Recyclable and Stable α-Methylproline-Derived Chiral Ligands for the Chemical Dynamic Kinetic Resolution of free C,N-Unprotected α-Amino Acids

Article abstract of DOI:10.3390/molecules24122218

A novel special designed, stable, and recyclable chiral ligand bearing a quaternary carbon was developed for chemical dynamic kinetic resolution (DKR) of free C,N-unprotected racemic α-amino acids via Schiff base intermediates. This method furnishes high yields with excellent enantioselectivity, has a broad substrate scope, and uses operationally simple and convenient conditions. The present chemical DKR is a practical and useful method for the preparation of enantiopure α-amino acids.

Full text of DOI:10.3390/molecules24122218

molecules
Article
Recyclable and Stable α-Methylproline-Derived
Chiral Ligands for the Chemical Dynamic Kinetic
Resolution of free C,N-Unprotected α-Amino Acids
Shuangjie Shu †, Liang Zhao †, Shengbin Zhou, Chenglin Wu, Hong Liu * and Jiang Wang *
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
555 Zu Chong Zhi Road, Shanghai 201203, China; shushuangjie@126.com (S.S.); frankzl@163.com (L.Z.);
stbin_06@163.com (S.Z.); wucl1990@mail.ustc.edu.cn (C.W.)
* Correspondence: hliu@simm.ac.cn (H.L.); jwang@simm.ac.cn (J.W.);
Tel.: +86-21-5080-7042 (H.L.); +86-21-5080-6600 (ext. 5418) (J.W.)
† These authors contributed equally to this work.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Derek J. McPhee
Received: 28 May 2019; Accepted: 6 June 2019; Published: 13 June 2019
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: A novel special designed, stable, and recyclable chiral ligand bearing a quaternary carbon
was developed for chemical dynamic kinetic resolution (DKR) of free C,N-unprotected racemic
α
-amino acids via Schiff base intermediates. This method furnishes high yields with excellent
enantioselectivity, has a broad substrate scope, and uses operationally simple and convenient
conditions. The present chemical DKR is a practical and useful method for the preparation of
enantiopure α-amino acids.
Keywords: quaternary carbon; dynamic kinetic resolution; unprotected α-amino acids; Schiff base
intermediates; ligands
1. Introduction
Unnatural
chemistry due to their promising biological and pharmaceutical activity [
pharmaceutical potential of unnatural -amino acids, the preparation of structurally varied and
enantiomerically pure -amino acids has been a focal point for synthetic chemists, thereby leading to
many truly ingenious approaches. By using enantioselective polymer membranes, optical resolution of
racemic -amino acids to obtain enantiopure isomers has been established [10 14]. Meanwhile, several
methods using chromatography were applied for the enantioselective separation of racemic -amino
α
-amino acids play an important role in modern organic synthesis and medicinal
1–9]. Considering the
α
α
α
–
α
acids and derivatives. Nevertheless, using enantioselective polymer membrane and chiral stationary
phase are unarguably not economic, especially on a large scale [15–17].
Large-scale preparation of unnatural
biocatalytic methods [18 22], and most enantioselective chemical methods are still undeveloped [23
Among established chemical methods to enantioselectively synthesize pure -amino acids, the dynamic
kinetic resolution (DKR) of -amino acids on large scale is the most efficient solution [30 33]. In 2012,
Oh et al. [26]. Synthesized -amino acids via DKR with limited substrate generality and using
expensive thiourea organocatalysts starting from N-protected racemic amino acids. Tokumaru et al. [29].
Demonstrated DKR of racemic 2-(1H-pyrrol-1-yl)alkanoic acids as -amino acid equivalents with
sound yields and enantioselectivities, although the substrate scope was limited and the preparation of
free -amino acids was complicated (Scheme 1). Several research groups have developed practical
methods for the preparation of chiral unnatural -amino acids and -amino acids [34 41]. In particular,
chiral ligands , and (Scheme 1) were successfully used for the preparation of structurally varied
α
-amino acids is virtually entirely accomplished by
–
–
29].
α
α
–
α
α
α
α
β
–
1,
2
3
Molecules 2019, 24, 2218; doi:10.3390/molecules24122218
www.mdpi.com/journal/molecules

Molecules 2019, 24, 2218
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α
-amino acids, respectively [42
–
46]. In 2015, our group realized chemical dynamic thermodynamic
resolution and S/R interconversion of unprotected unnatural
ligand has limited substrate generality and incomplete stereochemical outcome, and both of the
chiral ligands and were synthesized bearing axially chiral 1,1’-binaphthyl moieties, which were
rather expensive [43]. Our group used recyclable ligand for the dynamic kinetic resolution of -amino
acids [44]. We discovered that ligands bearing quaternary carbons could be used for chemical resolution
of unprotected -substituted- -amino acids and -substituted- -amino acids without racemization of
the -position of the proline moiety [47 48]. Herein, we have designed and synthesized a novel stable
ligand (Scheme 1) for the resolution of free unprotected -amino acids under operationally simple
and convenient conditions. The entioselective pure resolution of phenyl substituted -amino acids
α-amino acids [43,44]. Unfortunately,
1
1
2
3
α
α
β
β
β
α
,
4
α
α
could also be realized directly and efficiently, thus expanding the scope of substrates, which holds
great potential for preparation of enantiopure α-amino acids.
Scheme 1. Reported chemical resolution methods and chiral ligands used to obtain chiral α-amino
acids or their derivatives. Previous work cited from Oh et al. [26], and Tokumaru et al. [29].

Molecules 2019, 24, 2218
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2. Results and Discussions
To investigate the most favorable reaction conditions, we optimized the solvents, bases,
and temperature, using (S)- and racemic phenylalanine (5a) as the template reaction (Table 1).
4
Based on our previous study, DKR processes in protonic solvent may afford better yields and
stereochemical control [40]. To our delight, excellent diastereoselectivity (dr > 99:1) was observed,
both in ethanol using Ni(OAc)2 as Ni(II) ion resource and K2CO3 as base (Table 1, entry 1). Replacing
the ethanol solvent with methanol led to a significant improvement in the yield (up to 98%) and
also afforded product 6a with excellent diastereoselectivity (>99:1, Table 1, Entry 2), whereas using
sodium tert-butoxide (NaOt-Bu), sodium hydride (NaH), and 1,8-diazabicyclo[5.4.0] undec-7-ene
(DBU) as the base, all led to a significant drop in the reaction yield (Table 1, Entries 3–5). The yield
thus greatly depends on the conditions applied, while the stereochemical outcome does not appear to
be influenced by the nature of both the base and solvent used. Next, the effect of temperature was
explored, and a good yield with excellent diastereoselectivity (dr > 99:1, Table 1, Entry 6) could be
obtained at room temperature within 72 h. All diastereoselectivities were monitored by LC-MS, and the
(S,2S)-6a was obtained as the major product, which was determined by single-crystal X-ray diffraction
analysis (Table 1, X-ray, see the Materials and Methods Section for details).
a
Table 1. Optimization of reaction conditions for the DKR of racemic phenylalanine 5a using (S)-4.
Entry a
Base
Solvent
Temp (◦C)
dr c
Yield (%) b
1
2
3
K2CO3
K2CO3
t-BuONa
NaH
DBU
K2CO3
EtOH
MeOH
MeOH
MeOH
MeOH
MeOH
60
60
60
60
60
rt
66
98
20
28
15
75
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
4
5
6 d
a
Reaction conditions: (S)-4 (0.2 mmol), (rac)-5a (0.2 mmol), Ni(OAc)2 (0.2 mmol) and base (1.0 mmol) were run in
solvent (4 mL) for 8 h. Combined yield of isolated (S,2S)-6a and (S,2R)-6a. Determined by LC-MS. d 72 h.
b
c
With optimized reaction conditions in hand, we further investigated the scope of substrate
generality (Table 2, dr determination, see supplementary Figures S1–S15). In all cases the stereochemistry
outcome showed that all (S)-4 starting materials gave enantiomerically enriched compounds (S,2S)-6
as the major DKR products, respectively. We explored several phenylalanine derivatives. Simple
substituted phenylalanines proved to be good substrates (Table 2, Entries 2–5), providing the desired
products in high yields (88-91%) with excellent diastereoselectivity (dr > 99:1). The reactions of (S)-
4
with -amino acids containing functionalized phenylalanines (Table 2, Entry 6), fused aryl rings, and
α
heterocyclic aryl rings (Table 2, Entries 7–9) were conducted and high yields (89–94%) were obtained
with excellent stereochemical outcomes (dr > 99:1). We also investigate the phenyl-substituted glycine
(Table 2, Entries 10 and 11). Methoxy- and bromo-substitution on the para-position of phenyl both gave
good yields and diastereoselectivity outcomes. Furthermore, the reaction could be extended to alkyl
substituted α-amino acids (Table 2, Entries 12–17). All these reactions produced high yields (87–95%)
with excellent diastereoselectivity (dr 97:3 to >99:1).

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a
Table 2. DKR of unprotected racemic α-amino acids using (S)-4.
Entry a
R
6
t (h)
dr c
Yield (%) b
1
2
3
4
5
benzyl
2-MeO-benzyl (S,2S)-6b
3-MeO-benzyl
3-Me-benzyl
4-F-benzyl
(S,2S)-6a
8
98
90
90
88
91
>99:1
>99:1
>99:1
>99:1
>99:1
24
24
8
(S,2S)-6c
(S,2S)-6d
(S,2S)-6e
12
6
(S,2S)-6f
32
8
90
>99:1
7
(S,2S)-6g
92
99:1
8
9
(S,2S)-6h
(S,2S)-6i
8
94
89
>99:1
>99:1
12
10
11
12
13
14
15
16
17
3-MeO-phenyl (S,2S)-6j
12
20
16
26
12
8
87
85
89
87
92
93
95
93
97:3
98:2
>99:1
99:1
>99:1
>99:1
>99:1
99:1
3-Br-phenyl
cyclobutyl
CH2CF3
CH2CH2CH3
iPr
(S,2S)-6k
(S,2S)-6l
(S,2S)-6m
(S,2S)-6n
(S,2S)-6o
(S,2S)-6p
iBu
8
12
CH2CH2SCH3 (S,2S)-6q
a
Reaction conditions: (S)-
4
(0.2 mmol), (rac)-
5
(0.2 mmol), Ni(OAc)2 (0.2 mmol) and K2CO3 (1.0 mmol) were run in
methanol (4 mL). b Combined yield of isolated (S,2S)-6 and (S,2R)-6. Determined by LC-MS.
c
After successful exploration of (S)-
dr determination, see supplementary Figures S16–S32). We found that Ni(II)-complexes (R,2R)-
synthesized in high yields (70–98%) with excellent diastereoselectivity (dr 97:3 to > 99:1). As proved
by (S)- , the resolution of phenylalanine and substituted phenylalanines (Table 3, Entries 1-6) was
4, we turned our attention to the (R)-
4
ligand (Table 3,
6
were
4
realized in high yields (88–91%) with excellent diastereoselectivity (>99:1). Apart from that, α-amino
acids with fused rings and heterocyclic aryl rings (Table 3, Entries 7–9) all exhibited both excellent
yields (92–94%) and diastereoselectivity (>99:1). The resolution of phenyl-substituted glycines (Table 3,
Entries 10 and 11) by (R)-4 produced good yields and diastereoselective outcomes (97:3 and 98:2).
All alkyl substituted -amino acids (Table 3, Entries 12–17) obtained high yields (88–96%) with excellent
α
diastereoselectivity (dr 98:2 to >99:1). With these remarkable results, we can offer a potential method
to prepare unprotected (R)-α-amino acids with broad generality.

