Diastereocontrol by a Hydroxyl Auxiliary in the Synthesis of Pyrrolidines via Radical Cyclization

Article abstract of DOI:10.1021/ol026038t

(Matrix Presented) Organoselenium precursors of 3-aza-5-hexenyl radicals carrying a 1-hydroxyalkyl group in the 2-position were prepared by addition of organometallic reagents to N-allyl-2-aziridinecarbonitrile, reduction of the resulting aziridine ketone

Full text of DOI:10.1021/ol026038t

ORGANIC
LETTERS
2002
Vol. 4, No. 18
3023-3025
Diastereocontrol by a Hydroxyl Auxiliary
in the Synthesis of Pyrrolidines via
Radical Cyclization
Magnus Besev and Lars Engman*
Uppsala UniVersity, Institute of Chemistry, Department of Organic Chemistry,
Box 531, S-751 21 Uppsala, Sweden
lars.engman@kemi.uu.se
Received April 18, 2002
ABSTRACT
Organoselenium precursors of 3-aza-5-hexenyl radicals carrying a 1-hydroxyalkyl group in the 2-position were prepared by addition of
organometallic reagents to N-allyl-2-aziridinecarbonitrile, reduction of the resulting aziridine ketone, and regioselective benzeneselenol ring
opening of the aziridine. Reductive radical cyclization was highly selective, affording the corresponding trans-2,4-disubstituted pyrrolidine
(cis/trans ca. 1/10) as the major diastereomer. Recrystallization afforded material that was substantially more enriched in the trans isomer
(cis/trans < 1/25).
Radical carbon-carbon bond-forming reactions,1 especially
of the intramolecular type (radical cyclizations), are nowa-
days so versatile that they are routinely considered in
retrosynthetic analysis of complex organic molecules. These
reactions are not only restricted to carbocycle construction
but also well suited for the preparation of various hetero-
cycles such as tetrahydrofurans and pyrrolidines and deriva-
tives thereof. However, a problem frequently encountered
in the application of these radical cyclization reactions is
that of diastereocontrol.2
However, it turns out that the selectivity (cis/trans) in simple
disubstituted systems rarely exceeds 4/1 in favor of the
predominating isomer.4 We therefore thought it would be
interesting to try to develop a methodology that would allow
preparation of either of the cis and trans isomers of a
particular system with higher selectivity. Thus, we recently
found that trialkylaluminums directed radical cyclization of
(2) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
ReactionssConcepts, Guidelines and Synthetic Applications; VCH: New
York, 1996.
(3) Beckwith, A. L. J.; Easton, C. J.; Serelis, A. K. J. Chem. Soc., Chem.
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.
Chem. 1987, 52, 959.
By assuming a chairlike transition state, Beckwith and
Houk have provided a model that could predict the stereo-
chemical outcome of cyclization of variously substituted
5-hexenyl radicals (including oxa and aza derivatives).3
(4) 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.;
Hoffmann, P.; Mindt, T. Synlett 1993, 871. Keusenkothen, P. F.; Smith,
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:
Asymmetry 1991, 2, 793. Bachi, M. D.; De Mesmaeker, A.; Stevenart-De
Mesmaeker, N. Tetrahedron Lett. 1987, 28, 2637. Watanabe, Y.; Ueno,
Y.; Tanaka, C.; Okawara, M.; Endo, T. Tetrahedron Lett. 1987, 28, 3953.
(1) Giese, B. Radicals in Organic Synthesis: Formation of C-C bonds;
Pergamon Press: Oxford, 1986. Regitz, M., Giese, B., Eds. Houben-Weyl,
Methoden der Organishen Chemie; Band E19a, C.-Radikale, Teil 1+2;
Georg Thieme Verlag: Stuttgart, 1989. Curran, D. P. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Semmelhack, M. F., Eds.;
Pergamon Press: Oxford, 1991; Vol. 4, pp 715 and 779. Motherwell, W.
B.; Crich, D. Free Radical Chain Reactions in Organic Synthesis; Academic
Press: New York, 1992. Fossey, J.; Lefort, D.; Sorba, J. Free Radicals in
Organic Chemistry; Wiley: New York, 1995. Giese, B.; Kopping, B.; Go¨bel,
T.; Dickhaut, J.; Thoma, G.; Kulicke, K. J.; Trach, F. Org. React. 1996,
48, 301. Renaud, P., Sibi, M. P., Eds. Radicals in Organic Synthesis; Wiley-
VCH: Weinheim, 2001; Vol 1: Basic Principles, Vol 2: Applications.
10.1021/ol026038t CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/03/2002

