Promotion of Henry reactions using Cu(OTf)2 and a sterically hindered Schiff base: Access to enantioenriched β-hydroxynitroalkanes

Article abstract of DOI:10.1016/j.tet.2012.08.029

The steric and electronic properties of chiral Schiff base ligands derived from cinchona alkaloids were evaluated in asymmetric Henry reactions. Amongst these, the sterically hindered ligand 2 showed outstanding catalytic efficiency in the Cu(II) catalyze

Full text of DOI:10.1016/j.tet.2012.08.029

Tetrahedron 68 (2012) 9119e9124
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Promotion of Henry reactions using Cu(OTf)2 and a sterically hindered Schiff base:
access to enantioenriched b-hydroxynitroalkanes
*
*
Lin Yao, Yu Wei, Pingan Wang, Wei He , Shengyong Zhang
Department of Chemistry, School of Pharmacy, Fourth Military Medical University, Shaanxi Province, Xi’an 710032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 May 2012
Received in revised form 15 July 2012
Accepted 10 August 2012
Available online 16 August 2012
The steric and electronic properties of chiral Schiff base ligands derived from cinchona alkaloids were
evaluated in asymmetric Henry reactions. Amongst these, the sterically hindered ligand 2 showed
outstanding catalytic efficiency in the Cu(II) catalyzed asymmetric addition of nitroalkanes to a variety of
aldehydes to afford the desired adducts in high yields (up to 97%) with excellent enantioselectivities (up
to 99% ee) and moderate to good diastereoselectivities (up to 84:16 dr).
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Henry reaction
Schiff base ligands
Cinchona alkaloids
b
-Hydroxynitroalkanes
1. Introduction
compounds and polyfunctionalized molecules.11 In the last two
decades, since the pioneering work of Shibasaki,12 where a het-
Strategies for controlling the regio- and stereoselectivity of
reactions are at the heart of modern organic chemistry research.1
To obtain high selectivity in these reactions, an empirical ap-
proach to ligand design remains a powerful protocol.2 New li-
gands are usually based on some well-designed structures, which
have the desired steric and electronic features, or are based on
well-known chirality inducers, such as BINAP,3 BINOL,4 BOX,2d,5
TADDOL,6 cinchona alkaloid derivatives,7 and salen complexes8
etc. Some ligands have been designed by combining two or
more of these moieties, and others by subtle modification of
existing ligands to optimize their properties. With respect to the
latter strategy, the steric and electronic factors of existing ligands
are basic considerations in the development of more efficient
ligands. Amongst the groups used as substitutes, tert-butyl9 finds
use as a bulky substituent with electron-donating properties,
which exhibits excellent activity and selectivity in many
transformations.
erobimetallic lanthanoid catalyst was used, various versions of
metal-catalyzed (Zn,13 Cu,14 Co,15 Mg,16 or Cr17) asymmetric
Henry reactions have been developed. Amongst these metal
complexes, Cu-catalyzed Henry reactions have received much
attention since copper is cheap and of low toxicity, and also it has
excellent chelating properties to coordinate with bidentate as
well as polydentate ligands. Our previous study has revealed
a Cu-catalyzed enantioselective addition of nitroalkanes to al-
dehydes using a novel type of Schiff base ligand based on the
cinchona alkaloids.18 It is the first report of successful use of
cinchona-based Schiff base ligands in asymmetric catalysis.
However, only moderate conversions were obtained and high
ligand loading (20 mol %) were required. To further improve this
highly enantioselective catalytic system, we have varied the
steric and electronic properties of the cinchona-based ligands.
Herein, we report a number of new Schiff base ligands (Fig. 1)
and their activities in Cu(II)-catalyzed Henry reactions. The tert-
butyl group has proven to be able to increase the catalytic effi-
ciency dramatically.
