Complete reversal of enantioselection using oxazoline-containing Schiff base ligands derived from l-serine in enantioselective addition of diketene to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2006.09.026

Starting from one stereogenic center (in this case from l-serine), we obtained two chiral Schiff bases possessing oxazoline moieties, each of which recognized a different enantioface of aldehydes with a high enantiomeric excess [up to 93% ee (R) and 89% e

Full text of DOI:10.1016/j.tetasy.2006.09.026

Tetrahedron: Asymmetry 17 (2006) 2672–2677
Complete reversal of enantioselection using oxazoline-containing
Schiff base ligands derived from L-serine in enantioselective addition of
diketene to aldehydes
Changhu Chu, Koji Morishita, Takanori Tanaka and Masahiko Hayashi*
Department of Chemistry, Faculty of Science, Kobe University, Nada, Kobe 657-8501, Japan
Received 29 August 2006; accepted 21 September 2006
Abstract—Starting from one stereogenic center (in this case from L-serine), we obtained two chiral Schiff bases possessing oxazoline moi-
eties, each of which recognized a different enantioface of aldehydes with a high enantiomeric excess [up to 93% ee (R) and 89% ee (S)] in
the addition reaction of diketene to 2-furfural.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
from L-serine with 3,5-di-tert-butyl-2-hydroxybenzonitrile
in ethylene glycol–glycerol (2:1) at 120 ꢁC for 24 h afforded
a mixture of 1 and 2 in ratios of 1:1.3–3.3:1, which were
easily separated by silica-gel column chromatography.
The ratio of ligands 1 and 2 results from which one of
the two hydroxy groups will attack the imino group after
nucleophilic attack of the amino group to the nitrile.5
Attempts for obtaining both enantiomers in high enan-
tiomeric excess are attractive and important challenges,
because it is often the case that each enantiomer exhibits
different bioactivity. Since our first report on the chiral
Schiff base–Ti(O-i-Pr)4-catalyzed trimethylsilylcyanation
of aldehydes in 1991,1 this catalyst system was proven
to be efficient in a variety of asymmetric reactions.
One such reaction is the enantioselective addition of
diketene to aldehydes.2 We succeeded in obtaining opti-
cally active 5-hydroxy-3-ketoesters in up to 92% ee.3,4
Herein, we report the first example of complete reversal
of enantioselection using oxazoline-containing Schiff
bases derived from L-serine, that is, from one stereogenic
center of L-serine, both enantiomers of 5-hydroxy-3-keto-
esters were obtained in high enantiomeric excess (89–
93% ee).
2.2. Enantioselective addition of diketene to aldehydes
We first examined the reaction of diketene with benzalde-
hyde in the presence of Ti(O-i-Pr)4–Schiff base 1a–c and
2a–c. As shown in Table 1, the use of ligand 1a–c afforded
the (R)-product. Among 1a–c, 1a, which possessed the Me
group as R1, gave the product in 90% ee (67% yield),
whereas in the case of the 2 series, 2b (R1 = Et) gave (S)-
configured product in 87% ee (47% yield). The absolute
configuration was determined by the transformation of
optically active 5-hydroxy-3-ketoester into 4-hydroxy-6-
phenyl-5,6-dihydro-2-pyrone derivatives, as shown in
Scheme 2.6 To the best of our knowledge, this is the first
example of a complete reversal of enantioselection starting
from one stereogenic center (in this case from L-serine),
although there are some examples in which the change of
metal,7 solvent,8 temperature9 or substituent10 reverses
the enantioselectivity.
2. Results and discussion
2.1. Synthesis of chiral ligands
The chiral Schiff base ligands containing oxazoline moieties
were synthesized according to Scheme 1. The reaction of an
amino diol possessing a tertiary hydroxy group derived
We then examined a variety of aldehydes, and found, with-
out exception that when ligand 1a was used, (R)-configured
products were obtained, whereas (S)-products were pro-
*
Corresponding author. Tel.: +81 78 803 5687; fax: +81 78 803 5688;
e-mail: mhayashi@kobe-u.ac.jp
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.09.026

C. Chu et al. / Tetrahedron: Asymmetry 17 (2006) 2672–2677
2673
NHBoc
R1
R1
HO
HO
OH
NC
R1
R1
O
O
NH2HCl
R1
R1
+
OH
N
OH
N
OH
K2CO3
R1
R1 OH
OH
ethylene glycol:
OH
glycerol = 2:1
120 °C, 24 h
2a—2c
1a—1c
R1 = Me (1a:2a = 1:1.3)
R1 = Et (1b:2b = 1:2.6)
R1 = Ph (1c:2c = 3.3:1)
Scheme 1.
