Solvent free, fast and asymmetric Michael additions of ketones to nitroolefins using chiral pyrrolidine–pyridone conjugate bases as organocatalysts

Tetrahedron: Asymmetry 28 (2017) 511–515

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Solvent free, fast and asymmetric Michael additions of ketones to nitroolefins using chiral pyrrolidine–pyridone conjugate bases as organocatalysts Chandan K. Mahato a, Mrinalkanti Kundu a,⇑, Animesh Pramanik b,⇑ a b

TCG Lifesciences Pvt. Ltd., BN 7, Sector V, Salt Lake City, Kolkata 700091, India Department of Chemistry, University of Calcutta, 92, A. P. C. Road, Kolkata 700009, India

a r t i c l e

i n f o

Article history: Received 18 January 2017 Revised 20 February 2017 Accepted 24 February 2017 Available online 24 March 2017

a b s t r a c t New chiral organocatalysts are envisaged based on a pyrrolidine–pyridone conjugate and synthesized from commercially available proline employing standard protocols. These catalysts were found to be useful for asymmetric Michael additions of ketones to nitroolefins to afford the desired products in very good yields (up to 98%) with excellent diastereo- and enantioselectivities (>97:3 syn/anti and up to 98% ee) in very short reaction time compared with the existing reports. Ó 2017 Elsevier Ltd. All rights reserved.

1. Introduction In organic synthesis, the 1,4-conjugate Michael type reaction is widely recognized as one of the most important carbon-carbon bond-forming reactions.1 Stereoselective Michael additions are thus used for the evaluation of newly designed catalysts2 as these types of Michael adducts containing multiple stereogenic centers, are found to be prominent scaffolds in various bioactive compounds. Usually, one enantiomer is predominant in Nature; on many occasions, the physiological activity of the compound resides in only one of its enantiomers, such as chiral drug substances, hence the importance of a new methodology for the preparation of specific enantiomers. However, the generation of multiple stereogenic centers in one reaction is a challenging task in asymmetric synthesis.3 For these types of transformations, the reagent systems developed are mostly based on metal catalysts.4 Due to the growing need for the transformation to involve an environmentally friendly nonmetal-catalyzed asymmetric synthesis, considerable attention has also been focused on the development of efficient small-molecule chiral organocatalysts.5 Organocatalysis uses environmentally benign metal-free catalysts, thus making it more practical compared with catalytic reactions using inorganic catalysts. Over the past few years, this research area has gained much attention and witnessed important advancements in many divergent ways

⇑ Corresponding authors. E-mail addresses: [email protected] (M. Kundu), animesh_in2001@yahoo. co.in (A. Pramanik). http://dx.doi.org/10.1016/j.tetasy.2017.03.002 0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.

including new organocatalyst designs. Amino acid proline has become a crucial component in organocatalysis and has been well studied. Proline is abundant in Nature and both enantiomers are inexpensive; in addition, proline has two functional groups, a carboxylic acid and an amine, which allows it to play a role in bi-functional asymmetric catalysis, which has become a successful strategy for facilitating chemical transformations similar to enzymatic catalysis. Therefore, the development of proline derived small molecules to construct stereogenic centers in organic compounds with better selectivities is one of the major milestones in organocatalysis.2h,6 Amongst these, pyrrolidine–triazole,7 pyrrolidine–tetrazole,8 pyrrolidine–pyridine,9 pyrrolidine–pyrazole,10 pyrrolidine–oxyimides,11 pyrrolidine–HOBT,12 and pyrrolidinine– thioxotetrahydropyrimidinone13 are a few relevant examples. These catalysts have been used to achieve high productivity, enantioselectivity and diastereoselectivity although usually with very long reaction times.9a,10–13 Herein we have designed a new class of chiral pyrrolidine–pyridone conjugate bases 1 and 2 as promising organocatalysts for the addition of ketones to nitroolefins (Fig. 1a). To the best of our knowledge, these types of compounds have not been investigated in asymmetric catalysis. As well documented in the literature, the catalytic system operates by an enamine mechanism, wherein the pyrrolidine ring results in enamine formation; the pyridone component should thus effectively shield one side of an enamine double bond, which could possibly make the nitroolefin acceptors approach from the non-shielded side to give the desired Michael adducts with high enantio- and diastereoselectivity. Moreover, the carbonyl group of the pyridone ring should also provide

