New β-amino alcohols with a bicyclo[3.3.0]octane scaffold in an asymmetric Henry reaction

Article abstract of DOI:10.1016/j.tetasy.2003.11.040

A new category of β-amino alcohols with a bicyclo[3.3.0]octane scaffold has been synthesized and used in the direct asymmetric nitroaldol reaction (Henry reaction). Up to 74% ee was obtained with the addition of nitromethane to relatively bulky aldehydes.

Full text of DOI:10.1016/j.tetasy.2003.11.040

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 771–776
New b-amino alcohols with a bicyclo[3.3.0]octane scaffold in an
asymmetric Henry reaction
Yu-Wu Zhong, Ping Tian and Guo-Qiang Lin*
Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 354 Fenglin Road, Shanghai 200032, PR China
Received 12 October 2003; accepted 13 November 2003
Abstract—A new category of b-amino alcohols with a bicyclo[3.3.0]octane scaffold has been synthesized and used in the direct
asymmetric nitroaldol reaction (Henry reaction). Up to 74% ee was obtained with the addition of nitromethane to relatively bulky
aldehydes.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Ar
Ar
Et
O
O
Ar
Ar
O
N
Since its discovery in 1895,1 the nitroaldol reaction
(Henry reaction), one of the most powerful carbon–
carbon bond forming transformations, has been widely
used in the synthesis of numerous natural products and
other useful compounds.2 However, the asymmetric
version of this reaction promoted by chiral catalysts had
not appeared until the last decade. Shibasaki et al.3 first
reported the highly enantioselective and diastereoselec-
tive Henry reaction employing their elegant heterobi-
metallic system.4 Jørgensen et al.5 disclosed the
enantioselective Henry reaction of a-keto esters with
nitromethane catalyzed by copper salts in combination
with chiral bisoxazoline ligands. Ma et al.6 and Najera
et al.,7 using chiral guanidine as the organo catalyst,
developed another case for a direct asymmetric Henry
reaction.
Zn
Zn
N
R
Figure 1. TrostÕs catalyst.
In recent years, we have been interested in the synthesis
of chiral auxiliaries and ligands with a cis-bicy-
clo[3.3.0]octane framework.12 Pyridyl alcohol 2, derived
from chiral diketone (1R,5R)-1a,13 was found to induce
high enantioselectivities in the asymmetric addition of
diethylzinc to aldehydes (Scheme 1).12a The semi-caged
structure of the cis-bicyclo[3.3.0]octane was expected to
form a unique chiral environment for this asymmetric
process. It occurred to us that the chiral diketone 1a
could be converted into its analogous epoxide, and
subsequently attacked by amines, which is one of the
common procedures for the preparation of b-amino
alcohols.14
Recently, a novel type of dinuclear zinc catalyst8;9
(Fig. 1) developed by Trost has successfully been utilized
in an asymmetric Henry reaction.10 Following TrostÕs
work, Reiser et al.11 disclosed in detail that the Henry
reaction could be promoted by diethylzinc in the pres-
ence of either diamines or amino alcohols. However,
initial investigations with chiral amino alcohols to make
this process asymmetric were unsuccessful.
O
O
H
H
HO
H
H
N
O
(1R,5R)
1a
2
* Corresponding author. Tel.: +86-21-64163300; fax: +86-21-641662-
63; e-mail: lingq@mail.sioc.ac.cn
Scheme 1.
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.11.040

772
Y.-W. Zhong et al. / Tetrahedron: Asymmetry 15 (2004) 771–776
Herein we report the synthesis of this new kind of b-
amino alcohol with a bicyclo[3.3.0]octane framework.
