An unexpected rearrangement of the benzofurobenzazepine skeleton of galanthamine-type alkaloids Klára Herke a , László Hazai b , Zsuzsanna Sánta c , Zsófia Dubrovay c , Viktor Háda c , Csaba Szántay Jr. c , György Kalaus b , Csaba Szántay a,b,⇑ a Department of Organic Chemistry and Technology, University of Technology and Economics, H-1111 Budapest, Szt. Gellért tér 4., Hungary b Research Group for Alkaloid Chemistry of the Hungarian Academy of Sciences, H-1111 Budapest, Szt. Gellért tér 4., Hungary c Spectroscopic Research Division, Gedeon Richter Plc., H-1475 Budapest 10, PO Box 27, Hungary article info Article history: Received 14 June 2010 Revised 14 October 2010 Accepted 29 October 2010 Available online 4 November 2010 Keywords: Amaryllidaceae alkaloids Spirocyclohexenone Rearrangement Cyclopentanoisoquinolinone abstract Attempted cyclisation of N-methylated spiro benzazepine–cyclohexenone (5) into the corresponding N- methyl tetracyclic unit of galanthamine-type alkaloids (6) instead gave an unexpected rearrangement to yield a cyclopentanoisoquinolinone derivative (7). Methylation of the tetrahydrobenzofurobenzazepine tetracycle resulted in the expected N-methyl derivative 6, and the anomalous product 8, with structure similar to that of 7. Ó 2010 Elsevier Ltd. All rights reserved. (À)-Galanthamine (1) is an Amaryllidaceae alkaloid, 1 isolated from the flowers and bulbs of the Caucasian snowdrop (Galanthus woronowii), and exhibits competitive and reversible acetylcholine esterase (AChE) inhibition. Moreover, this molecule displays allosteric potentiation of neuronal nicotinic receptors for acetyl- choline. 2 (À)-Galanthamine hydrobromide (Razadyne, Reminyl) enhances significantly cognitive functions and is used for the treat- ment of mild to moderate Alzheimer’s disease. 3,4 A number of synthetic routes have been elaborated 1 for the preparation of (À)-galanthamine using different key steps to form the tetracyclic ring system characteristic of galanthamine-type Amaryllidaceae alkaloids. 5–9 Most synthetic strategies utilized a biomimetic approach via intramolecular phenolic oxidative coupling to install the quaternary spiro carbon. In relation to this type of synthetic processes, narwedine (2) as well as its biogenetic precursor 10 can be considered the most important intermediates. Recently, 11 we succeeded in synthesizing the hexahydro- benzofurobenzazepine trione 3 which represents the appropriate key intermediate for the preparation of the demethoxy derivative of narwedine (2). The synthesis of compound 3 was achieved starting from spirocyclohexenone derivative 4 in one step via demethylation of the methoxy group and cyclisation using methanesulfonic acid in the presence of methionine. 11 O OH N Me MeO O NH O O O O N Me MeO O 1 2 3 The spiro compound 4 11,12 was N-methylated with methyl io- dide in refluxing acetone in the presence of anhydrous potassium carbonate (Scheme 1) giving N-methyl derivative 5 in 53% yield. Next, the cyclisation reaction was performed like that used for the preparation of tetracycle 3. Compound 5 was allowed to react in methanesulfonic acid in the presence of racemic methionine at room temperature for several hours. After work-up, however, the N-methyl tetracycle 6 was not isolated, but instead the unexpected cyclopentanoisoquinolinone derivative 7 was obtained. This type of tricyclic dione is unknown in the literature. 0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2010.10.158 ⇑ Corresponding author. Tel.: +36 1 463 1195; fax: +36 1 463 3297. E-mail address: szantay@mail.bme.hu (C. Szántay). Tetrahedron Letters 51 (2010) 6932–6934 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet