Direct asymmetric three-component Mannich reactions catalyzed by a siloxy serine organocatalyst in water

Article abstract of DOI:10.1016/j.tetasy.2007.12.011

A siloxy-l-serine organocatalyst has been developed to catalyze the asymmetric three-component Mannich reactions in the presence of water via a biphasic system, furnishing the Mannich products in good yields and high enantioselectivities.

Full text of DOI:10.1016/j.tetasy.2007.12.011

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 186–190
Direct asymmetric three-component Mannich reactions
catalyzed by a siloxy serine organocatalyst in water
Yong-Chua Teo,* Jun-Jie Lau and Man-Chao Wu
Natural Sciences and Science Education, National Institute of Education, Nanyang Technological University,
Singapore 637616, Singapore
Received 18 October 2007; accepted 10 December 2007
Available online 24 January 2008
Abstract—A siloxy-L-serine organocatalyst has been developed to catalyze the asymmetric three-component Mannich reactions in the
presence of water via a biphasic system, furnishing the Mannich products in good yields and high enantioselectivities.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
environmental concerns, safety and cost.5 Thus, the develo-
pment of organocatalysts that can catalyze asymmetric
Mannich reactions in water is currently a challenge in con-
temporary asymmetric synthesis.
The direct asymmetric Mannich reaction is a highly effec-
tive carbon–carbon bond forming reaction used for the
construction of enantiomerically enriched nitrogenous
molecules including amino acids, amino alcohols and their
derivatives. The development of asymmetric Mannich
reaction has been stimulated by a wide variety of natural
products and drugs possessing optically active, nitrogen-
containing molecules, which have attracted attention from
synthetic chemists and the pharmaceutical industry.1
Herein, we report an efficient and highly enantioselective
three-component Mannich reaction catalyzed by an acyclic
silyl-protected serine derived organocatalyst in the presence
of water, via a two-phase system.
2. Results and discussion
Organocatalysis has recently experienced a renaissance in
asymmetric synthesis and emerged as a powerful synthetic
methodology.2 The development of small organic mole-
cules, which avoid the use of expensive and/or toxic metals
as useful catalysts in enantioselective reactions, is attracting
much interest. List et al. reported the first direct asymmet-
ric three-component Mannich reaction among an aldehyde,
4-methoxyaniline (p-anisidine) and a ketone catalyzed by
proline.3 The application of an organocatalytic strategy
to the asymmetric Mannich reactions was further broaden
by excellent work from the research groups of Barbas, Cor-
dova, Jacobsen and Lu.4 Some of these methods involve a
catalytic indirect asymmetric Mannich reaction, while oth-
ers involve direct methods. In addition to these aspects, a
very recent development has been the use of water as a sol-
vent for organocatalytic asymmetric reactions. Indeed,
water is a desirable solvent for catalysis with respect to
Recently, we have reported an efficient protocol for the
asymmetric direct aldol reaction in the presence of water
catalyzed by a siloxy serine organocatalyst.6 This method
has proven to be practical and environmentally friendly
since it precluded the use of organic solvents and toxic
metals. The siloxy serine catalyzed asymmetric direct aldol
reaction proceeded via a biphasic system, furnishing a wide
variety of b-hydroxy carbonyl scaffolds in good yields and
excellent enantioselectivities. Based on this precedent, we
envision that a Mannich reaction can also be performed
as a three-component reaction utilizing an aldehyde, a ke-
tone and a primary amine since nucleophilic addition of the
in situ generated siloxy serine enanamine would be faster to
an imine than to an aldehyde.3
In an initial study, we examined the three-component Man-
nich reaction among cyclohexanone, 4-nitrobenzaldehyde
and p-anisidine catalyzed by a TBDPS-L-serine organocat-
alyst in the presence of water (Table 1, entries 1–3). The
*
Corresponding author. Tel.: +65 6790 3846; fax: +65 6896 9414; e-mail:
yongchua.teo@nie.edu.sg
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.12.011

Y.-C. Teo et al. / Tetrahedron: Asymmetry 19 (2008) 186–190
187
Table 1. Optimization studies on the siloxy-L-serine catalyzed direct asymmetric Mannich reactiona
OMe
NH2
COOH
NH2
O
CHO
O
HN
TBDPSO
2
+
1'
+
+ anti- isomer
NO2
water, RT
OMe
NO2
1a
2a
3a
Entry
Cat. loading (mol %)
H2O (lL)
Yieldb (%)
syn:antic
eed (%)
1
2
3
4
5
6
7
8
20
20
20
20
20
10
5
65
100
150
—
82
86
85
81
82
86
86
83
81:19
82:18
82:18
78:22
75:25
84:16
84:16
84:16
78
80
82
40e
42e
80
65
100
100
100
82
80f
10
a Unless otherwise shown, the reaction was performed with aldehyde (0.5 mmol), ketone (1.5 mmol), p-anisidine (0.45 mmol) and catalyst in water at room
temperature for 18 h.
b Combined yield of isolated diastereomers.
c Diastereoselectivity was determined by 1H NMR analysis of the reaction mixture.
d Enantiomeric excess refers to the syn isomer and was determined by HPLC analysis on a chiral phase.
e 2.0 mL DMSO was used in the reaction.
f 2.5 mmol of ketone was used in the reaction.
optimum water concentration was achieved at 56 equiv rel-
ative to the catalyst, affording the product in good yield
and high enantioselectivity (entry 2). The addition of excess
water to the reaction mixture (84 equiv) does not have any
significant effects on both the diastereo- and the enantio-
selectivities of the Mannich product (entry 3). Moreover,
the reaction carried out in the absence of water or a
mixture of water and DMSO leads to significantly lower
diastereo- and enantioselectivities (entries 4 and 5). The
optimized conditions were achieved using 5 mol % catalyst
loading whereupon the product was isolated in a good yield
of 86% and enantiomeric excess of 82% (entry 7).
hydroxyacetone 1b under these conditions to afford the
1,2-protected aminoalcohols. In all the cases, the reaction
proceeded regioselectively with the carbon–carbon bond
formation occurring at the methylene carbon. Interestingly,
the reactions afforded anti selectivity and the correspond-
ing 1,2-protected aminoalcohols were obtained in good
enantioselectivities and yields (entries 5–8).
The stereochemistry of the Mannich products derived by
the acylic siloxy-L-serine catalysis was determined by chi-
ral-phase HPLC analysis and by comparison with the liter-
ature.4 Although the actual mechanism of the Mannich
reaction has yet to be elucidated at the moment, the stereo-
chemical course catalyzed by the siloxy-L-serine using
cyclohexanone as the cyclic donor can be envisaged in
terms of a plausible six-membered chair-like transition
state4f 4 whereby the catalytically generated enamine
favored a si-facial attack on the imine (Fig. 1).
In addition, the employment of a large excess of ketone in
the reaction also afforded the product in good yield, albeit
with a slight decrease in both diastereo- and enantioselec-
tivities (entry 8).
The optimized conditions were extended to a series of alde-
hyde acceptors and ketone donors to explore the generality
of this catalytic system and the results are summarized in
Table 2. In most cases, the Mannich products were ob-
tained in good yields and high enantioselectivities with only
trace amounts of aldol addition side products.
3. Conclusions
In summary, the one-pot direct Mannich reaction has been
realized with high enantioselectivities in the presence of
water by the catalytic use of a siloxy serine organocatalyst.
Noteworthy features in this system include (1) the direct
Mannich reaction proceeded in the presence of water via
a two-phase system and with simple procedures; (2) good
enantioselectivities were attained with aromatic aldehydes
for both cyclohexanone and O-benzyl hydroxyacetone as
ketone donors; (3) the siloxy serine catalyst can be easily
prepared economically from commercially sources, with
both enantiomers readily available.