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C. K. Mahato et al. / Tetrahedron: Asymmetry 28 (2017) 511–515 (a)

(b) O

N H

N

N

N 1: (S) 2: (R)

O

X

O

NO 2

O

O

N + O

H

neat/solvent, rt

9a

R

NO 2

1 (10 mol%) + 10

11a

Scheme 2. Asymmetric organocatalytic Michael reaction.

Figure 1. (a) Pyrrolidine–pyridone catalysts 1 and 2; (b) proposed transition state.

conducted reactions using various acids as the additive (2 mol %). The results are summarized in Table 2 and the data suggest that the addition of the acid used was always extremely beneficial, e.g., TFA resulted in 95% of the 1,4-addition product with 93% ee and with a significant improvement in diastereoselectivity (entry 1). Following the above results, we decided to check if the efficiency of the catalyst could be further increased by adding 4 mol % of TFA (entry 5, Table 2); considering the time, yield and % ee, this condition did not have any major advantage over the reaction that was carried out with 2 mol % of TFA. The use of a mixture of TFA and p-nitrobenzoic acid (1 mol % each) was equally effective as the neat reaction (entry 6 vs. entry 1). Considering the outcome from these experiments, we chose the conditions mentioned in entry 1 as the optimized conditions for our next reactions. We planned to test the effect of catalyst loading on the progress/efficiency of the Michael addition reaction of 9a with 10. The results are summarized in Table 3 which show that a decrease in catalyst concentration (from 20 to 10 mol %) resulted in similar yield and the selectivities (Table 3, entries 1, 2). Whereas, use of 5 mol % of catalyst loading led to significantly slow reaction as well as in a very low yield (the product was not isolated and syn/anti ratio as well as % ee were not checked either). Despite the very short reaction time that was observed for the reaction with 20 mol %, considering the economical point of view, we decided to use 10 mol % of catalyst loading in all of our future experiments. Once we established the optimal conditions, our next objective was to extend the scope and efficiency of catalyst 1 for the conjugate addition of 10 to other nitroolefin substrates (Scheme 3). To meet this goal, we conducted reactions with different nitrostyrenes and the findings are summarized in Table 4 below. As evident from Table 4, the catalyst 1 also works well for the asymmetric Michael addition to other nitroolefins using cyclohexanone as the donor. The phenyl ring containing both electron withdrawing and donating group/s resulted in high yields of the products with very good enantioselectivities. As an example, the addition of 10 to 9c as Michael acceptor provided 84% of product with as high as 98% ee (entry 2). When 2-naphthyl nitroolefin

H-bonding stabilization for a pre-organized transition state as proposed in Figure 1b.11b,14 2. Results and discussion The new chiral catalysts 1 and 2 were synthesized from L- and 3a and 3b respectively as depicted in Scheme 1. Accordingly, 3a and 3b were converted to N-Boc prolinols 5a and 5b (via prolinol intermediates 4a and 4b) followed by O-tosylation using p-tosyl chloride in DCM in the presence of TEA.10 The tosyl derivatives 6a and 6b were then coupled with 2-pyridone 7 using Cs2CO3 as base in DMF to provide the adducts 8a and 8b along with the corresponding O-alkylated derivatives (data not shown). Deprotection of the Boc-group was carried out by dry HCl in 1,4-dioxane and the crude materials were neutralized with solid NaHCO3. Finally, pyrrolidine–pyridone conjugate bases 1 and 2 were purified over silica gel column chromatography. With catalyst 1, we decided to check the efficiency and performed a model reaction using nitrostyrene 9a as the Michael acceptor and cyclohexanone 10 as the donor under neat conditions (Scheme 2). The reaction was carried out with 10 mol % catalyst loading, which gave excellent yield and high diastereo- and enantioselectivity (entry 1, Table 1). With the aim of improving the selectivity, various solvents were screened for the same reaction, in parallel. As can be seen from the results summarized in Table 1, the catalyst was found to be efficient in different solvents and the yields and enantioselectivities differed only slightly (entries 2–5) when compared to the neat reaction albeit with prolonged reaction times. The reactions in protic solvents, such as water and methanol, were non-beneficial with regards to both time and yields (% ee and syn/anti were not determined considering long reaction time and low chemical yield). The presence of an acid additive usually increased the catalyst efficiency by accelerating enamine formation as reported earlier.9a,15 Therefore, after screening of the solvents, we next optimized the reaction conditions by adding different acid additives. Accordingly, we tested solvent-free conditions and D-proline

OH

N H

LAH, THF Ref. 10

O

3a: (S) 3b: (R)

OH

N H

(BOC) 2 Ref. 10 O

4a: (S) 4b: (R)

TsCl, Et 3 N

OH

N O

5a: (S) 5b: (R)

DCM Ref. 10

HN OTs

N O

O

6a: (S) 6b: (R)

O 7 Cs2 CO 3, DMF O 0 oC - rt 27-41%

N

N O

i) dry HCl-dioxane 10 oC- rt O

ii) NaHCO 3

N H

N O

63-80% 8a: (S) 8b: (R)

Scheme 1. Synthesis of organocatalysts 1, 2.

1: (S) 2: (R)

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C. K. Mahato et al. / Tetrahedron: Asymmetry 28 (2017) 511–515 Table 1 Efficiency of catalyst 1 in different solventsa

a b c d

Entry

Solvent

1 2 3 4 5 6 7

Neat THF 2-Methyl THF DCE Toluene Water MeOH

% Yieldb

Time (h) 3.5 15 15 15 18 72 72

97 95 85 96 95 20 <5

syn/antic

eed (%)

89:11 95:5 >97:3 88:12 >97:3 — —

90 89 86 82 82 — —

Reaction conditions: nitrostyrene (1 equiv), cyclohexanone (5 mol equiv), neat or solvent (4 mL), catalyst 1 (10 mol %), rt. Isolated yields after column chromatography; GCMS of crude reaction mixture showed complete conversion—data not presented. Determined by the 1H NMR of the crude product; the ratio >97:3 has been kept despite there was no detectable anti-isomer present. Determined by chiral HPLC; corresponds to the syn-diastereomer.

Table 2 Screening of different additivesa

a b c d e f

Entry

Additive

1 2 3 4 5 6

TFA p-NO2-C6H4COOH CH3COOH pTSA TFAe TFA + p-NO2-C6H4COOHf

% Yieldb

Time (h) 4 3.5 4 5 4 2.5

95 92 98 96 87 80

syn/antic

eed (%)

>97:3 >97:3 >97:3 >97:3 >97:3 >97:3

93 89 92 87 94 91

Reaction conditions: nitrostyrene (1 equiv), cyclohexanone (5 mol equiv), catalyst 1 (10 mol %), additive (2 mol %), rt. Isolated yields after column chromatography; GCMS of crude reaction mixture showed complete conversion—data not presented. Determined by the 1H NMR of the crude product; the ratio >97:3 has been kept despite there was no detectable anti-isomer present. Determined by chiral HPLC; corresponds to the syn-diastereomer. 4 mol % TFA. 1 mol % TFA + 1 mol % p-NO2-C6H4COOH were used.

