Chemical Resolution of C, N-Unprotected α-Substituted β-Amino Acids Using Stable and Recyclable Proline-Derived Chiral Ligands

Article abstract of DOI:10.1021/acs.joc.8b01336

We report the first purely chemical method for the resolution of C,N-unprotected racemic α-substituted β-amino acids (β²-AAs) using thermodynamically stable and recyclable chiral proline-derived ligands. The ligands and racemic β²-AA

Full text of DOI:10.1021/acs.joc.8b01336

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Article
Chemical Resolution of C,N-Unprotected #-Substituted-#-Amino
Acids Using Stable and Recyclable Proline-derived Chiral Ligands
Shuni Wang, Yong Nian, Shengbin Zhou, Jiang Wang, and Hong Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01336 • Publication Date (Web): 13 Jul 2018
Downloaded from http://pubs.acs.org on July 15, 2018
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Chemical Resolution of C,NꢀUnprotected αꢀSubstitutedꢀβꢀAmino Acids Using
Stable and Recyclable Prolineꢀderived Chiral Ligands
†, ‡, §
†, ‡, §
†, ‡
†, ‡, *
†, ‡, *
Shuni Wang,
Yong Nian,
Shengbin Zhou, Jiang Wang
and Hong Liu
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†
State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research,
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Shanghai 201203, China.
‡
University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
§
These authors contributed equally.
Eꢀmail: hliu@simm.ac.cn (Hong Liu); jwang@simm.ac.cn (Jiang Wang)
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Abstract
We report the first purely chemical method for the resolution of C,Nꢀunprotected racemic
2
αꢀsubstitutedꢀβꢀamino acids (β ꢀAAs) using thermodynamically stable and recyclable chiral
2
prolineꢀderived ligands. The ligands and racemic β ꢀAAs along with Ni(II) could form a pair of
Ni(II) complex diastereoisomers with desirable diastereoselectivity (dr up to 91:9).
2
Enantiomerically pure C,Nꢀunprotected β ꢀAAs could be obtained by simple hydrolysis of isolated
favoredꢀNi(II) complex. The method featured unique versatility compared with enzymatic
approaches, and characterized by its broad synthetic generality, good stereochemical outcome and
mild reaction conditions, thus making it a powerful supplement in the field of chemical resolution
2
of β ꢀAAs.
Introduction
2
αꢀSubstitutedꢀβꢀamino acids (β ꢀAAs) are being widely used increasingly in the
1
ꢀ8
pharmaceutical and healthcare industries,
and play as the vital building blocks in the
9
ꢀ11
2
pharmaceuticals and natural products. Preparation of structurally varied β ꢀAAs in
enantiomerically pure forms has been a research focus in synthetic organic chemistry, leading to
12ꢀ13
several ingenious asymmetric synthesis approaches.
However, current asymmetric synthesis
2
methods to prepare enantiomerically pure β ꢀAAs are relatively cumbersome, involving expensive,
dangerous or toxic reagents, and requiring multiple steps to prepare substrates and elaborate
14ꢀ16
2
reaction conditions.
By contrast, the resolution of racemic β ꢀAAs is still used frequently in
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practice, because there are a variety of methods to prepare racemic β ꢀAAs.
However, the
2
19ꢀ25
enzymatic resolution of racemic β ꢀAA derivatives is limited to only a few examples.
For
1
9
example, Berkessel et al. reported the enzymatic dynamic kinetic resolution of oxazinones or
2
4
2
βꢀlactams to obtain optically pure β ꢀAAs. These enzymatic approaches require high throughput
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screening for selective enzymes and multiꢀstep preparation for special substrates. Similarly, the
2
exploration of purely chemical methods for the resolution of racemic β ꢀAAs is almost omitted
with limited literatures. Berkessel et al. reported the kinetic resolution of 5ꢀsubstituted oxazinone
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substrates with chiral squaramide organocatalysts to afford Nꢀprotected β ꢀamino esters via
26
alcoholytic ring opening. Zhang et al. reported chiral Lewis base organocatalyzed asymmetric
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hydrosilylation of αꢀsubstituted βꢀenamino ester to afford enantioenriched β ꢀamino esters via
27
2
dynamic kinetic resolution. Both methods require preparation of special β ꢀAAs derivatives and
2
resulted products are C,Nꢀprotected or substituted β ꢀAAs, thus unfriendly to following
2
applications (Scheme 1). Therefore, a purely chemical resolution of C,Nꢀunprotected β ꢀAAs,
starting from simple and cheap starting materials, to obtain enantiomerically pure C,Nꢀunprotected
2
β ꢀAAs, remains an important challenge for synthetic organic chemists.
2
Scheme 1. Reported chemical resolution methods to obtain chiral β ꢀAAs or their derivatives.
3
Various enantiomerically pure nonꢀnatural amino acids, including αꢀAAs and β ꢀAAs, could
be obtained by dynamic resolution of racemic AAs via forming Ni(II) complexes with chiral
28
ligands (Figure 1). On the other hand, we have previously synthesized a series of racemic
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αꢀarylꢀ/alkylꢀsubstituted βꢀamino acids using Ni(II) complexed with the achiral PBP ligand.
Encouraged by these works, we proposed to explore the possibility of chemical resolution of
2
C,Nꢀunprotected racemic β ꢀAAs via a chiral ligand by forming Ni(II) complex to obtain the
31ꢀ33
enantiomerically pure forms (Scheme 2). Unlike αꢀamino acids (αꢀAAs),
the kinetic rate of
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chelation reaction of β ꢀAAs with the chiral ligand and Ni(II) is comparatively lower, since the
resulted flexible sixꢀmembered ring goes against the Ni(II)ꢀcentered quadrilateral plane.
Figure 1. Dynamic resolution of racemic amino acids using Ni(II) complex
2
Scheme 2. Chemical resolution of C,Nꢀunprotected racemic β ꢀAAs by Ni(II) complexes.
Results and Discussion
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In initial stage of the attempts, we selected the chiral prolineꢀderived ligand 1 for the dynamic
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resolution of C,Nꢀunprotected β ꢀAAs, which has been successfully applied in the chemical
3
32, 34
resolution of αꢀAAs and βꢀsubstitutedꢀβꢀamino acids (β ꢀAAs).
Interestingly, the reaction of
racemic αꢀbenzylꢀβꢀalanine (rac)ꢀ2a (1 equiv) with (S)ꢀ1 (1 equiv) generated two expected Ni(II)
complex products, (S)(2R)ꢀ3a and (S)(2S)ꢀ3a, and two unexpected products, (R)(2S)ꢀ3a and
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(
R)(2R)ꢀ3a (Scheme 1, Figures S1 and S2). Theoretically, racemization was able to occur at the
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αꢀposition of both proline and β ꢀAA moieties in the structure of the Ni(II) complex 3a under
baseꢀcatalyzed epimerization. According to above results, we could reasonably assume that the
2
pK
a
of αꢀH of the proline moiety is comparable with that of the β ꢀAA moiety in the structure of
the Ni(II) complex 3a, which suggested that ligand (S)ꢀ1 is inappropriate as a chiral auxiliary for
2
the thermodynamic resolution of racemic β ꢀAAs. To solve the thermodynamic instability of
ligand 1, we then designed a ligand, (S)ꢀ4, with a quaternary carbon stereogenic center by
introducing a methyl at the αꢀposition of the proline moiety in the structure of ligand 1.
To confirm our ideas, we then reacted (S)ꢀ4 with (rac)ꢀ2a under the standard reaction
conditions: heating an ethanol solution of the ligand (S)ꢀ4, (rac)ꢀ2a, anhydrous Ni(OAc) and
2
DBU. In this case, as expected, we did not observe (R)(2R)ꢀ10a and (R)(2S)ꢀ10a (Figures S3 and
S4), and the target nickel(II) complexes, (S)(2R)ꢀ10a and (S)(2S)ꢀ10a, were obtained at a yield of
7
6% and in a ratio of 81:19 (Table 1, entry 1). These results were encouraging, as they established
2
that the direct chemical resolution of unprotected β ꢀAAs by a simple reaction with (S)ꢀ6 was
feasible. Fortunately, we could easily got the diastereoisomers (S)(2R)ꢀ10a and (S)(2S)ꢀ10a by
column chromatography on silica gel (v/v, dichloromethane/methanol = 20/1). After the
1
determination of dr value of the diastereoisomers by H NMR, the enantiomerically pure
(
S)(2R)ꢀ10a could be obtained by column chromatography on silica gel once again (v/v,
dichloromethane/acetone = 5/1, R ((S)(2R)ꢀ10a) = 0.4, R ((S)(2S)ꢀ10a) = 0.25). The definite and
absolute configurations of Ni(II) complexes (S)(2R)ꢀ10a and (S)(2S)ꢀ10a were determined by
f
f
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Xꢀray analysis (Figure S5).
