Catalytic asymmetric synthesis of β-hydroxy-α-amino acid esters by direct aldol reaction of glycinate Schiff bases

Article abstract of DOI:10.1016/S0040-4020(02)00979-1

A catalytic asymmetric synthesis of β-hydroxy-α-amino acid esters was developed using the direct aldol reaction of glycinate Schiff bases with aldehydes. The reaction was catalyzed by heterobimetallic asymmetric complexes without preformation of enol silyl ethers from glycinate Schiff bases. anti-β-Hydroxy-α-amino acid esters were obtained as the major diastereomer in most cases, and moderate enantiomeric excess (up to 76% ee) was achieved for the first time for this type of reaction. Various substrates were also examined to investigate the effects of the protective groups for the amine or for the carboxylic acid moiety in glycine.

Full text of DOI:10.1016/S0040-4020(02)00979-1

Tetrahedron 58 (2002) 8289–8298
Catalytic asymmetric synthesis of b-hydroxy-a-amino acid esters
by direct aldol reaction of glycinate Schiff bases
*
Naoki Yoshikawa and Masakatsu Shibasaki
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 14 May 2002; accepted 4 June 2002
Abstract—A catalytic asymmetric synthesis of b-hydroxy-a-amino acid esters was developed using the direct aldol reaction of glycinate
Schiff bases with aldehydes. The reaction was catalyzed by heterobimetallic asymmetric complexes without preformation of enol silyl ethers
from glycinate Schiff bases. anti-b-Hydroxy-a-amino acid esters were obtained as the major diastereomer in most cases, and moderate
enantiomeric excess (up to 76% ee) was achieved for the first time for this type of reaction. Various substrates were also examined to
investigate the effects of the protective groups for the amine or for the carboxylic acid moiety in glycine. q 2002 Elsevier Science Ltd. All
rights reserved.
1. Introduction
because the process involves the formation of a C–C
bond and construction of vicinal stereogenic centers. A few
elegant methods for the aldol strategy have been reported
employing only catalytic amounts of chiral sources. Ito and
Hayashi et al. reported the use of gold catalysts for the aldol
reaction of a-isocyano acetates with aldehydes.16 This
system works with small amounts of catalysts and gives
trans-4-alkoxycarbonyl-2-oxazolines in a highly stereo-
selective manner, which are easily transformed into syn-b-
hydroxy-a-amino acid esters. Corey et al. developed a
Mukaiyama-type aldol reaction of ketene silyl acetals
derived from glycinate Schiff bases.17 The reaction was
catalyzed by a cinchonidine-derived ammonium salt to
afford mostly syn-b-hydroxy-a-amino acid esters as the
major diastereomer. Recently, aluminum catalysts were
reported for the stereoselective synthesis of cis-4-alkoxy-
carbonyl-2-oxazolines,18 which are precursors to anti-b-
hydroxy-a-amino acid esters. While these catalysts provide
an efficient approach to the synthesis of anti-b-aryl-b-
hydroxy-a-amino acid esters from aromatic aldehydes,
aliphatic aldehydes were not suitable substrates. An
enzymatic approach was extensively studied by Wong
et al., and several types of aldolases give b-hydroxy-a-
amino acid esters.19 Although this process realizes ideal
atom efficiency by employing glycine as a donor substrate,
there some limitations remain, such as substrate generality.
b-Hydroxy-a-amino acids are the constituents of numerous
biologically active compounds. For example, the vanco-
mycin class of antibiotics1 contains either an erythro- or
threo-b-arylserine moiety, and a wide range of other
antibiotics incorporate b-hydroxy-a-amino acids.
b-Hydroxy-a-amino acids also occur in other classes of
biologically important compounds such as (þ)-lactacystin2
and cyclosporin. Moreover, b-hydroxy-a-amino acids serve
as versatile precursors for other types of building blocks:
reduction of the carboxylic acid gives a 2-amino-1,3-diol,3
which is the key component of sphingosine, and conversion
of the b-hydroxyl group leads to an efficient synthesis of
b-lactams.4 Some chiral ligands are also synthesized from
b-hydroxy-a-amino acids.5
A number of methods have been reported for the
enantioselective synthesis of b-hydroxy-a-amino acid
derivatives using different types of strategies, including
epoxidation/amination,6 aminohydroxylation of cinna-
mates,7 dihydroxylation of a,b-unsaturated esters,8 alkyl-
ation of a-amino-b-oxyaldehydes,9 hydrogenation of
b-oxyacetamidoacrylates,10 hydrogenation of 2-(N-acetyl-
amino)-3-oxoalkanoates,11 addition of acetylide to a
nitrone,12 Strecker reactions,13 rearrangements,14 aldol
reactions,15 etc. Among these methods, aldol reactions of
glycine equivalents with aldehydes provide an efficient and
direct access to b-hydroxy-a-amino acid derivatives,
During the past few years, we developed enantioselective
direct aldol reactions of unmodified ketones using several
types of heterobimetallic asymmetric catalysts.20–22 These
processes exclude the necessity of preforming enol ethers
from carbonyl compounds for enantioselective catalytic
aldol reactions.23 The use of methyl ketones and hydroxy
ketones as substrates enables efficient catalytic asymmetric
syntheses of b-hydroxy ketones20c–e and a,b-dihydroxy
Keywords: direct aldol reaction; heterobimetallic asymmetric catalyst;
glycinate Schiff base; b-hydroxy-a-amino acid; lanthanide; vancomycin;
benzophenone imine; glycine.
*
Corresponding author. Tel.: þ81-3-5684-0651; fax: þ81-3-5684-5206;
e-mail: mshibasa@mol.f.u-tokyo.ac.jp.
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00979-1

8290
N. Yoshikawa, M. Shibasaki / Tetrahedron 58 (2002) 8289–8298
Scheme 1. Determination of enantiomeric excess.
Figure 1. Heterobimetallic catalysts M3[La(S-binol)3].
ketones.20a,b This article focuses on the development of
catalytic asymmetric synthesis of b-hydroxy-a-amino acid
derivatives using the direct aldol reaction.
activate LLB.25 We previously reported that a heteropoly-
metallic catalyst, prepared from MOH (M¼alkali metal),
H2O, and LLB, is an effective promoter for the direct aldol
reactions of methyl ketones20d and a-hydroxy ketones.20a,b
In those cases, the addition of KOH rather than LiOH or
NaOH gave the best results in terms of reactivity and
stereoselectivity. In the present system, the addition of such
bases also accelerated the aldol reaction to afford the
products in much higher chemical yields. In contrast to the
previous cases, a catalyst prepared from LLB, LiOH, and
H2O gave the best result (yield 78%, anti/syn¼67:33)
(Table 1, entry 2). Moreover, the enantiomeric excess of the
anti-isomer was greatly improved to 54%.
2. Results and discussion
2.1. Catalyst screening
Glycinate Schiff bases were used as glycine equivalents for
the donor substrate because they can be enolized under
mildly basic conditions.24 Thus, a series of heterobimetallic
lanthanide complexes (Fig. 1),22 which were developed in
our group, were screened in the direct aldol reaction of
isobutyraldehyde (2a) with Schiff base 1 derived from tert-
butyl glycine ester and benzophenone (Table 1). The
reaction was conducted in THF, and the crude product
was treated with aqueous citric acid to hydrolyze the
benzophenone imine moiety of the aldol adducts, giving
b-hydroxy-a-amino acid esters 3a as a mixture of
diastereomers. The diastereomers (anti-3a and syn-3a)
were isolated by silica gel column chromatography, and
the enantiomeric excess was determined by HPLC after
conversion to the corresponding oxazolidinethione (4) by
treatment with thiocarbonyl diimidazole (5) (Scheme 1).17
As a result, LLB (M¼Li, Fig. 1) gave the anti-product
(anti-3a) in 19% ee (Table 1, entry 1), whereas two other
complexes (M¼Na or K, Fig. 1) afforded racemic products
(Table 1, entries 5 and 6). To improve the chemical yield,
we attempted to improve the LLB catalyst by addition of a
catalytic amount of bases (Table 1, entries 2–4) that can
2.2. Effects of substituents on the benzophenone imine
moiety
In the direct aldol reactions previously reported by our
group, the acidity of the a-proton of the carbonyl
compounds was a crucial factor.20d In this regard, we
examined the benzophenone imine moiety in the present
system. Thus, we synthesized glycinate Schiff bases
possessing an electron-withdrawing or electron-donating
diarylmethylene moiety, attempting to vary the acidity of
the donor substrate (Table 2). As a result, the reaction was
accelerated when electron-withdrawing substituents were
introduced. This phenomenon is consistent with the
expected increase in the acidity of the a-proton of
the glycinates. Moreover, the enantiomeric excess of the
anti-isomer (anti-3a) was further improved to 74% when
chloro-substituted benzophenone imine 8 was used as a
Table 1. Direct aldol reactions of glycinate Schiff base 1 with isobutyraldehyde (2a) promoted by heterobimetallic catalysts
Entry
Catalyst
Temperature (8C)
Time (h)
Yield (%)a
anti/synb
ee of anti (%)c
ee of syn (%)c
1
2
3
4
5
6
LLB (Li3[La(S-binol)3])
250
250
250
250
240
240
65
65
65
65
123
123
12
78
79
52
42
97
58:42
67:33
66:34
63:37
64:36
37:63
19
54
21
45
0
1
1
5
0
0
21
LLBþLiOH (0.9)þH2O (1.1)
LLBþNaOH (0.9)þH2O (1.1)
LLBþKOH (0.9)þH2O (1.1)
LSB (Na3[La(S-binol)3])
LPB (K3[La(S-binol)3])
0
a
Yield of isolated amino acid esters 3a.
