A new type of L-Tertiary leucine-derived ligand: Synthesis and application in Cu(II)-catalyzed asymmetric Henry reactions

Article abstract of DOI:10.1016/j.tet.2019.130469

A new series of Schiff bases derived from amino acids were developed as chiral ligands for Cu(II)-catalyzed asymmetric Henry reactions. The optimum ligand 7d exhibited outstanding catalytic efficiency in the Cu(II)-catalyzed asymmetric Henry additions of four nitroalkanes to different kinds of aldehydes to produce 76 desired adducts in high yields (up to 96%) with excellent enantioselectivities, up to 99% enantiomeric excess (ee).

Full text of DOI:10.1016/j.tet.2019.130469

Accepted Manuscript
A new type of L-Tertiary leucine-derived ligand: Synthesis and application in Cu (II)-
catalyzed asymmetric Henry reactions
Zedong Cai, Ting Lan, Pengfei Ma, Jingfang Zhang, Qingqing Yang, Wei He
PII:
S0040-4020(19)30783-5
DOI:
https://doi.org/10.1016/j.tet.2019.130469
Article Number: 130469
Reference:
TET 130469
To appear in: Tetrahedron
Received Date: 23 April 2019
Revised Date: 17 July 2019
Accepted Date: 19 July 2019
Please cite this article as: Cai Z, Lan T, Ma P, Zhang J, Yang Q, He W, A new type of L-Tertiary leucine-
derived ligand: Synthesis and application in Cu (II)-catalyzed asymmetric Henry reactions, Tetrahedron
(2019), doi: https://doi.org/10.1016/j.tet.2019.130469.
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ACCEPTED MANUSCRIPT

Tetrahedron xxx (xxxx) xxx–xxx
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
A New Type of L-Tertiary Leucine-Derived Ligand: Synthesis and Application in Cu
(II)-catalyzed Asymmetric Henry Reactions
, a
Zedong Cai1, a, Ting Lan1, a, Pengfei Maa, Jingfang Zhangb, Qingqing Yanga, Wei He
a Department of Chemistry, School of Pharmacy, The Fourth Military Medical University, Xi’an, 710032, People’s Republic of China.
b Key Laboratory of Functional Polymer Materials (Ministry of Education), Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin
300071, People’s Republic of China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new series of Schiff bases derived from amino acids were developed as chiral ligands for Cu
(II)-catalyzed asymmetric Henry reactions. The optimum ligand 7d exhibited outstanding
catalytic efficiency in the Cu (II)-catalyzed asymmetric Henry additions of four nitroalkanes to
different kinds of aldehydes to produce 76 desired adducts in high yields (up to 96%) with
excellent enantioselectivities, up to 99% enantiomeric excess (ee).
Available online
Keywords:
chirality
2009 Elsevier Ltd. All rights reserved
.
copper complexes
Henry reaction
L-tertiary leucine
Schiff base ligands
1. Introduction
[15] Mg, [16] or Cr [17]) systems have been developed for
asymmetric Henry reactions to obtain high enantioselectivity and
diastereoselectivity. Unlike the asymmetric Henry reaction of
aldehydes with only nitromethane or/and nitroethane, [18] the
asymmetric Henry reaction of aldehydes with different kinds of
nitroalkanes using only the same catalytic system, including 1-
nitropropane and 2-nitropropane, has not been reported
systematically. [19] Based on these reasons, we have developed
chiral ligands derived from amino acids to realize the asymmetric
Henry reaction with various nitroalkanes.
Controlling spatial selectivity and enantioselectivity is one of
the most important topics in organic reactions. [1] Transition-
metal catalysis is one of the most important methods to improve
the enantioselectivity of the transformations. [2] Amongst these
metal complexes, chiral copper complexes [3] have received
particular attention due to its low toxicity, low cost, ready
availability, and wide structural variability of the chiral ligands
such as Schiff base, [4] salen, [5] cinchona alkaloid derivatives,
[6] BINAP, [7] bisoxazolines, [8] and diamines. [9] To date,
there are still very few catalytic systems available for asymmetric
catalytic reactions with various substrates. Therefore, the design
of new chiral catalysts to solve this problem is still a major issue.
The Henry reaction is one of the most valuable and atomic-
economical reactions in the formation of carbon-carbon bonds.
