Radical cyclization of beta-aminoacrylates: synthesis of (-)-indolizidine 223AB.

Article abstract of DOI:10.1021/ol006094z

[reaction: see text] (-)-Indolizidine 223AB was synthesized via radical cyclization of the beta-aminoacrylate derivative of a trans-2,5-disubstituted pyrrolidine. The trans-2,5-disubstituted pyrrolidine substrate was prepared by radical cyclization of a S

Full text of DOI:10.1021/ol006094z

ORGANIC
LETTERS
2000
Vol. 2, No. 14
2169-2171
Radical Cyclization of
â-Aminoacrylates: Synthesis of
(−)-Indolizidine 223AB
Eun Lee,* Eun Jeong Jeong, Sun Joon Min, Sukwon Hong, Jaehong Lim,
Sang Kyun Kim, Hak Joong Kim, Bum Gyu Choi, and Ki Chul Koo
School of Chemistry and Molecular Engineering, Seoul National UniVersity,
Seoul, 151-742, Korea
eunlee@snu.ac.kr
Received May 23, 2000
ABSTRACT
(−)-Indolizidine 223AB was synthesized via radical cyclization of the â-aminoacrylate derivative of a trans-2,5-disubstituted pyrrolidine. The
trans-2,5-disubstituted pyrrolidine substrate was prepared by radical cyclization of a Ses-protected â-aminoacrylate.
Radical cyclization of â-alkoxyacrylates and â-aminoacry-
lates has developed into a useful general method in the
synthesis of oxacyclic1,2 and azacyclic3 compounds. In the
radical cyclization reactions of â-alkoxyacrylates derived
from secondary alcohols, cis-2,5-disubstituted tetrahydro-
furans and cis-2,6-disubstituted tetrahydropyrans are obtained
in high stereoselectivity. On the contrary, â-aminoacrylates
prepared from 2-amino-4-bromobutane were converted into
product mixtures favoring trans-2,5-disubstituted pyrrolidine
products. The level of trans/cis stereocontrol varied depend-
ing on the nature of amino protecting groups: the carbamate
substrates exhibited ∼3:2 selectivity whereas a useful level
of selectivity (∼4:1) was ascertained when the methane-
sulfonamide substrate was employed. For further studies on
the stereocontrol in the azacycle synthesis via radical
cyclization of â-aminoacrylates, the 2-(trimethylsilyl)ethane-
sulfonyl (Ses) protecting group was chosen;4 the Ses amides
were expected to behave like Ms amides,5 and they offer
further advantage of easier deprotection protocol. The results
of the 6-exo cyclization reactions for preparation of piperi-
dine products are summarized in Table 1.
(1) (a) Lee, E.; Tae, J. S.; Lee, C.; Park, C. M. Tetrahedron Lett. 1993,
34, 4831. (b) Lee, E.; Tae, J. S.; Chong, Y. H.; Park, Y. C.; Yun, M.; Kim,
S. Tetrahedron Lett. 1994, 35, 129. (c) Lee, E.; Park, C. M. J. Chem. Soc.,
Chem. Commun. 1994, 293. (d) Lee, E.; Jeong, J.-w.; Yu, Y. Tetrahedron
Lett. 1997, 38, 7765. (e) Lee, E.; Park, C. M.; Yun, J. S. J. Am. Chem. Soc.
1995, 117, 8017. (f) Lee, E.; Yoo, S.-K.; Cho, Y.-S.; Cheon, H.-S.; Chong,
Y. H. Tetrahedron Lett. 1997, 38, 7757. (g) Lee, E.; Yoo, S.-K.; Choo, H.;
Song, H. Y. Tetrahedron Lett. 1998, 39, 317. (h) Lee, E.; Choi, S. J. Org.
Lett. 1999, 1, 1127. (i) Lee, E.; Song, H. Y.; Kim, H. J. J. Chem. Soc.,
Perkin Trans. 1 1999, 3395.
(2) For further developments, see the following references. (a) Use of
acyl radicals: Evans, P. A.; Roseman, J. D.; Garber, L. T. J. Org. Chem.
1996, 61, 4880, and the references therein. (b) Formation of oxepanes in
the presence of a Lewis acid: Yuasa, Y.; Sato, W.; Shibuya, S. Synth.
Comm. 1997, 27, 573. (c) Photosensitized electron-transfer cyclization of
aldehydes: Pandey, G.; Hajra, S.; Ghorai, M. K.; Kumar, R. J. Org. Chem.
1997, 62, 5966. (d) SmI2-Induced cyclization of aldehydes: Hori, N.;
Matsukura, H.; Matsuo, G.; Nakata, T. Tetrahedron Lett. 1999, 40, 2811.
(e) O-Linked oxepane synthesis: Sasaki, M.; Noguchi, T.; Tachibana, K.
Tetrahedron Lett. 1999, 40, 1337.
From the results of reactions of the substrates 1a, 1b, and
1c, it appears that use of bulkier R′ improves overall
(3) (a) Lee, E.; Kang, T. S.; Joo, B. J.; Tae, J. S.; Li, K. S.; Chung, C.
K. Tetrahedron Lett. 1995, 36, 417. (b) Lee, E.; Li, K. S.; Lim, J.
Tetrahedron Lett. 1996, 37, 1445. (c) Lee, E.; Kang, T. S.; Chung, C. K.
Bull. Kor. Chem. Soc. 1996, 17, 212.
(4) Weinreb, S. M.; Demko, D. M.; Lessen, T. A. Tetrahedron Lett. 1986,
27, 2099.
(5) Cyclization products were not obtained from p-toluenesulfonamide
substrates, which were mainly recovered.
10.1021/ol006094z CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/17/2000

Synthesis of 7c/8c (Scheme 1) may serve as a typical
example for conversions in Tables 1 and 2. The Ses amide
Table 1
Scheme 1
efficiency but does not affect stereoselectivity. From the allyl
derivative 1d, a trans/cis ratio of ∼13:1 was obtained in the
product mixture. Use of bulkier R group was detrimental to
the stereoselectivity as shown in the case of the substrates
1e and 1f.
In the pyrrolidine synthesis, simple reduction products
were not isolated, which indicates higher efficiency for the
5-exo mode of cyclization (Table 2). Changing the R′ group
11 was prepared from the known diol 106 via TBS protection,
Mitsunobu reaction using Ses-NH-Boc,7 TBS deprotection,
and tosylation. Phenylselenide substitution of 11 proceeded
in high yield, and the formation of the â-aminoacrylate 6c8
was achieved via reaction with benzyl propiolate in the
presence of N-methylmorpholine. Radical cyclization reaction
of 6c under the standard high-dilution conditions then
provided a mixture of the products 7c and 8c in 83% yield.
Table 2
The major product 7c was used in the synthesis of (-)-
indolizidine 223AB, a representative alkaloid isolated from
the skin of the neotropical dart-poison frogs of the genus
Dendrobates.9
The product mixture 7c/8c was converted into the ho-
mologous alcohol mixture 12/13 via the Arndt-Eistert
protocol and LAH reduction (Scheme 2). The Boc-protected
Scheme 2
did not have much of an effect on the outcome, as the trans/
cis ratio ∼3:1 was obtained with the n-butyl substituent. The
allyl derivative 6d, however, afforded the pyrrolidine product
7d in a low yield; apparently, the alternative mode of 5-exo
cyclization affording cyclopentane products becomes more
competitive as manifested by the isolation of byproducts 8d
and 9d.
2170
Org. Lett., Vol. 2, No. 14, 2000

pyrrolidine alcohol mixture 14/15 was then transformed into
the phenylselenide via tosylation and selenide substitution.
The one-pot procedure consisted of Boc deprotection by
TMSI, and reaction with ethyl propiolate in acetonitrile led
to the isolation of the â-aminoacrylates 16 and 17 in 57 and
19% yields.10
the similar type of radical cyclization involving the substrate
without the n-butyl pendent3b was attenuated in the case of
the substrate 16.
Under identical conditions, conversion of the second
â-aminoacrylate 17 to the indolizidine products 22/23 was
inefficient (Scheme 4), and the simple reduction product 24
The second radical cyclization reaction using the major
product 16 proceeded to give the indolizidine derivatives 18
and 19 in 58 and 13% yields (Scheme 3). The major isomer
Scheme 4
Scheme 3
was isolated as the major product.13 Apparently, the cis
n-butyl substituent presented more serious steric congestion
in the preparation ofindolizidine products.
In the present work, radical cyclization reactions of Ses-
protected â-aminoacrylates were studied in some detail, and
(-)-indolizidine 223AB was synthesized employing two
consecutive radical cyclization reactions of â-aminoacrylate
substrates. Use of these reactions for preparation of more
complex azacyclic natural products will be the subject of
our future studies.
18 was converted into the tosylate 20 via reduction and
tosylation. Reaction of the tosylate 20 with lithium dimeth-
ylcuprate afforded (-)-indolizidine 223AB (21)11 in good
yield.12 It is interesting that the stereoselectivity shown in
Acknowledgment. The authors thank the Korea Science
and Engineering Foundation for financial support (98-
0501-05-01).
OL006094Z
(6) Taber, D. F.; Deker, P. B.; Silverberg, L. J. J. Org. Chem. 1992, 57,
5990.
(12) For synthesis of (-)-indolizidine 223AB, see the following refer-
ences; for synthesis of the racemic mixture, check the references therein.
(a) Royer, J.; Husson, H.-P. Tetrahedron Lett. 1985, 26, 1515. (b) The ref
6. (c) Machinaga, N.; Kibayashi, C. J. Org. Chem. 1992, 57, 5178. (d)
Fleurant, A.; Ce´le´rier, J. P.; Lhommet, G. Tetrahedron: Asymmetry 1993,
4, 1429. (e) Muraoka, O.; Okumura, K.; Maeda, T.; Tanabe, G.; Momose,
T. Tetrahedron: Asymmetry 1994, 5, 317. (f) Ce´lime`ne, C.; Dhimane, H.;
Lhommet, G. Tetrahedron 1998, 54, 10457.
(7) Campbell, J. A.; Hart, D. J. J. Org. Chem. 1993, 58, 2900.
(8) A ∼4:1 mixture of E/Z geometric isomers was obtained, and the
mixture was directly used in the radical cyclization reaction.
(9) (a) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: San Diego, 1993; Vol. 43, pp 185-
288. (b) Daly, J. W. J. Nat. Prod. 1998, 61, 162.
(10) Only E isomers were obtained.
(13) Using the methyl ester analogue of 17, methyl ester analogues of
22/23 (23%, 4.9:1, stereochemistry unknown) and 24 (60%) were obtained.
(11) [R]2D6 ) -100 (c 0.5, n-hexane).
Org. Lett., Vol. 2, No. 14, 2000
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