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a
Table 3. DKR of unprotected racemic α-amino acids using (R)-4.
Entry a
R
6
t (h)
dr c
Yield (%) b
1
2
3
4
5
benzyl
2-MeO-benzyl (R,2R)-6b
3-MeO-benzyl (R,2R)-6c
3-Me-benzyl
4-F-benzyl
(R,2R)-6a
8
91
88
93
90
89
>99:1
>99:1
>99:1
>99:1
>99:1
24
24
8
(R,2R)-6d
(R,2R)-6e
12
6
(R,2R)-6f
32
8
87
>99:1
7
(R,2R)-6g
94
>99:1
8
9
(R,2R)-6h
(R,2R)-6i
8
98
92
>99:1
>99:1
12
10
11
12
13
14
15
16
17
3-MeO-phenyl (R,2R)-6j
12
20
16
26
12
8
70
87
91
93
90
96
95
88
98:2
97:3
>99:1
>99:1
98:2
>99:1
>99:1
98:2
3-Br-phenyl
cyclobutyl
CH2CF3
CH2CH2CH3
iPr
(R,2R)-6k
(R,2R)-6l
(R,2R)-6m
(R,2R)-6n
(R,2R)-6o
(R,2R)-6p
iBu
8
12
CH2CH2SCH3 (R,2R)-6q
a
Reaction conditions: (R)-
4
(0.2 mmol), (rac)-
5
(0.2 mmol), Ni(OAc)2 (0.2 mmol) and K2CO3 (1.0 mmol) were run in
methanol (4 mL). b Combined yield of isolated (R,2R)-6 and (R,2S)-6. Determined by LC-MS.
c
Compared to reported methods [43,44], we realized good to excellent yields an diastereoselectivities
for phenyl-substituted glycine. We extended the substrate scope to include compounds such as
cyclobutyl- and trifluoroethyl-substituted glycine, again with excellent yields and diastereoselectivities.
Furthermore, the novel chiral ligand is more stable than the previous ligand.
With the aim of understanding the DKR progress of this reaction, LC-MS analysis was used to
monitor the stereochemical outcome over time (Figure 1). The DKR reaction was conducted using ligand
(R)-
(R)-
4
4
, 2-(3-methoxyphenyl)glycine (5j), Ni(OAc)2, and K2CO3 as base at 60 ◦C in methanol. The ligand
readily reacted with (R)-5j in the initial stages of the process, thus giving rise the products (R,2R)-6j
and (R,2S)-6j in 50% yield and a dr of 98:2 at 4 h. After 8 h, the yields of product increased steadily at a
slow rate. However, the ratio between two diastereomers (R,2R)-6j and (R,2S)-6j is almost the same as
after 4 h, which indicated that any base-catalyzed epimerization from (R,2R)-6j and (R,2S)-6j occured

Molecules 2019, 24, 2218
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at a relatively slow rate. Considering the yield is almost consistent, final thermodynamic control was
stopped at 16 h. The calculated yield of product (R,2R)-6j, as a single diastereomer, was 70% more than
theoretical percentage of 50%. Herein, we assume that the disfavored
α-amino acid (S)-5j undergoes
base-catalyzed α-epimerization before forming the major product (R,2R)-6j.
Figure 1. DKR process and stereochemistry outcome of (R)-4 with (rac)-5j (ligand (R)-4 (black), product
(R,2R)-6j (red), and product (R,2S)-6j (blue)).
Finally, decomposition of Ni(II) complex (S,2S)-6a under standard conditions afforded the target
amino acid (S)-configured phenylalanine ((S)-5a) in high yield (88%) with excellent enantioselectivity
(ee > 99%). The stable chiral ligand (S)-4 could be recycled and reused in high yield (90%) (Figure 2,
ee determination see supplementary Figures S33 and S34).
Figure 2. Decomposition of Ni(II) complex (S,2S)-6a and isolation of the target amino acid (S)-5a.

Molecules 2019, 24, 2218
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3. Materials and Methods
3.1. General Information
All commercially available compounds and solvents were used without further purification.
Anhydrous nickel acetate was prepared by heating Ni(II) acetate tetrahydrate at 110 ◦C under vacuum for
1
2 h. H- and 13C-NMR spectra were recorded in deuterochloroform (CDCl3) on a 400 or 500 MHz AV400
instrument (Bruker, Billerica, MA, USA) (see Supplementary Figures S35–S69). Chemical shifts were
reported in parts per million (ppm, δ) downfield from tetramethylsilane. Proton coupling patterns were
described as singlet (s), doublet (d), triplet (t), quartet (q), broad (br) and multiplet (m). High resolution
mass spectra (HRMS) were measured on a Finnigan MAT95 spectrometer (Thermo Fisher Scientific,
Waltham, MA, USA) The determination of dr was performed via LC-MS analysis (Finnigan MAT95,
Thermo Fisher Scientific). The determination of ee was performed via HPLC analysis (Agilent-1100,
Santa Clara, CA, USA). Optical rotations were measured using a 1 mL cell with a 10 cm path length on
an Autopol VI automatic polarimeter (Rudolph Research Analytical, Hackettstown, NJ, USA) and are
20
reported as follows: [
α
]
(c: g/100 mL, in solvent). Melting points were measured on a melting point
D
apparatus (SGW-X4; Shanghai ZiQi Laboratory Equipment Co., Ltd., Shanghai, China).
3.2. General Procedure for the Synthesis of (S,2S)-6a and (R,2R)-6a
A suspension of (S)-4 or (R)-4 (100.3 mg, 0.2 mmol, 1 equiv.), rac-phenylalanine 5a (33 mg, 0.2 mmol,
1 equiv.), Ni(OAc)2 (35.3 mg, 0.2 mmol, 1 equiv.), and K2CO3 (138.1 mg, 1.0 mmol, 5 equiv.) were
refluxed in methanol (4 mL) at 60 ◦C for 8 h. After cooling to room temperature, the mixture was diluted
with 5% aqueous acetic acid (15 mL) and extracted three times with dichloromethane. The combined
organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude mixture
was purified by column chromatography on silica gel (PE/EA = 4:1 to DCM/MeOH = 20:1) to afford
two diastereomers (S,2S)-6a and (S,2R)-6a (138 mg, yield 98%) for analysis (dr > 99:1). The mixture
was purified again by column chromatography on silica gel (DCM/MeOH = 40:1) to give the pure
diastereomer (S,2S)-6a as a red solid.
3.3. General Procedure for the Synthesis of (S)-5a
To a suspension of (S,2S)-6a (78 mg, 0.1 mmol, 1 equiv.) in 1,4-dioxane (2.2 mL) was added 6 N
HCl (618 µ
L) and the mixture was then heated at 70 ◦C for 10 min. The reaction was monitored by TLC
and disappearance of the red color of the solution was observed. After concentrating to dryness under
reduced pressure, ethyl acetate and water were added to the residue and then stirred. The organic phase
was extracted two times with water and washed with saturated sodium hydrogen carbonate solution,
water, brine, and finally dried over Na2SO4, filtered and concentrated to produce recovered (S)-
4
(50.8 mg, 90%). The combined aqueous phase was concentrated in vacuo and dissolved in ammonium
hydroxide solution (10%), which subsequently loaded onto a Dowex 50WX2-100 cation-exchange resin
column (Sigma-Aldrich, St. Louis, MI, USA). The column was preprocessed with deionized water until
neutral, and then obtained the desired amino acid using ammonium hydroxide (10%). The aqueous
solution was concentrated in vacuo to give (S)-5a (16.5 mg, 88%) as a white solid.
3.4. Analytical Characterization Data of Products
Nickel(II)-(S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(S)-
20
phenylalanine Schiff Base Complex (6a). Red solid (138 mg, yield 98%); mp 116–118 ◦C; [
α
]
D = +2502
(c = 1, CHCl3); 1H-NMR (400 MHz, CDCl3)
δ 9.08 (d, J = 2.1 Hz, 1H), 8.32 (d, J = 9.3 Hz, 1H), 7.61–7.49
(m, 3H), 7.42–7.27 (m, 6H), 7.15–7.02 (m, 3H), 6.65 (d, J = 7.7 Hz, 1H), 6.61 (d, J = 2.6 Hz, 1H), 4.22
(t, J = 5.2 Hz, 1H), 3.54 (dd, J = 59.9, 13.0 Hz, 2H), 3.36–3.24 (m, 1H), 3.14 (dt, J = 17.6, 6.8 Hz, 2H), 2.78
(dd, J = 13.8, 5.4 Hz, 1H), 2.42–2.23 (m, 1H), 2.14–2.03 (m, 1H), 1.98 (dd, J = 19.7, 9.7 Hz, 1H), 1.87–1.73
(m, 1H), 1.33 (s, 3H). 13C-NMR (125 MHz, CDCl3)
δ
180.5, 178.1, 170.8, 141.5, 135.8, 134.0, 133.4, 133.1,
133.0, 132.7, 132.6, 131.1, 130.5, 130.3, 129.8, 129.5, 129.3, 129.1, 127.9, 127.7, 127.5, 125.8, 124.3, 74.3,

