Isosteric expansion of the structural diversity of chiral ligands: Design and application of proline-based N,N′-dioxide ligands for copper-catalyzed enantioselective Henry reactions

Article abstract of DOI:10.1016/j.tet.2019.130492

Chiral N,N′-dioxide catalysts were designed based on isosteric approach. Using L-Proline as the starting material, a variety of chiral N,N′-dioxide ligands were obtained via conventional functional group transformations and were utilized in asymmetric Henry reactions between nitromethane and aromatic aldehydes. Using the N,N′-dioxide-copper(II) complexes as the catalysts, asymmetric Henry reaction produced the corresponding β-nitroalcohols in up to 66% yields and up to 83% ee's under mild conditions. The reactions were easy to carry out, and special care such as air or moisture-free conditions was not required.

Full text of DOI:10.1016/j.tet.2019.130492

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Isosteric expansion of the structural diversity of chiral ligands: Design and application
of proline-based N,N′-dioxide ligands for copper-catalyzed enantioselective Henry
reactions
En Gao, Meng Li, Lili Duan, Lin Li, Yue-Ming Li
PII:
S0040-4020(19)30819-1
https://doi.org/10.1016/j.tet.2019.130492
TET 130492
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 May 2019
Revised Date: 17 July 2019
Accepted Date: 27 July 2019
Please cite this article as: Gao E, Li M, Duan L, Li L, Li Y-M, Isosteric expansion of the structural
diversity of chiral ligands: Design and application of proline-based N,N′-dioxide ligands for copper-
catalyzed enantioselective Henry reactions, Tetrahedron (2019), doi: https://doi.org/10.1016/
j.tet.2019.130492.
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Isosteric Expansion of the Structural
Diversity of Chiral Ligands: Design and
Application of Proline-Based N,N′-Dioxide
Ligands for Copper-Catalyzed
Leave this area blank for abstract info.
Enantioselective Henry Reactions
En Gao, Meng Li, Lili Duan, Lin Li* and Yue-Ming Li*
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of
Molecular Drug Research, Nankai University, Tianjin, People’s Republic of China.
.

1
Tetrahedron
journal homepage: www.elsevier.com
Isosteric Expansion of the Structural Diversity of Chiral Ligands: Design and
Application of Proline-Based N,N′-Dioxide Ligands for Copper-Catalyzed
Enantioselective Henry Reactions
En Gao,a Meng Li,a Lili Duan,a Lin Lia* and Yue-Ming Lia,b*
aState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University,
Tianjin, People’s Republic of China.
bKey Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032,
People’s Republic of China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Chiral N,N′-dioxide catalysts were designed based on isosteric approach. Using L-Proline as the
starting material, a variety of chiral N,N′-dioxide ligands were obtained via conventional
functional group transformations and were utilized in asymmetric Henry reactions between
nitromethane and aromatic aldehydes. Using the N,N′-dioxide-copper(II) complexes as the
catalysts, asymmetric Henry reaction produced the corresponding β-nitroalcohols in up to 66%
yields and up to 83% ee’s under mild conditions. The reactions were easy to carry out, and
special care such as air or moisture-free conditions was not required.
Available online
Keywords:
asymmetric catalysis
chiral N,N′-dioxide ligand
copper(II) complex
Henry reaction
2009 Elsevier Ltd. All rights reserved
.
proline
Ph2P
Ph
Ph
Ph
Ph
1. Introduction
(
)
n
HO
N
H
OH
N
Ph
(
)
n
Ph
N+
O-
N+
-O
PPh2
O
O
O
N
N
OH
Chiral ligand design remains the focal point of asymmetric
catalysis, and significant efforts have been made for the design
and synthesis of chiral ligands for different asymmetric
reactions.1 As a result, numerous chiral ligands have been
prepared from easily available starting structures.2 Among the
various chiral ligands developed, L-proline-based chiral ligands
have shown great potential due to the unique structure feature,
the easy availability of the starting material and the outstanding
performance of the chiral catalysts in asymmetric organic
reactions.3
B
N
N
H
H
COR
H
Ar
Ar
CAPP/BPPM
Corey
Feng
Trost
Figure 1. Examples of Chiral Ligands Developed from
Proline and Related Compounds.
