Molecules 2014, 19(1), 826-845; doi:10.3390/molecules19010826

Article
Diastereoselective Three-Component Reactions of Chiral Nickel(II) Glycinate for Convenient Synthesis of Novel α-Amino-β-Substituted-γ,γ-Disubstituted Butyric Acids
Rui Zhou 1, Li Guo 1, Cheng Peng 2, Gu He 1,*, Liang Ouyang 1 and Wei Huang 1,2,*
1
State Key Laboratory of Biotherapy, West China Hospital, and West China School of Pharmacy, Sichuan University, Chengdu 610041, Sichuan, China; E-Mails: sklb_zhourui@126.com (R.Z.); guoli@scu.edu.cn (L.G.); ouyangliang@scu.edu.cn (L.O.)
2
State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610041, Sichuan, China; E-Mail: pengchengchengdu@126.com
*
Authors to whom correspondence should be addressed; E-Mails: hegu@scu.edu.cn (G.H.); huangwei@cdutcm.edu.cn (W.H.); Tel./Fax: +86-28-8550-3817 (G.H.).
Received: 9 December 2013; in revised form: 20 December 2013 / Accepted: 25 December 2013 /
Published: 10 January 2014

Abstract

: The convenient, high yielding and diastereoselective synthesis of α-amino-β-substituted-γ,γ-disubstituted butyric acid derivatives was carried out by a three-component tandem reaction of a chiral equivalent of nucleophilic glycine. The reaction was performed smoothly under mild conditions and enabled the construction of two or three adjacent chiral centers in one step, thus affording a novel and convenient route to α-amino-β-substituted-γ,γ-disubstituted butyric acid derivatives.
Keywords:
multi-component reaction; nickel(II); glycine; diastereoselectivity; unnatural amino acids

1. Introduction

Chiral α-amino-γ,γ-disubstituted fragments are frequently found in various bioactive compounds, such as anti-infective agents (compound 1), anti-tuberculosis agents (compound 2), modulators of RNA binding proteins (compound 3) and compositions for specific inhibition of protein splicing by small molecules, and used in the treatment of tuberculosis and other conditions (compound 4) (Figure 1) [1,2,3,4]. Catalytic diastereoselective synthesis of these chiral α-amino-β-substituted butyric acid derivatives rely on many reactions, for example, addition of α,β-unsaturated acyloxazolidinones, then the removal of the oxazolidinone portions [5], cycloaddition of chiral nitrones with (E)-1,4-dichlorobut-2-ene, followed by acid-catalyzed hydrolysis and then by amide hydrolysis [6], but the Michael addition should be considered the main method to get these products when a chiral equivalent of glycine is used. Indeed, several examples of such reactions using chiral auxiliaries have been reported [7,8,9,10,11,12,13,14,15]. However, to our knowledge, there are no reports about the synthesis of chiral α-amino-β-substituted-γ,γ-disubstituted butyric acid derivatives.

Molecules 19 00826 g001 200
Figure 1. Structures of some biologically important compounds containing α-amino-β-substituted γ,γ- disubstituted butyric acid motifs.

Click here to enlarge figure

Figure 1. Structures of some biologically important compounds containing α-amino-β-substituted γ,γ- disubstituted butyric acid motifs.
Molecules 19 00826 g001 1024

The chiral Ni(II) complex of the Schiff base of glycine (abbreviated as (S)-BPB) is commonly used in the asymmetric syntheses of unnatural amino acids. Product mixtures with a high excess of the (S)-amino acid diastereomer are always generated by the addition using (S)-BPB as a ligand [16,17,18]. The products can be easily isolated by column chromatography, and decomposed by acid to get chiral pure amino acids. Moreover, the recovery of (S)-BPB can be high (up to 85%). To the best of our knowledge, a variety of glutamic acid and proline derivatives with a high ee values can be synthesized through Michael additions of activated olefins to Ni(II) glycinate [19,20,21]. Recently, Liu et al. reported the efficient synthesis of β-substituted α,γ-diaminobutyric acid derivatives using asymmetric Michael addition reactions of chiral nickel(II) glycinate with nitroalkenes [22,23,24,25,26,27], Schneider et al. reported the stereoselectivity synthesis of γ-carboxyglutamic acids using asymmetric Michael addition reactions of chiral copper(II) glycinate with di-tert-butyl methylenemalonate [28]. This report focuses on the synthesis of α-amino-β-substituted-γ,γ-disubstituted butyric acid derivatives through the reaction of aromatic aldehydes, a chiral Ni(II) glycinate complex, and an α-carbanion of two electron-withdrawing groups (malononitrile or ethyl cyanoacetate) as a continuation of our previous research on new methods for the preparation of potentially bioactive compounds by multi-component reactions [29,30,31,32,33]. In the process, two carbon-carbon bonds were constructed and two or three chiral centers were generated in a convenient one-pot reaction with a high stereoselectivity.

2. Results and Discussion

The Michael addition reaction was considered as an effective way to get the products. Firstly, the optimization of the reaction conditions was undertaken using a model reaction of chiral nickel(II) glycinate with 2-benzylidenemalononitrile (Table 1). The reaction with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine(TEA), 4-methylmorpholine (NMM) and piperidine gave a little lower diastereoselectivities (Entries 1–5, Table 1) than Hunig’s base (DIEA) did, and all the reactions gave satisfactory yields, except the one in NMM.

Table 1. Optimization of the reaction conditions a. Molecules 19 00826 i001

Click here to display table

Table 1. Optimization of the reaction conditions a. Molecules 19 00826 i001
EntryBaseSolventYield (%) b de c
1DBU dCH3CN9488%
2TEACH3CN9794%
3DIEACH3CN9496%
4NMMCH3CN6392%
5PiperidineCH3CN8996%
6DIEADMF9988%
7DIEAEA9880%
8DIEAMeOH9988%
9DIEADCM9758%
10DIEAdioxane9197%
11DIEACHCl35990%
12DIEADMSO9176%

a All the reactions were conducted at ambient temperature; b Yield of the major products after silica gel column chromatography; c Determined by HPLC analysis; d DBU was used in 0.15 equiv.; and other bases were used in 3 equiv.

The reaction proceeded smoothly in most of the solvents tested, although the one in chloroform gave a bad yield and the one in dichloromethane (DCM) gave poor diastereoselectivity. Good diastereoselectivities and yields were observed with the use of acetonitrile, N,N-dimethylformamide (DMF), ethyl acetate (EA), methanol, dioxane and dimethyl sulfoxide (DMSO). Above all, diastereoselectivity was not obviously influenced by the kind of the bases used, and polar solvents seemed to be better than nonpolar ones. As 2-benzylidenemalononitrile can be easily generated from benzaldehyde and malononitrile under alkaline conditions, domino reaction of these three components was thought to be feasible. In fact, TLC showed that when these three components were mixed together under basic conditions, benzaldehyde first reacted quickly with malononitrile, then added to the nickel(II) glycinate and the product 7a appeared. The results showed no big difference with those in Table 1, so the substrate scope was investigated using DIEA as the base and dioxane as the solvent (entry 11, Table 1) without further optimization.

The aromatic aldehydes with substituents at different positions were introduced into this reaction (Table 2). Whether functionalized with either electron-withdrawing or electron-donating groups, these aldehydes gave the products in good to high yields. As the result obtained with malononitrile was inspiring, ethyl cyanoacetate was introduced into the reaction, and gave a satisfactory result, so the reactions with malononitrile and ethyl cyanoacetate could be looked as two series. The results of the ethyl cyanoacetate series seemed a little better than the malononitrile series on average, despite the fact three chiral centers are newly generated. In both series, the naphthyl-functionalized aldehydes had the best diastereoselectivities (Table 2, enties 9 and 10), and ortho-functionalized aromatic aldehydes gave relatively high yields and diastereoselectivities (Table 2, entries 12, 14 and 18). The results were quite different in this two series when t-Bu- and 3-Cl-substituted substrates were involved (Table 2, entries 2 and 22, 3 and 15). However, furaldehyde and thienaldehyde were not tolerated (Table 2, enties 13 and 14). To elucidate the relative and absolute configurations of the products, X-ray single crystal structures of (S,2S,3R)-7a (CCDC 951535) and (S,2S,3R,4S)-7q (CCDC 949234) are given below (Figure 2).

To further confirm the structure, diastereoselectivity and regioselectivity, detailed NMR spectral and X-ray analyses were carried out. The structures proposed for all products were in agreement with their NMR spectra, as discussed for compounds 7a and 7q as examples. In the 1H-NMR spectrum of 7a and 7q, the α-C proton of glycine exhibited double(d) peaks at δ 4.57 (d, J = 4 Hz, 1H) and δ 4.60 (d, J = 3.6 Hz, 1H), respectively. The α-C proton of malononitrile in 7a appeared as a doublet at δ 5.19 (d, J = 12 Hz, 1H), and the corresponding proton of ethyl cyanoacetate in 7q appeared as a doublet at δ 4.51 (d, J = 12.1 Hz, 1H). The relative configuration of these structures should be as same as compound 7a and 7q shown in Figure 2a,c, the configurations were further confirmed by the X-ray study of single crystals (Figure 2b,d). The 13C-NMR of compound 4b supported the proposed structure as well.

A plausible mechanism for the high diastereoselectivity of the reaction could be explained as follows (Scheme 1): malononitrile or cyanide ethyl acetate first reacted with aromatic aldehyde, and the intermediate formed continued to react with the complex. When (S)-N-benzylproline was used, the benzyl group was on a certain side of this complex, so the steric hindrance was large on this side, and the intermediate would prefer attacking from the other side. Still, steric hindrance from the phenyl groups of the intermediate could contribute to the diasteroselectivity, this may explain why naphthaldehydes provided a high de value. As the diastereoselectivity was mainly controlled by the substrates, the reaction was easy to carry, making it a convenient way to get chiral α-amino-β-substituted-γ,γ-disubstituted butyric acid derivatives.

Table 2. Asymmetric Michael reactions of chiral nickel(II) glycinate (S)-5 with aromatic aldehydes and α-carbanions a. Molecules 19 00826 i002

Click here to display table

Table 2. Asymmetric Michael reactions of chiral nickel(II) glycinate (S)-5 with aromatic aldehydes and α-carbanions a. Molecules 19 00826 i002
EntryProductREWGYield (%) bde c
1(S,2S,3R)-7aPhCN9197%
2(S,2S,3R)-7b4-(t-Bu)-C6H4CN86>99%
3(S,2S,3R)-7c3-Cl-C6H4CN5290%
4(S,2S,3R)-7d4-F-C6H4CN8393%
5(S,2S,3R)-7e4-Br-C6H4CN4498%
6(S,2S,3R)-7f3,4-di-Cl-C6H3CN8497%
7(S,2S,3R)-7g3-Br-C6H4CN3895%
8(S,2S,3R)-7h3-OMe-C6H4CN82>99%
9(S,2S,3R)-7i2-naphthylCN8098%
10(S,2S,3R)-7j1-naphthylCN2698%
11(S,2S,3R)-7k3-OH-C6H4CN4698%
12(S,2S,3R)-7l2-F-4-Br-C6H3CN90>99%
13(S,2S,3R,4S)-7mPhCOOEt7898%
14(S,2S,3R,4S)-7n2-Br-C6H4COOEt88>99%
15(S,2S,3R,4S)-7o3-Cl-C6H4COOEt8997%
16(S,2S,3R,4S)-7p4-F-C6H4COOEt7596%
17(S,2S,3R,4S)-7q3,4-di-Cl-C6H3COOEt8298%
18(S,2S,3R,4S)-7r2,4-di-Cl-C6H3COOEt9698%
19(S,2S,3R,4S)-7s4-CH3-C6H4COOEt76>99%
20(S,2S,3R,4S)-7t4-OCH3-C6H4COOEt7797%
21(S,2S,3R,4S)-7u4-NO2-C6H4COOEt6997%
22(S,2S,3R,4S)-7v4-(t-Bu)-C6H4COOEt5197%
23(S,2S,3R,4S)-7w1-naphthylCOOEt67>99%
24(S,2S,3R)-7x3-Br-thienylCNNR dNR d
25(S,2S,3R)-7y4-Me-FurylCNNR dNR d

a All the reactions were conducted at ambient temperature, 3 equiv. of all the bases were used; b Yield of the major products after silica gel column chromatography; c Determined by HPLC analysis; d Not Reaction.

Molecules 19 00826 g002 200
Figure 2. (a) Selected 1H- and 13C-NMR chemical shifts of (S,2S,3R)-7a; (b) Single crystal X-ray diffraction study of (S,2S,3R)-7a; (c) Selected 1H- and 13C-NMR chemical shifts of (S,2S,3R,4S)-7q and (d) Single crystal X-ray diffraction study of (S,2S,3R,4S)-7q.

Click here to enlarge figure

Figure 2. (a) Selected 1H- and 13C-NMR chemical shifts of (S,2S,3R)-7a; (b) Single crystal X-ray diffraction study of (S,2S,3R)-7a; (c) Selected 1H- and 13C-NMR chemical shifts of (S,2S,3R,4S)-7q and (d) Single crystal X-ray diffraction study of (S,2S,3R,4S)-7q.
Molecules 19 00826 g002 1024

With high diastereoselectivities and mild reaction conditions, the synthesis of (2S,3R)-8a (Scheme 2) was completed by optimizing the metal complex decomposition and Fmoc-protection conditions. Typically, the compound (S,2S,3R)-7a was decomposed by heating a suspension in methanol/6N HCl. However, we found that one of the nitrile groups was partly hydrolyzed in this process, so suitable conditions were sought to ensure that the nitrile groups remain inert. When we stirred (S,2S,3R)-7a in THF with a 3N concentration HCl at ambient temperature, the complex was decomposed and the nitrile group preserved (Scheme 2). The chiral ligand (S)-BPB can be easily recovered quantitatively. (2S,3R)-8a was synthesized after (S,2S,3R)-7a was decomposed, the (S)-BPB was extracted with ethyl acetate (EA) and the α-amino-β-substituted γ,γ-disubstituted butyric acid product was protected by a Fmoc group. Ultimately, the yield of (S,2R)-5a from (S,2S,3R)-7a was 62% over two steps.

Molecules 19 00826 g003 200
Scheme 1. Asymmetric domino reactions of chiral nickel(II) glycinate (S)-5 with aromatic aldehydes and α-carbanion.

Click here to enlarge figure

Scheme 1. Asymmetric domino reactions of chiral nickel(II) glycinate (S)-5 with aromatic aldehydes and α-carbanion.
Molecules 19 00826 g003 1024
Molecules 19 00826 g004 200
Scheme 2. Decomposition of Ni(II) complex 7a to release product 8a and recovery of the (S)-BPB.

Click here to enlarge figure

Scheme 2. Decomposition of Ni(II) complex 7a to release product 8a and recovery of the (S)-BPB.
Molecules 19 00826 g004 1024

3. Experimental

3.1. General

The reagents (chemicals) were purchased from commercial sources, and used without further purification. Analytical thin layer chromatography (TLC) was GF254 (0.15–0.2 mm thickness). The mass spectra and high resolution mass spectra were obtained using Bruker microTOF-Q instrument or TOF-MS instrument. The 1H- and 13C-NMR spectra have been respectively measured in CDCl3 or DMSO-d6 at 400 and 100 MHz using a Bruker Avance III 400 MHz instrument with TMS as an internal standard. Analytical high performance liquid chromatography was carried out using the Waters Alliance 2695 HPLC, using the Chiralpak IA column. The loading loop was 10 μL. The eluting employed was an isocratic mixture of n-hexane and i-propanol (50:50 respectively) at a flow of 1 mL/min unless stated. Retention times are reported in minutes. The enantiomeric excess was calculated from the integration of the absorption peaks at 220 nm.

3.2. Typical Procedure for the Synthesis of (S)-Nickel(II) Complex (5) [18]

(S)-BPB (1 g, 2.60 mmol), Ni(NO3)2·6H2O (1.52 g, 5.21 mmol) and glycine (976 mg, 13.0 mmol) were stirred in MeOH (50 mL). Then NaH (55%–65% in oil, 1.04 g, 26 mmol) and KOH (437 mg, 7.81 mmol) were added successively. The mixture was refluxed for 2 h then cooled to room temperature and neutralized with acetic acid. After 12 h the precipitate was filtered and washed with ethanol (100 mL), followed by stirring in methane/water (v/v) 1:2 (200 mL), then filtered to form a red crystalline solid (1.27 g, yield 98%). The complex was sufficiently pure for further use without additional purification.

3.3. General Procedure for the Synthesis of Ni(II) (7)

The nickel(II) complex of glycine (S)-5 (1.0 equiv.) was dissolved in dioxane, and DIEA (3.0 equiv.), aromatic aldehyde (1.2 equiv.) and malononitrile/ethyl cyanoacetate (1.2 equiv.) was added at room temperature. The mixture was then stirred at room temperature for 12 h, then poured into 10% citric acid solution, extracted with CH2Cl2 (three times), dried with anhydrous Na2SO4, concentrated, and purified on silica (petroleum ether/ethyl acetate = 1/1) to give 7 as a red solid.

3.3.1. Ni(II)-(S)-BPB/(2S,3R)-2-Amino-4,4'-dicyano-3-phenylbutyric Acid Schiff Base Complex (7a)

Yield = 91%, m.p. 202–204 °C. Molecules 19 00826 i003 = +1602 (ca. 0.2 g/100 mL, CHCl3). 1H-NMR (CDCl3) δ 8.25 (d, J = 8 Hz, 1H), 7.98 (d, J = 8 Hz, 2H), 7.68–7.63 (m, 6H), 7.39 (d, J = 8 Hz, 1H), 7.30–7.26 (m, 4H), 7.18–7.14 (m, 3H), 6.70 (d, J = 4 Hz, 1H), 5.19 (d, J = 12 Hz, 1H), 4.57 (d, J = 4 Hz, 1H), 4.15 (d, J = 12 Hz, 1H), 3.42 (d, J = 12 Hz, 1H), 3.29–3.21 (m, 2H), 2.97–2.91 (m, 1H), 2.32–2.20 (m, 1H), 2.06–2.02 (m, 1H), 1.95–1.91 (m, 1H), 1.85–1.83 (m, 1H), 1.56–1.50 (m, 1H). 13C-NMR (CDCl3) δ 180.2, 176.2, 173.5, 143.4, 133.9, 133.5, 133.2, 132.6, 131.4, 130.9, 130.6, 130.1, 129.9, 129.5, 128.9, 128.9, 127.5, 127.0, 125.5, 123.3, 120.8, 111.5, 111.3, 70.5, 69.7, 63.9, 57.4, 48.8, 29.7, 24.7, 23.1. ESI-MS (m/z): calcd. 652.2, found 652.2 ([M+H]+); HRMS (m/z): calcd. C37H32N5NiO3 for 652.1859, found 652.1857 ([M+H]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor = 32.3 min, tminor = 13.4 min, de = 97%.

3.3.2. Ni(II)-(S)-BPB/(2S,3R)-2-Amino-4,4'-dicyano-3-(4-tert-butyl)-phenylbutyric Acid Schiff Base Complex (7b)

Yield = 86%, m.p. 197–199 °C. Molecules 19 00826 i003 = +1602 (ca. 0.2 g/100 mL, CHCl3). 1H-NMR (CDCl3) δ 8.29 (d, J = 8.7 Hz, 1H), 7.95 (d, J = 7.5 Hz, 2H), 7.68 (dt, J = 13.0, 6.8 Hz, 3H), 7.60 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 7.2 Hz, 1H), 7.29 (dd, J = 14.5, 7.1 Hz, 3H), 7.19 (d, J = 7.9 Hz, 3H), 7.16–7.09 (m, 2H), 6.70 (d, J = 2.9 Hz, 2H), 5.16 (d, J = 12.0 Hz, 1H), 4.58 (d, J = 3.4 Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.79 (s, 1H), 3.49 (d, J = 12.7 Hz, 1H), 3.28–3.13 (m, 2H), 3.05–2.90 (m, 1H), 2.29–2.13 (m, 1H), 2.12–2.00 (m, 1H), 1.92 (dt, J = 27.0, 8.6 Hz, 1H), 1.78 (dt, J = 18.9, 9.3 Hz, 1H), 1.54 (s, 1H), 1.46–1.31 (m, 9H). 13C-NMR (CDCl3) δ 180.2, 176.3, 173.3, 160.9, 143.2, 133.9, 133.4, 133.3, 133.2, 131.4, 130.8, 130.5, 129.4, 128.9, 128.8, 127.4, 127.0, 125.6, 124.1, 123.2, 120.8, 115.2, 111.6, 111.3, 70.6, 69.8, 64.0, 57.6, 55.4, 48.1, 30.5, 24.7, 22.9. ESI-MS (m/z): calcd. 708.2, found 708.3 ([M+H]+); HRMS (m/z): calcd. C41H40N5NiO3 for 708.2485, found 708.2482 ([M+H]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor = 30.9 min, tminor = 17.3 min, de > 99%.