Molecules 2019, 24, 2218
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71.8, 57.3, 54.7, 41.4, 39.8, 20.7, 17.8. LRMS (ESI, m/z): 704.0 [M + H]+. HRMS (ESI, m/z): calcd for
C35H31Cl3N3NiO3, 704.0605 [M + H]+; found 704.0625. The dr was determined by LC-MS using
a system equipped with a binary pump, and a photodiode array detector (DAD), using an Eclipse
XDB-C18 column (250
tmajor = 15.966 min, tminor = not found, dr > 99:1.
×
4.6 mm, 5 µm) (CH3CN/H2O = 65:35, flow rate 1.0 mL/min, λ = 254 nm),
Nickel(II)-(S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(S)-2-
methoxyphenylalanine Schiff Base Complex (6b). Red solid (132 mg, yield 90%); mp 125–128 ◦C;
[α]20D = +2021 (c = 1, CHCl3); 1H-NMR (400 MHz, CDCl3)
δ 9.00 (d, J = 2.0 Hz, 1H), 8.36 (d, J = 9.3 Hz,
1H), 7.57–7.53 (m, 2H), 7.52–7.48 (m, 1H), 7.41–7.37 (m, 1H), 7.36–7.31 (m, 1H), 7.31–7.27 (m, 2H),
7.22–7.19 (m, 1H), 7.10 (dd, J = 9.3, 2.6 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 6.88–6.82 (m, 2H),
6.62 (d, J = 2.6 Hz, 1H), 4.15 (t, J = 4.9 Hz, 1H), 3.52 (q, J = 13.4 Hz, 2H), 3.31–3.22 (m, 4H), 3.21–3.16
(m, 1H), 3.11–3.06 (m, 1H), 2.91 (dd, J = 13.6, 4.9 Hz, 1H), 2.31–2.20 (m, 1H), 2.10–2.01 (m, 1H), 1.94
(q, J = 9.9 Hz, 1H), 1.83–1.73 (m, 1H), 1.31 (s, 3H). 13C-NMR (125 MHz, CDCl3)
δ 180.5, 178.6, 171.1,
158.5, 141.4, 135.9, 134.1, 133.7, 133.2, 133.1, 132.9, 132.7, 132.5, 131.2, 130.1, 130.0, 129.4, 129.3, 129.3,
128.4, 128.0, 127.7, 125.7, 124.5, 124.2, 121.5, 110.7, 74.6, 72.0, 57.7, 54.9, 54.6, 41.4, 34.8, 20.9, 18.1.
LRMS (ESI, m/z): 734.0 [M
found 734.0741. The dr was determined by LC-MS using an Eclipse XDB-C18 column (250
m) (CH3CN/H2O = 65:35, flow rate 1.0 mL/min, = 254 nm), tmajor = 19.059 min, tminor = not found,
dr > 99:1.
−
H]−. HRMS (ESI, m/z): calcd for C36H31Cl3N3NiO4, 734.0739 [M
−
H]−;
×
4.6 mm,
5
µ
λ
Nickel(II)-(S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(S)-3
-methoxyphenylalanine Schiff Base Complex (6c). Red solid (127 mg, yield 90%); mp 118–121 ◦C;
1
[α]20D = +3344 (c = 1, CHCl3); H-NMR (400 MHz, CDCl3)
δ 9.07–9.05 (m, 1H), 8.30 (d, J = 9.3 Hz,
1H), 7.59–7.45 (m, 3H), 7.36–7.27 (m, 3H), 7.23–7.18 (m, 1H), 7.09 (dd, J = 9.3, 2.6 Hz, 1H), 6.88–6.83
(m, 1H), 6.64 (d, J = 7.5 Hz, 1H), 6.59–6.56 (m, 2H), 6.55–6.50 (m, 1H), 4.19 (t, J = 5.3 Hz, 1H), 3.63
(s, 3H), 3.60 (d, J = 13.1 Hz, 1H), 3.45 (d, J = 13.2 Hz, 1H), 3.42–3.34 (m, 1H), 3.22–3.09 (m, 2H), 2.78
(dd, J = 13.8, 5.1 Hz, 1H), 2.49–2.36 (m, 1H), 2.17–2.08 (m, 1H), 2.04–1.94 (m, 1H), 1.91–1.79 (m, 1H),
1.33 (s, 3H). 13C-NMR (125 MHz, CDCl3)
133.1, 132.8, 132.7, 131.2, 130.4, 129.9, 129.7, 129.6, 129.4, 127.8, 127.5, 126.5, 125.9, 124.4, 124.4, 74.5,
71.4, 57.5, 54.9, 54.6, 41.6, 34.2, 21.0, 18.0. LRMS (ESI, m/z): 734.0 [M
H]−. HRMS (ESI, m/z): calcd
for C36H31Cl3N3NiO4, 734.0739 [M
H]−; found 734.0741. The dr was determined by LC-MS using
an Eclipse XDB-C18 column (250 4.6 mm, 5 m) (CH3CN/H2O = 65:35, flow rate 1.0 mL/min,
δ 180.8, 178.3, 171.0, 141.6, 135.9, 135.8, 134.1, 133.5, 133.2,
−
−
×
µ
λ = 254 nm), tmajor = 16.298 min, tminor = not found, dr > 99:1.
Nickel(II)-(S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(S)-3-
methylphenylalanine Schiff Base Complex (6d). Red solid (126 mg, yield 88%); mp 135–136 ◦C;
[α]20D = +2588 (c = 1, CHCl3); 1H-NMR (400 MHz, CDCl3)
δ 9.06–9.03 (m, 1H), 8.33 (d, J = 9.3 Hz, 1H),
7.56 (t, J = 7.7 Hz, 2H), 7.51 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.33–7.27 (m, 2H), 7.24–7.18 (m, 1H),
7.16–7.09 (m, 2H), 6.89–6.83 (m, 2H), 6.64 (d, J = 7.6 Hz, 1H), 6.61 (d, J = 2.5 Hz, 1H), 4.20 (t, J = 5.1 Hz,
1H), 3.63–3.55 (m, 1H), 3.50–3.42 (m, 1H), 3.35–3.24 (m, 1H), 3.16–3.06 (m, 2H), 2.74 (dd, J = 13.7
5.4 Hz, 1H), 2.41–2.29 (m, 1H), 2.26 (s, 3H), 2.15–2.03 (m, 1H), 2.02–1.94 (m, 1H), 1.88–1.76 (m, 1H), 1.32
(s, 3H). 13C-NMR (150 MHz, CDCl3)
180.2, 178.0, 170.5, 141.3, 138.5, 135.6, 135.4, 133.8, 133.1, 132.9,
,
δ
132.8, 132.4, 132.4, 131.1, 131.1, 130.9, 130.0, 129.6, 129.3, 128.9, 128.7, 128.2, 127.7, 127.5, 127.3, 127.3,
125.5, 124.0, 74.1, 71.6, 57.1, 54.5, 41.0, 39.6, 21.4, 20.4, 17.6. LRMS (ESI, m/z): 716.0 [M − H]−. HRMS
(ESI, m/z): calcd for C36H31Cl3N3NiO3, 716.0790 [M
−
H]−; found 716.0798. The dr was determined
4.6 mm, 5 µm) (CH3CN/H2O = 65:35, flow rate
by LC-MS using an Eclipse XDB-C18 column (250
×
1.0 mL/min, λ = 254 nm), tmajor = 21.599 min, tminor = not found, dr > 99:1.
Nickel(II)-(S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(S)-4-
fluorophenylalanine Schiff Base Complex (6e). Red solid (132 mg, yield 91%); mp 188–190 ◦C; [α]20D = +1786
1
(c = 1, CHCl3); H-NMR (400 MHz, CDCl3)
δ 9.09–9.06 (m, 1H), 8.33 (d, J = 9.3 Hz, 1H), 7.62–7.52

Molecules 2019, 24, 2218
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(m, 3H), 7.47–7.41 (m, 1H), 7.34 (d, J = 7.0 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.14 (dd, J = 9.3, 2.5 Hz, 1H),
7.08–7.03 (m, 4H), 6.74 (d, J = 7.5 Hz, 1H), 6.63 (d, J = 2.5 Hz, 1H), 4.21 (t, J = 5.0 Hz, 1H), 3.64–3.58
(m, 1H), 3.52–3.46 (m, 1H), 3.40–3.30 (m, 1H), 3.17–3.03 (m, 2H), 2.75 (dd, J = 14.0, 5.4 Hz, 1H), 2.42–2.30
(m, 1H), 2.23–2.14 (m, 1H), 2.06–1.96 (m, 1H), 1.90–1.84 (m, 1H), 1.35 (s, 3H). 13C-NMR (150 MHz,
CDCl3)
132.4, 131.7, 131.7, 131.3, 131.3, 130.9, 130.2, 129.6, 129.4, 129.1, 127.5, 127.4, 127.3, 125.7, 124.1, 115.8,
115.7, 74.2, 71.4, 57.2, 54.4, 41.0, 38.6, 20.5, 17.6. LRMS (ESI, m/z): 720.0 [M
H]−. HRMS (ESI, m/z):
calcd for C35H28Cl3FN3NiO3, 720.0539 [M
H]−; found 720.0547. The dr was determined by LC-MS
using an Eclipse XDB-C18 column (250 4.6 mm, 5 m) (CH3CN/H2O = 65:35, flow rate 1.0 mL/min,
δ 180.3, 177.7, 170.7, 162.3 (d, J = 246.68 Hz), 141.3, 135.5, 133.7, 133.1, 132.9, 132.8, 132.5,
−
−
×
µ
λ = 254 nm), tmajor = 17.940 min, tminor = not found, dr > 99:1.
Nickel(II)-(S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(S)-
3,5-diiodotyrosine Schiff Base Complex (6f). Red solid (175 mg, yield 90%); mp 286–288 ◦C; [α]20D = +2037
(c = 1, CHCl3); 1H-NMR (400 MHz, CDCl3)
δ 9.05 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 9.3 Hz, 1H), 7.66–7.53
(m, 3H), 7.47 (dd, J = 10.8, 5.7 Hz, 1H), 7.33 (t, J = 7.2 Hz, 2H), 7.27 (s, 2H), 7.16 (dd, J = 9.3, 2.6 Hz,
1H), 6.78 (d, J = 7.4 Hz, 1H), 6.66 (d, J = 2.5 Hz, 1H), 5.82 (s, 1H), 4.14–4.07 (m, 1H), 3.56 (dd, J = 29.2,
13.0 Hz, 2H), 3.46–3.34 (m, 1H), 3.17 (t, J = 8.8 Hz, 1H), 2.89 (dd, J = 14.1, 4.4 Hz, 1H), 2.67 (dd, J = 13.9,
6.2 Hz, 1H), 2.54–2.39 (m, 1H), 2.24 (dd, J = 13.8, 9.8 Hz, 1H), 2.02 (td, J = 18.7, 9.4 Hz, 2H), 1.37
(s, 3H). 13C-NMR (125 MHz, CDCl3)
δ 180.4, 177.6, 171.0, 153.4, 141.8, 140.6, 135.7, 134.0, 133.2,
133.1, 133.0, 132.6, 131.8, 131.2, 130.6, 129.8, 129.7, 129.4, 127.6, 127.5, 127.4, 125.8, 124.4, 82.8, 74.5,
71.2, 57.5, 54.7, 41.0, 38.0, 21.0, 17.9. LRMS (ESI, m/z): 971.8 [M + H]+. HRMS (ESI, m/z): calcd for
C35H29Cl3I2N3NiO4, 971.8487 [M
an Eclipse XDB-C18 column (250
λ = 254 nm), tmajor = 17.421 min, tminor = not found, dr > 99:1.
−
H]−; found 971.8509. The dr was determined by LC-MS using
×
4.6 mm, 5 µm) (CH3CN/H2O = 65:35, flow rate 1.0 mL/min,
Nickel(II)-(S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(S)-3-
(1-naphthyl)alanine Schiff Base Complex (6g). Red solid (139 mg, yield 92%); mp 182–184 ◦C;
[α]20D = +2432 (c = 1, CHCl3); 1H-NMR (400 MHz, CDCl3)
δ 9.12–9.09 (m, 1H), 8.31 (d, J = 9.3 Hz, 1H),
7.80 (t, J = 8.0 Hz, 2H), 7.69 (dd, J = 8.2, 2.0 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.42–7.37 (m, 1H), 7.36–7.28
(m, 4H), 7.21 (t, J = 7.7 Hz, 1H), 7.19–7.12 (m, 2H), 7.09 (dd, J = 9.3, 2.6 Hz, 1H), 6.69 (t, J = 7.6 Hz, 1H),
6.45 (d, J = 2.6 Hz, 1H), 5.65 (d, J = 7.7 Hz, 1H), 4.45–4.40 (m, 1H), 4.12–4.04 (m, 1H), 3.83–3.77 (m, 1H),
3.71 (d, J = 13.2 Hz, 1H), 3.67–3.57 (m, 1H), 3.47 (d, J = 13.2 Hz, 1H), 3.30–3.20 (m, 1H), 2.84–2.54
(m, 1H), 2.35–2.25 (m, 1H), 2.13 (q, J = 9.6 Hz, 1H), 2.07–1.95 (m, 1H), 1.41 (s, 3H). 13C-NMR (150 MHz,
CDCl3)
131.0, 129.5, 129.4, 128.6, 128.5, 128.4, 128.3, 128.3, 127.5, 127.3, 127.2, 126.3, 125.8, 125.5, 125.4, 123.9,
123.2, 74.2, 71.4, 56.7, 54.9, 41.4, 40.0, 20.7, 17.7. LRMS (ESI, m/z): 752.0 [M
H]−. HRMS (ESI, m/z):
calcd for C39H31Cl3N3NiO3, 752.0790 [M
H]−; found 752.0799. The dr was determined by LC-MS
using an Eclipse XDB-C18 column (250 4.6 mm, 5 m) (CH3CN/H2O = 65:35, flow rate 1.0 mL/min,
δ 180.1, 178.1, 170.3, 141.1, 135.6, 134.0, 133.6, 133.1, 132.7, 132.6, 132.4, 132.3, 132.1, 131.5,
−
−
×
µ
λ = 254 nm), tmajor = 24.156 min, tminor = not found, dr > 99:1.
Nickel(II)-(S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(S)-3-
◦
(3-benzothienyl)alanine Schiff Base Complex (6h). Red solid (142 mg, yield 94%); mp 138–141 C;
1
[α]20D = +2452 (c = 1, CHCl3); H-NMR (400 MHz, CDCl3)
δ 9.08–9.05 (m, 1H), 8.35 (d, J = 9.3 Hz,
1H), 7.87 (d, J = 8.0 Hz, 1H), 7.76–7.56 (m, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.38
(t, J = 7.5 Hz, 1H), 7.34–7.28 (m, 3H), 7.19–7.10 (m, 4H), 6.60 (d, J = 2.6 Hz, 1H), 6.49 (d, J = 7.5 Hz,
1H), 4.32 (t, J = 5.5 Hz, 1H), 3.65–3.57 (m, 2H), 3.48–3.41 (m, 1H), 3.23–3.15 (m, 1H), 3.11–2.98 (m, 2H),
2.13–1.90 (m, 3H), 1.82–1.70 (m, 1H), 1.31 (s, 3H). 13C-NMR (125 MHz, CDCl3)
δ 180.0, 178.1, 170.6,
141.3, 140.4, 139.1, 135.5, 133.7, 133.0, 132.8, 132.7, 132.5, 130.9, 130.3, 129.9, 129.6, 129.1, 128.8, 127.3,
127.3, 125.7, 125.5, 124.6, 124.3, 124.0, 122.7, 121.9, 74.1, 70.7, 57.0, 54.6, 40.8, 33.8, 20.2, 17.6. LRMS
(ESI, m/z): 758.0 [M − H]−. HRMS (ESI, m/z): calcd for C37H29Cl3N3NiO3S, 758.0354 [M
−
H]−; found
758.0362. The dr was determined by LC-MS using an Eclipse XDB-C18 column (250
×
4.6 mm, 5 m)
µ
(CH3CN/H2O = 65:35, flow rate 1.0 mL/min,
λ = 254 nm), tmajor = 27.103 min, tminor = 24.123, dr > 99:1.