Inspired by TrostÕs work, the asymmetric Henry reac-
NOE
H
H
H
OH
€
tion catalyzed by the Bronsted base–Lewis acid complex
H
N
Ph
generated from diethylzinc and these b-amino alcohols
was then tried. Although amino alcohols have been
widely used in asymmetric reactions, especially the
addition of organozinc reagents to aldehydes,15 there are
few reports about their use in asymmetric Henry reac-
tions. It is worth noting that Sundararajan has already
reported an asymmetric Michael reaction catalyzed by a
N
H
Ph
HO
H
H
H
NOE
Figure 2. The NOE analysis of 4b.
chiral amino alcohol–Al (or Na) complex, employing
16
€
the Bronsted base–Lewis acid catalysis.
2. Results and discussion
As shown in Scheme 2, treatment of the diketone
(1S,5S)-1b13 (the enantiomer of 1a) with trimethyl-
sulfonium bromide17 furnished bis-oxirane 3b. Due to
its wide availability and ample use in asymmetric syn-
thesis,18 homochiral (R) or (S)-1-phenylethylamine was
then chosen as the nucleophile to open the epoxide
ring of 3b, thus producing the bis-b-amino alcohols 4b
and 5 as two diastereomers. The relative configuration
of 4b was determined by its NOE (Fig. 2) and X-ray
analysis (Fig. 3). In another part, mono-b-amino alco-
hol 8 was obtained via the same procedure as described
above from mono-ketone (1S,5S)-6.12a Deprotection of
Figure 3. The X-ray analysis of 4b.
8 gave amino alcohol 9 with an unmasked carbonyl
group.
Amino alcohols 4b, 5, 8, and 9 were then tested in the
asymmetric Henry reaction under the conditions10 de-
scribed by Trost with minor modifications. The reaction
H
NH2
Ph
HO
N
H
H
N
Ph
OH
Ph
Ph
O
H
O
80%
NH2
H
O
H
(1S,2S,5S,6S,1'R,1''R)
Me3SBr, KOH
CH3CN / H2O, 600C, 90%
4b
H
H
H
O
HO
Ph
H
N
N
H
ph
(1S,2S,5S,6S)
(1S,5S)
1b
OH
3b
80%
H
(1S,2S,5S,6S,1'S,1''S)
5
O
H
O
NH2
H
O
O
O
O
O
H
H
OH
NH
Me3SBr, KOH
92%
Ph
HCl
quant.
OH
NH
H
89%
H
O
H
H
O
Ph
(1S,5S,6S,1'R)
(1S,5S)
(1S,5S,6S)
(1S,5S,6S,1'R)
Ph
9
6
7
8
NH2
O
O
H
H
OH
H
Me3SBr, KOH
90%
Ph
74%
NH
Ph
N
H
HO
H
Ph
H
H
O
O
(1R,5R)
1a
(1R,2R,5R,6R)
(1R,2R,5R,6R,1'S,1''S)
3a
4a
Scheme 2. The synthesis of b-amino alcohols with the bicyclo[3.3.0]octane scaffold.

Y.-W. Zhong et al. / Tetrahedron: Asymmetry 15 (2004) 771–776
773
between cyclohexanecarboxaldehyde and nitromethane
was selected as the representative reaction (Eq. 1). The
catalyst was prepared in situ from 5 mol % of one of the
above mentioned amino alcohols with two (for 8 and 9)
or three (for 4b and 5) equivalents of diethylzinc in THF
in the presence of 4 A MS at 0 °C, into which 6 equiv of
nitromethane was added, followed by the addition of the
aldehyde.
of equivalents of nitromethane and the reaction medium
failed. The use of additives such as Ph3PS and C2H5OH
also proved to be unbeneficial.20 When the ligand was 4a
(the enantiomer of 4b, prepared from 1a as shown in
Scheme 1), almost the same ee value of the product was
obtained, while the absolute configuration of the prod-
uct reversed as expected as indicated by the sign of the
specific rotation (entry 9).
