Published on Web 09/07/2006
Highly Enantioselective Synthesis of Atropisomeric Anilide
Derivatives through Catalytic Asymmetric N-Arylation:
Conformational Analysis and Application to Asymmetric
Enolate Chemistry
Osamu Kitagawa,* Masatoshi Yoshikawa, Hajime Tanabe, Tomofumi Morita,
Masashi Takahashi, Yasuo Dobashi, and Takeo Taguchi*
Contribution from the Tokyo UniVersity of Pharmacy and Life Science,
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received June 8, 2006; E-mail: taguchi@ps.toyaku.ac.jp; kitagawa@ps.toyaku.ac.jp
Abstract: In the presence of (R)-DTBM-SEGPHOS-Pd(OAc)2 catalyst, N-arylation (aromatic amination)
of various o-tert-butylanilides with p-iodonitrobenzene proceeds with high enantioselectivity (88-96% ee)
to give atropisomeric N-(p-nitrophenyl)anilides having an N-C chiral axis in good yields. Atropisomeric
anilide products highly prefer to exist as the E-rotamer which has trans-disposed o-tert-butylphenyl group
and carbonyl oxygen. The application of the present catalytic enantioselective N-arylation to an intramolecular
version gives atropisomeric lactam derivatives with high optical purity (92-98% ee). The reaction of the
lithium enolate prepared from the atropisomeric anilide and lactam products with various alkyl halides gives
R-alkylated products with high diastereoselectivity (diastereomer ratio ) 13:1 to 46:1).
Introduction
N-Substituted o-tert-butylanilide derivatives are known to
exist as stable atropisomers at room temperature and have a
large N-Ar torsion angle (∼90°) toward the amide plane (eq
1).1 In 1994, Curran et al. showed that N-C axial chirality of
such anilides highly controls the formation of a new chiral
center.2 Since this report, atropisomeric anilides have received
much attention as novel atropiosomeric molecules having an
N-C chiral axis.3 On the other hand, in early studies on
diastereoselective (atropselective) reactions reported by Curran
et al. followed by other groups, since racemic anilide derivatives
were employed,2,4 application of such anilides to an asymmetric
reaction had to wait until their optically pure forms were
available.
meric anilide derived from (S)-lactic acid derivative (eq 1).5a,b
Following our publications, although synthesis of various
optically active atropisomeric anilide derivatives was also
reported by other groups, in most cases, a multistep sequence
from a chiral pool precursor or HPLC separation using a chiral
column was required.6 Uemura and Simpkins reported the highly
enantioselective synthesis of atropisomeric o-disubstituted anil-
ides and N-(o-tert-butylphenyl)imides by an enantiotopic selec-
In 1997, we succeeded in the first synthesis of atropisomeric
o-tert-butylanilide with high optical purity (96% ee) and definite
absolute configuration through optical resolution of diastereo-
(5) Our papers in relation to optically active atropisomeric anilides: (a)
Kitagawa, O.; Izawa, H.; Taguchi, T.; Shiro, M. Tetrahedron Lett. 1997,
38, 4447. (b) Kitagawa, O.; Izawa, H.; Sato, K.; Dobashi, A.; Taguchi, T.;
Shiro, M. J. Org. Chem. 1998, 63, 2634. (c) Fujita, M.; Kitagawa, O.;
Izawa, H.; Dobashi, A.; Fukaya, H.; Taguchi, T. Tetrahedron Lett. 1999,
40, 1949 (correction: Tetrahedron Lett. 2000, 41, 4997). (d) Kitagawa,
O.; Momose, S.; Fushimi, Y.; Taguchi, T. Tetrahedron Lett. 1999, 40, 8827.
(e) Fujita, M.; Kitagawa, O.; Yamada, Y.; Izawa, H.; Hasegawa, H.;
Taguchi, T. J. Org. Chem. 2000, 65, 1108. (f) Kitagawa, O.; Fujita, M.;
Kohriyama, M.; Hasegawa, H.; Taguchi, T. Tetrahedron Lett. 2000, 41,
8539.
(6) Papers in relation to optically active atropisomeric anilides (a) Hughes, A.
D.; Simpkins, N. S. Synlett. 1998, 967. (b) Hughes, A. D.; Price, D. A.;
Simpkins, N. S. J. Chem. Soc., Perkin Trans. 1 1999, 1295. (c) Kondo,
K.; Fujita, H.; Suzuki, T.; Murakami, Y. Tetrahedron Lett. 1999, 40, 5577.
(d) Curran, D. P.; Liu, W.; Chen, C. H. J. Am. Chem. Soc. 1999, 121,
11012. (e) Shimizu, K. D.; Freyer, H. O.; Adams, R. D. Tetrahedron Lett.
2000, 41, 5431. (f) Kondo, K.; Iida, T.; Fujita, H.; Suzuki, T.; Yamaguchi,
K.; Murakami, Y. Tetrahedron, 2000, 56, 8883. (g) Godfrey, C. R. A.;
Simpkins, N. S.; Walker, M. D. Synlett 2000, 388. (h) Ates, A.; Curran,
D. P. J. Am. Chem. Soc. 2001, 123, 5130. (i) Sakamoto, M.; Iwamoto, T.;
Nono, N.; Ando, M.; Arai, W.; Mino, T.; Fujita, T. J. Org. Chem. 2003,
68, 942. (j) Betson, M. S.; Clayden, J.; Helliwell, M.; Mitjans, D. Org.
Biomol. Chem. 2005, 3, 3898.
(1) Examples of atropisomeric compounds having an N-C chiral axis: (a)
Bock, L. H.; Adams, R. J. Am. Chem. Soc. 1931, 53, 374. (b) Kashima,
C.; Katoh, A. J. Chem. Soc., Perkin Trans. 1980, 1599. (c) Roussel, C.;
Adjimi, M.; Chemlal, A.; Djafri, A. J. Org. Chem. 1988, 53, 5076. (d)
Kawamoto, T.; Tomishima, M.; Yoneda, F.; Hayami, J. Tetrahedron Lett.
1992, 33, 3169. (e) Dai, X.; Wong, A.; Virgil, S. C. J. Org. Chem. 1998,
63, 2597.
(2) Curran, D. P.; Qi, H.; Geib, S. J.; DeMello, N. C. J. Am. Chem. Soc. 1994,
116, 3131.
(3) (a) Clayden, J. Angew. Chem., Int. Ed. 1997, 36, 949. (b) Clayden, J., Ed.
Tetrahedron Symposium-in-print on Axially Chiral Amides. Tetrahedron
2004, 60, 4325-4558.
(4) (a) Kishikawa, K.; Tsuru, I.; Kohomoto, S.; Yamamoto, M.; Yamada, K.
Chem. Lett. 1994, 1605. (b) Hughes, A. D.; Price, D. A.; Shishkin, O.;
Simpkins, N. S. Tetrahedron Lett. 1996, 37, 7607. (c) Curran, D. P.; Hale,
G. R.; Geib, S. J.; Balog, A.; Cass, Q. B.; Degani, A. L. G.; Hernandes,
M. Z.; Freitas, L. C. G. Tetrahedron: Asymmetry 1997, 8, 3955. (d) Bach,
T.; Schro¨der, J.; Harms, K. Tetrahedron Lett. 1999, 40, 9003. (e) Dantale,
S.; Reboul, V.; Metzner, P.; Philouze, C. Chem.sEur. J. 2002, 8, 632.
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10.1021/ja064026n CCC: $33.50 © 2006 American Chemical Society
J. AM. CHEM. SOC. 2006, 128, 12923-12931
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