Catalytic asymmetric Michael addition of α,β-unsaturated aldehydes to Ni(ii) complexes of the Schiff base of glycine

Article abstract of DOI:10.1039/c0ob00221f

The conjugate addition of Ni(ii) complexes of glycine Schiff base to α,β-unsaturated aldehydes catalyzed by (S)-2- (diphenyl(trimethylsilyloxy)methyl)pyrrolidine afforded adducts in excellent yields with up to 49:1 dr and 95% ee. This method enables the construction of two adjacent chiral centers in one step, and offers an alternative route to chiral α-amino acid derivatives.

Full text of DOI:10.1039/c0ob00221f

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Catalytic asymmetric Michael addition of a,b-unsaturated aldehydes to Ni(II)
complexes of the Schiff base of glycine†
Xiaoyan Luo, Zhichao Jin, Pengfei Li, Jiabin Gao, Weimin Yue, Xinmiao Liang and Jinxing Ye*
Received 7th June 2010, Accepted 6th October 2010
DOI: 10.1039/c0ob00221f
The conjugate addition of Ni(II) complexes of glycine Schiff base to a,b-unsaturated aldehydes
catalyzed by (S)-2-(diphenyl(trimethylsilyloxy)methyl)pyrrolidine afforded adducts in excellent yields
with up to 49 : 1 dr and 95% ee. This method enables the construction of two adjacent chiral centers in
one step, and offers an alternative route to chiral a-amino acid derivatives.
complexed glycine derivative 5a under various conditions. Rep-
resentative results are shown in Table 1.
The screening of organocatalysts was initially carried out in a
CH2Cl2/MeOH mixed solvent system. The conjugate addition of
Introduction
a-Amino acids and their derivatives are important compounds,1,2
and their synthesis has attracted a great deal of attention.
Although countless approaches for the preparation of a-amino
acids and their derivatives have been developed,3 most have serious
drawbacks from the standpoint of practicality.4 As one of the most
promising approaches, glycine derivatives and their equivalents
have received considerable attention, and many impressive results
have been achieved.5–7 Among these nucleophilic glycine equiva-
lents, nickel(II) complexes of the Schiff base of glycine have been
successfully used for the synthesis of structurally varied tailor-
made a-amino acids.5d,6j However, these reports focused on the
reactions of nickel(II) complexes of chiral glycine Schiff base and
achiral reagents. To the best of our knowledge, there is no report on
the catalytic asymmetric Michael addition of nickel(II) complexes
of achiral glycine Schiff base to a,b-unsaturated aldehydes, which
would be an alternative methodology for the preparation of a-
amino acids or their derivatives. A chiral catalyst, an N-acyl
derivative of iso-NOBIN, has been used to catalyze the reaction
of nickel(II) complexes of achiral glycine Schiff base and propenal,
but this reaction proceeded in 50% yield and with 0% ee.6g
Recently, our group has successfully applied a Lewis base–
Brønsted base two-component catalytic system in the asym-
metric Michael addition of nitroalkanes8 and malonates9 to
various a,b-unsaturated aldehydes.10,11 We here describe the first
organocatalytic asymmetric Michael addition of achiral nickel(II)-
complexed glycine derivatives to a,b-unsaturated aldehydes, af-
fording adducts with good to excellent yields and asymmetric
inductions.
5a and 6a catalyzed by L-proline (1a) gave poor results (entry 1).
When lithium (S)-pyrrolidine-2-carboxylate (1b) was used as the
catalyst, the conversion improved to more than 99% (entry 2).
However, the enantioselectivities still remained poor, the Michael
addition with the catalyst 2 affording no more than 40% ee (entry
3). A remarkable enhancement was achieved when 3 was used as
catalyst. Using lithium benzoate as an additive base and 3a as
the catalyst, the conjugate addition proceeded with up to 86%
asymmetric induction (entry 4). In the presence of 3b, excellent
conversion and enantioselectivities were obtained, although the
diastereoselectivity remained low (entry 5). When LiOAc was
introduced into the catalytic system, more than 99% conversion
and 91% ee (94% ee for the minor isomer) was obtained, and the
diastereoselectivity was also improved slightly from 1.6 : 1 dr to
1.9 : 1 dr (entry 6).
As a result of these investigations, different additives were
screened (entries 7–9). Using 4 as an additive clearly did not
change the diastereo- or enantioselectivities, showing that the
chirality of the N-protected amino acid did not have an effect
on the stereoselectivity of the reaction (entry 7). However, it was
found that the reaction catalyzed by 3b and lithium benzoate gave
better results – more than 99% conversion, 1.9 : 1 dr and 90% (98%)
ee (entry 8). This prompted us to use these catalytic conditions in
subsequent experiments. As the choice of solvent could be very
important, we then optimized the reaction conditions with this
in mind. Reaction in methanol afforded high conversion and
diastereoselectivity with low enantioselectivities, in contrast to
that obtained in CH2Cl2 (entries 10 and 11). The results in other
solvents, such as CHCl3, EtOAc, THF and MeCN, were similar
to those in CH2Cl2 (entries 12–15).
Results and discussion
We started our investigation with the asymmetric conjugate
addition between cinnamaldehyde (6a) and achiral nickel(II)-
After full screening of solvents and additives, we found that the
best results (>99% conversion and 2.8 : 1 dr with 95% (96%) ee)
were obtained using the MeOH/CH2Cl2 mixed solvent system
(entry 17). Additionally, it should be noted that 1,4-adducts
with >99% asymmetric induction were formed smoothly in the
mixed solvent when lithium 4-methoxybenzoate or lithium 4-
nitrobenzoate were employed as additives (entries 18 and 19).
These encouraging results indicated that this two-component cat-
alytic system could also be applied successfully in the asymmetric
Engineering Research Center of Pharmaceutical Process Chemistry, Min-
istry of Education, School of Pharmacy, East China University of Science
and Technology, 130 Meilong Road, Shanghai, 200237, China. E-mail:
yejx@ecust.edu.cn
† Electronic supplementary information (ESI) available: Experimental
procedures and characterization of the Michael addition products. CCDC
reference number 772140. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c0ob00221f
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 793–801 | 793
©

View Article Online
Table 1 Catalyst and solvent screening for the conjugate additiona
Entry
Cat.
Additive
Solvent
Conv. (%)
dr b
eec (%)
1
2
3
4
5
6
7
8
1a
1b
2
None
None
None
PhCO2Li
None
LiOAc
4
PhCO2Li
PhCO2H
PhCO2Li
PhCO2Li
PhCO2Li
PhCO2Li
PhCO2Li
PhCO2Li
PhCO2Li
PhCO2Li
4-MeOC6H4CO2Li
4-NO2C6H4CO2Li
CH2Cl2/MeOH = 7/5
CH2Cl2/MeOH = 7/5
CH2Cl2/MeOH = 7/5
CH2Cl2/MeOH = 7/5
CH2Cl2/MeOH = 7/5
CH2Cl2/MeOH = 7/5
CH2Cl2/MeOH = 7/5
CH2Cl2/MeOH = 7/5
CH2Cl2/MeOH = 7/5
MeOH
CH2Cl2
CHCl3
EtOAc
THF
49
>99
78
48
95
>99
99
>99
63
>99
36
14
33
11
76
70
>99
>99
>99
3.0 : 1
7.3 : 1
2.1 : 1
1.3 : 1
1.6 : 1
1.9 : 1
1.6 : 1
1.9 : 1
1.5 : 1
8.1 : 1
2.2 : 1
2.4 : 1
2.1 : 1
1.9 : 1
2.0 : 1
1.6 : 1
2.8 : 1
2.1 : 1
2.0 : 1
nd (16)
18 (9)
32 (-32)
70 (86)
82 (93)
91 (94)
87 (95)
90 (98)
92 (89)
86 (49)
87 (91)
86 (85)
91 (88)
86 (93)
92 (84)
89 (91)
95 (96)
93 (>99)
95 (>99)
3a
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
9
10
11
12
13
14
15
16
17
18
19
MeCN
EtOAc/MeOH = 7/5
DCM/MeOH = 1/5
DCM/MeOH = 1/5
DCM/MeOH = 1/5
a Unless otherwise noted, all reactions were performed with 0.5 mmol of 5a, 0.6 mmol of 6a, 0.05 mmol of catalyst and 0.1 mmol of additive in 1.2
mL solvent at room temperature for 24 h. nd = not determined. b Determined by HPLC. c Determined by HPLC on chiral stationary phase (the data in
parenthesis relates to the minor isomer).
Table 2 Asymmetric Michael addition of 5 to 6aa
Michael addition of achiral nickel(II) complexes of glycine Schiff
bases to a,b-unsaturated aldehydes.
Under the optimized conditions, the asymmetric Michael
Entry
5
R1
R2
Yieldb (%)
drc
eed (%)
additions between a series of achiral nickel(II) complexes of
glycine Schiff bases and cinnamaldehyde were studied, and the
results are presented in Table 2. As Soloshonok5d stated, different
substituents (R1, R2) on the nitrogen atom lead to a different
performance of compound 5 in the reaction system – a result
that is truly remarkable, and underscores the synthetic power
of this type of nucleophilic glycine equivalent. The piperidine-
substituted achiral nickel(II) complex 5a reacted with enal 6a
quite successfully to afford 1,4-adducts in 98% isolated yield and
2.8 : 1 dr with 95% ee for major adduct and 95% ee for minor
adduct (entry 1). The dimethyl-substituted 5b also afforded 1,4-
adducts in 92% isolated yield and 1.6 : 1 dr with 81% (99%) ee
(entry 2). Even using the more sterically hindered diisopropyl-
substituted 5c, the adducts were formed in 83% yield with up
to 96% (97%) ee, although with low diastereoselectivity (1.3 : 1
dr, entry 3). The more lipophilic 5d and 5e were found to react
slowly, with lower isolated yields and diastereoselectivities, but the
enantioselectivities from 5d were still up to 89% (99%) (entries
4–5). Although all the diastereoselectivities of the conjugate
1
2
3
4
5
5a
5b
5c
5d
5e
–C5H10–
7aa, 98
7ba, 92
7ca, 83
7da, 44
7ea, 25e
2.8 : 1
1.6 : 1
1.3 : 1
1.3 : 1
1.6 : 1
95 (95)
81 (99)
96 (97)
89 (99)
75 (78)
Me
i-Pr
Me
Bn
Me
i-Pr
Bn
Bn
a Reaction conditions: A mixture of 5 (0.5 mmol), 6a (0.6 mmol), and 3b
(10 mol%) and PhCO2Li (20 mol%) in CH2Cl2 (0.2 mL)/MeOH (1.0 mL)
was stirred at room temperature for 24 h. b Isolated yield (the data relates
to the combined isolated yield of the diastereomers). c Determined by 1H
NMR of the crude product. d Determined by chiral HPLC (the data in
parenthesis relates to the minor isomer). e Conversion.
additions are not ideal, the diastereoisomers could be separated
easily by silica gel chromatography.
To further extend the scope of this type of Michael addition, a
series of a,b-unsaturated aldehydes 6b–n were reacted with 5a, and
the results are displayed in Table 3. It turned out that the electronic
nature of the substituent group and its position on the aromatic
794 | Org. Biomol. Chem., 2011, 9, 793–801
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Table 3 Asymmetric Michael addition of 5a to enal 6a
successfully, and afford the 1,4-adducts in 93% and 95% yield
and high diastereoselectivity, with 95% and 88% ee, respectively
(entries 12 and 13).
The reactions of 3-chlorocinnamaldehyde and 3-
fluorocinnamaldehyde with 5a under the same conditions
proceeded slowly, giving less than 20% conversion of 5a.
Unexpectedly, the reactions of 5a with aliphatic enals, such as
trans-2-pentanal and trans-2-hexenal, did not take place under the
same conditions, no desired products being found in the reaction
mixtures by NMR analysis. This may be attributable to the
formation of the dienamine, which decreased the electrophilicity
of the b-carbon of the enal.12
Entry
R
t (h) Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
2-ClC6H4, 6b
72
48
72
48
24
48
24
24
24
24
24
7ab, 52
7ac, 88
7ad, 59
7ae, 94
7af, 99
7ag, 93
7ah, 94
7ai, 96e
7aj, 99
7ak, 85e
7al, 98
7am, 93e
7an, 95e
1.9 : 1 95 (92)
2.3 : 1 91 (99)
1.5 : 1 92 (96)
2.2 : 1 89 (89)
10 : 1
2.4 : 1 92 (95)
5.7 : 1 89 (82)
4-ClC6H4, 6c
4-FC6H4, 6d
The absolute configurations of the two adjacent stereocenters
in the major adduct 7ai were unambiguously determined to be
(2R,3S) by X-ray crystallographic analysis (Fig. 1).
4-BrC6H4, 6e
2-MeC6H4, 6f
3-MeC6H4, 6g
4-MeC6H4, 6h
2-MeOC6H4, 6i
3-MeOC6H4, 6j
4-MeOC6H4, 6k
Naphthalen-2-yl, 6l
91 (91)
49 : 1
91 (nd)
9
2.6 : 1 90 (>99)
6.7 : 1 90 (nd)
3.8 : 1 87 (71)
19 : 1
24 : 1
10
11
12
13
2,3-(MeO)2C6H3, 6m 24
2,4-(MeO)2C6H3, 6n 24
95 (nd)
88 (nd)
a Reaction conditions: A mixture of 5a (0.5 mmol), 6 (0.6 mmol), and 3b
(10 mol%) and PhCO2Li (20 mol%) in CH2Cl2 (0.2 mL)/MeOH (1.0 mL)
was stirred at room temperature for the time given. b Isolated yield (the data
relates to the combined isolated yield of the diastereomers). c Determined
by 1H NMR of crude product. d Determined by HPLC on chiral stationary
phase (the data in parenthesis relates to the minor isomer). e The yield of
major product (2R,3S).
Fig. 1 X-ray crystal structure of 7ai.
The compound 7ai was easily hydrolyzed by hydrochloride in
methanol. Notably, the compound 8 could be easily recovered
quantitatively and reused to give 5a (Scheme 1), and the corre-
sponding amino acid could be further treated with TsCl to give
compound 9ai.
ring had a clear influence on the yield and diastereoselectivity,
while the enantioselectivities were less affected. For example,
using 2-chlorocinnamaldehyde 6b, 52% yield and 1.9 : 1 dr with
95% (92%) ee were obtained (entry 1). 4-Chlorocinnamaldehyde
6c afforded 88% yield and 2.3 : 1 dr with up to 91% (99%) ee
(entry 2). When 4-fluorocinnamaldehyde 6d was used, lower yield
and diastereoselectivity were obtained. However, the enantiose-
lectivities were still up to 92% (96%) (entry 3). It was found
that 4-bromocinnamaldehyde 6e reacted very well, giving 94%
yield and 2.2 : 1 dr with ee values for both isomers near 90%
(entry 4). In addition to weakly electron-withdrawing substituents,
electron-donating substituents could also be introduced onto
the aromatic ring (entries 5–13). In the presence of electron-
donating substituents on the aromatic ring, all the a,b-unsaturated
aldehydes gave excellent yields with good to excellent enantios-
electivities (88–95%). The reaction of 2-methylcinnamaldehyde
6f proceeded with 10 : 1 dr and 91% ee for both isomers (entry
5). The moderate to good diastereoselectivities (2.4 : 1, 5.7 : 1 dr)
with 82–95% of enantioselectivities were also obtained from 3-
methylcinnamaldehyde 6g and 4-methylcinnamaldehyde 6h re-
spectively (entries 6 and 7). It should be noted that 96% isolated
yield with up to 49 : 1 dr and 91% ee for major adduct were
obtained from 2-methoxycinnamaldehyde 6i (entry 8), while >99%
(90%) ee was obtained when 3-methoxycinnamaldehyde 6j was
used (entry 9). The major adduct was smoothly formed in 85%
yield with 6.7 : 1 dr and 90% ee from 4-methoxycinnamaldehyde
6k and 5a (entry 10). The large 3-(naphthalen-2-yl)acrylaldehyde
6l was also tested, and gave the Michael adduct in 98% yield and
3.8 : 1 dr with 87% (71%) ee (entry 11). The dimethoxy-substituted
enals 6m and 6n were found to react with the nucleophile quite
Scheme 1
Conclusions
In conclusion, we have extended the Lewis base–Brønsted base
two-component catalytic system to the asymmetric Michael
addition between a,b-unsaturated aldehydes and achiral nickel(II)
complexes of the Schiff base of glycine. Using this method,
we can construct two adjacent stereocenters in one step
with excellent yield and asymmetric induction, offering a
new approach for the preparation of chiral a-amino acid
derivatives.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 793–801 | 795
©

View Article Online
(d, J = 7.6 Hz, 1H), 6.74 (d, J = 4.0 Hz, 2H), 4.27 (d, J = 2.8 Hz,
1H), 3.66–3.63 (m, 1H), 3.45 (s, 2H), 3.28–3.17 (m, 2H), 3.00 (d,
J = 13.2 Hz, 1H), 2.61–2.52 (m, 1H), 2.42 (m, 1H), 2.39 (d, J =
13.2 Hz, 1H), 2.30 (brs, 1H), 2.05–1.94 (m, 2H), 1.70–1.23 (m,
6H). 13C NMR (100 MHz, CDCl3): d 177.6, 175.7, 171.5, 143.1,
139.3, 134.3, 133.6, 132.9, 130.0, 129.9, 129.8, 129.0, 128.7, 128.6,
128.0, 127.6, 127.0, 123.0, 120.9, 75.1, 60.6,59.9, 55.9, 54.3, 47.8,
35.0, 22.8, 19.8, 19.2. HRMS (EI) calculated for C31H33N3O4Ni
Experimental
General methods
All solvents and inorganic reagents were from commercial sources
and used without purification unless otherwise noted. 1H and 13
C
NMR spectra were recorded on a Bruker AV-400 spectrometer
(400 MHz and 100 MHz) or a Bruker AM 500 spectrometer
(500 MHz and 125 MHz). Chemical shifts for protons are reported
in parts per million downfield from tetramethylsilane and are ref-
erenced to the residual solvent peak (CDCl3: 7.26 ppm). Chemical
shifts for carbon are reported in parts per million downfield from
tetramethylsilane and are referenced to the residual solvent peak
(CDCl3: 77.16 ppm). Data are represented as follows: chemical
shift, integration, multiplicity (br = broad, s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet), coupling constants
in Hertz (Hz). High-resolution mass spectrometry (ESI) was
carried out using an ACQUITYTM Ultra Performance Liquid
Chromatography system (Waters, Milford, MA) coupled with a Q-
TOF premier instrument (Waters MS Technologies, Manchester,
UK). High-resolution mass spectra (EI) were measured on a
Waters Micromass GCT spectrometer. High-performance liquid
chromatography (HPLC) was performed on an Agilent 1200 Series
chromatograph using a Chiralpak IA-H or IC-H and Regis (R,R)-
Whelk O1 column (0.46 cm ¥ 25 cm) as noted. X-ray analysis of
7ai-major was performed at the X-ray crystallography facility of
Bruker–Nonius SMART APEX II CCD. Optical rotations were
measured on an Autopol III automatic polarimeter.
◦
[M]+: 569.1825, Found: 569.1837. mp >130 C (decomp.). [a]2D2
+1418 (c 0.205 g/100 mL, CH2Cl2). The enantiomeric excess was
determined by HPLC. [IA column, 254 nm, hexane/iPrOH = 5 : 1,
0.8 mL/min]: 30.850 min (major), 39.428 min (minor), ee = 95%.
7ba-major. 1H NMR (500 MHz, CDCl3): d 8.48 (d, J = 8.5 Hz,
1H), 7.65–7.50 (m, 8H), 7.31–7.28 (m, 2H), 7.14 (d, J = 7.0 Hz,
1H), 6.80–6.76 (m, 2H), 4.39 (d, J = 4.0 Hz, 1H), 3.21 (m, 1H),
3.20 (d, J = 15.5 Hz, 1H), 2.90–2.83 (m, 2H), 2.61 (d, J = 16.0 Hz,
1H), 2.44 (s, 3H), 2.26 (brs, 1H), 2.15–2.08 (m, 1H), 1.93–1.87 (m,
1H), 1.60 (s, 3H). 13C NMR (100 MHz, CDCl3): d 177.5, 174.8,
170.6, 142.8, 140.1, 133.8, 133.7, 132.8, 130.5, 130.1, 129.3, 129.0,
128.9, 128.1, 128.0, 127.4, 126.7, 123.4, 121.2, 73.6, 67.1, 60.3,
49.7, 47.5, 47.3, 33.8. HRMS (ESI) calculated for C28H30N3O4Ni
[M + H]+: 530.1590, found: 530.1567. mp >265 ◦C (decomp.).
[a]2D2 -1383 (c 0.240 g/100 mL, CH2Cl2). The enantiomeric excess
was determined by HPLC. [IA column, 240 nm, DCM/EtOH =
92.5 : 7.5, 0.4 mL/min]: 7.423 min (major), 8.112 min (minor), ee =
81%.