[10] Its resulting product, β-nitroalcohol, is a very vital
intermediate for some biologically active natural products,
medicines, chiral ligands (Figure 1). [11] For example, molecule
I is a powerful inhibitor of the ROMK (kir1.1) channel and can
be used as a diuretic and/or natriuretic agent for the therapy and
prophylaxis of cardiovascular diseases, including hypertension,
heart failure, and diseases associated with excessive salt and
water retention. However, the asymmetric Henry reaction with 2-
nitropropane as nucleophilic reagent has not been reported so far.
Over the past several decades, with Shibasaki's groundbreaking
work, [12] dozens of metal-catalyzed (Zn, [13] Cu, [6, 14] Co,
Corresponding author. Tel.: +86-29-84774470; e-mail: weihechem@fmmu.edu.cn
1 These authors contributed equally to this work.
1

Tetrahedron xxx (xxxx) xxx–xxx
Figure 1. Representative bioactive compounds containing structural units of To increase the reaction yield of the catalytic system, different
ACCEPTED MANUSCRIPT
o-Aryl aminoalcohols from natural and synthetic sources.
kinds of basic additives were tested (Table 2, entries 1–11). As
desired, the addition of a basic additive did increase the yield of
the reaction; however, the ee value decreased. The addition of
bipyridine, potassium hydroxide, sodium carbonate, cesium
carbonate, and potassium fluoride dihydrate gave low ee values
(Table 2, entries 2–5, 7). DABCO significantly increased the
yield, such that 77% ee and 83% yield were achieved using 5
mol% of DABCO as additive (Table 2, entries 11–14).
2. Results and discussion
A new series of Schiff base ligands was easily prepared (see
Experimental Section and Supplementary data) from
commercially available amino acids and salicylaldehyde
derivatives (Figure 2). Initially, benzaldehyde (8a) and 2-
nitropropane (9a) were used as model substrates to screen these
ligands.
Table 2. Effects of the base additives in the asymmetric
Henry reaction.a)
Loading of base (mol
%)
Yield
(%)b)
ee
Entry
1
Base
(%)c)
DMAP
2,2'-bipyridine
KOH
100
100
100
100
100
100
100
100
100
100
100
10
78
41
82
81
78
85
83
67
65
38
93
85
83
83
39
0
F
2
igure 2. The Schiff base ligands screened in asymmetric Henry reactions.
3
3
First, the reaction [6b] was performed in i-PrOH at 25°C using
10 mol% of various Schiff base ligands in combination with
copper acetate (Table 1, entries 1–4). To our delight, 7d proved
to be the most suitable ligand for this reaction. When the loading
of the catalyst was reduced to 5 mol%, the yield and ee value
were still maintained (Table 1, entries 4–6). From entry 7, we
can see that the absolute configuration of amino acids determined
the absolute configuration of products (Table 1, entry 7).
Reactions did not occur when only ligand was used instead of Cu
(II)-complex (Table 1, entry 8).
4
Na2CO3
Cs2CO3
K2CO3
8
5
3
6
15
0
7
KF·2H2O
NaF
8
47
25
81
51
74
74
77
Table 1. Evaluation of chiral Schiff base ligands and their
loading in the asymmetric Henry reaction.a)
9
Li2CO3
10
11
12
13
14
bipyridine
DABCO
DABCO
DABCO
DABCO
Entry
Ligand
Loading of Cat. (mol %)
Yield (%)b)
ee (%)c)
1
2
7a
7b
7c
7d
7d
7d
7e
7d
10
10
10
10
8
trace
13
n.d.d)
68 (S)e)
n.d.
8
3
trace
35
5
4
85 (S)
84 (S)
85 (S)
73 (R)
n.d.
a) All of the reactions were carried out with 0.2 mmol of benzaldehyde and 2
mmol of 2-nitropropane in 1 mL of i-PrOH in the presence of 5 mol% of
catalyst at 25°C. b) Isolated yield. c) Determined by HPLC analysis (Chiralcel
5
34
6
5
33
OD-H column, Hex:i-Pro
(minor)=9.725 min, tR(major)=14.165 min.
= , 210 nm) tR
90:10, 1.0 mL·min-1, 25
7
5
33
8f)
5
trace
Generally, the solvent has significant effects on the
enantioselectivity in catalytic asymmetric reactions. Therefore,
solvents were screened systematically (Table 3, entries 1-15). As
shown in Table 3, alcohols and ethers improved the
enantioselectivity of the reaction. Among the selected solvents,
n-propanol, 1, 4-dioxane and methyl tert-butyl ether all showed
excellent effects. After comprehensive consideration, we chose
methyl tert-butyl ether as the optimal reaction solvent. The
reaction temperature was further optimized (Table 3, entries 15-
19). The enantioselectivity of the reaction was greatly improved
a) All of the reactions were carried out with 0.2 mmol of benzaldehyde and 2
mmol of 2-nitropropane in 1 mL of i-PrOH in the presence of x mol% of
catalyst at 25°C. All of the catalysts were formed in situ, about 0.5 h before
b)
c)
addition of benzaldehyde. Isolated yield. Determined by HPLC analysis
(Chiralcel OD-H column, Hex:i-Pro = 90:10, 1.0 mL·min-1, 25 , 210 nm) tR
d)
e)
(minor)=9.725 min, tR(major)=14.165 min.
n.d. = not detected.
