Epiandrosterone-derived prolinamide as an efficient asymmetric catalyst for Michael addition reactions of aldehydes to nitroalkenes

Abstract

Epiandrosterone derivatives-organocatalyzed asymmetric Michael addition of aldehydes to nitroalkenes was investigated. Among the various catalysts, a novel type of epiandrosterone-derived L-prolineamide catalyst was synthesized and exhibited better performance in both catalytic activity and stereoselectivity, providing the products with high yields (up to 98%), excellent enantioselectivities (up to 99% ee) and diastereoselectivities (up to 99 : 1 dr), and low catalyst loading (5 mol%).

---

Introduction

Among the numerous asymmetric carbon–carbon bond-forming reactions in organic synthesis, catalytic asymmetric Michael addition plays a very important role.¹ In recent years, this type of reaction has been an effective strategy for the synthesis of natural products.² Among the variants of this reaction, the Michael addition of ketones or aldehydes to nitroalkenes has received more and more attention. This is because the nitro group can be easily transformed into various useful functional groups, such as amines, nitrile oxides, ketones, and carboxylic acids, etc.^3,4 As one of the most critical factors, organocatalysts have shown a strong advantage for achieving effective stereocontrol in addition reactions.⁵ Due to the growing need for an environmentally-friendly nonmetal-catalyzed asymmetric synthesis, considerable attention has recently been focused on the development of new, highly effective, relatively non-toxic, and small-molecule chiral organocatalysts.

As one of the most successfully and widely applicable modern organocatalyts based on covalent character, proline and proline derivatives play a dominant role in asymmetric catalysis.⁶ Among a variety of different catalysts, diarylprolinol silyl ethers, introduced as organocatalysts by Jørgensen and Hayashi independently in 2005,⁷ have demonstrated excellent performances in asymmetric enamine organocatalysis.⁸ More recently, many proline-derived organocatalysts, such as aminomethyl pyrrolidine,^9a–c prolinamide,^9d–h peptide,^9i,j and diarylprolinol silyl ether,^9k–m have been developed and exhibited high reactivities and enantioselectivities. Although these organocatalysts have provided satisfactory results in asymmetric Michael addition reactions, development of new, effective catalysts is still desired. In our recent studies directed toward devising highly enantioselective catalysts for the addition of aldehydes to nitroalkenes, we planned to design a new class of bifunctional chiral prolinamide catalysts with an epiandrosterone-derived primary amine based on the mechanism of enamine formation and hydrogen bonding. Epiandrosterone belongs to steroid compounds and could be prepared from natural product dioscin. Generally, as a weak androgen, it is widely recognized to inhibit the pentose phosphate pathway (PPP) and to decrease intracellular NADPH levels.¹⁰ To the best of our knowledge, there is no report to date of epiandrosterone as organocatalyst except for its analogs used as transition-metal steroid catalysts.¹¹ It was speculated that the optical activity and steric effect of epiandrosterone would be benefit for enantio- and diastereoselectivity of the Michael addition ketones or aldehydes to nitroalkenes. Herein, we describe the ability of the new bifunctional organocatalyst in performing asymmetric Michael addition reactions.

Results and discussion

The design and synthesis of highly stereoselective catalysts are always desirable for asymmetric catalysis. In this direction, we have developed an efficient synthesis of L-proline-epiandrosterone organocatalyst. The synthetic route of target compounds is shown in Scheme 1. Synthesis of amide 6a started from commercially available epiandrosterone. By treatment with methanesulfonyl chloride for 3 h at 0 °C, the mesylate 2a was prepared from epiandrosterone (1a). Subsequently, compound 2a was converted to the azide 3a in dimethylformamide with sodium azide. Then, hydrogenation of 3a with Pd/C in methanol provided amine 4a. Next, amine 4a was treated with N-Boc protected proline afford compound 5a. Finally, N-Boc of 5a was deprotected to afford 6a in TFA. In addition, the epimer (6b) of catalyst 6a and other epiandrosterone-derived amides 7–10 were also prepared according to the above-described synthesis method (for the general procedure sees ESI†). All the new compounds synthesized were characterized by ¹H NMR, ¹³C NMR, HRMS, and IR spectroscopy.

Scheme 1 Synthetic routes to organocatalyst 6a. Reagents and conditions: (a) MsCl, CH₂Cl₂, 0 °C, 3 h, 98%; (b) NaN₃, DMF, 80 °C, 8 h, 91%; (c) 10% Pd/C, H₂, MeOH, 12 h, 95%; (d) EDCI, DMAP, N-Boc protected proline, CH₂Cl₂, r.t., 20 h, 92%; (e) TFA, CH₂Cl₂, r.t., 95%.

