4-Fluoro-2,4-methanoproline Anton N. Tkachenko, Dmytro S. Radchenko, Pavel K. Mykhailiuk,* Oleksandr O. Grygorenko, and Igor V. Komarov Department of Chemistry, KyiV National Taras SheVchenko UniVersity, Vul. Volodymyrska 64, 01033 KyiV, Ukraine, and Enamine Ltd., Vul. Oleksandra MatrosoVa 23, 01103 KyiV, Ukraine pashamk@gmx.de Received October 15, 2009 ABSTRACT The first fluorinated analogue of the naturally occurring 2,4-methanoproline, 4-fluoro-2,4-methanoproline, has been synthesized in five steps from commercially available methyl 2-fluoroacrylate through a photochemical cyclization as a key step in generating a 2-azabicyclo[2.1.1]hexane skeleton. 2,4-Methanoproline (1) is a naturally occurring nonprotei- nogenic amino acid first isolated from the seeds of the legume Ateleia herbert smithii Pittier, growing in Costa Rica (Figure 1). 1,2 The seeds of this tree are ignored by more than 100 seed predators, and it was recently shown that derivatives of 1 have high insect antifeedant activity. 3 It is supposed that this biological activity is caused by the conformational rigidity of the 2-azabicyclo[2.1.1]hexane skeleton, which leads to the reduced metabolism of 1, compared to proline. Since the first synthesis of 2,4-methanoproline in 1980, 4 a large number of different synthetic approaches to 1 have appeared, 5 thereby indicating an intense interest in this amino acid. For example, 1 was found to stabilize the peptide tertiary trans-amide bonds, 6 which is of great potential in peptide design, since the cis-trans isomerization of peptide bonds is closely related to biologically relevant processes, primarily to folding and unfolding. 7 In particular, 1 was used instead of proline to synthesize a conformationally con- strained analogue of thyrotropin-releasing hormone (TRH) and to study the latter. 8 Moreover, 1 was also introduced into the oligopeptides bradykinin and angiotensin, which are neurotransmitters playing an important role in the regulation of blood pressure and heart function. 9 Last year, 1 was applied as a conformationally rigid building block to prepare new potential ligands of the nicotinic acetylcholine recep- tor. 10 The substitution of fluorine for hydrogen in organic compounds is widely used to modify their physical, chemical, and biological characteristics. 11 Surprisingly, despite the great potential of 2,4-methanoproline (1), there are, to the best of our knowledge, no fluorinated analogues of 1 described in (1) Bell, E. A.; Qureshi, M. Y.; Pryce, R. J.; Janzen, D. H.; Lemke, P.; Chardy, J. J. Am. Chem. Soc. 1980, 102, 1409. (2) Recently, 1 was also found in the legume Bocoa alterna: Kite, G. C.; Ireland, H. Phytochemistry 2002, 59, 163. (3) Stevens, C. V.; Smagghe, G.; Rammeloo, T.; De Kimpe, N. J. Agric. Food Chem. 2005, 53, 1945. (4) Pirrung, M. C. Tetrahedron Lett. 1980, 21, 4577. (5) (a) Hughes, P.; Martin, M.; Clardy, J. Tetrahedron Lett. 1980, 21, 4579. (b) Hughes, P.; Clardy, J. J. Org. Chem. 1988, 53, 4793. (c) Gaoni, Y. Org. Prep. Proced. Int. 1995, 27, 185. (d) Stevens, C.; De Kimpe, N. J. Org. Chem. 1996, 61, 2174. (e) Rammeloo, T.; Stevens, C. V.; De Kimpe, N. J. Org. Chem. 2002, 67, 6509. (f) Krow, G. R.; Herzon, S. B.; Lin, G.; Qiu, F.; Sonnet, P. E. Org. Lett. 2002, 4, 3151. (g) Rammeloo, T.; Stevens, C. V. Chem. Commun. 2002, 250. (h) Grygorenko, O. O.; Artamonov, O. S.; Palamarchuk, G. V.; Zubatyuk, R. I.; Shishkin, O. V.; Komarov, I. V. Tetrahedron: Asymmetry 2006, 17, 252. (6) (a) Montelione, G. T.; Hughes, P.; Scheraga, H. A. J. Am. Chem. Soc. 1986, 108, 6765. (b) Talluri, S.; Montelione, G. T.; van Duyne, G.; Piela, L.; Chardy, J.; Scheraga, H. A. J. Am. Chem. Soc. 1987, 109, 4473. (c) Piela, L.; Ne ´methy, G.; Scheraga, H. A. J. Am. Chem. Soc. 1987, 109, 4477. (7) (a) Ba ¨chinger, H. P.; Engel, J.; Bruckner, P.; Timpl, R. Eur. J. Biochem. 1978, 90, 605. (b) Salahuddin, A. J. Biosci. 1984, 6, 349. (c) Cis-trans isomerization in biochemistry; Dugave, C., Ed.; Wiley-VCH: Weinheim, 2006. (8) Mapelli, C.; Van Halbeek, H.; Stammer, C. H. Biopolymers 1990, 29, 407. (9) Juvvadi, P.; Dooley, D. J.; Humblet, C. C.; Lu, G. H.; Lunney, E. A.; Panek, R. L.; Skeean, R.; Marshall, G. R Int. J. Pept. Protein Res 1992, 40, 163. (10) (a) Malpass, J. R.; Patel, A. B.; Davies, J. W.; Fulford, S. Y. J. Org. Chem. 2003, 68, 9348. (b) Patel, A. B.; Malpass, J. R. J. Med. Chem. 2008, 51, 7005. ORGANIC LETTERS 2009 Vol. 11, No. 24 5674-5676 10.1021/ol902381w  2009 American Chemical Society Published on Web 11/11/2009