In the case of cyclohexanone 1a as the cyclic ketone donor,
the reactive aldehydes underwent the catalytic process to
afford the products with syn selectivity with both good
yields and enantioselectivities (Table 2, entries 1–3). More-
over, the reaction employing ethyl glyoxylate as the alde-
hyde acceptor also afforded the corresponding syn amino
acid derivative in 75% yield and 86% ee (entry 4). To
broaden the scope of this transformation, a number of aro-
matic aldehydes were reacted with the acyclic O-benzyl

188
Y.-C. Teo et al. / Tetrahedron: Asymmetry 19 (2008) 186–190
Table 2. The catalytic direct asymmetric Mannich reactiona catalyzed by siloxy-L-serine organocatalyst
5-10 mol%
NH2
NH2
TBDPSO
O
COOH
Ketone
+
syn- isomer
+
+
anti- isomer
R1
H
water, RT
3a - 3j
OMe
Entry
1
Ketone
R1
Product
Catalyst (mol %)
5
t (h)
Yieldb (%)
syn:antic
eed (%)
82
1a
3a
PMP
O
O
HN
4-NO2C6H4
18
86
84:16
NO2
PMP
PMP
3b
O
O
O
HN
HN
2
4-BrC6H4
5
20
78
74:26
74
Br
3c
O
O
3
4
5
6
4-CNC6H4
5
10
10
10
22
22
20
21
74
71
81
64
83:17
72:28
14:86
18:82
80
86
90
84
CN
3d
PMP
O
O
HN
CO2Et
CO2Et
PMP
PMP
3e
1b
HN
O
O
4-NO2C6H4
OBn
OBn
NO2
3f
O
HN
4-BrC6H4
OBn
OBn
Br
PMP
PMP
3g
O
O
O
O
HN
7
8
4-CNC6H4
2-Naphthyl
10
10
20
25
79
78
14:86
34:66
92
81
OBn
OBn
OBn
CN
3h
HN
OBn
a Unless otherwise shown, the reaction was performed with aldehyde (0.5 mmol), ketone (1.5 mmol), p-anisidine (0.45 mmol) and catalyst in water
(0.1 mL) at room temperature.
b Combined yield of isolated diastereomers.
c Diastereoselectivity was determined by 1H NMR analysis of the reaction mixture.
d Enantiomeric excess refers to the major isomer and was determined by HPLC analysis on a chiral phase.

Y.-C. Teo et al. / Tetrahedron: Asymmetry 19 (2008) 186–190
189
4.2. General procedure for the synthesis of siloxyserine
catalyst
OMe
4.2.1. Typical procedure for the synthesis of (2S)-2-benzyl-
oxycarbonylamino-3-(tert-butyl-diphenyl-silanyloxy)-propio-
nic acid. To a DMF solution (50 mL) of (2S)-2-benzyl-
oxycarbonylamino-3-hydroxy-propionic acid 2a (5.0 g,
20.9 mmol) were added imidazole (3.8 g, 55.8 mmol,
2.6 equiv) and TBDPSCl (6.0 mL, 23 mmol, 1.1 equiv) at
0 °C. The reaction was stirred for 18 h at room temperature
and quenched by the addition of water and ether. The
aqueous phase was extracted with ether (3 ꢀ 100 mL).
The combined organic extracts were dried with anhydrous
MgSO4 and the solvent removed under reduced pressure.
The crude siloxy ether product was purified by silica gel
column chromatography (hexane/ethyl acetate 2:1) to af-
ford 2b as a white solid (7.3 g, 73%).
TBDPSO
H
N
R2
N
H
R1
O
O
R3
4
Figure 1. Plausible transition state for the siloxyserine catalyzed asym-
metric Mannich reaction.
Further research to elucidate the mechanism of this reac-
tion and broaden the scope of the siloxyserine catalyst to
other asymmetric reactions is currently under investigation.
To a methanol solution (100 mL) of (2S)-2-benzyloxy-
carbonylamino-3-(tert-butyl-diphenyl-silanyloxy)-propionic
acid 2b (7.3 g, 15.3 mmol) was added Pd/C (4.89 g,
10 wt %, 4.6 mmol, 0.3 equiv) at room temperature. The
reaction mixture was stirred for 6 h at that temperature
under a hydrogen atmosphere in a closed system. The
filtration of the inorganic materials through Celite and
removal of methanol under reduced pressure afforded the
crude product. Purification by silica gel chromatography
(dichloromethane/methanol 9:1) afforded catalyst 2 as a
4. Experimental
4.1. General methods
Chemicals and solvents were either purchased from com-
mercial suppliers or purified by standard techniques. Ana-
lytical thin layer chromatography (TLC) was performed
using Merck 60 F254 precoated silica gel plate (0.2 mm
thickness). Subsequent to elution, plates were visualized
using UV radiation (254 nm) on Spectroline Model ENF-
24061/F 254 nm. Flash chromatography was performed
using Merck silica gel 60 with AR grade solvents. Proton
nuclear magnetic resonance spectra (1H NMR) were re-
corded on a Bruker Avance DPX 400 spectrophotometer
1
white solid (4.1 g, 79%). H NMR (300 MHz, DMSO-d6):
d (ppm) 0.98 (s, 9H), 3.35 (dd, J = 7.6, 3.2 Hz, 1H), 3.82
(dd, J = 10.8, 7.6 Hz, 1H), 3.92 (dd, J = 10.4, 3.2 Hz,
1H), 7.40–7.47 (m, 6H), 7.65–7.68 (m, 4H); 13C NMR
(100 MHz, DMSO-d6): d (ppm) 19.3, 27.1, 56.7, 64.4,
128.2, 128.3, 130.2, 130.3, 133.1, 133.3, 135.7, 135.8,
23
168.3 ½aꢁD ¼ þ2:6 (c 1.94, MeOH).
