diastereoselectivity in free-radical cyclization reactions have
so far been less successful.
diastereoselectivity in various types of azaalkenyl radical
cyclizations.15 The results presented in the following for
3-aza-5-hexenyl radicals show that the N-substituent has a
dramatic effect on the stereochemical outcome of cyclization.
Selenium-based radical precursors suitable for this inves-
tigation were prepared by two different routes. In contrast
to N-tosylaziridines, N-alkylaziridines are not ring-opened
by benzeneselenolate generated by sodium borohydride
reduction of diphenyl diselenide. However, on addition of
trifluoroacetic acid, ring opening occurred regioselectively
from the sterically least hindered side. Thus, aziridines 1,
prepared by allylation of the corresponding N-unsubstituted
aziridines, were converted to â-(allylamino)alkyl phenyl
selenides 2 in fair yields as shown in Scheme 2. In another
Diastereoselectivity is governed primarily by conforma-
tional and steric effects as described by the Beckwith-Houk
transition state model.8 Thus, 1- or 3-substituted 5-hexenyl
radicals afford predominantly cis-disubstituted products,
whereas 2- or 4-substituted radicals give mainly trans-
disubstituted ones. However, the selectivity in simple systems
rarely exceeds 4:1 in favor of the major diastereomer. Recent
successful strategies to perturb Beckwith-Houk diastereo-
selectivities in intramolecular radical cyclization reactions
are based on Lewis acid coordination,9 variation in the
hydrogen atom donor,10 or the stereochemical influence of
the anomeric effect.11
The model for radical cyclization proposed by Beckwith
and Houk is also applicable to various types of heterocycle
construction (e.g., tetrahydrofuran12 and pyrrolidine13 syn-
thesis). Some time ago, we reported the preparation of 2,4-
disubstituted N-tosylpyrrolidines from N-tosylaziridines via
benzeneselenolate ring opening, N-allylation, and reductive
radical cyclization (Scheme 1).14 In disagreement with the
Scheme 2
Scheme 1
approach, readily prepared16 R-(phenylselenenyl) ketones 3
were condensed with allylamine in the presence of titanium
tetrachloride as a dehydrating agent.17 Subsequent in situ
sodium cyanoborohydride reduction of the imines 4 afforded
the desired radical precursors 5 (Scheme 3).
Beckwith-Houk rules, the products were obtained predomi-
nantely (2/1-3/1) as cis isomers. These results prompted us
to study the N-substituent as a tool for controlling the
Scheme 3
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Commun. 1980, 482. Beckwith, A. L. J.; Lawrence, T.; Serelis, A. K. J.
Chem. Soc., Chem. Commun. 1980, 484. Beckwith, A. L. J.; Schiesser, C.
H. Tetrahedron 1985, 41, 3925. Spellmeyer, D. C.; Houk, K. N. J. Org.
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B.; Fensterbank, L.; Lacoˆte, E.; Malacria, M. J. Am. Chem. Soc. 1999, 121,
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numa, E.; Yonemitsu, O.; Nishida, A.; Kawahara, N. J. Am. Chem. Soc.
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B.; Weiler, L. J. Org. Chem. 1992, 57, 6099.
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A. L. J.; Page, D. M. J. Org. Chem. 1998, 63, 5144.
For initial screening of the effect of various N-protecting
groups on diastereoselectivity in 3-aza-5-hexenyl radical
cyclization, aminoselenide 2a was reacted with a selection
of acylating, sulfonylating, and phosphinoylating agents
(Table 1). Reductive radical cyclization was then effected
in 60-93% yields in benzene with thermal (80 °C) or
photochemical (15 °C) initiation in the presence of AIBN
and tri-n-butylstannane. Diastereoselectivities were deter-
mined by 1H NMR, sometimes after acidic hydrolysis of the
N-protecting groups. As shown in Table 1, cyclization of
the N-unprotected compound afforded predominantely the
(12) Engman, L.; Gupta, V. J. Org. Chem. 1997, 62, 157.
(13) For examples of 3-aza-5-hexenyl radical cyclizations of varying
diastereoselectivity, see: Andre´s, C.; Duque-Soladana, J. P.; Pedrosa, R.
J. Org. Chem. 1999, 64, 4273. Andre´s, C.; Duque-Soladana, J. P.; Pedrosa,
R. J. Org. Chem. 1999, 64, 4282. Bertrand, M.-P.; Gastaldi, S.; Nouguier,
R. Tetrahedron 1998, 54, 12829. De Mesmaeker, A.; Waldner, A.;
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M. B. Tetrahedron 1992, 48, 2977. Belvisi, L.; Gennari, C.; Poli, G.;
Scolastico, C.; Salom, B.; Vassallo, M. Tetrahedron 1992, 48, 3945.
Baldwin, J. E.; Moloney, M. G.; Parsons, A. F. Tetrahedron 1992, 48, 9373.
Soucy, F.; Wernic, D.; Beaulieu, P. J. Chem. Soc., Perkin Trans. 1 1991,
2885. Gennari, C.; Poli, G.; Scolastico, C.; Vassallo, M. Tetrahedron:
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