Determined by 1H NMR of the crude mixture of amino acid esters 3a after hydrolysis of the imine moiety of the aldol adducts.
Determined by HPLC after conversion to thioxooxazolines 4.
b
c

N. Yoshikawa, M. Shibasaki / Tetrahedron 58 (2002) 8289–8298
8291
Table 2. Direct aldol reaction of glycinate Schiff bases with p,p0-disubstituted benzophenone imine moiety
Entry
X
Temperature (8C)
Time (h)
Yield (%)a
anti/syn
ee of anti (%)b
ee of syn (%)b
1
2
3
4
5
6
CH3 (6)
H (1)
F (7)
Cl (8)
CF3 (9)
CF3 (9)
240
240
250
250
260
250
23
36
26
16
5
85 (0)
94 (0)
87 (0)
93 (19)
72 (22)
89 (46)
63:37c
62:38c
53:47c
59:41d
56:44d
44:56d
42
47
64
74
61
68
0
3
8
20
43
51
1
a
Combined yield of amino acid esters 3a and oxazolidine 10. Isolated yield of 10 is given in parentheses.
Determined by HPLC after conversion to thioxooxazolines 4.
b
c
d
Determined by 1H NMR of the crude mixture of amino acid esters 3a after hydrolysis of the imine moiety of the aldol adducts.
Determined by calculation on the basis of the isolated 3 and 10.
substrate (entry 4).26 As shown in entries 5 and 6, the
introduction of trifluoromethyl groups significantly
accelerated the aldol reaction, affording the products (3a)
in good yield after 5 h at 2608C (entry 5) or after 1 h at
2508C (entry 6). This substrate (9) is interesting because the
enantiomeric excess of the syn-adduct (syn-3a) was also
largely improved (51% ee, entry 6). In the case of imines
with electron-withdrawing substituents, portions of syn-
adducts underwent cyclization to afford the corresponding
trans-oxazolidines (10)27 after treatment with aqueous citric
acid at room temperature (entries 4–6). In the experiments
presented in Table 2, these oxazolidines were isolated by
flash silica gel column chromatography. Nevertheless,
conducting the hydrolysis at 408C successfully transformed
the oxazolidines (10) to the principal syn-amino acid esters
(syn-3).
(Table 3). Methyl ester 11 had higher reactivity in the aldol
reaction (entry 1), compared with the tert-butyl ester (8)
(entry 3), affording the aldol adducts in good yield. The
subsequent hydrolysis was performed at lower temperature
(208C) due to the lability of the methyl ester (15), and the
corresponding trans-oxazolidine was isolated in 29% yield.
The desired amino acid esters (15) were obtained in 58%
yield with 38% ee (anti). Diphenylmethyl ester 12 was also
highly reactive to give the corresponding amino acid esters
(16) with moderate enantiomeric excess (anti, 47% ee; syn,
42% ee) (entry 2). Amide 14 also reacted with 2a rapidly
to afford the syn-product as the major diastereomer (anti/
syn¼20:80), albeit with very low enantiomeric excess (3%)
(entry 5). In contrast to the above-mentioned substrates,
phenacyl ester 13 did not react with isobutyraldehyde (2a)
even at a higher temperature (entry 4). This result is likely
due to the ability of the phenacyl ester moiety to inactivate
the catalyst by forming a tight chelate complex.
2.3. Effects of the protective group for the carboxylic
acid in glycine
2.4. Catalyst amounts and solvents
With the best imine moiety in the substrates, we examined
the effects of the protective group for the carboxylic acid
Because the present system is highly reactive, the catalyst
Table 3. Direct aldol reaction of glycinate Schiff bases with different protective groups for the carboxylic acid
Entry
R
Product
Temperature (8C)
Time (h)
Yield (%)a
anti/synb
ee of anti (%)c
ee of syn (%)c
1
2
3
4
5
CH3 (11)
CHPh2 (12)
t-Bu (8)
CH2COPh (13)
N(CH3)OCH3 (14)
15d
16d
3a
17
18d,f
250
250
250
220
240
2
1
16
16
14
58 (29)
56e
93
0
98
89:11
78:22
59:41
–
38
47
74
–
ND
42
20
–
20:80
33
3
a
Isolate yield of amino acid esters. Figure in parenthesis shows the isolated yield of oxazolidine.
b
c
d
e
f
Determined by 1H NMR of the crude mixture of amino acid esters after hydrolysis of the imine moiety of the aldol adducts.
Determined by HPLC after conversion to thioxooxazolines 4.
The absolute configuration was not determined.
The formation of oxazolidine 10 was observed on TLC, but was not isolated.
The hydrolysis was conducted with HCl in MeOH/H2O.

8292
N. Yoshikawa, M. Shibasaki / Tetrahedron 58 (2002) 8289–8298
Table 4. Effects of catalyst amounts and solvents
Entry
Catalyst (mol%)
Solvent
Time (h)
Yield (%)a
anti/synb
ee of anti (%)c
ee of syn (%)c
1
2
3
4
5
6
5
THF
THF
THF
Ether
DME
Toluene
14
14
16
18
18
50
93
98
93
90
94
91
52:48
56:44
59:41
51:49
60:40
49:51
45
62
74
29
10
12
16
23
20
13
36
4
10
20
20
20
20
a
Isolate yield of amino acid esters 3a.
Determined by 1H NMR of the crude mixture of amino acid esters 3a after hydrolysis of the imine moiety of the aldol adducts.
Determined by HPLC after conversion to thioxooxazolines 4.
b
c
amount could be reduced. The reaction proceeded smoothly
in the presence of less catalyst and gave the product in
excellent yield with as little as 5 mol% of the catalyst (Table
4, entries 1 and 2). The selectivity was maintained at a
moderate level with 10 mol% of the catalyst (entry 2),
whereas a significant deterioration of the stereoselectivity
was observed after reducing the catalyst amount to 5 mol%
(entry 1). Among several solvents tested, tetrahydrofuran
(THF) gave the best result (entry 3).
comparable enantiomeric excess (anti: 69% ee) (entry 2).
Pivalaldehyde (2c) had a much better diastereoselectivity
(anti/syn 86:14) and gave the anti-adduct with 76% ee
(entry 3). Hexanal (2d), an enolizable aldehyde, also reacted
with 8 cleanly to afford the corresponding products in 89%
yield (entry 4). The diastereoselectivity was opposite to that
of the other cases, and the syn-adduct (syn-3d) was obtained
as the major diastereomer with poor enantiomeric excess.
Furfural (2e) also underwent a smooth conversion to afford
the products in good yield, albeit with poor enantiomeric
excess (entry 5).
2.5. Generality of aldehydes
Using 8 as the best donor substrate, the range of applicable
aldehydes was investigated (Table 5). Cyclohexanecarbox-
aldehyde (2b) afforded the amino acid esters (3b) in 73%
yield in a better diastereomeric ratio (70:30) with a
2.6. Reaction mechanism
The present reaction probably proceeds with the aid of the
Lewis acidity and the Brønsted basicity of the catalyst,
Table 5. Direct aldol reaction of glycinate Schiff base 8 with aldehydes
Entry
1
Aldehyde
Product
Temperature (8C)
250
Time (h)
16
Yield (%)a
93
anti/synb
ee of anti (%)c
ee of syn (%)c
3a
59:41
74
20
2
3bd
250
23
73
70:30
69
18
3
4
3cd
3dd
3ed
250
250
250
23
13
18
71
89
82
86:14
28:72
61:39
76
42
19
ND
1
5
2
a
Isolate yield of amino acid esters 3.
b
c
d
Determined by 1H NMR of the crude mixture of amino acid esters 3 after hydrolysis of the imine moiety of the aldol adducts.