It is our purpose to expand the structural diversity of these
chiral ligands. Herein, we wish to present our preliminary results
of isosteric approach to expanding the structural diversity of
proline-based chiral ligands, and the application of these chiral
ligands in asymmetric Henry reactions.
Proline-promoted asymmetric transformation can be dated
back to 1970s.4 It was well recognized as starting materials for
chiral auxiliaries in alkylation of carbonyl compounds5 and for
chiral ligands/catalysts in enantioselective reduction of prochiral
ketones.6 So far, many chiral ligands have been developed using
proline or hydroxyproline as the starting structures, and have
been successfully applied in a variety of asymmetric organic
reactions (Figure 1).7 Among these studies, chiral ligands
developed by Feng et al. have received significant success due to
the excellent performance of these N,N′-dioxide-type chiral
ligands in a large variety of asymmetric catalytic reactions.8 The
early achievements could be exemplified by asymmetric
cyanosilylation of ketones9 as well as asymmetric Strecker
reactions.10
2. Results and discussion
Feng et al. have shown that N,N′-dioxides are viable chiral
ligands in a variety of asymmetric reactions. The two N-oxide
functional groups were formed via N-oxidation of either proline
or pipecolinic acid, and acted as the main coordination atoms in a
variety of chiral catalysts. The catalytic activity of these chiral
catalysts came from the two N-oxide atoms as well as the
adjacent amide functional groups which could interact with the
two oxygen atoms via intramolecular hydrogen bonding. The
stereoelectronic property of the chiral ligand/catalyst could be
further regulated by changing the structure of aryl groups (Figure
2).

2
Tetrahedron
( )n
( )n
N+
O-
N+
-O
O
O
N
N
H
H
Ar
Ar
Figure 2. Example of Feng’s ligand.
Inspired by these rationales, we decided to expand the
structure diversity of these N,N′-dioxide chiral ligands using
isosteric approach. The concept of isostere or bioisotere was
originally formulated by Moir and refined by Langmuir,11 and
has been used as a general method in drug design and
discovery.12 Keeping this idea in mind, chiral ligands 1a-1e were
designed by replacing two carboxamide functional groups with
alcohol moieties. Tertiary alcohols were adopted to avoid the
introduction of additional chiral centers.
Figure 3. ORTEP Drawing of compound 1e at 30%
displacement ellipsoid probability (the hydrogen atoms and
the co-crystalized CH2Cl2 are omitted for clarity).
After the preparation of the chiral ligands, copper(II)
complex-catalyzed asymmetric Henry reaction was carried out as
model reaction to prove the isosteric concept and to evaluate the
performance of these chiral ligands. The Henry (nitroaldol)
reaction is a versatile C-C bond-forming reaction, and has been
proved as a useful method for the construction of different
nitroolefins, nitro carbonyl compounds and 1,2-amino alcohols.14
So far, different chiral catalysts have been developed for this
purpose, and chiral N,N′-dioxide-based chiral catalysts have been
successfully applied in asymmetric Henry15 and aza-Henry
reactions.16
The preparation of these chiral ligands started from N-
protected methyl prolinate. Reduction of the ester functional
group provided prolinol 3a (R = H). Reactions of N-Boc methyl
Thus, copper(II) complex-catalyzed asymmetric Henry
reaction of nitromethane with p-nitrobenzaldehyde was carried
out at 35 °C using chiral N,N′-dioxide 1a-1e as chiral ligands.
The copper salts were used based on literature studies on
asymmetric Henry reactions. The results are summarized in Table
1.
prolinate
2
with different Grignard reagents gave the
corresponding prolinols 3b-3e. Removal of the protective groups
produced prolinols 4, and subsequent reactions of 4 with 1,3-
dibromopropane gave compounds 5. The desired chiral ligands
1a-1e were obtained after N-oxidation of the prolinol dimers 5
with m-CPBA.