Initially, the model reaction of nitrostyrene (12a) with propanal (13a) was carried out in the presence of 10 mol% of catalyst and 10 mol% of benzoic acid as an additive in toluene under room temperature (Table 1). As shown in Table 1, catalysts 6–11 exhibited significantly different catalytic activity and enantioselectivity toward the process. Among the organocatalysts surveyed, when catalyst 6a was used, the result was observed with an excellent yield (92%), diastereoselectivities (syn/anti = 72 : 28) and enantioselectivity (89% ee) (entry 1). To further understand the role of epiandrosterone unit of catalyst, the epimer (6b) of catalyst 6a was synthesized and its catalytic activity was investigated (entry 2). The experiment result exhibited a moderate performance on both yield (81%) and stereoselectivity (84% ee). It was speculated that epiandrosterone or androsterone only acts as a steric hindrance to create a chiral environment and their steric effect is very obvious by comparison of the catalytic results of 6a with those of several non-chiral prolinamide derivatives in the model Michael reaction (for the result see ESI†). However, other epiandrosterone-derived amide catalysts 7–10 gave poor yields. In addition, L-proline (11) could catalyze this reaction, but rather poor yield and stereoselectivity were observed (entry 7). According to the above result, 3α-N-(pyrrolidine-2-formyl)-5α-androstan-17-one 6a was confirmed to be the most effective catalyst in terms of both the yield and enantioselectivity of the reaction.

Table 1 Screening of catalysts and solvents^a

Entry	Catalyst (mol%)	Solvent	Time (h)	Yield^b (%)	syn/anti^c	ee (syn)^d (%)
a All reactions were carried out using 12a (3.0 mmol) and 13a (1.0 mmol) in the presence of catalysts in solvent (1.0 mL).b Yield of the isolated product.c Determined by ^1H NMR analysis of the products.d Determined by chiral HPLC, the absolute configuration was established by comparison with literature data.
1	6a (10)	Toluene	12	92	72 : 28	89
2	6b (10)	Toluene	12	81	68 : 32	84
3	7 (10)	Toluene	36	10	88 : 12	90
4	8 (10)	Toluene	36	9	74 : 26	88
5	9 (10)	Toluene	36	<5	—	—
6	10 (10)	Toluene	36	<5	—	—
7	11 (10)	Toluene	24	34	65 : 35	20
8	6a (10)	CH2Cl2	18	82	71 : 29	79
9	6a (10)	CHCl3	18	85	68 : 32	81
10	6a (10)	Hexane	24	62	69 : 31	74
11	6a (10)	THF	48	<5	—	—
12	6a (10)	CH3CN	48	<5	—	—
13	6a (10)	CH3OH	48	<5	—	—
14	6a (5)	Toluene	12	90	74 : 26	89
15	6a (3)	Toluene	45	90	82 : 18	86
16	6a (1)	Toluene	87	89	81 : 19	84

---

With an optimum catalyst 6a in hand, other reaction parameters, including solvents, additives, temperatures, and amounts of catalyst were examined in order to further improve the reactivity and enantioselectivity, and the results are shown in Tables 1 and 2. A range of typical solvents were first screened in the presence of benzoic acid (10 mol%) and catalyst 6a (10 mol%) at room temperature. Besides toluene, some nonpolar and aprotic solvents, such as CH₂Cl₂, CHCl₃, hexane, and THF, were also investigated for this reaction (Table 1, entries 1 and 8–11). The excellent yield and enantioselectivity (92% yield, and 89% ee) could be obtained when the reaction was carried out in toluene (Table 1, entry 1). However, some polar solvents, such as acetonitrile and methanol, gave rather poor yield and stereoselectivity (Table 1, entries 12 and 13). Moreover, we examined the influence of catalyst loading on the reaction. When the catalyst 6a was reduced to 5 mol%, the reaction provided the same result as it using 10 mol% of catalyst (Table 1, entry 14). However, with lower catalyst loading, a prolonged time was required (Table 1, entries 15 and 16). Next, the effect of a series of different organic additives was tested and the results are summarized in Table 2. Apparently, the reaction proceeded very slowly in the absence of acid additives and provided poor yield and enantioselectivity after 48 h (Table 2, entries 1–3). When using PhCOOH as an acid additive, the better result was observed with an excellent yield (92%) and enantioselectivity (89% ee) (Table 1, entry 1). The other acid additives, such as HCOOH and CH₃COOH, were also benefit for this reaction, although their yields and enantioselectivities were slightly lower than the results with PhCOOH (Table 2, entries 5, 6 and 8). However, addition of a strong acid, such as p-TSA or TFA, was not favorable to the reaction (Table 2, entries 4 and 7). In addition, three chiral acid tartaric acid, N-Boc glycine and mandelic acid was employed (Table 2, entries 8–10), and the yield and stereoselectivity were moderate. It was implied that in the Michael addition the acid additives only provided the proton. The influence of acid loading on the reaction was also examined (Table 2, entries 11 and 12). It was observed that 10 mol% of PhCOOH gave the optimal results in terms of both activity and stereoselectivity. Additionally, the effect of reaction temperature was investigated. As revealed in Table 2 (entries 13–16), temperature has significant impact on the catalytic effect. It was obvious that good enantioselectivity could be obtained under low reaction temperature conditions. Based on the overall evaluation, −20 °C was selected to be the optimal reaction temperature.