Determined by HPLC after conversion to thioxooxazolines 4.
The absolute configuration was not determined.

N. Yoshikawa, M. Shibasaki / Tetrahedron 58 (2002) 8289–8298
8293
measured on a JASCO P-1010 polarimeter. EIMS were
measured on a JEOL JMS-BU20 GCmate. Column
chromatography was performed with silica gel Merck 60
(230–400 mesh ASTM). Preparative thin layer chroma-
tography (preparative TLC) was performed on Merck Art.
5715, Silica gel 60 F254 plates. The enantiomeric excess was
determined by HPLC analysis. HPLC was performed on
JASCO HPLC systems consisting of the following: pump,
PU-980; detector, UVIDEC-100-IV, measured at 254 nm;
column, DAICEL CHIRALPAK AS or AD; mobile phase,
hexane-2-propanol; flow rate, 0.3–1.5 mL/min. Reactions
were performed in dry solvents under an argon atmosphere.
THF was distilled from sodium benzophenone ketyl.
Toluene was distilled from sodium. Lanthanum triisopro-
poxide (La(O-i-Pr)3) was purchased from Kojundo Chemi-
cal Laboratory Co., Ltd, 5-1-28, Chiyoda, Sakado-shi,
Saitama 350-0214, Japan (fax: þ(81)-492-84-1351). Other
reagents were purified using standard methods.
Figure 2. Working model.
similar to previously reported direct aldol reactions with
methyl ketones20c–e and a-hydroxy ketones.20a,b Especially
in the latter case, both diastereomers of the aldol products
possessed identical stereochemistry at the a-position, which
led us to propose the formation of a chelate complex
between the enolate and the central lanthanide metal of the
catalyst.20a In the present system, however, a different
tendency was observed for the stereochemical outcome of
amino acid esters (2S,3S)-3a and (2R,3S)-3a. Hence the
‘chelation model’ is not applicable to the present system.
Based on this fact, we propose the working model presented
in Fig. 2, wherein the catalyst permits an enolate to attack
the Re-face of the aldehyde by shielding the Si-face.
Whereas the Z-enolate is presented in the working model, a
small amount of the E-enolate could also be involved in the
transition state, giving rise to the moderate stereoselec-
tivities (no more than 76% ee and 72% de). In this regard,
the geometry of the enolates remains to be investigated to
predict the precise mechanism.
4.2. Synthesis of glycinate Schiff bases
Glycinate Schiff bases were prepared according to the
reported procedure.29
4.2.1. tert-Butyl N-(diphenylmethylene)glycinate (1). This
compound was reported in Ref. 29.
4.2.2. tert-Butyl N-[bis(p-methylphenyl)methylene]glyci-
nate (6). 1H NMR (CDCl3) d 7.55 (d, J¼8.2 Hz, 2H), 7.25
(d, J¼8.2 Hz, 2H), 7.12 (d, J¼7.8 Hz, 2H), 7.06 (d, J¼
7.8 Hz, 2H), 4.11 (s, 2H), 2.42 (s, 3H), 2.35 (s, 3H), 1.46 (s,
9H). LRMS (EI) m/z 323 (Mþ), 222 (Mþ2CO2CH3).
4.2.3. tert-Butyl N-[bis(p-fluorophenyl)methylene]glyci-
1
nate (7). Colorless solid. Mp 86.58C. H NMR (CDCl3) d
3. Conclusions
7.65–7.61 (m, 2H), 7.17–7.16 (m, 4H), 7.03–6.99 (m, 2H),
4.09 (s, 2H), 1.46 (s, 9H). 13C NMR (CDCl3) d 169.6, 169.4,
164.3 (d, J¼250 Hz), 162.8 (d, J¼249 Hz), 135.5 (d, J¼
3.0 Hz), 131.6 (d, J¼4.1 Hz), 130.7 (d, J¼8.2 Hz), 129.7 (d,
J¼8.2 Hz), 115.8 (d, J¼21.7 Hz), 115.1 (d, J¼21.6 Hz),
81.3, 56.2, 28.1. FTIR (KBr) n 1741, 1227 cm21. LRMS
(EI) m/z 331 (Mþ), 230 (Mþ2CO2t-Bu, base peak). Anal.
Calcd for C19H19F2NO2: C, 68.87; H, 5.78; N, 4.23. Found:
C, 68.88; H, 5.89; N, 4.04.
We report a direct aldol reaction of glycinate Schiff bases
with aldehydes using heterobimetallic asymmetric com-
plexes as a catalyst. anti-b-Hydroxy-a-amino acid esters
were obtained as the major diastereomers with moderate
enantiomeric excess in the case of a-substituted aliphatic
aldehydes. To the best of our knowledge, this is the first
successful example of the direct aldol reaction of glycinate
Schiff bases with aldehydes, achieving moderate to good
stereoselectivity.28 Further investigation to improve the
efficiency and the generality, and mechanistic studies are
currently ongoing in our laboratory.
4.2.4. tert-Butyl N-[bis(p-chlorophenyl)methylene]glyci-
1
nate (8). Colorless solid. Mp 93.58C. H NMR (CDCl3) d
7.59–7.56 (m, 2H), 7.46–7.44 (m, 2H), 7.31–7.29 (m, 2H),
7.13–7.11 (m, 2H), 4.09 (s, 2H), 1.46 (s, 9H). 13C NMR
(CDCl3) d 169.4, 169.3, 137.4, 136.8, 135.1, 133.8, 129.9,
129.1, 129.1, 128.3, 81.4, 56.2, 28.8. FTIR (KBr) n
1747 cm21. LRMS (EI) m/z 365 (Mþþ2), 363 (Mþ), 262
(Mþ2CO2t-Bu). Anal. Calcd for C19H19Cl2NO2: C, 62.65;
H, 5.26; N, 3.85. Found: C, 62.74; H, 5.52; N, 3.80.
4. Experimental
4.1. General methods and materials
Infrared (IR) spectra were recorded on a JASCO FT/IR-410
Fourier transform infrared spectrophotometer. NMR spectra
were recorded on a JEOL JNM-LA500 spectrometer,
4.2.5. tert-Butyl N-[bis(p-(trifluoromethyl)phenyl)methyl-
1
ene]glycinate (9). Pale yellow solid. H NMR (CDCl3) d
1
operating at 500 MHz for H NMR and 125.65 MHz for
13C NMR. Chemical shifts in CDCl3 are reported on the d
scale relative to CHCl3 (7.26 ppm for 1H NMR and
77.00 ppm for 13C NMR) as an internal reference. The
following abbreviations are used to report multiplicities:
‘s’ (singlet), ‘d’ (doublet), ‘dd’ (doublet of doublets), ‘t’
(triplet), ‘m’ (multiplet), ‘br’ (broad). Optical rotations were
7.56 (d, J¼8.0 Hz, 2H), 7.27 (d, J¼8.0 Hz, 2H), 7.25 (d, J¼
8.0 Hz, 2H), 6.70 (d, J¼8.0 Hz, 2H), 4.01 (s, 2H), 1.34 (s, 9H).
LRMS (EI) m/z 431 (Mþ), 330 (Mþ2CO2t-Bu), 57 (t-Buþ).
4.2.6. Methyl N-[bis(p-chlorophenyl)methylene]glyci-
nate (11). Pale yellow solid. Mp 85–868C. 1H NMR

8294
N. Yoshikawa, M. Shibasaki / Tetrahedron 58 (2002) 8289–8298
(CDCl3) d 7.58–7.56 (m, 2H), 7.47–7.45 (m, 2H), 7.32–
7.30 (m, 2H), 4.19 (s, 2H), 3.74 (s, 3H). 13C NMR (CDCl3) d
170.6, 169.7, 137.2, 136.9, 135.2, 133.6, 130.0, 129.2,
129.1, 128.4, 55.5, 52.1. FTIR (KBr) n 1758 cm21. LRMS
(EI) m/z 323 (Mþþ2), 321 (Mþ), 262 (Mþ2CO2t-Bu).
Anal. Calcd for C16H13Cl2NO2: C, 59.65; H, 4.07; N, 4.35.