Table 1. Screening of Copper Salts and Chiral Ligands in
Asymmetric Henry Reactionsa
Boc
Boc
H
N
O
O
N
OH
R
OH
R
R
a
N
b
R
4
2
3
Entry
1
Ligandb
1a
Copper source
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuF2
Yield (%)c
33%
32%
38%
25%
12%
22%
11%
34%
38%
ND
ee (%)de
0
c
d
N
N
R
N
O
N
R
R
R
R
R
O
OH
OH
R
R
2
1b
1c
45%
60%
56%
0
HO
HO
5
1a: R = H (54 %)
1b: R = Me (80 %)
1c: R = Et (78 %)
1d: R = i-Pr (56 %)
1e: R = Ph (77 %)
3
4
1d
1e
5
Reaction conditions: a) 3a: LiAlH4 (1 equiv), 80%. 3b: MeMgBr (4.5 equiv),
75%. 3c: EtMgBr (4.5 equiv), 58%. 3d: i-PrMgBr (4.5 equiv), 55%. 3e:
C6H5MgBr (4.5 equiv), 86%. b) TFA (10 equiv), 4a: 90%. 4b: 92%. 4c: 94%.
4d: 93%. 4e: 91%. c) 1,3-dibromopropane (0.5 equiv). 5a: R = H, 54%. 5b: R
= Me, 93%. 5c: R = Et, 90%. 5d: R = i-Pr, 85%. 5e: R = Ph, 89%. d) m-
CPBA (2.2 equiv). 1a: 54%. 1b: 80%. 1c: 78%. 1d: 56%. 1e: 77%.
6
1c
19%
4.1%
0
7
1c
CuBr2
8
1c
CuCl
9
1c
Cu(NO3)2
CuSO4
0
Scheme 1. Synthesis of Chiral N,N′-dioxides 1a-1e.
To further prove the stereochemistry of N-oxide, ligands 1c
and 1e were carefully crystalized and subjected to X-ray
diffraction experiments. ORTEP drawing of these ligands
indicated the presence of intramolecular hydrogen bonds between
hydroxyl groups and the oxygen atoms of the N-oxide, and
clearly confirmed the absolute configurations of the nitrogen
atoms (Figure 3).13
10
11
12
13f
14g
15
16
17
1c
--
1c
CuOTf
ND
--
1c
Cu(OTf)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
ND
--
1c
30%
36%
37%
41%
39%
50%
55%
35%
0
1c
5c
1c'
1c"
0
Reaction conditions:
aReactions were carried out in 0.1 mmol scale of p-
nitrobenzaldehyde in 2.5 mL of DCM; ligand-to-metal ration=
1:1 (10 mol %); nitromethane (10 equiv).

3
bStructure identity of all ligands were determined by 1H
NMR, 13C NMR and HRMS.
(Table 2, entry 15), and further lowering the temperature led to
a dramatic decrease in reactivity without any improvement in
enantioselectivity (Table 2, entry 16-17). The effect of air and
moisture on the enantioselectivity of the Henry reaction was also
studied. The reaction was not sensitive to the air, and the results
in argon atmosphere were almost identical to that carried out in
open air. Therefore, the reactions was carried out without special
care of air. After the optimization of the reaction conditions, the
reaction was finally carried out in the presence of 10 mol% 1c-
Cu(OAc)2 (1:1), 10 equivalents nitromethane in 3 mL of mixed
solvents (chloroform : dioxane = 4:1) in the presence of 4 Å MS
(20 mg) at 25 °C (Table 2, entry 14).
cIsolated yields.
dDetermined by HPLC on a Chiralcel OD-H column.
eThe configurations was S, determined by comparison of the
optical rotation with reported results in the literature.17
fLigand-to-Cu(OAc)2 ratio = 1:2 (10 mol %).
gLigand-to-Cu(OAc)2 ratio = 1.25:1 (10 mol %).
As shown in Table 1, different results were obtained when
combination of Cu(OAc)2 and different chiral ligands were used
to promote the reactions. Catalyst with ligand 1a was able to
promote the reaction but showed no enantioselectivity, possibly
due to the unfavorable steric feature of the ligand. Gradually
increasing the steric hindrance of the chiral ligands by
introducing substituents into the hydroxymethyl group led to the
increase of the enantioselectivity, and chiral ligand 1c gave the
most promising result in the reactions. Further increasing the
steric hindrance of the ligands led to drops of the
enantioselectivity. Combination of 1c with CuBr2, CuCl or
Cu(NO3)2 was able to promote the reactions, but no
stereoselectivity was observed, possibly due to the background
reactions induced by the uncoordinated salts (Table 1, entries 7-
9). No desired product was observed when Cu(OTf)2, CuOTf or
CuSO4 was used as the copper source, possibly due to the poor
solubility of these salts in the reaction medium (Table 1, entries
10-12 ). Lower ee also observed when excess amount of
Cu(OAc)2 was used in the reaction, and the metal-to-ligand ratio
was finally fixed to 1:1. Lower ee was observed when compound
5c was subjected to the model reaction, suggesting the important
role of the N-oxide functionality. Methylation of one or two
hydroxyl groups in 1c gave ligands 1c’ and 1c”. Drops of
enantioselectivity were observed when these ligands were
subjected to the same reaction under otherwise identical
conditions, indicating the stereoelectronic demand of the ligands.
