2009
DOI: 10.1021/ja9085534
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Concise Syntheses of (−)-Galanthamine and (±)-Codeine via Intramolecular Alkylation of a Phenol Derivative

Abstract: Suzuki coupling of 7 to 8 gave the biphenyl derivative 9. Reaction of 9 with ethyl vinyl ether/bromine/base gave 10, which on treatment with CsF/DMF at 130 degrees C resulted in the cross-conjugated 2,5-cyclohexadienone 6. Acid hydrolysis of 6 gave 11, which was reductively aminated to give (+/-)-narwedine 2. Since 2 has been converted into (-)-galanthamine 1 in two steps, this synthesis proceeds in eight steps with an overall yield of 63%. Also treatment of the cross-conjugated cyclohexadienone 6 with nitrome… Show more

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Cited by 131 publications
(82 citation statements)
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“…Galanthamine is produced on a large scale from Bulgarian Leucojum aestivum [4] and also by chemical synthesis [5][6][7]. However, the synthesis is complicated and time consuming because galanthamine has three asymmetric carbons requiring stereochemically controlled synthesis.…”
Section: Introductionmentioning
confidence: 99%
“…Galanthamine is produced on a large scale from Bulgarian Leucojum aestivum [4] and also by chemical synthesis [5][6][7]. However, the synthesis is complicated and time consuming because galanthamine has three asymmetric carbons requiring stereochemically controlled synthesis.…”
Section: Introductionmentioning
confidence: 99%
“…In the search for morphine derivatives with reduced side effects, total synthesis offers an attractive opportunity although an economical route competitive to isolation is currently not within reach. [1,2] Several efforts in the recent past, for example, the elegant synthesis by Magnus, [3] the improved strategy of Fukuyama, [4] the chemoenzymatic approach of Hudlicky, [5] and the innovative route of Stork, [6] express the permanent interest of the scientific community. Among the numerous strategies for construction of the phenanthrene skeleton, an approach based on intramolecular nitrone cycloaddition starting from a suitably substituted aldehyde seems powerful enough for this challenging task.…”
mentioning
confidence: 99%
“…[4a,b] A commutable strategy in terms of ordering the coupling and oxidation events might be attractive for the construction of the necessary dienone moiety. Suzuki coupling with A [3] following the Magnus protocol provided biaryl 8 in excellent yield after basic hydrolysis of the TBS ether. [14] Phenolic oxidation [15] with PhI(OAc) 2 (PIDA) by inverse addition (8 was added slowly to PIDA in methanol) afforded the p-quinol ether in good overall yield along with a 2,2-dimethoxy-3,5-cyclohexadienone…”
mentioning
confidence: 99%
“…Bei der Suche nach Morphinderivaten mit reduzierten Nebenwirkungen bietet die Totalsynthese attraktive Möglichkeiten, allerdings ist eine ökonomische Route, die konkurrenzfähig zur Isolierung ist, bis heute nicht in Reichweite. [1,2] Etliche Anstrengungen in der jüngeren Vergangenheit, wie die elegante Synthese von Magnus, [3] die verbesserte Strategie von Fukuyama, [4] der chemoenzymatische Ansatz von Hudlicky [5] und die innovative Route von Stork, [6] zeugen vom andauernden Interesse der Forschung. Unter den zahlreichen Strategien zum Aufbau des Phenanthrengerüsts scheint ein Ansatz basierend auf einer intramolekularen Nitron-Cycloaddition ausgehend von einem geeignet substituierten Aldehyd dieser Herausforderung gewachsen zu sein.…”
unclassified
“…Die SuzukiKupplung mit A [3] nach dem Protokoll von Magnus lieferte nach basischer Hydrolyse des TBS-Ethers das Biaryl 8 in hervorragender Ausbeute. [14] Eine Phenoloxidation [15] mit PhI(OAc) 2 [19] Der gebräuchlichere Einsatz von Superhydrid [20] schlug wegen der möglicherweise begleitend auftretenden Reduktion des Isoxazolidins fehl.…”
unclassified