Found: C, 59.72; H, 4.23; N, 4.15.
aldol reaction of glycinate Schiff bases promoted by the
LLB·LiOH complex. A solution of BuLi in hexane
(33.3 mL, 0.054 mmol, 1.62 M) was added to a stirred
solution of H2O in THF (0.12 mL, 0.12 mmol, 1 M) at 08C.
The resulting mixture was stirred at the same temperature
for 20 min, and a solution of (S)-LLB in THF (0.6 mL,
0.06 mmol, 0.1 M) was added. After stirring for 30 min at
08C, the mixture was cooled to 2508C, and a solution of
imine 1 (0.3 mmol) in THF (0.9 mL) was added. The
resulting solution was stirred at the same temperature for
15 min, and aldehyde 2a (0.9 mmol) was added via syringe.
The reaction mixture was stirred until the starting imine was
consumed as determined by TLC analysis and quenched by
adding a solution of AcOH in ether (3 mL, 0.25 M). Water
was added, and the aqueous layer was extracted with ether
(£3). The combined organic layers were washed with water
and brine and dried over Na2SO4. The hydrolysis was
performed according to a procedure similar to that reported
in Ref. 17: the solvent was evaporated, and the resulting
residue was dissolved in THF (4 mL). Aqueous citric acid
(0.5 M, 2.22 mL) was added, and the resulting mixture was
stirred for 5 h at room temperature and for 13 h at 408C.
After evaporation of THF, the resulting mixture was washed
with ether (£2), and sodium bicarbonate (NaHCO3, 450 mg)
was carefully added to the aqueous layer. The aqueous layer
was saturated by addition of NaCl and extracted thoroughly
with CH2Cl2, and the combined organic layers were dried
over Na2SO4. Evaporation of solvents gave b-hydroxy-a-
amino acid esters 3a as a mixture of diastereomers,
which were purified by silica gel column chromatography
(CH2Cl2/MeOH 50:1 (v/v)) to afford anti-3a (32.4 mg,
53%) and syn-3a (25.5 mg, 42%).
4.2.7. Diphenylmethyl N-[bis(p-chlorophenyl)methylene]-
glycinate (12). Colorless solid. Mp 95–968C. 1H NMR
(CDCl3) d 7.59–7.56 (m, 2H), 7.41–7.38 (m, 2H), 7.34–
7.28 (m, 12H), 7.07–7.05 (m, 2H), 6.95 (s, 1H), 4.30 (s,
2H). 13C NMR (CDCl3) d 169.9, 169.2, 139.8, 137.3, 137.0,
135.2, 133.6, 130.0, 129.2, 129.0, 128.5, 128.4, 128.0,
127.2, 77.4, 55.7. FTIR (KBr) n 1742, 1173 cm21. LRMS
(EI) m/z 475 (Mþþ2), 473 (Mþ), 167 (Ph2CHþ, base peak).
Anal. Calcd for C28H21Cl2NO2: C, 70.89; H, 4.46; N, 2.95.
Found: C, 70.89; H, 4.62; N, 2.86.
4.2.8. N-Methoxy-N-methyl 2-[N-bis(p-chlorophenyl)-
methyleneamino]acetamide (14). Colorless solid. Mp
1
948C. H NMR (CDCl3) d 7.58–7.56 (m, 2H), 7.46–7.44
(m, 2H), 7.31–7.29 (m, 2H), 7.18–7.16 (m, 2H), 4.34 (s,
2H), 3.66 (s, 3H), 3.20 (s, 3H). 13C NMR (CDCl3) d 170.7,
169.4, 137.5, 136.6, 135.0, 133.8, 129.9, 129.3, 129.0,
128.3, 61.4, 54.5, 32.3. FTIR (KBr) n 1665 cm21. LRMS
(EI) m/z 321 (Mþþ22OCH3), 319 (Mþ2OCH3), 264
(Mþþ22CON(OCH3)CH3), 262 (Mþ2CON(OCH3)CH3).
Anal. Calcd for C17H16Cl2N2O2: C, 58.13; H, 4.59; N, 7.98.
Found: C, 58.24; H, 4.78; N, 7.79.
4.3. Direct aldol reaction of glycinate Schiff bases
promoted by a heterobimetallic catalyst
4.3.3. Methyl (2S,3S)-2-amino-3-hydroxy-4-methylpen-
tanoate (anti-15). Colorless oil. 38% ee. 1H NMR (CDCl3)
d 3.73 (s, 3H), 3.58 (d, J¼4.9 Hz, 1H), 3.40 (dd, J¼5.5,
4.9 Hz, 1H), 2.13 (br-s, 3H), 1.81–1.74 (m, 1H), 0.95 (d,
J¼5.6 Hz, 3H), 0.93 (d, J¼5.7 Hz, 3H). 13C NMR (CDCl3)
d 174.9, 78.5, 55.6, 52.0, 30.5, 19.4, 17.8. FTIR (KBr) n
1737 cm21. [a]D25þ9.9 (c 1.2, CHCl3). LRMS (EI) m/z 162
(Mþþ1), 118 (Mþ2i-Pr, base peak), 102 (Mþ2CO2CH3).
HRMS (EI) calcd for C7H16NO3 (Mþþ1) 162.1130, found
162.1126.
4.3.1. Preparation of (S)-LLB (Li3[La(S-binol)3]). A
200 mL flask equipped with a 3-way tap was charged with
solid La(O-i-Pr)3 (4.61 g, 14.57 mmol) in a glove box.
Addition of dry THF (72.8 mL) via syringe under argon
atmosphere gave a 0.2 M solution of La(O-i-Pr)3 (NOTE:
We recommend preparing the solution immediately before
use; otherwise, it must be stored below 2208C under argon
atmosphere. The decomposition of La(O-i-Pr)3 was
observed at higher temperatures in THF). A separate
100 mL flask was charged with (S)-BINOL (6.78 g,
24.0 mmol), equipped with a 3-way tap and a magnetic
stirrer, and heated at 458C under reduced pressure for 2 h.
After the BINOL was dissolved in dry THF (21 mL) under
argon, the La(O-i-Pr)3 solution (40.0 mL, 8.0 mmol) was
added at 08C, and the resulting pale yellow solution
was stirred at room temperature for 30 min. The solvent
was removed under reduced pressure at room temperature
by using a vacuum pump, and the resulting residue was
further dried at the same temperature under reduced
pressure for 1 h. The residue was dissolved in dry THF
(65.7 mL), and a solution of n-BuLi in hexanes (14.3 mL,
24.0 mmol, 1.68 M) was added at 08C. Stirring for another
12 h at room temperature gave a pale yellow solution of
(S)-LLB (0.1 M), which can be stored at room temperature
under argon atmosphere for 6 months without loss of
activity. The flask containing the LLB was also shielded
from light during storage.
4.3.4. Diphenylmethyl (2S p,3S p)-2-amino-3-hydroxy-4-
methylpentanoate (anti-16). Colorless oil. 47% ee. 1H
NMR (CDCl3) d 7.36–7.27 (m, 10H), 6.94 (s, 1H), 3.70 (d,
J¼5.0 Hz, 1H), 3.48 (dd, J¼6.4, 5.0 Hz, 1H), 1.87 (br-s,
3H), 1.74–1.64 (m, 1H), 0.91 (t, J¼6.7 Hz, 6H). 13C NMR
(CDCl3) d 173.7, 139.7, 139.5, 128.6, 128.5, 128.1, 128.1,
127.2, 78.4, 77.7, 57.1, 30.5. FTIR (neat) n 1733,
1169 cm21. [a]D25¼23.6 (c 0.5, CHCl3). LRMS (EI) m/z
314 (Mþþ1). HRMS (EI) calcd for C19H24NO3 (Mþþ1)
314.1756, found 314.1762.
4.3.5. Diphenylmethyl (2R p,3S p)-2-amino-3-hydroxy-4-
1
methylpentanoate (syn-16). Colorless solid. 42% ee. H
NMR (CDCl3) d 7.36–7.27 (m, 10H), 6.93 (s, 1H), 3.63 (d,
J¼4.2 Hz, 1H), 3.54 (dd, J¼6.5, 4.2 Hz, 1H), 1.86 (br-s,
3H), 1.75–1.67 (m, 1H), 1.00 (d, J¼6.4 Hz, 3H), 0.94 (d,
J¼6.7 Hz, 3H). 13C NMR (CDCl3) d 173.7, 139.7, 139.6,
128.6, 128.1, 128.1, 127.1, 127.0, 77.8, 56.3, 30.6, 19.4,
17.7. FTIR (KBr) n 1727, 1241 cm21. [a]D24þ4.4 (c 0.4,
4.3.2. Representative procedure for catalytic asymmetric

N. Yoshikawa, M. Shibasaki / Tetrahedron 58 (2002) 8289–8298
8295
CHCl3). LRMS (EI) m/z 314 (Mþþ1). HRMS (EI) calcd for
NMR (CDCl3) d 173.6, 81.6, 72.2, 58.8, 33.9, 31.8, 28.0,
25.3, 14.0. FTIR (neat) n 1731, 1157 cm21. LRMS (EI) m/z
232 (Mþþ1). HRMS (EI) calcd for C13H26NO3 (Mþþ1)
232.1913, found 232.1914.