ꢀ
Under the optimal conditions (Table 1, entry 9), the
complex formed in situ between 5 mol % of 4a and
10 mol % of diethylzinc, was used to catalyze the addi-
tion of nitromethane to a variety of aldehydes (Eq. 2),
with the results summarized in Table 2. Moderate
enantioselectivities were obtained for the relatively
bulky aldehydes, such as iso-butyraldehyde (entry 3),
pivalaldehyde (entry 4), and 2-ethylbutyraldehyde (entry
5). a,a-Dimethylhydrocinnamaldehyde21 was shown to
produce the highest ee among all the substrates exam-
ined (entry 6, 74% ee). When it came to the sterically less
encumbered hydrocinnamaldehyde (entry 2), the ee
value diminished to 37%. As far as aromatic aldehydes
were concerned, the enantioselectivities were relatively
poor (entries 7–9). However, a moderate ee of 49% was
achieved in the case of o-methoxybenzaldehyde (entry
10). The absolute configuration of all the products in
Table 2 is assigned as R based on the specific rotation
when compared with the reported data by Shibasaki
et al.3a and Trost et al.10
OH
O
5 mol % L* + ZnEt2
NO2
CH3NO2
+
H
10
ð1Þ
As can be seen from Table 1, in combination with di-
ethylzinc, all four amino alcohols catalyzed the addition
of nitromethane to cyclohexanecarboxaldehyde to pro-
duce the product with good to high yields. Considering
the relatively low reaction temperature, shorter reaction
time, and higher yield, bis-amino alcohols 4b and 5
(entries 1 and 2) were more active than the mono-amino
alcohols 8 and 9 (entries 3 and 4). As far as the
enantioselectivitiy was concerned, 4b was the most
effective among the four amino alcohols (entry 1, 38%
ee). It seems that the bis-amino alcohols catalyze this
reaction via a different mechanism compared to that of
the mono-amino alcohols. The bis-amino alcohol 4b
provided 10 in an (S)-configuration (entry 1), while the
mono-amino alcohol 8 or 9, with the same configuration
both on the bicyclo[3.3.0]octane scaffold and the phenyl-
ethylamine moiety, afforded 10 in an (R)-configuration
(entries 3 and 4). Perhaps the two amino alcohol–zinc
complex moieties in 4b operated cooperatively.
OH
4a + 2 ZnEt2
ð2Þ
RCHO
+ CH3NO2
NO2
R
THF
Compound 4b was then chosen as the standard ligand
for optimizing further the reaction conditions. We later
found that the molar ratio between 4b and diethylzinc
was crucial for the ee value of the product (entries 5–7).
The optimal result was obtained when 2 equiv of diethyl-
zinc were used (entry 6, 46% ee). A further improvement
in enantioselectivity was achieved by lowering the
reaction temperature to )25 °C (entry 8, 59% ee). At-
tempts to increase the ee value by changing the number
3. Conclusion
In summary, a new category of b-amino alcohols with a
bicyclo[3.3.0]octane scaffold was synthesized and used in
an asymmetric Henry reaction.22 Moderate enantio-
selectivities were obtained for the relatively bulky ali-
phatic aldehydes. Although the detailed mechanism of
this system calls for further investigation, it is reasonable
to assume a mechanism in which at least two zinc atoms
Table 1. Optimization of the Henry reaction between cyclohexylcarboxaldehyde and nitromethanea
20
D
Entry
Ligand
L:ZnEt2
Temperature
Time (h)
Yield (%)b
Ee (%)c
½aꢀ
Absolute
configurationd
1
2
3
4
5
6
7
8
9
4b
5
1:3
1:3
1:2
1:2
1:5
1:2
1:1
1:2
1:2
0 °C
0 °C
0 °C to rt
0 °C to rt
0 °C
0 °C
0 °C
)25 °C
)25 °C
10
10
24
24
7
87
81
70
50
93
77
59
75
90
38
12
27
17
25
46
38
59
52
+6.9
)2.8
)6.2
)4.0
+4.5
+8.3
+6.1
+10.3
)10.5
S
R
R
R
S
S
S
S
R
8
9
4b
4b
4b
4b
4a
7
9
8
8
a All reactions were conducted on a 1 mmol scale of cyclohexylcarboxaldehyde.
b Isolated yield.
c The ee value of the product was determined by the chiral HPLC analysis.
d The absolute configuration of 10 was established according to the optical rotation in comparison with the reported data by Trost, see Ref. 19.