Table 2 Screening of additive and temperature^a

Entry	Additive	Tem. (°C)	Time (h)	Yield^b (%)	syn/anti^c	ee^d (%)
a All reactions were carried out using 12a (3.0 mmol) and 13a (1.0 mmol) in the presence of catalyst 6a (5 mol%) in toluene (1.0 mL).b Yield of the isolated product.c Determined by ^1H NMR analysis of the crude products.d Determined by chiral HPLC.e 5 mol% of PhCOOH was used.f 1 mol% of PhCOOH was used.
1	None	r.t.	48	<5	—	—
2	H2O	r.t.	48	<5	—	—
3	Et3N	r.t.	48	<5	—	—
4	p-TSA	r.t.	48	<5	—	—
5	HCOOH	r.t.	12	90	70 : 30	88
6	CH3COOH	r.t.	18	82	76 : 24	86
7	CF3COOH	r.t.	18	<5	—	—
8	Tartaric acid	r.t.	48	62	70 : 30	83
9	N-Boc glycine	r.t.	48	71	62 : 38	72
10	Mandelic acid	r.t.	48	63	68 : 32	78
11^e	PhCOOH	r.t.	18	51	65 : 35	84
12^f	PhCOOH	r.t.	48	<5	—	—
13	PhCOOH	50	6	96	76 : 24	80
14	PhCOOH	0	24	90	74 : 26	90
15	PhCOOH	−20	24	88	61 : 39	94
16	PhCOOH	−40	48	68	82 : 18	95

---

Under the above optimized conditions, the scope of the asymmetric Michael addition reaction was investigated by applying different aldehydes and nitroalkenes in the presence of 5 mol% of catalyst 6a and 10 mol% PhCOOH in toluene at −20 °C. The results are summarized in Table 3. Products were obtained with good yields (88–98%) and excellent enantioselectivities (93–99% ee) (Table 3). The steric hindrance of the R₁ group for aliphatic aldehydes was benefit for the increase of diastereoselectivity to a large degree (entries 1–5). For examples, the reaction of propanal gave a moderate diastereoselectivity (61 : 39 dr) (entry 1), while that of 3-methylbutanal provided an excellent diastereoselectivity (98 : 2 dr) (entry 4). Moreover, aromatic nitroalkenes, regardless of electron-donating and electron-withdrawing substituents on the phenyl ring, participated in this process in high yield (90–98%) and excellent ee values (94–99%). The excellent enantioselectivities (93–97% ee) was also observed for the Michael addition of aldehydes to nitroalkenes containing heteroaryl groups. Additionally, on the basis of the condition, the Michael addition of an alkyl-substituted nitroalkene has also been investigated (entry 15). The high yield (94%) and excellent enantioselectivities (95%) were observed for the Michael addition product.

Table 3 Asymmetric Michael additions of aldehydes to nitroalkenes catalyzed by 6a^a

Entry	Product	Yield^b (%)	syn : anti^c	ee (syn)^d (%)	Entry	Product	Yield^b (%)	syn : anti^c	ee (syn)^d (%)
a All reactions were carried out using nitroalkenes (1.0 mmol) and aldehydes (3.0 mmol) in the presence of catalyst 6a (5 mol%) in toluene (1.0 mL) at −20 °C.b Yield of the isolated product.c Determined by ^1H NMR analysis of the crude products.d Determined by chiral HPLC, the absolute configuration was established by comparison with literature data.
1		88	61 : 39	94	9		91	80 : 20	96
2		94	83 : 17	98	10		90	87 : 13	98
3		90	94 : 6	95	11		98	84 : 16	98
4		91	98 : 2	99	12		95	82 : 16	99
5		91	96 : 4	96	13		95	57 : 43	93
6		96	99 : 1	99	14		92	53 : 47	97
7		98	68 : 32	98	15		94	95 : 5	95
8		95	92 : 8	97

---

In order to account for the good enantioselectivity of the reaction, a plausible transition-state model is proposed in Scheme 2. The pyrrolidine functionality activates the aldehyde through the formation of an enamine intermediate, and the nitro group of trans-β-nitrostyrene is directed toward the amide group by the hydrogen bond between the NH group of the amide and the nitro group. The enamine formed in situ attacks the Si face of the nitroalkene to furnish the Michael adduct. Some literatures^12–14 could be taken as a support of the hypothesis. Additionally, the bulky epiandrosterone group is considered to be important to the high catalytic activity and enantio- and diastereo-selectivity of the catalyzed reactions.