The Henry (Nitroaldol) reaction constitutes one of the most
useful methodologies for carbonecarbon bond formation.10 Ow-
ing to the chemical versatility of the nitro group, the resulting
The methodology herein provides several practical advantages:
(1) The most efficient Schiff base ligand 2 is easily synthesized in
two steps and in an overall 85% yield. (2) The method also features
a lower catalyst and ligand loading (both 5 mol %). (3) The scope of
the present catalytic system is quite extensive; It demonstrates
high efficiency in enantioselective Henry reactions of both aromatic
and aliphatic aldehydes with nitromethane or nitroethane.
b
-hydroxynitroalkanes, especially in an optically active form, are
useful fragments in the synthesis of biologically active
* Corresponding authors. Tel./fax: þ86 29 84774473 805; e-mail address:
weihechem@fmmu.edu.cn (W. He).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.029

9120
L. Yao et al. / Tetrahedron 68 (2012) 9119e9124
cinchona alkaloids. Also, the presence of a methoxy group at the 6-
position of quinine alkaloids resulted in a higher ee value (Table 1,
entries 1 and 2). However, the performances of these two ligands
were not satisfactory. On one hand, the electron-donating hydroxy
group at the 3-position of salicylaldehyde moiety in both of ligands
gave no benefits to activity or selectivity, while on the other, despite
the fact that the hydroxy group might coordinate well to Cu(II), it
failed to affect the possible transition state when compared to our
previous research. We then turned to ligands 2 and 3, which have
significantly different steric and electronic properties to 1a and 1b.
Ligand 2, with two hindered tert-butyl substituents, exhibited
a promising catalytic activity in the reaction (entry 3), while ligand
3, bearing an electron withdrawing group, was less efficient with
respect to both the yield and ee value of the model reaction (entry
4). Both the yield and ee value were maintained when the catalyst
loading of ligand 2 was further reduced to 5 mol % (entry 5 vs entry
3). Thus, it was notable that both the nature of the chiral backbones
and the substituents on the moieties are pivotal elements for the
asymmetric induction in the reaction, which again provided solid
evidence to the importance of steric and electronic factors in the
activity of the ligands.
HO
OH
N CH OH
N
8R
N
HO HC9NR
8S
9S
MeO
MeO
N
N
1b
1a
t-Bu
Br
t-Bu
N
8S
N
N CH OH
N CH OH
8S
9S
9S
MeO
N
N
2
3
Fig. 1. The Schiff base ligands screened in asymmetric Henry reactions.
Encouraged by the preliminary results, our attention was next
focused on the screening of a series of transition metal salts with
5 mol % catalyst loading. Generally, Cu salts demonstrated better
results than the others, and the enantioselectivity was dependent
on the counterions (Table 1). Amongst them, Cu(OTf)2 proved to be
the best choice, affording the Henry adduct in high yield with an
excellent ee value (entry 11). Although other Cu salts like
Cu(OAc)2$2H2O, CuCl, CuBr, and CuI gave promising ee values, the
reactions were sluggish (entries 5 and 8e10). In contrast, other
metals, such as Zn, Ag, Co, and Ni, showed inferior performances
both in activity and selectivity (entries 12e15). Furthermore, we
found no effect of the ligand 2/Cu(OTf)2 ratio on either the yield or
ee value (entry 16 vs entry 11). Thus, 5 mol % of ligand 2/Cu(OTf)2
1:1 complex was selected as the most efficient catalyst for the
model reaction.
2. Results and discussion
The Schiff base ligands were readily prepared in high yields from
commercially available cinchona alkaloids and salicylaldehyde de-
rivatives (Fig. 1). Reaction between benzaldehyde (4a) and nitro-
methane (5a) was carried out as the model reaction to screen these
ligands.
The pseudoenantiomeric cinchona alkaloid derivatives 1a and
1b were first explored as the chiral sources in the model reaction.