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Nickel(II)-(S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(S)-3-
(3-thienyl)alanine Schiff Base Complex (6i). Red solid (126 mg, yield 89%); mp 178–180 ◦C; [α]20D = +2012
1
(c = 1, CHCl3); H-NMR (400 MHz, CDCl3)
δ 9.10 (d, J = 2.1 Hz, 1H), 8.35 (d, J = 9.3 Hz, 1H),
7.61–7.51 (m, 3H), 7.46–7.41 (m, 1H), 7.37–7.30 (m, 3H), 7.14 (dd, J = 9.3, 2.6 Hz, 1H), 7.06–7.04
(m, 1H), 6.86 (dd, J = 4.9, 1.2 Hz, 1H), 6.73–6.69 (m, 1H), 6.63 (d, J = 2.6 Hz, 1H), 4.18 (t, J = 5.1 Hz,
1H), 3.67–3.61 (m, 1H), 3.56–3.46 (m, 2H), 3.22–3.15 (m, 2H), 2.82–2.75 (m, 1H), 2.58–2.44 (m, 1H),
2.25–2.15 (m, 1H), 2.03 (q, J = 9.6 Hz, 1H), 1.97–1.87 (m, 1H), 1.37 (s, 3H). 13C-NMR (125 MHz, CDCl3)
δ 180.4, 178.1, 170.7, 141.3, 135.6, 135.5, 133.8, 133.2, 132.9, 132.8, 132.5, 132.4, 130.9, 130.1, 129.6, 129.4,
129.3, 129.1, 127.5, 127.2, 126.2, 125.6, 124.1, 124.1, 74.2, 71.1, 57.2, 54.6, 41.3, 33.9, 20.7, 17.7. LRMS
(ESI, m/z): 708.0 [M − H]−. HRMS (ESI, m/z): calcd for C33H27Cl3N3NiO3S, 708.0198 [M
−
H]−; found
708.0200. The dr was determined by LC-MS using an Eclipse XDB-C18 column (250
×
4.6 mm, 5 m)
µ
(CH3CN/H2O = 65:35, flow rate 1.0 mL/min,
dr > 99:1.
λ = 254 nm), tmajor = 15.723 min, tminor = not found,
Nickel(II)-(S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(S)-2-
◦
(3-methoxyphenyl)glycine Schiff Base Complex (6j). Red solid (124 mg, yield 87%); mp 153–155 C;
1
[α]20D = +2183 (c = 1, CHCl3); H-NMR (400 MHz, CDCl3)
δ 9.21–9.17 (m, 1H), 8.24 (d, J = 9.3 Hz,
1H), 7.82–7.78 (m, 1H), 7.58–7.51 (m, 1H), 7.44–7.36 (m, 3H), 7.30 (d, J = 7.5 Hz, 1H), 7.23 (t, J = 7.9 Hz,
1H), 7.16 (dd, J = 9.3, 2.5 Hz, 1H), 7.11–7.05 (m, 2H), 6.83–6.78 (m, 1H), 6.67 (d, J = 2.5 Hz, 1H),
6.15 (d, J = 7.9 Hz, 1H), 4.72 (s, 1H), 4.08–3.99 (m, 1H), 3.84–3.78 (m, 1H), 3.72 (s, 3H), 3.65–3.58
(m, 1H), 3.39–3.31 (m, 1H), 3.26–3.08 (m, 1H), 2.51–2.41 (m, 1H), 2.27–2.08 (m, 2H), 1.50 (s, 3H).
13C-NMR (150 MHz, CDCl3)
132.9, 132.4, 132.2, 131.0, 129.8, 129.7, 129.5, 128.8, 128.7, 127.5, 126.8, 126.5, 125.8, 124.6, 118.2, 74.5,
74.2, 57.0, 55.2, 55.0, 41.5, 21.0, 18.1. LRMS (ESI, m/z): 718.0 [M
H]−. HRMS (ESI, m/z): calcd for
C35H29Cl3N3NiO4, 718.0583 [M
H]−; found 718.0602. The dr was determined by LC-MS using
m) (CH3CN/H2O = 65:35, flow rate 1.0 mL/min,
δ 180.6, 177.2, 171.5, 159.6, 141.1, 139.0, 135.6, 133.8, 133.1, 133.1,
−
−
an Eclipse XDB-C18 column (250 × 4.6 mm, 5
µ
λ = 254 nm), tmajor = 16.728 min, tminor = 18.308, dr = 97:3.
Nickel(II)-(S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(S)-2-
◦
(3-bromophenyl)glycine Schiff Base Complex (6k). Red solid (131 mg, yield 85%); mp 119–121 C;
[α]20D = +2543 (c = 1, CHCl3); 1H-NMR (400 MHz, CDCl3)
δ
9.20 (d, J = 2.1 Hz, 1H), 8.24 (d, J = 9.3 Hz,
1H), 8.17 (t, J = 1.9 Hz, 1H), 7.81 (dd, J = 8.2, 2.2 Hz, 1H), 7.62–7.55 (m, 1H), 7.49–7.40 (m, 3H), 7.36
(d, J = 7.9 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.22–7.10 (m, 3H), 6.69 (d, J = 2.5 Hz, 1H), 6.17–6.12 (m, 1H),
4.72 (s, 1H), 4.11–4.01 (m, 1H), 3.86–3.81 (m, 1H), 3.67–3.61 (m, 1H), 3.41–3.35 (m, 1H), 3.22–3.10
(m, 1H), 2.57–2.46 (m, 1H), 2.28–2.16 (m, 2H), 1.52 (s, 3H). 13C-NMR (150 MHz, CDCl3)
δ 180.6, 176.6,
171.9, 141.2, 139.7, 135.6, 133.8, 133.2, 132.7, 132.6, 132.2, 131.4, 131.1, 130.1, 130.0, 129.8, 129.1, 129.1,
128.9, 127.4, 126.7, 126.5, 125.9, 125.1, 124.7, 122.7, 74.3, 73.8, 57.1, 55.1, 41.6, 21.0, 18.1. LRMS (ESI, m/z):
765.9 [M
−
H]−. HRMS (ESI, m/z): calcd for C34H26BrCl3N3NiO3, 765.9582 [M
−
H]−; found 765.9579.
The dr was determined by LC-MS using an Eclipse XDB-C18 column (250
H2O = 65:35, flow rate 1.0 mL/min, λ = 254 nm), tmajor = 25.652 min, tminor = 28.939, dr = 98:2.
×
4.6 mm, 5 m) (CH3CN/
µ
Nickel(II)-(S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(S)-2-
20
cyclobutylglycine Schiff Base Complex (6l). Red solid (118 mg, yield 89%); mp 307–308 ◦C; [
α
]
= +3252
D
(c = 1, CHCl3); 1H-NMR (400 MHz, CDCl3)
δ 9.12 (s, 1H), 8.23 (d, J = 9.3 Hz, 1H), 7.70 (d, J = 8.2 Hz,
1H), 7.60–7.38 (m, 3H), 7.29 (t, J = 6.9 Hz, 2H), 7.09 (dd, J = 9.3, 2.5 Hz, 1H), 6.87 (d, J = 7.4 Hz, 1H), 6.58
(d, J = 2.5 Hz, 1H), 4.21–3.95 (m, 1H), 3.82–3.69 (m, 2H), 3.51 (d, J = 13.0 Hz, 1H), 3.40 (t, J = 8.7 Hz,
1H), 3.17–2.88 (m, 1H), 2.67 (q, J = 17.3 Hz, 1H), 2.58–2.33 (m, 3H), 2.29–2.12 (m, 2H), 2.09–1.96 (m, 1H),
1.81 (dd, J = 18.1, 8.2 Hz, 1H), 1.70 (dd, J = 18.3, 9.0 Hz, 2H), 1.44 (s, 3H). 13C-NMR (125 MHz, CDCl3)
δ
180.3, 177.2, 169.6, 140.9, 135.8, 133.9, 133.3, 133.1, 133.0, 132.5, 132.3, 131.1, 130.3, 129.8, 129.4, 129.1,
128.1, 128.0, 127.8, 125.8, 124.2, 74.5, 74.0, 57.2, 55.0, 41.9, 40.7, 26.0, 25.6, 20.7, 18.1, 17.5. LRMS
(ESI, m/z): 668.0 [M + H]+. HRMS (ESI, m/z): calcd for C32H31Cl3N3NiO3, 668.0604 [M + H]+; found
668.0624. The dr was determined by LC-MS using an Eclipse XDB-C18 column (250
×
4.6 mm, 5 µm)