Scheme 2 Possible transition state of the reaction.

Conclusions

In summary, we have developed a new prolinamide catalyst 6a for the asymmetric conjugate addition reactions between aldehydes and nitroalkenes. This catalyst exhibited rather high catalytic efficiency and good to excellent levels of stereoselectivity. Since the catalyst 6a is easily prepared from commercially available Boc-L-proline and epiandrosterone in several steps, we believe that catalyst 6a is an ideal candidate for laboratory or large-scale preparations. Further applications of the catalyst to a wider scope of reactions are being studied in our laboratory.

Experimental section

General information

Reagents and materials were of the highest commercially available grade and used without further purification. Solvents were purified by standard procedures and distilled before use. The reactions were monitored by thin layer chromatography (TLC) using silica gel GF₂₅₄. Column chromatography was performed on silica gel (200–300 mesh). Compounds were visualized by UV and spraying with H₂SO₄ (10%) in ethanol and followed by heating. The NMR spectra were recorded on a Bruker DRX400 (¹H: 400 MHz, ¹³C: 100 MHz) and DRX500 (¹H: 500 MHz, ¹³C: 125 MHz) with TMS as the internal standard, chemical shifts (δ) are expressed in ppm, and J values are given in Hz, and deuterated CDCl₃ and was used as solvent. IR spectra were recorded on a FT-IR Thermo Nicolet Avatar 360 using KBr pellet. The mass spectroscopic data were obtained at the Agilent 1100 LC/MSD Trap LC-mass spectrometer. HPLC analysis was performed with a Shimadzu LC-10A instrument equipped with Daicel HPLC columns.

Procedure for the synthesis of 3β-mesyloxy-5α-androstan-17-one (2a)¹⁵

To a 10 mmol solution of 1a in 100 mL of CH₂Cl₂ at 0 °C was added 20 mmol (2 eq., 2.8 mL) of Et₃N followed by slow addition of 12 mmol (1.2 eq., 929 μL) of methanesulfonyl chloride. The mixture was stirred for 3 h at 0 °C and diluted with cold water. The solution was extracted twice with 100 mL of CH₂Cl₂. The organic layer was washed successively with H₂O to neutral pH and with brine. The solution was dried over anhydrous MgSO₄, filtered, and concentrated to afford crude product which was chromatographed on silica gel using 30% ethyl acetate in n-hexane to afford 2a in 98% yield as amorphous solid (3.5 g). [α]²⁰_D = +67.6 (c 1.0, CDCl₃); IR (KBr) 525, 857, 936, 1171, 1350, 1738, 2854, 2932, 3459 cm⁻¹; m.p. 158–159 °C; HRMS (EI) calcd for C₂₀H₃₂O₄S [M + Na]⁺ 391.1913, found 391.1915. ¹H-NMR (500 MHz, CDCl₃) δ 4.61 (1H, m), 3.30 (3H, s), 2.43 (1H, dd, J = 19, 8.8 Hz), 2.07 (1H, dt, J = 19, 9 Hz), 1.98 (1H, m), 1.93 (1H, m), 1.79 (4H, d), 1.73 (1H, m), 1.62 (3H, m), 1.53 (3H, m), 1.28 (8H, m), 1.02 (3H, m), 0.86 (6H, s), 0.71 (1H, m); ¹³C-NMR (125 MHz, CDCl₃) δ 221.2, 82.2, 54.6, 51.7, 48.1, 45.2, 39.2, 37.1, 36.2, 35.8, 35.5, 35.4, 31.9, 31.1, 29.0, 28.6, 22.1, 20.9, 14.2, 12.6.

Procedure for the synthesis of 3α-azido-5α-androstan-17-one (3a)¹⁶

NaN₃ (2 eq., 1.24 g) was added to a solution of mesylate 2a (3.5 g, 9.51 mmol) in DMF (30 mL) and stirred overnight at room temperature. Water (50 mL) was added and the aqueous phase was extracted with ethyl acetate (3 × 30 mL). The combined organic extracts were washed with saturated aqueous NaCl solution (2 × 100 mL) and dried over anhydrous MgSO₄. The solvent was removed under reduced pressure. Silica gel column chromatography using 10% ethyl acetate in n-hexane to afford 3a in 91% yield as an amorphous solid (2.64 g). [α]²⁰_D = +55.9 (c 1.0, CDCl₃); IR (KBr) 538, 765, 979, 1129, 1310, 1736, 2104, 2932 cm⁻¹; m.p. 113–114 °C; HRMS (EI) calcd for C₁₉H₂₉N₃O [M + Na]⁺ 338.2202, found 338.2203. ¹H-NMR (500 MHz, CDCl₃) δ 3.81 (1H, m), 2.34 (1H, dd, J = 19, 8.8 Hz), 1.97 (1H, dd, J = 19, 9.4 Hz), 1.86 (1H, m), 1.72 (3H, m), 1.60 (4H, m), 1.44 (8H, m), 1.18 (8H, m), 0.94 (2H, m), 0.78 (3H, s), 0.74 (3H, s); ¹³C-NMR (125 MHz, CDCl₃) δ 221.4, 58.4, 54.6, 51.8, 48.1, 40.4, 36.4, 36.2, 35.3, 33.2, 32.9, 31.9, 31.1, 28.4, 25.9, 22.1, 20.4, 14.2, 11.9.