Table 1. Optimization of chiral ligands for chemical resolution of unprotected racemic
a
αꢀbenzylꢀβꢀalanine 2a.
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Entry
Ligand
Ni(II)ꢀcomplex
(S)(2R)ꢀ10a
(S)(2R)ꢀ11a
(S)(2R)ꢀ12a
(S)(2R)ꢀ13a
(S)(2R)ꢀ14a
(R)(2S)ꢀ15a
yield (%)
dr
1
2
3
4
5
6
(S)ꢀ4
(S)ꢀ5
(S)ꢀ6
(S)ꢀ7
(S)ꢀ8
(R)ꢀ9
76
74
89
83
69
82
81/19
83/17
68/32
69/31
82/18
91/9
a
Reaction condition: Ligand (0.1 mmol), (rac)ꢀ2a (0.1 mmol), anhydrous Ni(OAc)
2
(0.1 mmol)
o
b
and DBU (1 mmol) were refluxed in ethanol (2 mL) at 80 C for 96 h. Combined yield of
c
1
isolated products 10aꢀ15a. dr was determined by H NMR analysis of isolated products 10aꢀ15a.
To further improve the stereochemical outcome, various attempts at modifying of ligand 4
were conducted (Table 1, entries 2ꢀ6). The synthesis method of the prolineꢀderived ligands 4ꢀ9
was extremely similar with the previous reported method, and ligands 4ꢀ5 and 8ꢀ9 have been well
3
6
characterized. When we substituted 3,4ꢀdicholorobenzyl with a benzyl moiety on proline, it gave
a comparable yield and diastereoselectivity (Table 1, entry 2). An apparent increase in yield and
decrease in diastereoselectivity were observed when introducing electronꢀdonating groups on the
benzyl moiety (Table 1, entries 3ꢀ4). Prolonging benzyl to phenylpropyl gave a comparative
diastereoselectivity but an undesired decrease in yield (Table 1, entry 5). Finally, it was found that
ligand (R)ꢀ9 with an ethyl substitution on proline showed a relatively good yield (82%) and
diastereoselectivity (dr = 91:9) of the Ni(II) complex (Table 1, entry 6), which has been also
3
36
selected as the best prolineꢀderived ligand in the resolution of racemic β ꢀAAs. Further
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investigation on the reaction time of ligand (R)ꢀ9 with (rac)ꢀ2a revealed that the final
thermodynamic control stopped at 96 h was the best choice. And with the longer reaction time,
diastereoisomer (R)(2R)ꢀ15a could surely be interconverted to the thermodynamically more stable
diastereoisomer (R)(2S)ꢀ15a while accompanied with the decomposition of Ni(II) complex 15a
1
1
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1
1
1
1
1
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(Table S1).
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Furthermore, we investigated the generality of (R)ꢀ9 in the resolution of β ꢀAAs (Table 2).
2
First, the αꢀbenzylꢀsubstituted β ꢀAAs were applied successfully with satisfactory yields (≥ 70%)
and good diastereoselectivity (dr ≥ 84:16) (Table 2, entries 1ꢀ5). Importantly, for these
2
benzylꢀsubstituted β ꢀAAs, the electronic property of the substituents on the benzyl group did not
2
show any apparent effects on the stereochemical outcome of the reactions. In addition, β ꢀAAs
bearing aliphatic substituents, such as methyl, iꢀbutyl, iꢀpropyl, and cyclohexyl also exhibited
good yield (≥ 80%) and a slight decrease in diastereoselectivity compared with the
2
benzylꢀsubstituted β ꢀAAs (Table 2, entries 6ꢀ9). For the sterically hindered tꢀbutylꢀsubstituted
2
β ꢀAA, the Ni(II) complexes 15j were isolated with a moderate yield and diastereochemistry (dr =
62:38) (Table 2, entry 10). Unfortunately, the αꢀarylꢀsubstituted βꢀAAs (rac)ꢀ2kꢀ2n (Table 2,
entries 11ꢀ14), bearing electronꢀwithdrawing as well as electronꢀdonating groups, and the
sterically hindered 2ꢀnaphthyl, all resulted in products with poor diastereoselectivities (dr ≤ 62 :
38).
2
a
Table 2. Chemical resolution of various C,Nꢀunprotected β ꢀAAs (rac)ꢀ2 using ligand (R)ꢀ9.
O
O
O
N
O
N
N
N
N
N
N
O
Ni(OAc)2
Ni
R2
Ni
R2
+
H N
OH
O
NH
O
2
O
O
DBU/EtOH
+
R2
(rac)-2
80 o
C
Ph
Ph
Ph
Cl
Cl
Cl
(
R)-9
(
R)(2S)-15
(R)(2R)-15
b
c
Entry
R
2
Ni(II)ꢀcomplex
(R)(2S)ꢀ15a
(R)(2S)ꢀ15b
(R)(2S)ꢀ15c
(R)(2S)ꢀ15d
Yield (%)
dr
1
2
3
4
benzyl
82
83
70
76
91/9
88/12
84/16
89/11
4ꢀOMeꢀbenzyl
4ꢀMeꢀbenzyl
4ꢀFꢀbenzyl
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4ꢀCF
3
ꢀbenzyl
(R)(2S)ꢀ15e
(R)(2S)ꢀ15f
(R)(2S)ꢀ15g
(R)(2S)ꢀ15h
(R)(2S)ꢀ15i
(R)(2S)ꢀ15j
(R)(2S)ꢀ15k
(R)(2S)ꢀ15l
(R)(2S)ꢀ15m
(R)(2S)ꢀ15n
72
83
80
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69
73
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69
76
89/11
73/27
methyl
iꢀbutyl
83/17
iꢀpropyl
76/24
0
1
2
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0
1
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0
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0
1
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0
cyclohexyl
tꢀbutyl
83/17
1
0
62/38
1
1
2
3
4
phenyl
51/49
1
1
1
4ꢀMeOꢀphenyl
4ꢀClꢀphenyl
2ꢀnaphthyl
54/46
62/38
56/44
a
Reaction condition: (R)ꢀ9 (0.1 mmol), (rac)ꢀ2 (0.1 mmol), anhydrous Ni(OAc)
2
(0.1 mmol) and
o
b
DBU (1 mmol) were refluxed in ethanol (2 mL) at 80 C for 96 h. Combined yield of (R)(2S)ꢀ15
c
1
and (R)(2R)ꢀ15. dr was determined by H NMR analysis of the mixtures of (R)(2S)ꢀ15 and
(
R)(2R)ꢀ15.
As we can see in Table 2, the yield of (R)(2S)ꢀ15a was 75%, exceeding more than 50%,
2
convictively indicating that the resolution of racemic β ꢀAAs was a dynamic process. To further
understand this process, we isolated enantiomerically pure (R)(2S)ꢀ15a and (R)(2R)ꢀ15a,
respectively, and treated with DBU (10 equiv) in EtOH. After heating for 96 h, 7% of pure
(
R)(2S)ꢀ15a was converted to (R)(2R)ꢀ15a, and in contrast, 67% of pure (R)(2R)ꢀ15a was
transformed to (R)(2S)ꢀ15a, fully illustrating the two diastereisomers could be interconverted via
ketoꢀenol tautomerism (enol 16a as the possible intermediate), and (R)(2S)ꢀ15a was undoubtedly
identified as the thermodynamically favored diastereisomer (Scheme 3). When it came to Ni(II)
complex 15k, whether (R)(2S)ꢀ15k or (R)(2R)ꢀ15k as the starting diastereisomer, the ratio of
(
R)(2S)ꢀ15k and (R)(2R)ꢀ15k were both nearly 50:50 after the thermodynamic equilibrium
transformation (Scheme 2), which consistented with the resolution result (Table 2, entry 11). One
may agreed that the (R)(2S)ꢀ15k and (R)(2R)ꢀ15k featured with comparable intrinsic
thermodynamical stability, thus exhibiting low diastereoselectivity in the resolution process.