2-substituted 3-oxa-5-hexenyl radicals to occur in a highly
cis-selective fashion (the unperturbed reaction is trans-
selective).5 Similarly, cyclization of 2-substituted 3-aza-5-
hexenyl radicals 1 (Scheme 1) was found to occur in a highly
We envisioned suitable organoselenium radical precursors
could be prepared from readily available8 N-allyl-2-aziridi-
necarbonitrile (4) by addition of an organometallic reagent9
and hydrolysis of the resulting imine (Scheme 2).
Scheme 2
Scheme 1
cis-selective fashion (cis/trans ) 10/1-20/1) if the nitrogen
was carrying a bulky substitutent6 (the best results were
obtained with a diphenylphosphinoyl group), whereas cy-
clization of the corresponding N-unsubstituted radical pro-
vided the trans-2,4-disubstituted pyrrolidine as the major
product. Sterically demanding 2-substituents afforded a large
excess of trans-disubstituted pyrrolidine (Scheme 1; cis/trans
< 1/20 for R ) t-Bu and P ) H).
With less bulky substituents (R ) methyl, n-hexyl,
isopropyl), the cis/trans ratio was usually close to 1/4 when
the reaction was carried out at 15 °C. One notable exception
was the case with a phenoxymethyl substituent (Scheme 1;
cis/trans ) 1/14 for R ) CH2OPh and P ) H). We
hypothesized that this high trans-selectivity could be due to
intramolecular hydrogen bonding,7 favoring an equatorial
orientation of the 2-substituent in a chairlike transition state
2 (Figure 1).
PhLi added to compound 4 already at -78 °C. PhMgBr
was less reactive but provided a similar yield (92%) of
compound 5a. When aliphatic Grignard reagents were
employed, addition of a catalytic amount (0.1 equiv) of CuBr
was found to give cleaner and higher yielding reactions
(compounds 5c-e).10 Intermediate imines obtained from
addition of aliphatic organometallic reagents were hydrolyzed
during ammonium chloride workup. Those obtained from
aromatic reagents were hydrolyzed with lithium hydroxide
in methanol/water. The resulting ketoaziridines can be
diastereoselectively reduced to the corresponding alcohols11
and a phenylseleno group introduced by benzeneselenol ring
opening of the aziridine12 (Scheme 3).
After zinc complexation, aziridine ketones 5 on sodium
borohydride reduction afforded only the corresponding
erythro-configured aziridine alcohols 6. The following ring-
opening of the aziridine with benzeneselenol occurred
regioselectively from the sterically least hindered side to give
erythro-configured amino alcohols 7.
Reductive radical cyclization of compounds 7 was effected
in high yield by photolysis in benzene in the presence of
AIBN and tri-n-butyltin hydride. As shown in Table 1, the
diastereomeric mixtures of 2,4-disubstituted pyrrolidines 8
obtained were highly enriched in the trans isomer (1/12 <
cis/trans < 1/9). Although the level of selectivity does not
quite match the one obtained with a phenoxymethyl sub-
stituent in the 2-position (Figure 1, structure 2 cis/trans )
1/14; vide supra), it is clear that cyclization of radical
Figure 1. Hydrogen bonding in the transition state of the radical
ring closure.
As a further extension of this reasoning, it occurred to us
that it might be possible to employ a hydroxyl substitutent
in the side chain as an auxiliary (favoring transition state 3)
to increase trans-selectivity in the cyclization of 2-substituted
3-aza-5-hexenyl radicals. Provided the auxiliary could be
smoothly removed, a rather general synthesis of trans-2,4-
disubstituted pyrrolidines would be achieved.
(8) US Pat. 4,321,197, 1983.
(9) Deng, S. X.; Huang, D. W.; Landry, D. W. Tetrahedron Lett. 2001,
42, 6259. Sugimura, T.; Koguro, K.; Tai, A. Tetrahedron Lett. 1993, 34,
509. Apen, P. G.; Rasmussen, P. G. J. Heterocycl. Chem. 1992, 29, 1091.
De Kimpe, N.; Sulmon, P.; Schamp, N. Bull. Soc. Chim. Belg. 1986, 95,
567. Fuerstner, A.; Thiel, O. R.; Kindler, N.; Bartkowska, B. J. Org. Chem.
2000, 65, 7990. Kao, K.-H.; Sheu, R.-S.; Chen, Y.-S.; Lin, W.-W.; Liu,
J.-T.; Yao, C.-F. J. Chem. Soc., Perkin Trans. 1 1999, 2383. Paquette, L.
A.; Mendez-Andino, J. L. J. Org. Chem. 1998, 63, 9061. Estieu, K.; Ollivier,
J.; Salaun, J. Tetrahedron 1998, 54, 8075.
(5) Ericsson, C.; Engman, L. Org. Lett. 2001, 3, 3459.
(6) Besev, M., Engman, L. Org. Lett. 2000, 2, 1589.
(7) For an example of hydrogen bonding in the synthesis of 2,3-
disubstituted pyrrolidines, see: Pedrosa, R.; Andre´s, C.; Duque-Soladana,
J. P.; Mendiguchia, P. Eur. J. Org. Chem. 2000, 3727. See also: Hanessian,
S.; Yang, H.; Schaum, R. J. Am. Chem. Soc. 1996, 118, 2507. Ku¨ndig, E.
P.; Xu, L.-H.; Romanens, P. Tetrahedron Lett. 1995, 36, 4047.
(10) Weiberth, F. J.; Hall, S. S. J. Org. Chem. 1987, 52, 3901.
(11) Bartnik, R.; Laurent, A.; Lesniak, S. J. Chem. Res., Miniprint 1982,
2701.
(12) Katagiri, T.; Takahashi, M.; Fujiwara, Y.; Ihara, H.; Uneyama, K.
J. Org. Chem. 1999, 64, 7323. See also ref 6.
3024
Org. Lett., Vol. 4, No. 18, 2002

