Mendeleev Communications Electronic Version, Issue 2, 2002 1 Carbocyclic galanthamine analogues: construction of the novel 6H-benzo[a]cyclohepta[hi]benzofuran ring system Matthias Treu, Johannes Frohlich and Ulrich Jordis* Institute of Applied Synthetic Chemistry, Vienna University of Technology, A-1060 Vienna, Austria. Fax: +43 (1) 58 8011 5499; e-mail: ujordis@pop.tuwien.ac.at 10.1070/MC2002v012n02ABEH001557 Unnatural analogues of the anti-Alzheimer drug (.)-galanthamine have been synthesised using K3[Fe(CN)]6 at the key step to construct the novel (¡¾)-6H-benzo[a]cyclohepta[hi]benzofuran ring system via oxidative tandem cyclization.Galanthamine (or galantamine, Reminyl¢ç) is a tertiary alkaloid acetylcholinesterase inhibitor (AChEI), which has been approved in several countries for treating the symptoms of Alzheimer¡�s type senile dementia.1 The key step comprises the K3[Fe(CN)]6 induced oxidative tandem cyclization of suitable norbelladine analogues, whereby the tetracyclic ring system is established in a cascade of radical reactions and Michael addition.We are currently studying this phenol oxidation, which was developed for the synthesis of the galanthamine ring system2,3 and is now performed on an industrial scale.4 We have extended this reaction for the preparation of 6H-benzofuro[3a,3,2-ef][3]benzazepine5 and 12H-[2]benzothiepino[6,5a,5-bc]benzofuran6 ring systems (Figure 1).Here, we report the successful use of this reaction for the synthesis of the novel 6H-benzo[a]cyclohepta[hi]benzofuran ring system starting from diphenol compounds 1a.d.Generally, this type of reaction is successful for the creation of 5-6-6-7 ring systems¢Ó under conditions found to be optimal in the synthesis of galanthamine4 (Scheme 1 and Table 1). For all reactions, the quantitative conversion of diphenol was observed by TLC. These results were rationalised by molecular models generated using the CORINA software7 as described below. A low-energy conformation characterised by the interaction of the bromine atom and the carboxamide moiety show favourable distances between the carbon atoms to be engaged in the radical cyclization.Further attempts to cyclise compounds 3a.d, which were expected to give 5-6-6-6, 5-6-6-8 and unfunctionalised 5-6-6-7 ring systems, were unsuccessful (Scheme 2).These observations were rationalised by the ring tension of 5-6-6-6 ring systems in the case of 3a, as well as 1a, the lack of supportive conformative restriction and the comparatively high flexibility of 3b and 3c, and the formation of coloured decomposition products in the case of 3d (Scheme 2 and Table 2). MeO O OH H N Me (.)