C O M M U N I C A T I O N S
Table 2. Catalytic Enantio- and Diastereoselective Aldol
Reactions of Silicon Enolate 2 with Various Aldehydesa
which was recrystallized to an optically pure form (>99% ee) and
treated with C12H25MgBr in the presence of a catalytic amount of
Li2CuCl4 to afford 11. Finally, deprotection of 2-amino-1,3-diol
gave L-erythro-sphingosine. Compound 8 is highly functionalized
and considered to be a potentially useful intermediate for more
complex compounds containing a â-hydroxy-R-amino carbonyl
moiety.
In summary, we have developed an efficient process for the
asymmetric synthesis of anti-â-hydroxy-R-amino acid derivatives
based on highly enantio- and diastereoselective aldol reactions of
a glycine-derived silicon enolate with aldehydes using a chiral
zirconium catalyst. This is the first example of enantioselective aldol
reactions using silicon enolates prepared from N-trifluoroacetyl-
glycinate. The resulting N-trifluoroacetyl group is easily cleaved
under either acidic or basic conditions and can be used directly as
a protecting group for further transformations. Further improvement
of the efficiency and the generality of the process, as well as
exploration of the interesting features of silicon dienolate 2, are
now under investigation.
entry
R
yield (%)
anti/syn
ee (%)b
1
2
3
4
5
Ph (1a)
4-MeC6H4 (1b)
4-ClC6H4 (1c)
3-MeC6H4 (1d)
3-ClC6H4 (1e)
3-MeOC6H4 (1f)
3,5-(MeO)2C6H3 (1g)
2-Naphthyl (1h)
2-Furyl (1i)
92
87
91
83
93
93
93
93
71
81
85
90/10
85/15
84/16
91/9
92/8
91/9
87/13
94/6
87/13
78/22
80/20
95
94
94
93
96
95
97
95
90
85
95
6
7c
8c
9
10
11
Ph(CH2)3CtC (1j)
TBDPSOCH2CtC (1k)
a Reaction was performed according to the conditions of Table 1, entry
9. b Ee of the anti isomer. c Amount of H2O was 20 mol %, and 2.0 equiv
of 2 was added over 10 h.
Scheme 1. Efficient Asymmetric Synthesis of
L-erythro-Sphingosinea
Acknowledgment. This work was partially supported by
CREST, SORST, and ERATO, Japan Corporation of Science and
Technology, and by a Grant-in-Aid for Scientific Research from
the Japan Society of the Promotion of Science.
Supporting Information Available: Experimental procedures and
characterization of all new compounds (PDF). This material is available
a Conditions: (a) Chiral zirconium catalyst (10 mol %), toluene-
tBuOMe, -20 °C. (b) NaBH4, MeOH, rt (87%). (c) (i) PMPCH(OMe)2,
TsOH, DMF, rt (71%); (ii) isolation of trans-isomer. (d) (i) TBAF, THF,
rt; (ii) Ac2O, DMAP, pyridine, 0 °C (90%, two steps); (iii) recrystallization
(72%, >99% ee). (e) C12H25MgBr, Li2CuCl4, THF, -15 °C (57%). (f) 2 N
NaOH-EtOH, 80 °C (99%); 1 N HCl-THF, 40 °C (75%).
References
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Strelkova, T. V.; Harutyunyan, S. R.; Saghiyan, A. S. Tetrahedron:
Asymmetry 2001, 12, 481. (c) Felice, P. D.; Porzi, G.; Sandri, S.
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Hayashizaki, K.; Hayashi, T. Tetrahedron 1988, 44, 5253. With 5-alkoxy-
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(c) Evans, D. A.; Janey, J. M.; Magomedov, N.; Tedrow, J. S. Angew.
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(7) With enolates of glycine Schiff base: (a) Horikawa, M.; Busch-Petersen,
J.; Corey, E. J. Tetrahedron Lett. 1999, 40, 3843. Direct use of glycine
Schiff base: (b) Yoshikawa, N.; Shibasaki, M. Tetrahedron 2002, 58,
8289. (c) Ooi, T.; Taniguchi, M.; Kameda, M.; Maruoka, K. Angew.