By
comparison of the HPLC elution order of the enantiomers with the literature
data. [19h] f) Without metal.
2

Tetrahedron xxx (xxxx) xxx–xxx
when the temperature was reduced from room temperature to withdrawing substituents on the benzene ring, and the different
ACCEPTED MANUSCRIPT
10°C, and it reached 88% ee. The yield of the reaction was
positions of substituents, these substrates are applicable to the
catalytic system indiscriminately (Table 4, entries 1-11). To our
surprise, we found that benzaldehyde substrates with 2, 4-
substituents can also achieve excellent catalytic effects (Table 4,
entries 12-20). Heterocycles, fused rings, and different
cinnamaldehydes have also been proven to be suitable for the
catalytic system and have achieved excellent catalytic
performance (Table 4, entries 22-26). For single chiral centers,
we also attempted to expand Henry reactions using nitromethane
as a substrate (Table 4, entries 27-43). Unsurprisingly, excellent
catalytic effects were obtained. Remarkably, under this catalytic
system, many aldehydes can obtain more than 95% ee, and even
isobutyraldehyde (Table 4, entry 39) and cyclopropionaldehyde
(Table 4, entry 43) can produce almost chiral pure nitroalcohols.
maintained at a relatively high level. The enantioselectivity
increased slightly when the reaction temperature was further
lowered, but the yield seriously decreased. Therefore, we decided
to choose 10°C as the optimum reaction temperature.
Table 3. Screening the solvents and temperature in the
asymmetric Henry reaction.a)
Entry
1
Solvent
THF
Temp. (°C) Yield (%)b) ee (%)c)
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
10
0
89
78
81
85
56
78
54
83
84
78
83
87
trace
85
88
85
69
51
32
77
61
50
77
49
70
43
65
77
66
73
79
n.d.
Table 4. Asymmetric Henry reaction with a single chiral
a)
center catalyzed by 7d/Cu (OAc) 2.
toluene
DMSO
i-PrOH
DCM
2
3
4
5
Entry
1
Aldehyde
Nitroalkane
Product
10a
10b
10c
10d
10e
10f
Yield (%)b)
71
ee (%)c)
90
93
95
91
89
95
94
93
92
93
91
93
94
94
93
95
93
94
94
91
90
89
Et2O
6
Ph (8a)
9a R2=R3=Me
9a R2=R3=Me
9a R2=R3=Me
9a R2=R3=Me
9a R2=R3=Me
9a R2=R3=Me
9a R2=R3=Me
9a R2=R3=Me
9a R2=R3=Me
9a R2=R3=Me
9a R2=R3=Me
9a R2=R3=Me
9a R2=R3=Me
9a R2=R3=Me
9a R2=R3=Me
9a R2=R3=Me
9a R2=R3=Me
9a R2=R3=Me
9a R2=R3=Me
9a R2=R3=Me
9a R2=R3=Me
9a R2=R3=Me
n-Hex
7
2
2-MeC6H4 (8b)
2-MeOC6H4 (8c)
3-MeOC6H4 (8d)
4-MeSC6H4 (8e)
2-FC6H4 (8f)
70
DMF
8
3
72
MeOH
CH3CN
EtOH
9
4
73
10
11
12
13
14
15
16
17
18
19
5
75
6
83
n-PrOH
(CH2OH)2
1,4-dioxane
MTBE
MTBE
MTBE
MTBE
MTBE
7
2-ClC6H4 (8g)
10g
10h
10i
79
8
4-ClC6H4 (8h)
2-BrC6H4 (8i)
81
80
80
88
89
90
92
9
79
10
11
12
13
14
15
16
17
18
19
20
21
22
4-BrC6H4 (8j)
10j
81
2-IC6H4 (8k)
10k
10l
72
2,4-diFC6H4 (8l)
2,4-diClC6H4 (8m)
2,4-diBrC6H4 (8n)
4-Br-2-FC6H4 (8o)
4-Br-2-ClC6H4 (8p)
2-Br-4-ClC6H4 (8q)
2-F-4-MeC6H4 (8r)
2-Cl-4-MeC6H4 (8s)
2-Br-4-MeC6H4 (8t)
2-PhC6H4 (8u)
PhC=C (8v)
85
-10
-20
10m
10n
10o
10p
10q
10r
10s
81
81
a)
All of the reactions were carried out with 0.2 mmol of benzaldehyde, 2
mmol of 2-nitropropane, and 5 mol% DABCO in 1 mL of solvent in the
83
b)
c)
presence of 5 mol% of catalyst. Isolated yield. Determined by HPLC
83
analysis (Chiralcel OD-H column, Hex:i-Pro = 90:10, 1.0 mL·min-1, 25
,
83
210 nm) tR (minor)=9.725 min, tR(major)=14.165 min.