7ba-minor. 1H NMR (500 MHz, CDCl3): d 8.63 (d, J = 8.5 Hz,
1H), 7.50–7.39 (m, 6H), 7.29–7.27 (m, 2H), 7.22 (d, J = 7.5 Hz,
1H), 6.85 (d, J = 7.5 Hz, 1H), 6.78–6.73 (m, 2H), 4.29 (d, J =
3.0 Hz, 1H), 3.62 (d, J = 16.0 Hz, 1H), 3.59–3.57 (m, 1H), 3.17–
3.12 (m, 2H), 2.74 (d, J = 16.0 Hz, 1H), 2.65 (brs, 1H), 2.46 (s,
3H), 2.25–2.18 (m, 1H), 1.97–1.90 (m, 1H), 1.80 (s, 3H). 13C NMR
(100 MHz, CDCl3): d 180.1, 177.8, 171.7, 143.1, 139.3, 134.5,
133.6, 133.1, 130.2, 130.1, 129.9, 129.1, 128.8, 128.7, 128.1, 127.8,
126.9, 122.9, 121.0, 75.1, 67.6, 59.9, 49.5, 47.9, 47.8, 35.2. HRMS
(ESI) calculated for C28H30N3O4Ni [M + H]+: 530.1590, Found:
530.1576. mp >259 ◦C (decomp.). [a]2D2 +1790 (c 0.245 g/100 mL,
CH2Cl2). The enantiomeric excess was determined by HPLC. [IA
column, 240 nm, DCM/EtOH = 92.5 : 7.5, 0.4 mL/min]: 8.556
min (major), 7.782 min (minor), ee>99%.
General Procedure for asymmetric Michael addition and reduction
(S)-2-(Diphenyl(trimethylsilyloxy)methyl)pyrrolidine (16.2 mg,
0.05 mmol), lithium benzoate (12.8 mg, 0.1 mmol) and enal (0.6
mmol) were added to a solution of the Ni(II) complex of glycine
Schiff base (0.5 mmol) in CH2Cl2/MeOH = 1/5 (v/v, 1.2 mL).
The reaction mixture was stirred at room temperature for the time
indicated in the tables and then MeOH (1.5 mL) and NaBH4 (37.8
mg, 1 mmol) were added. The reaction mixture was stirred at room
temperature for 2.5 h. The solvent was removed under vacuum,
and the residue purified by silica gel chromatography to afford
the product as a red solid. Yields of the products are given in the
tables.
7aa-major. 1H NMR (400 MHz, CDCl3): d 8.41 (d, J = 8.8 Hz,
1H), 7.66–7.53 (m, 6H), 7.51–7.49 (m, 2H), 7.34–7.28 (m, 2H),
7.15–7.14 (m, 1H), 6.80–6.75 (m, 2H), 4.42 (d, J = 4.0 Hz, 1H),
3.28 (m, 2H), 3.27 (d, J = 16.4 Hz, 1H), 3.03 (d, J = 16.4 Hz,
1H), 2.95–2.90 (m, 1H), 2.88–2.82 (m, 2H), 2.39–2.31 (m, 1H),
2.21–2.12 (m, 1H), 1.97–1.86 (m, 2H), 1.67–1.58 (m, 1H), 1.51–
1.41 (m, 2H), 1.33–1.26 (m, 3H). 13C NMR (100 MHz, CDCl3): d
177.3, 175.3, 170.5, 142.8, 140.1, 133.8, 133.7, 132.7, 130.5, 130.0,
129.3, 129.0, 128.9, 128.0, 127.9, 127.4, 126.8, 123.5, 121.1, 73.5,
60.4, 60.2, 55.4, 54.6, 47.4, 33.8, 22.7, 19.7, 19.4. HRMS (EI)
calculated for C31H33N3O4Ni [M]+: 569.1825, Found: 569.1826.
mp >178 ◦C (decomp.). [a]D22 -1446 (c 0.175 g/100 mL, CH2Cl2).
The enantiomeric excess was determined by HPLC. [IA column,
254 nm, hexane/EtOH = 6 : 1, 0.8 mL/min]: 25.496 min (major),
34.427 min (minor), ee = 95%.
7ca-major. 1H NMR (500 MHz, CDCl3): d 8.53 (d, J = 8.5 Hz,
1H), 7.63–7.52 (m, 3H), 7.47–7.44 (m, 2H), 7.42–7.39 (m, 2H),
7.30–7.28 (m, 3H), 7.22 (d, J = 7.5 Hz, 1H), 6.83–6.81 (m, 1H),
6.77–6.74 (m, 1H), 4.41 (d, J = 3.5 Hz, 1H), 3.35 (d, J = 17.5 Hz,
1H), 3.19–3.14 (m, 1H), 2.95–2.91 (m, 1H), 2.72 (m, 2H), 2.68 (d,
J = 17.5 Hz, 1H), 2.45–2.40 (m, 1H), 2.05 (brs, 1H), 1.91–1.87 (m,
2H), 1.63 (d, J = 6.0 Hz, 3H), 1.60 (d, J = 6.5 Hz, 3H), 1.17 (d,
J = 6.5 Hz, 3H), 0.83 (d, J = 6.5 Hz, 3H). 13C NMR (100 MHz,
CDCl3): d 178.9, 177.8, 171.8, 142.9, 138.8, 134.6, 133.8, 132.9,
129.9, 129.4, 129.1, 128.9, 128.8, 128.0, 127.3, 126.3, 123.0, 120.8,
72.8, 60.3, 59.4, 55.4, 53.0, 46.6, 34.4, 22.1, 21.9, 20.7, 14.6. HRMS
(ESI) calculated for C32H38N3O4Ni [M + H]+: 586.2216, Found:
586.2199. mp >260 ◦C (decomp.). [a]2D2 -1936 (c 0.110 g/100 mL,
CH2Cl2). The enantiomeric excess was determined by HPLC. [IA
column, 240 nm, DCM/EtOH = 99.5 : 0.5, 0.65 mL/min]: 7.762
min (major), 10.949 min (minor), ee = 96%.
7aa-minor. 1H NMR (400 MHz, CDCl3): d 8.57 (d, J = 8.8 Hz,
1H), 7.51–7.45 (m, 2H),7.42–7.36 (m, 4H), 7.29–7.22 (m, 4H), 6.80
796 | Org. Biomol. Chem., 2011, 9, 793–801
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
7ca-minor. 1H NMR (400 MHz, CDCl3): d 8.55 (d, J = 8.4 Hz,
1H), 7.36–7.34 (m, 2H), 7.27–7.21 (m, 1H), 7.15–7.11 (m, 2H),
7.08–7.04 (m, 3H), 6.85 (d, J = 7.2 Hz,2H), 6.68–6.64 (m, 1H), 6.54
(d, J = 8.0 Hz,1H), 5.77 (d, J = 7.2 Hz, 1H), 4.49–4.43 (m,1H), 4.08
(d, J = 8.0 Hz, 1H), 3.98 (d, J = 17.6 Hz, 1H), 3.59–3.54 (m,1H),
3.34–3.28 (m,1H), 3.26–3.19 (m, 1H), 2.87 (d, J = 17.2 Hz, 1H),
2.61 (d, J = 6.0 Hz, 3H), 2.59–2.56 (m, 1H), 2.54–2.49 (m, 1H),
2.12–2.03 (m, 1H), 1.89 (brs, 1H), 1.78 (d, J = 6.4 Hz, 3H), 1.64
(d, J = 6.4 Hz, 3H), 1.08 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz,
CDCl3): d 178.6, 177.3, 170.9, 142.7, 138.4, 134.2, 133.4, 132.9,
129.2, 129.0, 128.7, 128.5, 128.4, 127.5, 127.1, 126.6, 122.5, 120.7,
75.3, 60.5, 59.9, 56.2, 52.6, 48.8, 34.1, 23.6, 22.8, 20.4, 14.4. HRMS
(ESI) calculated for C32H38N3O4Ni [M + H]+: 586.2216, Found:
586.2210. mp >215 ◦C (decomp.). [a]2D2 +1560 (c 0.135 g/100 mL,
CH2Cl2). The enantiomeric excess was determined by HPLC. [01
column, 240 nm, DCM/EtOH = 94 : 6, 0.8 mL/min]: 6.627 min
(major), 5.102 min (minor), ee = 97%.
1H).13C NMR (100 MHz, CDCl3): d 177.3, 175.6, 170.3, 142.2,
140.3, 134.3, 133.8, 133.1, 132.1, 131.8, 131.3, 130.8, 130.3, 130.0,
129.2, 129.1, 129.0, 128.9, 128.8, 128.7, 128.6, 128.1, 128.0, 127.6,
126.4, 123.6, 120.7, 73.4, 62.8, 62.6, 62.6, 60.4, 47.2, 33.9. HRMS
(ESI) calculated for C40H38N3O4Ni [M + H]+: 682.2216, Found:
682.2217. mp >274 ◦C (decomp.). [a]2D2 -862 (c 0.170 g/100 mL,
CH2Cl2). The enantiomeric excess was determined by HPLC. [O1
column, 240 nm, hexane/DCM/EtOH = 60 : 30 : 10, 0.8 mL/min]:
12.514 min (major), 17.158 min (minor), ee = 75%.
7ea-minor. 1H NMR (500 MHz, CDCl3): d 8.21 (d, J = 7.0 Hz,
2H), 7.98 (d, J = 8.5 Hz, 1H), 7.54–7.45 (m, 5H), 7.39–7.33 (m,
7H), 7.28 (d, J = 7.0 Hz, 2H), 7.19–7.16 (m, 2H), 7.00–6.94 (m,
2H), 6.67 (d, J = 8.0 Hz, 1H), 6.64–6.60 (m, 2H), 4.32 (d, J =
4.0 Hz, 1H), 3.95 (d, J = 16.5 Hz, 1H), 3.89 (d, J = 12.5 Hz,
1H), 3.82–3.78 (m, 1H), 3.63 (d, J = 13.5 Hz, 1H), 3.58 (d, J =
13.5 Hz, 1H), 3.23–3.19 (m, 1H), 3.14–3.09 (m, 1H), 2.97 (d,
J = 12.5 Hz, 1H), 2.74 (d, J = 16.5 Hz, 1H), 2.17–2.12 (m, 1H),
1.94–1.88 (m, 1H). 13C NMR (100 MHz, CDCl3): d 177.8, 176.0,
171.5, 142.5, 139.6, 134.3, 133.8, 133.7, 132.4, 131.8, 131.2, 130.5,
130.0, 129.9, 129.0, 128.9, 128.8, 128.7, 128.6, 128.5, 128.0, 127.8,
126.5, 122.8, 120.5, 75.0, 63.2, 63.2, 62.7, 59.8, 47.9, 35.5. HRMS
(ESI) calculated for C40H38N3O4Ni [M + H]+: 682.2216, Found:
682.2185. mp >255 ◦C (decomp.). [a]2D2 +438 (c 0.165 g/100 mL,
CH2Cl2). The enantiomeric excess was determined by HPLC. [O1
column, 240 nm, hexane/DCM/EtOH = 60 : 30 : 10, 0.8 mL/min]:
16.190 min (major), 10.708 min (minor), ee = 78%.
