Recyclable BINOL–quinine–squaramide as a highly efficient organocatalyst for α-amination of 1,3-dicarbonyl compounds and α-cyanoacetates

Abstract

An efficient organocatalytic asymmetric α-amination of 1,3-dicarbonyl and α-cyanoacetates compounds towards chiral α-amino acid precursors is reported. The enantioselective synthesis of these compounds was achieved with excellent yields and ee values (up to 99% yield and 99% ee) by treatment of 1,3-dicarbonyl compounds or α-cyanoacetates with azodicarboxylates in the presence of multiple hydrogen bond donor BINOL–quinine–squaramide organocatalyst 1a developed in our laboratory. The squaramide catalyst 1a can be recovered and reused for four cycles without loss of activity and enantioselectivity.

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Introduction

Organocatalysis has drawn intense research efforts in recent years due to its good performance and environmentally benign nature.^1–5 Since the pioneering work of MacMillan, Jørgensen, List, and Enders, asymmetric organocatalysis has emerged as a powerful tool in organic synthesis for the construction of a variety of enantiopure compounds.^6–11 Among them, hydrogen bond donor–acceptor organocatalyst, which can activate nucleophiles and electrophiles simultaneously through hydrogen-bonding, was particularly attractive in the field of asymmetric catalysis.^12–14 A large number of asymmetric transformations have been achieved with hydrogen-bonding organocatalysts based on urea (thiourea),^15–17 guanidines^16,18 and squaramides^19–25 (Scheme 1). With the focus on the catalyst practicality, our group is interested in the design, synthesis of variety of chiral squaramides and their application in series of asymmetric transformations and their applications.^26–35 Recently, we have reported that the BINOL–quinine–squaramide can function as a multiple H-bond donor organocatalyst and have showed highly catalytic activity and excellent enantioselectivity in asymmetric Michael addition of nitroalkenes to 1,3-dicarbonyl compounds.³² Encouraged by these preliminary results, we begun to examine other reactions to further assess the enantioselectivity of this kind of chiral squaramide organocatalyst.

Scheme 1 Representative chiral hydrogen-bonding organic catalysts.

In particular, we are quite interested in the enantioselective α-amination reaction, an important transformation that offers optically active α-amino acid derivatives, which are fundamental constituents of numerous natural products and pharmaceuticals.^36–38 So far, several examples of catalytic asymmetric α-hydrazination of 1,3-dicarbonyl compounds and cyano acid esters with azodicarboxylates,^39–53 have been reported. For example, Rawal and coworkers developed the chiral squaramide organocatalyst derived from cyclohexane-1,2-diamine, which shown excellent catalytic performance in enantioselective to various asymmetric α-hydrazination of 1,3-dicarbonylcompounds with azodicarboxylates.²¹ More recently, Wang reported the amine–thiourea organocatalyst catalyzed the asymmetric amination of cyclic β-keto esters reaction.⁵⁴ However, there is still room for improvement regarding this type of asymmetric reaction, the existing catalytic system is still limited. Accordingly, the development of a practical, highly efficient and recyclable chiral catalyst for this type of Michael addition reaction is particularly attractive.

Herein, we describe the BINOL–quinine–squaramide as a highly efficient, recyclable robust catalyst for the enantioselective amination of 1,3-dicarbonyl compounds and α-substituted α-cyanoacetates with azodicarboxylates, which afforded valuable chiral amino acids derivatives in high yields and excellent enantioselectivities (up to 99% ee).

Results and discussion

First, the chiral organocatalysts 1a–e (outlined in Scheme 2) were prepared according to our previous method.³²

Scheme 2 Chiral squaramide organocatalysts 1 applied in this study.