In general, the optimum reaction conditions were 5 mol%
7d/Cu (OAc)2 (1:1) complex as catalyst, MTBE as solvent, 5
mol% DABCO as basic additive, 10°C as reaction temperature,
and a reaction time of 12 hours.
77
73
10t
77
With the optimal reaction conditions in hand, the substrates
involved in the asymmetric Henry reaction were systematically
extended. Primarily, we extended the asymmetric Henry reaction
with 2-nitropropane (Table 4, entries 1-26). For benzaldehyde
substrates, no matter the electron-donating or electron-
10u
10v
71
77
3

Tetrahedron xxx (xxxx) xxx–xxx
Table 5. Diastereoselective Henry reactions catalyzed by
ACCEPTED MANUSCRIPT
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
2-NO2PhC=C (8w)
4-BrPhC=C (8x)
1-naphthyl (8y)
2-thienyl (8z)
Ph (8a)
9a R2=R3=Me
9a R2=R3=Me
9a R2=R3=Me
9a R2=R3=Me
9b R2=R3=H
9b R2=R3=H
9b R2=R3=H
9b R2=R3=H
9b R2=R3=H
9b R2=R3=H
9b R2=R3=H
9b R2=R3=H
9b R2=R3=H
9b R2=R3=H
9b R2=R3=H
9b R2=R3=H
9b R2=R3=H
9b R2=R3=H
9b R2=R3=H
9b R2=R3=H
9b R2=R3=H
10w
10x
10y
10z
11a
11b
11c
11d
11e
11f
78
82
77
79
95
91
92
92
93
88
89
87
85
89
92
91
91
91
89
93
95
91
89
93
89
96
95
93
88
96
96
98
95
86
94
91
91
＞99
95
91
95
99
a)
7d/Cu (OAc) 2.
ee (%)c)
Yield
(%)b)
anti:sync)
Nitroalkane
Entry
Aldehyde
Product
anti
syn
98
93
91
94
95
94
96
98
88
91
96
91
94
93
94
91
97
99
93
92
99
97
94
92
95
92
96
93
94
98
91
2-MeC6H4 (8b)
4-MeOC6H4 (8aa)
2-FC6H4 (8f)
2-thienyl (8z)
4-indolyl (8ab)
1-naphthyl (8y)
2-naphthyl (8ac)
2-MeO-1-naphthyl (8ad)
1-pyrenyl (8ae)
Et (8af)
1
Ph (8a)
9c R2= Me
9c R2= Me
9c R2= Me
9c R2= Me
9c R2= Me
9c R2= Me
9c R2= Me
9c R2= Me
9c R2= Me
9c R2= Me
9c R2= Me
9c R2= Me
9c R2= Me
9c R2= Me
9c R2= Me
9c R2= Me
9d R2= Et
9d R2= Et
9d R2= Et
9d R2= Et
9d R2= Et
9d R2= Et
9d R2= Et
9d R2= Et
9d R2= Et
9d R2= Et
9d R2= Et
9d R2= Et
9d R2= Et
9d R2= Et
9d R2= Et
12a
12b
12c
12d
12e
12f
95
90
92
94
89
91
94
92
92
97
91
88
91
90
91
91
95
92
93
94
93
94
94
96
95
96
91
92
87
90
91
85:15
85:15
80:20
80:20
85:15
21:79
81:19
74:26
83:17
78:22
83:17
67:33
74:26
76:24
77:23
64:36
71:29
69:31
68:32
66:34
65:35
76:24
73:27
68:32
71:29
66:34
68:32
70:30
71:29
72:28
69:31
95
90
92
93
96
94
96
95
93
92
86
84
93
87
95
94
94
90
91
94
95
95
92
93
92
92
93
91
92
96
91
2
2-MeC6H4 (8b)
3-MeC6H4 (8am)
4-MeC6H4 (8an)
2-MeOC6H4 (8c)
3-MeOC6H4(8d)
4-MeOC6H4 (8aa)
4-i-PrC6H4 (8ao)
2-FC6H4(8f)
3
4
5
11g
11h
11i
6
7
12g
12h
12i
8
11j
9
11k
11l
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
4-FC6H4 (8ap)
2-ClC6H4 (8g)
1-naphthyl(8y)
2-naphthyl (8ac)
4-indolyl (8ab)
2-thienyl (8z)
PhC=C (8v)
12j
n-Pr (8ag)
12k
12l
i-Pr (8ah)
11m
11n
11o
11p
11q
n-Bu (8ai)
12m
12n
12o
12p
13a
13b
13c
13d
13e
13f
t-Bu (8aj)
cyclohexyl (8ak)
epoxy (8al)
a) All of the reactions were carried out with 0.2 mmol of benzaldehyde and 2
mmol of nitroalkane and 5 mol% DABCO in 1 mL of MTBE in the presence
Ph (8a)
b)
c)
of 5 mol% of catalyst at 10°C. Isolated yield. Determined by HPLC
analysis (Chiralcel OD-H, OJ-H, or Chiralpak AD-H, AS-H column).