Scheme 3
Figure 2. Oxazolidinones.
The ring closure shown in the first entry of Table 1 (R )
Ph) was also tried in a protic solvent (tert-butyl alcohol).
However, the diastereoselectivity did not differ from that
1
observed in benzene. Also, H NMR studies of the radical
precursor 7a did not provide any evidence for hydrogen
bonding. This suggests that structure 3 (or a similar arrange-
ment where the hydroxyl is donating a proton) does not
contribute to preorganize the molecule prior to cyclization.
Rather, the observed trans-directing effect of the auxiliary
seems to be the result of increased steric bulk of the side
chain. In an effort to somehow mimic the effect of intra-
molecular hydrogen bonding, amino alcohol 7a was con-
verted into oxazolidinone 9 (Figure 2) by heating in dimethyl
carbonate with sodium hydride. Although reductive radical
cyclization produced mostly the diastereomer of oxazolidi-
none 10 where the 2,4-substituents of the pyrrolidine moiety
are oriented trans, the cis/trans selectivity (1/6) could not
match the one seen in the cyclization of compound 7a.
Cyclization of compound 7a was also carried out in the
presence of various aluminum-based Lewis acids that could
be expected to chelate to the amino alcohol moiety. However,
as compared with the unperturbed reaction, none of these
additives caused a notable change in the diastereoselectivity
of radical cyclization.
precursors carrying a hydroxyl auxiliary in the side chain
are much more trans-selective than they would be if the
hydroxyl was missing. As a further bonus of the hydroxyl
auxiliary, pyrrolidines 8 were found to be highly crystalline.
Thus, recrystallization of crude compound 8a from cyclo-
hexane and sublimation of 8d afforded material substantially
more enriched in the trans-isomer (cis/trans < 1/25). Several
protocols (including radical deoxygenation and displacement
of a suitable sulfonate ester with lithium aluminum hydride)
could be considered for removal of the hydroxyl auxiliary.
As an example, compound 8a was N-tosylated, converted
to a xanthate, and then subjected to treatment with AIBN
and tri-n-butyltin hydride (Barton-McCombie method13).
The product was a 1/9 mixture of cis and trans N-tosyl-2-
benzyl-4-methylpyrrolidine, the spectral characteristics of
which were in excellent agreement with those of authentic
samples of the materials.6
In conclusion, we have found that 5-exo-cyclization of
readily available organoselenium precursors of 3-aza-5-
hexenyl radicals carrying a 1-hydroxyalkyl group in the
2-position gives the corresponding 2,4-trans-disubstituted
pyrrolidines as the predominating products (cis/trans ratio
ca. 1/10). By recrystallization, the diastereoselectivity could
then be further improved. Since the hydroxyl auxiliary can
be easily removed, the methodology nicely complements
strategies for diastereocontrol that are based on variation in
the N-substituent (which provide cis-2,4-disubstituted pyr-
rolidines with high selectivity6).
Table 1. Diastereoselective Reductive Radical Cyclization of
3-Aza-5-hexenyl Phenyl Selenides 7
Acknowledgment. We thank the Swedish Research
Council for financial support.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds prepared.
This material is available free of charge via the Internet at
http://pubs.acs.org.
R
product yielda(%) cis/trans ratiob
Ph
8a
8b
8c
8d
8e
82
80
96
81
84
1/9
1/9
1/10
1/12
1/9
2-thienyl
n-pentyl
i-propyl
OL026038T
2-(1,3-dioxolan-2-yl)ethyl
1
a Isolated yield. b As determined by H NMR.
(13) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574.
Org. Lett., Vol. 4, No. 18, 2002
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