nucleophiles to R,â-unsaturated carboxylic acid derivatives is
one of the most attractive and versatile methods, as has been
shown by the reactions using chiral amine nucleophiles,5,6 chiral
enoates,7 and chiral catalysts.8 As part of our studies directed
toward the development of asymmetric conjugate addition
reactions9,10 of lithiated nucleophiles,11,12 we have been engaged
in the asymmetric conjugate addition of nitrogen nucleophiles
to enoates providing chiral â-amino acid equivalents.13 Our
methodology relies on the chiral ligand-mediated asymmetric
Asymmetric Synthesis of Intermediates for
Otamixaban and Premafloxacin by the Chiral
Ligand-Controlled Asymmetric Conjugate
Addition of a Lithium Amide
Takeo Sakai, Yoshito Kawamoto, and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity,
Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
(5) (a) Furukawa, M.; Okawara, T.; Terawaki, Y. Chem. Pharm. Bull.
1977, 25, 1319-1325. (b) Hawkins, J. M.; Fu, G. C. J. Org. Chem. 1986,
51, 2820-2822. (c) Rico, J. G.; Lindmark, R. J.; Rogers, T. E.; Bovy, P.
R. J. Org. Chem. 1993, 58, 7948-7951. (d) Enders, D.; Wahl, H.; Bettray,
W. Angew. Chem., Int. Ed. Engl. 1995, 34, 455-457. (e) Sewald, N.; Hiller,
K. D.; Helmreich, B. Liebigs Ann. 1995, 925-928. (f) Leroux, M.-L.; Gall,
T.; Mioskowski, C. Tetrahedron: Asymmetry 2001, 12 1817-1823. (g)
Bull, S. D.; Davies, S. G.; Robert, P. M.; Savory, E. D.; Smith, A. D.
Tetrahedron 2002, 58, 4629-4642.
ReceiVed March 16, 2006
(6) The review for the leading reference of the asymmetric conjugate
addition of chiral lithium amide: Davies, S. G.; Smith, A. D.; Price, P. D.
Tetrahedron: Asymmetry 2005, 16, 2833-2891.
(7) Yamamoto, Y.; Asano, N.; Uyehara, T. J. Am. Chem. Soc. 1992,
114, 5427-5429.
(8) (a) Falborg, L.; Jorgensen, K. A. J. Chem. Soc., Perkin Trans. 1 1996,
2823-2826. (b) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999,
121, 8959-8960. (c) Zhou, F.; Detty, M. R.; Lachicotte, R. J. Tetrahedron
Lett. 1999, 40, 585-588. (d) Horstman, T. E.; Guerin, E. J.; Miller, S. J.
Angew. Chem., Int. Ed. 2000, 39, 3635-3638. (e) Cardillo, G.; Gentilucci,
L.; Gianotti, M.; Kim, H.; Perciaccante, R.; Tolomelli, A. Tetrahedron:
Asymmetry 2001, 12, 2395-2398. (f) Kawatsura, M.; Hartwig, J. F.
Organometallics 2001, 20, 1960-1964. (g) Sundararajan, G.; Prabagaran,
N. Org. Lett. 2001, 3, 389-392. (h) Sibi, M. P.; Liu, M. Org. Lett. 2001,
3, 4181-4184. (i) Zhuang, W.; Hazell, R. G.; Jorgensen, K. A. Chem.
Commun. 2001, 1240-1241. (j) Nakama, K.; Seki, S.; Kanemasa, S.
Tetrahedron Lett. 2002, 43, 829-832. (k) Jin, X. L.; Sugihara, H.; Daikai,
K.; Takeishi, H.; Jin, Y. Z.; Furuno, H.; Inanaga, J. Tetrahedron 2002, 58,
8321-8329. (l) Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem.
Soc. 2003, 125, 16178-16179. (m) Sibi, M. P.; Prabagaran, N.; Ghorpade,
S. G.; Jasperse, C. P. J. Am. Chem. Soc. 2003, 125, 11796-11797. (n)
Fadini, L.; Togni, A. Chem. Commun. 2003, 30-31. (o) Palomo, C.;
Oiarbide, M.; Halder, R.; Kelso, M.; Go´mez-Bengoa, E.; Garc´ıa, J. M. J.
Am. Chem. Soc. 2004, 126, 9188-9189. (p) Hamashima, Y.; Somei, H.;
Shimura, Y.; Tamura, T.; Sodeoka, M. Org. Lett. 2004, 6, 1861-1864. (q)
Li, K.; Cheng, X.; Hii, K. K. Eur. J. Org. Chem. 2004, 959-964. (r)
Reboule, I.; Gil, R.; Collin, J. Tetrahedron: Asymmetry 2005, 16, 3881-
3886. (s) Taylor, M. S.; Zalatan, D. N.; Lerchner, A. M.; Jacobsen, E. N.
J. Am. Chem. Soc. 2005, 127, 1313-1317. (t) Gandelman, M.; Jacobsen,
E. N. Angew. Chem., Int. Ed. 2005, 44, 2393-2397.
(9) Copper- or zinc-catalyzed conjugate addition: (a) Tomioka, K.;
Suenaga, T.; Koga, K. Tetrahedron Lett. 1986, 27, 369-372. (b) Mori, T.;
Kosaka, K.; Nakagawa, Y.; Nagaoka, Y.; Tomioka, K. Tetrahedron:
Asymmetry 1998, 9, 3175-3178. (c) Kanai, M.; Nakagawa, Y.; Tomioka,
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M.; Tomioka, K. J. Org. Chem. 2005, 70, 297-300. (f) Valleix, F.; Nagai,
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(10) Chiral amidophosphane-rhodium-catalyzed conjugate arylation of
arylboron reagents: (a) Kuriyama, M.; Tomioka, K. Tetrahedron Lett. 2001,
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A chiral ligand-controlled conjugate addition reaction of
lithium benzyl(trimethylsilyl)amide with tert-butyl enoates
gave the corresponding lithium enolates that were then treated
with electrophiles, giving anti-alkylation products with high
ee up to 98%. The benzyl group on the amino nitrogen was
removed by the oxidation of secondary amines to imines and
subsequent transoximation to give 3-aminoalkanoates in good
yields. The products are the possible key intermediates of
otamixaban and premafloxacin.
Chiral â-amino acids are the established critical skeleton unit
of biologically potent peptidic natural products,1 as well as the
medicinally important class of nonpeptidic â-lactams2 and
pharmaceuticals.3 Among several strategies for the synthesis of
chiral â-amino acids,4 the conjugate addition of nitrogen
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Soloshonok, V. A., Eds.; Wiley-VCH: New York, 2005.
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Org. Chem. 2004, 69, 1959-1966.
(4) Recent reviews for the synthesis of â-amino acids: (a) Liu, M.; Sibi,
M. P. Tetrahedron 2002, 58, 7991-8035. (b) Ma, J.-A. Angew. Chem.,
Int. Ed. 2003, 42, 4290-4299. (c) Sewald, N. Angew. Chem., Int. Ed. 2003,
42, 5794-5795. (d) Xu, L.-W.; Xia, G.-G. Eur. J. Org. Chem. 2005, 633-
639.
10.1021/jo060588d CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/12/2006
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J. Org. Chem. 2006, 71, 4706-4709