Table 2. Enantioselective addition of diketene to aldehydes promoted by
Schiff base 1a (or 2b)–Ti(O-i-Pr)4 complexa
Table 1. Enantioselective addition of diketene to benzaldehydes promoted
by Ti(O-i-Pr)4–Schiff base (1a–2c) complexa
Yieldb/%
eec,d/%
__
Entry
Schiff base
Ti(O-i-Pr)4
OH O
O
Schiff base 1a or 2b
1
2
3
4
5e
6e
1a
1b
1c
2a
2b
2c
67
46
14
55
47
77
90
77
56
62
87
62
R2CHO
+
O
R2
O-i-Pr
CH2Cl2
O
Entry
Aldehyde
Yieldb,c/%
eec,d,e/%
1
2
3
4
5
6
7
8
9
Benzaldehyde
67 (64)
76 (57)
63 (66)
72 (46)
74 (51)
57 (44)
60 (50)
75 (55)
61 (59)
75 (56)
76 (62)
90; R (87; S)
87; R (79; S)
73; R (70; S)
92; R (84; S)
80; S (66; R)
73; R (47; S)
79; S (60; R)
88; R (73; S)
86; R (80; S)
93; R (89; S)
87; R (76; S)
4-Methylbenzaldehyde
4-Methoxybenzaldehyde
(E)-Cinnamaldehyde
3-Phenylpropionaldehyde
Cyclohexanecarbaldehyde
n-Butanal
Methacrolein
(E)-Crotonaldehyde
2-Furfural
a All reactions were carried out in CH2Cl2 at ꢀ40 ꢁC for 48 h using 5 equiv
of diketene unless otherwise noted.
b Isolated yield after silica-gel column chromatography.
c HPLC analysis using CHIRALPAK AD column.
d The absolute configurations of the products were determined as R
(entries 1–3) and those of entries 4–6 were S after derivatization to the
28
known enol ketone. ½aꢁD ¼ þ84:4 (c 0.33, CHCl3) for entry 1 (90% ee
28
20
(R)), ½aꢁD ¼ ꢀ80:8 (c 0.2, CHCl3) for entry 5 (87% ee (S)) [lit.6 ½aꢁD
10
11
2-Thiophenaldehyde
+99.9 (c 1.0, CHCl3) for 99.9% ee (R)].
e 2 equiv of diketene was used.
a All reactions were carried out using 1.0 equiv of Ti(O-i-Pr)4, 1.1 equiv of
Schiff base 1a or 2b, and 5 equiv of diketene in CH2Cl2 at ꢀ40 ꢁC for
48 h.
b Isolated yield after silica-gel column chromatography.
c The values in parentheses indicated in the case of ligand 2b were used.
d HPLC analysis using CHIRALPAK AD column.
e In all cases, by using 2b, the opposite enantiomer was obtained pre-
dominantly as indicated values.
OH
OH
OH
O
O
0.2 M NaOH
0.2 M NaOH
2.0 M HCl
2.0 M HCl
Ph
O-i-Pr
O-i-Pr
Ph
Ph
O
O
O
OH
O
O
chemistry of the products, we would like to propose the
following mechanism (Scheme 3). The multiplier effect of
the R1 group and tert-butyl group at the ortho-position
of phenolic hydroxy group may cause the high level of
reversal in asymmetric induction.
Ph
O
Scheme 2.
duced in the case of 2b.11 The highest ee was 93% (R), in
the case of 2-furfural and 89% (S), respectively (Table 2).
3. Conclusion
Concerning the mechanism of the reaction between the
aldehydes and diketene promoted by Schiff base–Ti(O-i-
Pr)4, we determined that the diketene directly attacked
aldehydes without the formation of the intermediate tita-
nium enolate based on careful NMR analysis.12 The
detailed reason for why chiral Schiff bases 1a and 2b recog-
nize the opposite enantioface of the aldehyde is still not
clear. However, judging from the outcome of the stereo-
In conclusion, starting from one stereogenic center (in this
case from L-serine), we obtained two chiral Schiff base pos-
sessing oxazoline moieties, each of which recognized a dif-
ferent enantioface of the aldehyde in high enantiomeric
excess [up to 93% ee (R) and 89% ee (S)] in the addition
reaction of diketene to 2-furfural. This is the first example
of complete reversal of enantioselection from the single chi-

2674
C. Chu et al. / Tetrahedron: Asymmetry 17 (2006) 2672–2677
ethanol (70 mL), and 35% (w/w) aqueous HCl (20 mL)
O-i-Pr
were combined in a 200-mL round bottomed flask, the mix-
ture was stirred at room temperature for 10 h, removing
the solvent to leave a residue, which was redissolved in
ethanol, and the solvent was removed by vacuum distilla-
tion. This distillation was repeated several times to remove
the hydrogen chloride, and then used in the synthesis of the
oxazoline ligands.
R1
H
R1
O
O
N
O
Ti
O-i-Pr
O
O
(R)-product
H
(R2 = Ph)
O
R2
Second step: Synthesis of the oxazoline ligands. With
mechanical stirring, the residues from the first step, ethyl-
ene glycol/glycerol = 2:1 (30 mL), anhydrous K2CO3
(3.2 g, 23.4 mmol, 1.0 equiv), and 3,5-di-tert-butyl-2-hy-
droxyl benzonitrile (5.4 g, 23.4 mmol, 1.0 equiv), were
combined in a 200-mL round bottomed flask. The mixture
was stirred at 120 ꢁC for 24 h. After the reaction, it was
cooled to room temperature, and ethyl acetate (50 mL)
and brine (50 mL) were added, collection of the organic
layer and water was done with ethyl acetate (50 mL · 3).
The combined organic phases were dried over anhydrous
sodium sulfate and evaporated to a residue. The residue
was purified on a silica gel column carefully (ethyl
acetate–hexane 1:40) in order to obtain chiral oxazoline
ligands 1 and 2 in pure form.