Table 2. Optimization of the Addition of nitromethane to p-
nitrobenzaldehyde in the Presence of Cu(II)-1c Complexa
O
OH
NO2
1c-Cu(OAc)2 (10 mol%)
H
10 equiv CH3NO2
solvent, rt, 48 h
O2N
O2N
6b
7b
Entry
1c
(mol%)
Solvent
Temp
(°C)
Yield
ee
(%)b
25
30
36
21
22
65
19
12
54
57
35
40
56
55
60
45
25
(%)c
1
10
CHCl3
toluene
THF
35
35
35
35
35
35
35
35
25
35
35
35
35
25
45
0
68
38
60
0
2
10
3
10
4
10
MeCN
i-PrOH
dioxane
chlorobenzene
DCE
5
10
37
43
53
52
70
60
63
62
72
79
55
78
77
6
10
7
10
8
10
9d
10
4:1
10d
11
12
13d,e
14d,e
15d,e
16d,e
17d,e
10
3:2
15
CHCl3
CHCl3
4:1
20
10
10
4:1
N
O
N
R
R
N
O
N
O
R
R
R
O
R
10
4:1
OMe
OMe
R
R
HO
MeO
1c'
10
4:1
1c"
10
4:1
-10
After the proof of the concept of the isosteric approach to the
design of chiral ligands, reactions in different solvents were
further carried out to get the most suitable media for the
reactions. A series of solvents such as chloroform, toluene, THF
were screened (Table 2, entries 1-8). Toluene and isopropanol
gave moderate yields and ee values (Table 2, entries 2 and 5).
Ether solvents were found to be superior to other solvents in
terms of the yields (Table 2, entries 3 and 6). Reaction in 1,4-
dioxane gave product in highest isolated yield (Table 2, entry 6),
and highest ee value was observed when reaction was carried out
in chloroform (Table 2, entry 1). The reaction was then carried
out in a mixture of chloroform and dioxane in an attempt to
increase both the yield and the ee, and the ratio of chloroform to
dioxane was finally fixed to 4:1 after careful screening of the
reaction conditions. Both the yield and the enantioselectivity
were dramatically influenced by catalyst loading, and the most
favorable catalyst loading was found to be 10 mol%. The effect
of additive also showed some impact on the reactions, and both
the yield and stereoselectivity were enhanced upon addition of
molecular sieve (4 Å MS) (Table 2, entry 13). Temperature also
showed some impact on the reaction, and the reaction
temperature was finally fixed at 25 °C (Table 2, entry 14).
Increasing the temperature caused a drop in enantioselectivity
a
Reaction conditions: Unless otherwise specified, reactions
were carried out on a 0.25 mmol scale of p-nitrobenzaldehyde in
3.0 mL of solvent; nitromethane (10 equiv); ligand-to-Cu(OAc)2
ratio = 1:1 (10 mol %). Reaction time = 48 h.
bIsolated yield.
cDetermined by HPLC on a Chiralcel OD-H column.
dRatio of CHCl3-to-dioxane.
eIn the presence of 4 Å MS (20 mg).