Procedure for the synthesis of 3α-amino-5α-androstan-17-one (4a)¹⁷

A mixture of 3a (2.64 g, 8.38 mmol), 5% Pd–C (177 mg, 5 mol%) in 100 mL methanol was hydrogenated under stirring overnight by using hydrogen balloon. After hydrogenation, the reaction mixture was filtered. The solvent was evaporated under reduced pressure. The crude product was purified by column chromatography over silica gel using 2% MeOH in CH₂Cl₂ to get the amine 4a in 95% yield as an amorphous solid (1.94 g). [α]²⁰_D = +95.5 (c 1.0, CDCl₃); IR (KBr) 837, 1008, 1049, 1368, 1446, 1593, 1736, 2835, 3371 cm⁻¹; m.p. 124–126 °C; HRMS (EI) calcd for C₁₉H₃₁NO [M + H]⁺ 290.2478, found 290.2479. ¹H-NMR (500 MHz, CD₃OD) δ 3.34 (1H, m), 2.85 (1H, m), 2.62 (2H, q, J = 7.1 Hz), 2.42 (1H, dd, J = 19, 8.8 Hz), 2.05 (1H, dt, J = 19, 9 Hz), 1.94 (1H, m), 1.81 (2H, m), 1.72 (2H, m), 1.67 (4H, m), 1.57 (3H, m), 1.50 (2H, m), 1.44 (4H, m), 1.18 (8H, m), 0.94 (2H, m), 0.85 (6H, s), 0.76 (1H, s); ¹³C-NMR (125 MHz, CD₃OD) δ 223.0, 54.8, 52.4 51.9, 47.5, 39.8, 36.4, 35.7, 35.4, 32.6, 32.3, 31.9, 31.0, 28.6, 25.2, 21.7, 20.2, 13.2, 10.9.

Procedure for the synthesis of 3α-N-(Boc-pyrrolidine-2-formyl)-5α-androstan-17-one (5a)

To a stirred solution of N-Boc-L-proline (1.075 g, 5 mmol) in dry dichloromethane (15 mL), was added DMAP (210 mg, 1.5 mmol). The mixture was allowed to stir for 15 min and then cooled to 0 °C and then EDCI (1.22 g, 5.5 mmol) was added. After 20 min, a solution of 4a (1.16 g, 4 mmol) in dichloromethane (15 mL) was added to the above reaction mixture. The resulting solution was stirred at room temperature until complete consumption of nitroalkene (monitored by TLC). The reaction was quenched with water and extracted with dichloromethane (3 × 50 mL). The combined organic layers were washed with saturated brine solution (20 mL), followed by drying over Na₂SO₄ and evaporating in vacuo. The crude product was purified by column chromatography to give the pure the prolineamide 5a in 92% yield as an amorphous solid (1.75 g). [α]²⁰_D = +14.1 (c 1.0, CHCl₃); IR (KBr) 768, 918, 1168, 1254, 1409, 1540, 1740, 2864, 2953, 3338 cm⁻¹; HRMS (EI) calcd for C₂₉H₄₆N₂O₄ [M + Na]⁺ 509.3385, found 509.3387. ¹H-NMR (500 MHz, CDCl₃) δ 4.12 (1H, m), 3.36 (1H, m), 2.62 (1H, m), 2.44 (1H, dd, J = 19, 8.8 Hz), 2.08 (1H, dt, J = 19, 9.6 Hz), 1.92 (3H, m), 1.80 (2H, m), 1.66 (2H, m), 1.57 (3H, m), 1.49 (9H, s), 1.28 (10H, m), 0.86 (3H, s), 0.77 (3H, s); ¹³C-NMR (125 MHz, CDCl₃) δ 221.4, 170.7, 156.3, 59.9, 54.4, 51.6, 48.0, 47.3, 44.6, 36.3, 35.8, 35.0, 34.0, 32.9, 31.5, 30.8, 28.6, 28.2, 26.7, 26.1, 25.0, 21.9, 20.0, 13.9, 11.5.