1a: R1 = Me
O-i-Pr
R1 R1
O
H
O
N
Ti
O
i-Pr-O
O
O
H
R2
(S)-product
(R2 = Ph)
O
2b: R1 = Et
4.2.1. (4S)-4-[(1-Hydroxyl-1-methyl)-ethyl]-2-[(2-hydroxyl-3,5-
di-tert-butyl)-phenyl]-4,5-dihydro-1,3-oxazoline 1a. Yield
27
Scheme 3.
(24%, 1886 mg): mp 109–110 ꢁC; ½aꢁD ¼ þ3:3 (c 1.0,
CHCl3); 1H NMR (CDCl3) d 12.41 (br, 1H), 7.52 (d,
J = 2.8 Hz, 1H), 7.46 (d, J = 2.8 Hz, 1H), 4.44–4.37 (m,
2H), 4.28 (dd, J = 10.4 Hz, J = 7.6 Hz, 1H), 1.44 (s, 9H),
1.38 (s, 3H), 1.30 (s, 9H), 1.23 (s, 3H); 13C NMR (CDCl3)
d 167.7, 157.0, 140.2, 136.5, 128.4, 122.3, 110.5, 74.5, 71.3,
67.7, 35.1, 34.3, 31.5, 29.5, 27.0, 25.7; IR (KBr) m 3414,
2960, 1633; Mass m/z (relative intensity) 333 (48.1), 318
(61.9), 274 (21.6), 233 (54.8), 217 (47.7), 149 (49.1), 59
(34.1), 57 (100.0). Anal. Calcd for C20H31NO3: C 72.04,
H 9.37, N 4.20; found: C 71.94, H 9.51, N 4.13.
rality of L-serine. It should be added that the products ob-
tained by the present reaction, 5-hydroxy-3-ketoesters, can
be used as the potential inhibitors of HMG coenzyme
reductase.
4. Experimental
4.1. General
4.2.2. (4S)-4-Hydroxymethyl-5,5-dimethyl-2-[(2-hydroxyl-3,5-
di-tert-butyl)-phenyl]-4,5-dihydro-1,3-oxazoline 2a. Yield
All melting points were measured on a Yanaco MP-500D
1
and are uncorrected. H and 13C NMR spectra (400 and
27
(29%, 2264 mg): mp 132–133 ꢁC; ½aꢁD ¼ ꢀ30:8 (c 1.0,
CHCl3); 1H NMR (CDCl3) d 7.52 (d, J = 2.8 Hz, 1H),
7.45 (d, J = 2.8 Hz, 1H), 3.99 (t, J = 6.0 Hz, 1H), 3.80 (d,
J = 6.0 Hz, 2H), 1.52 (s, 3H), 1.49 (s, 3H), 1.44 (s, 9H),
1.31 (s, 9H); 13C NMR (CDCl3) d 166.5, 157.0, 140.0,
136.5, 128.2, 122.3, 110.0, 85.1, 74.0, 62.3, 35.1, 34.3,
31.5, 29.4, 29.0, 21.3; IR (KBr) m 3564, 2961, 1629; Mass
m/z (relative intensity) 333 (51.9), 318 (55.8), 290 (29.3),
233 (41.8), 217 (100), 57 (60.3), 41 (71.0). Anal. Calcd for
C20H31NO3: C 72.04, H 9.37, N 4.20; found: C 71.83, H
9.42, N 3.92.
100.6 MHz, respectively) were recorded on a JEOL JNM-
LA 400 using Me4Si as the internal standard. IR spectra were
measured with a PERKIN ELMER FT-IR Spectrometer
SPECTRUM 1000. Elemental analyses were performed
with a Yanaco CHN Corder MT-5. Mass spectra were taken
on a Shimadzu GCMS-QP 2000A. Preparative column chro-
matography was carried out on Fuji Silysia BW-820MH.
Thin-layer chromatography (TLC) was carried out on foil
plates, Silica Gel 60 F254 (E. Merck; layer thickness
0.2 mm). Chiral HPLC was performed in a Shimadzu LC-
VP series instrument equipped with a diode array detector.
4.2.3. (4S)-4-[(1-Ethyl-1-hydroxyl-propyl)-2-[(2-hydroxyl-3,5-
di-tert-butyl)-phenyl]-4,5-dihydro-1,3-oxazoline 1b. Yield
4.2. General procedure for the preparation of chiral Schiff
base ligands
27
(11%, 409 mg): mp 74–75 ꢁC; ½aꢁD ¼ ꢀ1:2 (c 1.0, CHCl3);
1H NMR (CDCl3) d 12.5 (s, 1H), 7.55 (d, J = 2.8 Hz,
1H), 7.45 (d, J = 2.8 Hz, 1H), 4.45–4.37 (m, 3H), 1.83–
1.70 (m, 2H), 1.58–1.50 (m, 2H), 0.99–0.90 (m, 6H); 13C
NMR (CDCl3) d 167.6, 156.9, 140.2, 136.5, 128.3, 122.3,
110.3, 109.7, 75.1, 71.3, 67.2, 35.1, 34.3, 29.5, 28.8, 26.8,
7.9, 7.6; IR (KBr) m 3457, 2965, 1636; Mass m/z (relative
Chiral oxazoline ligands 1 and 2 were accessible from chiral
2-N-(Boc) amino-1,3-diol in two steps.
