Chiral squaric prolinols: A new type of ligand for the asymmetric reduction of prochiral ketones by borane

Article abstract of DOI:10.1016/S0957-4166(01)00333-0

A series of chiral bifunctional squaric prolinol ligands, having N, S substituents at C(3) of the squaric ring were synthesized and applied to the asymmetric borane reduction of prochiral ketones via an in situ formed chiral boron heterocycle, affording secondary alcohols with high yields and excellent enantiomeric excesses (up to 99%). The crystal structure of 5a was obtained and the mechanism of the catalytic asymmetric reduction is also discussed.

Full text of DOI:10.1016/S0957-4166(01)00333-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1907–1912
Chiral squaric prolinols: a new type of ligand for the asymmetric
reduction of prochiral ketones by borane
Ji Zhang,a Hai-Bing Zhou,a Shou-Mao Lu¨,a Mei-Ming Luo,a Ru-Gang Xie,a,* Michael C. K. Choi,b
Zhong-Yuan Zhou,b Albert S. C. Chanb and Teng-Kuei Yangc
aDepartment of Chemistry, Sichuan University, Chengdu 610064, PR China
bOpen Laboratory of Chirotechnology and Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic University, Hong Kong, PR China
cDepartment of Chemistry, National Chung-Hsing University, Taichung, Taiwan
Received 2 July 2001; accepted 25 July 2001
Abstract—A series of chiral bifunctional squaric prolinol ligands, having N, S substituents at C(3) of the squaric ring were
synthesized and applied to the asymmetric borane reduction of prochiral ketones via an in situ formed chiral boron heterocycle,
affording secondary alcohols with high yields and excellent enantiomeric excesses (up to 99%). The crystal structure of 5a was
obtained and the mechanism of the catalytic asymmetric reduction is also discussed. © 2001 Elsevier Science Ltd. All rights
reserved.
1. Introduction
ophiles.7 However, to date there have been no reports
of asymmetric catalysis using chiral squaric acid deriva-
tives. We have synthesized and utilized several
homochiral squaric aminoalcohol derivatives as ligands
in the asymmetric reduction of prochiral ketones and
found that the squaric prolinols showed superior
stereoinduction.8 The ligands based on the cyclobutene-
dione structure containing a prolinol residue could still
be modified easily with various substituents. Thus, a
series of new chiral ligands with different electronic
charge distributing and stereo structures were conve-
niently prepared. We studied the asymmetric catalytic
abilities of chiral squaric prolinol ligands systemati-
cally. Herein, we report several homochiral squaric
prolinol ligands having different substituents such as
alkoxy, amino and alkylthio groups on C(3) of the
squaric ring. These ligands have provided better
stereoinduction than other electron-withdrawing group
containing ligands.
The asymmetric reduction of prochiral ketones which
lead to almost enantiomerically pure secondary alco-
hols has been a hot field in organic chemistry.1 Chiral
oxazaborolidines, derived from b-amino alcohols by
Itsuno2 and Corey,3 have been widely used in the
asymmetric reduction of ketones. This method has been
recognized as one of the most efficient ways for the
preparation of homochiral alcohols and a number of
reports have appeared in recent years.4 It is clear that
obtaining versatile ligands that are easily prepared and
modified is very important work.
Some N-electron-withdrawing group substituted lig-
ands
such
as
sulfonamidoalcohols5
and
phosphinamidoalcohols6 were reported as efficient cata-
lysts for the asymmetric borane reduction of prochiral
ketones, but the details of the mechanism and reactive
intermediates involved in these reactions were poorly
understood. Furthermore, these ligands were difficult to
modify for better enantioselectivity. Squaric acid (3,4-
dihydroxy-3-cyclobutene-1,2-dione) has a unique four-
membered ring structure, its C(3) and C(4) hydroxy
groups can be easily substituted by several nucle-
2. Results and discussion
The synthesis of chiral squaric prolinol ligands is shown
in Scheme 1. Reaction of 3-amino-4-butoxy-3-
cyclobutene-1,2-dione 1 with prolinol 3 afforded 3-
amino squaric prolinol 4a. We also prepared 3-alkoxy
squaric prolinols 5 by dropping an ethanolic solution of
diphenylprolinol 3 into the squaric acid diesters.9 The
* Corresponding author. Tel./fax: +86-28-5412285; e-mail: schemorg
@mail.sc.cninfo.net
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00333-0

1908
J. Zhang et al. / Tetrahedron: Asymmetry 12 (2001) 1907–1912
Ph
Ph
Ph
OH
Ph
OH
O
O
OnBu
NH2
N
O
O
N
H
3
EtOH
NH2
1
4a
Ph
Ph
Ph
OH
Ph
OH
O
O
OR
OR
N
N
O
O
O
O
R1R2NH
EtOH
3
EtOH
NR1R2
4b R1=Bz; R2=H
4c R1=BzCH2; R2=H
4d R1=nBu; R2=H
4e R1R2=(CH2)5
OR
5a R=Et
5b R=nBu
2a R=Et
2b R=nBu
Ph
Ph
Ph
Ph
OH
N
N
O
O
OH
O
O
1) NaSH
2) HCl
RX
5a
K2CO3
6b R=Me
6c R=nBu
6d R=Bz
SR
SH
6a
Scheme 1.