Table 3 Effect of catalyst loadinga

a b c d e

Entry

mol %

1 2 3

20 10 5

Time (h)

% Yield 89b 95b 20c

0.5 4 96

syn/antid

eee (%)

>97:3 >97:3 —

91 93 —

Reaction conditions: nitrostyrene (1 equiv), cyclohexanone (5 mol equiv), catalyst 1 (10 mol %), TFA (2 mol %), rt. Isolated yields after column chromatography; GCMS of crude reaction mixture showed complete conversion—data not presented. From GCMS of crude reaction mixture. Determined by the 1H NMR of the crude product; the ratio >97:3 has been kept despite there was no detectable anti-isomer present. Determined by chiral HPLC; corresponds to the syn-diastereomer.

O NO2

R 9b-i

O

NO2

1 (10 mol%)

+

was used as a bulky acceptor (entry 5), the addition of cyclohexanone resulted in 97% of ee. Moreover, heteroaryl nitroolefins, such as 9g–i, were similarly effective in terms of both chemical yield and enantioselectivity (entries 6–8). Therefore, both 5-membered and 6-membered heteroarylolefinic systems afforded the required syn adducts in 89–94% ee (entries 6–8).

R

neat, TFA, rt 10

11b-i

Scheme 3. Michael addition of cyclohexanone to nitroolefins.

Table 4 Stereoselective Michael reaction of cyclohexanone with different olefins using catalyst 1a

a b c d

Entry

R

1 2 3 4 5 6 7 8

4-Fluorophenyl 9b 4-Methoxyphenyl 9c 2,4-Dimethoxyphenyl 9d 4-Methylphenyl 9e 2-Naphthyl 9f Thiophene-3-yl 9g Furan-3-yl 9h Pyridine-3-yl 9i

Time (h) 3.5 3 2 3 1.5 8 2.5 4

% Yieldb 70 84 95 75 76 94 86 76

syn/antic

eed (%)

82:18 >97:3 >97:3 >97:3 >97:3 81:19 >97:3 >97:3

92 98 85 94 97 92 89 94

Reaction conditions: nitrostyrene (1 equiv), cyclohexanone (5 mol equiv), catalyst 1 (10 mol %), TFA (2 mol %), rt. Isolated yields after column chromatography. Determined by the 1H NMR of the crude product; the ratio >97:3 has been kept despite there was no detectable anti-isomer present. Determined by chiral HPLC; corresponds to the syn-diastereomer.