7da-major. 1H NMR (500 MHz, CDCl3): d 8.26 (d, J = 8.5 Hz,
1H), 7.66–7.53 (m, 8H), 7.50 (d, J = 7.0 Hz, 2H), 7.38 (d, J =
7.5 Hz, 1H), 7.31–7.28 (m, 2H), 7.25–7.21 (m, 2H), 7.12 (d, J =
7.0 Hz, 1H), 6.78–6.74 (m, 2H), 4.43 (d, J = 4.0 Hz, 1H), 3.88
(d, J = 13.0 Hz, 1H), 3.64 (d, J = 13.0 Hz, 1H), 3.25–3.22 (m,
1H),3.08 (d, J = 16.0 Hz, 1H), 2.91 (d, J = 16.0 Hz, 1H), 2.87–2.82
(m, 2H), 2.21 (brs, 1H), 2.18–2.11 (m, 1H), 1.92–1.88 (m, 1H),
1.61 (s, 3H). 13C NMR (100 MHz, CDCl3): d 177.4, 174.9, 170.4,
142.7, 140.1, 133.8, 133.6, 132.6, 131.8, 130.6, 130.5, 130. 1, 129.3,
129.1, 129.0, 128.9, 128. 7, 128.0, 128. 1, 127.5, 126.7, 123.5, 121.0,
73.5, 64.8, 63.4, 60.5, 47.3, 45.4, 33.9. HRMS (ESI) calculated
for C34H34N3O4Ni [M + H]+: 606.1903, Found: 606.1882. mp
>170 ◦C (decomp.). [a]2D2 -1444 (c 0.240 g/100 mL, CH2Cl2). The
enantiomeric excess was determined by HPLC. [IA column, 240
nm, hexane/DCM/EtOH = 31 : 62 : 7, 0.7 mL/min]: 5.016 min
(major), 6.400 min (minor), ee = 89%.
7ab-major. 1H NMR (500 MHz, CDCl3): d 8.46 (d, J = 9.0 Hz,
1H), 7.80–7.78 (m, 1H),7.69 (m, 1H), 7.58–7.52 (m, 5H), 7.36–7.29
(m, 3H), 6.77–6.74 (m, 2H), 4.37 (d, J = 3.0 Hz, 1H), 3.62 (m, 1H),
3.32 (d, J = 16.0 Hz, 1H), 3.28–3.23 (m, 1H), 3.20–3.16 (m, 1H),
3.09 (d, J = 15.5 Hz, 1H), 2.91 (d, J = 9.5 Hz, 2H), 2.37–2.31
(m, 1H), 2.10–2.03 (m, 1H), 1.91–1.86 (m, 2H), 1.48–1.25 (m,6H).
13C NMR(100 MHz, CDCl3): d 177.3, 174.9, 171.5, 143.0, 138.4,
137.0, 133.8, 133.7, 132.8, 131.1, 130.1, 130.0, 129.2, 128.8, 127.8,
127.6, 127.0, 123.3, 120.9, 73.9, 60.5, 60.2, 55.6, 54.8, 42.1, 34.8,
22.8, 19.8, 19.5. HRMS (ESI) calculated for C31H33N3O4ClNi [M
7da-minor. 1H NMR (500 MHz, CDCl3): d 8.36 (d, J = 9.0 Hz,
1H), 7.74 (d, J = 7.0 Hz, 2H), 7.52–7.47 (m, 2H), 7.45–7.39 (m,
4H), 7.30–7.28 (m, 5H), 7.21–7.16 (m, 2H), 6.79 (d, J = 8.0 Hz,
1H), 6.72 (d, J = 4.0 Hz, 2H), 4.31 (d, J = 3.5 Hz, 1H), 3.96
(d, J = 13.0 Hz, 1H), 3.71–3.67 (m, 1H), 3.54 (d, J = 13.0 Hz,
1H), 3.48 (d, J = 16.5 Hz, 1H), 3.23 (m, 1H), 3.15 (m, 1H),
3.08 (d, J = 16.5 Hz, 1H), 2.19–2.13 (m, 1H), 2.04 (brs, 1H),
1.97–1.92 (m, 1H), 1.88 (s, 3H).13C NMR (100 MHz, CDCl3):
d 177.8, 175.2, 171.5, 142.9, 139.4, 134.2, 133.6, 132.8, 131.7,
131.0, 130.2, 130.0, 129.9, 129.0, 128.9, 128.8, 128.7, 128.1, 127.7,
126.8, 122.8, 120.8, 75.0, 64.9, 63.9, 59.8, 47.9, 46.3, 35.2. HRMS
(ESI) calculated for C34H34N3O4Ni [M + H]+: 606.1903,Found:
606.1887. mp >129 ◦C (decomp.). [a]2D2 +1709 (c 0.135 g/100 mL,
CH2Cl2). The enantiomeric excess was determined by HPLC. [O1
column, 240 nm, DCM/EtOH = 97 : 3, 0.8 mL/min]: 12.976 min
(major), 9.669 min (minor), ee = 99%.
◦
+ H]+: 604.1513, Found: 604.1509. mp >270 C (decomp.). [a]2D2
-1295 (c 0.210 g/100 mL, CH2Cl2). The enantiomeric excess was
determined by HPLC. [IC column, 240 nm, DCM/EtOH = 98 : 2,
0.9 mL/min]: 11.523 min (major), 21.614 min (minor), ee = 95%.
7ab-minor. 1H NMR (500 MHz, CDCl3): d 8.53 (d, J = 8.5 Hz,
1H), 7.40–7.33 (m, 4H), 7.18–7.06 (m, 5H), 6.72–6.60 (m, 2H),
6.40–6.30 (m, 1H), 5.07–4.98 (m, 1H), 4.29 (d, J = 1.5 Hz, 1H),
3.66 (dd, J = 15.5, 53.0 Hz, 2H), 3.50–3.46 (m, 1H), 3.37–3.33
(m, 2H), 3.12 (d, J = 12.0 Hz, 1H), 3.00 (d, J = 13.0 Hz, 1H),
2.92–2.87 (m, 1H), 2.68 (brs, 1H), 1.75–1.38 (m, 8H).13C NMR
(100 MHz, CDCl3): d 177.3, 175.7, 170.7, 142.9, 137.1, 135.3,
134.2, 133.2, 132.8, 129.7, 129.2, 128.7, 128.6, 128.3, 127.9, 127.2,
127.0, 123.2, 121.0, 74.5, 60.9, 60.0, 56.5, 54.2, 35.7, 29.2, 22.9,
20.0, 19.3. HRMS (ESI) calculated for C31H33N3O4ClNi [M +
7ea-major. 1H NMR (500 MHz, CDCl3): d 8.22 (d, J = 7.5 Hz,
2H), 7.76–7.73 (m, 2H), 7.70–7.67 (m, 2H), 7.64–7.51 (m, 5H),
7.41–7.37 (m, 4H), 7.24–7.21 (m, 2H), 7.19–7.18 (m, 2H), 7.08
(d, J = 7.5 Hz, 1H), 7.04–7.00 (m, 2H), 6.66–6.63 (m, 2H), 4.45
(d, J = 4.0 Hz, 1H), 3.76 (d, J = 12.5 Hz, 1H), 3.58 (d, J =
16.0 Hz, 1H), 3.44 (d, J = 14.0 Hz, 1H), 3.24–3.19 (m, 1H), 3.14
(d, J = 14.0 Hz, 1H), 2.97 (d, J = 12.5 Hz, 1H), 2.90–2.86 (m,
2H), 2.59 (d, J = 16.0 Hz, 1H), 2.19–2.12 (m, 1H), 1.95–1.89 (m,
◦
H]+: 604.1513, Found: 604.1511. mp >154 C (decomp.). [a]2D2
+1260 (c 0.230 g/100 mL, CH2Cl2). The enantiomeric excess was
determined by HPLC. [IC column, 240 nm, DCM/EtOH = 98 : 2,
0.9 mL/min]: 19.506 min (major), 16.329 min (minor), ee = 92%.
7ca-major. 1H NMR (400 MHz, CDCl3): d 8.43 (d, J = 8.4 Hz,
1H), 7.60–7.51 (m, 5H), 7.44–7.42 (m, 2H), 7.31–7.26 (m, 2H),
7.16–7.10 (m, 1H), 6.78–6.76 (m, 2H),4.32 (d, J = 4.0 Hz, 1H), 3.38
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 793–801 | 797
©

View Article Online
(d, J = 16.0 Hz, 1H), 3.27–3.21 (m, 1H), 3.19–3.16 (m, 1H), 3.08 (d,
J = 16.4 Hz, 1H), 2.99–2.95 (m, 1H), 2.90–2.88 (m, 1H), 2.87–2.82
(m, 1H), 2.37–2.28 (m, 1H), 2.13 (brs, 1H), 2.10–2.01 (m, 1H),1.94–
1.83 (m, 2H), 1.65–1.23 (m, 6H). 13C NMR(100 MHz, CDCl3): d
177.1,175.5, 170.8, 142.8, 138.5, 134.0, 133.8, 133.7, 132.9, 131.8,
130.1, 129.4, 129.1, 128.9,128.0, 127.4, 126.7, 123.5, 121.2, 73.4,
60.1, 60.0, 55.6, 54.6, 46.8, 33.6, 22.7, 19.7, 19.3.HRMS (EI)
calculated for C31H32N3O4ClNi [M]+: 603.1435, Found: 603.1436.
mp >268 ◦C (decomp.). [a]D22 -2101 (c 0.275 g/100 mL, CH2Cl2).
The enantiomeric excess was determined by HPLC. [IA column,
240 nm, DCM, 0.5 mL/min]: 12.132 min (major), 15.678 min
(minor), ee = 91%.
column, 240 nm, DCM/EtOH = 98 : 2, 0.5 mL/min]: 13.147 min
(major), 9.448 min (minor), ee = 96%.
7ae-major. 1H NMR (400 MHz, CDCl3): d 8.42 (d, J = 8.4 Hz,
1H), 7.71 (d, J = 8.0 Hz,2H), 7.57–7.49 (m, 3H), 7.36 (d, J =
8.0 Hz, 2H), 7.24–7.22 (m, 2H), 7.09 (d, J = 6.8 Hz, 1H), 6.76–
6.71 (m, 2H), 4.26 (d, J = 3.6 Hz, 1H), 3.36 (d, J = 16.4 Hz, 1H),
3.24–3.18 (m, 1H), 3.14 (m, 1H), 3.08 (d, J = 16.4 Hz, 1H),2.96
(d, J = 13.2 Hz, 1H), 2.87 (m, 1H), 2.84–2.79 (m, 1H), 2.33–
2.26 (m, 2H), 2.05–1.96 (m, 1H), 1.92–1.89 (m, 1H), 1.88–1.82
(m, 1H), 1.64–1.32 (m, 5H). 13C NMR (100 MHz, CDCl3): d
177.0, 175.5, 170.8, 142.8, 139.0, 133.7, 133.6, 132.8, 132.2, 131.8,
130.1, 129.3, 129.1, 127.9, 127.3, 126.6, 123.5, 122.0, 121.1, 73.5,
60.0, 59.9, 55.6, 54.5, 46.9, 33.6, 22.7, 19.6, 19.3. HRMS (EI)
calculated◦for C31H32N3O4NiBr [M]+: 649.0909, Found: 649.0908.
mp >260 C (decomp.). [a]2D2 -950 (c 0.205 g/100 mL, CH2Cl2).