774
Y.-W. Zhong et al. / Tetrahedron: Asymmetry 15 (2004) 771–776
Table 2. Enantioselective Henry reaction between aldehydes and nitromethanea
20
½aꢀ in CHCl3
Entry
1
Aldehyde
Reaction time (h)
8
Yield (%)b
90
Ee (%)c
52
D
)10.5 (c 5.40)
CHO
CHO
2
3
4
11
10
12
74
90
82
37
66
67
+4.6 (c 1.28)
)21.5 (c 1.75)
)19.7 (c 1.42)
Ph
CHO
CHO
5
CHO
20
20
8
50
40
80
69
74
33
)17.0 (c 1.20)
)4.1 (c 1.05)
)15.4 (c 2.15)
CHO
6
Ph
7d
CHO
CHO
8
36
42
23
81
73
75
25
21
49
)7.2 (c 1.70)
)7.1 (c 1.87)
)22.4 (c 3.75)
9
MeO
CHO
10
CHO
OMe
a All reactions were run on a 1 mmol scale of aldehyde using 5 mol % 4a, 6 equiv of nitromethane in THF at )25 °C unless otherwise noted.
b Isolated yield.
c The ee value of the product was determined by chiral HPLC analysis.
d 10 mol % of 4a and 20 mol % ZnEt2 was used.
are involved, one acting as a Lewis acid center to acti-
vate the aldehyde, while the other functioning as a
Enantiomeric excess determination was carried out
using HPLC with a Chiralcel OD, AS, AD, or OJ col-
umn. The silica gel used for flash chromatography was
300–400 mesh. All solvents were dried by standard
method. Unless otherwise noted, commercially available
reagents were used without further purification.
€
Bronsted base to generate a zinc-nitronate from nitro-
methane. Related works on the Bronsted base–Lewis
€
acid zinc complex, which was prepared in situ from
BINOL derivatives and ZnEt2 has been reported by
Shibasaki and co-workers.23 Further work to modify the
ligand in order to improve the enantioselectivities is
currently in progress. Expansion of this system to other
asymmetric reactions is also under investigation.
4.2. (1S,2S,5S,6S)-Bicyclo[3.3.0]octan-2,6-dione diepox-
ide, 3b
To 20 mL of CH3CN was added Me3SBr (3.27 g,
20.8 mmol), KOH (4.66 g, 83.3 mmol), and H2O (68 lL).
The resulting heterogeneous mixture was stirred for
5 min at 60 °C, followed by the addition of the solution
of chiral dione 1b (958 mg, 6.9 mmol) in CH3CN (7 mL).
The system was then stirred at 60 °C for 2 h, and filtered
through a pad of Celite. The volatile solvent was re-
moved under reduced pressure. Water (10 mL) was add-
ed to dissolve the residue. The mixture was extracted
4. Experimental
4.1. General
Melting points are uncorrected. Optical rotations were
1
measured on a Perkin–Elmer 241MC polarimeter. H
and 13C NMR spectra were taken in CDCl3 on 300 and
75 MHz FT-spectrometers, respectively, using TMS as
the internal reference. IR spectra were recorded on a
Digibal FT-IR spectrometer. Mass spectra were
recorded by the EI method, and HRMS were measured
on a Finnigan MAT-8430 mass spectrometer. Elemental
analysis was performed on Heraeus Rapid-CHNO.