3.3.3. Ni(II)-(S)-BPB/(2S,3R)-2-Amino-4,4'-dicyano-3-(3-chlorophenyl) Butyric Acid Schiff Base Complex (7c)

Yield = 52%, m.p. 211–213 °C. Molecules 19 00826 i003 = +1622 (ca. 0.2 g/100 mL, CHCl3). 1H-NMR (CDCl3) δ 8.27 (d, J = 8.7 Hz, 1H), 8.00 (d, J = 7.5 Hz, 2H), 7.75–7.60 (m, 4H), 7.55 (d, J = 15.7 Hz, 1H), 7.42–7.34 (m, 2H), 7.32 (dd, J = 14.6, 6.9 Hz, 3H), 7.22–7.09 (m, 4H), 6.70 (d, J = 3.7 Hz, 2H), 5.14 (d, J = 11.9 Hz, 1H), 4.56 (d, J = 3.8 Hz, 1H), 4.15 (d, J = 12.7 Hz, 1H), 3.43 (d, J = 12.6 Hz, 1H), 3.25 (ddd, J = 16.2, 10.7, 5.6 Hz, 2H), 3.02 (dd, J = 9.8, 5.5 Hz, 1H), 2.25 (dd, J = 18.6, 10.0 Hz, 1H), 2.10–1.98 (m, 3H), 1.70–1.63 (m, 1H). 13C-NMR (CDCl3) δ 180.2, 175.9, 173.7, 143.4, 136.3, 134.6, 133.9, 133.4, 133.4, 133.2, 131.3, 131.0, 131.0, 130.6, 130.4, 129.5, 129.0, 128.8, 127.4, 127.0, 125.4, 123.3, 120.8, 111.2, 110.9, 70.5, 69.4, 64.0, 57.6, 48.4, 30.7, 29.6, 24.6, 23.0. ESI-MS (m/z): calcd. 686.1, found 686.2 ([M+H]+). HRMS (m/z): calcd. C37H31ClN5NiO3 for 686.1469, found 686.1475 ([M+H]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor = 31.0 min, tminor = 13.0 min, de = 90%.

3.3.4. Ni(II)-(S)-BPB/(2S,3R)-2-Amino-4,4'-dicyano-3-(4-fluorophenyl)butyric Acid Schiff Base Complex (7d)

Yield = 83%, m.p. 207–209 °C. Molecules 19 00826 i003 = +1734 (ca. 0.2 g/100 mL, CHCl3). 1H-NMR (CDCl3) δ 8.25 (d, J = 8.6 Hz, 1H), 8.00 (d, J = 7.4 Hz, 2H), 7.73–7.62 (m, 3H), 7.34 (ddd, J = 14.8, 13.7, 7.2 Hz, 7H), 7.21–7.09 (m, 3H), 6.73–6.66 (m, 2H), 5.16 (d, J = 12.0 Hz, 1H), 4.55 (d, J = 3.7 Hz, 1H), 4.15 (d, J = 13.1 Hz, 1H), 3.48–3.37 (m, 1H), 3.32–3.22 (m, 2H), 3.02–2.90 (m, 1H), 2.33–2.23 (m, 1H), 2.13–2.05 (m, 1H), 1.97 (dd, J = 13.3, 7.4 Hz, 2H), 1.67–1.61 (m, 1H). 13C-NMR (CDCl3) δ 180.2, 176.1, 173.6, 165.1, 162.6, 143.3, 133.9, 133.4, 133.3, 133.2, 131.3, 131.2, 130.9, 130.6, 129.5, 129.0, 128.8, 128.4, 128.4, 127.3, 127.0, 125.4, 123.3, 120.8, 117.1, 116.9, 111.3, 111.0, 70.5, 69.6, 64.0, 57.5, 48.1, 30.6, 24.7, 22.9. ESI-MS (m/z): calcd. 670.2, found 670.2 ([M+H]+). HRMS (m/z): calcd. C37H31FN5NiO3 for 670.1764, found 670.1801 ([M+H]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor = 26.0 min, tminor = 10.1 min, de = 93%.

3.3.5. Ni(II)-(S)-BPB/(2S,3R)-2-amino-4,4'-dicyano-3-(4-bromophenyl) Butyric Acid Schiff Base Complex (7e)

Yield = 44%, m.p. 197–199 °C. Molecules 19 00826 i003 = +1972 (ca. 0.2 g/100 mL, CHCl3). 1H-NMR (CDCl3) δ 8.23 (d, J = 8.7 Hz, 1H), 8.01 (d, J = 7.4 Hz, 2H), 7.78–7.58 (m, 3H), 7.38 (d, J = 6.8 Hz, 1H), 7.29 (dd, J = 14.9, 7.4 Hz, 3H), 7.25–7.08 (m, 7H), 6.70 (d, J = 13.7 Hz, 2H), 5.14 (d, J = 12.0 Hz, 1H), 4.53 (d, J = 3.2 Hz, 1H), 4.15 (d, J = 12.7 Hz, 1H), 3.40 (d, J = 12.6 Hz, 1H), 3.31–3.18 (m, 2H), 2.99 (dd, J = 10.5, 6.0 Hz, 1H), 2.23 (dt, J = 24.1, 12.1 Hz, 1H), 2.13–2.02 (m, 1H), 2.02–1.87 (m, 2H), 1.55 (dd, J = 12.1, 6.5 Hz, 1H). 13C-NMR (CDCl3) δ 180.2, 176.3, 173.3, 160.9, 143.2, 133.9, 133.4, 133.3, 133.2, 131.4, 130.8, 130.5, 129.4, 128.9, 128.8, 127.4, 127.0, 125.6, 124.1, 123.2, 120.8, 115.2, 111.6, 111.3, 70.6, 69.8, 64.0, 57.6, 55.4, 48.1, 30.5, 24.7, 22.9. ESI-MS (m/z): calcd. 730.1, found 730.2 ([M+H]+). HRMS (m/z): calcd. C37H31BrN5NiO3 for 730.0966, found 730.0978 ([M+H]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor = 32.0 min, tminor = 15.3 min, de = 98%.

3.3.6. Ni(II)-(S)-BPB/(2S,3R)-2-Amino-4,4'-dicyano-3-(3,4-dichlorophenyl) Butyric Acid Schiff Base Complex (7f)

Yield = 84%, m.p. 213–215 °C. Molecules 19 00826 i003 = +1660 (ca. 0.2 g/100 mL, CHCl3). 1H-NMR (CDCl3) δ 8.27 (d, J = 8.7 Hz, 1H), 8.01 (d, J = 7.4 Hz, 2H), 7.69 (dd, J = 17.4, 7.8 Hz, 4H), 7.44 (s, 1H), 7.38 (d, J = 6.3 Hz, 1H), 7.31 (t, J = 7.4 Hz, 2H), 7.18 (dd, J = 15.9, 8.3 Hz, 2H), 7.09 (t, J = 7.8 Hz, 2H), 6.71 (d, J = 14.3 Hz, 2H), 5.15 (d, J = 11.9 Hz, 1H), 4.53 (s, 1H), 4.12 (dd, J = 17.0, 9.9 Hz, 1H), 3.42 (d, J = 12.6 Hz, 1H), 3.30 (t, J = 8.3 Hz, 1H), 3.22 (d, J = 11.9 Hz, 1H), 2.99 (d, J = 5.8 Hz, 1H), 2.33 (dd, J = 20.4, 8.8 Hz, 1H), 2.02 (qd, J = 13.8, 6.8 Hz, 3H), 1.77–1.66 (m, 1H). 13C-NMR (CDCl3) δ 180.2, 175.8, 173.8, 143.4, 135.0, 134.6, 134.0, 133.5, 133.3, 132.7, 131.7, 131.3, 131.1, 130.7, 129.6, 129.0, 128.9, 127.2, 126.9, 125.2, 123.3, 120.8, 111.1, 110.6, 70.5, 69.3, 64.1, 57.8, 48.0, 30.7, 24.4, 22.8. ESI-MS (m/z): calcd. 720.1, found 720.2 ([M+H]+); HRMS (m/z): calcd. C37H30Cl2N5NiO3 for 720.1079, found 720.1090 ([M+H]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor = 26.0 min, tminor = 12.5 min, de = 97%.

3.3.7. Ni(II)-(S)-BPB/(2S,3R)-2-Amino-4,4'-dicyano-3-(3-bromophenyl) Butyric Acid Schiff Base Complex (7g)

Yield = 38%, m.p. 208–210 °C. Molecules 19 00826 i003 = +1882 (ca. 0.2 g/100 mL, CHCl3). 1H-NMR (CDCl3) δ 8.28 (d, J = 8.7 Hz, 1H), 8.00 (d, J = 7.4 Hz, 2H), 7.80 (d, J = 8.0 Hz, 1H), 7.75–7.60 (m, 3H), 7.49 (t, J = 7.8 Hz, 2H), 7.39 (d, J = 6.7 Hz, 1H), 7.31 (t, J = 7.6 Hz, 2H), 7.24–7.08 (m, 4H), 6.70 (d, J = 4.0 Hz, 2H), 5.14 (d, J = 11.9 Hz, 1H), 4.55 (d, J = 3.7 Hz, 1H), 4.20–4.09 (m, 1H), 3.42 (d, J = 12.6 Hz, 1H), 3.25 (ddd, J = 15.7, 10.7, 5.6 Hz, 2H), 3.03 (dd, J = 10.0, 5.6 Hz, 1H), 2.25 (dt, J = 16.4, 8.4 Hz, 1H), 2.15–1.91 (m, 4H). 13C-NMR (CDCl3) δ 180.2, 176.3, 173.3, 160.9, 143.2, 133.9, 133.4, 133.3, 133.2, 131.4, 130.8, 130.5, 129.4, 128.9, 128.8, 127.4, 127.0, 125.6, 124.1, 123.2, 120.8, 115.2, 111.6, 111.3, 70.6, 69.8, 64.0, 57.6, 55.4, 48.1, 30.5, 24.7, 22.9. ESI-MS (m/z): calcd. 730.1, found 730.2 ([M+H]+); HRMS (m/z): calcd. C37H31BrN5NiO3 for 730.0966, found 730.0966 ([M+H]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor = 32.0, tminor = 14.0 min, de = 95%.

