Chiral ligand 2-(2′-piperidinyl)pyridine: synthesis, resolution and application in asymmetric diethylzinc addition to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2008.06.005

Chiral ligand 2-(2′-piperidinyl)pyridine 1 has been synthesized in good overall yield by sequential benzylation, hydrogenation and debenzylation of 2,2′-bipyridine. Its enantiomerically pure enantiomers have been obtained by resolution of 2-(1-benzyl-2-piperidinyl)pyridine 2 with d-tartaric acid (or l-tartaric acid) followed by debenzylation. The absolute configuration was determined by X-ray analysis of the (S)-2 d-tartrate. It was demonstrated that 1 can be used as an effective enantioselective catalyst in the addition of diethylzinc to aldehydes. Optically active secondary alcohols with up to 100% enantiomeric excess were obtained in high yields.

Full text of DOI:10.1016/j.tetasy.2008.06.005

Tetrahedron: Asymmetry 19 (2008) 1572–1575
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral ligand 2-(20-piperidinyl)pyridine: synthesis, resolution and application
in asymmetric diethylzinc addition to aldehydes
*
Yan-Qin Cheng, Zheng Bian, Chuan-Qing Kang, Hai-Quan Guo, Lian-Xun Gao
The State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences,
Graduate School of Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, PR China
a r t i c l e i n f o
a b s t r a c t
Chiral ligand 2-(20-piperidinyl)pyridine 1 has been synthesized in good overall yield by sequential ben-
Article history:
zylation, hydrogenation and debenzylation of 2,20-bipyridine. Its enantiomerically pure enantiomers have
Received 28 April 2008
Accepted 4 June 2008
Available online 17 July 2008
been obtained by resolution of 2-(1-benzyl-2-piperidinyl)pyridine 2 with
acid) followed by debenzylation. The absolute configuration was determined by X-ray analysis of the
(S)-2 -tartrate. It was demonstrated that 1 can be used as an effective enantioselective catalyst in the
D-tartaric acid (or L-tartaric
D
addition of diethylzinc to aldehydes. Optically active secondary alcohols with up to 100% enantiomeric
excess were obtained in high yields.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
of 2-(1-benzyl-2-piperidinyl)pyridine 2 was successfully resolved.
The absolute configurations were determined. The effectiveness
of the ligand in the asymmetric synthesis was primarily evaluated
by the addition reaction of diethylzinc to aldehydes.
N,N-Bidentate ligands, such as diamine derivatives,1 1-substi-
tuted-1-(pyridyl)methylamines(py-amines)2 and 2,20-bipyridines3
are under investigation in the field of coordination chemistry. Fur-
thermore, chiral N,N-ligands have attracted attention due to their
applications in metal complexes as asymmetric catalysts. For
example, py-amines have displayed medium to excellent enantio-
selectivities in transfer hydrogenations, palladium-catalyzed allylic
alkylations and additions of diethylzinc to aldehydes.2 However, it
is noteworthy that the chiral ligand 2-(20-piperidinyl)pyridine 1, an
analogue of the tobacco alkaloid anabasine, has so far hardly drawn
any attention. The racemate of 1 has only been prepared in very
low yield according to the literature.4 Recently, Gillespie et al.
demonstrated that the (S)-enantiomer of 1 could be used as the
fragment of inhibitors of 11B-hydroxysteroid dehydrogenase,
but no details about the preparation of the enantiomer were
reported.5
2. Results and discussion
2.1. Synthesis of racemic 1
Compound 1 can be obtained from 3 via two reported ap-
proaches. One involves the reduction of 3 by tin in hydrochloric
acid or with nickel-aluminum alloy, but the mixtures produced
were difficult to purify and the yields were no higher than 10%.4
Another approach was the oxidation of 3 followed by hydrogena-
tion with Pd/C.7 However, the yield of the target product based
on the second method is still too low in our laboratory. According
to the strategy for the synthesis of isoanabasine in our previous
work,6 we proposed another effective approach to prepare 1 in
three steps, as outlined in Scheme 1. Each step can be easily carried
out with the overall yield being 68%, much higher than the yield
reported previously. Pure benzyl salt 4 was obtained in 90% yield
by stirring 3 with benzyl bromide in boiling acetonitrile under a
dry nitrogen atmosphere for 3 days and then recrystallization of
the product from ethylacetate/acetonitrile. Benzylation of 3 was
more difficult than that of 2,30-bipyridine for steric reasons. Hence,
benzyl bromide was used as the nucleophilic acceptor instead of
benzyl chloride which was more time-consuming.8 Compound 2
was obtained in 85% yield by hydrogenation of 4 with PtO2 as a cat-
alyst in the presence of triethylamine. Removal of the benzyl group
of 2 with palladium catalyst9 gave 1 in 89% yield.