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Encouraged by these findings (Table 4) on the versatility of our catalyst 1, we envisaged doing the Michael addition with a few other ketones easily available with us and using nitrostyrene 9a as the acceptor. The results demonstrate that when pyran-4-one was used, excellent yield (isolated yield: 85%, 8 h) as well as stereoselectivities (syn/anti: >97:3, ee: 96%) were achieved. The reaction with cyclopentanone as donor was very sluggish (% ee and syn/anti were not determined considering long duration of reaction time and low conversion). Acyclic ketones, such as acetone and 2-butanone, also needed prolonged reaction times resulting in the desired adducts (isolated yield: 30%, 24 h, 35% ee and isolated yield: 28%, 24 h, 69% ee respectively). Having successfully obtained a new organocatalyst 1 and established its efficiency in asymmetric Michael addition reaction of ketones to nitroolefins, we envisioned checking the effect of the (R)-isomer of the catalyst 1. We thus prepared catalyst 2 starting from D-proline and conducted the same model reaction. As anticipated, the Michael reaction between 9a and 10 using catalyst 2 resulted in the opposite enantiomer {[a]25 D = +28.1 (c 0.99, CHCl3)} in comparison to the product obtained by catalyst 1 {[a]25 29.4 (c 0.94, CHCl3); Lit.13b: [a]20 27 (c 1.0, CHCl3)}, D = D = without compromising either the yield (91%, 3 h) or the diastereo and enantioselectivities (syn/anti: >97:3, ee: 93%). 3. Conclusion We have reported on the synthesis and application of pyrrolidine–pyridone conjugates as unique chiral organocatalysts, which are highly efficient for the 1,4-conjugate additions of ketones to nitroolefins under neat conditions at room temperature with 10% catalyst loading. The reactions produced the corresponding Michael adducts in very high yields and diastereo- and enantioselectivities in reasonably short reaction times in comparison to the previous reports available in the literature.9a,10–13 We are currently further investigating (Schemes 4 and 5)16 the usefulness of these catalysts and their derivatives for broader application and the results will be communicated in due course. 4. Experimental 4.1. General All reactions were conducted using oven-dried glassware. Commercial grade reagents were used without further purification. Solvents were dried and distilled following usual protocols. Column chromatography was carried out using silica gel (100–200 mesh). TLC was performed on aluminium-backed plates coated with Silica gel 60 with F254 indicator. 1H NMR spectra were recorded with a 400 MHz and 13C NMR spectra were recorded with a 100 MHz using CDCl3 and DMSO-d6; 1H NMR chemical shifts are expressed in parts per million (d) relative to CDCl3 (d = 7.26) and DMSO-d6 (d = 2.49) and 13C NMR chemical shifts are expressed in parts per million (d) relative to the CDCl3 resonance (d = 77.0) and DMSOd6 (d = 39.7). GCMS experiments were carried out on Agilent 6890 series GC coupled mass selective detector, with HP-5MS capillary column. LCMS chromatograms were recorded on LCMS/MS API 2000 instrument. Chiral HPLC analyses were carried out on chiralpak IA or IC column using either ethanol or a mixture of solvents viz., hexane, ethyl acetate and adding diethyl amine, where appropriate, as eluent. 4.1.1. Synthesis of (S)-2-(2-oxo-2H-pyridin-1-ylmethyl) pyrrolidine-1-carboxylic acid tert-butyl ester 8a To a stirred solution of 1H-pyridin-2-one (500 mg, 5.25 mmol) in dry DMF (5 mL) was added CS2CO3 (3.42 g, 10.51 mmol) at