C19H24NO3 (Mþþ1) 314.1756, found 314.1758.
4.3.6. tert-Butyl (2S,3S)-2-amino-3-hydroxy-4-methyl-
pentanoate (anti-3a). The absolute configuration was
determined by comparison of the optical rotation with the
reported one.17
4.3.14. tert-Butyl (2S p,3S p)-2-amino-3-(1-furyl)-3-
1
hydroxypropanoate (anti-3e). Colorless oil. 19% ee. H
NMR (CDCl3) d 7.33 (d, J¼1.8 Hz, 1H), 6.31 (dd, J¼3.0,
1.8 Hz, 1H), 6.27 (d, J¼3.0 Hz, 1H), 4.96 (d, J¼5.1 Hz,
1H), 3.74 (d, J¼5.1 Hz, 1H), 2.30 (br-s, 3H), 1.40 (s, 9H).
13C NMR (CDCl3) d 171.8, 153.6, 142.1, 110.1, 107.6, 82.0,
68.0, 58.6, 27.9. [a]D21¼23.1 (c 1.0, CHCl3). LRMS (EI)
m/z 228 (Mþþ1). HRMS (EI) calcd for C11H18NO4
(Mþþ1) 228.1236, found 228.1231.
4.3.15. tert-Butyl (2R p,3S p)-2-amino-3-(1-furyl)-3-
hydroxypropanoate (syn-3e). Colorless oil. 2% ee. 1H
NMR (CDCl3) d 7.38–7.37 (m, 1H), 6.35–6.31 (m, 2H),
4.77 (d, J¼5.1 Hz, 1H), 3.77 (d, J¼5.1 Hz, 1H), 2.31 (br-s,
3H), 1.40 (s, 9H). 13C NMR (CDCl3) d 172.0, 153.8, 142.2,
110.2, 107.7, 82.0, 68.7, 58.1, 27.8. LRMS (EI) m/z 228
(Mþþ1). HRMS (EI) calcd for C11H18NO4 (Mþþ1)
228.1236, found 228.1239.
4.3.7. tert-Butyl (2R,3S)-2-amino-3-hydroxy-4-methyl-
pentanoate (syn-3a). The absolute configuration was
determined after conversion to the corresponding oxazo-
lidine.17
4.3.8. (2R p,3S p)-2-Amino-3-hydroxy-4-methylpentanoic
acid N-methoxy-N-methylamide (syn-18). This compound
was transformed into the corresponding N a-(tert-butoxy-
carbonyl) amide, which was identified by comparison of
1
the H and 13C NMR with reported ones.16a The absolute
configuration was not determined.
4.3.9. tert-Butyl (2S p,3S p)-2-amino-3-cyclohexyl-3-
hydroxypropanoate (anti-3b). Colorless solid. 69% ee.
Mp 47–498C. 1H NMR (CDCl3) d 3.49 (d, J¼4.2 Hz, 1H),
3.40 (dd, J¼6.9, 4.2 Hz, 1H), 2.06 (br-s, 3H), 1.95–1.90 (m,
1H), 1.78–1.60 (m, 4H), 1.50–1.42 (m, 1H), 1.47 (s, 9H),
1.26–0.98 (m, 5H). 13C NMR (CDCl3) d 173.8, 81.7, 78.0,
56.6, 40.7, 29.5, 28.5, 28.0, 26.3, 26.1, 25.9. FTIR (KBr) n
3187, 1732, 1155 cm21. [a]D24þ12.7 (c 1.3, CHCl3). LRMS
(EI) m/z 244 (Mþþ1).
4.4. Conversion of amino acid esters to oxazolidine-
thiones
The b-hydroxy-a-amino acid esters were converted to the
corresponding oxazoline-2-thiones to determine the enantio-
meric excess.17 The relative configuration was assigned by
1H NOE.
4.3.10. tert-Butyl (2R p,3S p)-2-amino-3-cyclohexyl-3-
1
hydroxypropanoate (syn-3b). Colorless oil. 18% ee. H
NMR (CDCl3) d 3.45–3.42 (m, 2H), 1.96–1.91 (m, 1H),
1.90 (br-s, 3H), 1.81–1.73 (m, 2H), 1.68–1.60 (m, 2H),
1.47 (s, 9H), 1.47–1.37 (m, 1H), 1.30–1.04 (m, 5H). 13C
NMR (CDCl3) d 174.0, 81.5, 76.5, 55.9, 40.5, 29.6, 28.0,
26.3, 26.0. FTIR (neat) n 1773, 1156 cm21. [a]D23¼23.4 (c
0.6, CHCl3). LRMS (EI) m/z 244 (Mþþ1). HRMS (EI)
calcd for C13H26NO3 (Mþþ1) 244.1913, found 244.1918.
4.3.11. tert-Butyl (2S p,3S p)-2-amino-3-hydroxy-4,4-
dimethylpentanoate (anti-3c). Colorless solid. 76% ee.
Mp 74–768C. 1H NMR (CDCl3) d 3.40 (d, J¼3.0 Hz, 1H),
3.33 (d, J¼3.0 Hz, 1H), 2.08 (br-s, 3H), 1.46 (s, 9H), 0.93
(s, 9H). 13C NMR (CDCl3) d 175.2, 82.9, 82.0, 55.2, 35.1,
27.9, 26.4. FTIR (KBr) n 3188, 1733, 1150 cm21. [a]D25þ
14.7 (c 1.0, CHCl3). LRMS (EI) m/z 218 (Mþþ1), 116
(Mþ2CO2t-Bu), 57 (t-Buþ).
4.4.1. (4S p,5S p)-5-Isopropyl-2-thioxooxazolidine-4-
carboxylic acid methyl ester (from anti-15). Colorless
solid. 38% ee. Mp 103–1048C. H NMR (CDCl3) d 7.90
1
(br-s, 1H), 4.70 (dd, J¼8.3, 7.8 Hz, 1H), 4.60 (d, J¼8.3 Hz,
1H), 3.81 (s, 3H), 2.02–1.92 (m, 1H), 1.05 (d, J¼6.2 Hz,
3H), 1.03 (d, J¼6.5 Hz, 3H). 13C NMR (CDCl3) d 190.4,
168.4, 89.9, 60.6, 53.0, 29.1, 19.1, 17.9. FTIR (KBr) n 3185,
1736 cm21. [a]D24¼27.9 (c 1.2, CHCl3). LRMS (EI) m/z
203 (Mþ, base peak), 144 (Mþ2CO2CH3). HRMS (EI)
calcd for C8H13NO3S (Mþ) 203.0616, found 203.0613.
HPLC: column, Chiralpak AD; eluent, hexane/2-propanol
9:1 (v/v); flow, 0.3 mL/min; tR 42.4 min (major) and
49.9 min (minor).
4.3.12. tert-Butyl (2S p,3S p)-2-amino-3-hydroxyoctano-
1
ate (anti-3d). Colorless oil. 42% ee. H NMR (CDCl3) d
3.77–3.73 (m, 1H), 3.45 (d, J¼4.3 Hz, 1H), 1.99 (br-s, 3H),
1.54–1.24 (m, 8H), 1.46 (s, 9H), 0.89–0.86 (m, 3H). 13C
NMR (CDCl3) d 173.2, 81.6, 72.2, 59.0, 32.0, 31.7, 28.0,
4.4.2. (4S p,5S p)-5-Isopropyl-2-thiooxooxazoline-4-carb-
oxylic acid diphenylmethyl ester (from anti-16). Color-
less solid. 47% ee. Mp 126–1288C. H NMR (C6D6) d
25.4, 22.5, 14.0. FTIR (neat) n 1731, 1156 cm21
.
1
[a]2D5¼21.3 (c 1.0, CHCl3). LRMS (EI) m/z 232 (Mþþ1).
HRMS (EI) calcd for C13H26NO3 (Mþþ1) 232.1913, found
232.1910.