2-MeC6H4 (8b)
3-MeC6H4 (8am)
4-MeC6H4 (8an)
2-MeOC6H4 (8c)
4-MeOC6H4 (8aa)
2-FC6H4 (8f)
Afterwards, the nitroalkanes that can produce two chiral center
products were also systematically investigated (Table 5). First,
nitroethane was used as a substrate to expand aldehydes. To our
delight, both of the two diastereomers caused excellent
enantioselectivity, although the diastereoselectivity of the
products was not good.It seems that there is no difference
between the type of substituents on benzaldehyde substrates
(electron-donating or electron-withdrawing) and the position of
substituents (Table 5, entries 1-11). Similarly, nitroethane can be
extended to fused-ring, heterocyclic, fused-heterocyclic, and
cinnamaldehyde substrates with good-to-excellent performance
(Table 5, entries 12-16).
13g
13h
13i
4-FC6H4 (8ap)
4-ClC6H4 (8h)
4-BrC6H4 (8j)
1-naphthyl (8y)
2-naphthyl (8ac)
4-indolyl (8ab)
2-thienyl (8z)
2-furyl 8aq
13j
Second, the previously unexplored substrates, such as 1-
nitropropane, were expanded with different aldehydes (Table 5,
entries 17-33). It was anticipated that, like nitroethane, the
products with 1-nitropropane as a nucleophilic reagent would
also cause very excellent enantioselectivity, which would also be
applicable to aldehydes with different substituents on the benzene
ring (Table 5, entries 17-26). Therefore, we also extended the
types of aldehydes to fused ring, heterocycle, fused heterocycle,
aliphatic aldehyde, and cinnamaldehyde substrates and obtained
excellent catalytic selectivity (Table 5, entries 27-33).
13k
13l
13m
13n
13o
4

Tetrahedron xxx (xxxx) xxx–xxx
reactions, we further studied the role of hydroxy moiety by using
ACCEPTED MANUSCRIPT
32
33
PhC=C (8v)
Et (8af)
9d R2= Et
9d R2= Et
13p
13q
91
93
51:49
93
91
the hydroxyl-protected ligand 7f in catalytic reactions. The
asymmetric Henry reaction of three selected substrates was tested
under the same reaction conditions as Table 4 (Scheme 1). We
can see that compared with the reaction using 7d, both the yield
and ee value decreased significantly when 7f was used. In
addition, a new ligand 7g without piperidine structure was
synthesized to verify whether the quaternary ammonium ion of
piperidine structure participates in the formation of ion pairs. The
asymmetric Henry reaction of three selected substrates was tested
under the same reaction conditions as Table 4 (Scheme 1). The
results showed that under the same conditions, the ligand 7g
without piperidine structure was inferior to ligand 7d (Scheme 2)
in both yield and enantioselectivity, indicating that piperidine did
41:59
94
97
a)
All of the reactions were carried out with 0.2 mmol of benzaldehyde, 2
mmol of nitroalkane, and 5 mol% DABCO in 1 mL of MTBE in the presence
b)
c)
of 5 mol% of catalyst at 10°C. Isolated yield. Determined by HPLC
analysis (Chiralcel OD-H, OJ-H, or Chiralpak AD-H, AS-H column), by
comparison of the HPLC elution order of the enantiomers with the literature
data for the absolute configuration. [14f, 6b]
In order to elucidate the reaction mechanism of the catalytic
system, the absolute configuration of ligand 7d was identified by
X-ray single crystal diffraction (Figure 3). The spatial
configuration of ligand 7d shows that both the O1 and N1 atoms
may potentially coordinate with the copper center. [18]
1
play a key role in the transition state. Furthermore, the H NMR
spectra of ligand 7d and Cu (II)/ 7d complex were obtained in
THF substituted by deuterium (see Supplementary data). By
comparing the two NMR spectra, we found the change of
hydroxyl hydrogen signal at 13.96 ppm, which indicates that
hydroxyl is involved in the formation of metal complexes.