With these catalysts 1a–e in hand, their activity was tested in the Michael addition of β-ketoester 2a with diethyl azodicarboxylate 3a. The results were shown in Table 1. When 2 mol% of 1a was used, the reaction proceeded well in THF at −78 °C to provide the target product 4a in 99% yield and the best ee value (95% ee) (entry 5). For comparison, catalyst 1b exhibited a good enantioselectivity under the same reaction conditions, giving 97% yield and with 91% ee (entry 7). Catalysts 1c and 1e promoted the reaction to give 4a in 90%, 89% and 89% ee, respectively. To further determine optimum reaction conditions for the catalytic enantioselective, various solvents were examined at different temperature (entries 10–14). This asymmetric reaction could be carried out smoothly in several solvents such as DCM (85% ee), DMF (90% ee), toluene (87% ee). THF was found to be the most appropriate solvent for the study. Also, adjusting the catalyst loading demonstrated great influence on the enantioselectivity of the reaction. The use of 10 mol% of 1a gave the desired product 4a in only 75% ee (entry 1). While, reducing the loading of 1a to 1 mol% and prolonging the reaction time to 36 h resulted in good enantioselectivity (93% ee), but modest yield (79%) (entry 6). With respect to ee, further screening indicated that the reaction conducted in THF at −78 °C in the presence of 2 mol% 1a offered the best result.

Table 1 Optimized condition for the reaction of 2a with 3a catalyzed by 1a–d^a

Entry	1 (mol%)	T (°C)	Solvent	Yield^b (%)	ee^c (%)
a Reaction conditions: catalyst 1 and 2a (1.2 mmol) were stirred in 2 mL THF under −78 °C for 15 min, then added 3a (1.0 mmol) dissolved in 1 mL THF, the resulting solution was stirred for 5 h.b Isolated yield.c ee was determined by HPLC analysis.d 36 h.
1	1a (10)	−60	THF	99	75
2	1a (8)	−60	THF	99	82
3	1a (5)	−60	THF	99	85
4	1a (2)	−60	THF	99	90
5	1a (2)	−78	THF	99	95
6	1a (1)	−78	THF	79	94^d
7	1b (2)	−78	THF	97	91
8	1c (2)	−78	THF	95	90
9	1d (2)	−78	THF	95	89
10	1e (2)	−78	THF	96	89
11	1a (2)	−78	DCM	99	85
12	1a (2)	−78	EA	98	89
13	1a (2)	−78	DMF	98	90
14	1a (2)	−78	Toluene	95	87

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With the optimized reaction conditions in hand, we focused on the substrate scope. The results were shown in Table 2. To our delight, the Michael addition reaction underwent cleanly to give the desired adducts 4 in full conversion and up to 99% ee in the presence of 2 mol% BINOL–quinine–squaramide 1a (entries 1–16). As illustrated in Table 2, azodicarboxylates 3 bearing more bulky groups reacted smoothly with 1,3-dicarbonyl compound 2, exclusively affording the corresponding products in excellent ee values (99% ee) (entries 3, 4, 7–12). In particular, the reaction of prop-2-yn-1-yl 2-oxocyclopentane-1-carboxylate 2c with azodicarboxylate 3c and 3d afforded the corresponding adducts 4i–l with the highest enantioselectivity (99% ee) (entries 9–12). To the best of our knowledge, the results for azodicarboxylate are the best ever achieved.

Table 2 Asymmetric Michael addition of 1,3-dicarbonyl compounds 2 with 3 catalyzed by 1a^a

Entry	2/3	4	Time (h)	Yield^b (%)	ee^c (%)
a Reaction conditions: catalyst 1a (0.02 mmol) and 2 (1.2 mmol) were stirred in 2 mL THF under −78 °C for 15 min, then added 3 (1.0 mmol) dissolved in 1 mL THF, the resulting solution was stirred for 5–48 h.b Isolated yield.c ee was determined by HPLC analysis, absolute configuration was assigned by the sign of specific rotation with that reported in the literature. The products 4a, 4c, 4d, 4e, 4g, 4h and 4m were determined to be (S), and the products 4b, 4f, 4n were determined to be (R).
1	2a/3a	4a	6	99	95
2	2a/3b	4b	12	98	97
3	2a/3c	4c	5	99	99
4	2a/3d	4d	48	97	99
5	2b/3a	4e	7	99	93
6	2b/3b	4f	12	98	99
7	2b/3c	4g	6	99	98
8	2b/3d	4h	48	96	99
9	2c/3a	4i	5	99	99
10	2c/3b	4j	15	98	99
11	2c/3c	4k	5	99	99
12	2c/3d	4l	48	97	99
13	2d/3a	4m	6	99	91
14	2d/3b	4n	12	99	99
15	2d/3c	4o	6	99	99
16	2d/3d	4p	24	96	99

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Encouraged by the excellent results with 1,3-dicarbonyl compounds, we then investigated the Michael addition of cyano esters 2e–h with azodicarboxylates 3. As shown in Table 3, when ethyl-2-cyano-2-phenylacetate 2e was employed, the desired adducts 4q–t were formed in 98–99% ees. The reaction of 2f with 3c proceeded slowly to form the desired product 4u in 75% yield and 98% ee (entry 5). In case of alkyl substituted cyano ester 2g and 2h, the corresponding products 4w and 4u were obtained in 92% and 99% ee, respectively.