Herein, we have synthesized chiral ligand 1 in good yield by
reduction of mono-benzyl salt of 2,20-bipyridine according to a
similar procedure described in our previous work.6 The racemate
*
N
N
R
1 R = H
2
R = Bn
* Corresponding author. Tel.: +86 431 8526 2259; fax: +86 431 8568 5653.
E-mail address: lxgao@ciac.jl.cn (L.-X. Gao).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.06.005

Y.-Q. Cheng et al. / Tetrahedron: Asymmetry 19 (2008) 1572–1575
1573
PhCH2Br, CH3CN
Br
reflux, 3 d
90%
N
N
N
N
Bn
N
N
3
4
PtO2, H2, 50atm
Et3N, MeOH, 10 hr
85%
N
Bn
2
Pd(OH)2/C, H2, 1atm
EtOH, 2 d
89%
HN
1
Scheme 1. Synthetic route to ligand 1.
Figure 1. X-ray structure of
D
-tartaric acid and (S)-2 complex (hydrogens, except on
heteroatoms or stereogenic centers, omitted for clarity).
2.2. Resolution of the racemate and assignment of the absolute
configuration
2.3. Enantioselective diethylzinc addition to aldehydes
Resolution via diastereomeric salt formation is still an impor-
tant technique for the preparation of enantiopure compounds.10
Many optically active py-amines, such as nicotine,11 nornicotine,12
and 1-(pyridin-2-yl)ethylamine13 have been obtained by the reso-
lution of their racemates.
Five chiral organic acids, (+)-tartaric acid, dibenzoyl-(+)-tartaric
acid, (R)-1,10-bi-2-naphthol, (+)-camphoric acid and (+)-mandelic
acid were examined by complexation with rac-2 to find a suitable
resolving agent. Among these agents, (R)-1,10-bi-2-naphthol, (+)-
camphoric acid and (+)-mandelic acid produced salts that failed
to crystallize while dibenzoyl-(+)-tartaric acid gave crystalline
salts from water/ethanol or water/methanol without enantiomeric
It is well known that the enantioselective addition of diethyl-
zinc to aldehydes is one of the most reliable methods to prepare
chiral secondary alcohols, and it has been proven that many chiral
amines can be used as effective catalysts for this reaction.17 The
addition of diethylzinc to benzaldehyde was first examined in
the presence of catalytic amounts (5 mol %) of 1–2 in hexane/ethyl
ether. As shown in Table 1, a high yield and high ee were achieved
by using (R)-1, while (R)-2 afforded 1-phenylpropanol with satis-
factory yield but low enantioselectivity.
Table 1
enrichment. Fortunately, precipitation of rac-2 with 0.5 equiv of
tartaric acid from acetonitrile/tetrahydrofuran (5:1 in volume)
gave a 1:1 (S)-2
-tartrate, as shown by 1H NMR14 and X-ray anal-
D-
Enantioselective addition of diethylzinc to benzaldehydea
OH
*
O
D
ysis. Treatment of the salt with alkaline afforded an enantiomer in
93% ee,15 from which an enantiomerically pure (S)-2 was obtained
by recrystallization from ethanol/water in 65% yield based on half
5 mol% Catalyst
H
+
Et2Zn
hexane/ether
0 oC-rt
of the starting rac-2, with ½a D20
¼ ꢁ60:5 (c 0.55, ethanol). The
ꢀ
Entry
Ligand
Yieldb (%)
eec (%)
Configurationd
mother liquor enriched in (R)-2 was converted to the free base
1
2
(R)-1
(R)-2
91
96
93
12
(R)
(R)
and treated with
(Scheme 2).