7.41–7.32 (m, 4H), 7.18–6.96 (m, 6H), 6.95 (s, 1H), 6.30
(br-s, 0.28H), 6.16 (br-s, 0.72H), 3.58 (dd, J¼9.4, 7.7 Hz,
0.72H), 3.58 (m, 0.28H), 3.44 (d, J¼7.7 Hz, 0.28H), 3.43 (d,
J¼7.2 Hz, 0.72H), 1.46–1.38 (m, 1H), 0.69 (d, J¼6.3 Hz,
3H), 0.46 (d, J¼6.4 Hz, 3H). 13C NMR (CDCl3) d 190.9,
166.9, 138.7, 138.6, 128.7, 128.6, 128.6, 128.4, 127.5,
126.9, 90.4, 79.1, 61.0, 28.7, 19.0, 18.1. FTIR (KBr) n 3170,
1748, 1184 cm21. [a]D24¼211.8 (c 0.6, CHCl3). LRMS (EI)
4.3.13. tert-Butyl (2R p,3S p)-2-amino-3-hydroxyoctano-
1
ate (syn-3d). Colorless oil. 1% ee. H NMR (CDCl3) d
3.68–3.64 (m, 1H), 3.21 (d, J¼4.7 Hz, 1H), 2.15 (br-s, 3H),
1.52–1.40 (m, 8H), 1.46 (s, 9H), 0.89–0.86 (m, 3H). 13C

8296
N. Yoshikawa, M. Shibasaki / Tetrahedron 58 (2002) 8289–8298
1
m/z 355 (Mþ), 167 (Ph2CHþ, base peak). HRMS (EI) calcd
for C20H21NO3S (Mþ) 355.1242, found 355.1228. HPLC:
column, Chiralpak AS; eluent, hexane/2-propanol 9:1 (v/v);
flow, 1.5 mL/min; tR 28.5 min (minor) and 41.6 min
(major).
76% ee. Mp 1648C. H NMR (CDCl3) d 7.96 (br-s, 1H),
4.64 (d, J¼8.0 Hz, 1H), 4.36 (d, J¼8.0 Hz, 1H), 1.49 (s,
9H), 1.09 (s, 9H). 13C NMR (CDCl3) d 190.9, 167.6, 93.2,
84.4, 61.3, 33.4, 28.9, 25.8, 25.3. FTIR (KBr) d 3244, 2979,
1731, 1480 cm21. [a]D25þ26.4 (c 2.0, CHCl3). LRMS (EI)
m/z 259 (Mþ), 158 (Mþ2CO2t-Bu), 57 (t-Buþ, base peak).
HRMS (EI) calcd for C12H21NO3S (Mþ) 259.1242, found
259.1249. HPLC: column, Chiralpak AD; eluent, hexane/
2-propanol 9:1 (v/v); flow, 1.0 mL/min; tR 6.5 min (major)
and 10.1 min (minor).
4.4.3. (4R p,5S p)-5-Isopropyl-2-thiooxooxazoline-4-carb-
oxylic acid diphenylmethyl ester (from syn-16). Colorless
1
solid. 42% ee. H NMR (CDCl3) d 7.53 (br-s, 1H), 7.39–
7.30 (m, 10H), 6.94 (s, 1H), 4.72 (t, J¼5.5 Hz, 1H), 4.32 (d,
J¼5.5 Hz, 1H), 2.14–2.05 (m, 1H), 1.05 (d, J¼6.8 Hz, 3H),
1.03 (d, J¼6.8 Hz, 3H). 13C NMR (CDCl3) d 189.3, 167.8,
138.6, 128.8, 128.8, 128.6, 128.5, 127.1, 126.8, 89.9, 79.3,
4.4.9. (4S p,5S p)-5-Pentyl-2-thiooxooxazoline-4-carb-
oxylic acid tert-butyl ester (from anti-3d). Colorless
solid. 42% ee. H NMR (CDCl3) d 7.58 (br-s, 1H), 5.02–
59.6, 32.4, 17.1, 16.7. FTIR (KBr) n 3340, 1742, 1496 cm21
.
1
[a]2D3¼29.5 (c 0.3, CHCl3). LRMS (EI) m/z 355 (Mþ), 167
(Ph2CHþ, base peak). HRMS (EI) calcd for C20H21NO3S
(Mþ) 355.1242, found 355.1255. HPLC: column, Chiralpak
AD; eluent, hexane/2-propanol 9:1 (v/v); flow, 0.7 mL/min;
tR 22.0 min (major) and 25.9 min (minor).
4.97 (m, 1H), 4.46 (d, J¼8.9 Hz, 1H), 1.76–1.28 (m, 8H),
1.49 (s, 9H), 0.91–0.87 (m, 3H). 13C NMR (CDCl3) d 190.1,
166.7, 84.8, 84.2, 61.4, 31.3, 30.2, 28.0, 25.1, 22.4, 13.9.
FTIR (KBr) n 3160, 1735, 1180 cm21. [a]D26¼210.5 (c 0.8,
CHCl3). LRMS (EI) m/z 273 (Mþ), 172 (Mþ2CO2t-Bu), 57
(t-Buþ). HRMS (EI) calcd for C13H23NO3S (Mþ) 273.1398,
found 273.1391. HPLC: column, Chiralpak AD; eluent,
hexane/2-propanol 9:1 (v/v); flow, 1.0 mL/min; tR 6.8 min
(major) and 9.8 min (minor).
4.4.4. (4S,5S)-5-Isopropyl-2-thiooxooxazoline-4-carb-
oxylic acid tert-butyl ester (from anti-3a). This compound
was reported in Ref. 17. HPLC: column, Chiralpak AD;
eluent, hexane/2-propanol 9:1 (v/v); flow, 1.0 mL/min; tR
7.2 min (major) and 10.1 min (minor).
4.4.10. (4R p,5S p)-5-Pentyl-2-thiooxooxazoline-4-carb-
oxylic acid t-butyl ester (syn-3d). Colorless solid. 1% ee.
1
4.4.5. (4R,5S)-5-Isopropyl-2-thiooxooxazoline-4-car-
boxylic acid tert-butyl ester (from syn-3a). The absolute
configuration was determined by comparison of the optical
rotation with the reported one.17 HPLC: column, Chiralpak
AD; eluent, hexane/2-propanol 9:1 (v/v); flow, 1.0 mL/min;
tR 7.4 min (minor) and 10.6 min (major).
Mp 678C. H NMR (CDCl3) d 7.89 (br-s, 1H), 4.88 (dt,
J¼6.6, 5.4 Hz, 1H), 4.11 (d, J¼6.6 Hz, 1H), 1.91–1.76 (m,
2H), 1.58–1.41 (m, 2H), 1.36–1.30 (m, 4H), 1.48 (s, 9H),
0.92–0.87 (m, 3H). 13C NMR (CDCl3) d 189.1, 167.2, 85.6,
84.3, 62.6, 34.8, 31.1, 27.9, 24.0, 22.3, 13.9. FTIR (KBr) n
3198, 1743 cm21. LRMS (EI) m/z 273 (Mþ), 57 (t-Buþ,
base peak). HRMS (EI) calcd for C13H23NO3S (Mþ)
273.1398, found 273.1398. HPLC: column, Chiralpak AD;
eluent, hexane/2-propanol 9:1 (v/v); flow, 1.0 mL/min; tR
7.1 min and 11.1 min.
4.4.6. (4S p,5S p)-5-Cyclohexyl-2-thiooxooxazoline-4-
carboxylic acid tert-butyl ester (from anti-3b). Colorless
solid. 69% ee. 1H NMR (CDCl3) d 7.83 (br-s, 1H), 4.68 (dd,
J¼8.4, 7.7 Hz, 1H), 4.46 (d, J¼8.4 Hz, 1H), 1.98–1.94 (br,
1H), 1.80–1.64 (m, 5H), 1.49 (s, 9H), 1.26–1.10 (m, 5H).
13C NMR (CDCl3) d 190.4, 167.0, 89.1, 84.1, 61.1, 38.4,
29.3, 27.9, 25.8, 25.5, 25.2. FTIR (KBr) n 3330, 2928, 1719,
1507, 1478 cm21. [a]D25¼24.4 (c 1.4, CHCl3). LRMS (EI)
m/z 285 (Mþ, base peak), 184 (Mþ2CO2t-Bu). HRMS (EI)
calcd for C14H23NO3S (Mþ) 285.1398, found 285.1404.
HPLC: column, Chiralpak AD; eluent, hexane/2-propanol
9:1 (v/v); flow, 1.0 mL/min; tR 7.1 min (major) and
10.5 min (minor).