3.3.8. Ni(II)-(S)-BPB/(2S,3R)-2-Amino-4,4'-dicyano-3-(3-methoxyphenyl) Butyric Acid Schiff Base Complex (7h)

Yield = 82%, m.p. 222–224 °C. Molecules 19 00826 i003 = +1678 (ca. 0.2 g/100 mL, CHCl3). 1H-NMR (CDCl3) δ 8.18 (d, J = 8.7 Hz, 1H), 7.93 (d, J = 7.5 Hz, 2H), 7.59 (dd, J = 13.8, 7.2 Hz, 3H), 7.44 (t, J = 7.9 Hz, 1H), 7.32 (d, J = 6.9 Hz, 1H), 7.23 (t, J = 7.5 Hz, 2H), 7.07 (dd, J = 13.9, 6.8 Hz, 4H), 6.75 (d, J = 11.2 Hz, 2H), 6.62 (d, J = 4.0 Hz, 2H), 5.09 (d, J = 12.0 Hz, 1H), 4.47 (d, J = 3.4 Hz, 1H), 4.04 (dd, J = 15.5, 9.7 Hz, 1H), 3.71 (s, 3H), 3.34 (d, J = 12.6 Hz, 1H), 3.16 (dd, J = 16.1, 6.4 Hz, 2H), 2.89 (q, J = 10.2 Hz, 1H), 2.26–2.06 (m, 1H), 2.01 (dd, J = 13.8, 7.1 Hz, 1H), 1.87 (dd, J = 18.6, 6.4 Hz, 2H), 1.49 (dd, J = 14.2, 9.1 Hz, 1H). 13C-NMR (CDCl3) δ 180.1, 176.2, 173.3, 160.6, 143.3, 133.9, 133.8, 133.4, 133.3, 133.2, 131.4, 130.9, 130.9, 130.5, 129.4, 128.9, 128.8, 127.5, 127.0, 125.5, 123.2, 120.7, 115.7, 111.5, 111.2, 70.5, 69.6, 63.9, 57.4, 55.3, 48.6, 30.6, 24.6, 23.0. ESI-MS (m/z): calcd. 682.2, found 682.3 ([M+H]+); HRMS (m/z): calcd. C38H34N5NiO4 for 682.1964, found 682.1959 ([M+H]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor = 36.2, tminor = 16.5 min, de > 99%.

3.3.9. Ni(II)-(S)-BPB/(2S,3R)-2-Amino-4,4'-dicyano-3-(2-naphthyl) Butyric Acid Schiff Base Complex (7i)

Obtained as a red solid, yield = 80%, m.p. 187–189 °C. Molecules 19 00826 i003 = +1582 (ca. 0.2 g/100 mL, CHCl3). 1H-NMR (CDCl3) δ 8.19 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 7.5 Hz, 3H), 7.93 (d, J = 7.7 Hz, 1H), 7.81 (s, 1H), 7.70 (d, J = 7.8 Hz, 3H), 7.60 (p, J = 6.7 Hz, 2H), 7.41 (d, J = 7.0 Hz, 1H), 7.32 (d, J = 7.0 Hz, 1H), 7.26 (t, J = 7.6 Hz, 3H), 7.20–7.09 (m, 2H), 6.70 (d, J = 14.1 Hz, 2H), 5.34 (d, J = 12.0 Hz, 1H), 4.62 (d, J = 3.1 Hz, 1H), 4.12 (d, J = 7.1 Hz, 1H), 4.02 (d, J = 12.5 Hz, 1H), 3.46 (dd, J = 12.0, 3.1 Hz, 1H), 3.23 (d, J = 12.5 Hz, 1H), 3.05 (t, J = 8.5 Hz, 1H), 2.64–2.48 (m, 1H), 2.04 (s, 1H), 1.74 (d, J = 10.0 Hz, 2H), 1.24 (dd, J = 16.0, 8.8 Hz, 1H). 13C-NMR (CDCl3) δ 180.1, 176.2, 173.4, 143.3, 134.1, 133.9, 133.5, 133.3, 133.2, 131.3, 130.9, 130.5, 129.8, 129.5, 128.9, 128.8, 128.5, 127.8, 127.5, 127.5, 127.3, 127.1, 125.5, 123.3, 120.7, 111.6, 111.3, 70.3, 70.0, 64.0, 57.7, 48.9, 30.0, 24.6, 22.3. ESI-MS (m/z): calcd. 702.2, found 702.3 ([M+H]+); HRMS (m/z): calcd. C41H34N5NiO3 for 702.2015, found 702.2022 ([M+H]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor = 31.5 min, tminor = 18.8 min, de = 98%.

3.3.10. Ni(II)-(S)-BPB/(2S,3R)-2-Amino-4,4'-dicyano-3-(1-naphthyl) Butyric Acid Schiff Base Complex (7j)

Yield = 26%, m.p. 178–180 °C. Molecules 19 00826 i003 = +1614 (ca. 0.2 g/100 mL, CHCl3). 1H-NMR (CDCl3) δ 8.25 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 7.5 Hz, 2H), 7.80–7.65 (m, 4H), 7.57 (d, J = 7.3 Hz, 1H), 7.55–7.43 (m, 3H), 7.41 (d, J = 7.0 Hz, 1H), 7.29–7.21 (m, 3H), 7.21–7.07 (m, 3H), 6.80–6.67 (m, 2H), 5.36 (d, J = 11.8 Hz, 1H), 4.74 (d, J = 2.6 Hz, 1H), 4.20 (dd, J = 11.8, 2.2 Hz, 1H), 4.12 (q, J = 7.1 Hz, 1H), 3.97 (d, J = 12.6 Hz, 1H), 3.25 (d, J = 12.6 Hz, 1H), 2.95 (t, J = 8.7 Hz, 1H), 2.50 (dt, J = 11.4, 5.8 Hz, 1H), 1.86 (dd, J = 12.9, 9.2 Hz, 1H), 1.75 (dt, J = 22.7, 9.6 Hz, 2H), 0.97 (dt, J = 14.6, 7.4 Hz, 1H). 13C-NMR (CDCl3) δ 179.5, 176.1, 173.6, 143.4, 134.4, 134.0, 133.5, 133.4, 133.1, 133.0, 131.2, 130.6, 130.4, 130.1, 129.3, 129.2, 128.8, 128.7, 127.2, 127.1, 126.9, 126.7, 126.1, 126.0, 125.1, 123.0, 122.5, 120.5, 111.6, 111.1, 71.4, 70.3, 63.7, 57.2, 43.5, 30.2, 25.7, 22.9. ESI-MS (m/z): calcd. 702.2, found 702.3 ([M+H]+); HRMS (m/z): calcd. C41H34N5NiO3 for 702.2015, found 702.2019 ([M+H]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor = 55.7 min, tminor = 20.4 min, de = 98%.

3.3.11. Ni(II)-(S)-BPB/(2S,3R)-2-Amino-4,4'-dicyano-3-(3-hydroxyphenyl) Butyric Acid Schiff Base Complex (7k)

Yield = 46%, m.p. 222–224 °C. Molecules 19 00826 i003 = +1775 (ca. 0.2 g/100 mL, CHCl3). 1H-NMR (DMSO) δ 9.89 (s, 1H), 8.42 (d, J = 7.5 Hz, 2H), 8.11 (d, J = 8.7 Hz, 1H), 7.78 (d, J = 5.3 Hz, 1H), 7.69 (s, 3H), 7.54 (d, J = 4.9 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.37 (t, J = 7.5 Hz, 2H), 7.13 (dd, J = 16.4, 6.8 Hz, 3H), 6.93–6.80 (m, 2H), 6.73 (t, J = 7.6 Hz, 1H), 6.63 (d, J = 8.3 Hz, 1H), 5.40 (d, J = 12.4 Hz, 1H), 4.40 (d, J = 3.6 Hz, 1H), 4.09 (q, J = 7.1 Hz, 1H), 3.91 (d, J = 12.2 Hz, 1H), 3.15 (dd, J = 12.3, 3.5 Hz, 1H), 2.96–2.84 (m, 1H), 2.56 (s, 2H), 2.23 (dd, J = 15.2, 8.6 Hz, 1H), 2.17–2.07 (m, 1H), 1.99 (dd, J = 25.2, 14.2 Hz, 2H), 1.70 (d, J = 6.5 Hz, 1H). 13C-NMR (DMSO) δ 180.0, 174.8, 171.9, 158.2, 143.2, 134.5, 134.1, 133.5, 133.1, 131.8, 131.5, 130.2, 130.1, 129.7, 128.9, 128.4, 128.1, 127.8, 127.4, 125.1, 122.8, 119.8, 116.4, 113.1, 112.1, 69.7, 69.6, 63.2, 57.7, 47.5, 30.4, 25.2, 22.6. ESI-MS (m/z): calcd. 668.2, found 668.2 ([M+H]+); HRMS (m/z): calcd. C37H32N5NiO4 for 668.1808, found 668.1819 ([M+H]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor = 14.7 min, tminor = 7.1 min, de = 98%.

3.3.12. Ni(II)-(S)-BPB/(2S,3R)-2-Amino-4,4'-dicyano-3-(2-fluoro-4-bromophenyl) Butyric Acid Schiff Base Complex (7l)

Yield = 90%, m.p. 222–224 °C. Molecules 19 00826 i003 = +1624 (ca. 0.2 g/100 mL, CHCl3). 1H-NMR (CDCl3) δ 8.32 (d, J = 8.7 Hz, 1H), 8.01 (d, J = 7.5 Hz, 2H), 7.66 (d, J = 6.2 Hz, 3H), 7.60 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 5.2 Hz, 1H), 7.29 (dd, J = 13.5, 6.0 Hz, 3H), 7.24–7.11 (m, 3H), 6.68 (s, 2H), 5.23 (d, J = 12.0 Hz, 1H), 4.53 (d, J = 3.3 Hz, 1H), 4.20–4.05 (m, 1H), 3.80 (d, J = 9.4 Hz, 1H), 3.45 (d, J = 12.6 Hz, 1H), 3.30 (t, J = 8.5 Hz, 1H), 2.96 (q, J = 10.3 Hz, 1H), 2.44–2.25 (m, 1H), 2.25–2.08 (m, 1H), 2.02–1.89 (m, 2H), 1.79–1.64 (m, 1H). 13C-NMR (CDCl3) δ 180.2, 176.3, 173.3, 160.9, 143.2, 133.9, 133.4, 133.3, 133.2, 131.4, 130.8, 130.5, 129.4, 128.9, 128.8, 127.4, 127.0, 125.6, 124.1, 123.2, 120.8, 115.2, 111.6, 111.3, 70.6, 69.8, 64.0, 57.6, 55.4, 48.1, 30.5, 24.7, 22.9. ESI-MS (m/z): calcd. 748.1, found 748.1 ([M+H]+); HRMS (m/z): calcd. C37H30BrFN5NiO3 for 748.0869, found 748.0881 ([M+H]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor = 36.2 min, tminor = 15.3 min, de > 99%.

