ORGANIC
LETTERS
2
006
Vol. 8, No. 23
357-5360
â
-Isocupreidine-Catalyzed
Baylis Hillman Reaction of Chiral
N-Boc- -Amino Aldehydes
5
−
r
Ayako Nakano, Keisuke Takahashi, Jun Ishihara, and Susumi Hatakeyama*
Graduate School of Biomedical Sciences, Nagasaki UniVersity,
Nagasaki-852-8521, Japan
Received September 11, 2006
ABSTRACT
â
-Isocupreidine (
takes place without racemization and exhibits the match
amino aldehydes, -substrates show excellent syn selectivity and high reactivity in contrast to
of cyclic amino aldehydes,
â
-ICD)-catalyzed Baylis
−
Hillman reaction of chiral N-Boc-
mismatch relationship between the substrate and the catalyst. In the case of acyclic
-substrates. On the other hand, in the case
-substrates show excellent anti selectivity and high reactivity.
r-amino aldehydes and 1,1,1,3,3,3-hexafluoroisopropyl acrylate (HFIPA)
−
L
D
D-substrates rather than L
1
4
The Baylis-Hillman reaction of chiral R-amino aldehydes
has attracted considerable interest due to the synthetic utility
of the products having a multifunctional R-methylene-â-
hydroxy-γ-amino acid structure. However, the major problems
associated with this reaction are the racemization of the sub-
During the course of our synthesis of epopromycin B, we
demonstrated that â-isocupreidine (â-ICD)-catalyzed Baylis-
Hillman reaction of N-Fmoc-L-leucinal with 1,1,1,3,3,3-
5
hexafluoroisopropyl acrylate (HFIPA) took place without
racemization in DMF at -55 °C to produce the correspond-
ing adduct in excellent syn selectivity and in good yield.
Interestingly, N-Fmoc-D-leucinal was found to exhibit poor
reactivity and low diastereoselectivity, suggesting the match-
mismatch relationship between the substrate and the catalyst.
However, one serious drawback of this reaction is that 1
equiv of â-ICD is required to promote the reaction at a
reasonable rate. Recently, we found that the azeotropically
2
strate and the difficulty in securing high diastereoselectivity.
Recently, Coelho et al. successfully developed the racemiza-
tion-free DABCO-mediated reaction of chiral N-Boc-R-amino
aldehydes with methyl acrylate under the influence of
3
ultrasound; however, the diastereoselectivity was moderate.
(
1) For reviews, see: (a) Methot, J. L.; Roush, W. R. AdV. Synth. Catal.
2
004, 346, 1035-1050. (b) Basavaiah, D.; Rao, A. J.; Satyanarayana, T.
Chem. ReV. 2003, 103, 811-892. (c) Iwabuchi, Y.; Hatakeyama, S. J. Synth.
Org. Chem. Jpn. 2002, 60, 4-16. (d) Langer, P. Angew. Chem., Int. Ed.
(3) Coelho, F.; Diaz, G.; Abella, C. A. M.; Almeida, W. P. Synlett 2006,
435-439.
(4) Iwabuchi, Y.; Sugihara, T.; Esumi, T.; Hatakeyama, S. Tetrahedron
Lett. 2001, 42, 7867-7871.
(5) (a) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J.
Am. Chem. Soc. 1999, 121, 10219-10220. (b) Iwabuchi, Y.; Furukawa,
M.; Esumi, T.; Hatakeyama, S. Chem. Commun. 2001, 2030-3031. (c)
Kawahara, S.; Nakano, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Org.
Lett. 2003, 5, 3103-3105. (d) Nakano, A.; Kawahara, S.; Akamatsu, S.;
Morokuma, K.; Nakatani, M.; Iwabuchi, Y.; Takahashi, K.; Ishihara, J.;
Hatakeyama, S. Tetrahedron 2006, 62, 381-389.
2
000, 39, 3049-3052. (e) Ciganek, E. Org. React. 1997, 51, 201-350. (f)
Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001-8062.
Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653-4670.
(
2) (a) Ameer, F.; Drewes, S. E.; Houston-McMillan, M. S.; Kaye, P. T.
S. Afr. J. Chem. 1986, 39, 57-62. (b) Roos, G.; Manickum, T. Synth.
Commun. 1991, 21, 2269-2274. (c) Drewes, S. E.; Khan, A. A.; Rowland,
K. Synth. Commun. 1993, 23, 183-188. (d) Manickum, T.; Roos, G. H. P.
S. Afr. J. Chem. 1994, 47, 1-16. (e) Nayak, S. P.; Thijs, L.; Zwanenburg
Tetrahedron Lett. 1999, 40, 981-9984. (f) Almeida, B. W. P.; Coelho, F.
Tetrahedron Lett. 2003, 44, 937-940.
1
0.1021/ol0622561 CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/20/2006