1
(CDCl3 as solvent). Chemical shifts for H NMR spectra
are reported as d in units of parts per million (ppm) down-
field from SiMe4 (d 0.0) and relative to the signal of chlo-
roform-d (d 7.2600, singlet). Carbon nuclear magnetic
resonance spectra (13C NMR) are reported as d in units
of parts per million (ppm) downfield from SiMe4 (d 0.0)
and relative to the signal of chloroform-d (d 77.03, triplet).
Infrared spectra were recorded on a Bio-Rad FTS 165
FTIR spectrometer. HPLC was carried out using a AGI-
LENT 110 series LC—G1311A QUAT pump, G1315B
DAD detector and integrator. All Mannich reactions were
carried out under an atmosphere of air in a closed system.
4.3. General procedure for the asymmetric direct Mannich
reaction
4.3.1. Representative procedure for asymmetric direct Man-
nich reaction: Preparation of (2S,10S)-2-[(4-methoxy-phenyl-
amino)-(4-nitro-phenyl)-methyl]-cyclohexanone
3a.
A
catalytic amount of siloxyserine (7.75 mg, 0.0225 mmol,
0.05 equiv) was added to a vial containing 4-nitrobenzalde-
hyde (0.0760 g, 0.5 mmol, 1.1 equiv), p-anisidine (0.055 g,
0.45 mmol, 1.0 equiv), cyclohexanone (0.16 mL, 1.5 mmol,
3.3 equiv) and water (0.1 mL, 5.55 mmol, 12.3 equiv) under
air in a closed system. The reaction mixture was stirred at
room temperature for 18 h and subsequently poured into
an extraction funnel that contained brine (5 mL) and water
(5 mL). The reaction vial was also washed with 10 mL of
ethyl acetate. The aqueous phase was extracted with ethyl
acetate (3 ꢀ 15 mL). The combined organic extracts were
dried with anhydrous MgSO4 and the solvent removed
under reduced pressure. The crude Mannich product was
purified by silica gel column chromatography (hexane/ethyl
acetate 4:1) to afford 3a as a brown oil (0.1370 g, 86%
yield).
Organic substrates cyclohexanone, hydroxyacetone, 4-
nitrobenzaldehyde, 4-cyanobenzaldehyde, 4-bromobenz-
aldehyde, 2-naphthaldehyde, tert-butyldiphenyl chlorosi-
lane and Z-Ser-OH were all commercially available and
were used without any purification.
The Mannich adducts 3a–3h are all known compounds
that exhibited spectroscopic data identical to those re-
ported in the literature.4 The diastereomeric anti–syn ratio
1
was determined by H NMR analysis of the reaction mix-
ture and comparison to the known literature. The absolute
configuration of the Mannich products was extrapolated
by comparison of the HPLC data with those of 3a–3h
whose absolute configuration is known.
