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Many routes to reserpine. although abandoned for one reason or another, deserve attention. Cf., inter alia, Isobe, M.; Fukami, N.; Nishikawa, T.; Goto, T. Heterocycles 1987, 25, 521.
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The original Woodward synthesis of reserpine goes through the initial formation of isoreserpine, its C-3 epimer, via a borohydride reduction in methanol which presumably involves axial addition of hydride to a pre chair iminium intermediate. A variety of modified reduction conditions of an iminium intermediate have been explored in the hope of producing reserpine directly, rather than via its C-3 epimer. Catalytic hydrogenation (cf. Gottfredsen, W. O.; Vangedal, S. Acta Chem. Scand. 1956, 10, 1414) also gives isoreserpine. but zinc-aqueous acid processes have been reported to yield reserpine selectively,
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(a) For instance, Weisenborn et al. (Weisenborn, F. L.; Diassi, P. A. J. Am. Chem. Soc. 1956, 78, 2022) reported the formation of reserpine, in unspecified yield, by zinc-aqueous acetic acid reduction.
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Martin (J. Am. Chem. Soc: 1987, 109, 6124) reports, however, that his group's attempts to duplicate the favorable results reported earlier for these zinc-acid reductions gave, by contrast, ratios of 1:1.7-2.0 in favor of isoreserpine.
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A similar problem has been encountered with a 3-chloroacrylate: see ref 22b.
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(a) Tamao, K.; Kakui. T.; Akita, M.; Iwahara, T.; Kanatani, R.; Yoshida, I.; Kumada, M. Tetrahedron 1983, 39, 983.
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For experimental details for this construction of (±)-33, see: Smith, A. B.. III; Nolen. E G.: Shirai, R.; Blasé. F. R.; Ohta. M.; Chida, N.; Hartz. R.; Fitch. D. M.; Clark. W. M.; Sprengeler, P. A. J. Org. Chem. 1995. 60, 7837.
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The first observation of formation of the less stable epimer by addition of an indole ring to an intermediate iminium may be by van Tamelen in the course of his synthesis of yohimbine: van Tamelen, E. E.; Shamma, M.; Burgstahler, A. W.; Wolinsky. J.; Tamm, R.: Aldrich. P. E. J. Am. Chem. Soc. 1958, 80, 5006.
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The assignment of axial stereochemistry to the cyano group in 40 was supported by NMR data and by an X-ray structure determination of a related cyanopiperidine.
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81
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0026681079
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- in acetonitrile), so that kinetic arguments relating to the angle of initial entry (perpendicular chair) into the iminium ion intermediate may not be relevant to this case. Thermodynamic equilibrium is, in any case, also in favor of an axial cyano group in 2-cyanopiperidines, possibly because of an endo anomeric effect: cf. Booth. H.: Dixon, J. M.; Khedhair, K. A. Tetrahedron 1992, 48, 6161.
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