with ether, and purified by flash column chromatogra-
20
phy to provide 3b as oil (1.1 g, 90%). ½aꢀ ¼ +108.8 (c
D
2.15, CHCl3). 1H NMR (300 MHz, CDCl3, ppm): d
1.56–1.77 (m, 8H), 2.5 (m, 2H), 2.67 (d, J ¼ 5:1 Hz, 2H),
2.78 (d, J ¼ 5:4 Hz, 2H); FT-IR (film, cmꢁ1): 2961, 1459,
1164, 925; EIMS (m=z, %): 166 (Mþ, 0.97), 79 (100.00),
91 (63.26), 109 (62.18), 108 (57.27), 110 (56.09), 77

Y.-W. Zhong et al. / Tetrahedron: Asymmetry 15 (2004) 771–776
775
(54.61), 135 (52.71), 105 (48.25); 13C NMR (300 MHz,
CDCl3, ppm): d 23.82, 32.62, 44.60, 52.58, 66.23; HRMS
m=z calcd for C10H14O2 166.0994, found 166.1005.
2963, 1342, 1211, 1109; EI-MS (m=z, %): 196 (Mþ, 0.66),
166 (21.76), 165 (55.09), 100 (22.43), 99 (100.00), 87
(9.81), 86 (13.89), 79 (12.69), 55 (14.92); 13C NMR
(75 MHz, CDCl3, ppm): d 22.1, 25.8, 33.5, 34.2, 42.8,
49.6, 50.8, 63.7, 64.8, 66.3, 118.8; HRMS Mþ calcd for
C11H16O3: 196.1099, found: 196.1120.
4.3. (1S,2S,5S,6S,10R,100R)-2,6-Bis(1-phenylethyl-amino-
methyl)-bicyclo[3.3.0]octan-2,6-diol, 4b
4.6. 1S,5S,6S,10R)-6-Hydroxy-6-(1-phenylethyl-amino-
methyl)-bicyclo[3.3.0]octan-2-one ethylene ketal, 8
Compound 3b (500 mg, 3.0 mmol) and (R)-(+)-1-phen-
ylethylamine (2.3 mL, 18 mmol) was refluxed in ethanol
for 34 h under an argon atmosphere. The volatile solvent
was removed under reduced pressure and the residue
Compound 8 was prepared from 6 and (R)-(+)-1-phen-
ylethylamine in a similar way as described in Section 4.3.
subjected to flash column chromatography to afford 4b
20
D
20
D
Yield: 89%; ½aꢀ ¼ +70.7 (c 1.35, CHCl3); 1H NMR
(980 mg, 80%) as a white solid. mp: 78 °C; ½aꢀ ¼ +56.5
1
(c 0.85, CHCl3); H NMR (300 MHz, CDCl3, ppm): d
(300 MHz, CDCl3, ppm): d 1.40 (d, J ¼ 6:3 Hz, 3H),
1.46 (m, 1H), 1.69 (m, 7H), 2.25 (m, 1H), 2.38 (m, 1H),
2.44 (d, J ¼ 11:1 Hz, 1H), 2.59 (d, J ¼ 11:7 Hz, 1H),
3.00 (br, 2H), 3.82 (q, 1H), 3.89 (m, 4H), 7.27 (m, 5H);
FT-IR (film, cmꢁ1): 3477, 3026, 2961, 1107, 763, 702; EI-
MS (m=z, %): 318 (Mþ+H, 38.11), 134 (30.10), 120
(31.54), 106 (12.47), 105 (100.00), 99 (16.93), 79 (15.97),
77 (11.81); 13C NMR (75 MHz, CDCl3, ppm): d 21.68,
23.76, 24.42, 35.44, 38.71, 48.64, 49.23, 55.84, 58.44,
64.04, 64.75, 80.39, 118.26, 126.35, 126.81, 128.36,
145.44; HRMS (Mþ)CH3) calcd for C18H24NO3:
302.1756, found: 302.1773.