According to the previous report, the phenyl ring of the benzyl group could shield the Nickel atom
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to form extra metalꢀphenyl attraction, which possibly illustrated the better diastereoselectivity for
3
7
resolution of 2a than 2k.
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Scheme 3. Thermodynamic equilibrium transformation of 15a and 15k.
2
To achieve the final goal of this study, we selected 2a as an example of resolution of β ꢀAAs
to obtain the enantiomerically pure forms. After simple purification by column chromatography,
diastereoselectively pure (R)(2S)ꢀ15a was subjected to the disassembly procedure presented in
Scheme 4. The disassembly procedure was also conducted under simple reaction conditions, thus
producing the target αꢀbenzylꢀβꢀamino acid (S)ꢀ2a with an excellent chemical yield (93%) and
enantioselectivity (ee > 99%). Furthermore, (R)ꢀ9 could be recycled easily in almost quantitative
yield (98%) with high enantiomeric purity (ee > 99%). Thus, the recovered (R)ꢀ9 could be reused
2
for repetitive thermodynamic resolution of other racemic β ꢀAAs.
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Scheme 4. Disassembly of Nickel(II) complex (R)(2S)ꢀ15a to afford (S)ꢀ2a.
Conclusion
In conclusion, we have developed the first purely chemical method for the resolution of
2
C,Nꢀunprotected racemic β ꢀAAs using stable, and recyclable prolineꢀderived ligands with a
quaternary carbon stereogenic center. This new approach is more versatile compared with
biocatalytic methods, especially without requiring multiꢀstep preparation for resolution substrates.
The method showed a broad synthetic generality for various αꢀalkylꢀsubstituted C,Nꢀunprotected
βꢀAAs with good to moderate diastereoselectivities, featuring with simple operation and mild
reaction conditions.
Experimental Section
General Information
The commercially available chemicals were used without further purification. Anhydrous nickel
o
1
13
acetate was prepared by heating reagent grade tetrahydrate for 2 h at 110 C in vacuum. H and
C
NMR spectra was recorded on a 400 MHz or 500 MHz Bruker AV400 instrument. Chemical shifts
were reported in parts per million (ppm, δ) downfield from tetramethylsilane. Proton coupling
patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad
(
br). Highꢀresolution mass spectra (HRMS) was measured on Micromass Ultra QꢀTOF
1
spectrometer. The determination of dr was performed via H NMR or LC/MS analysis using
Agilent 6120 spectrometer. Optical rotations were measured using a 1 mL cell with a 1 dm path
20
length on an Autopol VI automatic polarimeter and are reported as follows: [α]
(c: g/100 mL,
D
in solvent).
General Procedures
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Nickel(II)ꢀ(S)ꢀNꢀ(2ꢀbenzoylꢀ4ꢀchlorophenyl)ꢀ1ꢀ(3,4ꢀdichlorobenzyl)ꢀ2ꢀmethylpyrrolidineꢀ2ꢀca
rboxamide/(R)ꢀ3ꢀaminoꢀ2ꢀbenzylpropanoic acid Schiff Base Complex ((S)(2R)ꢀ10a)
(S)ꢀ4 (50.20 mg, 0.10 mmol), 3ꢀaminoꢀ2ꢀbenzylpropanoic acid 2a (17.93 mg, 0.10 mmol),
Ni(OAc)
2
(17.68 mg, 0.10 mmol), were dissolved in EtOH (2 mL) followed by DBU (149.31 ꢁL,
.00 mmol) being added. After being refluxed for 96 h, the reaction was terminated by ice water of
% acetic acid (10 mL). The mixture was extracted with dichloromethane (10 mL × 3). The
SO , and then concentrated and purified by column
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combined organic layers were dried with Na
2
4
chromatography on silica gel (v/v, dichloromethane/methanol = 20/1) to give the crude products
10a (55.1 mg, yield 76%) for analysis (dr = 81/19). The crude product 10a was purified again by
f
column chromatography on silica gel (v/v, dichloromethane/acetone = 5/1, R ((S)(2R)ꢀ10a) = 0.4,
R ((S)(2S)ꢀ10a) = 0.25) to give the major pure diastereomer (S)(2R)ꢀ10a as a brown solid. mp
f
o
20
1
1
28ꢀ130 C. [α]
D 3 4
= +2426.5 (c = 0.034, CHCl ). H NMR (400 MHz, Methanolꢀd ) δ 8.91 (d, J =
2
.1 Hz, 1H), 8.32 (dd, J = 8.3, 2.1 Hz, 1H), 7.74 (d, J = 9.2 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.39
– 7.25 (m, 2H), 7.23 – 7.12 (m, 4H), 7.06 (dd, J = 9.2, 2.6 Hz, 1H), 7.03 – 6.95 (m, 3H), 6.64 (dt,
J = 7.6, 1.6 Hz, 1H), 6.42 (d, J = 2.6 Hz, 1H), 3.98 – 3.83 (m, 2H), 3.77 (d, J = 13.3 Hz, 1H), 3.58
–
3.48 (m, 1H), 3.40 (d, J = 13.3 Hz, 1H), 3.27 – 3.18 (m, 1H), 3.14 – 3.02 (m, 2H), 2.68 – 2.62
13
(
m, 1H), 2.51 – 2.10 (m, 4H), 1.43 (s, 3H). C NMR (125 MHz, Methanolꢀd
4
) δ 182.5, 180.4,
1
1
73.1, 141.3, 139.8, 138.2, 134.9, 134.6, 133.9, 133.5, 133.1, 132.7, 132.4, 132.2, 131.2, 131.0,
30.3, 130.2, 129.9, 129.6, 128.1, 127.7, 127.6, 126.8, 125.9, 74.9, 56.7, 56.3, 55.3, 49.3, 42.8,
+
37.2, 22.2, 18.6. LRMS (ESI+APCI) m/z: 718.0. HRMS (ESIꢀTOF) m/z: [M + H] Calcd for
C H Cl N NiO 718.0935; Found 718.0940.
3
6
33
3
3
3
(
S)ꢀNꢀ(2ꢀbenzoylꢀ4ꢀchlorophenyl)ꢀ1ꢀ(3,4ꢀdibromobenzyl)ꢀ2ꢀmethylpyrrolidineꢀ2ꢀcarboxamid
e ((S)ꢀ6)
20
1
Yellow oil (3.7 g, yield 90%). [α]
D 3 3
= ꢀ26.2 (c = 0.118, CHCl ). H NMR (500 MHz, CDCl ) δ
11.72 (s, 1H), 8.63 (d, J = 8.7 Hz, 1H), 7.83 (d, J = 1.9 Hz, 1H), 7.76 (dd, J = 8.2, 1.4 Hz, 2H),
7.65 – 7.62 (m, 1H), 7.55 – 7.47 (m, 4H), 7.31 (d, J = 8.2 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 3.77
(d, J = 13.5 Hz, 1H), 3.38 (d, J = 13.5 Hz, 1H), 3.16 (t, J = 8.1 Hz, 1H), 2.40 (q, J = 8.1 Hz, 1H),
1
3
2
1
3
.23 – 2.13 (m, 1H), 1.91 – 1.75 (m, 3H), 1.39 (s, 3H). C NMR (125 MHz, CDCl ) δ 197.0,
76.5, 140.0, 138.4, 137.9, 133.8, 133.4, 133.3, 133.0, 132.2, 130.1, 128.8, 128.5, 127.2, 125.9,
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24.7, 122.9, 122.8, 68.8, 53.4, 51.3, 40.1, 22.6, 16.4. LRMS (ESI+APCI) m/z: 590.8. HRMS
+
(ESIꢀTOF) m/z: [M + H] Calcd for C26
H
24Br
2
ClN
2
O
2
588.9888; Found 588.9877.