Procedure for the synthesis of 3α-N-(pyrrolidine-2-formyl)-5α-androstan-17-one (6a)

To a solution of 5a (1.75 g, 3.6 mmol) in CH₂Cl₂ (10 mL) was added TFA (3 mL). After stirring at 0 °C for 2.5 hour, the solution was concentrated under vacuum to leave a glutinous phase. The pH of the mixture was brought into the range of ∼12 by the addition of 2 M NaOH. The aqueous phase was extracted with ethyl acetate. The ethyl acetate extracts were pooled, washed with brine, dried over anhydrous Na₂SO₄, filtered off and the solvent was evaporated at low pressure to give a crude residue that was purified by column chromatography to give the pure 6a in 95% yield as amorphous solid (1.32 g). [α]²⁰_D = +40.5 (c 1.0, CHCl₃); IR (KBr) 768, 918, 1168, 1254, 1409, 1540, 1740, 2864, 2953, 3338 cm⁻¹; HRMS (EI) calcd C₂₄H₃₈N₂O₂, [M + H]⁺ 387.3006, found for 387.3008. ¹H NMR (400 MHz, CDCl₃) δ 7.92 (1H, d, J = 7.0 Hz), 3.99 (1H, br s), 3.65–3.62 (1H, m), 2.98–2.94 (1H, m), 2.88–2.82 (1H, m), 2.08–2.06 (1H, m), 2.05–2.1.85 (7H, m), 1.83–1.82 (2H, m), 1.75–1.41 (11H, m), 1.40–1.20 (9H, m), 1.02–0.98 (2H, m), 0.80 (3H, s), 0.77 (3H, s); ¹³C NMR (100 MHz, CDCl₃) δ 221.2, 174.0, 60.8, 54.7, 51.5, 47.8, 47.3, 43.8, 41.2, 36.2, 35.8, 35.0, 33.3, 33.0, 31.5, 30.9, 30.8, 28.2, 26.2, 26.0, 21.7, 20.1, 13.8, 11.5.

General procedure for the Michael addition

To a stirred mixture of corresponding nitroolefin (1 mmol, 1.0 equiv.) in 2 mL indicated solvent were added catalyst and benzoic acid. The mixture was stirred at the indicated temperature for 30 min, and then freshly distilled aldehyde (3 mmol, 3.0 equiv.) was added. The resulting solution was stirred at the same temperature until complete consumption of nitroalkene (monitored by TLC). The solvent was quenched with ice water (2 mL), and extracted with ethyl acetate (3 × 2 mL). The combined organic phase was dried over Na₂SO_4, after removing the solvent, the crude product was purified by flash chromatography to afford the corresponding Michael adducts. Enantiomeric excess was determined by chiral HPLC analysis.

Acknowledgements

This work was supported by Program for Changjiang Scholars and Innovative Research Team in University (IRT13095) and Training Plan for Young Teachers of Yunnan University.