4.4.11. (4S p,5S p)-5-(1-Furyl)-2-thiooxooxazoline-4-
carboxylic acid tert-butyl ester (from anti-3e). Pale
1
yellow solid. 19% ee. Mp 177–1808C. H NMR (CDCl3)
d 7.43 (d, J¼1.7 Hz, 1H), 7.31 (br-s, 1H), 6.53 (d, J¼3.2 Hz,
1H), 6.39 (dd, J¼3.2, 1.7 Hz, 1H), 6.00 (d, J¼9.8 Hz, 1H),
4.82 (d, J¼9.8 Hz, 1H), 1.25 (s, 9H). FTIR (KBr) n 3165,
1737 cm21. LRMS (EI) m/z 269 (Mþ), 57 (t-Buþ, base
peak). HPLC: column, Chiralpak AD; eluent, hexane/2-
propanol 9:1 (v/v); flow, 1.0 mL/min; tR 17.2 min (major)
and 31.1 min (minor).
4.4.7. (4R p,5S p)-5-Cyclohexyl-2-thiooxooxazoline-4-
carboxylic acid tert-butyl ester (from syn-3b). Colorless
4.4.12. (4R p,5S p)-5-(1-Furyl)-2-thiooxooxazoline-4-
carboxylic acid tert-butyl ester (from syn-3e). Colorless
1
solid. 18% ee. Mp 115–1168C. H NMR (CDCl3) d 7.66
1
(br-s, 1H), 4.72 (t, J¼5.6 Hz, 1H), 4.18 (d, J¼5.6 Hz, 1H),
1.89–1.67 (m, 6H), 1.48 (s, 9H), 1.30–1.05 (m, 5H). 13C
NMR (CDCl3) d 189.1, 167.6, 89.5, 84.2, 60.1, 41.9, 27.9,
27.5, 27.1, 26.0, 25.5, 25.3. FTIR (KBr) n 3185, 2927, 1751,
1511 cm21. [a]D25¼214.1 (c 0.6, CHCl3). LRMS (EI) m/z
285 (Mþ), 184 (Mþ2CO2t-Bu), 57 (t-Buþ, base peak).
HRMS (EI) calcd for C14H23NO3S (Mþ) 285.1398, found
285.1396. HPLC: column, Chiralpak AD; eluent, hexane/2-
propanol 9:1 (v/v); flow, 1.0 mL/min; tR 9.3 min (minor)
and 12.8 min (major).
solid. 2% ee. H NMR (CDCl3) d 7.49 (d, J¼1.8 Hz, 1H),
7.33 (br-s, 1H), 6.58 (d, J¼3.1 Hz, 1H), 6.42 (dd, J¼3.1,
1.8 Hz, 1H), 5.90 (d, J¼5.6 Hz, 1H), 4.72 (d, J¼5.6 Hz,
1H), 1.49 (s, 9H). FTIR (KBr) n 1732, 1515 cm21. LRMS
(EI) m/z 269 (Mþ), 57 (t-Buþ, bae peak). HRMS (EI) calcd
for C12H15NO4S (Mþ) 269.0722, found 269.0717. HPLC:
column, Chiralpak AD; eluent, hexane/2-propanol 9:1 (v/v);
flow, 1.0 mL/min; tR 19.6 and 23.6 min.
Acknowledgements
4.4.8. (4S p,5S p)-5-tert-Butyl-2-thiooxooxazoline-4-carb-
oxylic acid tert-butyl ester (from anti-3c). Colorless solid.
This study was financially supported by CREST, The Japan

N. Yoshikawa, M. Shibasaki / Tetrahedron 58 (2002) 8289–8298
8297
2195–2204. (c) Williams, L.; Zhang, Z.; Shao, F.; Carroll,
Science and Technology Corporation (JST), and by a Grant-
in-Aid for Scientific Research from the Ministry of
Education, Science, and Culture, Japan. Naoki Yoshikawa
thanks the Japan Society for the Promotion of Science
(JSPS) for a research fellowship.
´
P. J.; Joullie, M. M. Tetrahedron 1996, 52, 11673–11694.
10. Kuwano, R.; Okuda, S.; Ito, Y. J. Org. Chem. 1998, 63,
3499–3503.
11. Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura,
M.; Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi,
T.; Kumobayashi, H. J. Am. Chem. Soc. 1989, 111,
9134–9135.
12. Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T.
Tetrahedron: Asymmetry 1997, 8, 3489–3496.
References
13. Davis, F. A.; Srirajan, V.; Fanelli, D. L.; Portonovo, P. J. Org.
Chem. 2000, 65, 7663–7666.
¨
1. For a review, see: (a) Nicolaou, K. C.; Boddy, C. N. C.; Brase,
S.; Winssinger, N. Angew. Chem., Int. Ed. 1999, 38,
2096–2152. (b) Boger, D. L.; Miyazaki, S.; Kim, S. H.; Wu,
J. H.; Castle, S. L.; Loiseleur, O.; Jin, Q. J. Am. Chem. Soc.
1999, 121, 10004–10011. (c) Boger, D. L.; Kim, S. H.; Mori,
Y.; Weng, J.-H.; Rogel, O.; Castle, S. L.; McAtee, J. J. J. Am.
Chem. Soc. 2001, 123, 1862–1871. (d) Nicolaou, K. C.; Li, H.;
Boddy, C. N. C.; Ramanjulu, J. M.; Yue, T.-Y.; Natarajan, S.;
14. Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120,
11532–11533.
15. Belokon, Y. N.; Kochetkov, K. A.; Ikonnikov, N. S.;
Strelkova, T. V.; Harutyunyan, S. R.; Saghiyan, A. S.
Tetrahedron: Asymmetry 2001, 12, 481–485. (b) Caddick,
S.; Parr, N. J.; Pritchard, M. C. Tetrahedron Lett. 2000, 41,
5963–5966. (c) Felice, P. D.; Porzi, G.; Sandri, S.
Tetrahedron: Asymmetry 1999, 10, 2191–2201. (d) Alker,
D.; Hamblett, G.; Harwood, L. M.; Robertson, S. M.; Watkin,
D. J.; Williams, C. E. Tetrahedron 1998, 54, 6089–6098.
(e) Iwanowicz, E. J.; Blomgren, P.; Cheng, P. T. W.; Smith,
K.; Lau, W. F.; Pan, Y. Y.; Gu, H. H.; Malley, M. F.;
Gougoutas, J. Z. Synlett 1998, 664–666. (f) Kanemasa, S.;
Mori, T.; Wada, E.; Tatsukawa, A. Tetrahedron Lett. 1993, 34,
677–680. (g) Corey, E. J.; Lee, D.-H.; Choi, S. Tetrahedron
Lett. 1992, 33, 6735–6738. (h) Gasparski, C. M.; Miller, M. J.
Tetrahedron 1991, 47, 5367–5378. (i) Bold, G.; Duthaler,
R. O.; Riediker, M. Angew. Chem., Int. Ed. Engl. 1989, 28,
497–498. (j) Evans, D. A.; Sjogren, E. B.; Weber, A. E.;
Conn, R. E. Tetrahedron Lett. 1987, 28, 39–42. (k) Evans,
D. A.; Weber, A. E. J. Am. Chem. Soc. 1986, 108, 6757–6761.
(l) Belokon, Y. N.; Bulychev, A. G.; Vitt, S. V.; Struchkov,
Y. T.; Batsanov, A. S.; Timofeeva, T. V.; Tsyryapkin, V. A.;
Ryzhov, M. G.; Lysova, L. A.; Bakhmutov, V. I.; Belikov,
V. M. J. Am. Chem. Soc. 1985, 107, 4252–4259.
¨
¨
Chu, X.-J.; Brase, S.; Rubsam, F. Chem. Eur. J. 1999, 5,
2584–2601. (e) Nicolaou, K. C.; Boddy, C. N. C.; Li, H.;
Koumbis, A. E.; Hughes, R.; Natarajan, S.; Jain, N. F.;
¨
Ramanjulu, J. M.; Brase, S.; Solomon, M. E. Chem. Eur. J.
1999, 5, 2602–2621. (f) Nicolaou, K. C.; Koumbis, A. E.;
Takayanagi, M.; Natarajan, S.; Jain, N. F.; Bando, T.; Li, H.;
Hughes, R. Chem. Eur. J. 1999, 5, 2622–2647. (g) Nicolaou,
K. C.; Mitchell, H. J.; Jain, N. F.; Bando, T.; Hughes, R.;
Winssinger, N.; Natarajan, S.; Koumbis, A. E. Chem. Eur. J.