(
S)ꢀNꢀ(2ꢀbenzoylꢀ4ꢀchlorophenyl)ꢀ1ꢀ(3,4ꢀdimethoxybenzyl)ꢀ2ꢀmethylpyrrolidineꢀ2ꢀcarboxami
0
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de ((S)ꢀ7)
20
D
1
Yellow oil (3.5 g, yield 92%). [α]
= ꢀ34.3 (c = 0.103, CHCl
3
). H NMR (500 MHz, CDCl
3
) δ
11.64 (s, 1H), 8.56 (d, J = 9.0 Hz, 1H), 7.73 – 7.69 (m, 2H), 7.64 – 7.59 (m, 1H), 7.52 – 7.48 (m,
3H), 7.45 (d, J = 2.5 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.83 (dd, J = 8.2, 1.9 Hz, 1H), 6.58 (d, J =
8.2 Hz, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 3.37 (d, J = 13.0 Hz, 1H), 3.14 (td, J = 8.1, 7.6, 4.1 Hz,
13
1H), 2.43 – 2.36 (m, 1H), 2.18 – 2.08 (m, 1H), 1.85 – 1.69 (m, 4H), 1.39 (s, 3H). C NMR (125
MHz, CDCl ) δ 196.8, 176.9, 148.9, 147.9, 138.2, 137.9, 133.2, 132.9, 131.8, 131.5, 130.0, 128.5,
3
127.3, 126.6, 123.2, 120.6, 111.8, 110.7, 68.5, 55.8, 54.0, 51.1, 40.2, 22.6, 16.2. LRMS
+
(
ESI+APCI) m/z: 493.0. HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C28
H
30ClN O
2 4
493.1889;
Found 493.1875.
Nickel(II)ꢀ(S)ꢀNꢀ(2ꢀbenzoylꢀ4ꢀchlorophenyl)ꢀ1ꢀbenzylꢀ2ꢀmethylpyrrolidineꢀ2ꢀcarboxamide/
R)ꢀ3ꢀaminoꢀ2ꢀbenzylpropanoic acid Schiff Base Complex ((S)(2R)ꢀ11a)
(
o
20
D
1
Brown solid (48.1 mg, yield 74%). mp 128ꢀ130 C. [α] = +2739.1(c = 0.046, CHCl ). H NMR
3
4
(400 MHz, Methanolꢀd ) δ 8.58 – 8.50 (m, 2H), 7.59 (d, J = 9.1 Hz, 1H), 7.40 – 7.26 (m, 4H),
7.20 – 7.11 (m, 5H), 7.01 – 6.96 (m, 4H), 6.66 (dt, J = 7.3, 1.7 Hz, 1H), 6.40 (d, J = 2.6 Hz, 1H),
3.97 – 3.81 (m, 2H), 3.76 (d, J = 13.1 Hz, 1H), 3.65 – 3.53 (m, 1H), 3.40 (d, J = 13.1 Hz, 1H),
3
.30 – 3.21 (m, 1H), 3.12 – 3.04 (m, 2H), 2.65 – 2.59 (m, 1H), 2.47 – 2.11 (m, 4H), 1.46 (s, 3H).
13
4
C NMR (125 MHz, Methanolꢀd ) δ 182.8, 180.5, 172.9, 141.6, 139.9, 137.1, 135.0, 132.8, 132.6,
132.3, 131.2, 131.1, 130.2, 130.1, 130.1, 130.0, 129.6, 129.5, 128.1, 127.7, 127.6, 126.8, 126.5,
75.1, 57.9, 56.8, 55.3, 49.1, 42.9, 37.2, 22.6, 18.6. LRMS (ESI+APCI) m/z: 650.1. HRMS
+
(ESIꢀTOF) m/z: [M + H] Calcd for C36
H
35ClN
3
NiO
3
650.1715; Found 650.1721.
Nickel(II)ꢀ(S)ꢀNꢀ(2ꢀbenzoylꢀ4ꢀchlorophenyl)ꢀ1ꢀ(3,4ꢀdibromobenzyl)ꢀ2ꢀmethylpyrrolidineꢀ2ꢀca
rboxamide/(R)ꢀ3ꢀaminoꢀ2ꢀbenzylpropanoic acid Schiff Base Complex ((S)(2R)ꢀ12a)
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o
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Brown solid (57.2 mg, yield 89%). mp 132ꢀ134 C. [α] = +2723.3 (c = 0.048, CHCl ). H NMR
D
3
(500 MHz, Methanolꢀd
Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.23 – 7.15 (m,
H), 7.09 (dd, J = 9.2, 2.6 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 7.00 (dd, J = 6.5, 2.9 Hz, 2H), 6.67
d, J = 7.6 Hz, 1H), 6.45 (d, J = 2.5 Hz, 1H), 3.93 (td, J = 12.6, 5.0 Hz, 1H), 3.86 (t, J = 12.4 Hz,
4
) δ 9.34 (d, J = 2.1 Hz, 1H), 8.08 (dd, J = 8.2, 2.1 Hz, 1H), 7.77 (d, J = 9.2
4
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1
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1
2
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(
1
H), 3.78 (d, J = 13.3 Hz, 1H), 3.60 – 3.48 (m, 1H), 3.40 (d, J = 13.3 Hz, 1H), 3.29 – 3.23 (m, 1H),
.14 (dd, J = 13.8, 3.7 Hz, 1H), 3.05 (dd, J = 12.8, 3.8 Hz, 1H), 2.66 (dd, J = 13.8, 9.8 Hz, 1H),
3
1
3
2.49 – 2.36 (m, 2H), 2.33 – 2.24 (m, 1H), 2.22 – 2.13 (m, 1H), 1.45 (s, 3H). C NMR (125 MHz,
Methanolꢀd ) δ 181.1, 179.1, 171.8, 139.8, 138.5, 137.6, 136.7, 134.3, 133.6, 131.9, 131.5, 131.2,
29.8, 129.5, 128.9, 128.8, 128.6, 128.2, 126.7, 126.3, 126.2, 125.5, 125.0, 124.5, 124.3, 78.1,
4
1
7
3.5, 55.3, 54.8, 53.9, 41.4, 35.8, 20.9, 17.3. LRMS (ESI+APCI) m/z: 809.7. HRMS (ESIꢀTOF)
+
m/z: [M + H] Calcd for C36
2
H33Br ClN
3
NiO
3
805.9925; Found 805.9912.
Nickel(II)ꢀ(S)ꢀNꢀ(2ꢀbenzoylꢀ4ꢀchlorophenyl)ꢀ1ꢀ(3,4ꢀdimethoxybenzyl)ꢀ2ꢀmethylpyrrolidineꢀ2ꢀ
carboxamide/(R)ꢀ3ꢀaminoꢀ2ꢀbenzylpropanoic acid Schiff Base Complex ((S)(2R)ꢀ13a)
o
20
1
Brown solid (53.8 mg, yield 83%). mp 130ꢀ132 C. [α]
NMR (500 MHz, Methanolꢀd ) δ 8.37 (d, J = 2.1 Hz, 1H), 7.88 (dd, J = 8.2, 2.1 Hz, 1H), 7.70 (d,
J = 9.2 Hz, 1H), 7.39 (tt, J = 7.5, 1.3 Hz, 1H), 7.33 (t, J = 7.3 Hz, 1H), 7.24 – 7.17 (m, 4H), 7.04 –
.97 (m, 4H), 6.90 (d, J = 8.2 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.41 (d, J = 2.5 Hz, 1H), 3.96 (t, J
D
= +2690.6 (c = 0.050, CHCl
3
).
H
4
6
= 12.5 Hz, 1H), 3.93 – 3.90 (m, 1H), 3.89 (s, 3H), 3.76 (d, J = 13.3 Hz, 1H), 3.71 (s, 3H), 3.65 –
3.56 (m, 1H), 3.23 (ddd, J = 11.2, 8.2, 1.5 Hz, 1H), 3.11 (dd, J = 13.8, 3.8 Hz, 1H), 3.08 (dd, J =
1
2.9, 3.9 Hz, 1H), 2.70 (dd, J = 13.8, 9.7 Hz, 1H), 2.50 – 2.36 (m, 3H), 2.34 – 2.25 (m, 1H), 2.18
13
(
td, J = 10.9, 8.3 Hz, 1H), 1.48 (s, 3H). C NMR (125 MHz, Methanolꢀd
4
) δ 181.8, 179.2, 171.5,
1
1
49.3, 149.0, 140.4, 138.4, 133.6, 131.2, 130.9, 129.8, 129.8, 128.8, 128.8, 128.8, 128.6, 128.2,
26.8, 126.2, 125.1, 125.0, 123.7, 114.6, 111.7, 78.1, 73.3, 55.7, 55.4, 55.0, 54.7, 54.1, 41.8, 35.9,
+
21.0, 17.2. LRMS (ESI+APCI) m/z: 710.7. HRMS (ESIꢀTOF) m/z: [M + H] Calcd for
38 3 5
C H39ClN NiO 710.1926; Found 710.1926.