The enantiomeric excess was determined by HPLC. [IA column,
240 nm, DCM/EtOH = 99.5 : 0.5, 0.8 mL/min]: 8.095 min (major),
9.249 min (minor), ee = 89%.
7ca-minor. 1H NMR (400 MHz, CDCl3): d 8.59 (d, J = 8.8 Hz,
1H), 7.54–7.41 (m, 3H), 7.33–7.29 (m, 3H), 7.24 (d, J = 7.6 Hz,
1H), 7.02 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 7.6 Hz, 1H), 6.79–6.73
(m, 2H), 4.24 (d, J = 4.0 Hz, 1H), 3.58 (s, 2H), 3.51–3.46 (m, 1H),
3.38–3.26 (m, 2H), 3.12 (d, J = 13.2 Hz, 1H), 2.98–2.90 (m, 1H),
2.76–2.69 (m, 1H), 2.63–2.58 (m, 1H), 2.17–2.06 (m, 1H), 1.77–
1.59 (m, 4H), 1.50–1.41 (m, 3H). 13C NMR (100 MHz, CDCl3): d
177.0, 175.9, 171.6, 143.0, 137.4, 134.2, 133.7, 133.4, 133.0, 130.9,
130.0, 129.4, 129.1, 128.8, 128.6, 127.9, 127.0, 123.2, 121.1, 74.9,
60.6, 60.0, 56.4, 54.4, 46.9, 34.1, 22.8, 19.9, 19.3. HRMS (EI)
calculated for C31H32N3O4ClNi [M]+:603.1435, Found: 603.1437.
mp >260 ◦C (decomp.). [a]D22 +1421(c 0.200 g/100 mL, CH2Cl2).
The enantiomeric excess was determined by HPLC. [IA column,
254 nm, DCM/EtOH = 98 : 2, 0.65 mL/min]: 9.491 min (major),
7.124 min (minor), ee = 99%.
7ae-minor. 1H NMR (500 MHz, CDCl3): d 8.60 (d, J = 8.5 Hz,
1H), 7.54–7.46 (m, 5H),7.32–7.30 (m, 1H), 7.24 (d, J = 7.0 Hz, 1H),
6.98 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 7.0 Hz, 1H), 6.79–6.76 (m, 2H),
4.24 (d, J = 2.5 Hz, 1H), 3.58 (s, 2H), 3.46 (m, 1H), 3.34 (d, J = 12.5
Hz,1H), 3.30 (m, 1H), 3.12 (d, J = 12.5 Hz, 1H), 2.87–2.89 (m, 1H),
2.70 (t, J = 12.5 Hz, 1H), 2.57 (d, J = 12.5 Hz, 1H), 2.09 (brs, 1H),
1.70 (m, 2H), 1.61–1.31 (m, 6H). 13C NMR (100 MHz, CDCl3): d
177.0, 175.9, 171.7, 143.0, 138.0, 134.3, 133.7, 133.0, 131.6, 131.3,
130.0,129.4, 129.1, 128.8, 127.9, 126.9, 123.2, 121.6, 121.1, 74.8,
60.6, 59.9, 56.4, 54.4, 46.9, 34.2, 22.8, 19.9, 19.3. HRMS (EI)
calculated◦for C31H32N3O4NiBr [M]+: 649.0909, Found: 649.0905.
mp >249 C (decomp.). [a]2D2 +937 (c 0.205 g/100 mL, CH2Cl2).
The enantiomeric excess was determined by HPLC. [IA column,
240 nm, DCM/EtOH = 95 : 5, 0.8 mL/min]: 6.007 min (major),
5.196 min (minor), ee = 89%.
7ad-major. 1H NMR (500 MHz, CDCl3): d 8.44 (d, J = 8.5 Hz,
1H), 7.63–7.54 (m, 3H),7.49–7.46 (m, 2H), 7.35–7.29 (m, 4H), 7.12
(d, J = 7.0 Hz, 1H), 6.78 (d, J = 4.0 Hz, 2H), 4.39 (d, J = 3.5 Hz,
1H), 3.37 (d, J = 16.5 Hz, 1H), 3.30 (d, J = 12.5 Hz, 1H), 3.26–
3.22 (m, 1H), 3.08 (d, J = 16.0 Hz, 1H), 2.98 (d, J = 13.0 Hz,
1H), 2.90–2.84 (m, 2H), 2.43–2.37 (m, 1H), 2.14–2.07 (m, 1H),
1.99 (m, 1H), 1.90–1.84 (m, 1H), 1.76 (brs, 1H), 1.67–1.62 (m,
2H), 1.53–1.34 (m,4H). 13C NMR (100 MHz, CDCl3): d 177.2,
175.3, 170.7, 142.9, 135.8, 135.7, 133.8, 133.7,132.9, 131.9, 131.8,
130.1, 129.4, 129.0, 128.0, 127.5, 126.7, 123.5, 121.1, 115.7, 115.5,
73.4, 60.4, 60.3, 55.8, 54.7, 46.7, 34.0, 22.8, 19.8, 19.4. HRMS
(ESI) calculated for C31H33N3O4FNi [M + H]+: 588.1809, Found:
588.1795. mp >262 ◦C (decomp.). [a]2D2 -1684 (c 0.280 g/100 mL,
CH2Cl2). The enantiomeric excess was determined by HPLC. [IC
column, 240 nm, DCM/EtOH = 98 : 2, 0.9 mL/min]: 11.936 min
(major), 19.113 min (minor), ee = 92%.
7af-major. 1H NMR (400 MHz, CDCl3): d 8.45 (d, J = 8.4 Hz,
1H), 7.58–7.55 (m, 5H),7.47–7.40 (m, 2H), 7.31–7.28 (m, 2H), 7.15
(d, J = 6.8 Hz, 1H), 6.79–6.75 (m, 2H), 4.31 (d, J = 2.4 Hz, 1H),
3.26 (d, J = 16.0 Hz, 2H), 3.20 (d, J = 13.6 Hz, 1H), 3.12 (d, J =
16.0 Hz, 2H), 2.94–2.92 (m, 1H), 2.85 (d, J = 13.2 Hz, 1H), 2.29
(brs, 1H), 2.24 (s, 3H), 1.95 (m, 2H), 1.89 (m, 2H), 1.64–1.29 (m,
6H). 13C NMR (100 MHz, CDCl3): d 177.4, 175.2, 170.6, 142.8,
139.1, 138.6, 133.7, 133.5, 132.8, 130.1, 129.3, 129.2, 127.6, 127.4,
127.1, 126.8, 123.4, 121.0, 75.0, 60.4, 60.0, 55.4, 54.7, 42.1, 35.6,
22.7, 20.5, 19.7, 19.5. HRMS (ESI) calculated for C32H36N3O4Ni
[M + H]+: 584.2059, Found: 584.2031. mp >280 ◦C (decomp.).
[a]2D2 -2178 (c 0.245 g/100 mL, CH2Cl2). The enantiomeric excess
was determined by HPLC. [IC column, 240 nm, DCM/EtOH =
98 : 2, 0.8 mL/min]: 14.010 min (major), 27.034 min (minor), ee =
91%.
7ad-minor. 1H NMR (400 MHz, CDCl3): d 8.59 (d, J = 8.8 Hz,
1H), 7.54–7.44 (m, 3H),7.33–7.29 (m, 1H), 7.23 (d, J = 7.6 Hz,
1H), 7.00 (d, J = 6.8 Hz, 4H), 6.85 (d, J = 7.2 Hz, 1H), 6.79–
6.73 (m, 2H), 4.22 (d, J = 3.6 Hz, 1H), 3.59 (s, 2H), 3.52–3.46
(m, 1H), 3.39–3.27 (m, 2H), 3.14–3.05 (m, 2H), 2.81–2.65 (m,
2H), 2.16–2.10 (m, 1H), 1.96 (brs, 1H), 1.75–1.68 (m, 1H), 1.62–
1.53 (m, 2H), 1.50–1.29 (m, 4H). 13C NMR (100 MHz, CDCl3): d
177.2, 175.9, 171.5,142.9, 134.7, 134.2, 133.6, 132.9, 131.0, 130.9,
130.0, 129.3, 129.1, 128.8, 127.8, 127.0, 123.2, 121.1, 115.4, 115.2,
74.9, 60.7, 59.9, 56.5, 54.4, 46.7, 34.3, 22.8, 19.9, 19.3. HRMS
(ESI) calculated for C31H33N3O4FNi [M + H]+: 588.1809, Found:
588.1791. mp >271 ◦C (decomp.). [a]2D2 +1309 (c 0.250 g/100 mL,
CH2Cl2). The enantiomeric excess was determined by HPLC. [IA
7af-minor. 1H NMR (400 MHz, CDCl3): d 8.57 (d, J = 8.8 Hz,
1H), 7.47–7.45 (m, 2H),7.30–7.28 (m, 5H), 7.24–7.19 (m, 2H),
6.89–6.61 (m, 3H), 4.48 (m, 1H), 4.34 (d, J = 4.4 Hz, 1H), 3.42
(dd, J = 16.0, 28.0 Hz, 2H), 3.26–3.20 (m, 2H), 3.08–3.00 (m, 2H),
2.62–2.54 (m, 1H), 2.49 (s, 3H), 2.40–2.36 (m, 1H), 1.82–1.56 (m,
5H), 1.42–1.32 (m, 3H). 13C NMR (100 MHz, CDCl3): d 178.2,
175.6, 171.0, 143.1, 138.9, 138.0, 134.4, 133.5, 132.9, 131.1, 130.0,
129.8, 128.7, 128.6, 128.1, 127.2, 127.0, 126.3, 123.0, 120.9, 75.0,
60.6, 59.8, 55.7, 54.1, 37.2, 29.7, 22.8, 20.0, 19.8, 19.2. HRMS
798 | Org. Biomol. Chem., 2011, 9, 793–801
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
(ESI) calculated for C32H36N3O4Ni [M + H]+: 584.2059, Found
584.2058. mp >247 ◦C (decomp.). [a]2D2 +825 (c 0.250 g/100 mL,
CH2Cl2). The enantiomeric excess was determined by HPLC. [IA
column, 240 nm, DCM/EtOH = 98 : 2, 0.65 mL/min]: 6.463 min
(major), 5.702 min (minor), ee = 91%.
