enzyme (BBE) in the asymmetric key step. This unique reaction yielded enantiomerically pure (R)-benzylisoquinoline derivatives and (S)-berbines such as the natural product (S)-scoulerine, a sedative and muscle relaxing agent. The racemic substrates rac-1 required for the biotransformation were prepared in 4-8 linear steps using either a Bischler-Napieralski cyclization or a C1-Cα alkylation approach. The chemoenzymatic synthesis was applied to the preparation of fourteen enantiomerically pure alkaloids, including the natural products (S)-scoulerine and (R)-reticuline, and gave overall yields of up to 20% over 5-9 linear steps.
4.Enantioselective synthesis of tetrahydroprotoberberines and bisbenzylisoquinoline alkaloids from a deprotonated α-aminonitrile.
Blank N1, Opatz T. J Org Chem. 2011 Dec 2;76(23):9777-84. doi: 10.1021/jo201871c. Epub 2011 Oct 26.
Under controlled conditions, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile can be quantitatively deprotonated in the α-position. Its alkylation directly furnishes 3,4-dihydroisoquinolines which can serve as starting materials for the preparation of various alkaloids. Here, the preparation of the benzylisoquinolines (+)-laudanidine, (+)-armepavine, and (+)-laudanosine as well as the tetrahydroprotoberberines (-)-corytenchine and (-)-tetrahydropseudoepiberberine using Noyori's asymmetric transfer hydrogenation are described. The dimeric alkaloids (+)-O-methylthalibrine and (+)-tetramethylmagnolamine were obtained from nonracemic precursors in Ullmann diaryl ether syntheses.