L-tartaric acid to generate (R)-2 with 100% ee
a
Debenzylation of both enantiomers of 2 produced the corre-
Reaction was carried out in hexane/ether at 0 °C–rt with a molar ratio of Et2Zn/
sponding pure enantiomers of 1, with ½a D20
¼ þ47:0 (c 0.62, etha-
ꢀ
benzaldehyde/ligand = 2/1/0.05.
b
Isolated yield.
nol) in the same rotary direction to their benzyl precursors. It is
reasonable to assume that no racemization occurred during
debenzylation.9
c
The ee values were determined by HPLC with a Chiralcel-OD column.
Configurations were assigned by comparison with the sign of the specific
d
rotation of known compounds.
To determine the absolute configuration, the complex of D-tar-
taric acid and (S)-2 was crystallized and investigated by X-ray crys-
The high enantioselectivity of ligand (R)-1 for the addition of
diethylzinc to benzaldehyde prompted us to examine its use for
the reaction of various aldehydes. These results are summarized
tallography (Fig. 1).16 The structure definitively indicates that the
D
-tartaric acid has crystallized with 1.0 equiv of (S)-2.
D-tartaric acid
base
(S)-1
(R)-1
(RS)-2
(S)-2
(R)-2
(S)-2 D-tartrate
(R)-2 L-tartrate
recrystallization
filtration
1) base
base
2) L-tartaric acid
filtrate
filtration
recrystallization
Scheme 2. Resolution of racemic 2.

1574
Y.-Q. Cheng et al. / Tetrahedron: Asymmetry 19 (2008) 1572–1575
in Table 2. Aromatic aldehydes underwent the reaction smoothly
to afford the desired ethyl carbinols with high yields (87–93%)
and excellent enantioselectivities (91–100% ee). With heteroaro-
matic and aliphatic aldehydes (entries 8–10) good yields and good
enantioselectivities were obtained as well. However, low enanti-
oselectivity (40% ee) was observed when trans-cinnamaldehyde
was used as the substrate. In all the cases examined, the absolute
configurations of corresponding ethyl carbinols were (R).
3. Conclusions
In conclusion, the preparation of enantiomerically pure 2-(20-
piperidinyl)pyridine 1 has been described. Its evaluation as a chiral
ligand in the asymmetric addition of diethylzinc to a variety of
aldehydes was demonstrated, showing satisfactory results of up
to 100% ee. Future efforts will be directed toward modifying the
steric and electronic characteristics of the ligand and investigating
applications in new asymmetric catalytic strategies.
Table 2
Enantioselective addition of diethylzinc to various aldehydes with (R)-1a
4. Experimental
4.1. General
OH
*
O
5 mol% Catalyst 1
+
Et2Zn
R
R
H
hexane/ether
0 °C-rt
Yieldb (%)
The 1H and 13C NMR spectra were recorded in deuterium chlo-
roform or DMSO on a Bruker 600 MHz spectrometer with TMS as
internal standard. Melting points were measured with a hot-stage
microscope XT-4. ESI-MS measurements were conducted with an
LCQ instrument. Optical rotations were measured on a Perkin
Elmer 341LC polarimeter in an 1 dm tube. HPLC utilized a Shima-
dzu LC-6AD pump, a Shimadzu SPD-10A UV dectector, and Shima-
dzu Class-VP system controller software. Separations were carried
out on Chiralcel-OD or AD analytical column with hexane/2-propyl
alcohol as eluent. TLC was performed on aluminum TLC-layers
Silica Gel GF-254 and Detected by UV light (254 and 365 nm). Silica
gel (100–200 mesh) was used for column chromatography. All
reactions were carried out under an argon atmosphere unless
otherwise stated. All reagents and solvents employed were reagent
grade materials purified by standard methods and redistilled be-
fore use. All the aldehydes employed were obtained by purification
of commercial products.
Entry
R
eec (%)
Configurationd
1
2
3
4
5
6
7
8
9
p-ClC6H4
91
93
89
92
87
93
93
87
89
90
89
100
91
94
96
91
100
100
85e
88e
85e
40
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
p-CH3OC6H4
o-CH3OC6H4
1-Naphthyl
2-Naphthyl
p-CH3C6H4
p-BrC6H4
2-Furyl
2-Thienyl
Pentyl
trans–PhCH@CH
10
11
a
Reaction was carried out in hexane/ether at 0 °C–rt with a molar ratio of Et2Zn/
benzaldehyde/ligand = 2/1/0.05.
b
Isolated yield.
c
The ee values were determined by HPLC with a Chiralcel-OD or AD column.