1H), 3.24–3.20 (m, 1H), 3.04 (d, J = 13.2 Hz, 1H), 2.62–2.54 (m,
1H), 2.37 (m, 1H), 2.39 (s, 3H), 2.05–1.97 (m, 1H), 1.73–1.57 (m,
4H), 1.44–1.38 (m, 3H). 13C NMR (100 MHz, CDCl3): d 177.5,
175.7, 171.4, 143.0, 137.3, 136.0, 134.3, 133.7, 132.9, 130.0, 129.9,
129.8, 129.4, 129.0, 128.7, 128.1, 127.1, 123.0, 121.0, 75.3, 60.4,
60.2, 55.9, 54.2, 47.4, 34.9, 22.8, 21.2, 19.8, 19.2. HRMS (EI)
calculated for C32H35N3O4Ni [M]+: 583.1981, Found: 583.1964.
mp >278 ◦C (decomp.). [a]D22 +1424 (c 0.225 g/100 mL, CH2Cl2).
The enantiomeric excess was determined by HPLC. [IA column,
254 nm, DCM/EtOH = 98 : 2, 0.65 mL/min]: 8.796 min (major),
6.701 min (minor), ee = 82%.
7ag-major. 1H NMR (500 MHz, CDCl3): d 8.44 (d, J = 8.5 Hz,
1H), 7.62–7.52 (m, 4H),7.43 (d, J = 7.5 Hz, 1H), 7.33–7.30 (m, 4H),
7.16 (d, J = 7.0 Hz, 1H), 6.81–6.76 (m, 2H), 4.38 (d, J = 4.0 Hz,
1H), 3.30 (d, J = 16.0 Hz, 1H), 3.27–3.22 (m, 2H), 3.04 (d, J =
16.0 Hz, 1H), 2.95 (d, J = 13.0 Hz, 1H), 2.89 (m, 1H),2.79–2.83
(m, 1H), 2.43 (s, 3H), 2.39–2.34 (m, 1H), 2.28 (brs, 1H), 2.18–
2.10 (m, 1H), 1.99–1.88 (m, 2H), 1.67–1.60 (m, 1H), 1.52–1.42 (m,
2H), 1.35–1.26 (m, 3H). 13C NMR (100 MHz, CDCl3): d 177.4,
175.4, 170.3, 142.8, 140.0, 138.8, 133.8, 133.7, 132.7, 130.0, 129.3,
129.0, 128.8, 128.7, 128.0, 127.5, 126.8, 123.5, 121.1, 73.5, 60.5,
60.1, 55.4, 54.5, 47.3, 33.8, 22.8, 21.6, 19.7, 19.3. HRMS (EI)
calculated for C32H35N3O4Ni [M]+: 583.1981, Found: 583.1981.
mp >246 ◦C (decomp.). [a]D22 -1719 (c 0.260 g/100 mL, CH2Cl2).
The enantiomeric excess was determined by HPLC. [IA column,
254 nm, DCM/EtOH = 99 : 1, 0.65 mL/min]: 5.848 min (major),
6.921 min (minor), ee = 92%.
7ai-major. 1H NMR (400 MHz, CDCl3): d 8.32 (d, J = 8.4 Hz,
1H), 7.55–7.48 (m, 5H), 7.25–7.16 (m, 4H), 7.10 (d, J = 8.0 Hz,
1H), 6.75–6.68 (m, 2H), 4.25 (d, J = 4.4 Hz, 1H), 3.62–3.57 (m,
1H), 3.27 (s, 3H), 3.22 (m, 1H), 3.21 (d, J = 16.0 Hz, 1H), 3.14 (t,
J = 5.2 Hz, 1H), 2.96 (d, J = 16.0 Hz, 1H), 2.85 (d, J = 13.2 Hz, 2H),
2.54 (brs, 1H), 2.35–2.28 (m, 1H), 2.17–2.08 (m, 1H), 1.97–1.94
(m, 1H), 1.76–1.68 (m, 1 H), 1.59–1.52 (m, 1H), 1.41–1.38 (m, 2H),
1.26–1.17 (m, 3H).13C NMR (100 MHz, CDCl3): d 177.6, 175.3,
170.9, 158.4, 142.4, 133.9, 133.4, 132.2,130.0, 129.9, 129.1, 129.0,
128.9, 128.7, 128.1, 127.4, 126.8, 123.3, 121.2, 120.8, 110.1,73.5,
60.6, 60.3, 55.4, 54.8, 54.7, 37.6, 33.7, 22.8, 19.7, 19.4. HRMS (ESI)
calculated for C32H35N3O5Ni [M]+: 599.1930, Found: 599.1935. mp
>259 ◦C (decomp.). [a]2D2 -1554 (c 0.150 g/100 mL, CH2Cl2). The
enantiomeric excess was determined by HPLC. [IA column, 254
nm, DCM/EtOH = 99 : 1, 0.65 mL/min]: 6.053 min (major), 7.379
min (minor), ee = 91%.
7ag-minor. 1H NMR (500 MHz, CDCl3): d 8.60 (d, J = 8.5 Hz,
1H), 7.52–7.45 (m, 2H),7.43–7.40 (m, 1H), 7.32–7.27 (m, 2H),
7.23–7.18 (m, 2H), 7.09 (d, J = 7.5 Hz, 1H), 6.92 (d, J = 6.0 Hz,
1H), 6.80 (d, J = 7.5 Hz, 1H), 6.74 (d, J = 4.0 Hz, 2H), 4.25
(d, J = 3.5 Hz, 1H), 3.64–3.61 (m, 1H), 3.47 (s, 2H), 3.30–3.26
(m, 1H), 3.23–3.17 (m, 1H), 3.03 (d, J = 13.0 Hz, 1H), 2.62–2.56
(m, 1H), 2.42 (d, J = 15.0 Hz, 1H), 2.39–2.35 (m, 1H), 2.28 (s,
3H), 2.07 (brs, 1H), 2.01–1.97 (m, 2H),1.70–1.53 (m, 2H), 1.43–
1.26 (m, 4H). 13C NMR (100 MHz, CDCl3): d 177.7, 175.8, 171.4,
143.0, 139.1, 138.4, 134.3, 133.6, 132.9, 130.8, 130.0, 129.8, 129.0,
128.7, 128.5, 128.4, 128.1, 127.1, 127.0, 123.0, 121.0, 75.1, 60.5,
60.0, 55.9, 54.2, 47.7, 34.8, 22.8, 21.5, 19.8, 19.2. HRMS (EI)
calculated for C32H35N3O4Ni [M]+: 583.1981, Found: 583.1978.
mp >147 ◦C (decomp.). [a]D22 +1548 (c 0.230 g/100 mL, CH2Cl2).
The enantiomeric excess was determined by HPLC. [IA column,
254 nm, DCM/EtOH = 98 : 2, 0.65 mL/min]: 8.635 min (major),
6.425 min (minor),ee = 95%.
Note: Recrystallization by slow evaporation of CHCl3 and ether
gave red crystalsof the major stereoisomer of adduct 7ai suitable
for single-crystal X-ray diffraction.
7aj-major. 1H NMR (400 MHz, CDCl3): d 8.42 (d, J = 8.8 Hz,
1H), 7.56–7.48 (m, 4H),7.28–7.24 (m, 2H), 7.13–7.11 (m, 2H),
7.05–7.00 (m, 2H), 6.75–6.72 (m, 2H), 4.33 (d, J = 4.0 Hz, 1H),
3.76 (s, 3H), 3.29 (d, J = 16.0 Hz, 1H), 3.23–3.19 (m, 2H), 3.08
(d, J = 16.0 Hz, 1H), 2.94 (d, J = 12.8 Hz, 1H), 2.87 (m,1H),
2.82–2.77 (m, 1H), 2.39 (brs, 1H), 2.36–2.33 (m, 1H), 2.14–2.00
(m, 2H), 1.91–1.86 (m, 1H), 1.66–1.56 (m, 1H), 1.28–1.22 (m,
5H).13C NMR (100 MHz, CDCl3): d 177.4, 175.4, 170.4, 160.1,
142.9, 141.6, 133.7, 133.6, 132.7, 130.0, 129.8, 129.3, 129.0, 128.0,
127.4, 126.7, 123.5, 122.9, 121.0, 115.1, 113.9, 73.5, 60.4, 60.1, 55.4,
55.2, 54.5, 47.4, 33.8, 22.8, 19.7, 19.3. HRMS (ESI) calculated
for C32H36N3O5Ni [M + H]+: 600.2008, Found: 600.1998. mp
>258 ◦C (decomp.). [a]2D2 -1641 (c 0.165 g/100 mL, CH2Cl2). The
enantiomeric excess was determined by HPLC. [IA column, 240
nm,DCM/EtOH = 98 : 2, 0.65 mL/min]: 5.298 min (major), 5.703
min (minor), ee = 90%.
7ah-major. 1H NMR (400 MHz, CDCl3): d 8.37 (d, J = 8.4 Hz,
1H), 7.55–7.47 (m, 3H), 7.39–7.34 (m, 4H), 7.25–7.20 (m, 2H), 7.08
(d, J = 6.0 Hz, 1H), 6.74–6.69 (m, 2H), 4.27 (d, J = 4.0 Hz, 1H), 3.26
(d, J = 15.6 Hz, 1H), 3.21–3.11 (m, 2H), 2.96 (d, J = 16.0 Hz, 1H),
2.89–2.81 (m, 2H), 2.80–2.75 (m, 1H), 2.47 (brs, 1H), 2.45 (s, 3H),
2.30–2.23 (m, 1H), 2.07–1.98 (m, 1H), 1.88–1.81 (m, 2H), 1.63–
1.20 (m, 6H).13C NMR (100 MHz, CDCl3): d 177.2, 175.2, 170.3,
142.7, 137.3, 136.9, 133.6, 132.5, 130.3, 130.0, 129.4, 129.2, 129.0,
127.9, 127.2, 126.8, 123.4, 121.0, 73.9, 60.1, 55.3, 54.5, 47.0, 33.9,
22.7, 21.2, 19.6, 19.3. HRMS (EI) calculated for C32H35N3O4Ni
7aj-minor. 1H NMR (400 MHz, CDCl3): d 8.62 (d, J = 8.4 Hz,
1H), 7.51–7.44 (m, 2H),7.41–7.38 (m, 1H), 7.32–7.23 (m, 3H), 6.92
(d, J = 8.0 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.77–6.72 (m, 4H),
4.26 (d, J = 3.2 Hz, 1H), 3.79–3.76 (m, 1H), 3.70 (s, 3H), 3.54 (dd,
J = 16.4 Hz, 30.8 Hz, 2H), 3.39–3.33 (m, 1H), 3.29–3.23 (m, 2H),
3.06 (d, J = 13.2 Hz, 1H), 2.69–2.63 (m, 1H), 2.55 (d, J = 13.2 Hz,
1H), 2.46–2.38 (m, 1H), 2.04–1.98 (m, 1H), 1.91 (brs, 1H), 1.74–
1.56 (m, 2H), 1.46–1.29 (m, 4H).13C NMR (100 MHz, CDCl3): d
177.6, 175.9, 171.3, 159.9, 143.1, 140.7,134.3, 133.6, 132.9, 129.9,
129.7, 129.5, 128.9, 128.6, 128.0, 126.9, 123.0, 122.3, 120.9, 114.8,
113.7, 75.2, 60.5, 60.0, 56.0, 55.2, 54.2, 48.2, 34.9, 22.8, 19.8, 19.2.