1999, 5, 2648–2667. (h) Evans, D. A.; Wood, M. R.; Trotter,
B. W.; Richardson, T. I.; Barrow, J. C.; Katz, J. L. Angew.
Chem., Int. Ed. 1998, 37, 2700–2704.
2. For a stereoselective total systhesis of (þ)-lactacystin, see:
¯
Nagamitsu, T.; Sunazuka, T.; Tanaka, H.; Omura, S.;
Sprengeler, P. A.; Smith, A. B., III. J. Am. Chem. Soc. 1996,
118, 3584–3590.
3. For a recent example of a diastereoselective synthesis of
g-hydroxy-b-amino alcohols from a serine derivative, see:
¨
Laıb, T.; Chastanet, J.; Zhu, J. J. Org. Chem. 1998, 63,
1709–1713.
¨
(m) Schollkopf, U. Tetrahedron 1983, 39, 2085–2091.
(n) Nakatsuka, T.; Miwa, T.; Mukaiyama, T. Chem. Lett.
1981, 279–282, See also Ref. 16–19.
4. For pioneer works, see: (a) Mattingly, P. G.; Kerwin, Jr. J. F.;
Miller, M. J. J. Am. Chem. Soc. 1979, 101, 3983–3985.
(b) Floyd, D. M.; Fritz, A. W.; Pluscec, J.; Weaver, E. R.;
Cimarusti, C. M. J. Org. Chem. 1982, 47, 5160–5167.
(c) Teng, M.; Miller, M. J. J. Am. Chem. Soc. 1993, 115,
548–554. (d) For a recent example, see: Jackson, B. G.;
Pedersen, S. W.; Fisher, J. W.; Misner, J. W.; Gardner, J. P.;
Staszak, M. A.; Doecke, C.; Rizzo, J.; Aikins, J.; Farkas, E.;
Trinkle, K. L.; Vicenzi, J.; Reinhard, M.; Kroeff, E. P.;
Higginbotham, C. A.; Gazak, R. J.; Zhang, T. Y. Tetrahedron
2000, 56, 5667–5677.
16. (a) Sawamura, M.; Nakayama, Y.; Kato, T.; Ito, Y. J. Org.
Chem. 1995, 60, 1727–1732. (b) Ito, Y.; Sawamura, M.;
Shirakawa, E.; Hayashizaki, K.; Hayashi, T. Tetrahedron
1988, 44, 5253–5262. (c) Ito, Y.; Sawamura, M.; Shirakawa,
E.; Hayashizaki, K.; Hayashi, T. Tetrahedron Lett. 1988, 29,
235–238. (d) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem.
Soc. 1986, 108, 6405–6406.
17. Horikawa, M.; Busch-Petersen, J.; Corey, E. J. Tetrahedron
Lett. 1999, 40, 3843–3846.
18. Suga, H.; Ikai, K.; Ibata, T. Tetrahedron Lett. 1998, 39,
869–879. (b) Evans, D. A.; Janey, J. M.; Magomedov, N.;
Tedrow, J. S. Angew. Chem., Int. Ed. 2001, 40, 1884–1888.
19. Kimura, T.; Vassilev, V. P.; Shen, G.-J.; Wong, C.-H. J. Am.
Chem. Soc. 1997, 119, 11734–11742.
5. Buono, G.; Siv, C.; Peiffer, G.; Triantaphylides, C.; Denis, P.;
Mortreux, A.; Petit, F. J. Org. Chem. 1985, 50, 1781–1782.
6. Righi, G.; Rumboldt, G.; Bonini, C. Tetrahedron 1995, 51,
13401–13408. See also Ref. 2.
7. Tao, B.; Schlingloff, G.; Sharpless, K. B. Tetrahedron Lett.
´
1998, 39, 2507–2510. (b) Park, H.; Cao, B.; Joullie, M. M.
20. Yoshikawa, N.; Suzuki, T.; Shibasaki, M. J. Org. Chem. 2002,
67, 2556–2565. (b) Yoshikawa, N.; Kumagai, N.; Matsunaga,
S.; Moll, G.; Ohshima, T.; Suzuki, T.; Shibasaki, M. J. Am.
Chem. Soc. 2001, 123, 2466–2467. (c) Yoshikawa, N.;
Shibasaki, M. Tetrahedron 2001, 57, 2569–2579.
(d) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.;
Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168–4178.
(e) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki,
M. Angew. Chem., Int. Ed. Engl. 1997, 36, 1871–1873.
J. Org. Chem. 2001, 66, 7223–7226. See also Ref. 1e.
8. Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1990, 31,
4317–4320. (b) Shao, H.; Goodman, M. J. Org. Chem. 1996,
61, 2582–2583. See also Ref. 1e.
9. Blaskovich, M. A.; Evindar, G.; Rose, N. G. W.; Wilkinson,
S.; Luo, Y.; Lajoie, G. A. J. Org. Chem. 1998, 63, 3631–3646.
(b) Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J. M.;
Zurbano, M. M. Tetrahedron: Asymmetry 2000, 11,

8298
N. Yoshikawa, M. Shibasaki / Tetrahedron 58 (2002) 8289–8298
¨
1998, 9, 357–389. (e) Groger, H.; Vogl, E. M.; Shibasaki,
M. Chem. Eur. J. 1998, 4, 1137–1141.
21. For a review of catalytic asymmetric direct aldol reactions,
see: Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2002,
1595–1601.
24. For catalytic asymmetric alkylations of glycinate Schiff bases,
see: (a) O’Donnell, M. J.; Wu, S.; Huffman, J. C. Tetrahedron
1994, 50, 4507–4518. (b) Ooi, T.; Takeuchi, M.; Kameda, M.;
Maruoka, K. J. Am. Chem. Soc. 2000, 122, 5228–5229, and
references cited therein.
22. For reviews of enantioselective transformations catalyzed
by heterobimetallic complexes, see: (a) Shibasaki, M.;
Yoshikawa, N. Chem. Rev. 2002, 102, 2187–2209.
(b) Shibasaki, M.; Yamada, K.-i.; Yoshikawa, N. Lewis
Acids in Organic Synthesis, Yamamoto, H., Ed.; Wiley-VCH:
Weinheim, 2000; Vol. 2. Chapter 20. (c) Shibasaki, M.
Enantiomer 1999, 4, 513–527. (d) Shibasaki, M. Chemtracts-
Org. Chem. 1999, 12, 979–998. (e) Shibasaki, M.; Iida, T.;
Yamada, Y. M. A. J. Synth. Org. Chem. Jpn. 1998, 56,
344–356. (f) Shibasaki, M.; Sasai, H.; Arai, T.; Iida, T. Pure
Appl. Chem. 1998, 70, 1027–1034. (g) Shibasaki, M.; Sasai,
H.; Arai, T. Angew. Chem., Int. Ed. Engl. 1997, 36,
1236–1256.
25. Arai, T.; Yamada, Y. M. A.; Yamamoto, N.; Sasai, H.;
Shibasaki, M. Chem. Eur. J. 1996, 2, 1368–1372. See also
Refs. 20a,b,d and 22.
26. The use of heterobimetallic complexes containing other
lanthanide (Pr, Sm, Gd, Dy, or Yb) gave similar results, in
contrast to the previous report: Sasai, H.; Suzuki, T.; Itoh, N.;
Arai, S.; Shibasaki, M. Tetrahedron Lett. 1993, 34,
2657–2660.
27. The enantiomeric excess of the oxazolidines was comparable
to that of syn-3. Corey et al. also reported the formation of
oxazolidines in aldol reactions. See Ref. 17.
23. For recent reviews of aldol reactions of modified carbonyl
compounds (Mukaiyama aldol reaction), see: (a) Carreira,
E. M. In Catalytic Asymmetric Synthesis. 2nd ed. Ojima, I.,
Ed.; Wiley: New York, 2000; Chapter 8B2. (b) Sawamura, M.;
Ito, Y. In Catalytic Asymmetric Synthesis. 2nd ed. Ojima, I.,
Ed.; Wiley: New York, 2000; Chapter 8B1. (c) Machajewski,
T. D.; Wong, C.-H. Angew. Chem., Int. Ed. 2000, 39,
1352–1374. (d) Nelson, S. G. Tetrahedron: Asymmetry
28. Miller et al. have obtained 12% ee. See Ref. 15h.
29. O’Donnell, M. J.; Polt, R. L. J. Org. Chem. 1982, 47,
2663–2666. (b) Pickard, P. L.; Tolbert, T. L. Organic
Syntheses; Wiley: New York, 1973; Collect. Vol. V. pp
520–522.