Notes and references

1. P. Perlmutter, Conjugate Addition Reactions in Organic Synthesis, ed. J. E. Baldwin and P. D. Magnus, Pergamon Press, Oxford, 1992.
2. For some recent references in this area, see: (a) S. I. Lee, J. H. Jang, G.-S. Hwang and D. H. Ryu, J. Org. Chem., 2013, 78, 770; (b) M. Charpentier, M. Hans and J. Jauch, Eur. J. Org. Chem., 2013, 4078l; (c) Z.-Y. Lu, Y. Li, J. Deng and A. Li, Nat. Chem., 2013, 5, 679; (d) J. S. Wzorek, T. F. Knopfel, I. Sapountzis and D. A. Evans, Org. Lett., 2012, 14, 5840; (e) P. Ghosal, D. Sharma, B. Kumar, S. Meena, S. Sinha and A. K. Shaw, Org. Biomol. Chem., 2011, 9, 7372; (f) H. Yang and R. G. Carter, J. Org. Chem., 2010, 75, 4929.
3. (a) N. Ono, The Nitro Group in Organic Synthesis, Wiley-VCH, New York, 2001; (b) V. V. Perekalin, E. S. Lipina, V. M. Berestovitskaya and D. A. Efremov, Nitroalkenes: Conjugated Nitro Compounds, Wiley-VCH, New York, 1994.
4. (a) A. G. M. Barrett and G. G. Grabowski, Chem. Rev., 1986, 86, 751; (b) R. Somanathan, D. Chavez, F. A. Servin, J. A. Romero, A. Navarrete, M. Parra-Hake, G. Aguirre, C. Anaya de Parrodi and J. Gonzalez, Curr. Org. Chem., 2012, 16, 2440; (c) O. M. Berner, L. Tedeschi and D. Enders, Eur. J. Org. Chem., 2002, 1877; (d) T. Ikariya and I. D. Gridnev, Top. Catal., 2010, 53, 894.
5. For some selected references in this area, see: (a) R. Somanathan, D. Chavez, F. A. Servin, J. A. Romero, A. Navarrete, M. Parra-Hake, G. Aguirre, C. Anaya de Parrodi and J. Gonzalez, Curr. Org. Chem., 2012, 16, 2440; (b) P. Chauhan, J. Kaur and S. S. Chimni, Chem. – Asian J., 2013, 8, 328; (c) J. Wang, P.-F. Li, P. Y. Choy, A. S. C. Chan and F. Y. Kwong, ChemCatChem, 2012, 4, 917; (d) R. Miyaji, K. Asano and S. Matsubara, Org. Biomol. Chem., 2014, 12, 119; (e) C. G. Kokotos, Org. Lett., 2013, 15, 2406; (f) W. Wang, J.-F. Wang, S. Zhou, Q. Sun, Z.-M. Ge, X. Wang and R.-T. Li, Chem. Commun., 2013, 49, 1333; (g) R. Chowdhury and S. K. Ghosh, Eur. J. Org. Chem., 2013, 6167; (h) R. Miyaji, K. Asano and S. Matsubara, Org. Lett., 2013, 15, 3658; (i) L.-L. Wen, L. Yin, Q.-L. Shen and L. Lu, ACS Catal., 2013, 3, 502; (j) K. Dudzinski, A. M. Pakulska and P. Kwiatkowski, Org. Lett., 2012, 14, 4222; (k) M. Joerres, I. Schiffers, I. Atodiresei and C. Bolm, Org. Lett., 2012, 14, 4518; (l) Z.-X. Jia, Y.-C. Luo, Y. Wang, L. Chen, P.-F. Xu and B.-H. Wang, Chem.–Eur. J., 2012, 18, 12958; (m) J. Xiao, Y.-P. Lu, Y.-L. Liu, P.-S. Wong and T.-P. Loh, Org. Lett., 2011, 13, 876; (n) L. Lykke, D. Monge, M. Nielsen and K. A. Jørgensen, Chem.–Eur. J., 2010, 16, 13330; (o) D. Enders, C. Wang and A. Greb, Adv. Synth. Catal., 2010, 352, 987.
6. (a) S. Indumathi, J. C. Menendez and S. Perumal, Curr. Org. Chem., 2013, 17, 2038; (b) S. K. Panday, Tetrahedron: Asymmetry, 2011, 22, 1817; (c) L.-W. Xu and Y.-X. Lu, Org. Biomol. Chem., 2008, 6, 2047; (d) H. Kotsuki, H. Ikishima and A. Okuyama, Heterocycles, 2008, 75, 757.
7. (a) M. Marigo, T. C. Wabnitz, D. Fielenbach and K. A. Jørgensen, Angew. Chem., Int. Ed., 2005, 44, 794; (b) Y. Hayashi, H. Gotoh, T. Hayashi and M. Shoji, Angew. Chem., Int. Ed., 2005, 44, 4212.
8. For selected reviews, see: (a) K. L. Jensen, G. Dickmeiss, H. Jiang, L. K. Albrecht and K. A. Jørgensen, Acc. Chem. Res., 2012, 45, 248; (b) L.-W. Xu, L. Li and Z. H. Shi, Adv. Synth. Catal., 2010, 352, 243; (c) A. Mielgo and C. Palomo, Chem. – Asian J., 2008, 3, 922; (d) C. Palomo and A. Mielgo, Angew. Chem., Int. Ed., 2006, 45, 7876; (e) Y. He, T.-R. Kang, Q.-Z. Liu, L.-M. Chen, Y.-L. Tu, Y.-J. Liu, T.-B. Chen, Z.-Q. Wang, J. Liu., Y.-M. Xie, J.-L. Yang and L. He, Org. Lett., 2013, 15, 4054.