Configurations were assigned by comparison with the sign of the specific
d
rotation of known compounds.
e
Determined for the corresponding benzoate.
4.2. Preparation of 10-benzyl-2,20-bipyridinium bromide 4
Inspired by the general catalytic model,2e,f,18 the stereochemis-
try of the products can be interpreted by molecular models derived
from the geometry optimization of transition states (TS) based on
molecular mechanism. Three potential transition states are pre-
sented in Figure 2 when (R)-1 is utilized as a catalyst and benz-
aldehyde as a substrate. As shown in TS I, the diethyl zinc
coordinated on piperidyl nitrogen stands with aldehyde in the
same side of the cyclopentyl plane composed of bidendate N–Zn
complex. For this TS, one ethyl localizes in short contact with car-
bonyl nucleophile acceptor from the Re face of the aldehyde result-
ing in enantioselectivity of the (R)-form in high reaction rate. In TS
II the aldehyde coordinates in another direction resulting in (S)-
form enantioselectivity. In this case, a steric barrier between the
hydrogen of the aldehyde and pyridyl ring and large distance be-
tween the ethyl and carbonyl may disfavor the reaction. Obviously
the reaction is forbidden for diethylzinc and aldehyde in anti-con-
formation in TS III. Hence, (R)-form products are predominantly
obtained over the (S)-form product in the addition of diethylzinc
to aldehyde catalyzed by (R)-1 through TS I catalysis model.
A stirred solution of 2,20-bipyridine 3 (15.60 g, 0.10 mol) and
benzyl bromide (35.9 mL, 0.30 mol) in dry acetonitrile (300 mL)
under a nitrogen atmosphere was heated at reflux for 3 days. The
solution was concentrated in vacuum and a precipitate was formed
after ethyl acetate was added. The mixture was filtered and recrys-
tallization of the precipitate from CH3CN/AcOEt gave 29.4 g of 10-
benzyl-2,20-bipyridinium bromide 4 as buff granules (90% yield).
Mp 140–142 °C. 1H NMR (600 MHz, DMSO-d6): d 6.09 (s, 1H),
6.93 (d, J = 6.49 Hz, 1H), 7.24 (m, 1H), 7.67 (dd, J = 7.64, 4.86 Hz,
1H), 7.72 (d, J = 7.84 Hz, 1H), 8.04 (dt, J = 7.80, 7.79, 1.62 Hz, 1H),
8.32 (dd, J = 15.40, 7.24 Hz, 1H), 8.82 (m, 1H), 9.42 (d, J = 5.80 Hz,
1H). 13C NMR (150 MHz): d 151.83, 149.76, 149.66, 147.42,
146.93, 138.19, 133.74, 130.67, 128.68, 128.63, 128.12, 127.67,
126.11, 125.83, 60.90. ESI-MS (m/z): [MꢁBr]+ 247.0.
4.3. Preparation of racemic 2-(1-benzyl-2 piperidinyl)-
pyridine 2
A suspension of 4 (12 g, 0.037 mol), triethylamine (5.1 mL,
0.037 mol), and PtO2 (0.6 g) in methanol (100 mL) was stirred in
an autoclave under a hydrogen atmosphere at 50 atm for 10 h at
40 °C. Upon deflation of the hydrogen, the insoluble species were
removed by filtration through Celite. After evaporation of the
methanol, the residues were dissolved in dichloromethane
(100 mL) and dried over Na2SO4. The solvent was removed by
evaporation to give the crude product which was recrystallized
from EtOH/H2O to give 7.9 g of pure 2-(1-benzyl-2-piperidi-
nyl)pyridine 2 as white needles (85% yield). Mp 65–68 °C. 1H
NMR (600 MHz, CDCl3) d 1.40 (m, 1H), 1.81 (d, J = 12.89 Hz, 1H),
1.89 (d, J = 13.06 Hz, 1H), 2.02 (s, 1H), 3.01 (m, 1H), 3.40 (d,
J = 10.06 Hz, 1H), 3.68 (dd, J = 13.55, 5.73 Hz, 1H), 7.15 (m, 1H),
Figure 2. Transition states of addition of diethylzinc to aldehyde (H omitted for
clarity).