Molecules 2019, 24, 2218
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(CH3CN/H2O = 65:35, flow rate 1.0 mL/min,
dr > 99:1.
λ
= 254 nm), tmajor = 16.283 min, tminor = not found,
Nickel(II)-(S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(S)-2-
amino-4,4,4-trifluorobutyric acid Schiff Base Complex (6m). Red solid (121 mg, yield 87%); mp 244–246 ◦C;
20
[α
]
D = +2830 (c = 1, CHCl3); 1H-NMR (400 MHz, CDCl3)
δ
9.17 (d, J = 1.8 Hz, 1H), 8.35 (d, J = 9.3 Hz,
1H), 7.66–7.55 (m, 3H), 7.55–7.50 (m, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 6.8 Hz, 1H), 7.17
(dd, J = 9.3, 2.5 Hz, 1H), 6.90 (d, J = 7.4 Hz, 1H), 6.61 (d, J = 2.5 Hz, 1H), 4.23–4.11 (m, 2H), 3.74–3.57
(m, 2H), 3.39 (t, J = 8.7 Hz, 1H), 3.06–2.92 (m, 1H), 2.63–2.37 (m, 2H), 2.21–2.10 (m, 2H), 2.05–1.93
(m, 1H), 1.44 (s, 3H). 13C-NMR (125 MHz, CDCl3)
δ
180.4, 177.2, 172.4, 141.9, 135.8, 134.0, 133.2, 133.2,
133.2, 133.1, 132.5, 131.3, 130.8, 129.9, 129.8, 129.7, 127.6, 127.6, 126.8, 125.8, 124.6, 74.9, 64.5, 57.8,
54.8, 41.2, 35.6 (q, J = 28.9 Hz), 20.3, 17.4. LRMS (ESI, m/z): 694.0 [M
H]−. HRMS (ESI, m/z): calcd
H]−; found 694.0203. The dr was determined by LC-MS
4.6 mm, 5 m) (CH3CN/H2O = 65:35, flow rate 1.0 mL/min,
−
for C30H24Cl3F3N3NiO3, 694.0194 [M
using an Eclipse XDB-C18 column (250
−
×
µ
λ = 254 nm), tmajor = 13.938 min, tminor = 15.440, dr = 99:1.
Nickel(II)-(S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(S)-
norvaline Schiff Base Complex (6n). Red solid (121 mg, yield 92%); mp 244–247 ◦C; [α]20D = +2842 (c = 1,
CHCl3); 1H-NMR (400 MHz, CDCl3)
δ 9.14–9.12 (m, 1H), 8.22 (d, J = 9.3 Hz, 1H), 7.75 (dd, J = 8.2, 2.0 Hz,
1H), 7.60–7.51 (m, 2H), 7.50–7.45 (m, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.33–7.29 (m, 1H), 7.13 (dd, J = 9.3,
2.6 Hz, 1H), 6.89–6.85 (m, 1H), 6.62 (d, J = 2.6 Hz, 1H), 4.09–3.99 (m, 1H), 3.89 (dd, J = 7.6, 3.6 Hz, 1H),
3.77 (d, J = 13.0 Hz, 1H), 3.57 (d, J = 13.1 Hz, 1H), 3.40 (t, J = 8.8 Hz, 1H), 3.22–3.10 (m, 1H), 2.50–2.38
(m, 1H), 2.29–2.16 (m, 2H), 2.15–1.99 (m, 1H), 1.95–1.82 (m, 1H), 1.71 (dd, J = 13.1, 6.3 Hz, 1H), 1.62–1.56
(m, 1H), 1.47 (s, 3H), 0.81 (t, J = 7.2 Hz, 3H). 13C-NMR (150 MHz, CDCl3)
135.6, 133.7, 133.0, 132.9, 132.8, 132.1, 131.0, 130.1, 129.7, 129.3, 129.1, 127.9, 127.3, 127.3, 125.7, 124.3,
74.3, 70.3, 57.0, 54.8, 41.4, 37.2, 20.8, 18.2, 17.7, 13.7. LRMS (ESI, m/z): 654.1 [M
H]−. HRMS (ESI, m/z):
calcd for C31H29Cl3N3NiO3, 654.0633 [M
H]−; found 654.0643. The dr was determined by LC-MS
using an Eclipse XDB-C18 column (250 4.6 mm, 5 m) (CH3CN/H2O = 65:35, flow rate 1.0 mL/min,
δ 180.2, 178.8, 169.6, 140.7,
−
−
×
µ
λ = 254 nm), tmajor = 14.871 min, tminor = not found, dr > 99:1.
Nickel(II)-(S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(S)-valine
Schiff Base Complex (6o). Red solid (122 mg, yield 93%); mp 267–269 ◦C; [α]20 = +3016 (c = 1, CHCl3);
D
1H-NMR (400 MHz, CDCl3)
δ 9.17 (d, J = 2.1 Hz, 1H), 8.28 (d, J = 9.3 Hz, 1H), 7.65 (dd, J = 8.2, 2.1 Hz,
1H), 7.54 (dt, J = 16.1, 7.9 Hz, 2H), 7.45 (t, J = 6.9 Hz, 1H), 7.31 (dd, J = 7.7, 4.2 Hz, 2H), 7.10 (dd, J = 9.3,
2.6 Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H), 6.61 (d, J = 2.6 Hz, 1H), 4.14–3.97 (m, 1H), 3.83–3.72 (m, 2H),
3.53 (d, J = 13.1 Hz, 1H), 3.40 (t, J = 9.0 Hz, 1H), 3.00 (td, J = 12.5, 4.0 Hz, 1H), 2.53–2.34 (m, 1H),
2.27–2.08 (m, 2H), 1.84 (d, J = 6.6 Hz, 3H), 1.80–1.67 (m, 1H), 1.45 (s, 3H), 0.73 (d, J = 6.8 Hz, 3H).
13C-NMR (125 MHz, CDCl3)
δ 180.4, 177.4, 170.3, 141.0, 135.9, 134.0, 133.2, 133.2, 133.0, 132.5, 132.4,
131.2, 130.2, 129.8, 129.5, 129.1, 127.9, 127.9, 127.5, 125.8, 124.2, 75.6, 74.4, 57.3, 54.9, 41.7, 34.4, 20.5, 19.9,
17.8, 17.7. LRMS (ESI, m/z): 656.0 [M + H]+. HRMS (ESI, m/z): calcd for C31H31Cl3N3NiO3, 656.0604
[M + H]+; found 656.0606. The dr was determined by LC-MS with binary pump, photodiode array
detector (DAD), using Eclipse XDB-C18 column (250
1.0 mL/min, λ = 254 nm), tmajor = 14.594 min, tminor = not found, dr > 99:1.
×
4.6 mm, 5 µm) (CH3CN/H2O = 65:35, flow rate
Nickel(II)-(S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(S)-leucine
20
Schiff Base Complex (6p). Red solid (127 mg, yield 95%); mp 156–159 ◦C; [
α
]
D = +2731 (c = 1, CHCl3);
1H-NMR (500 MHz, CDCl3)
δ 9.14–9.11 (m, 1H), 8.16 (d, J = 9.3 Hz, 1H), 7.80 (dd, J = 8.2, 2.1 Hz, 1H),
7.59–7.55 (m, 1H), 7.53 (t, J = 7.4 Hz, 1H), 7.50–7.45 (m, 1H), 7.36–7.32 (m, 2H), 7.12 (dd, J = 9.3, 2.6 Hz,
1H), 6.88 (d, J = 7.6 Hz, 1H), 6.62 (d, J = 2.6 Hz, 1H), 4.06–3.97 (m, 1H), 3.85 (dd, J = 10.5, 4.1 Hz, 1H),
3.82 (d, J = 13.2 Hz, 1H), 3.54 (d, J = 13.1 Hz, 1H), 3.40 (t, J = 8.8 Hz, 1H), 3.34–3.17 (m, 1H), 2.48–2.34
(m, 2H), 2.28–2.18 (m, 2H), 1.97–1.86 (m, 1H), 1.47 (s, 3H), 1.39–1.32 (m, 1H), 0.83 (d, J = 6.7 Hz, 3H),
0.40 (d, J = 6.5 Hz, 3H). 13C-NMR (125 MHz, CDCl3)
δ 180.2, 178.6, 169.0, 140.6, 135.6, 133.7, 133.1,

Molecules 2019, 24, 2218
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132.9, 132.7, 132.0, 130.9, 130.1, 129.7, 129.2, 129.1, 127.9, 127.6, 127.4, 125.7, 124.3, 74.1, 69.1, 56.7, 55.1,
46.0, 41.6, 24.3, 23.7, 21.2, 20.8, 17.9. LRMS (ESI, m/z): 668.0 [M
H]−. HRMS (ESI, m/z): calcd for
C32H31Cl3N3NiO3, 668.0955 [M
H]−; found 668.0947. The dr was determined by LC-MS using an
Eclipse XDB-C18 column (250 4.6 mm, 5 m) (CH3CN/H2O = 65:35, flow rate 1.0 mL/min, = 254 nm),
tmajor = 20.065 min, tminor = not found, dr > 99:1.
−
−
×
µ
λ
Nickel(II)-(S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(S)-
20
methionine Schiff Base Complex (6q). Red solid (127 mg, yield 93%); mp 143–145 ◦C; [
(c = 1, CHCl3); H-NMR (400 MHz, CDCl3)
α
]
= +1883
D
1
δ 9.15–9.11 (m, 1H), 8.23 (d, J = 9.3 Hz, 1H), 7.76–7.71
(m, 1H), 7.62–7.52 (m, 2H), 7.52–7.46 (m, 1H), 7.38–7.34 (m, 1H), 7.34–7.30 (m, 1H), 7.14 (dd, J = 9.3,
2.5 Hz, 1H), 6.90 (d, J = 7.5 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 4.07–3.98 (m, 1H), 3.97–3.92 (m, 1H),
3.81–3.72 (m, 1H), 3.61–3.54 (m, 1H), 3.39 (t, J = 8.9 Hz, 1H), 3.23–3.12 (m, 1H), 3.11–3.03 (m, 1H),
2.65–2.54 (m, 1H), 2.50–2.38 (m, 1H), 2.30–2.14 (m, 3H), 1.99 (s, 3H), 1.93–1.83 (m, 1H), 1.47 (s, 3H).
13C-NMR (150 MHz, CDCl3)
132.4, 131.2, 130.4, 129.9, 129.6, 129.6, 129.4, 127.9, 127.5, 127.4, 125.9, 124.6, 74.5, 69.8, 57.3, 55.0,
δ 180.4, 178.3, 170.3, 141.1, 135.7, 133.9, 133.3, 133.1, 132.9, 132.5,
41.6, 35.1, 29.8, 21.2, 18.0, 15.8. LRMS (ESI, m/z): 686.0 [M
−
H]−. HRMS (ESI, m/z): calcd for
C31H29Cl3N3NiO3S, 686.0354 [M − H]−; found 686.0371. The dr was determined by LC-MS using
an Eclipse XDB-C18 column (250
×
4.6 mm, 5 µm) (CH3CN/H2O = 65:35, flow rate 1.0 mL/min,
λ = 254 nm), tmajor = 13.877 min, tminor = 15.012, dr = 99:1.
Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(R)-
20
phenylalanine Schiff Base Complex (6a). Red solid (128 mg, yield 91%); mp 121–124 ◦C; [
α]
D = –1684
(c = 1, CHCl3); 1H-NMR (400 MHz, CDCl3)
δ 9.09 (d, J = 2.1 Hz, 1H), 8.34 (d, J = 9.3 Hz, 1H), 7.62–7.56
(m, 2H), 7.56–7.51 (m, 1H), 7.43–7.32 (m, 5H), 7.31–7.29 (m, 1H), 7.16–7.09 (m, 3H), 6.68–6.64 (m, 1H),
6.62 (d, J = 2.6 Hz, 1H), 4.24 (t, J = 5.2 Hz, 1H), 3.65–3.60 (m, 1H), 3.51–3.45 (m, 1H), 3.36–3.26 (m, 1H),
3.20–3.09 (m, 2H), 2.83–2.76 (m, 1H), 2.41–2.27 (m, 1H), 2.16–2.05 (m, 1H), 2.05–1.95 (m, 1H), 1.88–1.77
(m, 1H), 1.35 (s, 3H). 13C-NMR (125 MHz, CDCl3)
δ
180.3, 177.9, 170.6, 141.3, 135.6, 133.8, 133.2, 132.9,
132.8, 132.4, 132.4, 130.9, 130.3, 130.1, 129.6, 129.3, 129.1, 128.9, 127.7, 127.5, 127.3, 125.6, 124.1, 74.1,
71.6, 57.1, 54.5, 41.2, 39.6, 20.5, 17.6. LRMS (ESI, m/z): 702.0 [M
H]−. HRMS (ESI, m/z): calcd for
C35H29Cl3N3NiO3, 702.0633 [M
H]−; found 702.0650. The dr was determined by LC-MS using an
Eclipse XDB-C18 column (250 4.6 mm, 5 m) (CH3CN/H2O = 65:35, flow rate 1.0 mL/min, = 254 nm),
tmajor = 15.665 min, tminor = not found, dr > 99:1.
−
−
×
µ
λ
Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(R)-2-
methoxyphenylalanine Schiff Base Complex (6b). Red solid (129 mg, yield 88%); mp 112–114 ◦C;
[α]20D = –1818 (c = 1, CHCl3); 1H-NMR (500 MHz, CDCl3)
δ 9.01 (d, J = 2.0 Hz, 1H), 8.37 (d, J = 9.3 Hz,
1H), 7.60–7.53 (m, 2H), 7.51 (t, J = 7.5 Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.36–7.32 (m, 1H),
7.30 (d, J = 8.1 Hz, 2H), 7.21 (dd, J = 7.4, 1.3 Hz, 1H), 7.11 (dd, J = 9.3, 2.6 Hz, 1H), 6.97 (t, J = 7.4 Hz,
1H), 6.86 (dd, J = 11.1, 8.1 Hz, 2H), 6.63 (d, J = 2.6 Hz, 1H), 4.15 (t, J = 4.9 Hz, 1H), 3.52 (dd, J = 30.2,
13.0 Hz, 2H), 3.31–3.23 (m, 4H), 3.19 (dd, J = 13.6, 5.0 Hz, 1H), 3.09 (t, J = 8.9 Hz, 1H), 2.91 (dd, J = 13.6,
4.9 Hz, 1H), 2.33–2.20 (m, 1H), 2.10–2.02 (m, 1H), 1.95 (dd, J = 19.5, 9.9 Hz, 1H), 1.84–1.72 (m, 1H),
1.32 (s, 3H). 13C-NMR (125 MHz, CDCl3)
δ 180.4, 178.4, 170.9, 158.3, 141.2, 135.8, 134.0, 133.5, 133.0,
132.9, 132.7, 132.6, 132.3, 131.0, 130.0, 129.8, 129.3, 129.2, 129.2, 128.3, 127.9, 127.6, 125.6, 124.3, 124.1,
121.3, 110.5, 74.5, 71.9, 57.5, 54.7, 54.5, 41.3, 34.6, 20.8, 17.9. LRMS (ESI, m/z): 734.0 [M + H]+. HRMS
(ESI, m/z): calcd for C36H33Cl3N3NiO4, 734.0885, [M + H]+; found 734.0887. The dr was determined
by LC-MS using an Eclipse XDB-C18 column (250
1.0 mL/min, λ = 254 nm), tmajor = 19.227 min, tminor = not found, dr > 99:1.
×
4.6 mm, 5 µm) (CH3CN/H2O = 65:35, flow rate
Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(R)-3-
methoxyphenylalanine Schiff Base Complex (6c). Red solid (131 mg, yield 93%); mp 104–106 ◦C;
[α]20D = –2923 (c = 1, CHCl3); 1H-NMR (400 MHz, CDCl3)
δ
9.08 (d, J = 2.0 Hz, 1H), 8.33 (d, J = 9.3 Hz,
1H), 7.62–7.47 (m, 3H), 7.40–7.28 (m, 3H), 7.26–7.18 (m, 1H), 7.12 (dd, J = 9.3, 2.6 Hz, 1H), 6.88