9. For some selected reports in this area, see: (a) Y.-R. Zhou, J.-F. Dong, F.-L. Zhang and Y.-F. Gong, J. Org. Chem., 2011, 76, 588; (b) Y.-R. Zhou, Y.-Q. Zhu, S.-B. Yan and Y.-F. Gong, Angew. Chem., Int. Ed., 2013, 52, 10265; (c) L. Wang, J. Liu, T. Miao, W. P. Zhou, H. Li, K. Ren and X. L. Zhang, Adv. Synth. Catal., 2010, 352, 2571; (d) S. Pedatella, M. D. Nisco, D. Mastroianni, D. Naviglio, A. Nucci and R. Caputoa, Adv. Synth. Catal., 2011, 353, 1443; (e) A. Bañón-Caballero, G. Guillena and C. Nájera, J. Org. Chem., 2013, 78, 5349; (f) C. G. Kokotos, J. Org. Chem., 2012, 77, 1131; (g) N. Hara, R. Tamura, Y. Funahashi and S. Nakamura, Org. Lett., 2011, 13, 1662; (h) R. J. Reddy, H.-H. Kuan, T.-Y. Chou and K. Chen, Chem.–Eur. J., 2009, 15, 9294; (i) A. F. Torre, D. G. Rivera, M. A. B. Ferreira, A. G. Correa and M. W. Paixao, J. Org. Chem., 2013, 78, 10221; (j) K. Akagawa and K. Kudo, Angew. Chem., Int. Ed., 2012, 51, 12786; (k) C. A. Wang, Z. K. Zhang, T. Yue, Y. L. Sun, L. Wang, W. D. Wang, Y. Zhang, C. Liu and W. Wang, Chem.–Eur. J., 2012, 18, 6718; (l) S. K. Ghosh, Z. L. Zheng and B. Ni, Adv. Synth. Catal., 2010, 352, 2378; (m) B. G. Wang, B. C. Ma, Q. Wang and W. Wang, Adv. Synth. Catal., 2010, 352, 2923.
10. (a) E. Heftmann, Androgens. In: Steroid Biochemistry, Academic Press, London, 1970; (b) G. Gordon, M. C. Mackow and H. R. Levy, Arch. Biochem. Biophys., 1995, 318, 25.
11. F. L. Bideau and S. Dagorne, Chem. Rev., 2013, 113, 7793.
12. For some selected references of empirical discoveries in this area, see: (a) C. M. R. Volla, I. Atodiresei and M. Rueping, Chem. Rev., 2014, 114, 2390; (b) A. Moyano and R. Rios, Chem. Rev., 2011, 111, 473; (c) A. Tsybizova, M. Remeš, J. Veselý, S. Hybelbauerová and J. Roithová, J. Org. Chem., 2014, 79, 1563; (d) K. Xu, S. Zhang, Y.-B. Hu, Z.-G. Zha and Z.-Y. Wang, Eur. J. Org. Chem., 2013, 19, 3573; (e) Z. Tang, F. Jiang, L.-T. Yu, X. Cui, L.-Z. Gong, A.-Q. Mi, Y.-Z. Jiang and Y.-D. Wu, J. Am. Chem. Soc., 2013, 125, 5262; (f) R. J. Reddy, H. H. Kuan, T. Y. Chou and K. Chen, Chem.–Eur. J., 2009, 15, 9294; (g) S. Mukherjee, J. W. Yang, S. Huffman and B. List, Chem. Rev., 2007, 107, 5471; (h) S. Pedatella, M. D. Nisco, D. Mastroianni, D. Naviglio, A. Nucci and R. Caputo, Adv. Synth. Catal., 2011, 353, 1443.
13. For some selected references of computational insights in this area, see: (a) P. H. Y. Cheong, C. Y. Legault, J. M. Um, N. Çelebi-Ölçüm and K. N. Houk, Chem. Rev., 2011, 111, 5042; (b) C. Palomo, S. Vera, A. Mielgo and E. Gómez-Bengoa, Angew. Chem., Int. Ed., 2006, 45, 5984; (c) M. Wiesner, J. D. Revell and H. Wennemers, Angew. Chem., Int. Ed., 2008, 47, 1874.
14. For some selected references including similar N-protected chiral catalysts in this area, see: (a) F. Bächle, J. Duschmalé, C. Ebner, A. Pfaltz and H. Wennemers, Angew. Chem., Int. Ed., 2013, 52, 12619; (b) Y. Arakawa, M. Wiesner and H. Wennemers, Adv. Synth. Catal., 2011, 353, 1201; (c) R.-S. Luo, J. Weng, H.-B. Ai, G. Lu and A. S. C. Chan, Adv. Synth. Catal., 2009, 351, 2449; (d) J. Duschmalé, J. Wiest, M. Wiesner and H. Wennermers, Chem. Sci., 2013, 4, 1312; (e) L. Zhao, J.-F. Shen, D.-L. Liu, Y.-G. Liu and W.-B. Zhang, Org. Biomol. Chem., 2012, 10, 2840; (f) Y.-Q. Cheng, Z. Bian, Y.-B. He, F.-S. Han, C.-Q. Kang, Z.-L. Ning and L.-X. Gao, Tetrahedron: Asymmetry, 2009, 20, 1753; (g) M. Wiesner and H. Wennemers, Synthesis, 2010, 9, 1568.
15. S. Kamijo, S. Matsumura and M. Inoue, Org. Lett., 2010, 12, 4195.
16. W. G. Kerr and J. D. Chisholm, WO2011/127465 A2, 2011.
17. N. Hamilton, M. Dawson, E. E. Fairweather, N. S. Hamilton, J. R. Hitchin, D. I. James, S. D. Jones, A. M. Jordan, A. J. Lyons, H. F. Small, G. J. Thomson, I. D. Waddell and D. J. Ogilvie, J. Med. Chem., 2012, 55, 4431.

---

Footnote

† Electronic supplementary information (ESI) available: Synthesis of catalysts 6b and 7–10, ¹H and ¹³C NMR spectra for compounds 2–10, 14a–14o, and spectra of chiral HPLC for compounds 14a–14o. See DOI: 10.1039/c4ra03075c

---