Y.-Q. Cheng et al. / Tetrahedron: Asymmetry 19 (2008) 1572–1575
1575
7.21 (dd, J = 8.45, 4.34 Hz, 1H), 7.28 (d, J = 4.41 Hz, 1H), 7.63 (d,
J = 7.41 Hz, 1H), 7.68 (t, J = 7.56, 7.56 Hz, 1H), 8.54 (d, J = 4.61 Hz,
1H). 13C NMR (150 MHz):
164.85, 148.80, 139.07, 136.51,
References
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X.; Schenkel, L. B.; Kozlowski, M. C. Org. Lett. 2000, 2, 875–878; (c) Hoppe, D.;
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Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552–
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d
128.55, 127.90, 126.50, 121.76, 121.33, 77.32, 77.00, 76.68, 70.37,
59.91, 52.88, 35.21, 25.66, 24.62. ESI-MS (m/z): [M+H]+ 253.1.
2. (a) Baratta, W.; Chelucci, G.; Herdtweck, E.; Magnolia, S.; Rigo, P. Angew. Chem.,
Int. Ed. 2007, 46, 7651–7654; (b) Chelucci, G. Tetrahedron: Asymmetry 2005, 16,
2353–2383; (c) Fiore, K.; Martelli, G.; Monari, M.; Savoia, D. Tetrahedron:
Asymmetry 1999, 10, 4803–4810; (d) Chelucci, G.; Caria, V.; Saba, A. J. Mol. Catal.
A: Chem. 1998, 130, 51–55; (e) Conti, S.; Falorni, M.; Giacomelli, G.; Soccolini, F.
Tetrahedron 1992, 48, 8993–9000; (f) Chelucci, G.; Conti, S.; Falorni, M.;
Giacomelli, G. Tetrahedron 1991, 47, 8251–8258; (g) Chelucci, G.; Falorni, M.;
Giacomelli, G. Synthesis 1990, 1121–1122.
3. (a) Uenishi, J.; Hamada, M.; Aburatani, S.; Matsui, K. J. Org. Chem. 2004, 69,
6781–6789; (b) Mamula, O.; von Zelewsky, A. Coordin. Chem. Rev. 2003, 242,
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Malkov, A. V.; Baxandale, I. R.; Bella, M.; Langer, V.; Fawcett, J.; Russell, D. R.;
Mansfield, D. J.; Valko, M.; Kocovsky, P. Organometallics 2001, 20, 673–690; (e)
Hesek, D.; Inoue, Y.; Everitt, S.; Ishida, H.; Kunieda, M.; Drew, M. Inorg. Chem.
2000, 39, 308–316.
4.4. Preparation of racemic 2-(20-piperidinyl)pyridine 1
A suspension of 2 (2.5 g, 0.01 mol) and 20% Pd(OH)2 on carbon
(0.2 g) in ethanol (30 mL) was stirred under a hydrogen atmo-
sphere of 3–4 atm at room temperature for 2 days. The catalyst
was filtered off, washed with ethanol. After evaporation of the eth-
anol, the residues were dissolved in dichloromethane (100 mL) and
dried over Na2SO4. The solvent was removed by evaporation to
give the crude product, which was purified by chromatography
on silica using a solvent mixture (AcOEt/MeOH/Et3N) into 1.42 g
of 1 as a pale yellow oil (89% yield). Bp 115 °C/0.3 torr. 1H NMR
(600 MHz, CDCl3): d 1.52 (m, 1H), 1.66 (m, 1H), 1.94 (m, 1H),
2.13 (s br, 1H), 2.82 (td, J = 11.75, 2.85 Hz, 1H), 3.22 (m, 1H), 3.75
(m, 1H), 7.14 (m, 1H), 7.34 (d, J = 7.87 Hz, 1H), 7.64 (dt, J = 7.70,
7.69, 1.72 Hz, 1H), 8.53 (d, J = 4.20 Hz, 1H). 13C NMR (150 MHz):
d 163.47, 148.99, 136.59, 121.96, 120.53, 62.47, 47.18, 33.13,
26.09, 25.04. ESI-MS (m/z): [M+H]+ 163.1.