Molecules 2019, 24, 2218
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(dd, J = 8.3, 2.3 Hz, 1H), 6.67 (d, J = 7.5 Hz, 1H), 6.60 (d, J = 2.6 Hz, 2H), 6.55 (d, J = 7.9 Hz, 1H), 4.21
(t, J = 5.3 Hz, 1H), 3.65 (s, 3H), 3.55 (dd, J = 59.3, 13.1 Hz, 2H), 3.45–3.31 (m, 1H), 3.26–3.03 (m, 2H), 2.81
(dd, J = 13.8, 5.1 Hz, 1H), 2.46 (dq, J = 14.1, 7.2 Hz, 1H), 2.25–2.11 (m, 1H), 2.07–1.96 (m, 1H), 1.95–1.78
(m, 1H), 1.35 (s, 3H). 13C-NMR (125 MHz, CDCl3)
δ 180.6, 178.3, 170.9, 141.5, 135.8, 135.7, 134.0, 133.4,
133.1, 133.0, 132.7, 132.6, 131.1, 130.3, 129.8, 129.6, 129.5, 129.3, 127.7, 127.4, 126.4, 125.8, 124.3, 124.3,
74.4, 71.3, 57.4, 54.8, 41.5, 34.1, 20.9, 17.9. LRMS (ESI, m/z): 734.0 [M + H]+. HRMS (ESI, m/z): calcd for
C36H33Cl3N3NiO4, 734.0711 [M + H]+; found 734.0718. The dr was determined by LC-MS using an
Eclipse XDB-C18 column (250
tmajor = 16.492 min, tminor = not found, dr > 99:1.
×
4.6 mm, 5 µm) (CH3CN/H2O = 65:35, flow rate 1.0 mL/min, λ = 254 nm),
Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(R)-3-
methylphenylalanine Schiff Base Complex (6d). Red solid (129 mg, yield 90%); mp 105–107 ◦C;
[α]20D = –1898 (c = 1, CHCl3); 1H-NMR (400 MHz, CDCl3)
δ 9.06 (d, J = 1.5 Hz, 1H), 8.34 (d, J = 9.3 Hz,
1H), 7.55 (dt, J = 17.5, 7.4 Hz, 3H), 7.38 (t, J = 7.5 Hz, 1H), 7.31 (t, J = 6.7 Hz, 2H), 7.23 (t, J = 7.5 Hz,
1H), 7.17–7.09 (m, 2H), 6.87 (d, J = 7.8 Hz, 2H), 6.63 (dd, J = 12.2, 5.1 Hz, 2H), 4.21 (t, J = 5.1 Hz, 1H),
3.53 (dd, J = 47.7, 13.1 Hz, 2H), 3.31 (td, J = 12.6, 5.8 Hz, 1H), 3.11 (dd, J = 13.7, 4.7 Hz, 2H), 2.75
(dd, J = 13.7, 5.4 Hz, 1H), 2.47–2.31 (m, 1H), 2.27 (s, 3H), 2.13–2.06 (m, 1H), 1.99 (dd, J = 19.4, 9.7 Hz,
1H), 1.84 (dt, J = 14.9, 6.7 Hz, 1H), 1.33 (s, 3H). 13C-NMR (125 MHz, CDCl3)
δ 180.4, 178.2, 170.7, 141.5,
138.7, 135.8, 135.6, 134.0, 133.3, 133.1, 133.0, 132.6, 132.6, 131.3, 131.1, 130.2, 129.8, 129.5, 129.2, 128.9,
128.4, 127.9, 127.7, 127.5, 127.5, 125.7, 124.2, 74.3, 71.8, 57.3, 54.7, 41.2, 39.8, 21.6, 20.6, 17.8. LRMS
(ESI, m/z): 718.0 [M + H]+. HRMS (ESI, m/z): calcd for C36H33Cl3N3NiO3, 718.0762 [M + H]+; found
718.0773. The dr was determined by LC-MS using an Eclipse XDB-C18 column (250
×
4.6 mm, 5
µm)
(CH3CN/H2O = 65:35, flow rate 1.0 mL/min,
dr > 99:1.
λ = 254 nm), tmajor = 21.866 min, tminor = not found,
Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(R)-4-
fluorophenylalanine Schiff Base Complex (6e). Red solid (129 mg, yield 89%); mp 235–237 ◦C;
[α]20D = −2300 (c = 1, CHCl3); 1H-NMR (400 MHz, CDCl3)
δ 9.06 (d, J = 1.5 Hz, 1H), 8.32 (d, J = 9.3 Hz,
1H), 7.56 (p, J = 7.5 Hz, 3H), 7.43 (t, J = 7.3 Hz, 1H), 7.37–7.28 (m, 2H), 7.13 (dd, J = 9.3, 2.5 Hz, 1H),
7.05 (d, J = 7.0 Hz, 4H), 6.73 (d, J = 7.5 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 4.21 (t, J = 5.0 Hz, 1H), 3.54
(dd, J = 47.7, 13.0 Hz, 2H), 3.34 (td, J = 12.6, 6.0 Hz, 1H), 3.20–3.01 (m, 2H), 2.74 (dd, J = 14.0, 5.4
Hz, 1H), 2.45–2.26 (m, 1H), 2.26–2.12 (m, 1H), 2.00 (dd, J = 19.3, 9.6 Hz, 1H), 1.90–1.83 (m, 1H), 1.35
(s, 3H). 13C- NMR (125 MHz, CDCl3)
δ 180.5, 177.9, 170.9, 163.4, 161.8, 141.5, 135.7, 133.9, 133.3, 133.1,
133.0, 132.7, 132.6, 131.9, 131.9, 131.5, 131.5, 131.1, 130.4, 129.8, 129.6, 129.3, 127.7, 127.6, 127.4, 125.9,
124.3, 116.0, 115.8, 74.3, 71.6, 57.4, 54.6, 41.2, 38.8, 20.7, 17.8. LRMS (ESI, m/z): 722.0 [M + H]+. HRMS
(ESI, m/z): calcd for C35H30Cl3FN3NiO3, 722.0511 [M + H]+; found 722.0517. The dr was determined
by LC-MS using an Eclipse XDB-C18 column (250
1.0 mL/min, λ = 254 nm), tmajor = 18.447 min, tminor = not found, dr > 99:1.
×
4.6 mm, 5 µm) (CH3CN/H2O = 65:35, flow rate
Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(R)-3,5-
20
diiodotyrosine Schiff Base Complex (6f): red solid (169 mg, yield 87%); mp 233–235 ◦C; [
α
]
= –1774
D
(c = 1, CHCl3); 1H-NMR (400 MHz, CDCl3)
δ 9.08–9.05 (m, 1H), 8.47–8.42 (m, 1H), 7.63–7.59 (m, 2H),
7.59–7.55 (m, 1H), 7.52–7.46 (m, 1H), 7.37–7.32 (m, 2H), 7.29–7.27 (m, 2H), 7.20–7.15 (m, 1H), 6.79
(d, J = 7.4 Hz, 1H), 6.67 (d, J = 2.5 Hz, 1H), 5.83 (s, 1H), 4.14–4.10 (m, 1H), 3.57 (q, J = 13.8 Hz, 2H),
3.48–3.38 (m, 1H), 3.23–3.16 (m, 1H), 2.94–2.87 (m, 1H), 2.73–2.65 (m, 1H), 2.56–2.46 (m, 1H), 2.31–2.19
(m, 1H), 2.10–1.96 (m, 2H), 1.38 (s, 3H). 13C-NMR (150 MHz, CDCl3)
δ
180.4, 177.6, 171.0, 153.4, 141.7,
140.6, 135.6, 134.0, 133.2, 133.1, 133.0, 132.6, 131.8, 131.1, 130.6, 129.8, 129.7, 129.4, 127.6, 127.5, 127.4,
125.8, 124.4, 82.8, 74.5, 71.2, 57.5, 54.6, 41.0, 38.0, 21.0, 17.9. LRMS (ESI, m/z): 969.8 [M
H]−. HRMS
(ESI, m/z): calcd for C35H28Cl3I2N3NiO4, 969.8515 [M
H]−; found 969.8511. The dr was determined
by LC-MS using an Eclipse XDB-C18 column (250 4.6 mm, 5 m) (CH3CN/H2O = 65:35, flow rate
1.0 mL/min, λ = 254 nm), tmajor = 17.454 min, tminor = not found, dr > 99:1.
−
−
×
µ

