Pergamon Tetrahedron Letters 41 (2000) 759–762 TETRAHEDRON LETTERS A novel approach to conformationally restricted analogues of nicotine and anabasine by an intramolecular Hamaguchi–Ibata reaction Tarun K. Sarkar, * Sankar Basak and Sunil K. Ghosh Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India Received 8 September 1999; revised 12 November 1999; accepted 17 November 1999 Abstract A short synthesis of methyl (SR)-8,10-dichloro-1,2,3,4,5,6-hexahydro-6-hydroxy-1-methyl-1,9-phenanthroline- 6-carboxylate (14) has been achieved en route to conformationally restricted analogues of nicotine and anabasine. The key feature of this process involves an efficient intramolecular Hamaguchi–Ibata reaction of 11. © 2000 Elsevier Science Ltd. All rights reserved. Keywords: azaisobenzofuran; intramolecular cycloaddition; domino reaction; 1,9-phenanthroline. The examination of the role of particular conformations on the pharmacological properties of important biologically active molecules has remained an active area of investigation. One approach to such a study is to modify the parent molecule in such a fashion that its original conformational mobility is severely limited to one particular conformation. 1 In light of this, recently a series of conformationally restricted analogues, e.g. 1 and 2 of nicotine (3) and anabasine (4) have been synthesized and evaluated as agonists of neuronal acetylcholine receptors (nAChRs). 2 In particular, compound 1 which selectively activates human recombinant α2β4 and α4β4 nAChRs has been shown to be active in animal models of Parkinson’s disease and pain. The long and circuitous synthetic route 2 described for the ring systems 1 and 2 does not appear to be viable for the synthesis of a large variety of bridged nicotines and anabasines required for biological testing. Hence, the development of an alternative and more flexible route which overcomes these limitations was felt desirable. * Corresponding author. 0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S0040-4039(99)02148-6 tetl 16076