1.41 (d, J ¼ 6:3 Hz, 6H), 1.59 (m, 4H), 1.78 (m, 2H),
1.93 (m, 2H), 2.31 (m, 2H), 2.41 (d, J ¼ 11:7 Hz, 2H),
2.58 (d, J ¼ 11:7 Hz, 2H), 2.50–3.40 (br, 4H), 3.80 (q,
2H), 7.29 (m, 10H); FT-IR (KBr, cmꢁ1): 3343, 3154,
2956, 1454, 1119, 761, 700; EI-MS (m=z, %): 408 (Mþ,
1.69), 289 (7.96), 275 (9.71), 274 (23.49), 120 (18.20), 134
(22.27), 106 (13.50), 105 (100.00), 79 (10.99); 13C NMR
(75 MHz, CDCl3, ppm): d 20.66, 24.39, 41.34, 51.85,
55.09, 58.69, 78.91, 126.50, 126.89, 128.41, 145.30;
HRMS Mþ calcd for C16H36N2O2: 408.2777, found:
408.2788. X-ray data of 3b: C26H36N2O2 space group
P212121. a 8.4987(9), b 9.4805(10), c 29.272(3). Crys-
tallographic data for 3b has been deposited with the
Cambridge Crystallographic Data Centre as supple-
mentary publication number CCDC 230028. Copies of
the data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB2 IEZ, UK
[fax: +44(0)-1223-336033 or e-mail: deposit@ccdc.cam.
ac.uk].
4.7. (1S,5S,6S,10R)-6-Hydroxy-6-(1-phenylethyl-amino-
methyl)-bicyclo[3.3.0]octan-2-one, 9
To a solution of 5% HCl and acetone (10/1, v/v) was
added 8. The mixture was stirred at rt for 5 h. THF was
evaporated under reduced pressure. Then, saturated
aqueous NaHCO3 solution was added to neutralize the
mixture. The mixture was extracted with ethyl acetate.
The combined organic layers were washed with water
and brine and dried over with anhydrous Na2SO4. The
solvent was evaporated under reduced pressure and
the crude product was purified by flash column chro-
4.4. (1S,2S,5S,6S,10S,100S)-2,6-Bis(1-phenylethyl-amino-
methyl)-bicyclo[3.3.0]octan-2,6-diol, 5
Compound 5 was prepared from 3b and (S)-())-1-
phenylethylamine in a similar way as described in Sec-
20
D
matography to give 9 in quantitative yield. mp: 92 °C;
1
tion 4.3. Yield: 80%; ½aꢀ ¼ )12.5 (c 3.20, CHCl3); H
20
½aꢀ ¼ +146.5 (c 0.85, CHCl3); 1H NMR (300 MHz,
D
NMR (300 MHz, CDCl3, ppm): d 1.32 (d, J ¼ 6:6 Hz,
6H), 1.52 (m, 4H), 1.71–1.84 (m, 4H), 2.22 (m, 2H), 2.36
(d, J ¼ 12:0 Hz, 2H), 2.50 (d, J ¼ 11:7 Hz, 2H), 2.00–
3.40 (br, 4H), 3.72 (q, 2H), 7.28 (m, 10H); FT-IR (film,
cmꢁ1): 3338, 3026, 2960, 1451, 1128, 762, 701; EI-MS
(m=z, %): 408 (Mþ, 1.59), 275 (8.73), 274 (21.53), 134
(20.60), 120 (18.58), 106 (14.02), 105 (100.00), 79 (13.22),
77 (9.60); 13C NMR (75 MHz, CDCl3, ppm): d 20.89,
24.40, 41.58, 51.89, 55.03, 58.40, 78.88, 126.36, 126.73,
128.30, 145.43; HRMS Mþ calcd for C16H36N2O2:
408.2777, found: 408.2761.