Molecules 2019, 24, 2218
14 of 19
Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(R)-3-
(1-naphthyl)alanine Schiff Base Complex (6g). Red solid (142 mg, yield 94%); mp 114–116 ◦C;
[α]20D = −1812 (c = 1, CHCl3); 1H-NMR (400 MHz, CDCl3)
δ 9.09 (d, J = 2.0 Hz, 1H), 8.30 (d, J = 9.3 Hz,
1H), 7.78 (t, J = 8.0 Hz, 2H), 7.68 (dd, J = 8.2, 2.0 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.43–7.35 (m, 1H),
7.30 (dd, J = 15.6, 7.6 Hz, 4H), 7.23–7.11 (m, 3H), 7.08 (dd, J = 9.3, 2.6 Hz, 1H), 6.68 (t, J = 7.6 Hz,
1H), 6.44 (d, J = 2.6 Hz, 1H), 5.64 (d, J = 7.7 Hz, 1H), 4.41 (dd, J = 8.3, 4.3 Hz, 1H), 4.07 (dd, J = 14.2,
8.5 Hz, 1H), 3.79 (dd, J = 14.1, 4.3 Hz, 1H), 3.70 (d, J = 13.2 Hz, 1H), 3.61 (td, J = 13.1, 5.9 Hz, 1H), 3.46
(d, J = 13.2 Hz, 1H), 3.24 (t, J = 9.1 Hz, 1H), 2.83–2.53 (m, 1H), 2.39–2.22 (m, 1H), 2.12 (dd, J = 19.8,
9.6 Hz, 1H), 2.00 (dt, J = 15.0, 8.9 Hz, 1H), 1.40 (s, 3H). 13C-NMR (125 MHz, CDCl3)
δ 180.3, 178.3,
170.5, 141.3, 135.8, 134.2, 133.8, 133.3, 133.0, 132.8, 132.6, 132.5, 132.3, 131.7, 131.2, 129.8, 129.6, 128.8,
128.7, 128.6, 128.6, 128.5, 127.7, 127.5, 127.4, 126.5, 126.1, 125.7, 125.6, 124.1, 123.4, 74.4, 71.6, 56.9, 55.1,
41.6, 40.2, 20.9, 17.9. LRMS (ESI, m/z): 754.0 [M + H]+. HRMS (ESI, m/z): calcd for C39H33Cl3N3NiO3,
754.0763 [M + H]+; found 754.0779. The dr was determined by LC-MS using an Eclipse XDB-C18 column
(250
×
4.6 mm, 5 µm) (CH3CN/H2O = 65:35, flow rate 1.0 mL/min, λ = 254 nm), tmajor = 23.723 min, tminor
= not found, dr > 99:1.
Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(R)-3-
◦
(3-benzothienyl)alanine Schiff Base Complex (6h). Red solid (148 mg, yield 98%); mp 127–129 C;
[α]20D = –1836 (c = 1, CHCl3); 1H-NMR (400 MHz, CDCl3)
δ
9.06 (d, J = 2.0 Hz, 1H), 8.34 (d, J = 9.3 Hz,
1H), 7.86 (d, J = 8.0 Hz, 1H), 7.57 (dd, J = 8.2, 2.0 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.45–7.34 (m, 2H),
7.30 (dd, J = 11.9, 6.2 Hz, 3H), 7.19–7.08 (m, 4H), 6.59 (d, J = 2.6 Hz, 1H), 6.48 (d, J = 7.5 Hz, 1H), 4.31
(t, J = 5.5 Hz, 1H), 3.71–3.59 (m, 1H), 3.51 (dd, J = 57.6, 9.8 Hz, 2H), 3.18 (dd, J = 14.5, 4.7 Hz, 1H),
3.11–2.97 (m, 2H), 2.12–1.90 (m, 3H), 1.81–1.69 (m, 1H), 1.30 (s, 3H). 13C-NMR (125 MHz, CDCl3)
δ
180.3, 178.3, 170.8, 141.5, 140.6, 139.3, 135.7, 133.9, 133.2, 133.0, 132.9, 132.7, 131.1, 130.5, 130.1,
129.8, 129.3, 129.0, 127.5, 127.5, 125.9, 125.8, 124.8, 124.5, 124.3, 122.9, 122.1, 74.3, 70.9, 57.2, 54.8, 41.0,
34.0, 20.4, 17.8. LRMS (ESI, m/z): 760.0 [M + H]+. HRMS (ESI, m/z): calcd for C37H31Cl3N3NiO3S,
760.0326 [M + H]+; found 760.0333. The dr was determined by LC-MS using an Eclipse XDB-C18 column
(250 × 4.6 mm, 5
µm) (CH3CN/H2O = 65:35, flow rate 1.0 mL/min, λ = 254 nm), tmajor = 27.103 min,
minor = not dound, dr > 99:1.
t
Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(R)-3-
20
(3-thienyl)alanine Schiff Base Complex (6i). Red solid (128 mg, yield 92%); mp 208–210 ◦C; [
α
]
= 2419
−
D
(c = 1, CHCl3); 1H-NMR (400 MHz, CDCl3)
δ 9.09 (d, J = 2.1 Hz, 1H), 8.34 (d, J = 9.3 Hz, 1H), 7.63–7.49
(m, 3H), 7.46–7.39 (m, 1H), 7.38–7.28 (m, 3H), 7.13 (dd, J = 9.3, 2.6 Hz, 1H), 7.04 (d, J = 1.8 Hz, 1H),
6.86 (dd, J = 4.9, 1.2 Hz, 1H), 6.70 (d, J = 7.7 Hz, 1H), 6.62 (d, J = 2.6 Hz, 1H), 4.18 (t, J = 5.1 Hz, 1H),
3.63 (d, J = 13.1 Hz, 1H), 3.50 (dq, J = 11.9, 5.9 Hz, 2H), 3.25–3.05 (m, 2H), 2.77 (dd, J = 14.3, 5.4 Hz,
1H), 2.62–2.41 (m, 1H), 2.29–2.12 (m, 1H), 2.09–1.98 (m, 1H), 1.96–1.84 (m, 1H), 1.36 (s, 3H). 13C-NMR
(125 MHz, CDCl3)
δ 180.6, 178.3, 170.9, 141.5, 135.8, 135.7, 134.0, 133.4, 133.1, 133.0, 132.7, 132.6, 131.1,
130.3, 129.8, 129.6, 129.5, 129.3, 127.7, 127.4, 126.4, 125.8, 124.3, 124.3, 74.4, 71.3, 57.4, 54.8, 41.5, 34.1,
20.9, 17.9. LRMS (ESI, m/z): 710.0 [M + H]+. HRMS (ESI, m/z): calcd for C33H29Cl3N3NiO3S, 710.0168
[M + H]+; found 710.0175. The dr was determined by LC-MS using an Eclipse XDB-C18 column
(250 × 4.6 mm,
5 µm) (CH3CN/H2O = 65:35, flow rate 1.0 mL/min, λ = 254 nm), tmajor = 16.027 min,
minor = not found, dr > 99:1.
t
Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(R)-2-
◦
(3-methoxyphenyl)glycine Schiff Base Complex (6j). Red solid (99 mg, yield 70%); mp 135–137 C;
[α]20D = –2183 (c = 1, CHCl3); 1H-NMR (400 MHz, CDCl3)
δ 9.18 (d, J = 1.6 Hz, 1H), 8.23 (d, J = 9.3 Hz,
1H), 7.79 (d, J = 8.2 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.39 (dd, J = 15.2, 7.2 Hz, 3H), 7.29 (d, J = 7.5 Hz,
1H), 7.22 (t, J = 7.9 Hz, 1H), 7.16 (dd, J = 9.3, 2.5 Hz, 1H), 7.11–7.02 (m, 2H), 6.80 (dd, J = 8.2, 2.3 Hz,
1H), 6.66 (d, J = 2.5 Hz, 1H), 6.14 (d, J = 7.9 Hz, 1H), 4.71 (s, 1H), 4.08–3.95 (m, 1H), 3.80 (d, J = 13.0 Hz,
1H), 3.71 (s, 3H), 3.61 (d, J = 13.0 Hz, 1H), 3.34 (t, J = 8.9 Hz, 1H), 3.14 (dd, J = 18.8, 9.9 Hz, 1H), 2.46
(dd, J = 14.1, 9.9 Hz, 1H), 2.19 (dd, J = 17.6, 7.9 Hz, 2H), 1.49 (s, 3H). 13C-NMR (125 MHz, CDCl3)
δ

Molecules 2019, 24, 2218
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180.80, 177.4, 171.7, 159.8, 141.3, 139.2, 135.8, 134.0, 133.3, 133.3, 133.1, 132.6, 132.4, 131.2, 130.0, 129.9,
129.7, 129.0, 128.9, 127.7, 127.1, 126.7, 126.0, 124.9, 118.4, 113.8, 112.6, 74.7, 74.4, 57.3, 55.4, 55.3, 41.7,
21.2, 18.3. LRMS (ESI, m/z): 720.0 [M + H]+. HRMS (ESI, m/z): calcd for C35H31Cl3N3NiO4, 720.0554
[M + H]+; found 720.0574. The dr was determined by LC-MS using an Eclipse XDB-C18 column
(250 × 4.6 mm, 5
µm) (CH3CN/H2O = 65:35, flow rate 1.0 mL/min, λ = 254 nm), tmajor = 16.851 min,
minor = 18.454, dr = 98:2.
t
Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(R)-2-
◦
(3-bromophenyl)glycine Schiff Base Complex (6k). Red solid (134 mg, yield 87%); mp 102–104 C;
[α]20D = –2069 (c = 1, CHCl3); 1H-NMR (400 MHz, CDCl3)
δ
9.18 (d, J = 2.1 Hz, 1H), 8.22 (d, J = 9.3 Hz
,
1H), 8.15 (s, 1H), 7.80 (dd, J = 8.2, 2.2 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.50–7.38 (m, 3H), 7.32
(dd, J = 18.2, 7.8 Hz, 2H), 7.20–7.08 (m, 3H), 6.67 (d, J = 2.5 Hz, 1H), 6.13 (d, J = 7.8 Hz, 1H), 4.71 (s, 1H),
4.04 (t, J = 10.9 Hz, 1H), 3.72 (dd, J = 78.9, 13.1 Hz, 2H), 3.41–3.29 (m, 1H), 3.14 (dd, J = 21.0, 13.1 Hz,
1H), 2.50 (dd, J = 13.7, 10.0 Hz, 1H), 2.30–2.04 (m, 2H), 1.50 (s, 3H), 13C-NMR (125 MHz, CDCl3)
δ 180.8,
176.8, 172.1, 141.4, 139.9, 135.8, 134.0, 133.4, 132.9, 132.9, 132.4, 131.6, 131.3, 130.3, 130.2, 130.0, 129.3,
129.3, 129.1, 127.6, 127.0, 126.7, 126.1, 125.3, 125.0, 122.9, 74.5, 74.1, 57.3, 55.3, 41.8, 21.2, 18.3. LRMS
(ESI, m/z): 767.9 [M + H]+. HRMS (ESI, m/z): calcd for C34H28BrCl3N3NiO3, 767.9557 [M + H]+; found
767.9561. The dr was determined by LC-MS using an Eclipse XDB-C18 column (250
×
4.6 mm, 5 µm)
(CH3CN/H2O = 65:35, flow rate 1.0 mL/min, = 254 nm), tmajor = 25.867 min, tminor = 29.203, dr = 97:3.
λ
Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(R)-2-
20
cyclobutylglycine Schiff Base Complex (6l). Red solid (121 mg, yield 91%); mp 266–269 ◦C; [
α]
= –2560
D
(c = 1, CHCl3); 1H-NMR (400 MHz, CDCl3)
δ 9.14 (s, 1H), 8.24 (d, J = 9.3 Hz, 1H), 7.74–7.69 (m, 1H),
7.58–7.49 (m, 2H), 7.49–7.43 (m, 1H), 7.34–7.27 (m, 2H), 7.10 (dd, J = 9.3, 2.5 Hz, 1H), 6.88 (d, J = 7.4 Hz,
1H), 6.60 (d, J = 2.5 Hz, 1H), 4.21–4.05 (m, 1H), 3.84–3.75 (m, 2H), 3.52 (d, J = 13.0 Hz, 1H), 3.45–3.38
(m, 1H), 3.17–3.00 (m, 1H), 2.78–2.60 (m, 1H), 2.59–2.34 (m, 3H), 2.31–2.14 (m, 2H), 2.11–2.09 (m, 1H),
1.91–1.77 (m, 1H), 1.75–1.62 (m, 2H), 1.46 (s, 3H). 13C-NMR (125 MHz, CDCl3)
δ 180.1, 177.0, 169.4,
140.7, 135.6, 133.7, 133.1, 132.9, 132.8, 132.3, 132.1, 130.9, 130.0, 129.6, 129.2, 128.9, 127.9, 127.8, 127.5,
125.6, 124.0, 74.3, 73.8, 57.0, 54.8, 41.7, 40.5, 25.8, 25.4, 20.5, 17.9, 17.3. LRMS (ESI, m/z): 666.0 [M − H]−
.
HRMS (ESI, m/z): calcd for C32H29Cl3N3NiO3, 666.0633 [M
−
H]−; found 666.0632. The dr was
determined by LC-MS using Eclipse XDB-C18 column (250
×
4.6 mm, 5 µm) (CH3CN/H2O = 65:35,
flow rate 1.0 mL/min, λ = 254 nm), tmajor = 16.198 min, tminor = not found, dr > 99:1.
Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(R)-2-
amino-4,4,4-trifluorobutyric acid Schiff Base Complex (6m). Red solid (129 mg, yield 93%); mp 274–276 ◦C;
20
[α
]
= –3150 (c = 1, CHCl3); 1H-NMR (400 MHz, CDCl3)
δ 9.16 (d, J = 1.8 Hz, 1H), 8.35 (d, J = 9.3 Hz,
D
1H), 7.68–7.47 (m, 4H), 7.36 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 6.8 Hz, 1H), 7.16 (dd, J = 9.3, 2.5 Hz, 1H),
6.90 (d, J = 7.4 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 4.22–4.10 (m, 2H), 3.74–3.49 (m, 2H), 3.38 (t, J = 8.7 Hz,
1H), 3.09–2.80 (m, 1H), 2.63–2.46 (m, 1H), 2.42 (dd, J = 13.7, 9.8 Hz, 1H), 2.23–2.09 (m, 2H), 2.06–1.90
(m, 1H), 1.44 (s, 3H). 13C-NMR (125 MHz, CDCl3)
δ 180.5, 177.2, 172.4, 141.9, 135.8, 134.0, 133.2, 133.2,
133.2, 133.1, 132.5, 131.3, 130.8, 129.9, 129.8, 129.7, 127.6, 127.6, 126.8, 125.8, 124.6, 74.9, 64.5, 57.8, 54.8,
41.2, 35.6 (d, J = 29.2 Hz), 20.3, 17.4. LRMS (ESI, m/z): 696.0 [M + H]+. HRMS (ESI, m/z): calcd for
C30H26Cl3F3N3NiO3, 696.0164 [M + H]+; found 696.0171. The dr was determined by LC-MS using an
Eclipse XDB-C18 column (250
tmajor = 13.464 min, tminor = not found, dr > 99:1.
×
4.6 mm, 5 µm) (CH3CN/H2O = 65:35, flow rate 1.0 mL/min, λ = 254 nm),
Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(R)-
20
norvaline Schiff Base Complex (6n). Red solid (118 mg, yield 90%); mp 227–228 ◦C; [
α
]
= –2430 (c = 1,
D
CHCl3); 1H-NMR (400 MHz, CDCl3)
δ 9.11 (d, J = 2.0 Hz, 1H), 8.21 (d, J = 9.3 Hz, 1H), 7.73 (dd, J = 8.2,
2.0 Hz, 1H), 7.61–7.49 (m, 2H), 7.46 (t, J = 7.4 Hz, 1H), 7.31 (dd, J = 15.9, 7.6 Hz, 2H), 7.12 (dd, J = 9.3,
2.6 Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H), 6.60 (d, J = 2.6 Hz, 1H), 4.11–3.98 (m, 1H), 3.87 (dd, J = 7.6, 3.6
Hz, 1H), 3.65 (dd, J = 82.3, 13.0 Hz, 2H), 3.38 (t, J = 8.8 Hz, 1H), 3.25–3.02 (m, 1H), 2.48–2.37 (m, 1H),