3.3.13. Ni(II)-(S)-BPB/(2S,3R,4S)-2-Amino-4-cyano-5-ethoxy-5-oxo-3-phenylpentanoic Acid Schiff Base Complex (7m)

Yield = 78%, m.p. 192.2–193.5 °C. Molecules 19 00826 i004 = +2323 (ca. 0.03 g/100 mL, CH2Cl2). 1H-NMR (CDCl3) δ 8.24 (d, J = 8.6 Hz, 1H), 7.99 (d, J = 7.1 Hz, 2H), 7.74–7.58 (m, 3H), 7.53 (s, 3H), 7.40 (d, J = 7.3 Hz, 1H), 7.35–7.26 (m, 4H), 7.22–7.08 (m, 3H), 6.70 (q, J = 7.7 Hz, 2H), 4.63 (s, 1H), 4.57 (d, J = 12.0 Hz, 1H), 4.18 (d, J = 12.6 Hz, 1H), 3.85 (q, J = 6.9 Hz, 2H), 3.39 (t, J = 12.9 Hz, 2H), 3.22 (t, J = 8.4 Hz, 1H), 2.93 (dt, J = 9.3, 4.6 Hz, 1H), 2.17 (dt, J = 16.0, 8.1 Hz, 1H), 2.02 (dd, J = 12.6, 6.5 Hz, 1H), 1.94 (dd, J = 18.3, 8.6 Hz, 1H), 1.82 (dt, J = 19.5, 6.8 Hz, 1H), 1.47 (ddd, J = 19.2, 12.4, 6.7 Hz, 1H), 0.90 (t, J = 6.9 Hz, 3H). 13C-NMR (CDCl3) δ 180.28, 176.58, 173.02, 164.34, 143.18, 134.17, 133.89, 133.71, 133.30, 132.85, 131.46, 130.59, 130.36, 129.32, 129.19, 129.12, 128.88, 128.80, 127.70, 127.12, 125.83, 123.20, 120.67, 114.69, 71.09, 70.50, 63.81, 62.42, 57.36, 48.45, 38.92, 30.62, 23.06, 13.48. HRMS (m/z): calcd. C39H36N4NaNiO5+ for 721.1931, found 721.1931 ([M+Na]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor = 31.7 min, tminor = 8.0 min, de = 98%.

3.3.14. Ni(II)-(S)-BPB/(2S,3R,4S)-2-Amino-3-(2-bromophenyl)-4-cyano-5-ethoxy-5-oxopentanoic Acid Schiff Base Complex (7n)

Yield = 88%, m.p. 191.3–192.1 °C. Molecules 19 00826 i004 = +2120 (ca. 0.03 g/100 mL, CH2Cl2). 1H-NMR (CDCl3) δ 8.44 (d, J = 8.7 Hz, 1H), 7.96 (d, J = 7.3 Hz, 2H), 7.88 (d, J = 7.8 Hz, 1H), 7.69–7.61 (m, 3H), 7.58–7.53 (m, 1H), 7.53–7.44 (m, 2H), 7.43–7.36 (m, 1H), 7.29 (dd, J = 10.5, 4.9 Hz, 3H), 7.16 (dt, J = 13.7, 5.3 Hz, 2H), 6.73–6.63 (m, 2H), 4.62 (d, J = 3.0 Hz, 1H), 4.49 (d, J = 12.2 Hz, 1H), 4.17 (d, J = 12.6 Hz, 1H), 4.06 (dd, J = 12.2, 3.0 Hz, 1H), 3.89 (qd, J = 7.1, 2.3 Hz, 2H), 3.43 (d, J = 12.6 Hz, 1H), 3.25 (t, J = 8.6 Hz, 1H), 2.85-2.75 (m, 1H), 2.19 (ddd, J = 19.3, 13.1, 7.3 Hz, 2H), 1.92 (dt, J = 11.2, 8.1 Hz, 1H), 1.70 (dt, J = 13.6, 7.5 Hz, 1H), 1.46 (dt, J = 18.8, 6.4 Hz, 1H), 0.95 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3) δ 180.14, 176.38, 174.21, 163.71, 143.31, 134.68, 134.06, 133.87, 133.70, 133.24, 133.05, 131.42, 130.80, 130.31, 130.03, 129.76, 128.87, 128.79, 128.55, 128.06, 127.12, 127.05, 125.84, 122.92, 120.52, 113.84, 71.89, 70.74, 63.75, 62.67, 57.14, 46.61, 39.74, 30.89, 23.02, 13.50, 0.01. HRMS (m/z): calcd. C39H35BrN4NaNiO5+for 799.1037, found 799.1034 ([M+Na]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor =42.8 min, tminor =10.6 min, de > 99%.

3.3.15. Ni(II)-(S)-BPB/(2S,3R,4S)-2-Amino-(3-chlorophenyl)-4-cyano-5-ethoxy-3-5-oxopentanoic Acid Schiff Base Complex (7o)

Yield = 89%, m.p. 191.2–193.4 °C. Molecules 19 00826 i004 = +2376 (ca. 0.03 g/100 mL, CH2Cl2). 1H-NMR (CDCl3) δ 8.27 (d, J = 8.7 Hz, 1H), 8.00 (d, J = 7.4 Hz, 2H), 7.70 (dd, J = 11.3, 4.9 Hz, 1H), 7.67–7.59 (m, 2H), 7.53 (d, J = 8.2 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.42–7.34 (m, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.21–7.13 (m, 3H), 7.11 (d, J = 7.2 Hz, 1H), 6.76–6.64 (m, 2H), 4.62 (d, J = 3.7 Hz, 1H), 4.53 (d, J = 12.2 Hz, 1H), 4.19 (d, J = 12.6 Hz, 1H), 3.89 (q, J = 7.1 Hz, 2H), 3.42 (d, J = 12.6 Hz, 1H), 3.33 (dd, J = 12.2, 3.7 Hz, 1H), 3.26 (dd, J = 9.3, 7.7 Hz, 1H), 3.02 (dd, J = 10.6, 5.8 Hz, 1H), 2.23 (td, J = 17.0, 7.6 Hz, 1H), 2.09 (dd, J = 13.4, 7.4 Hz, 1H), 1.99 (dd, J = 10.8, 6.3 Hz, 1H), 1.93 (dd, J = 14.0, 7.2 Hz, 1H), 1.62 (d, J = 12.7 Hz, 1H), 0.96 (t, J = 7.1 Hz, 3H). 13C-NMR () δ 180.29, 176.27, 173.26, 164.17, 143.30, 136.44, 135.58, 133.91, 133.62, 133.34, 133.04, 131.45, 130.68, 130.43, 129.42, 129.26, 128.92, 128.83, 127.58, 127.06, 125.66, 123.25, 120.68, 114.35, 70.79, 70.54, 63.88, 62.61, 57.57, 48.07, 38.81, 30.76, 23.03, 13.51. HRMS (m/z): calcd. C39H35ClN4NaNiO5+for 755.1542, found 755.1541 ([M+Na]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor = 26.6 min, tminor = 8.1 min, de = 97%.

3.3.16. Ni(II)-(S)-BPB/(2S,3R,4S)-2-Amino-4-cyano-5-ethoxy-3-(4-fluorophenyl)-5-oxopentanoic Acid Schiff Base Complex (7p)

Yield = 75%, m.p. 192.3–193.5 °C. Molecules 19 00826 i004 = +2250 (ca. 0.03 g/100 mL, CH2Cl2). 1H-NMR (CDCl3) δ 8.25 (d, J = 8.7 Hz, 1H), 8.00 (d, J = 7.5 Hz, 2H), 7.69 (t, J = 7.0 Hz, 1H), 7.67–7.59 (m, 2H), 7.39 (d, J = 7.3 Hz, 1H), 7.30 (dd, J = 14.3, 6.6 Hz, 4H), 7.22(d, J = 8.5, 2H), 7.16 (t, J = 7.3 Hz, 3H), 6.70 (q, J = 8.2 Hz, 2H), 4.62 (d, J = 3.4 Hz, 1H), 4.52 (d, J = 12.2 Hz, 1H), 4.19 (d, J = 12.6 Hz, 1H), 3.88 (q, J = 7.1 Hz, 2H), 3.41 (d, J = 12.6 Hz, 1H), 3.36 (dd, J = 12.2, 3.5 Hz, 1H), 3.29–3.22 (m, 1H), 2.99 (dd, J = 10.1, 5.7 Hz, 1H), 2.25 (td, J = 16.7, 7.6 Hz, 1H), 2.09 (dt, J = 16.1, 8.6 Hz, 1H), 1.96 (dt, J = 14.1, 9.6 Hz, 2H), 1.66–1.55 (m, 1H), 0.95 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3) δ 180.32, 176.43, 173.22, 164.62, 164.23, 162.15, 143.22, 133.90, 133.68, 133.33, 132.97, 131.43, 130.65, 130.44, 130.04, 130.00, 129.23, 128.93, 128.83, 127.58, 127.09, 125.70, 123.22, 120.70, 116.40, 116.19, 114.44, 99.99, 70.99, 70.48, 63.91, 62.55, 57.48, 47.82, 38.99, 30.68, 22.94, 13.55. HRMS (m/z): calcd. C39H35FN4NaNiO5+for 739.1837, found 739.1837 ([M+Na]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor = 53.2 min, tminor = 6.9 min, de = 96%.