First step: Deprotection of Boc. With mechanical stirring,
chiral 2-N-(Boc) amino-1,3-diol (23.4 mmol, 1.0 equiv),

C. Chu et al. / Tetrahedron: Asymmetry 17 (2006) 2672–2677
2675
intensity) 361 (32.0), 233 (85.0), 217 (42.1), 175 (29.1), 87
(32.0), 57 (100.0), 41 (66.6). Anal. Calcd for C22H35NO3:
C 73.09, H 9.76, N 3.87; found: C 72.92, H 9.90, N 3.68.
at room temperature. The mixture was then extracted with
ethyl acetate (30 mL · 3), and the combined extracts were
washed with satd NaHCO3 (30 mL · 3), brine (30 mL ·
3), and dried over Na2SO4, then evaporated. The residue
was column chromatographed on silica gel [eluent, hex-
ane–ethyl acetate (5:1)] to give 5-hydroxy-3-oxoesters.
The enantiomeric excess for each of the 5-hydroxy-3-oxo-
esters was determined by HPLC analysis (CHIRALPAK
AD) [eluent, hexane–ethanol (95:5) + trifluoroacetic acid
(0.01%), 1.0 mL/min].
4.2.4. (4S)-4-Hydroxymethyl-5,5-diethyl-2-[(2-hydroxyl-3,5-
di-tert-butyl)-phenyl]-4,5-dihydro-1,3-oxazoline 2b. Yield
27
(31%, 1154 mg): mp 110–111 ꢁC; ½aꢁD ¼ ꢀ24:5 (c 1.0,
CHCl3); 1H NMR (CDCl3) d 12.5 (br, 1H), 7.54 (d,
J = 2.8 Hz, 1H), 7.45 (d, J = 2.8 Hz, 1H), 4.13–4.09 (m,
1H), 3.85–3.77 (m, 2H), 1.96–1.69 (m, 4H), 1.44 (s, 9H),
1.31 (s, 9H), 1.06 (t, J = 7.2 Hz, 3H), 0.96 (t, J = 7.2 Hz,
3H); 13C NMR (CDCl3) d 166.3, 157.0, 140.0, 136.5,
128.1, 122.2, 109.9, 89.7, 72.5, 62.5, 35.1, 34.2, 31.5, 29.6,
29.5, 24.3, 8.3, 7.4; IR (KBr) m 3597, 2963, 1633; Mass
m/z (relative intensity) 361 (43.8), 346 (21.8), 233 (52.3),
217 (70.9), 175 (23.9), 98 (93.9), 69 (25.0), 57 (100.0), 41
(85.5). Anal. Calcd for C22H35NO3: C 73.09, H 9.76, N
3.87; found: C 73.21, H 9.77, N 3.86.
4.3.1. (S)-Isopropyl 5-hydroxy-5-phenyl-3-oxopentanoate.
59.3 mg (47%). The enantiomeric excess of the product was
determined as 87% ee by HPLC analysis. (CHIRALPAK
AD) [eluent, hexane–ethanol (95:5) + trifluoroacetic acid
(0.01%), 1.0 mL/min, 254 nm]. tR of (R)-isomer, 12 min;
tR of (S)-isomer, 19 min. Absolute configuration of the
major isomer was determined as (S) by the comparison of
the specific rotation value after conversion into (S)-4-hydro-
xy-6-phenyl-5,6-dihydro-2-pyrone.6
4.2.5. (4S)-4-[(Hydroxyl-diphenyl)-methyl]-2-[(2-hydroxyl-3,5-
di-tert-butyl)-phenyl]-4,5-dihydro-1,3-oxazoline 1c. Yield
27
(53%, 242.5 mg): mp 111–112 ꢁC; ½aꢁD ¼ ꢀ41:2 (c 1.0,
4.3.2. (R)-Isopropyl 5-hydroxy-5-phenyl-3-oxopentanoate.
28
1
CHCl3); H NMR (CDCl3) d 7.64–7.20 (m, 12H), 5.54 (t,
84.3 mg (67%). ½aꢁD ¼ þ47:6 (c 1.0, CHCl3). The enantio-
J = 9.2 Hz, 1H), 4.30 (t, J = 9.2 Hz, 1H), 4.19 (t,
J = 9.2 Hz, 1H), 1.40 (s, 9H), 1.29 (s, 9H); 13C NMR
(CDCl3) d 169.0, 157.0, 145.5, 143.8, 140.2, 136.5, 128.5,
128.4, 128.3, 127.2, 127.0, 126.8, 125.6, 122.4, 109.5, 78.2,
72.1, 68.0, 35.1, 34.2, 31.4, 30.8, 29.4; IR (KBr) m 3426,
2961, 1631; Mass m/z (relative intensity) 457 (19.8), 275
(55.9), 260 (22.1), 233 (75.3), 217 (27.6), 183 (53.8), 105
(96.9), 77 (58.3), 57 (100.0), 41 (45.1). Anal. Calcd for
C30H35NO3: C 78.74, H 7.71, N 3.06; found: C 78.44, H
7.96, N 3.14.
meric excess of the product was determined as 90% ee by
HPLC analysis (CHIRALPAK AD) [eluent, hexane–etha-
nol (95:5) + trifluoroacetic acid (0.01%), 1.0 mL/min,
254 nm]. tR of (R)-isomer, 12 min; tR of (S)-isomer,
19 min. Absolute configuration of the major isomer was
determined as (R) by the comparison of the specific rota-
tion value after conversion into (R)-4-hydroxy-6-phenyl-
5,6-dihydro-2-pyrone.6
4.3.3. (S)-Isopropyl 5-hydroxy-5-(4-methylphenyl)-3-oxo-
28
pentanoate. 75.5 mg (57%). ½aꢁD ¼ ꢀ41:3 (c 1.0, CHCl3).
4.2.6. (4S)-4-Hydroxymethyl-5,5-diphenyl-2-[(2-hydroxyl-3,5-
di-tert-butyl)-phenyl]-4,5-dihydro-1,3-oxazoline 2c. Yield
The enantiomeric excess of the product was determined
as 79% ee by HPLC analysis. (CHIRALPAK AD) [eluent,
hexane–ethanol (95:5) + trifluoroacetic acid (0.01%),
1.0 mL/min, 254 nm]. tR of (R)-isomer, 12 min; tR of (S)-
isomer, 17 min. Absolute configuration of the major isomer
was determined as (S) by the comparison of the specific
rotation value and the order of the retention time in HPLC
analysis.
27
(16%, 73.2 mg): mp 88–89 ꢁC; ½aꢁD ꢀ 232:5 (c 1.0, CHCl3);
1H NMR (CDCl3) d 7.79–7.25 (m, 12H), 5.09 (t,
J = 6.4 Hz, 1H), 3.47 (d, J = 6.4 Hz, 2H), 1.45 (s, 9H),
1.35 (s, 9H); 13C NMR (CDCl3) d 169.1, 157.3, 146.3,
144.4, 140.3, 137.1, 128.5, 128.4, 127.3, 127.1, 126.8,
125.1, 122.4, 109.7, 77.7, 72.2, 68.1, 35.1, 34.2, 31.5, 30.7,
29.5; IR (KBr) m 3429, 2959, 1639; Mass m/z (relative inten-
sity) 457 (15.0), 427 (6.4), 260 (22.2), 233 (30.8), 225 (33.5),
207 (22.0), 195 (100.0), 180 (24.3), 57 (29.6). Anal. Calcd
for C30H35NO3: C 78.74, H 7.71, N 3.06; found: C 78.63,
H 7.94, N 2.94.
4.3.4. (R)-Isopropyl 5-hydroxy-5-(4-methylphenyl)-3-oxo-
27
pentanoate. 100.0 mg (76%). ½aꢁD ¼ þ38:9 (c 1.0, CHCl3).
The enantiomeric excess of the product was determined as
87% ee by HPLC analysis. (CHIRALPAK AD) [eluent,
hexane–ethanol (95:5) + trifluoroacetic acid (0.01%),
1.0 mL/min, 254 nm]. tR of (R)-isomer, 12 min; tR of (S)-
isomer, 17 min. Absolute configuration of the major isomer
was determined as (R) by the comparison of the specific
rotation value and the order of the retention time in HPLC
analysis.
4.3. General procedure for the addition of diketene to
aldehydes promoted by chiral Schiff base–Ti(O-i-Pr)4
complexes
In a Schlenk tube were placed either Schiff base 1a or 2b
(198.9 mg, 0.55 mmol), and CH2Cl2 (5 mL). To this solu-
tion was added Ti(O-i-Pr)4 (0.5 mmol) at room tempera-
ture and stirred for 1 h, then the mixture was cooled to
ꢀ40 ꢁC. Aldehyde (0.5 mmol, 1.0 equiv) and diketene
(2.5 mmol) were added to it and the whole mixture was stir-
red for 48 h at ꢀ40 ꢁC. After this, isopropyl alcohol (2 mL)
was added to the mixture, and then stirred for 3 h. The
mixture was poured into a mixture of 1 M HCl (10 mL)
and diethyl ether (10 mL), then stirred vigorously for 1 h
4.3.5. (S)-Isopropyl 5-hydroxy-5-(4-methoxyphenyl)-3-oxo-
27
pentanoate. 92.2 mg (66%). ½aꢁD ¼ ꢀ40:9 (c 1.0, CHCl3).
The enantiomeric excess of the product was determined
as 70% ee by HPLC analysis. (CHIRALPAK AD) [eluent,
hexane–ethanol (95:5) + trifluoroacetic acid (0.01%),
1.0 mL/min, 254 nm]. tR of (R)-isomer, 22 min; tR of (S)-
isomer, 33 min. Absolute configuration of the major isomer
was determined as (S) by the comparison of the specific

2676
C. Chu et al. / Tetrahedron: Asymmetry 17 (2006) 2672–2677
rotation value and the order of the retention time in HPLC
analysis.
J = 3.7 Hz, 1H), 2.67 (d, J = 6.6 Hz, 1H), 2.2 (br s, 1H),
1.9–1.6 (m, 6H), 1.26 (d, J = 6.1 Hz, 6H), 1.5–1.1 (m,
5H). Absolute configuration of the major isomer was deter-
mined as (S) by the comparison of the specific rotation va-
lue and the order of the retention time in HPLC analysis.
4.3.6. (R)-Isopropyl 5-hydroxy-5-(4-methoxyphenyl)-3-oxo-
24
pentanoate. 88.2 mg (63%). ½aꢁD ¼ þ33:0 (c 1.0, CHCl3).
The enantiomeric excess of the product was determined
as 73% ee by HPLC analysis. (CHIRALPAK AD) [eluent,
hexane–ethanol (95:5) + trifluoroacetic acid (0.01%),
1.0 mL/min, 254 nm]. tR of (R)-isomer, 22 min; tR of (S)-
isomer, 33 min. Absolute configuration of the major isomer
was determined as (R) by the comparison of the specific
rotation value and the order of the retention time in HPLC
analysis.
4.3.12. (R)-Isopropyl 5-hydroxy-5-cyclohexyl-3-oxopentano-
27
ate. 72.5 mg (57%). ½aꢁD ¼ þ17:3 (c 1.0, CHCl3). The
enantiomeric excess of the product was determined as
73% ee by HPLC analysis. (CHIRALPAK AD) [eluent,
hexane–ethanol (95:5) + trifluoroacetic acid (0.01%),
1.0 mL/min, 254 nm]. tR of (R)-isomer, 10 min; tR of (S)-
isomer, 15 min. Absolute configuration of the major isomer
was determined as (R) by the comparison of the specific
rotation value and the order of the retention time in HPLC
analysis.
4.3.7. (S)-(E)-Isopropyl 5-hydroxy-7-phenyl-3-oxo-6-hept-
29
anoate. 64.0 mg (46%). ½aꢁD ¼ ꢀ23:4 (c 1.0, CHCl3).
The enantiomeric excess of the product was determined
as 84% ee by HPLC analysis. (CHIRALPAK AD) [eluent,
hexane–ethanol (95:5) + trifluoroacetic acid (0.01%),
1.0 mL/min, 254 nm]. tR of (R)-isomer, 16 min; tR of (S)-
isomer, 24 min. Absolute configuration of the major isomer
was determined as (S) by the comparison of the specific
rotation value with those previously published.2b
4.3.13. (R)-Isopropyl 5-hydroxy-3-oxooctanoate. 53.7 mg
27
(50%). ½aꢁD ¼ ꢀ20:0 (c 1.0, CHCl3). The enantiomeric
excess of the product was determined as 60% ee by HPLC
analysis. (CHIRALPAK AD) [eluent, hexane–ethanol
(95:5) + trifluoroacetic acid (0.01%), 1.0 mL/min, 254
nm]. tR of (S)-isomer, 8 min; tR of (R)-isomer, 11 min.
Absolute configuration of the major isomer was deter-
mined as (R) by the comparison of the specific rotation
value with those previously published.2b
4.3.8. (R)-(E)-Isopropyl 5-hydroxy-7-phenyl-3-oxo-6-hept-
28
anoate. 99.8 mg (72%). ½aꢁD ¼ þ18:2 (c 1.0, CHCl3).
The enantiomeric excess of the product was determined
as 92% ee by HPLC analysis. (CHIRALPAK AD) [eluent,
hexane–ethanol (95:5) + trifluoroacetic acid (0.01%),
1.0 mL/min, 254 nm]. tR of (R)-isomer, 16 min; tR of (S)-
isomer, 24 min. Absolute configuration of the major isomer
was determined as (R) by the comparison of the specific
rotation value with those previously published.2b
4.3.14. (S)-Isopropyl 5-hydroxy-3-oxooctanoate. 64.5 mg
25
(60%). ½aꢁD ¼ þ16:6 (c 1.0, CHCl3). The enantiomeric
excess of the product was determined as 79% ee by HPLC
analysis. (CHIRALPAK AD) [eluent, hexane–ethanol
(95:5) + trifluoroacetic acid (0.01%), 1.0 mL/min, 254 nm].
tR of (S)-isomer, 8 min; tR of (R)-isomer, 11 min. Absolute
configuration of the major isomer was determined as (S) by
the comparison of the specific rotation value with those
previously published.2b
4.3.9. (R)-Isopropyl 5-hydroxy-7-phenyl-3-oxoheptanoate.
29
70.7 mg (51%). ½aꢁD ¼ ꢀ10:5 (c 1.0, CHCl3). The enantio-
meric excess of the product was determined as 66% ee by
HPLC analysis. (CHIRALPAK AD) [eluent, hexane–etha-
nol (95:5) + trifluoroacetic acid (0.01%), 1.0 mL/min,
254 nm]. tR of (S)-isomer, 12 min; tR of (R)-isomer,
19 min. Absolute configuration of the major isomer was
determined as (R) by the comparison of the specific rota-
tion value with those previously published.2b
4.3.15. (S)-Isopropyl 5-hydroxy-6-methyl-3-oxo-6-heptano-
27
ate. 59.0 mg (55%). ½aꢁD ¼ ꢀ28:7 (c 1.0, CHCl3). The enan-
tiomeric excess of the product was determined as 73% ee by
HPLC analysis. (CHIRALPAK AD) [eluent, hexane–etha-
nol (95:5) + trifluoroacetic acid (0.01%), 1.0 mL/min,
254 nm]. tR of (R)-isomer, 8 min; tR of (S)-isomer,
11 min. Absolute configuration of the major isomer was
determined as (S) by the comparison of the specific rota-
tion value and the order of the retention time in HPLC
analysis.
4.3.10. (S)-Isopropyl 5-hydroxy-7-phenyl-3-oxoheptanoate.
28
103.2 mg (74%). ½aꢁD ¼ þ8:3 (c 1.0, CHCl3). The enantio-
meric excess of the product was determined as 80% ee by
HPLC analysis. (CHIRALPAK AD) [eluent, hexane–etha-
nol (97.5:2.5) + trifluoroacetic acid (0.01%), 0.5 mL/min,
254 nm]. tR of (S)-isomer, 43 min; tR of (R)-isomer,
69 min. Absolute configuration of the major isomer was
determined as (S) by the comparison of the specific rota-
tion value with those previously published.2b
4.3.16. (R)-Isopropyl 5-hydroxy-6-methyl-3-oxo-6-heptano-
29
ate. 80.0 mg (75%). ½aꢁD ¼ þ44:3 (c 1.0, CHCl3). The enan-
tiomeric excess of the product was determined as 88% ee by
HPLC analysis. (CHIRALPAK AD) [eluent, hexane–etha-
nol (95:5) + trifluoroacetic acid (0.01%), 1.0 mL/min,
254 nm]. tR of (R)-isomer, 8 min; tR of (S)-isomer,
11 min. Absolute configuration of the major isomer was
determined as (R) by the comparison of the specific rota-
tion value and the order of the retention time in HPLC
analysis.
4.3.11. (S)-Isopropyl 5-hydroxy-5-cyclohexyl-3-oxopentano-
28
ate. 56.7 mg (44%). ½aꢁD ¼ ꢀ18:8 (c 1.0, CHCl3). The
enantiomeric excess of the product was determined as
47% ee by HPLC analysis. (CHIRALPAK AD) [eluent,
hexane–ethanol (95:5) + trifluoroacetic acid (0.01%),
1.0 mL/min, 254 nm]. tR of (S)-isomer, 10 min; tR of (R)-
4.3.17. (S)-(E)-Isopropyl 5-hydroxy-3-oxo-6-octanoate.
27
isomer, 15 min. 1H NMR (CDCl3)
d
5.05 (sept,
62.7 mg (59%). ½aꢁD ¼ ꢀ27:9 (c 1.0, CHCl3). The enantio-
J = 6.1 Hz, 1H), 3.9–3.8 (m, 1H), 3.45 (s, 2H), 2.71 (d,
meric excess of the product was determined as 80% ee by

C. Chu et al. / Tetrahedron: Asymmetry 17 (2006) 2672–2677
2677
HPLC analysis. (CHIRALPAK AD) [eluent, hexane–etha-
nol (95:5) + trifluoroacetic acid (0.01%), 1.0 mL/min,
254 nm]. tR of (R)-isomer, 8 min; tR of (S)-isomer,
was determined as (R) by the comparison of the specific
rotation value and the order of the retention time in HPLC
analysis.
1
11 min. H NMR (CDCl3) d 5.8–5.7 (m, 1H), 5.6–5.4 (m,
1H), 5.1–5.0 (m, 1H), 4.55 (dd, J = 12.2 Hz, 6.1 Hz, 1H),
3.45 (s, 2H), 2.75 (d, J = 6.10 Hz, 2H), 1.70 (d,
J = 6.10 Hz, 3H), 1.6 (br s, 1H), 1.27 (d, J = 6.1 Hz, 6H).
Absolute configuration of the major isomer was deter-
mined as (S) by the comparison of the specific rotation
value with those previously published.2b
Acknowledgments
This research was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan (No. 17340020)
and Hyogo COE program. We also thank Prof. Oliver
Reiser of the University of Regensburg for helpful
discussion.
4.3.18.
(R)-(E)-Isopropyl
5-hydroxy-3-oxo-6-octano-
29
ate. 66.8 mg (61%). ½aꢁD ¼ þ27:1 (c 1.0, CHCl3). The
enantiomeric excess of the product was determined as
86% ee by HPLC analysis. (CHIRALPAK AD) [eluent,
hexane–ethanol (95:5) + trifluoroacetic acid (0.01%),
1.0 mL/min, 254 nm]. tR of (R)-isomer, 8 min; tR of (S)-iso-
mer, 11 min. Absolute configuration of the major isomer
was determined as (R) by the comparison of the specific
rotation value.
References
1. (a) Hayashi, M.; Miyamoto, Y.; Inoue, T.; Oguni, N. J.
Chem. Soc., Chem. Commun. 1991, 1752–1753; (b) Hayashi,
M.; Miyamoto, Y.; Inoue, T.; Oguni, N. J. Org. Chem. 1993,
58, 1515–1522.
2. (a) Hayashi, M.; Inoue, T.; Oguni, N. J. Chem. Soc., Chem.
Commun. 1994, 341–342; (b) Hayashi, M.; Inoue, T.;
Miyamoto, Y.; Oguni, N. Tetrahedron 1994, 50, 4385–
4398.
3. (a) Hayashi, M.; Tanaka, K.; Oguni, N. Tetrahedron:
Asymmetry 1995, 6, 1833–1836; (b) Hayashi, M.; Yoshimoto,
K.; Hirata, N.; Tanaka, K.; Oguni, N.; Harada, K.; Mat-
sushita, A.; Kawachi, Y.; Sasaki, H. Isr. J. Chem. 2001, 41,
241–246.