◦
[M]+: 583.1981, Found: 583.1983. mp >266 C (decomp.). [a]2D2
-1952 (c 0.215 g/100 mL, CH2Cl2). The enantiomeric excess was
determined by HPLC. [IA column, 254 nm, DCM/EtOH = 98 : 2,
0.65 mL/min]: 5.463 min (major), 6.423 min (minor), ee = 89%.
7ah-minor. 1H NMR (400 MHz, CDCl3): d 8.60 (d, J = 8.8 Hz,
1H), 7.53–7.40 (m, 4H), 7.31–7.28 (m, 1H), 7.22 (d, J = 8.0 Hz,
2H), 7.13 (d, J = 7.6 Hz, 2H), 6.83 (d, J = 7.6 Hz, 1H), 6.75 (d, J =
4.0 Hz, 2H), 4.26 (d, J = 2.8 Hz, 1H), 3.61–3.58 (m, 1H), 3.47 (dd,
J = 16.4, 24.0 Hz, 2H), 3.38–3.33 (m, 1H), 3.28 (d, J = 13.2 Hz,
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 793–801 | 799
©

View Article Online
HRMS (ESI) calculated for C32H36N3O5Ni [M + H]+: 600.2008,
CDCl3): d 177.9, 174.8, 171.0, 153.1, 149.0, 142.8, 133.9, 133.8,
133.5, 132.4, 129.8, 129.0, 128.8, 128.2, 127.4, 127.0, 124.1, 123.3,
121.7, 120.7, 111.9, 73.4, 60.6, 60.5, 60.3, 56.1, 55.6, 54.6, 38.0,
34.6, 22.8, 19.8, 19.5. HRMS (ESI) calculated for C33H38N3O6Ni
[M + H]+: 630.2114, Found: 630.2093. mp >257 ◦C (decomp.).
[a]2D2 -1546 (c 0.240 g/100 mL, CH2Cl2). The enantiomeric excess
was determined by HPLC. [IA column, 240 nm, DCM/EtOH =
98 : 2, 0.65 mL/min]: 5.234 min (major), 6.179 min (minor), ee =
95%.
◦
Found: 600.1988. mp >252 C (decomp.). [a]2D2 +1147 (c 0.275
g/100 mL, CH2Cl2). The enantiomeric excess was determined by
HPLC. [IC column, 240 nm, DCM/EtOH = 98 : 2, 0.9 mL/min]:
19.210 min (major), 13.171 min (minor), ee = 100%.
7ak-major. 1H NMR (400 MHz, CDCl3): d 8.40 (d, J = 8.4 Hz,
1H), 7.61–7.52 (m, 3H),7.40 (d, J = 8.0 Hz, 2H), 7.32–7.29 (m, 2H),
7.17–7.11 (m, 3H), 6.78–6.75 (m, 2H), 4.37 (d, J = 4.0 Hz, 1H), 3.89
(s, 3H), 3.31 (d, J = 16.0 Hz, 1H), 3.26 (d, J = 10.8 Hz, 1H), 3.05
(d, J = 16.0 Hz, 1H), 2.92 (t, J = 13.6 Hz, 2H),2.80 (t, J = 9.2 Hz,
1H), 2.43–2.36 (m, 1H), 2.23 (brs, 1H), 2.16–2.05 (m, 2H), 1.90–
1.78 (m, 2H), 1.65–1.24 (m, 6H).13C NMR (100 MHz, CDCl3):
d 177.5, 175.3, 170.3, 159.6, 142.8, 133.8, 133.7, 132.7, 131.8,
131.4, 130.0, 129.3, 129.0, 128.1, 127.5, 126.8, 123.4, 121.0, 114.2,
73.5, 60.6, 60.2, 55.5, 54.7, 46.7, 33.9, 22.8, 19.7, 19.4. HRMS
(ESI) calculated for C32H36N3O5Ni [M + H]+: 600.2008, Found:
600.1982. mp >272 ◦C (decomp.). [a]2D2 -1362 (c 0.230 g/100 mL,
CH2Cl2). The enantiomeric excess was determined by HPLC. [IC
column, 240 nm, DCM/EtOH = 98 : 2, 0.9 mL/min]: 13.245 min
(major), 25.841 min (minor), ee = 90%.
7an-major. 1H NMR (400 MHz, CDCl3): d 8.33 (d, J = 8.8 Hz,
1H), 7.50–7.42 (m, 4H),7.20 (m, 3H), 6.74–6.67 (m, 4H), 4.20
(d, J = 3.6 Hz, 1H), 3.84 (s, 3H), 3.51 (m, 1H), 3.26 (s, 3H),
3.24 (m, 2H), 3.16–3.14 (m, 1H), 3.00 (d, J = 16.0 Hz, 1H), 2.87
(d, J = 14.0 Hz, 1H), 2.81 (m, 1H), 2.52 (brs, 1H), 2.39–2.32
(m, 1H), 2.10–2.05 (m, 2H), 1.73–1.68 (m, 1H), 1.60–1.55 (m,
1H), 1.42–1.19 (m, 5H).13 C NMR (100 MHz, CDCl3): d 177.8,
175.3, 170.8, 160.3, 159.4, 142.5, 133.9, 133.4,132.2, 130.4, 129.8,
129.0, 128.9, 128.1, 127.4, 126.8, 123.3, 120.9, 120.8, 105.4,97.6,
73.7,60.7, 60.2, 55.5, 55.4, 54.8, 54.7, 37.4, 33.7, 22.8, 19.6, 19.4.
HRMS (ESI) calculated for C33H38N3O6Ni [M + H]+: 630.2114,
◦
Found: 630.2090. mp >272 C (decomp.). [a]2D2 -2156 (c 0.265
7al-major. 1H NMR (400 MHz, CDCl3): d 8.42 (d, J = 8.4 Hz,
1H), 8.06 (d, J = 7.6 Hz, 2H), 7.99–7.93 (m, 2H), 7.59–7.52 (m, 6H),
7.31–7.29 (m, 2H), 7.24 (d, J = 6.4 Hz, 1H), 6.82–6.76 (m, 2H), 4.42
(d, J = 2.8 Hz, 1H), 3.27 (m, 1H), 3.09 (d, J = 14.4 Hz, 1H), 3.04 (m,
1H), 2.96 (m, 1H), 2.89 (d, J = 16.0 Hz,1H), 2.82 (d, J = 12.8 Hz,
1H), 2.25–2.20 (m, 1H), 2.10–1.94 (m, 2H), 1.87 (m, 1H), 1.48–1.41
(m, 1H), 1.34–1.28 (m, 2H), 1.12–1.00 (m, 2H), 0.89–0.80 (m, 2H).
13C NMR (100 MHz, CDCl3): d 177.3, 175.6, 170.5, 142.9, 137.3,
133.8, 133.7, 133.4, 132.8, 130.8, 129.3, 129.1, 128.3, 128.0, 127.5,
126.8, 126.7, 126.6, 123.5, 121.0, 73.8, 60.4, 59.2, 54.9, 54.2, 47.5,
33.7, 22.5, 19.2, 19.0. HRMS (ESI) calculated for C35H36N3O4Ni
[M + H]+:620.2059, Found: 620.2028. mp >277 ◦C (decomp.). [a]2D2
-1767 (c 0.230 g/100 mL, CH2Cl2). The enantiomeric excess was
determined by HPLC. [IC column, 240 nm, DCM/EtOH = 98 : 2,
0.65 mL/min]: 16.318 min (major), 31.464 min (minor), ee = 87%.
g/100 mL, CH2Cl2). The enantiomeric excess was determined by
HPLC. [IA column, 240 nm, DCM/EtOH = 98 : 2, 0.5 mL/min]:
6.972 min (major), 8.193 min (minor), ee = 88%.
General Procedure for the preparation of the corresponding
derivative of the related amino acid
To a solution of 7ai (0.2 mmol) in methanol (2 mL) was added an
aqueous solution of hydrochloride (6 N, 0.2 mL), and the mixture
was refluxed in a sealed tube for 20 min. Then the reaction mixture
was evaporated in vacuo to dryness. The residue was dissolved in
MeCN (1 mL), then K2CO3 (0.8 mmol) and TsCl (4.4 mmol)
were added successively. The reaction mixture was then stirred
vigorously for 6 h, followed by quenching with 1 N HCl (to pH
2) and extraction of the product with CH2Cl2. The organic phase
was evaporated in vacuo. After removal of the solvent, the crude
product was purified by column chromatography to give pure 9ai
as a white solid.
7al-minor. 1H NMR (400 MHz, CDCl3): d 8.60 (d, J = 8.8 Hz,
1H), 7.88 (t, J = 8.8 Hz, 2H), 7.80–7.76 (m, 2H), 7.48–7.34 (m,
6H), 7.22 (d, J = 7.2 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.75–6.71
(m, 2H), 4.38 (d, J = 2.4 Hz, 1H), 3.78 (t, J = 4.4 Hz, 1H), 3.28–
3.22 (m, 1H), 3.18 (d, J = 16.0 Hz, 2H), 3.11 (d, J = 12.0 Hz, 1H),
2.91 (d, J = 13.2 Hz, 1H), 2.69 (d, J = 16.4 Hz, 1H), 2.57 (brs,
1H), 2.31–2.26 (m, 2H), 2.11–2.02 (m, 1H), 1.70 (m, 1H), 1.56–
1.39 (m, 2H), 1.31–1.04 (m, 4H).13C NMR (100 MHz, CDCl3): d
177.7, 175.9, 171.7, 143.2, 136.7, 134.4, 133.7, 133.6, 133.1, 133.0,
130.0, 129.9, 129.1, 129.0, 128.7, 128.1, 128.0, 127.9, 127.5, 127.0,
126.4, 126.3, 122.9, 120.9, 75.2, 59.9, 59.8, 55.5, 54.0, 47.8, 35.0,
22.7, 19.4, 19.0. HRMS (ESI) calculated for◦C35H36N3O4Ni [M
+ H]+: 620.2059, Found: 620.2029. mp >266 C (decomp.). [a]2D2
+1561 (c 0.255 g/100 mL, CH2Cl2). The enantiomeric excess was
determined by HPLC. [IA column, 240 nm, DCM/EtOH = 98 : 2,
0.65 mL/min]: 8.000 min (major), 6.221 min (minor), ee = 71%.
