1Enantioselective Total Synthesis of(+)-Homochelidonine by a PdII-Catalyzed Asymmetric Ring-OpeningReaction of a meso-AzabicyclicAlkene with an Aryl Boronic AcidHelen A. McManus, Matthew J. Flemingand Mark Lautens*Angew. Chem. Int. Ed. 2007, 46, 433Introduction• Hexahydrobenzo[c]phenanthridine class of alkaloids• 1 and 2 isolated from the roots of Chelidonium majus• Cytotoxic, inhibits tubulin polymerization• Major component of the drug Ukrain, a semisyntheticpreparation from C. majus alkaloids• Fully aromatic A and D rings, partially hydrogenated B andC rings, C11-hydroxy group and 3-contiguous syn-stereocentersA.-H. YehChem 23201/10/20072Total Synthesis of Chelidonine• First total synthesis of dl-chelidonine using intramolecular[4+2] cycloaddition strategyOppolzer, W. and Keller, K. J. Am. Chem. Soc. 1971, 93, 3836Total Synthesis of Homochelidonine• 15 linear steps, 11 % overall yieldYoshida, M.; Watanabe, T; Ishikawa, T. Tetrahedron Lett. 2002, 43, 6751A.-H. YehChem 23201/10/20073Homochelidonine: RetrosyntheticAnalysis• Ring-opening of azabicyclo-alkene with arylboronic acid as the key step in synthesisMcManus, H.; Flemming, M.J.; Lautens, M. Angew. Chem. Int. Ed. 2007, 46, 433Pd-Catalyzed AlkylativeRing Opening• The product was obtained in good yield andas a single diastereomerLautens, M.; Renaud, J.-L.; Hibbert, S. J. Am. Chem. Soc. 2000, 122, 1804A.-H. YehChem 23201/10/20074Proposed Mechanism• Carbopalladation: rate-limiting stepLautens, M.; Hibbert, S.; Renaud, J.-L. J. Am. Chem. Soc. 2001, 123, 6834Addition of Aryl Boronic Acids toBicyclic Alkenes• Addition of heteroaryl boronic acids to oxa- and aza-bicyclic alkenesLautens, M.; Dockendorff, C. Org. Lett. 2003, 5, 3695A.-H. YehChem 23201/10/20075Homochelidonine: RetrosyntheticAnalysisMcManus, H.; Flemming, M.J.; Lautens, M. Angew. Chem. Int. Ed. 2007, 46, 433Synthesis of the IntermediatesMcManus, H.; Flemming, M.J.; Lautens, M. Angew. Chem. Int. Ed. 2007, 46, 433A.-H. YehChem 23201/10/20076Asymmetric Ring-Opening ReactionMcManus, H.; Flemming, M.J.; Lautens, M. Angew. Chem. Int. Ed. 2007, 46, 433• Acid-stable protecting group on the NitrogenMcManus, H.; Flemming, M.J.; Lautens, M. Angew. Chem. Int. Ed. 2007, 46, 433Protecting Group ManipulationsA.-H. YehChem 23201/10/20077Completion of the SynthesisMcManus, H.; Flemming, M.J.; Lautens, M. Angew. Chem. Int. Ed. 2007, 46, 433Conclusion• Enantioselective total synthesis of (+)-Homochelidonine was achieved in 14 steps with15 % overall yield from 4,5-dibromovertrole.• A new and general strategy for the synthesis ofhexahydrobenzo[c]phenanthridine alkaloids usinghighly enantioselective Pd(II)-catalyzed ring-opening reaction of a meso-azabicycle with arylboronic acid has been established.• Application of this methodology to the synthesisof other alkaloids is under investigation.A.-H. YehChem 23201/10/20078Phosphine LigandsA.-H. YehChem
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