Unexpected Synthesis Of Conformationally Restricted Analogues Of γ-amino Butyric Acid (gaba): Mechanism Elucidation By Electrospray Ionization Mass Spectrometry

(Chemical Equation Presented). From previous results with lower homologues, dehydroiodination of the three alkenyl-β-enamino esters 3a-c was expected to provide six-membered N-heterocyclic products. The reactions of 3a-c with triethylamine are found to lead, however, to the unexpected stereoselective synthesis of the trisubstituted cyclopentane derivatives 4a-c, as confirmed by IR and NMR spectroscopy. Cyclopentanes 4a-c bear two chiral centers and a γ-amino ester moiety, and are therefore conformationally restricted analogues of γ-amino butyric acid (GABA), which is the major inhibitory neurotransmitter in the central nervous system. Use of electrospray ionization mass (ESI-MS) and tandem mass spectrometry (ESI-MS/MS) allowed the key iminium ion intermediates 5a-c+, as well as the protonated molecules of both the reactant and final products, [3a-c + H]+ and [4a-c + H] +, to be intercepted and structurally characterized. From these findings a mechanism for this unexpected but synthetically attractive and efficient stereoselective reaction is proposed.701110114Krogsgaard-Larsen, P., (1988) Med. Res. Rev., 8, p. 27Andersen, K.E., Sorensen, J.L., Lau, J., Lundt, B.F., Petersen, H., Huusfeldt, P.O., Suzdak, P.D., Swedberg, M.D.B., (2001) J. Med. Chem., 44, p. 2152Moglioni, A.G., Brousse, B.N., Álvarez-Larena, A., Moltrasio, G.Y., Ortuño, R.M., (2002) Tetrahedron: Asymmetry, 13, p. 451Carpes, M.J., Correia, C.R.D., (2002) Tetrahedron Lett., 43, p. 741Dumond, Y.R., Montchamp, J.L., (2002) J. Organomet. Chem., 653, p. 252Ito, H., Omodera, K., Takigawa, Y., Taguchi, T., (2002) Org. Lett., 4, p. 1499Aitken, R.A., Karodia, N., Massil, T., Young, R.J., (2002) J. Chem. Soc., Perkin Trans. 1, p. 533Blay, G., Fernàndez, I., Monje, B., Pedro, J.R., (2004) Tetrahedron, 60, p. 165Eberlin, M.N., Kascheres, C., (1988) J. Org. Chem., 53, p. 2084Augusti, R., Eberlin, M.N., Kascheres, C., (1995) J. Heterocycl. Chem., 32, p. 1355Augusti, R., Kascheres, C., (1993) J. Org. Chem., 58, p. 7079Fustero, S., Torre, M.G., Jofre, V., Carlón, R.P., Navarro, A., Fuentes, A.S., Carrió, J.S., (1998) J. Org. Chem., 63, p. 8825Gilchrist, T.L., (1998) J. Chem. Soc., Perkin Trans. 1, p. 615Ferraz, H.M.C., Pereira, F.L.C., (2004) Quim. Nova, 27, p. 89Kascheres, C.M., (2003) J. Braz. Chem. Soc., 14, p. 945Elassar, A.Z.A., El-Khair, A.A., (2003) Tetrahedron, 59, p. 8463Melo, J.O.F., Ratton, P.M., Augusti, R., Donnici, C.L., (2004) Synthetic Commun., 34, p. 369Ferraz, H.M.C., Oliveira, E.O., Payret-Arrúa, M.E., Brandt, C.A., (1995) J. Org. Chem., 60, p. 7357Ferraz, H.M.C., Pereira, F.L.C., Leite, F.S., Nunes, M.R.S., Payret-Arrúa, M.E., (1999) Tetrahedron, 55, p. 10915Triggle, D.J., Langs, D.A., Janis, R.A., (1989) Med. Res. Rev., 9, p. 123Triggle, D.J., Janis, R.A., (1987) Annu. Rev. Pharmacol. Toxicol., 27, p. 347Elmslie, K.S., (2004) J. Neurosci. Res., 75, p. 733Stout, D.M., Meyers, A.I., (1982) Chem. Rev., 82, p. 233Sausins, A., Duburs, G., (1988) Heterocycles, 27, p. 291Goldman, S., Stoltefuss, J., (1991) Angew. Chem., Int. Ed. Engl., 30, p. 1559Whitehouse, C.M., Dreyer, R.N., Yamashita, M., Fenn, J.B., (1985) Anal. Chem., 57, p. 675Fenn, J.B., Mann, M., Meng, C.K., Wong, S.F., Whitehouse, C.M., (1989) Science, 246, p. 64Cole, R.B., (1997) Electrospray Ionization Mass Spectroscopy, , John Wiley & Sons, Inc.: New YorkCooks, R.G., Zhang, D.X., Koch, K.J., Gozzo, F.C., Eberlin, M.N., (2001) Anal. Chem., 73, p. 3646Gozzo, F.C., Santos, L.S., Augusti, R., Consorti, C.S., Dupont, J., Eberlin, M.N., (2004) Chem. Eur. J., 10, p. 6187Koch, K.J., Gozzo, F.C., Nanita, S.C., Takats, Z., Eberlin, M.N., Cooks, R.G., (2002) Angew. Chem., Int. Ed., 41, p. 1721Santos, L.S., Pavam, C.H., Almeida, W.P., Coelho, F., Eberlin, M.N., (2004) Angew. Chem., Int. Ed., 43, p. 4330Raminelli, C., Prechtl, M.H.G., Santos, L.S., Eberlin, M.N., Comasseto, J.V., (2004) Organometallics, 23, p. 3990Domingos, J.B., Longhinotti, E., Brandão, T.A.S., Bunton, C.A., Santos, L.S., Eberlin, M.N., Nome, F., (2004) J. Org. Chem., 69, p. 6024Meyer, S., Metzger, J.O., (2003) Anal. Bioanal. Chem., 377, p. 1108Meyer, S., Koch, R., Metzger, J.O., (2003) Angew. Chem., Int. Ed., 42, p. 4700Meurer, E.C., Santos, L.S., Pilli, R.A., Eberlin, M.N., (2003) Org. Lett., 5, p. 1391Griep-Raming, J., Meyer, S., Bruhn, T., Metzger, J.O., (2002) Angew. Chem., 114, p. 2863Hilderling, C., Adlhart, C., Chen, P., (1998) Angew. Chem., Int. Ed., 37, p. 2685Chen, P., (2003) Angew. Chem., Int. Ed., 42, p. 2832Tomazela, D.M., Gozzo, F.C., Ebeling, G., Dupont, J., Eberlin, M.N., (2004) Inorg. Chim. Acta, 357, p. 2349Neto, B.A.S., Ebeling, G., Gonçalves, R.S., Gozzo, F.C., Eberlin, M.N., Dupont, J., (2004) Synthesis, p. 1155Pereira, R.M.S., Paula, V.I., Buffon, R., Tomazela, D.M., Eberlin, M.N., (2004) Inorg. Chim. Acta, 357, p. 2100Ferraz, H.M.C., Sano, M.K., Nunes, M.R.S., Bianco, G.G., (2002) J. Org. Chem., 67, p. 412