other amines 4b–4e were obtained by the reaction
between 5a and a slight excess of the corresponding
amines in ethanol for 1 day. The prolinol 6a was
obtained by treatment of 5a with aqueous NaSH and
then a 1N aqueous HCl solution. Further reaction of 6a
with the corresponding alkyl halides using anhydrous
K2CO3 as base led to the alkylthiosquaric acid prolinols
gen or sulfur anion, which might be prone to coordi-
nate with borane. The ligands having substituents with
high acidity on C(3) gave higher e.e.s (entries 1 and 8).
On the contrary, lower e.e.s were obtained when the
C(3) substituent lacked an acidic proton (entries 5, 9
and 10). For ligands 4 and 6, with an N- or S-benzyl
substituent, the prochiral ketone directs itself to the
boron-heterocycle catalyst with higher selectivity due to
the bulky benzyl group and high e.e.s were obtained
(entries 2 and 11). However, when using phenylethyl-
amino substituted ligand 4c, an e.e. of only 82% was
obtained (entry 3), this phenomenon may due to the
lower rigidity of the ligand.
1
6b–6d. All new ligands were characterized by IR, H
NMR, MS and elemental analysis.
As a proven excellent squaric acid-derivative ligand and
a useful synthetic intermediate for several asymmetric
reactions,10 the crystal of 3-ethoxy-squaric prolinol 5a
was obtained by slow volatilization in petroleum ether
and ethyl acetate. The structure is shown in Fig. 1.
Selected bond length and angles are listed in Table 1.
The asymmetric reductions were carried out under the
optimized conditions we studied previously.9,10 The cat-
alysts were formed in situ by mixing the ligands (0.1
equiv.) and BH3·Me2S (1.2 equiv.) at 0°C, and the
subsequent reduction of prochiral ketones was carried
out at 50°C in toluene. We applied the ligands in the
asymmetric reduction of v-bromoacetophenone giving
the alcohol product with e.e. of up to 99% (Table 2).
All the listed ligands have good to excellent asymmetric
inductivity. In the asymmetric reduction, ligand 5 in
general gave higher e.e.s than that of ligands 4 and 6
(entries 6 and 7). However, when the C(3) substituent
contained an acidic hydrogen (viz NH2, NHR or SH),
the proton would leave more easily to form the nitro-
Figure 1. Crystal structure of 5a.

J. Zhang et al. / Tetrahedron: Asymmetry 12 (2001) 1907–1912
1909
,
Table 1. Selected bond lengths (A) and angles (°) for crys-
tal 5a
The excellent asymmetric induction led us to choose
ligand 6a to catalyze the borane reduction of several
aromatic ketones. High enantiomeric excesses were
achieved. For a,b-unsaturated ketones such as benza-
lacetone, moderate e.e. was obtained. The results are
summarized in Table 3.
