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Total Synthesis of Vinblastine, Vincristine, Related Natural Products, and Key Structural Analogues
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Section:Abstract
Full details of the development of a direct coupling of catharanthine with vindoline to provide vinblastine are described along with key mechanistic and labeling studies. Following an Fe(III)-promoted coupling reaction initiated by generation of a presumed catharanthine radical cation that undergoes a subsequent oxidative fragmentation and diastereoselective coupling with vindoline, addition of the resulting reaction mixture to an Fe(III)−NaBH4/air solution leads to oxidation of the C15′−C20′ double bond and reduction of the intermediate iminium ion directly providing vinblastine (40−43%) and leurosidine (20−23%), its naturally occurring C20′ alcohol isomer. The yield of coupled products, which exclusively possess the natural C16′ stereochemistry, approaches or exceeds 80% and the combined yield of the isomeric C20′ alcohols is >60%. Preliminary studies of Fe(III)−NaBH4/air oxidation reaction illustrate a generalizable trisubstituted olefin scope, identify alternatives to O2 trap at the oxidized carbon, provide a unique entry into C20′ functionalized vinblastines, and afford initial insights into the observed C20′ diastereoselectivity. The first disclosure of the use of exo-catharanthine proceeding through Δ19′,20′-anhydrovinblastine in such coupling reactions is also detailed with identical stereochemical consequences. Incorporating either a catharanthine N-methyl group or a vindoline N-formyl group precludes Fe(III)-promoted coupling, whereas the removal of the potentially key C16 methoxy group of vindoline does not adversely impact the coupling efficiency. Extension of these studies provided a total synthesis of vincristine (2) via N-desmethylvinblastine (36, also a natural product), 16-desmethoxyvinblastine (44) and 4-desacetoxy-16-desmethoxyvinblastine (47) both of which we can now suggest are likely natural products produced by C. roseus, desacetylvinblastine (62) and 4-desacetoxyvinblastine (59), as well as a series of key analogues bearing systematic modifications in the vindoline subunit. Their biological evaluation provided additional insights into the key functionality within the vindoline subunit contributing to the activity and sets the foundation on which further, more deep-seated changes in the structures of 1 and 2 will be explored in future studies.
Citing Articles
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This article has been cited by 13 ACS Journal articles (5 most recent appear below).
10′-Fluorovinblastine and 10′-Fluorovincristine: Synthesis of a Key Series of Modified Vinca Alkaloids
Hiroaki Gotoh, Katharine K. Duncan, William M. Robertson, and Dale L. BogerACS Medicinal Chemistry Letters2011 2 (12), 948-95210′-Fluorovinblastine and 10′-Fluorovincristine: Synthesis of a Key Series of Modified Vinca Alkaloids
Hiroaki Gotoh, Katharine K. Duncan, William M. Robertson, and Dale L. BogerACS Medicinal Chemistry Letters2011 2 (12), 948-952A study on the impact of catharanthine C10 and C12 indole substituents on the biomimetic Fe(III)-mediated coupling with vindoline led to the discovery and characterization of two new and substantially more potent derivatives, 10′-fluorovinblastine and 10′-...
Ring Closure Reactions of 2,6-Diazaheptatrienyl Metal Compounds: Synthesis of 3-Aminoindole Derivatives and 14-Membered Macrocyclic Dimers
Benedikt Neue, Ralph Reiermann, Klaus Gerdes, Roland Fröhlich, Birgit Wibbeling, and Ernst-Ulrich WürthweinThe Journal of Organic Chemistry2011 76 (21), 8794-8806Ring Closure Reactions of 2,6-Diazaheptatrienyl Metal Compounds: Synthesis of 3-Aminoindole Derivatives and 14-Membered Macrocyclic Dimers
Benedikt Neue, Ralph Reiermann, Klaus Gerdes, Roland Fröhlich, Birgit Wibbeling, and Ernst-Ulrich WürthweinThe Journal of Organic Chemistry2011 76 (21), 8794-88062,6-Diazaheptatrienyl metal compounds 6–K+ are easily accessible from the corresponding diimines 6 by deprotonation using KO-t-Bu as base. According to quantum chemical calculations, they are, in comparison to other isomeric species with nitrogen atoms in ...
Inverse Electron Demand Diels–Alder Reactions of 1,2,3-Triazines: Pronounced Substituent Effects on Reactivity and Cycloaddition Scope
Erin D. Anderson and Dale L. BogerJournal of the American Chemical Society 0 (ja),Inverse Electron Demand Diels–Alder Reactions of 1,2,3-Triazines: Pronounced Substituent Effects on Reactivity and Cycloaddition Scope
Erin D. Anderson and Dale L. BogerJournal of the American Chemical Society 0 (ja),Abstract. A systematic study of the inverse electron demand Diels–Alder reactions of 1,2,3-triazines is disclosed, including an examination of the impact of a C5 substituent. Such substituents were found to exhibit a remarkable impact on the ...
On the Elucidation of the Mechanism of Vinca Alkaloid Fluorination in Superacidic Medium
Emerson Giovanelli, Sébastien Leroux, Lionel Moisan, Hélène Carreyre, Pierre Thuéry, David-Alexandre Buisson, Abdelkrim Meddour, Jean-Marie Coustard, Sébastien Thibaudeau, Bernard Rousseau, Marc Nicolas, Paul Hellier, and Eric DorisOrganic Letters2011 Article ASAPOn the Elucidation of the Mechanism of Vinca Alkaloid Fluorination in Superacidic Medium
Emerson Giovanelli, Sébastien Leroux, Lionel Moisan, Hélène Carreyre, Pierre Thuéry, David-Alexandre Buisson, Abdelkrim Meddour, Jean-Marie Coustard, Sébastien Thibaudeau, Bernard Rousseau, Marc Nicolas, Paul Hellier, and Eric DorisOrganic Letters2011 Article ASAPDetailed investigations on one of the key steps of the superacidic fluorination of Vinca alkaloids that is the origin of C20′ activation are reported. While two different pathways can be envisioned for the emergence of the transient secondary ...
Scope of the Inverse Electron Demand Diels–Alder Reactions of 1,2,3-Triazine
Erin D. Anderson and Dale L. BogerOrganic Letters2011 Article ASAPScope of the Inverse Electron Demand Diels–Alder Reactions of 1,2,3-Triazine
Erin D. Anderson and Dale L. BogerOrganic Letters2011 Article ASAPAn examination of the scope of the inverse electron demand Diels–Alder reactions of the parent unsubstituted 1,2,3-triazine is described including the first report of its unique capabilities for participating in previously unexplored [4 + 2] cycloaddition ...
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- Published In Issue April 08, 2009
- Article ASAPMarch 17, 2009
- Received: December 17, 2008
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