Figure 3. X-ray crystal structure of ligand 7d. (CCDC 1888078).
Based on the experimental investigations above and previous
mechanistic studies, [6b, 18c] we proposed a possible transition
state as shown in Figure 4. From the single crystal structure of
ligand 7d and the coplanarity of the entire structure of phenol and
phenylimine, we speculated that the phenolic hydroxyl oxygen
and the phenylimine nitrogen participate in the coordination of
the metal copper. The tertiary leucine derivative is partially
perpendicular to the salicylaldehyde moiety. The quaternized
piperidine forms an ion pair with the deprotonated nitromethane,
while another oxygen of the nitro group coordinates with the
metal copper. The carbonyl oxygen of the substrate aldehyde is
also coordinated to the metal copper. It is favorable that the
nitromethane attacks the carbonyl carbon from the Re face.
Scheme 1. Control experiments for the investigation of 7d’s hydroxy moiety.
Scheme 2. Control experiments for the investigation of 7d’s piperidine
moiety.
Since β-nitroalcohols are very important raw materials for
synthetic drug intermediates and natural active molecules, the
asymmetric Henry reaction of benzaldehyde and nitroethane was
performed on a gram scale, and the desired product (12a) was
obtained with 95% yield and 95% ee (anti), 92% ee (syn), and
80:20 dr (Scheme 3). As illustrated in Scheme 3, product 12a
obtained by this method was converted into oxazolidinone 14.
First, β-nitroalcohols were reduced to primary amines in
hydrogen/palladium-carbon. Subsequently, compound 14 was
obtained by triphosgene treatment. Diaryl 15 was synthesized
according to the reported method and further combined with 14
to obtain an analogue of anacetrapib. [21] Ancetrapib, identified
by Merck as an effective CETP inhibitor, has shown good safety
and no targeting effect in clinical trials for hypercholesterolemia
(phase III). [21]
Figure 4. Plausible transition state for the enantioselective Henry reaction.
Regrettably, we have not been able to cultivate the single
crystal structure of ligand 7d/Cu (OAc) 2 complex. However, the
formation of ligand 7d/Cu(II) (1:1) complex was confirmed by
HRMS (ESI) for C26H44N2O Cu(OAc)2 [M-H]-: calcd 580.2943,
and we found 580.2947 (see Supplementary data). To elucidate
the pathway of 7d/Cu (II) complex catalyzing asymmetric Henry
5

Tetrahedron xxx (xxxx) xxx–xxx
ACCEPTED MANUSCRIPT
Scheme 4. The synthetic route of the ligands 7.
Scheme 3. Gram-scale experiment and conversion of the β-nitroalcohol
product to construct biologically active molecules.
4.2.1 Preparation of 7a: To a stirred 40 mL methanol
solution of 5a (1.63 g, 8 mmol) in a 100 mL round-bottom flask
equipped with a magnetic stirring bar was added 3, 5-di-tert-
butyl salicylaldehyde 6 (2.06 g, 8.8 mmol) portionwise, and the
reaction was refluxed at 70°C. When the reaction was complete,
the mixture was filtrated. After concentration of the filtrate,
methanol was added to recrystallize it. After being filtrated, the
filtrate was concentrated and recrystallized again. We combined
three crystals, washed them with a small amount of methanol,
and then dried them in vacuum. Finally, yellow crystal 7a (3.06
g, yield 91%) was obtained. m.p. 69.5ꢀ°C–70.9ꢀ°C; [α]D25ꢀ=ꢀ-
1.331° (cꢀ=ꢀ1.0, CHCl3); 1H NMR (400 MHz, Methanol-d) δ 8.50
(s, 1H), 7.47 – 7.32 (m, 5H), 7.30 – 7.24 (m, 1H), 7.22 – 7.15 (m,
1H), 4.65 – 4.55 (m, 1H), 2.99 – 2.85 (m, 1H), 2.75 – 2.65 (m,
1H), 2.58 (s, 1H), 2.55 – 2.41 (m, 2H), 1.60 – 1.51 (m, 4H), 1.50
– 1.35 (m, 13H), 1.33 – 1.25 (m, 9H); 13C NMR (100 MHz,
Chloroform-d) δ 165.82, 158.07, 142.37, 139.97, 136.54, 128.57,
127.22, 127.09, 126.86, 126.10, 118.14, 71.65, 66.78, 55.06,
35.05, 34.14, 31.53, 29.48, 26.02, 24.27; HRMS (ESI) for
C28H40N2O [M + H]+: calcd 421.3213, found 421.3209.