3.3.17. Ni(II)-(S)-BPB/(2S,3R,4S)-2-Amino-4-cyano-3-(3,4-dichlorophenyl)-5-ethoxy-5-oxopentanoic Acid Schiff Base Complex (7q)

Yield = 82%, m.p. 192.7–194.7 °C. Molecules 19 00826 i004 = +2353 (ca. 0.03 g/100 mL, CH2Cl2). 1H-NMR (CDCl3) δ 8.27 (d, J = 8.7 Hz, 1H), 8.02 (d, J = 7.6 Hz, 2H), 7.70 (t, J = 7.1 Hz, 1H), 7.63 (dd, J = 13.5, 8.8 Hz, 3H), 7.44 (s, 1H), 7.38 (d, J = 7.4 Hz, 1H), 7.31 (t, J = 7.6 Hz, 2H), 7.20–7.11 (m, 3H), 7.08 (d, J = 7.6 Hz, 1H), 6.78–6.64 (m, 2H), 4.60 (d, J = 3.6 Hz, 1H), 4.51 (d, J = 12.1 Hz, 1H), 4.19 (d, J = 12.5 Hz, 1H), 3.94 (q, J = 7.1 Hz, 2H), 3.41 (d, J = 12.6 Hz, 1H), 3.35–3.25 (m, 2H), 3.00 (dt, J = 10.2, 5.2 Hz, 1H), 2.30 (dt, J = 16.8, 7.7 Hz, 1H), 2.09 (dd, J = 13.3, 6.0 Hz, 1H), 2.02 (dd, J = 11.8, 7.4 Hz, 1H), 1.95 (dd, J = 13.4, 6.3 Hz, 1H), 1.67 (dt, J = 13.0, 6.4 Hz, 1H), 1.02 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3) δ 180.36, 176.15, 173.45, 164.02, 143.31, 134.66, 133.94, 133.80, 133.56, 133.37, 133.17, 131.42, 131.08, 130.75, 130.50, 129.30, 128.96, 128.86, 127.48, 127.04, 125.53, 123.27, 120.75, 114.12, 70.67, 70.54, 64.03, 62.82, 57.78, 47.57, 38.59, 30.75, 22.83, 13.59. HRMS (m/z): calcd. C39H34Cl2N4NaNiO5+for 789.1152, found 789.1151 ([M+Na]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor = 44.5 min, tminor = 7.6 min, de = 98%.

3.3.18. Ni(II)-(S)-BPB/(2S,3R,4S)-2-Amino-4-cyano-3-(2,4-dichlorophenyl)-5-ethoxy-5-oxopentanoic Acid Schiff Base Complex (7r)

Yield = 96%, m.p. 192.6–194.5 °C. Molecules 19 00826 i004 = +1960 (ca. 0.03 g/100 mL, CH2Cl2). 1H-NMR (CDCl3) δ 8.42 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 7.6 Hz, 2H), 7.71 (s, 1H), 7.69–7.59 (m, 3H), 7.44 (s, 2H), 7.41 (d, J = 3.5 Hz, 1H), 7.30 (dd, J = 13.9, 6.7 Hz, 3H), 7.19–7.11 (m, 2H), 6.72–6.63 (m, 2H), 4.60 (d, J = 3.1 Hz, 1H), 4.48 (d, J = 12.2 Hz, 1H), 4.18 (d, J = 12.6 Hz, 1H), 4.05 (dd, J = 12.2, 3.1 Hz, 1H), 3.99–3.88 (m, 2H), 3.43 (d, J = 12.6 Hz, 1H), 3.34–3.22 (m, 1H), 2.90 (dt, J = 11.0, 5.6 Hz, 1H), 2.33 (dt, J = 16.8, 7.7 Hz, 1H), 2.16 (td, J = 13.6, 7.7 Hz, 1H), 2.00 (dt, J = 10.9, 7.6 Hz, 1H), 1.88 (dt, J = 14.2, 7.4 Hz, 1H), 1.69–1.53 (m, 1H), 1.01 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3) δ 180.23, 176.30, 174.38, 163.63, 143.32, 137.69, 135.70, 134.05, 133.59, 133.31, 133.17, 131.56, 131.39, 130.83, 130.43, 130.19, 130.14, 129.65, 128.91, 128.83, 128.28, 127.08, 125.58, 122.92, 120.58, 113.73, 71.39, 70.71, 63.95, 62.85, 57.45, 43.63, 39.21, 30.98, 22.89, 13.56. HRMS (m/z): calcd. C39H34Cl2N4NaNiO5+for 789.1152, found 789.1151 ([M+Na]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor = 77.3, tminor = 8.8 min, de = 98%.

3.3.19. Ni(II)-(S)-BPB/(2S,3R,4S)-2-Amino-4-cyano-5-ethoxy-5-oxo-3-(p-tolyl)pentanoic Acid Schiff Base Complex (7s)

Yield = 76%, m.p. 182.3–183.7 °C. Molecules 19 00826 i004 = +2570 (ca. 0.03 g/100 mL, CH2Cl2). 1H-NMR (CDCl3) δ 8.24 (d, J = 8.7 Hz, 1H), 8.00 (d, J = 7.3 Hz, 2H), 7.68 (dt, J = 9.7, 4.3 Hz, 1H), 7.61 (dd, J = 9.1, 5.4 Hz, 2H), 7.39 (d, J = 7.4 Hz, 1H), 7.31 (dd, J = 16.1, 8.0 Hz, 4H), 7.21–7.10 (m, 5H), 6.75–6.65 (m, 2H), 4.60 (d, J = 3.7 Hz, 1H), 4.54 (d, J = 12.2 Hz, 1H), 4.19 (d, J = 12.6 Hz, 1H), 3.86 (q, J = 7.1 Hz, 2H), 3.41 (d, J = 12.6 Hz, 1H), 3.33 (dd, J = 12.2, 3.7 Hz, 1H), 3.26–3.19 (m, 1H), 3.01–2.93 (m, 1H), 2.43 (s, 3H), 2.20 (dt, J = 16.7, 7.9 Hz, 1H), 2.04 (dt, J = 13.1, 6.8 Hz, 1H), 1.95 (dd, J = 11.1, 7.2 Hz, 1H), 1.83 (tt, J = 15.3, 7.6 Hz, 1H), 1.49 (tt, J = 12.8, 6.4 Hz, 1H), 0.94 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3) δ 180.19, 176.62, 172.87, 164.36, 143.12, 138.95, 133.86, 133.71, 133.31, 132.80, 131.45, 130.97, 130.55, 130.30, 129.97, 129.17, 128.87, 128.79, 127.70, 127.11, 125.83, 123.17, 120.65, 114.76, 71.12, 70.55, 63.87, 62.37, 57.40, 48.10, 38.85, 30.47, 22.78, 21.27, 13.51. HRMS (m/z): calcd. C40H38N4NaNiO5+for 735.2088, found 735.2089 ([M+Na]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor = 46.3 min, tminor = 7.5 min, de > 99%.

3.3.20. Ni(II)-(S)-BPB/(2S,3R,4S)-2-Amino-4-cyano-5-ethoxy-3-(4-methoxylphenyl)-5-oxopentanoic Acid Schiff Base Complex (7t)

Yield = 77%, m.p. 188.5–189.4 °C. Molecules 19 00826 i004 = +2376 (ca. 0.03 g/100 mL, CH2Cl2). 1H-NMR (CDCl3) δ 8.23 (d, J = 8.7 Hz, 1H), 8.01 (d, J = 7.5 Hz, 2H), 7.68 (t, J = 6.9 Hz, 1H), 7.65–7.58 (m, 2H), 7.38 (d, J = 7.4 Hz, 1H), 7.30 (t, J = 7.6 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 7.15 (dd, J = 13.2, 6.6 Hz, 3H), 7.04 (d, J = 8.5 Hz, 2H), 6.74–6.65 (m, 2H), 4.60 (d, J = 3.5 Hz, 1H), 4.52 (d, J = 12.2 Hz, 1H), 4.19 (d, J = 12.6 Hz, 1H), 3.91–3.86 (m, 2H), 3.85 (s, 3H), 3.40 (d, J = 12.6 Hz, 1H), 3.32 (dd, J = 12.2, 3.5 Hz, 1H), 3.24 (t, J = 8.5 Hz, 1H), 3.04–2.96 (m, 1H), 2.21 (dt, J = 16.3, 7.6 Hz, 1H), 2.08 (dd, J = 13.3, 6.2 Hz, 1H), 1.98 (dd, J = 11.0, 6.9 Hz, 1H), 1.90 (dd, J = 13.5, 6.8 Hz, 1H), 1.56–1.47 (m, 1H), 0.95 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3) δ 180.28, 176.63, 172.88, 164.42, 160.34, 143.15, 133.85, 133.73, 133.37, 132.79, 131.46, 130.56, 130.32, 129.17, 128.88, 128.79, 127.67, 127.13, 125.85, 125.78, 123.18, 120.65, 114.73, 114.59, 71.20, 70.59, 63.92, 62.37, 57.55, 55.34, 47.89, 38.97, 30.62, 22.94, 13.56. HRMS (m/z): calcd. C40H38N4NaNiO6+for 751.2037, found 751.2037 ([M+Na]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor = 71.2 min, tminor = 8.5 min, de = 97%.

3.3.21. Ni(II)-(S)-BPB/(2S,3R,4S)-2-Amino-4-cyano-5-ethoxy-3-(4-nitrophenyl)-5-oxopentanoic Acid Schiff Base Complex (7u)

Yield = 69%, m.p. 206.5–208.6 °C. Molecules 19 00826 i004 = +2163 (ca. 0.03 g/100 mL, CH2Cl2). 1H-NMR (CDCl3) δ 8.40 (d, J = 8.5 Hz, 2H), 8.28 (d, J = 8.7 Hz, 1H), 7.98 (d, J = 7.5 Hz, 2H), 7.72 (t, J = 7.1 Hz, 1H), 7.69–7.60 (m, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 7.4 Hz, 1H), 7.30 (t, J = 7.6 Hz, 2H), 7.21–7.11 (m, 3H), 6.75–6.67 (m, 2H), 4.67 (d, J = 3.5 Hz, 1H), 4.62 (d, J = 12.1 Hz, 1H), 4.17 (d, J = 12.6 Hz, 1H), 3.96–3.86 (m, 2H), 3.48 (dd, J = 12.1, 3.5 Hz, 1H), 3.40 (d, J = 12.6 Hz, 1H), 3.23 (dd, J = 9.7, 7.1 Hz, 1H), 2.95–2.87 (m, 1H), 2.17 (dt, J = 17.7, 8.9 Hz, 1H), 1.97–1.86 (m, 2H), 1.68 (dd, J = 17.8, 10.7 Hz, 1H), 1.55–1.46 (m, 1H), 1.00 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3) δ 180.25, 176.03, 173.78, 163.86, 148.69, 143.31, 142.00, 134.01, 133.59, 133.32, 133.25, 131.36, 130.83, 130.64, 129.33, 129.00, 128.89, 127.47, 127.03, 125.46, 124.23, 123.26, 120.85, 113.96, 70.71, 70.32, 63.95, 62.93, 57.36, 47.97, 38.63, 30.64, 22.83, 13.61. HRMS (m/z): calcd. C39H35N5NaNiO7+for 766.1782, found 766.1782 ([M+Na]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor = 69.0 min, tminor = 8.6 min, de = 97%.