Nickel(II)ꢀ(S)ꢀNꢀ(2ꢀbenzoylꢀ4ꢀchlorophenyl)ꢀ2ꢀmethylꢀ1ꢀ(3ꢀphenylpropyl)pyrrolidineꢀ2ꢀcarbo
xamide/(R)ꢀ3ꢀaminoꢀ2ꢀbenzylpropanoic acid Schiff Base Complex ((S)(2R)ꢀ14a)
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o
20
1
Brown solid (46.8 mg, yield 69%). mp 103ꢀ105 C. [α] = +2756.3 (c = 0.048, CHCl ). H NMR
D
3
(400 MHz, Methanolꢀd
4
) δ 7.99 (d, J = 9.1 Hz, 1H), 7.38 – 7.29 (m, 2H), 7.25 – 7.10 (m, 10H),
7.02 – 6.93 (m, 3H), 6.73 – 6.68 (m, 1H), 6.52 (d, J = 2.6 Hz, 1H), 3.95 – 3.82 (m, 2H), 3.69 –
3
1
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.56 (m, 1H), 3.20 – 3.04 (m, 5H), 2.85 – 2.78 (m, 1H), 2.67 – 2.43 (m, 4H), 2.36 – 2.19 (m, 3H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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8
9
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9
0
1
2
3
4
5
6
7
8
9
0
13
4
.88 – 1.81 (m, 1H), 1.14 (s, 3H). C NMR (125 MHz, Methanolꢀd ) δ 183.3, 180.6, 173.1, 142.1,
41.8, 140.0, 135.0, 133.5, 133.1, 131.7, 131.1, 130.2, 130.1, 129.9, 129.6, 129.4, 129.4, 128.1,
27.8, 127.6, 127.1, 126.9, 126.5, 75.5, 57.0, 54.7, 54.3, 49.0, 41.7, 37.2, 34.7, 31.9, 23.4, 18.1.
+
LRMS (ESI+APCI) m/z: 678.2. HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H ClN NiO
3
8
39
3
3
678.2028; Found 678.2035.
Nickel(II)ꢀ(R)ꢀNꢀ(2ꢀbenzoylꢀ4ꢀchlorophenyl)ꢀ1ꢀethylꢀ2ꢀmethylpyrrolidineꢀ2ꢀcarboxamide/(S)ꢀ
ꢀaminoꢀ2ꢀbenzylpropanoic acid Schiff Base Complex ((R)(2S)ꢀ15a)
3
o
20
1
Brown solid (48.2 mg, yield 82%). mp 120ꢀ122 C. [α]
(400 MHz, Methanolꢀd ) δ 8.14 (d, J = 9.2 Hz, 1H), 7.38 – 7.34 (m, 2H), 7.26 (dd, J = 9.1, 2.6 Hz,
1H), 7.17 – 7.11 (m, 4H), 7.04 – 6.92 (m, 3H), 6.81 – 6.70 (m, 1H), 6.53 (d, J = 2.6 Hz, 1H), 3.95
D 3
= ꢀ2726.5 (c = 0.034, CHCl ). H NMR
4
(
t, J = 12.4 Hz, 1H), 3.86 – 3.61 (m, 2H), 3.23 – 3.07 (m, 3H), 2.66 – 2.41 (m, 3H), 2.39 – 2.24 (m,
1
3
3
1
1
4
H), 1.93 – 1.86 (m, 4H), 1.24 (s, 3H). C NMR (100 MHz, Methanolꢀd ) δ 183.7, 180.6, 173.0,
41.9, 140.0, 135.0, 133.5, 133.0, 131.7, 131.1, 130.2, 130.1, 129.9, 129.6, 128.1, 127.9, 127.6,
26.9, 126.5, 74.9, 57.0, 54.6, 49.7, 48.9, 41.9, 37.2, 23.4, 18.1, 15.5. LRMS (ESI+APCI) m/z:
+
588.2. HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C31
H33ClN
3
NiO
3
588.1558; Found 588.1564.
Nickel(II)ꢀ(R)ꢀNꢀ(2ꢀbenzoylꢀ4ꢀchlorophenyl)ꢀ1ꢀethylꢀ2ꢀmethylpyrrolidineꢀ2ꢀcarboxamide/(S)ꢀ
ꢀaminoꢀ2ꢀ(4ꢀmethoxybenzyl)propanoic acid Schiff Base Complex ((R)(2S)ꢀ15b)
3
o
20
1
Brown solid (51.3 mg, yield 83%). mp 127ꢀ129 C. [α]
D 3
= ꢀ3618.8 (c = 0.032, CHCl ). H NMR
(
400 MHz, Methanolꢀd ) δ 8.14 (d, J = 9.1 Hz, 1H), 7.41 – 7.32 (m, 2H), 7.26 (d, J = 9.1 Hz, 1H),
4
7.15 (t, J = 8.5 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.91 – 6.84 (m, 2H), 6.77 (d, J = 7.6 Hz, 1H),
6.72 – 6.66 (m, 2H), 6.53 (d, J = 2.6 Hz, 1H), 3.94 (t, J = 12.4 Hz, 1H), 3.79 (s, 3H), 3.78 – 3.71
(
m, 1H), 3.20 – 3.02 (m, 3H), 2.64 – 2.49 (m, 2H), 2.45 – 2.26 (m, 4H), 1.91 (t, J = 7.4 Hz, 3H),
13
1
1
4
.24 (s, 3H). C NMR (125 MHz, Methanolꢀd ) δ 183.7, 180.7, 173.0, 159.8, 142.0, 135.1, 133.5,
33.0, 131.9, 131.7, 131.0, 131.0, 130.2, 130.2, 128.1, 127.9, 126.9, 126.6, 115.0, 75.0, 57.0, 55.7,
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4.58, 49.7, 49.3, 42.0, 36.3, 23.4, 18.1, 15.5. LRMS (ESI+APCI) m/z: 618.1. HRMS (ESIꢀTOF)
+
m/z: [M + H] Calcd for C32
H35ClN
3
NiO
4
618.1664; Found 618.1667.
Nickel(II)ꢀ(R)ꢀNꢀ(2ꢀbenzoylꢀ4ꢀchlorophenyl)ꢀ1ꢀethylꢀ2ꢀmethylpyrrolidineꢀ2ꢀcarboxamide/(S)ꢀ
ꢀaminoꢀ2ꢀ(4ꢀmethylbenzyl)propanoic acid Schiff Base Complex ((R)(2S)ꢀ15c)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
o
20
1
Brown solid (42.1 mg, yield 70%). mp 124ꢀ126 C. [α]
D 3
= ꢀ3277.3 (c = 0.034, CHCl ). H NMR
(400 MHz, Methanolꢀd ) δ 8.13 (d, J = 9.1 Hz, 1H), 7.40 – 7.32 (m, 2H), 7.28 – 7.21 (m, 1H),
4
7.15 – 7.09 (m, 1H), 6.99 – 6.93 (m, 3H), 6.85 (d, J = 8.0 Hz, 2H), 6.77 (d, J = 7.2 Hz, 1H), 6.53
(d, J = 2.6 Hz, 1H), 3.93 (t, J = 12.4 Hz, 1H), 3.84 – 3.68 (m, 2H), 3.20 – 3.06 (m, 3H), 2.62 –
2
1
1
5
.53 (m, 2H), 2.44 – 2.39 (m, 1H), 2.39 – 2.34 (m, 1H), 2.32 (s, 3H), 2.31 – 2.22 (m, 2H), 1.92 –
1
3
.87 (m, 4H), 1.24 (s, 3H). C NMR (125 MHz, Methanolꢀd ) δ 183.7, 180.6, 173.0, 142.0, 137.1,
4
36.9, 135.1, 133.5, 133.0, 131.7, 130.8, 130.3, 130.1, 129.9, 128.1, 127.9, 126.9, 126.6, 75.0,
7.0, 54.7, 49.69, 42.0, 36.8, 23.4, 21.1, 18.1, 15.5. LRMS (ESI+APCI) m/z: 601.8. HRMS
+
(ESIꢀTOF) m/z: [M + H] Calcd for C32
H
35ClN
3
NiO
3
602.1715; Found 602.1705.