C(18)ꢀC(19)
C(20)ꢀC(21)
O(2)ꢀC(19)
N(1)ꢀC(18)
1.4780(15)
1.4546(16)
1.2123(13)
1.3263(13)
C(19)ꢀC(20)
C(18)ꢀC(21)
O(3)ꢀC(20)
O(4)ꢀC(21)
1.5201(15)
1.3947(14)
1.2177(14)
1.3262(13)
C(18)ꢀC(19)ꢀ
C(20)
C(19)ꢀC(18)ꢀ
C(21)
O(2)ꢀC(19)ꢀ
C(20)
O(3)ꢀC(20)ꢀ
C(19)
O(4)ꢀC(21)ꢀ
C(18)
N(1)ꢀC(18)ꢀ
C(19)
88.15
C(18)ꢀC(21)ꢀ
C(20)
C(19)ꢀC(20)ꢀ
C(21)
O(2)ꢀC(19)ꢀ
C(18)
O(3)ꢀC(20)ꢀ
C(21)
O(4)ꢀC(21)ꢀ
C(20)
N(1)ꢀC(18)ꢀ
C(21)
94.09
The asymmetric borane reduction catalyzed by squaric
prolinol ligands such as 6a may be rationalized through
two proposed mechanisms. Owing to the blocking
effect of the squaric ring on the nitrogen of prolinol, it
is likely that two borane molecules cannot complex
with the nitrogen atom simultaneously to form a transi-
tion state like Corey’s.1c Thus we proposed A–D as the
possible mechanisms for facial attack of hydride to the
carbonyl group. The first borane molecule could com-
bine to nitrogen or sulfur atoms to form Corey’s oxaz-
aborolidine A or an eight-membered boron heterocycle
B, respectively. In the case of A, the second borane
90.83
86.93
137.41
136.03
128.04
135.02
134.42
137.03
137.84
134.11
Table 2. Asymmetric reduction of v-bromo-acetophenone using chiral squaric prolinols
O
OH
ligand (0.1 equiv.), toluene, 50 0C
Br
Br
.
BH3 SMe2 (1.2 equiv.)
Entry
Ligands
Yield (%)a
E.e. (%)b
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
5a
5b
6a
6b
6c
6d
83
99
90
82
88
91
93
92
85
95
94
90
96
82
94
77
99
98
99
82
87
95
9
10
11
a Isolated yield.
b Determined by HPLC analysis, the configuration of all products is
(S).
Table 3. Asymmetric reduction of prochiral ketones using 6a
O
H
HO
RL
.
(0.1 equiv.), BH
ligand 6a
3 SMe2 (1.2 equiv.)
toluene, 50 0C
RS
RS
RL
Entry
Ketone
Acetophenone
v-Bromoacetophenone
Propiophenone
p-Chloroacetophenone
b-Acetonaphthalone
Benzalacetone
Yield (%)a
E.e. (%)b
Config.c
1
2
3
4
5
6
7
95
92
89
90
92
87
85
95
99
85
93
91
76
87
R
S
R
R
R
R
R
Tetralone
a Isolated yield.
b Determined by HPLC analysis.
c Determined by specific rotations.

1910
J. Zhang et al. / Tetrahedron: Asymmetry 12 (2001) 1907–1912
Ph
Ph
Ph
+
Ph
N
O
N
O
O
O
-
B
O
H2
BH
O
S
SH
B
A
Ph
N
Ph
Ph
N
RS
RL
Ph
O
RS
RL
O
B
O
H
+
-
O
B
H
H2
S
B
H
S
B
O
H
H
H
O
O
H
O
D
C
Scheme 2.
molecule will be difficult to connect nitrogen for steric
and electric reasons. So it can only combine to sulfur as
another Lewis base atom. As a result the facial attack
of hydride to ketone substrate occurs through a
nine-membered cycle shown as C. In another proposed
transition state, the first borane reacts with the
hydroxyl group and 3-heteroatom of the ligand to form
B. This bifunctional boron heterocycle also contains
both a Lewis acid and Lewis base site, which can
interact with a molecule of borane and ketone. Hydride
will attack the ketone through the more stable
six-membered-cyclic transition state D (Scheme 2). In
contrast with transition state C, the transition state D
has a ‘free’ nitrogen atom. However, it may also
interact with a boron atom and some enantiofacial
differentiation may result in the hydride-attack step.
Obviously a more in-depth study is needed to elucidate
the mechanism of the asymmetric borane reduction.
a Finnigan MAT 4510 spectrometer. Flash chromatog-
raphy was carried out using SiO2 (230–400 mesh).
Elemental analyses were performed with a Carlo Erba
1106 elemental analyzer. HPLC analyses were carried
out through Chiracel OD column. Prolinol 3 and 3-
alkoxy-squaric prolinol 5 were prepared according to
Refs. 11 and 9, respectively. BH3·Me2S (2 M) was
purchased from Aldrich. The solvent (toluene) and all
prochiral ketones were purified before use. Other chem-
icals were obtained and used without any further
purification.
4.2. Preparation of squaric prolinol amides 4
Method 1. To a solution of 3-amino-4-butoxy-3-
cyclobutene-1,2-dione 1 (1 mmol) in ethanol (10 mL)
was added diphenyl prolinol 3 (1 mmol) and the mix-
ture was stirred at room temperature for 1 day. The
mixture was filtered, and the filter cake dried, and
recrystallized from absolute ethanol and THF to afford
a colorless flaky solid of 3-amino-4-[(2%S)-2%-(diphenyl-
hydroxymethyl)pyrrolidino]-3-cyclobutene-1,2-dione 4a:
79% yield. Mp 146–148°C. [h]2D0 −95.4 (c 0.5, CH2Cl2).
IR w: 3296, 1801, 1664, 1566, 1507 cm−1. 1H NMR
(DMSO-d6) l: 1.58–1.75 (m, 2H, -CH2-), 1.99–2.18 (m,
2H, -CH2N-), 3.57–3.69 (m, 2H, -CH2N-), 5.20 (s, 1H,
OH), 5.76 (br, 1H, -CHN-), 7.14–7.39 (m, 10H, ArH),
7.47 (d, J=7.4 Hz, 2H, NH). MS (m/z): 349 (M++1,
100). Anal. calcd for C21H20N2O3: C, 72.40; H, 5.79; N,
8.04. Found: C, 72.54; H, 5.63; N, 7.96%.
3. Conclusion
In summary, we have synthesized a series of chiral
squaric prolinol ligands with different substituents at
C(3) of the squaric ring. The boron heterocycle
catalysts were formed in situ to catalyze the asymmetric
borane reduction of aromatic ketones with good to
excellent e.e.s. A possible mechanism was discussed.
4. Experimental
Method 2. To a solution of 5a (1.0 mmol) in ethanol (10
mL) was added amine (1.1 mmol) and the mixture was
stirred at room temperature for 1 day. The reaction was
monitored by TLC until completion. Column chro-
matography (dichloromethane:ethyl acetate, 5/1, v/v)
gave the pure products as colorless flaky solids.
4.1. Instruments and materials
Melting points were taken on a micro-melting appara-
tus and the data were not corrected. Optical rotations
were measured on a WZZ-1 polarimeter. IR spectra
were measured on a FT-IR 16PC infrared spectropho-
1
tometer with KBr disc. H NMR spectra were recorded
4.2.1.3-Benzylamino-4-[(2%S)-2%-(diphenylhydroxymethyl)-
pyrrolidino]-3-cyclobutene-1,2-dione 4b. 80% yield. Mp
172–174°C. [h]2D0 −210 (c 1.15, CH2Cl2). IR w: 3275,
at Bruker DPX-400 MHz and Bruker AC-E 200 MHz
with chemical shift in ppm and tetramethylsilicon as
internal standard. Mass spectra data were obtained on
1
1790, 1666, 1565, 1509 cm−1. H NMR (DMSO-d6) l:

J. Zhang et al. / Tetrahedron: Asymmetry 12 (2001) 1907–1912
1911
0.93 (d, J=6.7 Hz, 2H, -CH2-), 1.73–1.76 (m, 2H,
4.4. Preparation of 3-alkylthio squaric prolinol 6b–6d
-CH2-), 1.89–2.14 (m, 2H, -CH2N-), 3.67 (br, 2H,
-CH2N-), 4.69 (t, J=7.6 Hz, 1H, -CHN-), 5.92 (s, 1H,
OH), 7.12–7.49 (m, 15H, ArH), 7.71 (d, J=9.8 Hz, 1H,
NH). MS (m/z): 440 (M++2, 20). Anal. calcd for
C28H26N2O3: C, 76.69; H, 5.98; N, 6.39. Found: C,
77.47; H, 5.91; N, 6.29%.
To a solution of 6a (1 mmol) in acetone (10 mL) was
added anhydrous K2CO3 (69 mg, 0.5 mmol). The mix-
ture was stirred at 40°C until K2CO3 disappeared. Then
a catalytic amount of KI and corresponding alkyl
halide (1.1 mmol) was added into the reaction mix-
ture.12 Stirring was continued overnight at 40°C, the
insoluble solid was filtered and the filtrate was evapo-
rated under reduced pressure. The residue was sub-
jected to column chromatography (petroleum
ether:ethyl acetate, 2/1, v/v) to give 6b–6d as pale
yellow flakes.
4.2.2. 3-Phenylethylamino-4-[(2%S)-2%-(diphenylhydroxy-
methyl)pyrrolidino]-3-cyclobutene-1,2-dione 4c. 95%
yield. Mp 222–224°C. [h]2D0 −229 (c 0.35, CH2Cl2). IR w:
1
3267, 1792, 1667, 1561, 1510 cm−1. H NMR (CDCl3)
l: 2.92 (t, J=6.0 Hz, 2H, -CH2N-), 3.95 (q, J=6.5 Hz,
2H, -CH2N-), 4.89 (d, J=8.5 Hz, 1H, -CHN-), 5.93 (s,
1H, OH), 7.17–7.60 (m, 15H, ArH), 7.81 (d, J=7.1 Hz,
1H, NH). MS (m/z): 269 (M+−Ph2COH, 34). Anal.
calcd for C29H28N2O3: C, 76.97; H, 6.24; N, 6.19.
Found: C, 77.12; H, 6.18; N, 6.01%.
4.4.1. 3-Methylthio-4-[(2%S)-2%-(diphenylhydroxymethyl)-
pyrrolidino]-3-cyclobutene-1,2-dione 6b. 55% yield. Mp
183–185°C. [h]2D0 −148.8 (c 0.42, CH2Cl2). IR w: 3315,
1
1772, 1649, 1562 cm−1. H NMR (DMSO-d6) l: 1.90–
2.15 (m, 4H, -CH2-), 2.74 (s, 3H, CH3), 3.72–3.89 (m,
2H, -CH2N-), 5.27 (d, J=7.7 Hz, 1H, -CHN-), 6.05 (s,
1H, OH), 7.12–7.50 (m, 10H, ArH). MS (m/z): 380
(M++1, 24). Anal. calcd for C22H21NO3S: C, 69.63; H,
5.58; N, 3.69. Found: C, 69.92; H, 5.51; N, 3.64%.
4.2.3. 3-Butylamino-4-[(2%S)-2%-(diphenylhydroxymethyl)-
pyrrolidino]-3-cyclobutene-1,2-dione 4d. 96% yield. Mp
62–64°C. [h]2D0 −159.7 (c 0.72, AcOEt). IR w: 3279,
1
3075, 1791, 1662, 1566, 1512 cm−1. H NMR (CDCl3)
4.4.2. 3-n-Butylthio-4-[(2%S)-2%-(diphenylhydroxymethyl)-
pyrrolidino]-3-cyclobutene-1,2-dione 6c. 88% yield. Mp
159–160°C. [h]2D0 −108.8 (c 0.74, CH2Cl2). IR w: 3320,
l: 0.93 (t, J=7.3 Hz, 3H, CH3), 1.52–1.64 (m, 6H,
-CH2-), 3.68 (qd, J=6.7, 2.0 Hz, 2H, -CH2N-), 3.77 (t,
J=9.9 Hz, 2H, -CH2N-), 5.10 (d, J=7.1 Hz, 1H,
-CHN-), 5.86 (s, 1H, OH), 7.26–7.39 (m, 10H, ArH),
7.81 (d, J=7.1 Hz, 1H, NH). MS (m/z): 405 (M++1,
95). Anal. calcd for C25H28N2O3: C, 74.23; H, 6.98; N,
6.93. Found: C, 74.67; H, 6.87; N, 6.89%.
1
1774, 1650, 1561 cm−1. H NMR (DMSO-d6) l: 0.91 (t,
J=7.2 Hz, 3H, CH3), 2.11–2.27 (m, 2H, -CH2S-), 3.75–
3.92 (m, 2H, -CH2N-), 5.28 (d, J=7.5 Hz, 1H, -CHN-),
6.06 (s, 1H, OH), 7.12–7.51 (m, 10H, ArH). MS (m/z):
422 (M++1, 100). Anal. calcd for C25H27NO3S: C,
71.23; H, 6.46; N, 3.32. Found: C, 71.08; H, 6.59; N,
3.36%.