After optimization of the reaction conditions, the scope of the
catalytic enantioselective Henry reaction was then investigated
by reacting various aldehydes with nitromethane. The results are
summarized in Table 3. As these results showed, asymmetric
Henry reaction of aromatic aldehydes proceeded smoothly,
providing the corresponding nitroalcohols in high yields and
moderate to good enantioselectivities (Table 3). Both electron-
rich or electron-deficient aromatic aldehydes were found to be
good substrates for this reaction. Aromatic aldehydes bearing
electron-withdrawing nitro groups gave results better than from
substrates bearing the electron-donating groups (Table 3, entries

4
Tetrahedron
2-8). Substrates 6d and 6h with the ortho substituents gave
higher ee (80% ee and 83% ee, Table 3, entries 4 and 8) possibly
due to larger steric hindrance of the ortho substituent in the
substrates. Even with the bulker aldehydes such as 2-
naphthaldehyde, the reactivity and enantioselectivity were still
maintained (68% ee and 45% yield, Table 3, entries 17).
Reactions of heteroaromatic aldehydes were less successful,
possibly due to the coordination of heteroatom with the catalyst.
The absolute configurations were assigned to be S based on
previous reports.17
Table 3. Asymmetric Henry reactions between nitromethane
and various aldehydes
OH
catalyst (10 mol%)
O
NO2
Confige
Ar
10 equiv CH3NO2
solvent, rt, 48 h
Ar
H
7
6
Entr
y
Aldehydes
Yield
ee
(%)bc
40 (95)
66 (99)
55 (99)
63 (81)
56
(%)cd
Figure 4. Computed model of catalyst Cu(OAc)2-1c.
This preliminary model indicated that the central metal
adopted a distorted square pyramidal structure, and was highly
crowded comparing to Feng’s catalyst.18 The aldehyde
approached the catalyst from the axial position opposite to one of
the N-oxide oxygen atom with Si-face exposing to nucleophilic
attack (Figure 5). Due to the highly hindered nature of the central
metal, the approaching of the substrate to the metal was less
effective comparing to Feng’s catalyst, thus causing the low
activity of the catalyst system.
1
benzaldehyde (6a)
40 (95) (S)
77 (85) (S)
82 (85) (S)
80 (73) (S)
2
4-nitrobenzaldehyde (6b)
3-nitrobenzaldehyde (6c)
2-nitrobenzaldehyde (6d)
4-fluorobenzaldehyde (6e)
3-fluorobenzaldehyde (6f)
4-chlorobenzaldehyde (6g)
2-chlorobenzaldehyde (6h)
4-bromobenzaldehyde (6i)
2-bromobenzaldehyde (6j)
4-methoxybenzaldehyde (6k)
3-methoxybenzaldehyde (6l)
2-methoxybenzaldehyde (6m)
4-methylbenzaldehyde (6n)
3-methylbenzaldehyde (6o)
3,4-dimethylbenzaldehyde (6p)
2-naphthaldehyde (6q)
3
4
5
60
66
(S)
(S)
6
58
7
50 (99)
58
55 (86) (S)
8
83
63
76
60
(S)
(S)
(S)
(S)
N
Et
Et
9
56
O
HO
N
10
11
12
13
14
15
16
17
18
61
O
H
OAc
Cu
O
O
32
OAc
Et
Et
35 (99)
48
65 (95) (S)
71 (S)
CH3NO2
H
Ph
Figure 5. Proposed working model for the Henry reaction of
aldehyde with nitro-methane.
40 (44)
32 (87)
30
46 (91) (S)
60 (93) (S)
3. Conclusion
59
(S)
45 (88)
30 (80)
68 (95) (S)
35 (95) (S)
In summary, new chiral N,N′-dioxide ligands were designed
based on isosteric approach and have been used in Cu(II)-
catalyzed asymmetric Henry reactions. A computation model on
the catalyst indicated that the central metal was sterically
hindered, and rendering the catalyst system less efficient as
compared with the original N,N'-dioxide catalyst systems.
Further study focusing on tackling the problem of
stereoselectivity by replacing copper with different metals was
carrying out in the group, and the results will be reported in due
time.
2-thiophenaldehyde (6r)
Reaction conditions:
aAll the reaction were carried out with 0.1 mmol p-
nitrobenzaldehyde and 1.0 mmol nitromethane in 3.0 mL of
mixed solvents (chloroform : dioxane = 4:1) in the presence of 10
mol % Cu(OAc)2 and 10 mol % ligand.
bIsolated yield.
cData in parentheses are results from Feng’s work. (Ref. 18)
dDetermined by HPLC analysis on a chiralcel OD-H or AD-H
column.
4. Experimental Section
4.1 General Experimental Information
eBy comparison with the literature data.