Table 3 Asymmetric Michael addition of cyano acid ester 2e with compounds 3 catalyzed by 1a^a

Entry	2	3	4	Time (h)	Yield^b (%)	ee^c (%)
a Catalyst 1 (0.1 mmol) and 2e (6.0 mmol) were stirred in 2 mL THF under −78 °C for 15 min, then added solution of 3 (5.0 mmol) in 1 mL THF.b Isolated yield.c ee was determined by HPLC analysis.d 2 mol% of 1a was used.
1	2e	3a	4q	5	99	99
2	2e	3b	4r	12	98	99
3	2e	3c	4s	7	99	98
4	2e	3d	4t	20	97	99
5	2f	3c	4u	24	75	98
6	2f	3d	4v	6	92	91
7	2g^d	3c	4w	3	95	92
8	2h^d	3c	4x	5	97	99

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Moreover, the poor solubility of our catalyst 1a in organic solvents enabled its easy recovery by a simple precipitation. Therefore, to determine the recycling ability of catalyst, 1a was recovered after the catalytic process and was reused in the Michael addition of 2b with 3c under the optimized reaction condition (Table 4). As summarized in Table 4, recycled 1a was carried through at least five runs of amination that simply involved transfer the recovered catalyst to a new reaction vessel followed by the addition of substrate and solvent. It is noteworthy that in each case the catalyst was recovered in high yield (89–99%) after the reaction was completed and maintained its catalytic activity even after four cycles (97–99% ee).

Table 4 Recycling experiments of 1a in the reaction of 2b with 3c^a

Entry	Recovery rate (%)	Cycle	Time (h)	Yield^b (%)	ee^c (%)
a Reaction conditions: catalyst 1 (0.02 mmol) and 2b (1.2 mmol) were stirred in 2 mL THF under −78 °C for 15 min, then added 3c (1.0 mmol) dissolved in 1 mL THF, the resulting solution was stirred for 6–12 h.b Isolated yield.c ee was determined by HPLC analysis.
1	97	1	6	99	99
2	96	2	6	97	99
3	95	3	7	98	98
4	93	4	10	95	97
5	90	5	12	89	69

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The possible transition state model to explain the excellent enantioselectivities of the aminated adducts formed in this catalytic system was proposed (Scheme 3). The squaramide organocatalyst was assumed to create multiple hydrogen-bonding sites in which squaramide and cinchonine moiety interacted through hydrogen bonding with diketone simultaneously. Meanwhile, the two OH groups of binaphthyl moiety provide hydrogen bondings to azodicarboxylate. The tertiary amine of cinchonine moiety plays the role of the base to deprotonate α-carbon of the carbonyl group, forming the enolate to attack the electrophile, which leads to the formation the products. While, we are now working on further study aimed at clarifying the mechanism.

Scheme 3 Proposed transition state of amination.

Conclusions

A BINOL–quinine–squaramide 1a was identified as the best catalyst for the asymmetric α-amination of 1,3-dicarbonyl compounds and α-cyanoacetates with azodicarboxylates. A number of chiral amino acid derivatives were prepared in high yields and excellent enantioselectivities. The squaramide organocatalyst 1a can be recovered and reused for four times without loss the activity and enantioselectivity. Investigation of further application of this transformation to the construction of other pharmaceutically active substances is in progress.

Experimental

Materials and methods

All glassware was dried overnight in an oven prior to use. Unless otherwise noted, reagents and materials were obtained from commercial suppliers and used without further purification. All solvents were purified according to reported procedures. The catalysts 1a–e were prepared according to the literature procedure. Reactions were monitored by thin layer chromatography (TLC) and column chromatography purifications were performed using 230–400 mesh silica gel. ¹H and ¹³C NMR spectra were measured on Bruker DRX and DMX spectrometers at 400 MHz for ¹H spectra and 100 MHz for ¹³C spectra and calibrated from residual solvent signal. Mass spectra (MS) were measured on IonSpec 4.7 Tesla FTMS using DART Positive. Enantiomeric excesses (ees) were determined by HPLC analysis using a SHIMADZU Series instrument with Daicel Chiralpak AD-H, AS-H columns, as indicated. The data of these known products 4a,^52,55 4b,^54,56 4c,^40,57 4d,^43,52 4e and 4f,⁴³ 4g,³⁸ 4h,^21,43 4i,²⁴ 4m,^21,24 was consistent with those reported in the corresponding references.

General procedure for α-hydrazination reaction of 1,3-dicarbonyl compound

In a 10 mL round-bottomed flask, the 1,3-dicarbonyl compound 2 (1 mmol) was added to the agitated solution of catalyst 1a (2 mol%) in 2 mL THF at −78 °C. After 15 min, compound 3 (1.2 mmol) in 1 mL THF was added. The reaction was monitored by TLC and condensed under reduced pressure and subjected to flash chromatography column to give the pure product 4.

4a. [α]²⁰_D = +2.1 (c 0.75, CHCl₃), Lit.⁵² [α]²⁵_D = +1.92 (c 0.85, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 6.73 (br, 1H), 4.45–3.86 (m, 6H), 2.80–1.79 (m, 6H), 1.19 (dd, J = 15.8, 8.2 Hz, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 167.71, 156.08, 155.53, 63.15, 62.34, 62.22, 18.69, 14.35, 14.24, 13.99. ESI [M + H]⁺ m/z, 331. Chiralpak AD-H column (250 mm × 4.6 mm), 5% iPrOH/hexane; 1 mL min⁻¹, 210 nm; t_major = 23.128 min, t_minor = 27.308 min, ee = 95%.

4b. [α]²⁰_D = −6.28 (c 0.45, CHCl₃), Lit.⁵⁶ [α]²⁵_D = −0.32 (c 0.99, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 6.57 (br, 1H), 5.09–4.73 (m, 2H), 4.35–4.03 (m, 2H), 2.92–1.69 (m, 6H), 1.24 (dq, J = 11.0, 6.8 Hz, 15H). ¹³C NMR (100 MHz, CDCl₃) δ 167.57, 155.76, 154.97, 76.94, 71.07, 69.89, 62.14, 36.54, 33.25, 31.82, 21.72, 18.55, 13.90. ESI [M + H]⁺ m/z, 359. Chiralpak AD-H column (250 mm × 4.6 mm), 10% iPrOH/hexane, 1 mL min⁻¹, 210 nm. t_major = 6.983 min, t_minor = 8.315 min, ee = 97%.

4c. [α]²⁰_D = +3.79 (c 0.67, CHCl₃), Lit.⁵⁷ [α]²⁰_D = + 3.70 (c 1.1, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 7.28–7.09 (m, 10H), 7.00 (br, 1H), 5.03 (d, J = 9.8 Hz, 4H), 4.22–3.89 (m, 2H), 2.82–0.89 (m, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 156.02, 135.23, 128.58, 128.53, 128.44, 128.36, 128.10, 128.02, 68.74, 67.89, 62.46, 18.75, 13.97. ESI [M + H]⁺ m/z, 455. Chiralpak AS-H column (250 mm × 4.6 mm), 30% iPrOH/hexane, 0.65 mL min⁻¹, 254 nm. t_major = 17.058 min; t_minor = 30.793 min, ee = 99%.

4d. [α]²⁰_D = +3.65 (c 1.23, CHCl₃), Lit.⁵² [α]²⁶_D = −2.38 (c 1.23, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 6.38 (br, 1H), 4.19 (s, 2H), 2.81–1.67 (m, 6H), 1.41 (s, 18H), 1.25 (t, J = 6.4 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 167.85, 155.04, 154.24, 82.47, 81.22, 76.01, 61.98, 37.09, 31.95, 27.97, 27.86, 18.44, 13.93. ESI [M + H]⁺ m/z, 387. Chiralpak AD-H column (250 mm × 4.6 mm), 20% iPrOH/hexane, 0.8 mL min⁻¹, 220 nm. t_major = 6.867 min; t_minor = 9.840 min, ee = 99%.

4e. [α]²⁰_D = +1.95 (c 0.48, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 6.81 (br, 1H), 4.28–4.10 (m, 4H), 3.78 (s, 3H), 2.86–1.86 (m, 6H), 1.26 (dt, J = 10.6, 7.1 Hz, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 168.06, 156.11, 155.44, 76.95, 63.11, 62.17, 53.13, 36.62, 31.72, 18.59, 14.29, 14.18. ESI [M]⁺ m/z, 316 found 316. Chiralpak AD-H column (250 mm × 4.6 mm), 5% iPrOH/hexane, 1 mL min⁻¹, 210 nm. t_major = 18.317 min; t_minor = 24.238 min, ee = 91%.

4f. [α]²⁰_D = +0.77 (c 0.19, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 6.65 (br, 1H), 4.91 (s, 2H), 3.76 (s, 3H), 2.99–1.58 (m, 6H), 1.23 (dd, J = 12, 6.4 Hz, 12H). ¹³C NMR (100 MHz, CDCl₃) δ 168.05, 155.84, 155.00, 71.25, 70.47, 70.09, 53.14, 36.63, 21.89, 21.83, 21.79, 18.62. ESI [M + H]⁺ m/z, 345. Chiralpak AD-H column (250 mm × 4.6 mm), 20% iPrOH/hexane, 1.0 mL min⁻¹, 210 nm. t_major = 5.238 min; t_minor = 6.905 min, ee = 97%.

4g. [α]²⁰_D = +5.84 (c 1.49, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 7.68–7.14 (m, 10H), 7.00 (br, 1H), 5.11 (d, J = 8.5 Hz, 4H), 3.68 (s, 3H), 2.86–1.76 (m, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 135.35, 135.18, 128.59, 128.54, 128.47, 128.39, 128.11, 68.81, 67.95, 53.26, 18.71. ESI [M + H]⁺ m/z, 441 found 441. Chiralpak AS-H column (250 mm × 4.6 mm), 3% iPrOH/hexane, 0.65 mL min⁻¹, 254 nm. t_major = 19.557 min; t_minor = 39.188 min, ee = 99%.

4h. [α]²⁰_D = +5.89 (c 0.39, CHCl₃), Lit.²¹ [α]²⁹_D = −5.74 (c 1.44, CHCl₃), ¹H NMR (400 MHz, methanol-d₄) δ 3.73 (s, 3H), 2.79–1.78 (m, 6H), 1.44 (d, J = 11.4 Hz, 18H). ¹³C NMR (100 MHz, CDCl₃) δ 205.12, 155.12, 154.25, 82.66, 81.37, 52.96, 36.82, 31.96, 28.07, 28.01, 27.89, 18.46. ESI [M]⁺ m/z, 372 found 372. Chiralpak AD-H column (250 mm × 4.6 mm), 5% iPrOH/hexane, 1 mL min⁻¹, 210 nm. t_major = 13.385 min; t_minor = 22.527 min, ee = 99%.

4i. [α]²⁰_D = −3.7 (c 0.25, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 6.82 (br, 1H), 4.94–4.57 (m, 2H), 4.37–3.97 (m, 4H), 2.84–1.74 (m, 7H), 1.24 (q, J = 7.4 Hz, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 156.15, 76.65, 75.74, 63.35, 62.33, 53.55, 18.64, 14.36, 14.24. Calcd for C₁₅H₂₀N₂O₇Na (M + Na)⁺: 363.1163, found: 363.1172. Chiralpak AD-H column (250 mm × 4.6 mm), 10% iPrOH/hexane, 1.0 mL min⁻¹, 210 nm. t_major = 14.555 min, t_minor = 17.320 min, ee = 95%.

4j. [α]²⁰_D = 1.35 (c 0.19, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 6.56 (br, 1H), 5.08–4.85 (m, 2H), 4.74 (dd, J = 15.3, 2.1 Hz, 2H), 2.94–1.69 (m, 7H), 1.46–1.06 (m, 12H). ¹³C NMR (100 MHz, CDCl₃) δ 155.85, 154.96, 75.73, 71.48, 70.21, 53.52, 21.84, 18.65. Calcd for C₁₇H₂₄N₂O₇Na (M + Na)⁺: 391.1476, found: 391.1481. Chiralpak AD-H column (250 mm × 4.6 mm), 10% iPrOH/hexane, 1.0 mL min⁻¹, 210 nm. t_major = 9.847 min, t_minor = 13.930 min, ee = 99%.

4k. [α]²⁰_D = 11.70 (c 1.37, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 7.51–7.16 (m, 10H), 6.94 (br, 1H), 5.11 (d, J = 10.0 Hz, 4H), 4.67 (s, 2H), 2.70 (s, 2H), 2.51–2.40 (m, 1H), 2.28 (br, 2H), 1.98 (s, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 156.02, 135.33, 135.09, 128.59, 128.56, 128.47, 128.41, 128.06, 75.82, 68.88, 67.96, 53.61, 18.66. Calcd for C₂₅H₂₄N₂O₇Na (M + Na)⁺: 487.1476, found: 487.1473. Chiralpak AS-H column (250 mm × 4.6 mm), 30% iPrOH/hexane, 0.8 mL min⁻¹, 254 nm. t_major = 29.105 min, t_minor = 52.150 min, ee = 99%.

4l. [α]²⁰_D = 2.58 (c 0.86, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 6.40 (br, 1H), 5.01–4.48 (m, 2H), 2.63–1.57 (m, 7H), 1.52–1.36 (m, 18H). ¹³C NMR (100 MHz, CDCl₃) δ 155.18, 154.24, 83.02, 81.59, 76.82, 75.62, 53.41, 28.09, 28.00, 18.54. Calcd for C₁₉H₂₈N₂O₇Na (M + Na)⁺: 419.1816, found: 419.1801. Chiralpak AD-H column (250 mm × 4.6 mm), 5% iPrOH/hexane, 1.0 mL min⁻¹, 210 nm. t_major = 19.463 min, t_minor = 34.853 min, ee = 99%.

4m. [α]²⁰_D = +123.17 (c 1.19, CHCl₃), Lit.²¹ [α]³⁰_D = 119.29 (c 0.54, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 6.76 (br, 1H), 4.21 (d, J = 7.0 Hz, 4H), 2.31 (d, 9H), 1.27 (dt, J = 11.6, 7.1 Hz, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 156.44, 155.84, 82.36, 63.43, 62.42, 36.87, 30.31, 17.95, 14.34, 14.19. ESI [M + H]⁺ m/z, 301. Chiralpak AD-H column (250 mm × 4.6 mm), 5% iPrOH/hexane, 1 mL min⁻¹, 210 nm. t_major = 21.878 min; t_minor = 26.520 min, ee = 90%.

4n. [α]²⁰_D = −12.4 (c 0.16, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 6.62 (br, 1H), 4.94 (dt, J = 10.9, 5.6 Hz, 2H), 2.88–1.54 (m, 9H), 1.21 (d, J = 14.1 Hz, 12H). ¹³C NMR (100 MHz, CDCl₃) δ 199.85, 156.08, 155.31, 82.13, 71.33, 70.12, 36.89, 30.19, 29.55, 21.81, 21.75, 17.91. ESI [M + H]⁺ m/z, 329. Chiralpak AD-H column (250 mm × 4.6 mm), 10% iPrOH/hexane, 1 mL min⁻¹, 211 nm. t_major = 9.298 min; t_minor = 13.065 min, ee = 99%.

4o. [α]²⁰_D = 13.42 (c 0.35, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 7.54–7.17 (m, 10H), 7.05 (br, 1H), 5.12 (br, 4H), 2.86–1.65 (m, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 199.99, 156.33, 155.80, 128.60, 128.57, 128.51, 128.16, 82.44, 68.95, 68.03, 36.88, 30.33, 24.95, 18.01. Calcd for C₂₃H₂₄N₂O₆Na (M + Na)⁺: 447.1527, found: 447.1523. Chiralpak AD-H column (250 mm × 4.6 mm), 10% iPrOH/hexane, 0.8 mL min⁻¹, 254 nm. t_major = 31.878 min; t_minor = 36.422 min, ee = 99%.

4p. [α]²⁰_D = −9.40 (c 0.12, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 6.46 (br, 1H), 2.70–1.69 (m, 9H), 1.44 (d, J = 8.8 Hz, 18H). ¹³C NMR (100 MHz, CDCl₃), 199.82, 155.11, 82.77, 82.09, 81.57, 37.00, 29.98, 28.09, 28.04, 27.89, 24.77, 17.92. ESI [M]⁺ m/z, 356. Chiralpak AD-H column (250 mm × 4.6 mm), 15% iPrOH/hexane, 1 mL min⁻¹, 210 nm. t_major = 9.040 min, t_minor = 17.323 min, ee = 98%.

4q. [α]²⁰_D = −5.56 (c 0.38, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 7.80–7.35 (m, 5H), 6.40 (br, 1H), 4.41–3.93 (m, 6H), 1.35–0.99 (m, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 155.13, 130.68, 130.44, 129.28, 129.07, 128.77, 128.22, 128.04, 77.25, 64.42, 64.09, 62.82, 62.37, 25.32, 14.35, 14.26, 13.77. Calcd for C₁₇H₂₁N₃O₆Na (M + Na)⁺: 386.1323, found: 386.1330. Chiralpak AD-H column (250 mm × 4.6 mm), 15% iPrOH/hexane, 0.8 mL min⁻¹, 210 nm. t_major = 17.302 min, t_minor = 24.263 min, ee = 99%.

4r. [α]²⁰_D = −6.94 (c 0.29, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 7.86–7.32 (m, 5H), 6.20 (br, 1H), 5.13–4.73 (m, 2H), 4.42–4.19 (m, 2H), 1.39–0.95 (m, 15H). ¹³C NMR (100 MHz, CDCl₃) δ 154.78, 130.59, 130.31, 129.72, 129.18, 129.01, 128.68, 128.19, 128.07, 77.28, 72.53, 71.10, 70.20, 69.01, 63.99, 21.96, 21.86, 21.76, 21.66, 21.55, 13.76. Calcd for C₁₉H₂₅N₃O₆Na (M + Na)⁺: 414.1636, found: 414.1645. Chiralpak AD-H column (250 mm × 4.6 mm), 30% iPrOH/hexane, 0.8 mL min⁻¹, 210 nm. t_major = 8.727 min, t_minor = 11.513 min, ee = 99%.

4s. [α]²⁰_D = −7.43 (c 0.92, CHCl₃), ¹H NMR (400 MHz, DMSO-d₆) δ 7.71–6.97 (m, 15H), 5.32–4.89 (m, 4H), 4.49–3.99 (m, 2H), 1.14 (d, J = 8.4 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 165.07, 155.31, 154.94, 135.40, 134.75, 130.61, 130.53, 129.23, 129.18, 129.14, 128.83, 128.60, 128.55, 128.48, 128.27, 128.14, 127.97, 115.36, 69.57, 69.15, 67.97, 67.70, 64.18, 25.22, 13.63. Calcd for C₂₇H₂₅N₃O₆Na (M + Na)⁺: 510.1636, found: 510.1619. Chiralpak OD-H column (250 mm × 4.6 mm), 15% iPrOH/hexane, 1.0 mL min⁻¹, 210 nm. t_major = 13.787 min, t_minor = 17.308 min, ee = 98%.

4t. [α]²⁰_D = −36.59 (c 0.74, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 7.84–7.36 (m, 5H), 6.05 (br, 1H), 4.31 (dt, J = 15.0, 7.3 Hz, 2H), 1.66–1.21 (m, 21H). ¹³C NMR (100 MHz, CDCl₃) δ 154.06, 130.14, 129.19, 128.90, 128.20, 128.01, 77.23, 63.85, 28.15, 28.00, 27.89, 13.78. Calcd for C₂₁H₂₉N₃O₆Na (M + Na)⁺: 442.1949, found: 442.1947. Chiralpak AD-H column (250 mm × 4.6 mm), 30% iPrOH/hexane, 0.8 mL min⁻¹, 210 nm. t_major = 7.922 min, t_minor = 17.823 min, ee = 99%.

4u. [α]²⁰_D = −2.44 (c 0.78, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 7.74–7.27 (m, 11H), 7.11–6.75 (m, 3H), 6.61 (br, 1H), 5.29–5.01 (m, 4H), 4.10 (q, J = 7.2 Hz, 2H), 3.76 (d, J = 9.6 Hz, 3H), 1.16 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 161.05, 155.16, 134.75, 129.76, 129.59, 129.24, 128.58, 128.47, 128.29, 128.03, 120.93, 115.50, 114.54, 114.43, 114.12, 69.56, 68.51, 68.00, 67.85, 67.75, 64.06, 55.40, 13.68. Calcd for C₂₈H₂₈N₃O₇ (M + H)⁺: 518.1927, found: 518.1939. Chiralpak OD-H column (250 mm × 4.6 mm), 20% iPrOH/hexane, 0.8 mL min⁻¹, 254 nm. t_major = 15.165 min; t_minor = 18.845 min, ee = 98%.

4v. [α]²⁰_D = −3.43 (c 0.85, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 7.76–7.43 (m, 2H), 6.92 (d, J = 9.2 Hz, 2H), 5.97 (br, 1H), 4.30 (d, J = 13.4 Hz, 2H), 3.83 (s, 3H), 1.59–1.25 (m, 21H). ¹³C NMR (100 MHz, CDCl₃) δ 128.60, 128.28, 63.64, 13.89, 8.63. Calcd for C₂₂H₃₂N₃O₇ (M + H)⁺: 450.2240, found: 450.2252. Chiralpak OD-H column (250 mm × 4.6 mm), 15% iPrOH/hexane, 1 mL min⁻¹, 254 nm. t_major = 24.563 min; t_minor = 30.925 min, ee = 91%.

4w. [α]²⁰_D = −4.29 (c 1.25, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 7.30 (m, 10H), 5.43–4.84 (m, 4H), 4.15 (d, J = 56.2 Hz, 2H), 2.16–0.93 (m, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 135.26, 134.66, 128.63, 128.59, 128.34, 128.17, 116.43, 69.38, 68.31, 63.90, 60.35, 22.33, 13.77. Calcd for C₂₂H₂₄N₃O₆ (M + H)⁺: 426.1665, found: 426.1674. Chiralpak AS-H column (250 mm × 4.6 mm), 20% iPrOH/hexane, 0.8 mL min⁻¹, 254 nm. t_major = 14.178 min; t_minor = 17.223 min, ee = 92%.

4x. [α]²⁰_D = −2.69 (c 1.32, CHCl₃), ¹H NMR (400 MHz, CDCl₃) δ 7.30 (m, 10H), 6.77 (br, 1H), 5.18 (d, J = 13.2 Hz, 4H), 4.70–3.89 (m, 2H), 2.41–0.81 (m, 8H). ¹³C NMR (100 MHz, CDCl₃) δ 135.26, 134.66, 128.63, 128.59, 128.34, 128.17, 116.43, 69.38, 68.31, 63.90, 60.35, 22.33, 13.77. Calcd for C₂₃H₂₆N₃O₆ (M + H)⁺: 440.1822, found: 440.1832. Chiralpak AS-H column (250 mm × 4.6 mm), 5% iPrOH/hexane, 1 mL min⁻¹, 254 nm. t_major = 36.165 min; t_minor = 48.025 min, ee = 99%.

Procedure for recycling of catalyst

For the catalyst recycling experiment, after Michael addition the mixture was centrifuged and the catalyst deposited at the bottom of the vial. The liquid layer was siphoned out; the residual solid was washed again until no more compounds were detected by TLC. Then the vial with remaining catalyst was dried under vacuum.

Acknowledgements

We are grateful to the NSFC (81172935, 81373255, 21202125), Key Project of Ministry of Education (313040), Hubei Province's Outstanding Medical Academic Leader Program, the Scientific and Technological Innovative Research Team of Wuhan (2013070204020048), Hubei Province Natural Science Foundation (no. 2014CFB241), and the Fundamental Research Funds for the Central Universities (2042014kf0204 and 2042014kf0248) for support of this research.

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Footnote

† Electronic supplementary information (ESI) available: NMR and HPLC spectra of compounds 4. See DOI: 10.1039/c4ra13789b

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