CDCl3, ppm): d 1.48 (d, J ¼ 6:6 Hz, 3H), 1.50 (m, 1H),
1.90 (m, 5H), 2.17 (m, 1H), 2.26 (m, 2H), 2.40 (d,
J ¼ 11:4 Hz, 1H), 2.58 (m, 1H), 2.66 (d, J ¼ 12:0 Hz,
1H), 3.48 (br, 2H), 3.84 (q, 1H), 7.29 (m, 5H); FT-IR
(film, cmꢁ1): 3416, 3359, 3029, 2961, 1718, 766, 707; EI-
MS (m=z, %): 274 (Mþ+H, 2.15), 134 (39.39), 106
(11.86), 105 (100.00), 103 (9.53), 79 (13.99), 77 (13.34),
57 (7.01), 41 (6.71); 13C NMR (75 MHz, CDCl3, ppm): d
20.15, 23.48, 25.26, 37.97, 38.33, 48.50, 51.26, 54.47,
59.04, 80.96, 126.53, 127.50, 128.73, 143.68, 223.25;
HRMS Mþ calcd for C17H23NO2:273.1729, found:
273.1702.
4.5. (1S,5S,6S)-Bicyclo[3.3.0]octan-2,6-dione 2-epoxide
6-ethylene ketal, 7
4.8. (1R,2R,5R,6R)-Bicyclo[3.3.0]octan-2,6-dione diep-
oxide, 3a
Compound 7 was prepared from 6 and Me3SBr in a
similar way as described in Section 4.2. Yield: 92%;
20
D
½aꢀ ¼ +63.6 (c 1.15, CHCl3); 1H NMR (300 MHz,
Compound 3a was prepared from 1a and Me3SBr in a
similar way as described in Section 4.2. Yield: 90%;
CDCl3, ppm): d 1.72 (m, 8H), 2.55 (m, 2H), 2.70 (m,
20
D
1H), 2.84 (m, 1H), 3.90 (m, 4H); FT-IR (film, cmꢁ1):
½aꢀ ¼ )111.6 (c 1.20, CHCl3).

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Y.-W. Zhong et al. / Tetrahedron: Asymmetry 15 (2004) 771–776
4.9. (1R,2R,5R,6R,10S,100S)-2,6-Bis(1-phenylethyl-amino-
methyl)-bicyclo[3.3.0]octan-2,6-diol, 4a
7. Chinchilla, R.; Najera, C.; Sanchez-Agullo, P. Tetrahe-
dron: Asymmetry 1994, 5, 1393.
8. (a) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122,
12003; (b) Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am.
Chem. Soc. 2001, 123, 3367; (c) Trost, B. M.; Silcoff, E. R.
Org. Lett. 2001, 3, 2497.
9. Recently, the catalyst has been used in the direct catalytic
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Prepared from 3a and S-())-1-phenylethylamine in a
similar way as described in Section 4.3. Yield: 74%;
½aꢀ ¼ )53.0 (c 1.55, CHCl3).
20
D
4.10. Typical procedure for the asymmetric addition of
nitromethane to aldehydes
Under an argon atmosphere, diethylzinc (91 lL of 1.1 M
solution in toluene, 0.10 mmol) was added to 4a (21 mg,
ꢀ
0.05 mmol) and pre-dried 4 A MS (100 mg) in anhydrous
THF (4 mL) at 0 °C. The mixture was stirred for 30 min,
and then cooled to )25 °C. After the addition of the
corresponding aldehyde (1.0 mmol) and nitromethane
(0.32 mL, 6.0 mmol), the suspension was stirred for the
indicated time and quenched by aqueous HCl (4 mL,
1.0 M). Extraction with diethyl ether and purification by
flash column chromatography afforded the desired
product.
Acknowledgements
We are grateful to the financial assistance of the NSFC
(20172063 and 203900506), the Major State Basic
Development Program (6200077506) and Chinese
Academy of Sciences.
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20
D
S configuration, see Ref. 10.
19. ½aꢀ ¼ +15.87 (c 5.01, CHCl3) for 10 with 86% ee in
20. The same additives have been used in TrostÕs work, see
Ref. 10.
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