0 °C and stirred at rt for 30 min. A solution of (S)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester 6a10 (2.05 g, 5.78 mmol) in dry DMF (4 mL) was added at 0 °C and stirred at rt for 72 h. After completion of the reaction, it was quenched with ice water and the organic parts were extracted with ethyl acetate (3  100 mL), washed with brine solution, dried over sodium sulfate and concentrated. The crude material was purified over silica gel flash chromatography using a mixture of ethyl acetate-hexane to give (S)-2-(2-oxo-2H-pyridin-1-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester 8a (600 mg, 41%) as a colorless semisolid. [a]25 D = +13.6 (c 0.3, CHCl3). IR (Neat): m 1686 (ANCOOtBu), 1662 (ANCOA) cm 1. 1H NMR (DMSO-d6, 400 MHz): d 7.45–7.41 (m, 2H), 6.36 (br d, 1H, J = 9.1 Hz), 6.18 (br s, 1H), 4.19–4.00 (m, 2H), 3.82–3.66 (m, 1H), 3.34–3.25 (m, 2H), 1.78–1.68 (m, 4H), 1.35 and 1.24 (2 s, 9H, rotamers). 1H NMR at 100 °C (DMSO-d6, 400 MHz): d 7.40–7.32 (m, 2H), 6.35 (d, 1H, J = 9.1 Hz), 6.15–6.10 (m, 1H), 4.16 (m, 1H), 4.03–4.00 (m, 1H), 3.90–3.85 (m, 1H), 3.37–3.31 (m, 1H), 3.26–3.22 (m, 1H), 1.82–1.74 (m, 4H), 1.36 (s, 9H). 13C NMR (CDCl3, 100 MHz): d 162.99 and 162.81 (rotamers), 154.69 and 154.48 (rotamers), 139.36 and 139.25 (rotamers), 138.02 and 137.9 (rotamers), 120.96 and 120.73 (rotamers), 105.85, 79.84 and 79.49 (rotamers), 57.86 and 56.58 (rotamers), 50.96 and 48.86 (rotamers), 46.68 and 46.09 (rotamers), 28.68 and 28.19 (rotamers), 28.34, 23.63 and 22.76 (rotamers). LC–MS (ESI): 278.9 [M+H]+. 4.1.1.1. (R)-2-(2-Oxo-2H-pyridin-1-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester 8b. This compound was prepared following above protocol used for compound 8a. Yield = 27%. [a]25 14.9 (c 0.2, CHCl3). IR (Neat): m 1672 D = (ANCOOtBu), 1660 (ANCOA) cm 1. 1H NMR (CDCl3, 400 MHz): d 7.32–7.14 (m, 2H), 6.55 (br s, 1H), 6.12 (t, 1H, J = 6.2 Hz), 4.34– 3.75 (m, 3H), 3.43 and 3.28 (br s, 2H, rotamers-2), 1.99–1.81 (m, 4H), 1.45 and 1.40 (2 s, 9H, rotamers). 13C NMR (CDCl3, 100 MHz): d 163.09 and 162.94 (rotamers), 154.82 and 154.59 (rotamers), 139.31, 138.10 and 137.97 (rotamers), 121.08 and 120.86 (rotamers), 105.88, 79.94 and 79.58 (rotamers), 57.98 and 56.72 (rotamers), 51.04 and 48.95 (rotamers), 46.77 and 46.20 (rotamers), 29.67 and 28.77 (rotamers), 28.41, 23.72 and 22.86 (rotamers). LC–MS (ESI): 279.0 [M+H]+. 4.1.2. Synthesis of 1-(S)-1-pyrrolidin-2-ylmethyl-1H-pyridin-2one 1 To a stirred solution of (S)-2-(2-oxo-2H-pyridin-1-ylmethyl)pyrrolidine-1-carboxylic acid tert-butyl ester 8a (1.0 g, 3.59 mmol) in 1,4-dioxane, dry HCl gas was purged through the solution over 15 minutes at 5–10 °C. The reaction mixture was then stirred at rt for 1 h. After completion of the reaction, volatile matters were removed in vacuo. The crude reaction mixture was triturated with diethyl ether, dried and the residue was taken into a mixture of 1,4-dioxane and THF (3:1, v/v). Solid sodium bicarbonate was added to it and the mixture was stirred at rt for 5 h. The mixture was filtered through Celite and washed with a mixture of 1,4-dioxane/THF (1:1, v/v) and the filtrate was concentrated in vacuo. The crude material was finally purified over silica gel column chromatography using a mixture of MeOH/DCM/Et3N (14.5:85:0.5, v/v) to give 1-(S)-1-pyrrolidin-2-ylmethyl-1H-pyridin-2-one (400 mg, 63%) as light brown liquid. [a]25 D = +92.0 (c 0.8, CHCl3). IR (Neat): m 1655 (ANCOA) cm 1. 1H NMR (DMSOd6, 400 MHz): d 7.64 (d, 1H, J = 6.6 Hz), 7.39 (t, 1H, J = 6.9 Hz), 6.36 (d, 1H, J = 9.1 Hz), 6.17 (t, 1H, J = 6.2 Hz), 3.98–3.94 (m, 1H), 3.67–3.62 (m, 1H), 3.41–3.36 (m, 1H), 2.84–2.79 (m, 2H), 1.76– 1.59 (m, 3H), 1.41–1.34 (m, 1H). 13C NMR (CDCl3, 100 MHz): d 162.89, 139.54, 138.64, 120.59, 105.58, 57.0, 54.62, 46.27, 29.24, 25.34. LCMS (ESI): 179 [M+H]+. Chiral HPLC using chiralpak IC (EtOH/diethyl amine: 100/0.1) tR (S) = 11.87 min.