-Galanthamine MeO O OH H N Me (4a¥á,6¥â,8aR*)-4a,5,9,10,11,12-Hexahydro- 3-methoxy-10-methyl-6Hbenzofuro[ 3a,3,2-ef]-[3]- benzazepin-6-ol (see ref. 5) MeO O OH H S (4a¥á,6¥â,8aR*)-4a,5,9,10-Tetrahydro- 3-methoxy-11,11-dioxo- 12H-[2]benzothiepino[6,5a,5-bc]- benzofuran-6-ol (see ref. 6) O O Figure 1 Table 1 Tandem cyclization of 1a.d. Compound m n yield of 2 (%) 1a 1 1 0 1b 0 3 8 1c 1 2 19 1d 2 1 6 ¢Ó Representative example of tandem cyclization: (4ab,8ab,12R*)-1-bromo- 4a,5,9,10,11,12-hexahydro-3-methoxy-6-oxa-6H-benzo[a]cyclohepta[hi]- benzofuran-12-carboxamide 2b.K3[Fe(CN)6] (13.2 g, 40.0 mmol) and K2CO3 (7.50 g, 53.1 mmol) in water (75 ml) were added to a suspension of 1b (3.00 g, 7.61 mmol) in CHCl3 (300 ml), and the mixture was stirred vigorously for 45 min at room temperature. The mixture was filtered using diatomaceous earth, and the filtrate was washed with water (3¡¿200 ml) and brine (200 ml), dried over Na2SO4, filtered and concentrated in vacuo.The crude product was obtained as a mixture of diastereomers and purified by flash chromatography (SiO2; CHCl3.MeOH, 96:4). A diastereomer with the higher Rf was formed as colourless crystals (0.24 g, 8%), mp 257.258 ¡ÆC (decomp.), Rf 0.6 (EtOAc). 1H NMR ([2H6]DMSO) d: 7.57 (s, 1H), 7.48 (d, 1H, J 14.5 Hz), 7.14 (s, 2H), 5.89 (d, 1H, J 14.5 Hz), 4.66 (s, 1H), 4.32 (s, 1H), 4.01 (q, 1H, J 7.7 Hz), 3.78 (s, 3H), 3.02 (d, J 19.6 Hz, 1H), 2.79 (d, 1H, J 19.6 Hz), 2.52 (d, 1H, J 16.5 Hz), 2.16 (d, J 16.5 Hz, 1H), 1.96.1.67 (m, 2H), 1.14 (t, 1H, J 7.7 Hz). 13CNMR ([2H6]DMSO) d: 195.6 (s), 174.6 (s), 149.5 (d), 147.9 (s), 144.4 (s), 133.6 (s), 130.6 (s), 126.5 (d), 117.5 (s), 117.1 (d), 88.4 (d), 56.8 (q), 52.1 (s), 51.6 (d), 37.9 (t), 36.6 (t), 33.3 (t), 21.5 (t).Found (%): C, 55.15; H, 4.71; N, 3.38. Calc. for C18H18BrNO4 (%): C, 55.12; H, 4.63; N, 3.57. The diastereomer with the lower Rf which was formed as a minor by-product was detected using TLC and NMR spectroscopy, it was isomerised to the main isomer.Rf 0.45 (EtOAc). Found (%): C, 55.10; H, 4.59; N, 3.46. Calc. for C18H18BrNO4 (%): C, 55.12; H, 4.63; N, 3.57. Table 2 Unsuccessful cyclization attempts. Compound G Ring system expected 3a .N(CHO). 5-6-6-6 3b .N(CHO).(CH2)2. 5-6-6-8 3c .(CH2)2. 5-6-6-7 3d 5-6-6-6-7 CH2 CH2 MeO NH2 O OH Br n m MeO O H O Br CONH2 m n K3[Fe(CN)6]/ K2CO3 1a.d 2a.d Scheme 1 HOMendeleev Communications Electronic Version, Issue 2, 2002 2 In all cases, the starting material was quantitatively consumed under the reaction conditions as observed by TLC.This study was supported by Sanochemia Pharmazeutika AG. References 1 L. J. Scott and K. L. Goa, Drugs, 2000, 60, 1095. 2 (a) B. M. Trost and F. D. Toste, J. Am. Chem. Soc., 2000, 122, 11262; (b) M. Node, S. Kodama, Y. Hamashima, T. Baba, N. Hamamichi and K. Nishide, Angew. Chem., Int. Ed. Engl., 2001, 40, 3060. 3 (a) D. H. R. Barton and G. W. Kirby, Proc. Chem. Soc., 1960, 392; (b) T. Kametani, K. Yamaki, H. Yagi and K. Fukumoto, J. Chem. Soc. C, 1969, 2602. 4 B. Kueenburg, L. Czollner, J. Froehlich and U. Jordis, Org. Process Res. Dev., 1999, 3, 425. 5 A. Poschalko, S.Welzig, M. Treu, S. Nerdinger, K. Mereiter and U. Jordis, Tetrahedron, 2002, 58, 1513. 6 M. Treu, K. Mereiter and U. Jordis, Heterocycles, 2001, 55, 1727. 7 http://www2.organik.uni-erlangen.de/software/corina/index.html. HO OMe Br G OH O O H O Br G K3[Fe(CN)6]/ K2CO3 3a–d Scheme 2 Received: 22nd January 2002; Com. 02/18