4. (a) Bokorny, S.; Connor, J. A.; Kaspar, H. J. Organomet. Chem. 1994, 471, 157–
160; (b) Lunn, G. J. Org. Chem. 1992, 57, 6317–6320; (c) Beck, M. T.; Halmos, M.
Nature 1961, 191, 1090–1091; (d) Smith, C. R. J. Am. Chem. Soc. 1931, 53, 277–
283.
5. Gillespie, P.; Goodnow, R. A.; Kowalczyk, A.; Le, K.; Zhang, Q. US Patent Appl.
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A.; Bloom, L. B.; Kem, W. R. J. Org. Chem. 1992, 57, 2392–2395.
9. (a) Bernotas, R. C.; Cube, R. V. Synth. Commun. 1990, 20, 1209–1212; (b) Hattori,
K.; Yamamoto, H. J. Org. Chem. 1992, 57, 3264–3265.
10. (a) Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates, and Resolutions;
Wiley-InterScience, 1981; (b) Kozma, D. Optical Resolutions via Diastereomeric
Salt Formation; CRC Press, 2002; (c) Nohira, H.; Sakai, K. Optical Resolution by
Means of Crystallization. In Enantiomer Separation, Fundamental and Practical
Method, January; Toda, F., Ed.; Kluwer Academic: Netherlands, 2005; pp 165–
191.
4.5. Resolution of rac-2 to enantiomers (R)-(+)-2 and (S)-(ꢁ)-2
To a stirred solution of
D-tartaric acid (4.74 g, 31.6 mmol,
0.5 equiv) in a boiling mixture of tetrahydrofuran (30 mL) and ace-
tonitrile (150 mL) was added rac-2 (16 g, 63.2 mmol). Stirring was
continued for 1 h at 70 °C. The mixture solution was allowed to
stand at room temperature. Precipitates were formed, collected
by filtration, suspended in 15% NaOH (50 mL) and extracted with
dichloromethane (100 mL ꢂ 3). The extract was dried over Na2SO4
and evaporated to give the crude (S)-2, which was recrystallized
from ethanol/water to furnish 5.2 g (S)-2 of the 100% enantiomer
as white needles in 65% yield. All filtrates were combined and
evaporated in vacuum. The residues were dissolved in dichloro-
methane (100 mL) and washed with 15% NaOH (20 mL ꢂ 2) to re-
move the acid. The organic phase enriched with (R)-2 was dried
over Na2SO4 and evaporated to give a solid, which was resolved
11. Aceto, M. D.; Martin, B. R.; Uwaydah, I. A.; May, E. L.; Harris, L. S.; Izazola-
Conde, C.; Dewey, W. L.; Bradshaw, T. J.; Vincek, W. C. J. Med. Chem. 1979, 22,
174–177.
12. Jacob, P., III J. Org. Chem. 1982, 47, 4165–4167.
13. Smith, H. E.; Schaad, L. J.; Bancks, R.; Wiant, C. J. B.; Jordan, C. F. J. Am. Chem. Soc.
1973, 95, 811–818.
14. The integrals of all proton peaks in 1H NMR spectra were matched with the
formula of molecular complex (S)-2 D
-tartrate. 1H NMR (600 MHz, DMSO-d6) d
ppm 1.35 (q, J = 12.81, 12.72, 12.72 Hz, 1H), 1.53 (m, 1H), 1.76 (dd, J = 25.80,
12.78 Hz, 1H), 2.07 (s, 1H), 2.50 (s, 1H), 2.89 (d, J = 11.30 Hz, 1H), 3.02 (d,
J = 13.45 Hz, 1H), 3.44 (d, J = 10.29 Hz, 1H), 3.55 (d, J = 13.55 Hz, 1H), 4.26 (s,
1H), 7.26 (m, 1H), 7.61 (d, J = 7.83 Hz, 1H), 7.81 (t, J = 7.38, 7.38 Hz, 1H), 8.51 (d,
J = 4.13 Hz, 1H).
with L-tartaric acid (4.74 g, 31.6 mmol) in a similar procedure as
described above to furnish 5.7 g (R)-2 of the 100% enantiomer in
71% yield. Mp 82–84 °C. (R)-2: ½a D20
ꢀ
¼ þ60:5 (c 0.55, ethanol),
15. Enantiomeric excess analysis was determined by HPLC with a Chiralcel-OD
column at 254 nm (hexane/iPrOH in the ratio of 97/3, flow 0.5 mL/min; the
retention time of (R)-2 was 17.6 min, while that of (S)-2 was 19.5 min).