As depicted in Table 1, the absolute configuration of the product
was highly dependent upon the configuration at C8- and C9- of the
Table 1
As the reaction temperature typically plays a significant role in
determining the ee values of adducts in asymmetric catalysis, the
optimization of the temperature was then carried out. The catalytic
reaction performed at room temperature only resulted in moderate
ee value though the yield reached 96% (Table 2, entry 1). On
Evaluation of chiral Schiff base ligands and central metals in the asymmetric Henry
reactiona
CHO
OH
Chiral ligand / Metal
*
NO2
+
CH3NO2
0.5 equiv Na2CO3, THF, -20oC
6a
4a
5a
Entry Metal
Ligand Ratio of metal:ligand Yieldb (%) ee (%)c
Table 2
Screening the temperature and solvents in the asymmetric Henry reactiona
1e
2
3
Cu(OAc)2$H2O 1a
Cu(OAc)2$H2O 1b
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:1
1:1
1:1
1:2
1:2
1:1
1:2
1:2
1:1
61
53
86
73
85
13
63
65
52
73
92
13
27
76
72
92
70 (S)d
43 (R)
87 (S)
73 (S)
87 (S)
18 (S)
51 (S)
68 (S)
73 (S)
73 (S)
87 (S)
18 (S)
7 (S)
CHO
OH
5 mol% 2/Cu(OTf)2 (1:1)
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
CuCl2$2H2O
CuBr2
2
3
2
2
2
2
2
2
2
2
2
2
2
2
NO2
+
CH3NO2
4
5f
6
0.5 equiv Na2CO3
6a
5a
4a
7
8
9
10
11
12
13
14
15
16
Entry
Solvent
Temp (ꢁC)
Yieldb (%)
ee (%)c
CuCl
CuBr
1
2
3
4
5
6
7
8
THF
THF
THF
THF
rt
0
96
96
94
92
52
81
96
93
90
NR
82
83
68
76
51
64
72
88
78
66
22
62
68
d
CuI
Cu(OTf)2
Zn(OTf)2
AgOTf
ꢀ10
ꢀ20
ꢀ40
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
THF
CoCl2$2H2O
NiCl2$6H2O
Cu(OTf)2
39 (S)
19 (S)
88 (S)
Toluene
MeOH
EtOH
i-PrOH
Neat
CH3CN
TBME
CH2Cl2
CHCl3
9
a
All reactions were carried out with 0.5 mmol of benzaldehyde, 5 mmol of
nitromethane and 50 mol % Na2CO3 in 2 mL of THF in the presence of 5 mol % of
catalyst at ꢀ20 ꢁC. All the catalysts were formed in situ, about 1 h before addition of
benzaldehyde.
10
11
12
13
14
76
62
46
58
b
Isolated yield.
Determined by HPLC analysis (Chiralcel OD-H column).
By comparison of the HPLC elution order of the enantiomers with the literature
c
d
a
All reactions were carried out with 0.5 mmol of benzaldehyde and 5 mmol of
nitromethane in 2 mL of solvent in the presence of 5 mol % of catalyst.
data.14
e
b
With 10 mol % of catalyst loading in entries 1e4.
With 5 mol % of catalyst loading in entries 5e16.
Isolated yield.
Determined by HPLC analysis (Chiralcel OD-H column).
f
c

L. Yao et al. / Tetrahedron 68 (2012) 9119e9124
9121
Table 4
lowering the temperature, the ee value increased, accompanied by
a slight decrease in yield. However, at ꢀ40 ꢁC, the selectivity was
not further improved as expected (entry 5). It was obvious that
ꢀ20 ꢁC was the most suitable temperature in view of both the yield
and the ee value (entry 4).
In addition, a series of solvents (e.g., methanol, ethanol, iso-
propanol, nitromethane, THF, TBME, acetonitrile, toluene,
dichloromethane, and chloroform) were also tested in the catalytic
enantioselective Henry reaction between benzaldehyde and ni-
tromethane in combination with ligand 2, Cu(OTf)2, and Na2CO3
(Table 2, entries 4 and 6e14). Generally, nonprotonic solvents were
found to be superior to protonic and halogenated ones, and among
the different solvents tested, THF was clearly the best choice for this
reaction, with 92% yield and 88% ee (entry 4).
It is believed that the deprotonation of nucleophiles is necessary
for the proceeding of Henry reaction, which has also been clearly
demonstrated in our case (Table 3, entry 1).19 To increase the re-
activity, a series of Brønsted bases were tested in the reaction be-
tween benzaldehyde and nitromethane in the presence of 5 mol %
of ligand 2/Cu(OTf)2 1:1 complex and 50 mol % of base. As illus-
trated in Table 3, KOH, K2CO3, DBU, CsCO3, Et3N gave good yields
but poor enantioselectivities (entries 4e8). DIPEA, DMAP gave
lower yields and the ee values were moderate (entries 9 and 10). In
addition, use of the much weaker base 2,20-bipyridine gave no re-
action even with a longer reaction time (>72 h) (entry 11). Amongst
the bases evaluated, Na2CO3 and DABCO showed the best activities
and ee values (entries 2 and 3). Using Na2CO3, we also tested the
effect of reducing its loading to 20 mol %; the yield decreased
dramatically, albeit with a maintained ee value (entry 12).
Ligand 2/Cu(OTf)2 complex catalyzed enantioselective Henry reactions of nitro-
methane with different aldehydesa
O
OH
5 mol% 2/Cu(OTf)2 (1:1)
+
CH3NO2
NO2
R
R
H
0.5 equiv Na2CO3, THF, -20 o
C
4a-o
5a
6a-o
Entry
Aldehyde
Time (h)
Yieldb (%)
ee (%)c
1
2
3
4
5
6
7
8
Benzaldehyde (4a)
20
12
12
12
12
10
10
10
10
10
24
24
24
30
28
92
92
93
95
94
97
95
96
96
96
91
89
83
85
89
88
85
84
88
90
88
93
99
90
91
99
99
98
87
85
4-Chlorobenzaldehyde (4b)
3-Chlorobenzaldehyde (4c)
2-Chlorobenzaldehyde (4d)
4-Bromobenzaldehyde (4e)
4-Methylbenzaldehyde (4f)
2-Methoxybenzaldehyde (4g)
4-Methoxybenzaldehyde (4h)
4-Fluorbenzaldehyde (4i)
1-Naphthaldehyde (4j)
9
10
11
12
13
14
15
3-Phenylpropanal (4k)
Furan-2-carbaldehyde (4l)
Cyclohexanecarbaldehyde (4m)
Isovaleraldehyde (4n)
Butyraldehyde (4o)
a
All reactions were carried out with 0.5 mmol of the aldehyde and 5 mmol of
nitromethane in 2 mL of THF in the presence of 5 mol % of catalyst, 50 mol % of
Na2CO3 at ꢀ20 ꢁC.
b
Isolated yield.
c
Determined by chiral HPLC analysis using Chiralcel OD-H, OJ-H or Chiralpak AD-
H column.
corresponding adduct in excellent yield and with a high ee (entry
10). The heteroaromatic aldehyde furan-2-carbaldehyde 4l also fur-
nished the adduct with 99% ee (entry 12). Most remarkably, all ali-
phatic aldehydes investigated, (cyclic, branched and nonbranched)
reacted smoothly with nitromethane under mild conditions to afford
the optically active Henry adducts 6k, 6m, 6n, and 6o in reasonable
yields with excellent enantioselectivities (entries 11 and 13e15).
To date, although various highly efficient catalytic systems have
been developed for enantioselective Henry reactions, nitroalkanes
other than nitromethane have been less explored.14p,20 Therefore, to
further evaluate our catalytic system, we examined nitroethane as
the nucleophile in diastereoselective Henry reactions. As showed in
Table 5, in most cases, the reactions were carried out with moderate
to good diastereoselectivities, and both the anti and syn products
could be obtained with high enantioselectivity. For the benzalde-
hyde derivatives investigated, the ee values of the syn products
reached up to 99% (entries 1e5). The aryl substituted aliphatic al-
dehyde 3-phenylpropanal 4k and the heteroaryl aldehyde furan-2-
carbaldehyde 4l afforded products with moderate diaster-
eoselectivities, while the ee values of the both anti and syn products
were excellent (entries 6 and 7). Gratifyingly, the mainly anti adduct
(anti/syn¼84:16) with up to 99% ee was obtained when the aliphatic
aldehyde cyclohexanal 4m reacted with nitroethane (entry 8).
To account for the stereochemical outcome of the reaction, the
absolute configuration of ligand 2 was identified by its crystal
structure (Fig. 2). Unfortunately, despite many efforts, we could not
obtain the X-ray crystal structure of the ligand 2/Cu(II) complex.
However, the stereochemistry of ligand 2 revealed that the atoms O1,
N1, and N2 could all potentially coordinate to the copper center. In
addition, other efforts were made to elucidate a possible transition
state. Initially, the formation of the ligand 2/Cu(II) 1:1 complex was
evidenced by MS (ES, MþH) calcd for: C35H46N3O2Cu(OTf)2 901.42,
found: 901.28. Furthermore, IR spectra of both ligand 2 and its Cu(II)
complex (see Supplementary data) showed the disappearance of the
hydroxyl signal in the latter, suggesting coordination of the depro-
tonated hydroxyl on the salicylaldehyde moiety to the copper center.
On the basis of the preliminary experimental investigations and
previously mentioned steric and electronic considerations, we
Table 3
Effects of the base additives in the asymmetric Henry reactiona
OH
CHO
5 mol% 2/Cu(OTf)2 (1:1)
Base, THF, -20 o
NO2
+
CH3NO2
6a
C
5a
4a
Entry
Base additive
Loading of base (mol %)
Yieldb (%)
ee (%)c
1
2
3
4
5
6
7
8
d
d
NR
92
88
93
87
91
97
83
63
47
NR
56
ND
88
87
52
38
25
45
45
49
76
ND
87
Na2CO3
DABCO
KOH
K2CO3
DBU
CsCO3
Et3N
DIPEA
DMAP
2,20-Bipyridine
Na2CO3
50
50
50
50
50
50
50
50
50
50
20
9
10
11d
12
a
All reactions were carried out with 0.5 mmol of benzaldehyde and 5 mmol of
nitromethane in 2 mL of THF in the presence of 5 mol % of catalyst at ꢀ20 ꢁC.
b
Isolated yield.
Determined by HPLC analysis (Chiralcel OD-H column).
After 72 h.
c
d
With the optimized conditions in hand, the scope of the catalytic
enantioselective nitroaldol reaction was demonstrated by treatment
of various aldehydes with nitromethane in the presence of 5 mol % of
the ligand 2/Cu(OTf)2 1:1 complex and 50 mol % of Na2CO3 in THF at
ꢀ20 ꢁC. As illustrated in Table 4, all the Henry reactions with aro-
matic and aliphatic aldehydes gave adducts in good yields and
enantioselectivities. For the aromatic aldehydes, substrates with
electron-donating groups or electron-withdrawing groups at the
phenyl ring demonstrated no significant differences (Table 4, entries
1e9). The position of the substituent on the phenyl ring of aromatic
aldehydes also showed little effect on the ee value (entries 2e4 and
entries 7e8). The bulky aldehyde 1-naphthaldehyde 4j afforded the

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L. Yao et al. / Tetrahedron 68 (2012) 9119e9124
Table 5
adduct with the S configuration, while Si-face attack of nitro-
methane to the aldehyde is hindered by steric repulsion between
the phenyl ring of the aldehyde and the tert-butyl substituent on
the ligand.
Ligand 2/Cu(OTf)2 complex catalyzed diastereoselective Henry reactions of nitro-
ethane with different aldehydesa
OH
O
NO2
CH3
7b-d,g-h,k-m
5 mol% 2/Cu(OTf)2 (1:1)
R
+
CH3CH2NO2
R
H
0.5 equiv Na2CO3, THF, -20 o
C
3. Conclusion
4b-d,g-h,k-m
5b
In summary, the new Schiff base 2, which was easily prepared
from cinchona alkaloids, together with Cu(OTf)2, showed high ef-
ficiency in enantioselective Henry reactions between nitroalkanes
and a wide range of aromatic and aliphatic aldehydes. Furthermore,
the reaction proceeded with a low catalyst loading (5 mol %). A
possible transition state was also proposed based on the X-ray
crystal structure of ligand 2 and the absolute configuration of the b-
nitro alcohol adduct. The exploration of these chiral skeletons in
other asymmetric reactions is ongoing in our laboratory.
Entry Aldehyde
Time (h) Yield (%)b anti/sync ee (%)d
anti syn
1
2
3
4
5
6
7
8
4-Chlorobenzaldehyde (4b)
3-Chlorobenzaldehyde (4c)
2-Chlorobenzaldehyde (4d)
2-Methoxybenzaldehyde (4g)
4-Methoxybenzaldehyde (4h) 18
3-Phenylpropanal (4k)
20
20
20
18
92
95
91
96
87
81
86
83
58:42
57:43
84:16
75:25
42:58
44:56
41:59
84:16
74 99
99 99
76 99
73 99
75 99
99 99
99 82
99 70
30
36
Furan-2-carbaldehyde (4l)
Cyclohexanecarbaldehyde (4m) 48
a
All reactions were carried out with 0.5 mmol of the aldehyde and 5 mmol of
4. Experimental section
4.1. General
nitroethane in 2 mL of THF in the presence of 5 mol % of catalyst, 50 mol % of Na2CO3
at ꢀ20 ꢁC.
b
Isolated yield.
c
By comparison with literature data.20
d
Determined by chiral HPLC analysis using Chiralcel OD-H, OJ-H or Chiralpak AD-
All the starting materials and reagents were purchased from
commercial suppliers and used without further purification. Sol-
vents were purified by standard procedures. Routine monitoring of
reactions was performed by TLC, visualization was done by fluo-
rescence quenching at 254 nm or exposure to iodine vapor. Flash
chromatography was carried out on silica gel (Acme,
60e120 mesh). Melting points were determined using YG252A
apparatus and were uncorrected. Optical rotations were measured
on a PerkineElmer 343 polarimeter in the solvent indicated. NMR
spectra were recorded on INOVA 400 MHz (1H NMR) and 100 MHz
H column.
(
13C NMR) spectrometers (with TMS as an internal standard), and
coupling constants are reported in hertz. High-resolution mass
spectra (HRMS) were carried out on a BRUKER APEX-II. IR spectra
were recorded as KBr disks on a FTIR-8400S (CE). High performance
liquid chromatography (HPLC) was performed by an Agilent 1100
interfaced to an HP 71 series computer workstation with Daicel
Chiralcel OD-H, OJ-H column or Chiralpak AD-H column.
4.2. Preparation of the ligands
(8S, 9S)-9-amino(9-deoxy)-epiquinine and (8R,9R)-9-amino(9-
deoxy)-epicinchonine were prepared according to the literature.22
Fig. 2. X-ray crystal structure of ligand 2.21
4.2.1. Synthesis of ligand 2. A solution of 3,5-di-tert-butyl-salicy-
laldehyde (257 mg, 1.1 mmol) and (8S,9S)-9-amino-(9-deoxy)-epi-
quinine (323.4 mg, 1.0 mmol) in absolute ethanol (20 mL) was
heated to reflux. After that, 1.5 g MgSO4 (dried at 110 ꢁC for 2 h
before use) was added to the solution.
After 8 h, the mixture was slowly cooled down to room tem-
perature and filtrated. The solvent was evaporated under reduced
pressure. The crude product was purified by flash chromatography
propose the possible transition state illustrated in Fig. 3. In the
assumed active species, the carbonyl oxygen atom of the electro-
phile is coordinated at one of the more Lewis acidic equatorial sites
for maximum activation. Thus, the deprotonated nitromethane as
nucleophile binds its oxygen atom to the metal center from the
axial side favoring Re-face attack at the aldehyde, affording the
on silica gel (petroleum ether/CH2Cl2 1:0 to 1:1) to afford the Schiff
25
base ligand 2 as a yellow solid (501 mg, 93% yield). [
a
]
D
¼ꢀ55 (c 0.5,
CH2Cl2); mp 122e123 ꢁC; IR (KBr) nmax: 3403, 2962, 2864, 1627,
Si unfavoured:
Re favoured:
1278 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
13.49 (s, 1H, OH), 8.76
O
N
(d, J¼6 Hz, 1H, ArH), 8.41 (s, 1H, CH]N), 8.05 (d, J¼12 Hz, 1H, ArH),
7.66 (d, J¼2.4 Hz, 1H, ArH), 7.47 (d, J¼5.6 Hz, 1H, ArH), 7.40 (dd,
J¼2.8, 3.2 Hz, 1H, ArH), 7.33 (d, J¼2.4 Hz, 1H, ArH), 7.04 (d, J¼2.8 Hz,
1H, ArH), 5.83e5.76 (m, 1H, CH2]CH), 4.99 (dd, J¼16.8, 7.2 Hz, 2H,
CH2]CH), 4.86 (d, J¼12.8 Hz, 1H, CH), 4.03 (s, 3H, OCH3), 3.62 (q,
J¼11.6 Hz, 1H, CH), 3.27e3.19 (m, 2H, CH2), 2.84e2.80 (m, 2H, CH2),
2.27 (br s, 1H, CH), 1.67 (br s, 1H, CH), 1.62e1.54 (m, 2H, CH2), 1.40 (s,
9H, t-Bu), 1.26 (s, 9H, t-Bu), 0.91e0.84 (m, 2H, CH2); 13C NMR
O
N
CH2
H2C
O
O
O
N
Cu
H
Cu
O
O
N
H
N
O
N
MeO
MeO
N
N
(100 MHz, CDCl3)
d 165.9, 157.4, 157.3, 147.1, 144.8, 143.9, 141.3,
Fig. 3. Plausible transition state for the enantioselective Henry reaction.
139.6,136.0,131.6,127.2,126.6, 125.8,121.2,120.9,120.8,117.4,113.8,

L. Yao et al. / Tetrahedron 68 (2012) 9119e9124
9123
101.6, 60.1, 56.0, 55.0, 40.4, 39.4, 34.5, 33.7, 30.9, 28.9, 27.6, 27.3,
4.4. General procedure for asymmetric Henry reaction
25.5. HRMS (ESI, MþH) calcd for C35H46N3O2 540.3590, found
540.3591.
The ligand 2 (13.5 mg, 0.025 mmol), and Cu(OTf)2 (9.1 mg,
0.025 mmol) were suspended in THF (2 mL). After stirring for 1 h at
room temperature, aldehyde (53 mg, 0.5 mmol) and nitroalkane
(325 mg, 5 mmol) were added, the mixture was cooled down to
ꢀ20 ꢁC and Na2CO3 (26.5 mg, 0.25 mmol) was added. The stirring
was continued for the indicated time and the reaction mixture was
then diluted with ether (6 mL). The resulting mixture was filtered
through a pad of Celite, and the solution was evaporated under
reduced pressure. The residue was purified by silica gel flash col-
umn chromatography (petroleum ether/ethyl acetate¼5:1) to af-
ford the corresponding product. The enantiomeric purity of the
product was determined by HPLC analysis. The absolute configu-
rations of the products were assigned by comparison to literature
data.
4.2.2. Synthesis of ligand 1a. Ligand 1a was prepared in the same
way as ligand 2 from (8S,9S)-9-amino-(9-deoxy)-epiquinine and
2,3-dihydroxybenzaldehyde. The product was obtained as a yellow
25
solid (394 mg, 89% yield).
[
a]
¼ꢀ74.0 (c 1.0, CH2Cl2); mp
D
102e103 ꢁC; IR (KBr) nmax: 3423, 2935, 2864, 1722, 1623, 1272,
1240 cmꢀ1; 1H NMR (400 MHz, CDCl3)
8.80 (d, J¼5.2 Hz, 1H, ArH),
d
8.19 (s, 1H, CH]N), 8.09 (d, J¼12.4 Hz, 1H, ArH), 7.51 (br s, 1H, ArH),
7.47e7.42 (m, 2H, ArH), 6.87 (d, J¼9.6 Hz, 1H, ArH), 6.66 (d,
J¼9.6 Hz, 1H), 6.59 (t, J¼10.4 Hz, 1H, ArH), 5.86e5.75 (m, 1H, CH2]
CH), 5.05e4.99 (m, 2H, CH2]CH), 3.98 (s, 3H, OCH3), 3.62e3.57 (m,
1H, CH), 3.33e3.20 (m, 2H, CH2), 3.07 (q, J¼9.6 Hz, 1H, CH),
2.91e2.86 (m, 2H, CH2), 2.32 (br s, 1H, OH), 1.71 (br s, 1H, OH),
1.64e1.59 (m, 2H, CH2), 1.51e1.46 (m, 1H, CH), 1.42e1.37 (m, 2H,
CH2), 0.92e0.85 (m, 1H, CH); 13C NMR (100 MHz, DMSO)
d 165.9,
Acknowledgements
157.4, 150.4, 147.7, 145.7, 144.3, 142.2, 131.5, 127.5, 121.7, 121.5, 118.3,
117.9, 114.1, 102.2, 59.7, 55.6, 51.9, 45.6, 39.6, 33.2, 27.4, 25.5, 22.6.
HRMS (ESI, MþH) calcd for C27H30N3O3 444.2242, found 444.2270.
We thank the National Natural Science Foundation of China
(NSFC 21072228, 21172262 and 20702063) for financial support.
And we also would like to thank Professor Weiping Chen for
valuable discussion and Dr. Allen Blackman for language revision.
4.2.3. Synthesis of ligand 1b. Ligand 1b was prepared in the same
way as ligand 2 from (8S,9S)-9-amino-(9-deoxy)-epicinchonine
with 2,3-dihydroxybenzaldehyde. The product was obtained as
Supplementary data
25
a yellow solid (347 mg, 84% yield). [
a]
¼þ62.32 (c 1.0, CH2Cl2); mp
D
71e73 ꢁC; IR (KBr) nmax: 3060, 2935, 2869, 1627, 1463, 1272 cmꢀ1
1H NMR (400 MHz, CDCl3)
8.97 (d, J¼4.4 Hz, 1H, ArH), 8.36e834
;
Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.tet.2012.08.029.
d
(m, 1H, ArH), 8.23 (s, 1H, CH]N), 8.28 (d, J¼8.4 Hz, 1H, ArH), 7.78 (t,
J¼7.6 Hz,1H, ArH), 7.67 (t, J¼8 Hz,1H, ArH), 7.57 (br s,1H, ArH), 6.80
(dd, J¼1.2,1.2 Hz,1H, ArH), 6.65e6.62 (m,1H, ArH), 6.55 (t, J¼7.6 Hz,
1H, ArH), 5.92e5.83 (m, 1H, CH2]CH), 5.14e5.09 (m, 2H, CH2]CH),
3.59 (br s, 1H, CH), 3.16e3.10 (m, 2H, CH2), 3.01e2.92 (m, 2H, CH2),
2.32 (q, J¼7.2 Hz, 1H, CH), 1.68 (br s, 1H, CH), 1.61e1.58 (m, 2H, CH2),
1.25e1.18 (m, 2H, CH2), 1.07e1.00 (m, 1H, CH); 13C NMR (100 MHz,
References and notes
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CDCl3)
d 165.7, 160.2, 148.7, 145.5, 139.9, 130.8, 129.3, 128.8, 128.7,
123.3, 123.2, 122.1, 120.8, 117.9, 117.5, 114.9, 49.2, 47.1, 39.1, 27.6, 26.1,
24.9. HRMS (ESI, MþH) calcd for C26H28N3O2 414.2182, found
414.2177.
4.2.4. Synthesis of ligand 3. Ligand 3 was prepared in the same way
as ligand 2 from (8S,9S)-9-amino-(9-deoxy)-epiquinine with 5-
bromosalicylaldehyde. The product was obtained as a yellow solid
25
(419 mg, 83% yield). [
a
]
¼ꢀ48.6 (c 0.5, CH2Cl2); mp 87e88 ꢁC; IR
D
(KBr) nmax: 3392, 2987, 2948, 1618, 1456 cmꢀ1; 1H NMR (400 MHz,
CDCl3) 8.78 (d, J¼4.4 Hz, 1H, ArH), 8.31 (s, 1H, CH]N), 8.07 (d,
J¼9.2 Hz, 1H, ArH), 7.53 (d, J¼2.4 Hz, 1H, ArH), 7.46e7.45 (m, 2H,
ArH), 7.37e7.35 (m, 2H, ArH), 6.83 (d, J¼9.2 Hz, 1H, ArH),
5.83e5.875 (m, 1H, CH2]CH), 5.00 (t, J¼10 Hz, 2H, CH2]CH), 4.92
(br s, 1H, CH), 4.01 (s, 3H, OCH3), 3.26e3.15 (m, 2H, CH2), 2.85e2.78
(m, 2H, CH2), 2.34 (br s, 1H, CH), 1.69 (br s, 2H, CH2), 1.46e1.43 (m,
2H, CH2), 1.27 (t, J¼7.2 Hz, 1H, CH), 0.89e0.84 (m, 1H, CH); 13C NMR
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d 158.6, 154.3, 152.3, 142.0, 139.3, 137.9, 135.8,
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129.4, 128.2, 126.5, 121.9, 116.0, 114.5, 113.3, 108.9, 104.4, 96.1, 55.7,
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