N-((3R,4S)-4-(2-Methoxyphenyl)-2-oxotetrahydro-2H-pyran-
3-yl)-4-methylbenzenesulfonamide (9ai). The product was
obtained in 79% yield as a white solid. 1H NMR (400 MHz,
CDCl3): d (ppm) 7.66–7.64 (m, 2H), 7.29–7.24 (m, 3H), 6.98–6.96
(dd, J = 7.2, 1.6 Hz, 1H), 6.91–6.85 (m, 2H), 5.23–5.21 (d, J =
6.4 Hz, 1H), 4.35–4.27 (m, 3H), 3.92–3.85 (q, J = 26.4 Hz, 1H),
3.73 (s, 3H), 2.42 (s, 3H), 2.32–2.25 (m, 1H), 2.17–2.07 (m, 1H).
13C-NMR (100 MHz, CDCl3): d (ppm) 170.7, 156.7, 143.5, 136.8,
131.1, 129.6, 128.9, 127.1, 121.0, 110.7, 66.3, 54.1, 53.2, 29.7, 29.3,
21.5. HRMS (EI): exact mass calculated for [M]+ (C19H21NO5S)
◦
requires m/z 375.1140, found m/z 375.1143. mp 55 C. [a]D20
-161.9 (c 1.0 g/100 mL, CH2Cl2).
=
7am-major. 1H NMR (400 MHz, CDCl3): d 8.37 (d, J = 8.4 Hz,
1H), 7.51 (m, 3H), 7.24–7.17 (m, 5H), 7.12 (d, J = 8.0 Hz, 1H),
6.71–6.66 (m, 2H), 4.25 (d, J = 4.4 Hz, 1H), 3.86 (s, 3H), 3.60 (s,
3H), 3.51 (m, 1H), 3.23 (d, J = 15.6 Hz, 2H), 3.19 (m, 1H), 3.04 (d,
J = 16.0 Hz, 1H), 2.86 (m, 2H), 2.46–2.40 (m, 2H), 2.00–1.94 (m,
1H), 1.82–1.77 (m, 1H), 1.60–1.25 (m, 6H). 13C NMR (100 MHz,
Acknowledgements
We are grateful for the financial support from National Natural
Science Foundation of China (20902018), Shanghai Pujiang
Program (08PJ1403300) and the Fundamental Research Funds
for the Central Universities.
800 | Org. Biomol. Chem., 2011, 9, 793–801
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
ˇ
V. V. Prisyazhnyuk and S. Vyskocˇil, J. Am. Chem. Soc., 2003, 125, 12860;
(h) R. E. Looper and R. M. Williams, Angew. Chem., Int. Ed., 2004,
43, 2930; (i) R. E. Looper, M. T. C. Runnegar and R. M. Williams,
Angew. Chem., Int. Ed., 2005, 44, 3879; (j) V. A. Soloshonok, C. Cai,
T. Yamada, H. Ueki, Y. Ohfune and V. J. Hruby, J. Am. Chem. Soc.,
2005, 127, 15296; (k) T. Yamada, T. Okada, K. Sakaguchi, Y. Ohfune,
H. Ueki and V. A. Soloshonok, Org. Lett., 2006, 8, 5625.
References
1 (a) G. C. Barret, Chemistry and Biochemistry of Amino Acids, Chapman
and Hall, London, 1985; (b) S. V. Bhat, B. A. Nagasampagi, M.
Sivakumar, Chemistry of Natural Products, Springer, Narosa, 2005,
p. 317.
2 For some representative applications, see, for example: (a) J. F. Sardina
and H. Rapoport, Chem. Rev., 1996, 96, 1825; (b) F. P. J. T. Rutjes, L.
B. Wolf and H. E. Schoemaker, J. Chem. Soc., Perkin Trans. 1, 2000,
4197; (c) E. R. Jarvo and S. J. Miller, Tetrahedron, 2002, 58, 2481; (d) U.
Kazmaier, Angew. Chem., Int. Ed., 2005, 44, 2186; (e) J. Kaiser, S. S.
Kinderman, B. C. J. van Esseveldt, F. L. van Delft, H. E. Schoemaker,
R. H. Blaauw and F. P. J. T. Rutjes, Org. Biomol. Chem., 2005, 3,
3435.
7 For selected books see: (a) I. Ojima, Catalytic Asymmetric Syntheses,
2nd edn, Wiley-VCH, New York, 2000; (b) F. Vogtle, J. F. Stoddart and
M. Shibasaki, Stimulating Concepts in Chemistry, Wiley-VCH, Wein-
heim, 2000; (c) K. Maruoka, Asymmetric Phase Transfer Catalysis,
Wiley-VCH, Weinheim, 2008.
8 Y. Wang, P. Li, X. Liang, T. Y. Zhang and J. Ye, Chem. Commun., 2008,
1232.
9 Y. Wang, P. Li, X. Liang and J. Ye, Adv. Synth. Catal., 2008, 350, 1383.
10 For some reviews, see: (a) A. Erkkila¨, Z. Majander and P. M. Pihko,
Chem. Rev., 2007, 107, 5416; (b) S. Mukherjee, J. W. Yang, S. Hoffmann
and B. List, Chem. Rev., 2007, 107, 5471; (c) A. G. Doyle and E. N.
Jacobsen, Chem. Rev., 2007, 107, 5713. For selected examples, see:
(d) S. P. Brown, N. C. Goodwin and D. W. C. MacMillan, J. Am. Chem.
Soc., 2003, 125, 1192; (e) M. Marigo, T. Schulte, J. Franze´n and K.
A. Jørgensen, J. Am. Chem. Soc., 2005, 127, 15710; (f) W. Wang, H.
Li and J. Wang, Org. Lett., 2005, 7, 1637; (g) F.-H. Wu, R. Hong, J.
Khan, X.-F. Liu and L. Deng, Angew. Chem., Int. Ed., 2006, 45, 4301;
(h) S. Brandau, A. Landa, J. Franze´n, M. Marigo and K. A. Jørgensen,
Angew. Chem., Int. Ed., 2006, 45, 4305; (i) J.-W. Xie, L. Yue, D. Xue,
X.-L. Ma, Y.-C. Chen, Y. Wu, J. Zhu and J.-G. Deng, Chem. Commun.,
2006, 1563; (j) H. Gotoh, R. Masui, H. Ogino, M. Shoji and Y. Hayashi,
Angew. Chem., Int. Ed., 2006, 45, 6853; (k) W. Wang, H. Li, J. Wang and
L.-S. Zu, J. Am. Chem. Soc., 2006, 128, 10354; (l) J. Vesely, I. Ibrahem,
3 For reviews of the synthesis of a-amino acids, see: (a) R. M. Williams,
Synthesis of Optically Active a-Amino Acids Pergamon, Oxford, 1989;
(b) R. O. Duthaler, Tetrahedron, 1994, 50, 1539; (c) C. Cativiela and
M. D. Diaz-de-Villegas, Tetrahedron: Asymmetry, 1998, 9, 3517; (d) C.
Cativiela and M. D. Diaz-de-Villegas, Tetrahedron: Asymmetry, 2000,
11, 645; (e) C. Na´jera and J. M. Sansano, Chem. Rev., 2007, 107, 4584;
(f) V. A. Soloshonok and K. Izawa, Current Frontiers in Asymmetric
Synthesis and Application of a-Amino Acids, ACS Symposium Series
1009.
4 (a) M. Breuer, K. Ditrich, T. Habicher, B. Hauer, M. Kesseler, R.
Stuermer and T. Zelinski, Angew. Chem., Int. Ed., 2004, 43, 788; (b) E.
Fogassy, M. Nogradi, E. Palovics and J. Schindler, Synthesis, 2005,
1555.
5 For some reviews, see: (a) K. Maruoka and T. Ooi, Chem. Rev., 2003,
103, 3013; (b) M. J. O’Donnell, Acc. Chem. Res., 2004, 37, 506; (c) T.
Hashimoto and K. Maruoka, Chem. Rev., 2007, 107, 5656; (d) V. A.
Soloshonak, H. Ueki and T. K. Ellis, Synlett, 2009, 704.
´
G. L. Zhao, R. Rios and A. COrdova, Angew. Chem., Int. Ed., 2007, 46,
778; (m) L.-S. Zu, H. Li, H.-X. Xie, J. Wang, W. Jiang, Y. Tang and W.
Wang, Angew. Chem., Int. Ed., 2007, 46, 3732; (n) I. Ibrahem, R. Rios,
6 For some typical studies, see: (a) Yu. N. Belokon, A. G. Bulychev,
S. V. Vitt, Yu. T. Struchkov, A. S. Batsanov, T. V. Timofeeva, V. A.
Tsyryapkin, M. G. Ryzhov and L. A. Lysova, J. Am. Chem. Soc., 1985,
107, 4252; (b) R. Fitzi and D. Seebach, Angew. Chem., Int. Ed. Engl.,
1986, 25, 345; (c) D. A. Evans and A. E. Weber, J. Am. Chem. Soc.,
1986, 108, 6757; (d) D. A. Evans and A. E. Weber, J. Am. Chem. Soc.,
1987, 109, 7151; (e) U. Schoellkopf, R. Hinrichs and R. Lonsky, Angew.
Chem., Int. Ed. Engl., 1987, 26, 143; (f) A. G. Myers, J. L. Gleason and
T. Yoon, J. Am. Chem. Soc., 1995, 117, 8488; (g) Y. N. Belokon, N.
B. Bespalova, T. D. Churkina, I. C´ısarˇova´, M. G. Ezernitskaya, S. R.
Harutyunyan, R. Hrdina, H. B. Kagan, P. Kocˇovsky;, K. A. Kochetkov,
O. V. Larionov, K. A. Lyssenko, M. North, M. Pola´sˇek, A. S. Peregudov,
´
J. Vesely, P. Hammar, L. Eriksson, F. Himo and A. COrdova, Angew.
Chem., Int. Ed., 2007, 46, 4507; (o) Y. Hayashi, H. Gotoh, R. Masui
and H. Ishikawa, Angew. Chem., Int. Ed., 2008, 47, 4012; (p) L.-M.
Yang, B. Tan, F. Wang and G.-F. Zhong, J. Org. Chem., 2009, 74, 1744.
11 For catalyst using a chiral lithium prolinate, see: (a) M. Yamaguchi, T.
Shiraishi and M. Hirama, J. Org. Chem., 1996, 61, 3520; (b) P. Renzi,
J. Overgaard and M. Bella, Org. Biomol. Chem., 2010, 8, 980.
12 (a) S. Bertelsen, M. Marigo, S. Brandes, P. Diner and K. A. Jørgensen,
J. Am. Chem. Soc., 2006, 128, 12973; (b) B. Han, Y.-C. Xiao, Z.-Q. He
and Y.-C. Chen, Org. Lett., 2009, 11, 4660.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 793–801 | 801
©