100% ee [tR (R) = 17.6 min]. (S)-2: ½a D20
ꢀ ¼ ꢁ60:5 (c 0.55, ethanol),
100% ee [tR (S) = 19.5 min].15
16. Crystal data for (S)-2 D-tartrate: C23H29N3O6, M = 443.49, colourless prism, size
0.28 ꢂ 0.14 ꢂ 0.05 mm3, orthorhombic, space group P212121, a = 8.3905(9),
4.6. (R)-(+)-1 and (S)-(ꢁ)-1
b = 14.2190(14), c = 19.911(2) Å, V = 2375.4(4) Å3, T = 185 K, Z = 4, dcalc
=
1.240 g cmꢁ3
,
l
= 0.090 mmꢁ1
,
F(000) = 944, 12405 reflections in h(ꢁ9/
9),k(ꢁ16/13), l(ꢁ23/23), measured in the range 1.76° 6
H
6 25.05°,
Compound (R)-1 was prepared from (R)-2 and (S)-1 was pre-
pared from (S)-2 in a similar procedure to rac-1 from rac-2. (S)-1:
completeness Hmax = 99.9%, 4176 independent reflections, Rint = 0.0720,
R1obs = 0.0606, wR2obs ¼ 0:0884, R1all = 0.1149, wR2all ¼ 0:1046, GOF = 1.006,
(I), largest difference peak and hole: 0.140/ꢁ0.149 e Åꢁ3. X-ray
½
a 2D0
ꢀ
¼ ꢁ47:0 (c 0.62, ethanol).
with I > 2
r
data were collected with Bruker SMART APEX CCD diffractometer with
graphite-monochromatized MoK
a radiation (k = 0.71073 Å) operated at
4.7. General procedure for the asymmetric addition of
diethylzinc to aromatic aldehydes
2.0 kW (50 kV, 40 mA). The structures were solved by direct methods with
the program SHELXS-97. All non-hydrogen atoms were refined anisotropically.
The details of the crystallographic data have been deposited with
Cambridge Crystallographic Data Centre as supplementary publication NO.
CCDC 682454.
A solution of the ligand (0.05 mmol, 5 mol %) in ether (1 mL)
was cooled at 0 °C. Diethylzinc (15% w/w, 2.3 mL, 2 mmol) in hex-
ane was added over a period of 3 min. The mixture was stirred at
0 °C-rt for 30 min, added with aldehyde (1 mmol) then stirred for
an additional 20 h. The reaction mixture was quenched with 10%
H2SO4 (1.6 mL) then was extracted with ether (5 mL ꢂ 3) and the
organic layer was washed with 10% H2SO4 (3 mL), saturated NaH-
CO3 (3 mL) and dried over Na2SO4. The residue was distilled and
purified by flash chromatography with dichloromethane as eluent.
Enantiomeric excesses for the products were determined by HPLC
analysis using a chiral column (OD or AD column).
17. (a) Yang, X. F.; Wang, Z. H.; Hirose, T. Tetrahedron: Asymmetry 2007, 18, 1257–
1263; (b) Bai, X.; Kang, C.; Liu, X.; Gao, L. Tetrahedron: Asymmetry 2005, 16,
727–731; (c) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008–2022; (d) Asami,
M.; Watanabe, H.; Honda, K.; Inoue, S. Tetrahedron: Asymmetry 1998, 9, 4165–
4173; (e) Asami, M.; Inoue, S. Bull. Chem. Soc. Jpn. 1997, 70, 1687–
1690.
18. (a) Braga, A. L.; Milani, P.; Paixao, M. W.; Zeni, G.; Rodrigues, O. E. D.; Alves, E. F.
Chem. Commun. 2004, 2488–2489; (b) Paleo, M. R.; Cabeza, I.; Sardina, F. J. J.
Org. Chem. 2000, 65, 2108–2113; (c) Kitamura, M.; Oka, H.; Noyori, R.
Tetrahedron 1999, 55, 3605–3614; (d) Kitamura, M.; Suga, S.; Oka, H.; Noyori,
R. J. Am. Chem. Soc. 1998, 120, 9800–9809.