Nickel(II)ꢀ(R)ꢀNꢀ(2ꢀbenzoylꢀ4ꢀchlorophenyl)ꢀ1ꢀethylꢀ2ꢀmethylpyrrolidineꢀ2ꢀcarboxamide/(S)ꢀ
ꢀaminoꢀ2ꢀ(4ꢀfluorobenzyl)propanoic acid Schiff Base Complex ((R)(2S)ꢀ15d)
3
o
20
D
1
Brown solid (46.1 mg, yield 76%). mp 123ꢀ124 C. [α] = ꢀ3310.5 (c = 0.038, CHCl ). H NMR
3
4
(400 MHz, Methanolꢀd ) δ 8.15 (d, J = 9.1 Hz, 1H), 7.41 – 7.33 (m, 2H), 7.26 (dd, J = 9.1, 2.6 Hz,
1H), 7.21 – 7.13 (m, 1H), 7.03 – 6.94 (m, 3H), 6.90 – 6.82 (m, 2H), 6.78 (dt, J = 6.6, 1.9 Hz, 1H),
6.53 (d, J = 2.6 Hz, 1H), 3.96 (t, J = 12.3 Hz, 1H), 3.86 – 3.73 (m, 2H), 3.22 – 3.06 (m, 3H), 2.62
13
–
1
1
1
4
2.29 (m, 6H), 1.94 – 1.86 (m, 4H), 1.24 (s, 3H). C NMR (125 MHz, Methanolꢀd ) δ 183.7,
80.3, 173.0, 163.9, 162.0, 141.9, 136.1, 136.1, 135.1, 133.4, 133.0, 131.7, 131.6, 131.6, 130.9,
30.2, 130.2, 128.1, 127.8, 126.9, 126.6, 116.3, 116.1, 75.0, 56.9, 54.5, 49.7, 49.1, 41.9, 36.3, 23.4,
+
8.1, 15.5. LRMS (ESI+APCI) m/z: 606.1. HRMS (ESIꢀTOF) m/z: [M + H] Calcd for
31 3 3
C H32ClFN NiO 606.1464; Found 606.1476.
Nickel(II)ꢀ(R)ꢀNꢀ(2ꢀbenzoylꢀ4ꢀchlorophenyl)ꢀ1ꢀethylꢀ2ꢀmethylpyrrolidineꢀ2ꢀcarboxamide/(S)ꢀ
3ꢀaminoꢀ2ꢀ(4ꢀ(trifluoromethyl)benzyl)propanoic acid Schiff Base Complex ((R)(2S)ꢀ15e)
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5
5
5
6
o
20
1
Brown solid (47.2 mg, yield 72%). mp 137ꢀ139 C. [α] = ꢀ3950.5 (c = 0.046, CHCl ). H NMR
D
3
(400 MHz, Methanolꢀd
4
) δ 8.14 (d, J = 9.1 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.35 – 7.25 (m, 3H),
7.17 (d, J = 8.1 Hz, 2H), 7.05 – 6.95 (m, 2H), 6.78 (d, J = 7.6 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H),
4
3
1
1
.00 (t, J = 12.3 Hz, 1H), 3.88 – 3.78 (m, 2H), 3.30 – 3.26 (m, 1H), 3.21 (dd, J = 11.1, 7.4 Hz, 1H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
.07 (dd, J = 12.7, 3.4 Hz, 1H), 2.61 – 2.44 (m, 3H), 2.39 – 2.30 (m, 3H), 1.94 – 1.87 (m, 4H),
13
.25 (s, 3H). C NMR (125 MHz, Methanolꢀd
4
) δ 183.7, 179.9, 173.1, 145.1, 142.0, 135.1, 133.4,
33.1, 131.4, 131.0, 130.6, 130.1, 130.0, 129.8, 129.5, 128.0, 127.7, 126.9, 126.6, 126.5, 126.5,
75.0, 56.8, 54.5, 49.7, 42.0, 36.9, 23.4, 18.1, 15.5. LRMS (ESI+APCI) m/z: 655.8. HRMS
+
(ESIꢀTOF) m/z: [M + H] Calcd for C32
H
32ClF
3
N
3
NiO
3
656.1432; Found 656.1431.
Nickel(II)ꢀ(R)ꢀNꢀ(2ꢀbenzoylꢀ4ꢀchlorophenyl)ꢀ1ꢀethylꢀ2ꢀmethylpyrrolidineꢀ2ꢀcarboxamide/(S)ꢀ
ꢀaminoꢀ2ꢀmethylpropanoic acid Schiff Base Complex ((R)(2S)ꢀ15f)
3
o
20
1
Brown solid (42.5 mg, yield 83%). mp 257ꢀ259 C. [α]
(400 MHz, Methanolꢀd ) δ 8.17 (d, J = 9.1 Hz, 1H), 7.66 – 7.49 (m, 3H), 7.45 – 7.35 (m, 1H),
7.29 (dd, J = 9.1, 2.5 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.65 (d, J = 2.6 Hz, 1H), 4.26 – 3.53 (m,
D 3
= ꢀ4854.5 (c = 0.044, CHCl ). H NMR
4
3
3
1
4
H), 3.29 – 3.18 (m, 1H), 3.12 – 2.90 (m, 1H), 2.64 – 2.18 (m, 5H), 2.06 – 1.76 (m, 4H), 1.26 (s,
1
3
4
H), 0.98 (d, J = 7.3 Hz, 3H). C NMR (125 MHz, Methanolꢀd ) δ 183.7, 182.0, 172.7, 142.0,
35.8, 133.6, 133.1, 131.5, 130.6, 130.1, 128.7, 128.3, 126.9, 126.6, 75.1, 59.8, 54.4, 49.8, 42.1,
+
1.9, 23.4, 18.1, 15.5, 15.2. LRMS (ESI+APCI) m/z: 512.0. HRMS (ESIꢀTOF) m/z: [M + H]
Calcd for C25
Nickel(II)ꢀ(R)ꢀNꢀ(2ꢀbenzoylꢀ4ꢀchlorophenyl)ꢀ1ꢀethylꢀ2ꢀmethylpyrrolidineꢀ2ꢀcarboxamide/(S)ꢀ
ꢀ(aminomethyl)ꢀ4ꢀmethylpentanoic acid Schiff Base Complex ((R)(2S)ꢀ15g)
3 3
H29ClN NiO 512.1245; Found 512.1259.
2
o
20
1
Brown solid (44.3 mg, yield 80%). mp 120ꢀ122 C. [α]
400 MHz, Methanolꢀd ) δ 8.19 (d, J = 9.1 Hz, 1H), 7.60 – 7.52 (m, 3H), 7.44 – 7.42 (m, 1H),
.29 (dd, J = 9.1, 2.6 Hz, 1H), 6.99 (dd, J = 7.7, 1.7 Hz, 1H), 6.67 (d, J = 2.6 Hz, 1H), 3.95 – 3.73
D 3
= ꢀ4383.3 (c = 0.048, CHCl ). H NMR
(
4
7
(m, 3H), 3.25 – 3.14 (m, 2H), 2.62 – 2.53 (m, 1H), 2.41 – 2.32 (m, 3H), 2.24 – 2.17 (m, 1H), 1.94
– 1.86 (m, 4H), 1.74 – 1.67 (m, 1H), 1.26 (s, 3H), 1.25 – 1.05 (m, 2H), 0.78 (dd, J = 6.5, 3.8 Hz,
1
3
6
H). C NMR (125 MHz, Methanolꢀd ) δ 183.6, 181.9, 172.9, 142.0, 135.9, 133.5, 133.1, 131.4,
4
1
31.3, 130.7, 130.2, 128.5, 128.4, 126.9, 126.6, 75.1, 58.0, 54.3, 49.8, 45.2, 41.9, 40.8, 26.8, 23.6,
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3.4, 22.2, 18.1, 15.5.LRMS (ESI+APCI) m/z: 554.2. HRMS (ESIꢀTOF) m/z: [M + H] Calcd for
NiO 554.1715; Found 554.1720.
Nickel(II)ꢀ(R)ꢀNꢀ(2ꢀbenzoylꢀ4ꢀchlorophenyl)ꢀ1ꢀethylꢀ2ꢀmethylpyrrolidineꢀ2ꢀcarboxamide/(S)ꢀ
ꢀ(aminomethyl)ꢀ3ꢀmethylbutanoic acid Schiff Base Complex ((R)(2S)ꢀ15h)
C
28
H
35ClN
3
3
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
20
1
Brown solid (43.7 mg, yield 81%). mp 130ꢀ132 C. [α]
400 MHz, Methanolꢀd ) δ 8.18 (d, J = 9.1 Hz, 1H), 7.61 – 7.53 (m, 3H), 7.46 – 7.39 (m, 1H),
.29 (dd, J = 9.1, 2.6 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.66 (d, J = 2.6 Hz, 1H), 4.03 – 3.87 (m,
D 3
= ꢀ3241.0 (c = 0.034, CHCl ). H NMR
(
4
7
2H), 3.85 – 3.74 (m, 1H), 3.24 – 3.16 (m, 2H), 2.60 – 2.46 (m, 2H), 2.41 – 2.32 (m, 3H), 2.14 –
2.08 (m, 1H), 1.95 – 1.87 (m, 4H), 1.26 (s, 3H), 0.72 (d, J = 6.9 Hz, 3H), 0.65 (d, J = 7.1 Hz, 3H).
13
4
C NMR (125 MHz, Methanolꢀd ) δ 183.6, 181.0, 173.1, 142.1, 135.7, 133.4, 133.1, 131.5, 130.6,
1
30.2, 128.6, 128.5, 126.9, 126.6, 75.1, 54.3, 54.0, 53.1, 49.8, 42.0, 29.7, 23.4, 20.9, 18.1, 17.9,
+
1
5.5. LRMS (ESI+APCI) m/z: 539.9. HRMS (ESIꢀTOF) m/z: [M + H] Calcd for
27 3 3
C H33ClN NiO 540.1558; Found 540.1566.
Nickel(II)ꢀ(R)ꢀNꢀ(2ꢀbenzoylꢀ4ꢀchlorophenyl)ꢀ1ꢀethylꢀ2ꢀmethylpyrrolidineꢀ2ꢀcarboxamide/(S)ꢀ
3ꢀaminoꢀ2ꢀcyclohexylpropanoic acid Schiff Base Complex ((R)(2S)ꢀ15i)
o
20
1
Brown solid (48.7 mg, yield 84%). mp 145ꢀ147 C. [α]
400 MHz, Methanolꢀd ) δ 8.18 (d, J = 9.1 Hz, 1H), 7.66 – 7.51 (m, 3H), 7.42 – 7.37 (m, 1H),
.28 (dd, J = 9.1, 2.6 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.65 (d, J = 2.6 Hz, 1H), 4.02 – 3.69 (m,
H), 3.26 – 3.03 (m, 2H), 2.65 – 2.50 (m, 1H), 2.41 – 2.32 (m, 2H), 2.27 – 2.19 (m, 1H), 2.14 –
D 3
= ꢀ3161.8 (c = 0.034, CHCl ). H NMR
(
4
7
2
1
3
2.05 (m, 1H), 1.96 – 1.54 (m, 8H), 1.46 – 0.54 (m, 11H). C NMR (125 MHz, Methanolꢀd
4
) δ
183.6, 180.9, 173.0, 142.0, 135.7, 133.5, 133.0, 131.5, 131.4, 130.6, 130.2, 128.6, 128.4, 126.9,
1
26.6, 75.1, 54.8, 54.3, 52.9, 49.9, 41.9, 40.2, 32.5, 29.3, 27.8, 27.6, 27.2, 23.3, 18.0, 15.5. LRMS
+
(
ESI+APCI) m/z: 580.2. HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C30
H37ClN
3
NiO
3
580.1871;
Found 580.1876.
Nickel(II)ꢀ(R)ꢀNꢀ(2ꢀbenzoylꢀ4ꢀchlorophenyl)ꢀ1ꢀethylꢀ2ꢀmethylpyrrolidineꢀ2ꢀcarboxamide/(S)ꢀ
2ꢀ(aminomethyl)ꢀ3,3ꢀdimethylbutanoic acid Schiff Base Complex ((R)(2S)ꢀ15j)
o
20
1
Brown solid (38.2 mg, yield 69%). mp = 136ꢀ137 C. [α]
= ꢀ3670.0 (c = 0.048, CHCl ). H
D
3
NMR (400 MHz, Methanolꢀd
4
) δ 8.21 (d, J = 9.1 Hz, 1H), 7.63 – 7.58 (m, 2H), 7.56 – 7.52 (m,
1
H), 7.42 – 7.37 (m, 1H), 7.29 (dd, J = 9.1, 2.6 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.67 (d, J = 2.6
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Hz, 1H), 4.27 (t, J = 12.5 Hz, 1H), 4.07 – 3.97 (m, 1H), 3.93 – 3.84 (m, 1H), 3.33 (d, J = 4.7 Hz,
1H), 3.13 (dd, J = 10.9, 7.8 Hz, 1H), 2.66 (dq, J = 15.0, 7.5 Hz, 1H), 2.44 – 2.34 (m, 2H), 2.28 (dq,
J = 14.1, 7.1 Hz, 1H), 2.07 (dd, J = 12.5, 4.7 Hz, 1H), 2.03 – 1.95 (m, 1H), 1.89 (t, J = 7.3 Hz, 3H),
1
3
1
1
4
4
.24 (s, 3H), 0.84 (s, 9H). C NMR (125 MHz, Methanolꢀd ) δ 183.8, 181.5, 173.1, 142.3, 135.6,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
9
0
1
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3
4
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9
0
33.5, 133.2, 131.7, 131.7, 130.6, 130.1, 128.8, 128.6, 126.9, 126.5, 74.9, 57.8, 56.4, 55.0, 49.5,
2.2, 33.9, 28.5, 23.7, 18.1, 15.5. LRMS (ESI+APCI) m/z: 655.8. HRMS (ESIꢀTOF) m/z: [M +
+
H] Calcd for C28
H
35ClN
3
NiO
3
554.1715; Found 554.1728.
Nickel(II)ꢀ(R)ꢀNꢀ(2ꢀbenzoylꢀ4ꢀchlorophenyl)ꢀ1ꢀethylꢀ2ꢀmethylpyrrolidineꢀ2ꢀcarboxamide/(S)ꢀ
3ꢀaminoꢀ2ꢀphenylpropanoic acid Schiff Base Complex ((R)(2S)ꢀ15k)
o
20
1
Brown solid (41.9 mg, yield 73%). mp 150ꢀ151 C. [α]
D 3
= ꢀ3648.0 (c = 0.05, CHCl ). H NMR
(
400 MHz, Methanolꢀd ) δ 8.20 (d, J = 9.1 Hz, 1H), 7.66 – 7.52 (m, 3H), 7.46 (t, J = 7.6 Hz, 1H),
4
7
6
.31 (dd, J = 9.1, 2.6 Hz, 1H), 7.28 – 7.16 (m, 3H), 7.10 – 7.03 (m, 2H), 6.91 (d, J = 7.7 Hz, 1H),
.69 (d, J = 2.6 Hz, 1H), 4.34 (t, J = 13.0 Hz, 1H), 3.89 – 3.86 (m, 2H), 3.53 (dd, J = 11.8, 3.5 Hz,
1H), 3.29 – 3.97 (m, 1H), 3.15 (dd, J = 13.0, 3.6 Hz, 1H), 2.65 – 2.56 (m, 1H), 2.46 – 2.29 (m,
1
3
3H), 1.99 – 1.90 (m, 4H), 1.27 (s, 3H). C NMR (125 MHz, Methanolꢀd
4
) δ 183.7, 180.1, 173.3,
1
1
42.2, 139.1, 135.8, 133.7, 133.2, 131.6, 131.4, 130.6, 130.1, 129.8, 129.1, 128.5, 128.4, 128.4,
26.9, 126.7, 75.2, 60.1, 54.5, 54.3, 49.9, 41.9, 23.5, 18.1, 15.5. LRMS (ESI+APCI) m/z: 574.1.
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H ClN NiO 574.1402; Found 574.1405.
30
31
3
3
Nickel(II)ꢀ(R)ꢀNꢀ(2ꢀbenzoylꢀ4ꢀchlorophenyl)ꢀ1ꢀethylꢀ2ꢀmethylpyrrolidineꢀ2ꢀcarboxamide/(S)ꢀ
ꢀaminoꢀ2ꢀ(4ꢀmethoxyphenyl)propanoic acid Schiff Base Complex ((R)(2S)ꢀ15l)
3
o
20
1
Brown solid (39.3 mg, yield 65%). mp = 146ꢀ148 C. [α]
= ꢀ3052.4 (c = 0.042, CHCl ). H
D
3
NMR (400 MHz, Methanolꢀd
4
) δ 8.19 (d, J = 9.1 Hz, 1H), 7.68 – 7.52 (m, 3H), 7.48 (t, J = 7.5 Hz,
H), 7.31 (dd, J = 9.1, 2.6 Hz, 1H), 7.01 – 6.95 (m, 2H), 6.93 (d, J = 7.7 Hz, 1H), 6.84 – 6.77 (m,
H), 6.69 (d, J = 2.6 Hz, 1H), 4.29 (t, J = 12.9 Hz, 1H), 3.91 – 3.78 (m, 2H), 3.73 (s, 3H), 3.48 (dd,
1
2
J = 11.7, 3.6 Hz, 1H), 3.29 – 3.23 (m, 1H), 3.12 (dd, J = 13.0, 3.6 Hz, 1H), 2.64 – 2.56 (m, 1H),
13
2.44 – 2.34 (m, 3H), 1.95 (q, J = 10.3, 8.7 Hz, 4H), 1.27 (s, 3H). C NMR (125 MHz,
Methanolꢀd ) δ 183.7, 180.6, 173.3, 160.4, 142.2, 135.8, 133.7, 133.2, 131.6, 131.4, 131.0, 130.6,
30.1, 128.5, 128.5, 126.9, 126.6, 115.2, 75.2, 60.2, 55.7, 54.4, 53.5, 49.9, 41.9, 23.5, 18.1, 15.5.
4
1
+
LRMS (ESI+APCI) m/z: 604.1. HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C31
3 4
H33ClN NiO
604.1508; Found 604.1518.
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Nickel(II)ꢀ(R)ꢀNꢀ(2ꢀbenzoylꢀ4ꢀchlorophenyl)ꢀ1ꢀethylꢀ2ꢀmethylpyrrolidineꢀ2ꢀcarboxamide/(S)ꢀ
3ꢀaminoꢀ2ꢀ(4ꢀchlorophenyl)propanoic acid Schiff Base Complex ((R)(2S)ꢀ15m)
o
20
1
Brown solid (42.0 mg, yield 69%). mp = 130ꢀ132 C. [α]
NMR (400 MHz, Methanolꢀd ) δ 8.20 (d, J = 9.1 Hz, 1H), 7.65 – 7.44 (m, 4H), 7.31 (dd, J = 9.1,
.6 Hz, 1H), 7.28 – 7.23 (m, 2H), 7.08 – 7.01 (m, 2H), 6.93 (d, J = 7.7 Hz, 1H), 6.69 (d, J = 2.6
Hz, 1H), 4.35 (t, J = 12.5 Hz, 1H), 3.97 – 3.81 (m, 2H), 3.54 (dd, J = 12.0, 3.4 Hz, 1H), 3.29 –
.27 (m, 1H), 3.12 (dd, J = 12.9, 3.5 Hz, 1H), 2.63 – 2.50 (m, 1H), 2.46 – 2.31 (m, 3H), 1.98 –
D 3
= ꢀ3312.5 (c = 0.048, CHCl ). H
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
1
3
1.90 (m, 4H), 1.27 (s, 3H). C NMR (125 MHz, Methanolꢀd ) δ 183.7, 179.6, 173.4, 142.2, 137.8,
4
135.7, 134.2, 133.7, 133.3, 131.6, 131.4, 130.8, 130.7, 130.1, 129.8, 128.6, 128.4, 127.0, 126.7,
75.2, 59.8, 54.4, 49.5, 41.9, 23.5, 18.1, 15.5. LRMS (ESI+APCI) m/z: 608.0. HRMS (ESIꢀTOF)
+
m/z: [M + H] Calcd for C H Cl N NiO 608.1012; Found 608.1027.
30
30
2
3
3
Nickel(II)ꢀ(R)ꢀNꢀ(2ꢀbenzoylꢀ4ꢀchlorophenyl)ꢀ1ꢀethylꢀ2ꢀmethylpyrrolidineꢀ2ꢀcarboxamide/(S)ꢀ
ꢀaminoꢀ2ꢀ(naphthalenꢀ1ꢀyl)propanoic acid Schiff Base Complex ((R)(2S)ꢀ15n)
3
o
20
1
Brown solid (47.4 mg, yield 76%). mp = 146ꢀ147 C. [α]
NMR (400 MHz, Methanolꢀd ) δ 8.21 (d, J = 9.1 Hz, 1H), 7.80 – 7.72 (m, 3H), 7.65 (d, J = 4.6 Hz,
H), 7.58 – 7.37 (m, 5H), 7.32 (dd, J = 9.1, 2.6 Hz, 1H), 7.18 (dd, J = 8.5, 1.8 Hz, 1H), 6.89 (dd, J
D 3
= ꢀ3440.0 (c = 0.046, CHCl ). H
4
2
=
7.8, 1.4 Hz, 1H), 6.70 (d, J = 2.6 Hz, 1H), 4.45 (t, J = 12.9, 11.8 Hz, 1H), 3.92 – 3.79 (m, 2H),
3
.71 (dd, J = 11.7, 3.5 Hz, 1H), 3.38 – 3.32 (m, 1H), 3.22 (dd, J = 13.0, 3.5 Hz, 1H), 2.69 – 2.53
13
(
m, 1H), 2.48 – 2.27 (m, 3H), 2.02 – 1.87 (m, 4H), 1.26 (s, 3H). C NMR (125 MHz, Methanolꢀd
4
)
δ 183.7, 180.1, 173.4, 142.2, 136.4, 135.8, 134.9, 134.0, 133.7, 133.3, 131.6, 131.4, 130.6, 130.1,
129.5, 128.7, 128.6, 128.5, 128.5, 128.2, 127.3, 127.0, 127.0, 126.9, 126.7, 75.2, 60.0, 54.4, 54.4,
+
4
9.9, 41.9, 23.5, 18.1, 15.5.LRMS(ESI+APCI) m/z: 624.1. HRMS (ESIꢀTOF) m/z: [M + H]
Calcd for C34 NiO 624.1558; Found 624.1576.
S)ꢀ3ꢀAminoꢀ2ꢀbenzylpropanoic acid ((S)ꢀ2a)
H33ClN
3
3
(
A solution of (R)(2S)ꢀ15a (1.50 g, 2.55 mmol) in MeOH (20 mL) was added to a stirring solution
of 3N HCl in MeOH (1/1, v/v) 40 mL at 50 °C. The mixture was gently heated under reflux for 30
min, the solution was evaporated to dryness. Water (50 mL) was added, and the resultant mixture
was treated with an excess of concentrated NH OH and extracted with CH Cl . The CH Cl
4
2
2
2
2
2 4
extracts were dried (Na SO ) and evaporated under vacuum to afford the free chiral ligand (R)ꢀ9
(930 mg, yield 98%). The aqueous phase was evaporated under vacuum and dissolved in a
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minimum amount of H O and loaded on a Dowex 50×2 100 ionꢀexchange column, which was
2
washed with H
2 4
O until neutral. The column was then washed with 10% aq NH OH. The first
fraction (400 mL) was collected and evaporated under vacuum to afford the corresponding amino
o
20
acid (S)ꢀ2a as a white solid (425 mg, yield 93%). mp = 208ꢀ210 C. [α]
D
= ꢀ 16.5 (c = 1, 1 M
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
25
D
1
HCl). [ref.[38] [α]
= ꢀ 16.0 (c = 1, 1 M HCl)]. H NMR (400 MHz, D
2
O) δ 7.39 – 7.16 (m, 5H),
13
3
3
.08 – 2.69 (m, 5H). C NMR (100 MHz, D
2
O) δ 181.5, 140.4, 130.8, 130.5, 128.6, 49.0, 42.5,
+
8.0. LRMS (ESI+APCI) m/z: 180.1. HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C10
H14NO
2
180.1019; Found 180.1014.
Supporting Information
Xꢀray crystal structures of (S)(2R)ꢀ10a and (S)(2S)ꢀ10a.
1
H NMR spectra for dr value determination of 10aꢀ15a and 15bꢀ15n.
HPLC spectra for ee value determination of (S)ꢀ2a and (R)ꢀ9.
1
13
H and C NMR spectra for all compounds.
Acknowledgments
We gratefully acknowledge financial support from the National Natural Science Foundation
of China (81620108027, 21632008, 21672231, and 21472209), the Major Project of Chinese
National Programs for Fundamental Research and Development (2015CB910304).
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