3.3.22. Ni(II)-(S)-BPB/(2S,3R,4S)-2-Amino-3-(4-(tert-butyl)phenyl)-4-cyano-5-ethoxy-5-oxopentanoic Acid Schiff Base Complex (7v)

Yield = 51%, m.p. 200.8–201.7 °C. Molecules 19 00826 i004 = +2260 (ca. 0.03 g/100 mL, CH2Cl2). 1H-NMR (CDCl3) δ 8.29 (d, J = 8.7 Hz, 1H), 7.95 (d, J = 7.4 Hz, 2H), 7.72–7.66 (m, 1H), 7.66–7.59 (m, 2H), 7.50 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 7.4 Hz, 1H), 7.30 (t, J = 7.6 Hz, 2H), 7.17 (dt, J = 15.7, 7.6 Hz, 5H), 6.75–6.66 (m, 2H), 4.63 (d, J = 3.7 Hz, 1H), 4.53 (d, J = 12.2 Hz, 1H), 4.20 (d, J = 12.7 Hz, 1H), 3.86–3.76 (m, 2H), 3.49 (d, J = 12.7 Hz, 1H), 3.32 (dd, J = 12.2, 3.7 Hz, 1H), 3.17 (dd, J = 9.8, 7.4 Hz, 1H), 3.00 (dd, J = 10.3, 6.8 Hz, 1H), 2.18 (dt, J = 18.1, 8.3 Hz, 1H), 2.06 (dd, J = 11.2, 6.6 Hz, 1H), 1.89 (dd, J = 19.4, 8.6 Hz, 1H), 1.80 (dd, J = 10.3, 6.2 Hz, 1H), 1.48 (d, J = 8.3 Hz, 1H), 1.34 (s, 9H), 0.79 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3) δ 180.08, 176.69, 173.06, 164.52, 151.93, 143.13, 133.93, 133.77, 133.17, 132.84, 131.41, 130.88, 130.56, 130.34, 129.16, 128.85, 128.80, 127.82, 127.07, 126.29, 126.25, 125.92, 123.10, 120.69, 114.80, 70.98, 70.48, 63.49, 62.22, 56.56, 48.08, 39.24, 34.76, 31.35, 30.72, 22.77, 13.35. HRMS (m/z): calcd. C43H44N4NaNiO5+for 777.2557, found 777.2557 ([M+Na]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor = 58.6 min, tminor = 8.7 min, de = 97%.

3.3.23. Ni(II)-(S)-BPB/(2S,3R,4S)-2-Amino-4-cyano-5-ethoxy-3-(naphthalen-1-y)-5-oxopentanoic Acid Schiff Base Complex (7w)

Yield = 67%, m.p. 188.4–190.3 °C. Molecules 19 00826 i004 = +1793 (ca. 0.03 g/100 mL, CH2Cl2). 1H-NMR (CDCl3) δ 8.25 (d, J = 8.7 Hz, 1H), 8.00 (dd, J = 16.3, 8.0 Hz, 2H), 7.90 (d, J = 7.5 Hz, 2H), 7.71 (dd, J = 16.1, 8.1 Hz, 3H), 7.66–7.56 (m, 3H), 7.54–7.44 (m, 2H), 7.41 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 7.4 Hz, 2H), 7.18–7.07 (m, 3H), 6.77 (d, J = 8.2 Hz, 1H), 6.71 (t, J = 7.5 Hz, 1H), 4.80 (s, 1H), 4.76 (d, J = 12.1 Hz, 1H), 4.30 (d, J = 10.7 Hz, 1H), 4.02 (d, J = 12.6 Hz, 1H), 3.80–3.65 (m, 2H), 3.25 (d, J = 12.5 Hz, 1H), 2.94 (t, J = 8.7 Hz, 1H), 2.51 (dt, J = 11.5, 5.9 Hz, 1H), 1.89–1.72 (m, 2H), 1.24 (dt, J = 13.6, 6.8 Hz, 2H), 0.94 (dt, J = 21.1, 7.7 Hz, 1H), 0.67 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3) δ 179.70, 176.53, 173.06, 164.07, 143.34, 134.19, 133.94, 133.72, 133.47, 133.23, 133.08, 131.36, 131.22, 130.96, 130.45, 129.86, 129.42, 128.98, 128.76, 128.69, 127.37, 126.94, 126.86, 126.59, 126.02, 125.80, 125.42, 122.98, 122.94, 120.40, 114.48, 72.69, 70.32, 63.60, 62.39, 57.23, 43.09, 39.99, 30.34, 22.94, 13.28. HRMS (m/z): calcd. C43H38N4NaNiO5+for 771.2088, found 771.2088 ([M+Na]+). HPLC (Chiralpak IA, n-hexane/i-propanol = 50/50, flow rate 1.0 mL/min, λ = 220 nm), tmajor = 31.7 min, tminor = 12.3 min, de > 99%.

3.4. Procedure for the Synthesis of (2S,3R)-8a

In a typical procedure, 3 mol/L HCl (3.33 mL, 5.0 mmol) was added to a solution of the (S,2S,3R)-7a (1.0 mmol) dissolved in THF (13 mL). The reaction was stirred for 12 h or until the red color of the solution disappeared and was then concentrated under vacuum to half of the original volume. In the case of (S,2S,3R)-7a, the (S)-BPB was recovered from the aqueous portion by extracting with ethyl acetate (EA) and was washed with water. The organic layer was removed, and the aqueous portion was diluted with water (2 mL). The aqueous portion was transferred to a clean flask, and solid NaHCO3 (336 mg, 4.0 mmol) was carefully added with stirring to neutralize the solution, followed by Na2EDTA (372 mg, 1.0 mmol), and was stirred for 5 min. Additional solid NaHCO3 (336 mg, 4.0 mmol) was added, followed by a solution of Fmoc-OSu (337 mg,1.0 mmol) in acetonitrile (5 mL). The reaction was stirred for 24 h under nitrogen, concentrated in vacuum to half of the original volume, adjusted to pH = 3 with 10% citric acid, and extracted with EtOAc twice. Combined organic layers were washed with brine, dried with anhydrous MgSO4, concentrated, and purified on silica gel using a flash chromatography (petroleum ether/ethyl acetate = 1/2) to give (2S,3R)-8a as a white solid.

3.5. 2-(((9H-Fluoren-9-yl)methoxy)carbonyl)-4,4-dicyano-3-phenylbutanoic Acid (8a)

1H-NMR (CDCl3) δ 8.02 (s, 1H), 7.68–7.54 (m, 3H), 7.54–7.41 (m, 2H), 7.21–6.97 (m, 6H), 6.58 (s, 1H), 4.42 (s, 1H), 4.35–4.17 (m, 2H), 4.11 (s, 1H), 4.06 (s, 1H), 3.82 (s, 1H). 13C-NMR (DMSO) δ 172.8, 162.3, 150.4, 143.2, 140.6, 140.6, 128.9, 128.8, 127.8, 127.7, 127.2, 127.2, 127.1, 126.4, 121.3, 120.1, 120.0, 109.7, 67.8, 59.7, 46.1, 25.1, 20.7. ESI-MS (m/z): calcd. 450.2, found 450.4 ([M−H]).

4. Conclusions

We have reported the first asymmetric three-component reaction of chiral nickel(II) glycinate, aromatic aldehydes, and an α-carbanion of two electron-withdrawing groups (malononitrile or ethyl cyanoacetate) to give a series of novel α-amino-β-substituted γ,γ-disubstituted butyric acid derivatives. We have screened a series of reaction conditions and developed a practical system to promote the asymmetric three component reaction of chiral nicke(II) glycinate. This reaction, which constructed two carbon-carbon bonds and formed two or three chiral centers, provides a convenient synthesis of functionalized chiral Fmoc-α-amino-β-substituted γ,γ-disubstituted butyric acid derivatives. The transformation performed well with electron-deficient, electron-rich, condensed ring and sterically hindered aromatic aldehydes and addorded functionalized products. To our excitement, some of them had amazingly high diastereoselectivities, but the heteroaryl substitutes were not well tolerated. The absolute configurations of the typical products were determined. Further studies will focus on mechanistic aspects, expansion of substrate ranges, and further applications of other chiral nickel(II) complexes in important carbon-carbon bond-forming reactions.

Supplementary Materials

Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/19/1/826/s1.