4. After our first report on the reaction of aldehyde with
diketene, see: (a) Yanagisawa, A.; Matsumoto, Y.; Asakawa,
K.; Yamamoto, H. J. Am. Chem. Soc. 1999, 121, 892–893;
Yanagisawa, A.; Matsumoto, Y.; Asakawa, K.; Yamamoto,
H. Tetrahedron 2002, 58, 8331–8339; (b) Kawase, T.; Taki-
zawa, S.; Jayaprakash, D.; Sasai, H. Synth. Commun. 2004,
34, 4487–4492; (c) Mareno, R. M.; Moyano, A. Tetrahedron:
Asymmetry 2006, 17, 1104–1110.
5. For the synthesis of salicyloxazoline ligand, see: Brunner, H.;
Berghofer, J. J. Organomet. Chem. 1995, 501, 161–166.
6. Xu, C.; Yuan, C. Tetrahedron 2005, 61, 2169–2186.
7. Gd versus Ti: (a) Yabu, K.; Matsumoto, S.; Yamasaki, S.;
Hamashima, Y.; Kanai, M.; Du, W.; Curran, D. P.;
Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 9908–9909; Yb
versus Zr: (b) Hamashima, Y.; Kanai, M.; Du, W.; Curran,
D. P.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 9908–9909;
Cu versus Ni: (c) Shibata, N.; Ishimaru, T.; Nagai, T.;
Kohno, J.; Toru, T. Synlett 2004, 1703–1706; Cu versus Zn:
(d) Du, Da-M.; Lu, S-F.; Fang, T.; Xu, J. J. Org. Chem. 2005,
70, 3712–3715.
8. (a) Kanai, M.; Nakagawa, Y.; Tomioka, K. Tetrahedron
1999, 55, 3831–3842; (b) Fernandez, A. I.; Fraile, J. M.;
Garcia, J. I.; Herrerias, C. I.; Mayoral, J. A.; Salvatella, L.
Catal. Commun. 2001, 2, 165–170.
9. Casey, C. P.; Martins, S. C.; Fagan, M. A. J. Am. Chem. Soc.
2004, 126, 5585–5592.
10. (a) Altava, B.; Burguete, M. I.; Fraile, J. M.; Garcia, J. I.;
Luis, S. V.; Mayoral, J. A.; Royo, A. J.; Vicent, M. J.
Tetrahedron: Asymmetry 1997, 8, 2561–2570; (b) Li, X.-G.;
Chen, X.; Ma, J.-A.; Zhou, Q.-L. J. Organomet. Chem. 2001,
640, 65–71.
11. The notations of R and S are different in entries 5 and 7,
because of the priority of substituents. The same enantio-
meric face of aldehyde was selected by the use of 1a or 2b.
12. Hayashi, M.; Nakamura, N.; Yamashita, K. Tetrahedron
2004, 60, 6777–6783.
4.3.19. (S)-Isopropyl 5-hydroxy-5-(2-furyl)-3-oxopentano-
28
ate. 67.7 mg (56%). ½aꢁD ¼ ꢀ33:4 (c 1.0, CHCl3). The
enantiomeric excess of the product was determined as
89% ee by HPLC analysis. (CHIRALPAK AD) [eluent,
hexane–ethanol (95:5) + trifluoroacetic acid (0.01%),
1.0 mL/min, 254 nm]. tR of (R)-isomer, 15 min; tR of (S)-
isomer, 22 min. Absolute configuration of the major isomer
was determined as (S) by the comparison of the specific
rotation value and the order of the retention time in HPLC
analysis.
4.3.20. (R)-Isopropyl 5-hydroxy-5-(2-furyl)-3-oxopentano-
29
ate. 89.9 mg (75%). ½aꢁD ¼ þ26:8 (c 1.0, CHCl3). The
enantiomeric excess of the product was determined as
93% ee by HPLC analysis. (CHIRALPAK AD) [eluent,
hexane–ethanol (95:5) + trifluoroacetic acid (0.01%),
1.0 mL/min, 254 nm]. tR of (R)-isomer, 15 min; tR of (S)-
isomer, 22 min. Absolute configuration of the major isomer
was determined as (R) by the comparison of the specific
rotation value and the order of the retention time in HPLC
analysis.
4.3.21. (S)-Isopropyl 5-hydroxy-5-(2-thienyl)-3-oxopenta-
28
noate. 80.0 mg (62%). ½aꢁD ¼ ꢀ36:4 (c 1.0, CHCl3). The
enantiomeric excess of the product was determined as
76% ee by HPLC analysis. (CHIRALPAK AD) [eluent,
hexane–ethanol (95:5) + trifluoroacetic acid (0.01%),
1.0 mL/min, 254 nm]. tR of (R)-isomer, 15 min; tR of (S)-
isomer, 22 min. Absolute configuration of the major isomer
was determined as (S) by the comparison of the specific
rotation value and the order of the retention time in HPLC
analysis.
4.3.22. (R)-Isopropyl 5-hydroxy-5-(2-thienyl)-3-oxopenta-
28
noate. 97.6 mg (76%). ½aꢁD ¼ þ28:3 (c 1.0, CHCl3). The
enantiomeric excess of the product was determined as
87% ee by HPLC analysis. (CHIRALPAK AD) [eluent,
hexane–ethanol (95:5) + trifluoroacetic acid (0.01%),
1.0 mL/min, 254 nm]. tR of (R)-isomer, 14 min; tR of (S)-
isomer, 25 min. Absolute configuration of the major isomer