Molecules 2019, 24, 2218
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2.27–2.14 (m, 2H), 2.13–1.97 (m, 1H), 1.84 (dt, J = 13.1, 8.4 Hz, 1H), 1.69 (dd, J = 13.1, 6.3 Hz, 1H),
1.59–1.49 (m, 1H), 1.45 (s, 3H), 0.79 (t, J = 7.2 Hz, 3H). 13C-NMR (125 MHz, CDCl3)
180.4, 179.0, 169.8,
δ
140.9, 135.8, 133.9, 133.3, 133.1, 133.1, 132.4, 131.2, 130.3, 129.9, 129.5, 129.3, 128.1, 127.5, 127.5, 125.9,
124.5, 74.5, 70.5, 57.2, 55.0, 41.6, 37.4, 21.0, 18.4, 17.9, 13.9. LRMS (ESI, m/z): 656.1 [M + H]+. HRMS
(ESI, m/z): calcd for C31H31Cl3N3NiO3, 656.0604 [M + H]+; found 656.0601. The dr was determined
by LC-MS using an Eclipse XDB-C18 column (250
1.0 mL/min, λ = 254 nm), tmajor = 14.850 min, tminor = 17.260, dr = 98:2.
×
4.6 mm, 5 µm) (CH3CN/H2O = 65:35, flow rate
Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(R)-valine
Schiff Base Complex (6o). Red solid (126 mg, yield 96%); mp 224–226 ◦C; [α]20 = −2566 (c = 1, CHCl3);
D
1H-NMR (400 MHz, CDCl3)
δ 9.18 (d, J = 2.1 Hz, 1H), 8.29 (d, J = 9.3 Hz, 1H), 7.68–7.64 (m, 1H),
7.60–7.50 (m, 2H), 7.49–7.43 (m, 1H), 7.35–7.30 (m, 2H), 7.12 (dd, J = 9.3, 2.6 Hz, 1H), 6.88–6.84 (m, 1H),
6.62 (d, J = 2.6 Hz, 1H), 4.13–4.01 (m, 1H), 3.82–3.76 (m, 2H), 3.58–3.52 (m, 1H), 3.45–3.38 (m, 1H),
3.07–2.87 (m, 1H), 2.49–2.39 (m, 1H), 2.25–2.10 (m, 2H), 1.86 (d, J = 6.6 Hz, 3H), 1.81–1.70 (m, 1H), 1.46
(s, 3H), 0.75 (d, J = 6.8 Hz, 3H). 13C-NMR (150 MHz, CDCl3)
δ
180.2, 177.1, 170.1, 140.8, 135.7, 133.8,
133.0, 133.0, 132.8, 132.3, 132.2, 130.9, 130.0, 129.6, 129.3, 128.9, 127.7, 127.6, 127.3, 125.6, 124.0, 75.4, 74.2,
57.1, 54.7, 41.5, 34.2, 20.3, 19.7, 17.6, 17.5. LRMS (ESI, m/z): 656.0 [M
H]−. HRMS (ESI, m/z): calcd for
C31H29Cl3N3NiO3, 656.0633 [M
H]−; found 656.0629. The dr was determined by LC-MS using an
Eclipse XDB-C18 column (250 4.6 mm, 5 m) (CH3CN/H2O = 65:35, flow rate 1.0 mL/min, = 254 nm),
tmajor = 14.706 min, tminor = not found, dr > 99:1.
−
−
×
µ
λ
Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(R)-leucine
20
Schiff Base Complex (6p). Red solid (127 mg, yield 95%); mp 126–127 ◦C; [
α]
= 1898 (c = 1, CHCl3);
−
D
1H-NMR (500 MHz, CDCl3)
δ 9.11 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 9.3 Hz, 1H), 7.78 (dd, J = 8.2, 2.1 Hz,
1H), 7.60–7.49 (m, 2H), 7.46 (td, J = 7.5, 1.0 Hz, 1H), 7.32 (t, J = 6.8 Hz, 2H), 7.10 (dd, J = 9.3, 2.6 Hz,
1H), 6.87 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 2.6 Hz, 1H), 4.06–3.98 (m, 1H), 3.83 (dd, J = 10.5, 4.1 Hz, 1H),
3.80 (d, J = 13.2 Hz, 1H), 3.53 (d, J = 13.1 Hz, 1H), 3.39 (t, J = 8.8 Hz, 1H), 3.32–3.15 (m, 1H), 2.49–2.31
(m, 2H), 2.29–2.16 (m, 2H), 1.99–1.81 (m, 1H), 1.45 (s, 3H), 1.38–1.32 (m, 1H), 0.81 (d, J = 6.7 Hz, 3H),
0.38 (d, J = 6.5 Hz, 3H). 13C-NMR (125 MHz, CDCl3)
δ 180.4, 178.8, 169.2, 140.8, 135.8, 133.9, 133.3,
133.1, 132.9, 132.2, 131.1, 130.3, 129.9, 129.4, 129.3, 128.1, 127.8, 127.6, 125.9, 124.5, 74.4, 69.3, 56.9, 55.3,
46.2, 41.8, 24.5, 23.9, 21.4, 21.0, 18.1. LRMS (ESI, m/z): 669.9 [M + H]+. HRMS (ESI, m/z): calcd for
C32H33Cl3N3NiO3, 670.0935 [M + H]+; found 670.0935. The dr was determined by LC-MS using an
Eclipse XDB-C18 column (250
tmajor = 19.979 min, tminor = not found, dr > 99:1.
×
4.6 mm, 5 µm) (CH3CN/H2O = 65:35, flow rate 1.0 mL/min, λ = 254 nm),
Nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(R)-
20
methionine Schiff Base Complex (6q). Red solid (120 mg, yield 88%); mp 123–125 ◦C; [
(c = 1, CHCl3); H-NMR (400 MHz, CDCl3)
α
]
= 2202
−
D
1
δ 9.11 (d, J = 1.5 Hz, 1H), 8.21 (d, J = 9.3 Hz, 1H), 7.72
(d, J = 6.7 Hz, 1H), 7.60–7.51 (m, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.32 (dd, J = 14.6, 7.6 Hz, 2H), 7.13
(dd, J = 9.3, 2.5 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 4.09–3.96 (m, 1H), 3.93
(dd, J = 8.3, 3.6 Hz, 1H), 3.66 (dd, J = 74.8, 13.0 Hz, 2H), 3.37 (t, J = 8.9 Hz, 1H), 3.17 (dd, J = 16.5, 10.3
Hz, 1H), 3.09–3.01 (m, 1H), 2.67–2.53 (m, 1H), 2.49–2.37 (m, 1H), 2.19 (dd, J = 15.7, 6.7 Hz, 3H), 1.97
(s, 3H), 1.91–1.77 (m, 1H), 1.45 (s, 3H). 13C-NMR (125 MHz, CDCl3)
133.9, 133.3, 133.2, 132.9, 132.6, 132.4, 131.2, 130.4, 129.9, 129.6, 129.4, 127.9, 127.5, 127.4, 125.9, 124.6,
74.5, 69.8, 57.3, 55.0, 41.6, 35.1, 29.8, 21.3, 18.0, 15.8. LRMS (ESI, m/z): 688.0 [M
H]−. HRMS (ESI, m/z):
calcd for C31H31Cl3N3NiO3S, 688.0324 [M
H]−; found 688.0339. The dr was determined by LC-MS
using an Eclipse XDB-C18 column (250 4.6 mm, 5 m) (CH3CN/H2O = 65:35, flow rate 1.0 mL/min,
δ 180.4, 178.3, 170.3, 141.1, 135.7,
−
−
×
µ
λ = 254 nm), tmajor = 13.870 min, tminor = 14.997, dr = 98:2.
20
(S)-Phenylalanine (5a). White solid (16.5 mg, yield 88%); mp 273–275 ◦C; [
α] D = – 38 (c = 1, MeOH);
1H-NMR (500 MHz, D2O)
δ
7.41 (m, J = 14.6, 7.2 Hz, 3H), 7.33 (d, J = 7.1 Hz, 2H), 4.00 (dd, J = 7.9,
5.2 Hz, 1H), 3.30 (dd, J = 14.5, 5.2 Hz, 1H), 3.13 (dd, J = 14.5, 8.0 Hz, 1H), 2.00 (s, 1H), 1.96 (s, 2H).

Molecules 2019, 24, 2218
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13C-NMR (125 MHz, D2O)
δ
173.4, 134.6, 128.8, 128.6, 127.2, 55.5, 35.8, 22.1, 20.7. LRMS (ESI, m/z):
166.0 [M + H]+. HRMS (ESI, m/z): calcd for C9H11NO2, 166.0863 [M + H]+; found 166.0865. The ee was
determined by HPLC using an Astec CHIROBIOTIC
(MeOH/H2O = 90/10, λ = 210 nm, 1 mL/min). tS = 7.472 min, tR = not found, ee > 99 %.
™
T chiral HPLC column (4.6 mm
×
25 cm, 5 µm)
X-ray Single Crystal Structure Analysis of (S,2S)-6a: (S,2S)-6a (100 mg) was dissolved in DCM
(10 mL) and crystals suitable for X-ray single crystal structure determination were obtained after all the
solvent had evaporated at room temperature. The X-ray structure of (S,2S)-6a was resolved at T = 293(2)
K: C35H30Cl3N3NiO3, Mr = 705.68, monoclinic. Space group P2 (1), a = 10.1494 (12) Å, b = 15.7644 (19)
Å, c = 22.968 (3) Å,
α β γ
= 90◦, = 90◦, = 90◦, V = 3674.9 (8) Å3, Z = 4. These data can be obtained free
of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif,
the CCDC number is 1472366.
4. Conclusions
In conclusion, we have developed a generalized method for DKR of C,N-unprotected racemic
α
-amino acids with a novel, stable, and recyclable α-methylproline-derived chiral ligand under
operationally convenient conditions. Compared to the reported methods, we realized good to excellent
yields and diastereoselectivities of phenyl-substituted glycines. In addition, the substrates scope range
includes compounds such as cyclobutyl- and trifluoroethyl-substituted glycine, also with excellent
yields and diastereoselectivities. This new approach offers versatile access to various chiral
acids in high yields (up to 98%) with excellent ee values (ee >99%). Particularly noteworthy is that
the novel designed -methylproline-derived chiral ligand is more stable than the previous reported
α-amino
α
proline-derived chiral ligand.
Supplementary Materials: The Supporting Information contains characterization data Figures S1–S15: HPLC
Spectra for dr Determination of (S, 2S)-6; Figures S16–S32: HPLC Spectra for dr Determination of (R, 2R)-6;
Figures S33–S34: HPLC Spectra for ee determination; Figures S35–S69: copies of the 1H- NMR, 13C-NMR spectra.
Author Contributions: Conceptualization, S.J.S. and S.B.Z.; methodology, S.J.S.; validation, S.J.S., L.Z.;
investigation, S.J.S. and L.Z.; data curation, S.J.S.; writing—original draft preparation, S.J.S.; writing—review and
editing, C.L.W. and J.W.; supervision, H.L.; project administration, J.W. and H.L.; funding acquisition, H.L.
Funding: This work is supported the National Natural Science Foundation of China (nos. 21632008, 21602234,
21672231, 21877118, and 81620108027), the Major Project of Chinese National Programs for Fundamental Research
and Development (2015CB910304).
Acknowledgments: We gratefully acknowledge financial support from the National Natural Science Foundation
of China and the Major Project of Chinese National Programs for Fundamental Research and Development.
We would like to thank all the reviewers for their great comments.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are not available from the authors.
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