Acknowledgments

This research has received financial support from the National Natural Science Foundation of China (No. 81001357, 81273471 and 81303208) and the Open Research Fund of State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Or, Y.S.; Ying, L.; Wang, C.; Long, J.; Qui, Y.L. Preparation of Substituted Pyrrolidine Derivatives for Use as Anti-Infective Agents. WO 2009003009, 31 December 2008.
  2. Edwards, D.L.; Berens, M.E.; Beaudry, C. Identification of Chemical Useful for Treating e.g., Cancer, Comprising Depositing Cancer Cells on Substrate Using Guided Cell Sedimentation, Treating Cancer Cells with Library of Chemicals, and Measuring Cell Migration Rate. WO 2003102153, 11 December 2003.
  3. Jones, D.T.; Harris, A.L. Identification of novel small-molecule inhibitors of hypoxia-inducible factor-1 transactivation and DNA binding. Mol. Cancer Ther. 2006, 5, 2193–2202, doi:10.1158/1535-7163.MCT-05-0443.
  4. Dandia, A.; Jain, A.K.; Laxkar, A.K.; Bhati, D.S. Synthesis and stereochemical investigation of highly functionalized novel dispirobisoxindole derivatives via [3+2] cycloaddition reaction in ionic liquid. Tetrahedron 2013, 69, 2062–2069, doi:10.1016/j.tet.2012.12.021.
  5. Erdbrink, H.; Peuser, I.; Gerling, U.I.M.; Lentz, D.; Koksch, B.; Czekelius, C. Conjugate hydrotrifluoromethylation of α,β-unsaturated acyl-oxazolidinones: Synthesis of chiral fluorinated amino acids. Org. Biomol. Chem. 2012, 10, 8583–8586, doi:10.1039/c2ob26810h.
  6. Aouadi, K.; Jeanneau, E.; Msaddek, M.; Praly, J.P. 1,3-Dipolar cycloaddition of a chiral nitrone to (E)-1,4-dichloro-2-butene: A new efficient synthesis of (2S,3S,4R)-4-hydroxyisoleucine. Tetrahedron Lett. 2012, 53, 1817–1821.
  7. Tong, B.M.K.; Chiba, S. Diamine-catalyzed conjugate addition to acrylate derivatives. Org. Lett. 2011, 13, 2948–2951.
  8. Dugave, C.; Cluzeau, J.; Menez, A.; Gaudry, M.; Marquet, A. Chemo-enzymic synthesis of protected cyano derivatives of glutamate. Tetrahedron Lett. 1998, 39, 5775–5778, doi:10.1016/S0040-4039(98)01207-6.
  9. Heimgartner, H. 3-Amino-2H-azirines. Synthons for α,α-disubstituted α-amino acids in heterocycle and peptide synthesis. Angew. Chem. Int. Ed. 1991, 30, 238–264, doi:10.1002/anie.199102381.
  10. Duthaler, R.O. Recent developments in the stereoselective synthesis of α-amino acids. Tetrahedron 1994, 50, 1539–1650, doi:10.1016/S0040-4020(01)80840-1.
  11. Wirth, T. New strategies to alpha-alkylated alpha-amino acids. Angew. Chem. Int. Ed. 1997, 36, 225–227, doi:10.1002/anie.199702251.
  12. Gibson, S.E.; Guillo, N.; Tozer, M.J. Towards control of chi-space: Conformationally constrained analogues of Phe, Tyr, Trp and His. Tetrahedron 1999, 55, 585–615, doi:10.1016/S0040-4020(98)00942-9.
  13. Cativiela, C.; Diaz-de-Villegas, M.D. Stereoselective synthesis of quaternary alpha-amino acids. Part 1: Acyclic compounds. Tetrahedron Asymmetry 1998, 9, 3517–3599, doi:10.1016/S0957-4166(98)00391-7.
  14. Cativiela, C.; Diaz-de-Villegas, M.D. Stereoselective synthesis of quaternary alpha-amino acids. Part 2. Cyclic compounds. Tetrahedron Asymmetry 2000, 11, 645–732, doi:10.1016/S0957-4166(99)00565-0.
  15. Flores-Conde, M.I.; Reyes, L.; Herrera, R.; Rios, H.; Vazquez, M.A.; Miranda, R.; Tamariz, J.; Delgado, F. Highly regio- and stereoselective diels-alder cycloadditions via two-step and multicomponent reactions promoted by infrared irradiation under solvent-free conditions. Int. J. Mol. Sci. 2012, 13, 2590–2617, doi:10.3390/ijms13032590.
  16. Belokon, Y.N. Chiral complexes of Ni(II), Cu(II), and Cu(I) as reagents, catalysts and receptors for asymmetric-synthesis and chiral recognition of amino-acids. Pure Appl. Chem. 1992, 64, 1917–1924, doi:10.1351/pac199264121917.
  17. Belokon, Y.N.; Bespalova, N.B.; Churkina, T.D.; Cisarova, I.; Ezernitskaya, M.G.; Harutyunyan, S.R.; Hrdina, R.; Kagan, H.B.; Kocovsky, P.; Kochetkov, K.A.; et al. Synthesis of alpha-amino acids via asymmetric phase transfer-catalyzed alkylation of achiral nickel(II) complexes of glycine-derived Schiff bases. J. Am. Chem. Soc. 2003, 125, 12860–12871.
  18. Belokon, Y.N.; Tararov, V.I.; Maleev, V.I.; Saveleva, T.F.; Ryzhov, M.G. Improved procedures for the synthesis of (S)-2-N-(N'-benzylprolyl)amino benzophenone (BPB) and Ni(II) complexes of Schiff’s bases derived from BPB and amino acids. Tetrahedron Asymmetry 1998, 9, 4249–4252, doi:10.1016/S0957-4166(98)00449-2.
  19. Hayashi, T.; Kishi, E.; Soloshonok, V.A.; Uozumi, Y. Erythro-selective aldol-type reaction of N-sulfonylaldimines with methyl isocyanoacetate catalyzed by gold(I). Tetrahedron Lett. 1996, 37, 4969–4972, doi:10.1016/0040-4039(96)00981-1.
  20. Soloshonok, V.A.; Fokina, N.A.; Rybakova, A.V.; Shishkina, I.P.; Galushko, S.V.; Sorochinsky, A.E.; Kukhar, V.P.; Savchenko, M.V.; Svedas, V.K. Biocatalytic approach to enantiomerically pure beta-amino acids. Tetrahedron Asymmetry 1995, 6, 1601–1610, doi:10.1016/0957-4166(95)00204-3.
  21. Soloshonok, V.A.; Soloshonok, I.V.; Kukhar, V.P.; Svedas, V.K. Biomimetic transamination of alpha-alkyl beta-keto carboxylic esters. Chemoenzymatic approach to the stereochemically defined alpha-alkyl beta-fluoroalkyl beta-amino acids. J. Org. Chem. 1998, 63, 1878–1884, doi:10.1021/jo971777m.
  22. Deng, G.H.; Wang, J.; Zhou, Y.; Jiang, H.L.; Liu, H. One-pot, large-scale synthesis of Nickel(II) complexes derived from 2-N-(alpha-picolyl)amino benzophenone (PABP) and α- or β-amino acids. J. Org. Chem. 2007, 72, 8932–8934, doi:10.1021/jo071011e.
  23. Lin, D.Z.; Deng, G.H.; Wang, J.; Ding, X.; Jiang, H.L.; Liu, H. Efficient Synthesis of Symmetrical alpha,alpha-Disubstituted beta-Amino Acids and alpha,alpha-Disubstituted Aldehydes via Dialkylation of Nucleophilic beta-Alanine Equivalent. J. Org. Chem. 2010, 75, 1717–1722, doi:10.1021/jo902699t.
  24. Wang, J.; Lin, D.Z.; Shi, J.M.; Ding, X.; Zhang, L.; Jiang, H.L.; Liu, H. Highly enantio- and diastereoselective mannich reaction of a chiral Nickel(II) glycinate with an alpha-imino ester for asymmetric synthesis of a 3-aminoaspartate. Synthesis 2010, 7, 1205–1208.
  25. Wang, J.; Zhou, S.B.; Lin, D.Z.; Ding, X.; Jiang, H.L.; Liu, H. Highly diastereo- and enantioselective synthesis of syn-beta-substituted tryptophans via asymmetric Michael addition of a chiral equivalent of nucleophilic glycine and sulfonylindoles. Chem. Commun. 2011, 47, 8355–8257.
  26. Wang, J.; Ji, X.; Shi, J.M.; Sun, H.F.; Jiang, H.L.; Liu, H. Diastereoselective Michael reaction of chiral nickel(II) glycinate with nitroalkenes for asymmetric synthesis of beta-substituted alpha,gamma-diaminobutyric acid derivatives in water. Amino Acids 2012, 42, 1685–1694, doi:10.1007/s00726-011-0870-x.
  27. Wang, J.; Liu, H.; Acena, J.L.; Houck, D.; Takeda, R.; Moriwaki, H.; Sato, T.; Soloshonok, V.A. Synthesis of bis-α,α'-amino acids through diastereoselective bis-alkylations of chiral Ni(II)-complexes of glycine. Org. Biomol. Chem. 2013, 11, 4508–4515, doi:10.1039/c3ob40594j.
  28. Smith, D.J.; Yap, G.P.A.; Kelley, J.A.; Schneider, J.P. Enhanced stereoselectivity of a Cu(II) complex chiral auxiliary in the synthesis of Fmoc-L-γ-carboxyglutamic acid. J. Org. Chem. 2011, 76, 1513–1520, doi:10.1021/jo101940k.
  29. Xie, X.; Peng, C.; He, G.; Leng, H.-J.; Wang, B.; Huang, W.; Han, B. Asymmetric synthesis of a structurally and stereochemically complex spirooxindole pyran scaffold through an organocatalytic multicomponent cascade reaction. Chem. Commun. 2012, 48, 10487–10489.
  30. He, J.; Ouyang, G.; Yuan, Z.; Tong, R.; Shi, J.; Ouyang, L. A facile synthesis of functionalized dispirooxindole derivatives via a three-component 1,3-dipolar cycloaddition reaction. Molecules 2013, 18, 5142–5154, doi:10.3390/molecules18055142.
  31. Hou, X.; Luo, H.; Zhong, H.; Wu, F.; Zhou, M.; Zhang, W.; Han, X.; Yan, G.; Zhang, M.; Lu, L.; et al. Analysis of furo 3,2-c tetrahydroquinoline and pyrano 3,2-c tetrahydroquinoline derivatives as antitumor agents and their metabolites by liquid chromatography/electrospray ionization tandem mass spectrometry. Rapid Commun. Mass Spectr. 2013, 27, 1222–1230, doi:10.1002/rcm.6562.
  32. Li, X.; Yang, L.; Peng, C.; Xie, X.; Leng, H.-J.; Wang, B.; Tang, Z.-W.; He, G.; Ouyang, L.; Huang, W.; et al. Organocatalytic tandem Morita-Baylis-Hillman-Michael reaction for asymmetric synthesis of a drug-like oxa-spirocyclic indanone scaffold. Chem. Commun. 2013, 49, 8692–8694, doi:10.1039/c3cc44004d.
  33. Wu, G.; Ouyang, L.; Liu, J.; Zeng, S.; Huang, W.; Han, B.; Wu, F.; He, G.; Xiang, M. Synthesis of novel spirooxindolo-pyrrolidines, pyrrolizidines, and pyrrolothiazoles via a regioselective three-component 3+2 cycloaddition and their preliminary antimicrobial evaluation. Mol. Diver. 2013, 17, 271–283, doi:10.1007/s11030-013-9432-3.
  • Sample Availability: Samples of the compounds 7ay and 8a are available from the authors.
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert