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D-prolyl-2-(trifluoromethylsulfonamidopropyl)pyrrolidine: An Organocatalyst for Asymmetric Michael Addition of Aldehydes to #-Nitroalkenes at Ambient Conditions Amol B Gorde, and Ramesh Ramapanicker J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02945 • Publication Date (Web): 04 Jan 2019 Downloaded from http://pubs.acs.org on January 7, 2019

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The Journal of Organic Chemistry

D-prolyl-2-(trifluoromethylsulfonamidopropyl)pyrrolidine: An Organocatalyst for Asymmetric Michael Addition of Aldehydes to βNitroalkenes at Ambient Conditions Amol B. Gorde and Ramesh Ramapanicker* Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India 208016 [email protected]

HN NO2

Ar + R

CHO

N O TfHN

10 mol%, toluene, 30 ºC

Ar O

NO2

R Yield: up to 95% ee: up to 97% dr: up to 99:1

Abstract: Four 2-(trifluoromethylsulfonamidoalkyl)pyrrolidines and their D- prolinamides were prepared and screened as organocatalysts for the Michael addition reaction of aldehydes with βnitroalkenes at rt and without the use of additives. D-prolyl-2(trifluoromethylsulfonamidopropyl)pyrrolidine was found to be the best among the molecules studied, which yielded γ-nitro aldehydes in very high yields (up to 95%), with high diastereoselectivity (up to >99:1) and with up to 97% ee.

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Introduction Ever since the advent of organocatalysis as an efficient tool for sustainable asymmetric synthesis, organocatalytic Michael addition reaction of aldehydes to nitroolefins has remained as an active field of research.1 While proline itself is not an efficient catalyst for Michael addition reactions,2 certain compounds derived from proline, such as (S)-23 trifluoromethylsulfonamidomethylpyrrolidine (1a) developed by Wang et al, show excellent catalytic activity towards conjugate addition reactions. Particular attention has been given over the years to design short peptides,4 which have better catalytic activity than proline. Among them, peptides containing proline as one of the residues5 have gained notable success as organocatalysts. Wennemers’s group has achieved commendable success in using D-Pro-ProAsp/Glu-NH2 for enantioselective aldol and Michael addition reactions.6 Encouraged by the results on using these peptides, various modifications of the tripeptide unit were attempted by Wennemers’s group.7 Detailed analysis on the influence of peptide conformations on catalysis has also been carried out,6e-f and the group has succeeded in developing catalysts that effect C-C bond formations with as little as 0.05 mol% of the catalyst. Recently, Marc Lecouvey and coworkers have developed tripeptides, similar to those developed by Wennemers group, bearing a phosphonic acid side-chain, as efficient organocatalysts for the Michael addition reaction of aldehydes to nitroalkenes.8 While, Wennemers’s catalysts had an aspartic acid or a glutamic acid residue in the C-terminus, whose carboxylic acid side-chains were essential for the catalytic activity, Lecouvey’s peptides contained phosphonic acid side-chains. These catalysts had comparable catalytic activity to that of peptides with carboxylic acid side chains, but produced compounds with the opposite configuration. As another interesting modification of the Wennemers’s catalyst system, Tomás Martín’s group developed organocatalysts based on prolinamides of pyranoid sugar amino acids for Michael addition reactions. They could achieve up to 96% ee with a catalyst loading of 5 mol%.9

N H

NHTf n

1a; n = 1 1b; n = 2 1c; n = 3 1d, n = 4

N H

N O

n

NHTf

1e; n = 1 1f; n = 2 1g; n = 3 1h, n = 4

N H

N O 1i TfHN

Figure 1. Catalysts prepared for this study We envisaged that incorporating a trifluoromethanesulfonamide (-NHTf) group instead of carboxylic or phosphonic acid groups onto a prolinamide could offer interesting catalytic systems. Despite the very useful results obtained by Wang and coworkers,3 studies on organocatalysts utilizing -NHTf as the H-bond donor are rare. Accordingly, we synthesized four 2-(trifluoromethylsulfonamidoalkyl)pyrrolidines (1a-d) and their amides with D-proline (1e-h) (Figure 1) and studied their catalytic activity towards 1,4-addition of aldehydes to β-


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nitrostyrenes. We have found that catalyst 1g is the best among all those studied, which offers ee up to 97% and diastereomeric ratios up to 99:1 for the γ-nitro aldehydes formed. It is notable that 1g is a better catalyst than Wang’s catalyst 1a at rt (30 ºC).

Results and Discussion Compounds 1a-d were prepared from the corresponding aldehydes 2a-d10, 11 (Scheme 1). The reductive amination of aldehydes 2a-d with dibenzylamine and NaBH(OAc)3 led to tertiary amines 3a-d in very good yields. Hydrogenolysis of the benzyl groups gave primary amines, which were treated with triflic anhydride to get 4a-d. Acidolysis of the N-Boc groups with TFA in DCM yielded the desired alkylaminotriflates 1a-d. The D-prolinamides 1e-h were prepared by coupling 1a-d with Boc-(D)Pro-OH using standard peptide coupling conditions (EDC·HCl, HOBt, DIPEA, DCM, 0 ºC – rt) and subsequently removing the N-Boc group by acidolysis (Scheme 2). An L-prolinamide 1i was prepared by coupling 1c with Boc-Pro-OH. The catalysts 1a-i, which were initialy obtained as TFA salts, were treated with NaOH solution and the free amines were extracted with ethyl acetate. 19F NMR of the free catalysts were recorded to ensure that no residual TFA was present in the samples used for catalytic screening. CHO NHBn2, NaBH(OAc)3 N n Boc 2a; n = 0 2b; n = 1 2c; n = 2 2d, n = 3

1,2-DCE, r.t, 16 h

NBn2 N n Boc 3a (92%) 3b (90%) 3c (86%) 3d (84%)

1. H2, Pd/C, MeOH rt, 24 h. 2. Tf2O, NEt3, DMAP DCM, 0 °C - rt, 1 h

N H

n

NHTf

TFA, DCM

NHTf N n Boc 4a (70%) 4b (73%) 4c (77%) 4d (72%)

0 °C - rt, 6 h

1a (90%) 1b (88%) 1c (93%) 1d (86%)

Scheme 1. Preparation of catalysts 1a-d The inital catalytic screening was done for the reaction of β-nitrostyrene (1 equiv) with isobutyraldehyde (6 equiv) at rt in various solvents (Table 1). The reactions were slow and took 2-3 days for the complete consumption of β-nitrostyrene. The products were isolated through column chromatography and the enantiomeric excess was estimated through chiral HPLC. The chromatograms were compared with that of a racemic mixture of 5a, which was prepared by carrying out the reaction in the presence of DL-proline (Table 1).



NHTf + n

N H

COOH N Boc

1a; n = 1 1b; n = 2 1c; n = 3 1d, n = 4 1. EDC·HCl, HOBt DIPEA, DCM 0 ºC - rt

N H

2. TFA, DCM 0 °C - rt, 6 h

N O

n

NHTf

1e; n = 1 (80%) 1f; n = 2 (81%) 1g; n = 3 (81%) 1h, n = 4 (70%)

Scheme 2. Preparation of catalysts 1e-h For the reactions catalyzed by the trifluoromethylsulfonamidoalkylpyrrolidines 1a-d, the major product formed is compound ent-5a. This was expected and is consistent with the observations of Wang et al. Wang’s catalyst 1a was the best among these four compounds in most of the solvents except for the reactions in toluene (entry 4), where compound 1c was found to be a better catalyst. As was observed by Wang et al., the best result for catalyst 1a was obtained in isopropanol (entry 1). The improved efficiency of 1c in toluene is interesting. In a nonpolar solvent, the longer alkyl chain in 1c seems to help the association of reactants and the catalyst better. However, increasing the length of the alkyl chain to four carbons as in 1d, reduced the catalytic efficiency. Unlike 1a-d, the prolinamide catalysts 1e-h yielded 5a as the major product, and with 1i, the major product is ent-5a. This difference in selectivity is expected as the configuration of the secondary amine involved in the formation of the enamine is shown to determine the stereochemistry of the products. For reactions using the five prolinamides 1e-i, chloroform and toluene were the most suitable solvents both in terms of yields and enantioselectivity (entries 3 and 4). Among all the catalysts studied, 1g gave the best results; up to 97% ee was observed for the reaction in toluene. Catalyst 1i, which is a diastereomer of 1g is not as good as the latter. When the reactions were performed with 10 mol% of the catalysts in toluene (entry 8) the reactions took longer time to complete, while the enantioselectivity of the reactions were not compromised in comparison to the reactions done with 20 mol% of the catalysts in toluene (entry 4). However, reducing the catalyst loading to 5 mol% reduced the reactivity considerably and the reactions were not complete to useful limits even after 4 days. When the reaction was carried out with 1g in chloroform, isopropanol and toluene at lower temperatures, the reactions were slower and there was no improvement in enantioselectivity.


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The above results prompted us to conclude that 1g is the best among the catalysts studied, when the reactions are carried out at rt in toluene and that it is not possible to improve the enantioselectivity further by doing the reactions at lower temperatures. The superiority of 1g over 1e, 1f and 1h suggests that an optimal distance is required between the secondary amino function in the catalyst and the hydrogen bond donor (NHTf) group. This is consistent with the improved activity of peptide catalysts developed by Wennemers, Marc Lecouvey and Tomás Martín over the activities of catalysts such as proline, where the COOH group and the secondary amino group are closer.