3. Conclusion
In conclusion, the new Schiff base ligand 7d, which is easily
prepared from L-tert-leucine, after complexing with copper
acetate, exhibits excellent catalytic efficiency in the
enantioselective Henry reaction of four nitroalkanes with
different kinds of aldehydes, and it resulted in 76 types of β-
nitroalcohol, with up to 99% ee and 96% yield. A possible
transition state was proposed based on X-ray single crystal
diffraction of ligand 7d, control experiments, and absolute
configurations of nitroalcohols. With our own catalytic system,
we further converted the synthesized nitroalcohols to vital
intermediate of anacetrapib analogues. Further investigations on
the reaction mechanism and the use of these β-nitroalcohols in
other transformations are underway in our laboratory.
4. Experimental Section
4.1 General Information
All starting materials and reagents for synthesis were
purchased from suppliers without any further purification. All
solvents are treated without water according to standard
operation. The reaction process was monitored by thin layer
chromatography (TLC), and the TLC results were analyzed by
ultraviolet lamp or phosphomolybdic acid. The optical rotation of
the product was measured by Perkin Elmer 343 polarimeter. High
resolution mass spectrometry (HRMS) was measured on Bruer-
McToof QII. Infrared spectra were recorded on FTIR-8400S
4.2.2 Preparation of 7b: The synthetic route is the same as 7a
except that the starting material is L- phenylalanine. 7b is yellow
oil and the characterization data is: [α]D25ꢀ=ꢀ-0.622° (cꢀ=ꢀ1.0,
CHCl3); 1H NMR (400 MHz, ) δ 8.07 (s, 1H), 7.38 (s, 1H), 7.30 –
7.15 (m, 5H), 6.97 (s, 1H), 4.15 (q, J = 7.2 Hz, 1H), 3.63 (s, 1H),
3.10 (dd, J = 14.00 Hz, J = 4.40 Hz, 1H), 2.87 (dd, J = 13.6 Hz, J
= 8.4 Hz, 1H), 2.71 – 2.64 (m, 1H), 2.48 (s, 3H), 2.07 (s, 1H),
1.65 – 1.55 (m, 4H), 1.50 – 1.41 (m, 12H), 1.35 – 1.25 (m, 10H);
13C NMR (100 MHz, Chloroform-d) δ 165.57, 158.25, 139.06,
136.54, 129.73, 128.31, 126.72, 126.16, 125.92, 117.96, 69.06,
64.25, 55.21, 41.15, 35.10, 34.16, 31.59, 29.55, 26.11, 24.40;
HRMS (ESI) for C29H42N2O [M + H]+: calcd 435.3370, found
435.3361.
1
(CE) as KBr discs. Using CDCl3 (7.26 ppm, H; 77.00 ppm, 13C)
as solvent and TMS as internal standard, NMR spectra were
determined on Bruker Avance (400 MHz) spectrometer.
Represent multiplicity in NMR spectra with the following
abbreviations:s = singlet; d =doublet; t = triplet; q = quartet; dd =
double doublet; ddd = double doublet of doublet; m =multiplet.
Enantiomeric excess was determined by HPLC analysis on
Daicel Chiralcel OD-H, OJ-H or Chiralpak AD-H, AS-H column.
4.2.3 Preparation of 7c: The synthetic route is the same as 7a
except that the starting material is L- tryptophan. 7c is yellow
crystal and the spectra data for 7c is: m.p. 114.2ꢀ°C–115ꢀ°C;
[α]D25ꢀ=ꢀ-1.146° (cꢀ=ꢀ1.0, CHCl3); 1H NMR (400 MHz, Methanol-
d) δ 8.00 (s, 1H), 7.61 – 7.52 (m, 1H), 7.38 – 7.28 (m, 2H), 7.10
– 7.03 (m, 1H), 7.02 – 6.91 (m, 3H), 4.12 (q, J = 7.2 Hz, 1H),
3.78 – 3.70 (m, 1H), 3.19 (dd, J = 14.4 Hz, J = 5.2 Hz, 1H), 2.91
(dd, J = 14.0 Hz, J = 8.0 Hz, 1H), 2.85 – 2.70 (m, 2H), 2.49 (s,
2H), 2.03 (s, 1H), 1.62 – 1.52 (m, 4H), 1.48 – 1.41 (m, 11H),
1.36 (s, 1H), 1.33 – 1.22 (m, 10H); 13C NMR (100 MHz,
Chloroform-d) δ 165.36, 158.28, 139.70, 136.50, 136.16, 127.70,
4.2 General procedure for the preparation of Chiral Schiff base
ligands 7
The primary amine 5 were synthesized from Amino acids
according to the reported literature. [22-24]
6

Tetrahedron xxx (xxxx) xxx–xxx
126.62, 125.85, 123.05, 121.80, 119.22, 118.85, 117.92, 112.84,
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ACCEPTED MANUSCRIPT
111.06, 67.82, 64.49, 55.26, 35.05, 34.11, 31.52, 30.52, 29.50,
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26.07, 24.37; HRMS (ESI) for C31H43N3O [M + H]+: calcd
474.3479, found 474.3474.
4.2.4 Preparation of 7d: The synthetic route is the same as 7a
except that the starting material is L-tertleucine. 7d is yellow
crystal and the spectra data for 7d is: m.p. 107.9ꢀ°C–108.6ꢀ°C;
[α]D25ꢀ=ꢀ52.122° (cꢀ=ꢀ1.0, CHCl3); 1H NMR (400 MHz,
Chloroform-d) δ 14.09 (s, 1H), 8.26 (s, 1H), 7.39 – 7.35 (m, 1H),
7.20 – 7.10 (m, 1H), 2.90 – 2.87 (m, 1H), 2.60 – 2.50 (m, 1H),
2.46 (s, 2H), 2.42 – 2.36 (m, 1H), 2.26 (s, 2H), 1.50 – 1.48 (m,
1H), 1.46 (s, 9H), 1.42 – 1.35 (m, 1H), 1.33 (s, 9H), 0.96 (s, 9H);
13C NMR (100 MHz, Chloroform-d) δ 165.10, 158.40, 139.58,
136.50, 126.39, 125.83, 118.14, 76.21, 60.32, 55.21, 35.08,
34.16, 33.52, 31.60, 29.52, 26.99, 26.23, 24.45; HRMS (ESI) for
C26H44N2O [M + H]+: calcd 401.3526, found 401.3519.
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crystal and the spectra data for 7e is: m.p. 108.3ꢀ°C–109.1ꢀ°C;
[α]D25ꢀ=ꢀ-49.683° (cꢀ=ꢀ1.0, CHCl3); 1H NMR (400 MHz,
Chloroform-d) δ 14.09 (s, 1H), 8.26 (s, 1H), 7.38 (d, J = 2.4 Hz,
1H), 7.11 (d, J = 2.4 Hz, 1H), 2.87 (d, J = 8.8 Hz, 1H), 2.57 (d, J
= 13.2 Hz, 1H), 2.47 (s, 2H), 2.26 (s, 1H), 1.49 (s, 4H), 1.46 (s,
9H), 1.44 (s, 1H), 1.41 – 1.35 (m, 2H), 1.33 (s, 9H), 1.32 – 1.31
(m, 1H), 0.96 (s, 9H); 13C NMR (100 MHz, Chloroform-d) δ
165.09, 158.39, 139.57, 136.48, 126.39, 125.84, 118.12, 76.18,
60.31, 55.21, 35.07, 34.15, 33.52, 31.59, 29.50, 26.98, 26.21,
24.44; HRMS (ESI) for C26H44N2O [M + H]+: calcd 401.3526,
found 401.3524.
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Acknowledgments
We thank the National Science and Technology Major Project
of China on “Key New Drug Creation and Development
Program” (Project No. 2014ZX09J14104-06C) and Shaanxi
Province Key Research and Development Program (S2019-YF-
ZDCXL-ZDLSF-0138). We also thank Professor Shengyong
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8

ACCEPTED MANUSCRIPT
ꢀ
The new Schiff bases derived from amino acids were synthesized
with simple methods.
ꢀ A wide-range of substrates was examed to obtain 76 β-nitroalcohols
with high yields and excellent enantioselectivities.
ꢀ The transition state was initially verified by some mechanistic
investigations.