4.3.2. Representative data of 3a
4.3.2.1. (2S,10S)-2-[(4-Methoxy-phenylamino)-(4-nitro-
phenyl)-methyl]-cyclohexanone 3a. Brown oil (137 mg,

190
Y.-C. Teo et al. / Tetrahedron: Asymmetry 19 (2008) 186–190
86%); 1H NMR (400 MHz, CDCl3): d (ppm) 1.60–2.15 (m,
4H), 2.03–2.06 (m, 2H), 2.30–2.46 (m, 2H), 2.79–2.84 (m,
1H), 3.67 (s, 3H), 4.34 (br s, 1H), 4.79 (d, J = 4.1 Hz,
1H), 6.46 (d, J = 8.7 Hz, 2H), 6.66 (d, J = 8.7 Hz, 2H),
7.54 (d, J = 8.7 Hz, 2H), 8.212 (d, J = 8.7 Hz, 2H) ppm;
13C NMR (100 MHz, CDCl3): d 24.8, 27.0, 28.9, 42.6,
55.5, 56.3, 57.9, 114.7, 115.5, 123.6, 128.5, 140.7, 147.0,
149.8, 152.6, 210.6 ppm.
was determined by HPLC with a Chiralcel OD-H (hex-
ane/i-PrOH = 90/10, 0.5 mL/min, k = 254 nm, 20 °C):
tR = 33.9 min (major) and 40.6 min (minor).
1H NMR (400 MHz, CDCl3): d (ppm) 1.60–2.15 (m, 4H),
2.03–2.06 (m, 2H), 2.30–2.46 (m, 2H), 2.79–2.84 (m, 1H),
3.67 (s, 3H), 4.34 (br s, 1H), 4.79 (d, J = 4.1 Hz, 1H),
6.46 (d, J = 8.7 Hz, 2H), 6.66 (d, J = 8.7 Hz, 2H), 7.54
(d, J = 8.7 Hz, 2H), 8.212 (d, J = 8.7 Hz, 2H) ppm; 13C
NMR (100 MHz, CDCl3): d 24.8, 27.0, 28.9, 42.6, 55.5,
56.3, 57.9, 114.7, 115.5, 123.6, 128.5, 140.7, 147.0, 149.8,
152.6, 210.6 ppm. The diastereomeric anti–syn ratio was
1
The diastereomeric anti–syn ratio was determined by H
NMR analysis of the reaction mixture: d (ppm) 4.79 (d,
1H, J = 4.1 Hz, syn, major), d 4.64 (d, 1H, J = 8.2 Hz, anti,
minor).
1
determined by H NMR analysis of the reaction mixture:
d (ppm) 4.79 (d, 1H, J = 4.1 Hz, syn, major), d 4.64 (d,
1H, J = 8.2 Hz, anti, minor). Enantiomeric excess was
determined by HPLC with a Chiralcel AD-H (hexane/
i-PrOH = 85/15, 0.5 mL/min, k = 254 nm, 20 °C): tR =
71.1 min (minor) and 74.7 min (major).
Enantiomeric excess was determined by HPLC with a Chi-
ralcel AD-H (hexane/i-PrOH = 85/15, 0.5 mL/min, k =
254 nm, 20 °C): tR = 71.1 min (minor) and 74.7 min
(major).
The absolute configuration of 3a was extrapolated by com-
parison of the HPLC data of the literature4f whose abso-
lute configuration is known.
Acknowledgement
We would like to thank the National Institute of Educa-
tion, Nanyang Technological University for their generous
financial support.
4.3.3. HPLC data for Mannich products 3b–3h
4.3.3.1. (2R,10S)-2-[(4-Bromo-phenyl)-(4-methoxy-phenyl-
amino)-methyl]-cyclohexanone. Enantiomeric excess was
determined by HPLC with a Chiralcel AS-H (hexane/i-
References
PrOH = 80/20,
tR = 26.9 min (major) and 32.1 min (minor).
0.5 mL/min,
k = 254 nm,
20 °C):
1. (a) Kleinmann, E. F. In Comprehensive Organic Synthesis; Trost,
B. M., Flemming, T., Eds.; Pergamon Press: New York, 1991;
Vol. 2, Chapter 4.1; (b) Arend, M.; Westermann, B.; Risch, N.
Angew. Chem., Int. Ed. 1998, 37, 1044; (c) Denmark, S.; Nicaise,
O. J.-C. In Comprehensive Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol.
2, p 93; (d) Kobayshi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069;
(e) Cordova, A. Acc. Chem. Res. 2004, 37, 102; (f) Tramontini,
M.; Angiolini, L. Tetrahedron 1990, 46, 1791.
4.3.3.2.
