Catalytic enantio- and diastereoselective aldol reactions of glycine-derived silicon enolate with aldehydes: An efficient approach to the asymmetric synthesis of anti-β-hydroxy-α-amino acid derivatives

Article abstract of DOI:10.1021/ja047597t

We have developed an efficient method for the asymmetric synthesis of anti-β-hydroxy-α-amino acid derivatives based on highly enantio- and diastereoselective aldol reactions of the silicon enolate derived from N-trifluoroacetylglycinate with aldehydes using a chiral zirconium catalyst. 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. Copyright

Full text of DOI:10.1021/ja047597t

Published on Web 07/13/2004
Catalytic Enantio- and Diastereoselective Aldol Reactions of Glycine-Derived
Silicon Enolate with Aldehydes: An Efficient Approach to the Asymmetric
Synthesis of anti-â-Hydroxy-r-Amino Acid Derivatives
Jun Kobayashi, Masayuki Nakamura, Yuichiro Mori, Yasuhiro Yamashita, and Shuj Kobayashi*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received April 26, 2004; E-mail: skobayas@mol.f.u-tokyo.ac.jp
Table 1. Catalytic Enantio- and Diastereo Selective Aldol
â-Hydroxy-R-amino acids are ubiquitous, important components
of various nitrogen-containing biologically active compounds and
Reactions of Silicon Enolate 2 with Benzaldehyde (1a (R ) Ph))a
natural products. For example, the vancomycin class of antibiotics1
incorporates an erythro- and a threo-â-arylserine moiety, and the
promising antifungal agents, sphingofungins,2 contain a â-hydroxy-
R-amino acid in the polar headgroup of their structure. In addition,
BINOL
derivative
PrOH
(mol %)
time
(h)b
yield
(%)
ee
â-hydroxy-R-amino carbonyl compounds are often used as inter-
mediates for synthesis of 2-amino-1,3-diols, â-lactams,3 aziridines,4
and so on. Among a number of methods reported to date for the
asymmetric synthesis of â-hydroxy-R-amino acids, the aldol
reaction of glycine derivatives with aldehydes has been considered
to be the most synthetically efficient approach.5 However, there
have been few successful examples demonstrating a catalytic
asymmetric process: several groups reported Lewis acid-catalyzed
asymmetric synthesis of 2-oxazoline-4-carboxylates as surrogates
of â-hydroxy-R-amino acids,6 while recently more direct approaches
to â-hydroxy-R-amino carbonyl compounds have been developed
using glycine Schiff base derivatives.7 Although each of these
approaches involves an elegant methodology, there still remain some
limitations such as substrate generality, and very little is known
concerning actual applications to efficient synthesis of biologically
important compounds. Herein we describe a new synthetic protocol
based on catalytic enantio- and diastereoselective aldol reactions
of N-trifluoroacetylglycine-derived silicon enolate with aldehydes
using a chiral zirconium catalyst.
entry
anti/syn
(%) (anti)
1c
2e
3e,f
4
5
6
7
8
9
3a
3a
3a
3a
3b
3b
3b
3b
3b
80
80
80
150
150
150
150
150
300
0
0
0
0
0
1
4
8
8
71
80
18
50
74
97
92
93
92
43/57
29/71
17/83
55/45
58/42
72/28
75/25
78/22
90/10
46d
63d
93d
75
32
71
77
87
95
a Unless noted otherwise, the reaction was carried out with 1.5 equiv of
2 in toluene-tBuOMe (1:1) at -20 °C for 12 h in the presence of a chiral
zirconium catalyst prepared from Zr(OtBu)4 (10 mol %), (R)-BINOL
derivative 3 (12 mol %), PrOH, and H2O (10 mol %). b Addition time of
silicon enolate. c In toluene at 0 °C. d Ee of syn isomer. e At 0 °C. f Silicon
enolate 5 was used, and the major product was syn-6.
We have previously shown that chiral zirconium complexes
prepared from zirconium alkoxide and BINOL derivatives activate
both azomethine compounds and aldehydes effectively, and various
catalytic asymmetric reactions such as Mannich-type reactions,8a
Mukaiyama aldol reactions,8b hetero Diels-Alder reactions,8c etc.
have been performed. In our initial investigations, we conducted
aldol reactions of benzaldehyde with several types of glycine-
derived silicon enolates under the conditions of toluene, 0 °C
in the presence of a chiral zirconium catalyst prepared from
preparation, and cosolvents used during addition of silicon enolates
were next examined. When tBuOMe was used (final solvent ratio:
toluene/tBuOMe ) 1/1), the yield was increased to 80% and the
selectivity was also improved; syn selectivity was raised to anti/
syn ) 29/71, and the enantiomeric excess of the syn adduct was
63% ee (entry 2). Instead of 2, we also tested silicon enolate 59b
derived from N-methyl-N-trifluoroacethylglycine methyl ester.
Although the reactivity of 5 was much lower than that of 2, the
diastereo- and enantioselectivity were remarkably increased to anti/
syn ) 17/83, syn ) 93% ee (entry 3). To improve the yield and
selectivity, we investigated the reaction conditions further and
obtained very surprising results concerning the diastereoselectivity.
Thus, when the amount of nPrOH was increased to trap the cationic
silicon species more efficiently, the diastereoselectivity was reversed
(toluene-tBuOMe, -20 °C, anti/syn ) 55/45, entry 4). With the
use of (R)-3,3′,6,6′-I4BINOL bearing electron-withdrawing iodo
groups at the 6,6′-positions, a slight increase of the yield and anti
selectivity was obtained, although enantioselectivity was decreased
under these reaction conditions (entry 5). Moreover, when silicon
enolate 2 was slowly added over 1 h to the reaction solution of the
catalyst and aldehyde, the result was dramatically improved favoring
the anti-isomer (97%, anti/syn ) 72/28, anti ) 71% ee, entry 6).
The slow addition method was found to be particularly effective
in this reaction. Extension of the addition time resulted in marked
n
Zr(OtBu)4 (10 mol %), (R)-3,3′-I2BINOL (3a, 12 mol %), PrOH
(80 mol %), and H2O (20 mol %), which are the optimal conditions
for aldol reactions of propionate-derived silicon enolates.8b As a
result, the reaction of silicon enolate 29 prepared from N-
trifluoroacetylglycine methyl ester proceeded to give the desired
â-hydroxy-R-amino acid derivative 4a (R ) Ph) in good yield
(71%) but with disappointing selectivity (anti/syn ) 43/57, anti )
6% ee, syn ) 46% ee, Table 1, entry 1). We also tested other
trimethylsilyl enol ether derivatives of tert-butyl N-(diphenylmeth-
ylene)-glycinate7a or 2-oxazolin-5-ones;10 however, they resulted
in no reaction or very low yield with almost no selectivity. Silicon
enolate 2 is particularly useful because it can be easily prepared in
large scale from glycine methyl ester and stored over a long period.
Moreover, the trifluoroacetyl group of the corresponding product
is utilized as a useful protecting group for further transformations.
As for reaction solvents, toluene was the best for the catalyst
9
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J. AM. CHEM. SOC. 2004, 126, 9192-9193
10.1021/ja047597t CCC: $27.50 © 2004 American Chemical Society

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
free of charge via the Internet at http://pubs.acs.org.
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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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,
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Kobayashi, S. J. Am. Chem. Soc. 2003, 125, 3793.
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(11) For further discussion on the stereochemistry, see Supporting Information.
(12) Aliphatic aldehydes reacted sluggishly (<30% yield) under the conditions.
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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,
JA047597T
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J. AM. CHEM. SOC. VOL. 126, NO. 30, 2004 9193