All reactions were carried out with commercially available
reagents in oven-dried apparatus. Thin layer chromatography
A side-by-side comparison with Feng’s catalyst system
indicated that the current catalysts system compared unfavorably
with Feng’s catalyst (Table 3, entries 1-4,7,12,14-15,17 and
18).18 To get structural insights into the current catalyst system,
computation on Cu(II)-1c was carried out with 6-31G(d,p)19 basis
set at ωB97XD20 level of theory using Gaussian 09 D01
package.21 Preliminary result was shown in Figure 4.
(TLC) was performed on silica gel GF254
.
Column
chromatography was performed employing 200-300 mesh silica
gel unless otherwise noted. Melting points were measured on a
digital melting-point apparatus without correction of the
1
thermometer. H and 13C NMR spectra were recorded at 298 K
using deuterated chloroform as solvent and TMS as internal
reference. Infrared spectra were reported in wave number (cm-1).
HRMS analyses were carried out with Varian FTICR-MS 7.0T.
The enantiomeric excesses were determined by HPLC analysis

5
on chiral DAICEL CHIRALCEL OD-H or CHIRALPAK AD-H
6H), 0.78 (t, J = 7.5 Hz,6H); 13C NMR(100 MHz, CDCl3) δ
column. Optical rotations are measured on a commercial
78.6, 75.7,70.3, 68.2, 28.9, 28.7, 25.1, 21.4, 20.3, 8.0, 7.2. IR
(KBr): υ = 3673, 2968, 1487, 1462, 1143, 977 cm-1. HRMS (ESI,
M+H+) calcd. for C21H42N2O4, 387.3217; found 387.3220.
T
polarimeter and are reported as follows: [α] (c = g/100 mL,
D
solvent). Unless otherwise indicated, starting materials and
reagents used in the study were purchased and were used as
received without further purification.
4.2.4.
(1R,2S)-2-(3-hydroxy-2,4-dimethylpentan-3-yl)-1-(3-
((1R,2S)-2-(3-hydroxy-2,4-dimethylpentan-3-yl)-1-
4.2. Typical Procedure for the preparation of chiral ligands
1a-1e.22
oxidopyrrolidin-1-yl)propyl)pyrrolidine 1-oxide (1d)
Compound 1d was prepared according to the general
Amino alcohol 4b (1.07 g, 8.3 mmol) was added to a 100 mL
round-bottomed flask containing 50 mL acetonitrile, then 1,3-
dibromopropane (0.83 g, 4.2 mmol) and potassium carbonate
(3.50 g, 2.5 mmol) was slowly added portionwise to the flask
over 10 min. The mixture was stirred overnight at 95 °C, then
cooled to room temperature. The solvent was removed in vacuo,
water (20 mL) was added to the residue, and the mixture was
extracted with ethyl acetate (3 × 10 mL). The combined organic
phase was dried over Na2SO4, filtered and concentrated. The
obtained amino alcohol 5b was used without further purification.
procedure and was isolated as brown oil (56% yield) after flash
1
chromatography. [α]2D0 = -8.00 (c = 0.1, CHCl3); H NMR (400
◦
MHz, Chloroform-d, 25 C, TMS): δ=3.89 (dt, J = 13.9, 7.6 Hz,
2H), 3.54-3.26 (m, 8H), 2.62-2.53 (m, 2H), 2.46-2.22 (m, 7H),
2.05-1.72 (m, 7H), 1.10 (d, J = 6.6 Hz, 6H), 1.01 (d, J = 6.9 Hz,
6H), 0.92 (d, J = 6.6 Hz, 3H), 0.85 (d, J = 6.9 Hz, 6H); 13C
NMR(101 MHz, CDCl3) δ 78.7, 76.5, 69.7,68.2, 34.3, 32.4, 27.6,
22.5, 20.2, 19.3, 18.2, 17.9, 16.8. IR (KBr): υ = 3394, 2964,
1469, 1367, 1068, 942 cm-1. HRMS (ESI, M+H+) calcd. for
C25H50N2O4, 343.3843; found 343.3843.
To a solution of amino alcohol 5b (0.95 g, 3.2 mmol) in 15
mL dichloromethane, was added m-chloroperoxybenzoic acid
(1.61 g, 7.0 mmol). The mixture was stirred at room temperature
for 12 h, and the solvent was removed in vacuo to give the crude
product. Compound 1b was obtained in 80% (1.02 g) after
column chromatography through silica gel (ethyl acetate as
eluent).
4.2.5.
(1R,2S)-2-(hydroxydiphenylmethyl)-1-(3-((1R,2S)-2-
(hydroxydiphenylmethyl)-1-oxidopyrrolidin-1-
yl)propyl)pyrrolidine 1-oxide (1e)
Compound 1e was prepared according to the general procedure
and was isolated as brown solid (77% yield) after flash
◦
chromatography. mp: 212-216 C; [α]2D0 = 22.00 (c = 0.1, CHCl3);
1H NMR (400 MHz, Chloroform-d, 25 C, TMS): δ= 11.36 (s,
◦
4.2.1. (1R,1'R,2S,2'S)-1,1'-(propane-1,3-diyl)bis(2-(2-
hydroxypropan-2-yl)pyrrolidine 1-oxide) (1b).
2H), 7.71-7.61 (m, 4H), 7.56-7.43 (m, 4H), 7.33-7.22 (m, 10H),
7.18-7.09 (m, 2H), 4.22 (t, J = 9.0 Hz, 2H), 3.34 (t, J = 9.2 Hz,
2H), 3.23-3.08 (m, 2H), 2.55-2.17 (m, 7H), 2.17-2.03 (m, 2H),
2.00-1.86 (m, 2H), 1.86-1.77 (m, 2H), 1.77-1.65 (m, 1H). 13C
NMR (101 MHz, CDCl3) δ 147.3, 146.6, 128.2, 128.2, 126.8,
126.6, 125.9, 124.6, 77.8, 77.6, 68.7, 66.0, 26.1, 19.8, 19.5. IR
(KBr): υ = 3743, 2958, 1534, 1490, 689, 657 cm-1. HRMS (ESI,
M+H+) calcd. for C37H42N2O4, 579.3217; found 579.3213.
Compound 1b was prepared according to the general
procedure and was isolated as brown solid; mp: 130-138 °C; [α]D20
= -43.99 (c = 0.1, CHCl3); 1H NMR (400 MHz, Chloroform-d, 25
◦C, TMS): δ= 8.70 (s, 2H), 3.98-3.68 (m, 2H), 3.63-3.32 (m, 6H),
3.24 (t, J = 8.7 Hz, 2H), 2.62 (t, J = 7.3 Hz, 2H), 2.53-2.39 (m,
2H),2.33-2.19 (m, 2H), 2.13-1.98 (m, 2H), 1.95-1.76 (m, 2H),
1.50 (s, 6H), 1.23 (s, 6H). 13C NMR(101 MHz, CDCl3) δ 80.9,
71.2, 69.5, 67.7, 29.9, 28.2, 25.6, 21.3, 20.0. IR (KBr): υ = 3433,
2974, 1480, 1362, 962, 652 cm-1. HRMS (ESI, M+H+) calcd. for
C17H34N2O4 331.2591; found 331.2595.
Crystal data for 1e: C37H42N2O4, M = 578.72, a = 9.0796(2) ? b =
10.8989(2) Å c = 15.9762(3) ? α = 90°, β = 92.534(2)°, γ = 90°, V
= 1579.42(5) Å3, T = 298.80(10) K, space group P1211, Z = 2,
ꢀ(CuKα) = 0.622 mm-1, 8675 reflections measured, 4667
independent reflections (Rint = 0.0150). The final R1 values were
0.0355 (I > 2σ(I)). The final wR(F2) values were 0.0961 (I >
2σ(I)). The final R1 values were 0.0371 (all data). The final
wR(F2) values were 0.0980 (all data). The goodness of fit on F2
was 1.007. Flack parameter = -0.04(10). CCDC 1911346.
4.2.2.
(1R,1'R,2S,2'S)-1,1'-(propane-1,3-diyl)bis(2-
(hydroxymethyl)pyrrolidine 1-oxide) (1a)
Compound 1a was prepared according to the general
procedure and was isolated as brown oil (54% yield) after flash
1
chromatography. brown oil; [α]2D0 = -2.36 ; (c =0.1, MeOH); H
4.3. General procedure for asymmetric Henry reaction.
◦
NMR (400 MHz, Chloroform-d, 25 C, TMS): δ = 4.17 (d, J =
13.1 Hz, 2H), 3.87 (dd, J = 13.1, 4.4 Hz, 2H), 3.82-3.72 (m, 2H),
3.60-3.46 (m, 4H), 3.43-3.26 (m, 4H), 2.74-2.60(m, 2H), 2.58-
2.45 (m, 2H), 2.40-2.27 (m, 2H), 2.12-1.89 (m, 6H)ppm. 13C
NMR (101 MHz, DMSO) δ 74.7, 66.6, 63.2, 58.8, 8.7, 23.8,
20.2, 19.6. IR (KBr): υ = 3392, 2958, 1452, 1055, 734, 652 cm-1.
HRMS (ESI, M+H+) calcd. for C13H26N2O4 275.1965; found
275.1970.
A mixture of Ligand 1c (3.86 mg, 0.01 mmol, 10 mol%),
Cu(OAc)2 (1.8 mg, 0.01 mmol, 10 mol%) and 4 Å molecular
sieves (20 mg) was stirred in anhydrous chloroform and dioxane
(2.4/0.6 mL) at room temperature for 20 min to allow the
formation of the complex. Then nitromethane (61 mg, 1.0 mmol)
was added to the mixture. Nitrobenzaldehyde 6b (0.1 mmol) was
then added and the mixture was stirred for 48 h. The reaction
mixture was purified by column chromatography through silica
gel (petroleum ether/ethyl acetate = 8:1) to afford the nitroaldol
product 7b (11.8 mg, 66% yield) as a colourless oil. Chiralcel
OD-H hexane/i-PrOH. 85:15, 1.0 mL/min, R : tr(minor) = 15.9
min, S: tr(major) = 19.9 min; 1H NMR (400 MHz, Chloroform-d,
TMS): δ= 8.33-8.22 (m, 2H), 7.67-7.61 (m, 2H), 5.67-5.55 (m,
1H), 4.64-4.53 (m, 2H), 3.17 (s, 1H) ppm.
4.2.3. (1R,2S)-2-(3-hydroxypentan-3-yl)-1-(3-((1R,2S)-2-(3-
hydroxypentan-3-yl)-1-oxidopyrrolidin-1-yl)propyl)pyrrolidine
1-oxide) (1c)
Compound 1c was prepared according to the general
procedure and was isolated as brown solid (78% yield) after flash
chromatography. mp: 165-168 ◦C; [α]D20 = -27.86 (c = 0.1, CHCl3);
◦
1H NMR (400 MHz, Chloroform-d, 25 C, TMS): δ= 8.53 (s,
5. Appendix A. Supplementary data
2H), 3.86-3.68 (m, 2H), 3.55-3.44 (m, 2H), 3.40 (dd, J = 7.9, 6.1
Hz, 4H), 3.26 (t, J = 8.8 Hz, 1H), 2.63-2.46 (m, 4H), 2.31-2.17
(m, 2H), 2.15-2.03 (m, 2H), 2.02-1.89 (m, 2H), 1.86-1.73 (m,
4H), 1.70-1.57 (m, 2H), 1.37-1.25 (m, 2H), 0.90 (t, J = 7.4 Hz,
Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2018.XX.XXX.

6
Tetrahedron
Acknowledgments
17. Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am.
Chem. Soc. 1992, 114, 4418.
18. Qin, B.; Xiao, X.; Liu, X.; Huang, J.; Wen, Y.; Feng, X. J. Org.
Chem. 2007, 72, 9323.
19. (a) Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys.
1971, 54, 724; (b) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J.
Chem. Phys. 1972, 56, 2257; (c) Hariharan, P. C.; Pople, J. A.
Theoret. Chim. Acta 1973, 28, 213; (d) Rassolov, V. A.; Pople,
J. A.; Ratner, M. A.; Windus, T. L. J. Chem. Phys. 1998, 109,
1223.
We acknowledge the financial support from the National
Natural Science Foundation of China (NSFC 21672106 and
NSFC 21272121) and the Ministry of Tianjin Municipal
Commission of Science and Technology (15JCZDJC33300). En
Gao acknowledges the support from Nankai University Ph.D.
Students Innovative Research Program.
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