(2S,10S)-4-[(4-Methoxy-phenylamino)-(2-oxo-
cyclohexyl)-methyl]-benzonitrile. Enantiomeric excess
was determined by HPLC with a Chiralcel AD-H (hex-
ane/i-PrOH = 95/5, 1.0 mL/min, k = 254 nm, 20 °C):
tR = 80.6 min (minor) and 108.4 min (major).
2. (a) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481; (b)
Alexakis, A.; Bernardinelli, G.; Andrey, O. Org. Lett. 2003, 5,
2559; (c) Duthaler, R. O. Angew. Chem., Int. Ed. 2003, 42, 975;
(d) Northrup, A. B.; Mangion, I. K. F.; Hettche, F.;
MacMillan, D. W. C. Angew. Chem., Int. Ed. 2004, 43, 4138;
(e) Barbas, C. F., III; Chowdari, N. S.; Suri, J. T. Org. Lett.
2004, 6, 2507; (f) Dalko, P. I.; Moisan, L. Angew. Chem., Int.
Ed. 2004, 43, 5138; (g) Berkssel, A.; Groger, H. Asymmetric
Organocatalysis; Wiley-VCH: Weinheim, 2005; (h) Guillena,
G.; Ramon, D. J. Tetrahedron: Asymmetry 2006, 17, 1465.
3. (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336; (b) List, B.;
Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc.
2002, 124, 827.
4.3.3.3. (2S,10S)-(4-Methoxy-phenylamino)-(2-oxo-cyclo-
hexyl)-acetic acid ethyl ester. Enantiomeric excess was
determined by HPLC with a Chiralcel AS-H (hexane/
i-PrOH = 96/4, 0.5 mL/min, k = 254 nm, 20 °C): tR =
42.1 min (major) and 55.1 min (minor).
4.3.3.4. (3R,4R)-3-Benzyloxy-4-(4-methoxy-phenylamino)-
4-(4-nitro-phenyl)-butan-2-one. Enantiomeric excess was
determined by HPLC with a Chiralcel AD-H (hexane/
i-PrOH = 85/15,
tR = 20.9 min (minor) and 25.3 min (major).
1.0 mL/min,
k = 254 nm,
20 °C):
4. (a) Notz, W.; Sakthievel, K.; Bui, T.; Zhong, G.; Barbas, C. F.,
III. Tetrahedron Lett. 2001, 42, 199; (b) Watanabe, S.-I.;
Cordova, A.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2002, 4,
4519; (c) Cordova, A.; Notz, W.; Zhong, G.; Betancort, J. M.;
Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1842; (d)
Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
12964; (e) Cordova, A.; Barbas, C. F., III. Tetrahedron Lett.
2003, 44, 1923; (f) Ismail, I.; Zou, W.; Engqvist, M.; Xu, Y.;
Cordova, A. Chem. Eur. J. 2005, 11, 7024; (g) Cheng, L.; Wu,
X.; Lu, Y. Org. Biol. Chem. 2007, 5, 1018.
5. (a) Organic Synthesis in Water; Grieco, P., Ed.; Blackie:
London, 1998; (b) Lindstrom, U. M. Chem. Rev. 2002, 102,
2751; (c) Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35,
209; (d) Li, C.-J. Chem. Rev. 2005, 105, 3095. See also
references cited therein.
4.3.3.5.
(3R,4R)-3-Benzyloxy-4-(4-bromo-phenyl)-4-
(4-methoxy-phenylamino)-butan-2-one 3f. Enantiomeric
excess was determined by HPLC with a Chiralcel AD-H
(hexane/i-PrOH = 90/10,
20 °C): tR = 11.5 min (minor) and 16.8 min (major).
1.0 mL/min,
k = 254 nm,
4.3.3.6.
(3R,4R)-4-[2-Benzyloxy-1-(4-methoxy-phenyl-
amino)-3-oxo-butyl]-benzonitrile. Enantiomeric excess
was determined by HPLC with a Chiralcel AS-H (hex-
ane/i-PrOH = 90/10, 1.0 mL/min, k = 254 nm, 20 °C):
tR = 27.6 min (minor) and 32.9 min (major).
4.3.3.7. (3R,4R)-3-Benzyloxy-4-(4-methoxy-phenylami-
no)-4-naphthalen-2-yl-butan-2-one. Enantiomeric excess
6. Teo, Y.-C. Tetrahedron: Asymmetry 2007, 18, 1155.