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4.1.2.1. 1-(R)-1-Pyrrolidin-2-ylmethyl-1H-pyridin-2-one 2. This compound was prepared following above protocol used for catalyst 1. Yield = 80%. [a]25 82.5 (c 0.85, CHCl3). IR D = (Neat): m 1656 (ANCOA) cm 1. 1H NMR (DMSO-d6, 400 MHz): d 7.62 (d, 1H, J = 6.4 Hz), 7.38 (t, 1H. J = 6.8 Hz), 6.34 (d, 1H, J = 9 Hz), 6.16 (t, 1H, J = 6.1 Hz), 3.94 (dd, 1H, J = 4.8, 4.9 Hz), 3.59 (m, 1H), 3.3 (br s, 1H), 2.77 (br s, 2H), 1.71–1.32 (m, 4H). 13C NMR (CDCl3, 100 MHz): d 162.90, 139.56, 138.67, 120.63, 105.58, 57.13, 54.58, 46.27, 29.23, 25.35. LCMS (ESI): 179 [M+H]+. Chiral HPLC using chiralpak IC (EtOH/diethyl amine: 100/0.1), tR (R) = 10.66 min. 4.1.3. General procedure: Michael addition reaction of ketones and nitroolefins Catalyst (10 mol %) was added to a mixture of ketone (5 mmol) and TFA (2 mol %) at room temperature and stirred for 10 min, followed by the addition of nitroolefin (1 mmol) and the resulting mixture was stirred at the same temperature for the appropriate time. After completion of the reaction (monitored by GCMS), the crude product was purified by silica-gel column chromatography to give the corresponding Michael adducts. The relative and absolute configurations of the products were determined by comparison of 1H NMR and specific rotation values with those reported in the literature. Enantiomeric excess was determined by chiral HPLC. Acknowledgments CKM thanks TCGLS for the opportunity to pursue this work. CKM and MK are thankful to the analytical team at TCGLS for structural elucidation and discussion on the spectral data. CK and MK gratefully acknowledge University of Calcutta, India for this collaborative research work.

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N H

O NO2

N

Cl O

O

NO2

12 (10 mol%) + neat, 2 mol% TFA rt, 2 h

9a

10

11a

Scheme 4. Michael addition with catalyst 12. Moreover, instead of nitrostyrene, we used benzylidene malonate 13 as an acceptor in the reaction using 10 mol % catalyst 1 which eventually afforded the corresponding 1,4-addition product 14 {[a]25 40.5 (c 1.03, CHCl3); Lit.:18 D = [a]20 38.3 (c 1.38, CHCl3)} with 87% ee (Scheme 5). D =

+

neat, rt 2 mol% TFA

O 13

O

1 (10 mol%)

O O

O

O

O

10

O O

O 14

Scheme 5. Addition of 10 to benzylidene malonate 13. Extensive studies on these aspects and related are currently ongoing in our laboratory. 1 1 17. [a]25 . H NMR (DMSOD = +86.8 (c 0.52, CHCl3). IR (Neat): m 1651 (ANCOA) cm d6, 400 MHz): d 7.93 (s, 2H), 4.01 (dd, 1H, J = 3.9, 4.1 Hz), 3.6–3.55 (m, 1H), 3.31 (br s, 1H), 2.75 (t, 2H, J = 6.3 Hz), 2.32 (br s, 1H), 1.77–1.71 (m, 2H), 1.57–1.55 (m, 1H), 1.33–1.28 (m, 1H). 13C NMR (CDCl3, 100 MHz): d 157.62, 138.15, 135.12, 126.53, 110.22, 56.46, 55.95, 46.49, 29.40, 25.79. LCMS (ESI): 246.8 [M +H]+. Chiral HPLC using chiralpak IA (Hexane/ethyl acetate/EtOH/diethyl amine: 70:15:15:0.1), tR (S) = 8.22 min. 18. Cao, C.-Li.; Sun, X.-Li.; Zhao, J.-Long.; Tang, Y. J. Org. Chem. 2007, 72, 4073–4076.