4.2.4. 3-Pyperidinyl-4-[(2%S)-2%-(diphenylhydroxymethyl)-
pyrrolidino]-3-cyclobutene-1,2-dione 4e. 98% yield. Mp
241–243°C. [h]2D0 +44.0 (c 0.96, CHCl3). IR w: 2967,
1794, 1663, 1569, 1507 cm−1. 1H NMR (CDCl3) l:
1.23–1.78 (m, 10H, -CH2-), 2.72 (q, J=8.5 Hz, 2H,
-CH2N-), 3.24 (td, J=9.0, 3.2 Hz, 1H, -CHN-), 3.49–
3.54 (m, 2H, -CH2N-), 3.69–3.72 (m, 2H, -CH2N-), 5.80
(dd, J=3.6, 5.2 Hz, 1H, OH), 7.25–7.32 (m, 10H,
ArH). MS (m/z): 417 (M++1, 75). Anal. calcd for
C26H28N2O3: C, 74.98; H, 6.78; N, 6.73. Found: C,
74.76; H, 6.74; N, 6.59%.
4.4.3. 3-Benzylthio-4-[(2%S)-2%-(diphenylhydroxymethyl)-
pyrrolidino]-3-cyclobutene-1,2-dione 6d. 70% yield. Mp
203–204°C. [h]2D0 −74.4 (c 0.45, CH2Cl2). IR w: 3307,
1
1769, 1646, 1559 cm−1. H NMR (DMSO-d6) l: 1.17–
1.24 (m, 2H, -CH2-), 1.85–1.94 (m, 2H, -CH2-), 2.09 (t,
J=7.3 Hz, 2H, -CH2S-), 3.65–3.87 (m, 2H, -CH2N-),
4.56 (t, J=14.5 Hz, 1H, -CHN-), 6.04 (s, 1H, OH),
6.96–7.49 (m, 15H, ArH). MS (m/z): 456 (M++1, 68).
Anal. calcd for C28H25NO3S: C, 73.82; H, 5.53; N, 3.07.
Found: C, 73.57; H, 5.56; N, 3.10%.
4.3. Preparation of squaric prolinol mercaptan 6a
4.5. General procedure for the catalytic reduction of
prochiral ketones
To a solution of 5a (377 mg, 1 mmol) in ethanol (10
mL) was added aqueous sodium hydrosulfide (62 mg,
1.1 mmol) dropwise at room temperature. The reaction
was complete soon after the end of the addition. The
yellow solution was treated with diluted hydrochloride
acid and yellow precipitates appeared. The solid was
filtered off and recrystallized from water and acetone to
afford 3-mercapto-4-[(2%S)-2%-(diphenylhydroxymethyl)-
pyrrolidino]-3-cyclobutene-1,2-dione 6a (330 mg, 91%)
as a yellow flaky solid. Mp 163–165°C. [h]2D0 −82.0 (c
0.7, EtOH). IR w: 3446, 3064, 1774, 1662, 1563 cm−1.
1H NMR (DMSO-d6) l: 1.98 (m, 2H, -CH2-), 2.19 (m,
2H, -CH2-), 3.86 (s, 2H, -CH2N-), 4.00 (m, 1H, SH),
5.27 (br, 1H, -CHN-), 6.15 (s, 1H, OH), 7.18–7.50 (m,
10H, ArH). MS (m/z): 366 (M++1, 37). Anal. calcd for
C21H19NO3S: C, 69.04; H, 5.21; N, 3.84. Found: C,
68.87; H, 5.28; N, 3.90%.
To a 25 mL round-bottom flask was added 0.05 mmol
(0.1 equiv.) of chiral ligand. Under an argon atmo-
sphere and at 0°C, BH3·Me2S (0.6 mmol, 1.2 equiv.)
was added. The mixture was stirred at ambient temper-
ature for 2 h and warmed to 50°C for a further hour.
The ketone (0.5 mmol) was added slowly over a period
of 1.5 h under the same temperature and stirred for a
further hour. The reaction mixture was cooled to 0°C
and quenched with a 1N aqueous HCl solution (8 mL),
then extracted with ethyl acetate (3×10 mL). The com-
bined ethyl acetate solution was washed twice with
brine and dried with anhydrous MgSO4. The solvent
was removed under reduced pressure. The residue was
passed through a short silica column to afford the pure
product.

1912
J. Zhang et al. / Tetrahedron: Asymmetry 12 (2001) 1907–1912
Crystallographic data (excluding structure factors) for
compound 5a have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publi-
cation number CCDC 161178. Copies of the data can
be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge, CB2 1EZ, UK [fax:
+44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
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G.-S.; Hu, J.-B.; Zhao, G.; Ding, Y.; Tang, M.-H. Tetra-
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Acknowledgements
The financial support of The Hong Kong Polytechnic
University ASD Fund is gratefully acknowledged.
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