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improvement of both yield and selectivity (entries 7 and 8). Finally,
n
when 300 mol % of PrOH was used and 2 was added over 8 h,
the reaction proceeded smoothly in high yield and high anti
selectivity with excellent enantioselectivity (92%, anti/syn ) 90/
10, anti ) 95% ee, entry 9).11
We then examined reactions of other aldehydes under the optimal
conditions, in which silicon enolate 2 (1.5-2.0 equiv) was slowly
added over 8-10 h (toluene-tBuOMe, -20 °C), and the results
are summarized in Table 2. In most cases, the reactions proceeded
smoothly to provide the desired â-hydroxy-R-amino acid derivatives
in high yields with good anti selectivity and excellent enantiose-
lectivity. Various types of benzaldehyde derivatives containing
electron-withdrawing or -donating substituents at the para or meta
positions were found to be good substrates. Furfural also afforded
the corresponding product in good yield with high stereoselection
(entry 9). The reaction of propargyl aldehydes cleanly produced
anti-â-hydroxy-R-amino acid derivatives in good yield with good
enantio- and diastereoselectivity (entries 10 and 11), which can be
converted to various compounds.12
(8) (a) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122,
8180. (b) Yamashita, Y.; Ishitani, H.; Shimizu, H.; Kobayashi, S. J. Am.
Chem. Soc. 2002, 124, 3292. (c) Yamashita, Y.; Saito, S.; Ishitani, H.;
Kobayashi, S. J. Am. Chem. Soc. 2003, 125, 3793.
(9) For the synthesis and utilization of 2: (a) Oesterle, T.; Simchen, G.
Synthesis 1985, 403. (b) Simchen, G.; Schulz, D.; Seethaler, T. Synthesis
1988, 127. (c) Seethaler, T.; Simchen, G. Liebigs Ann. Chem. 1991, 11.
(10) Takagaki, H.; Tanabe, S.; Asaoka, M.; Takei, H. Chem. Lett. 1979, 347.
(11) For further discussion on the stereochemistry, see Supporting Information.
(12) Aliphatic aldehydes reacted sluggishly (<30% yield) under the conditions.
(13) Asymmetric syntheses of sphingosine based on aldol reactions: (a) Ito,
Y.; Sawamura, M.; Hayashi, T. Tetrahedron Lett. 1988, 29, 239. (b)
Nicolaou, K. C.; Caulfield, T.; Kataoka, H.; Kumazawa, T. J. Am. Chem.
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Casiraghi, G. Tetrahedron: Asymmetry 1997, 8, 3237. (g) Corey, E. J.;
Choi, S. Tetrahedron Lett. 2000, 41, 2765.
Finally, to demonstrate the synthetic utility of this aldol reactions,
we performed efficient asymmetric synthesis of L-erythro-sphin-
gosine.13 Sphingosine is the backbone of an essential cell membrane
component, sphingolipid, and has been widely studied from both
biological and chemical points of view.14 As shown in Scheme 1,
the aldol reaction of 2 with aldehyde 7 was conducted in the
presence of the chiral zirconium catalyst affording the desired anti-
aldol adduct 8 in high yield (95%) with high stereoselectivity (anti/
syn ) 80/20, anti ) 97% ee). Reduction of 8 with NaBH4, followed
by protection of the resulting 1,3-diol as its p-methoxybenzylidene
(14) (a) Hannun, Y. A.; Loomis, C. R.; Merrill, A. H., Jr.; Bell, R. M. J. Biol.
Chem. 1986, 261, 12604. (b) Koskinen, P. M.; Koskinen, A. M. P.
Synthesis 1998, 1075.
t
acetal and isolation of the trans isomer provided 9. The butyl-
diphenylsilyl ether was converted to the corresponding acetate 10,
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