Table 1. Screening of catalysts in various solvents O

NO2 + 1 equiv

entry

solvent

1

H

Catalyst (20 mol%) 30 ºC, 2-3 days

NO2

O

+

5a

6 equiv

NO2

O ent-5a

(yield %)a and eeb of the major products formed with each catalyst 1ac, g

1bc

1cc

1dc

1ed

1fd

1gd

1hd

1ic

IPA

(89) 83

(83) 10

(82) 44

(94) 34

(79) 23

(92) 22

(87) 70

(91) 57

(93) 32

2

CH3CN

(64) 73

(61) 9

(63) 51

(67) 53

(66) 39

(80) 57

(91) 93

(78) 64

(85) 49

3

CHCl3

(43) 79

(51) 5

(47) 60

(70) 51

(78) 81

(82) 79

(84) 91

(81) 85

(79) 89

4

Toluene

(41) 61

(50) 12

(64) 78

(69) 58

(68) 76

(82) 88

(92) 97

(78) 81

(83) 74

5

DMSO

(93) 63

(82) 0

(85) 51

(90) 40

(60) 0

(93) 23

(90) 45

(87) 37

(92) 51

6

THF

(>10) nd

(>10) nd

(>10) nd

(65) 50

(>10) nd

(64) 76

(78) 89

(72) 72

(70) 82

7

DMF

(87) 73

(78) 0

(81) 15

(86) 23

(78) –7

(89) 14

(86) 30

(80) 25

(87) 31

8e

Toluene

(30)f 61

(45)f 12

(56)f 78

(68)f 58

(80) 76

(78) 87

(86) 97

(88) 85

(81) 74

aIsolated

yield after column chromatography; bee as determined by chiral HPLC analysis using a Chiralpak OD-H column; cmajor product is ent-5a; dmajor product is 5a; e10mol% of catalyst was used; freactions were incomplete, yields are as observed after 4 days; g10 equiv of isobutyraldehyde was used.



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Table 2: Michael addition reactions of various aldehydes with nitroalkenes in the presence of 1g O2N

O Ar

+

NO2

R2

1g (10 mol%) H

toluene, 30 ºC

1

R 4 equiv

1 equiv

entry

1

2

R

R 5

product (5)

reactants

Ar

O

reaction time

yielda

eeb

drc

60 h

86%

97%

---

60 h

88%

95%

---

60 h

90%

95%

---

60 h

85%

96%

---

60 h

92%

96%

---

60 h

84%

95%

---

72 h

80%

93%

---

O2N 1

Ar = Ph R1 = R2 = Me

O 5a O2N

2

Ar = 4-Me-C6H4 R1 = R2 = Me

O 5b O2N

3

Ar = 4-OMe-C6H4 R1 = R2 = Me

O OMe

5c O2N 4

Ar = 4-F-C6H4 R1 = R2 = Me

O 5d

F

O2N 5

Ar = furyl R = R2 = Me 1

O

O O2N

6

Ar = 3-Cl-C6H4 R1 = R2 = Me

5e Cl

O 5f O2N

7

Ar = 2-Cl-C6H4 R1 = R2 = Me

Cl

O 5g

Continued…


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O2N

Ar = Ph R = H, R2 = Me

8

1

O

48 h

95%

95%

85:15

48 h

93%

92%

91:9

48 h

86%

88%

86:14

48 h

84%

94%

>99:1

48 h

83%

80%

73:27

48 h

94%

96%

83:17

48 h

90%

94%

72:28

48 h

91%

94%

85:15

48 h

90%

96%

76:24

48 h

95%

92%

75:25

5h O2N

Ar = Ph R = H, R2 = Et

9

1

O

5i O2N

Ar = Ph R1 = H, R2 = Pr

10

O

5j O2N

Ar = Ph R = H, R2 = i-Pr

11

1

O

5k O2N

12

Ar = Ph R1 = H, R2 = CH2Ph

O

5l

Ph O2N

13

Ar = 4-Me-C6H4 R1 = H, R2 = Me

O

5m O2N

14

Ar = 4-F-C6H4 R1 = H, R2 = Me

O 5n

F

O2N

15

Ar = 4-OMe-C6H4 R1 = H, R2 = Me

O 5o

OMe

O2N

16

17

Ar = 3-Cl-C6H4 R1 = H, R2 = Me

Ar = furyl R1 = H, R2 = Me

Cl

O

5p O2N

O

O 5q

aIsolated

yield after column chromatography; bee as determined by chiral HPLC analysis using a Chiralpak OD-H/IC column; cdiastereomeric ratio is calculated from 1H NMR spectra of the crude reaction mixture.



Having found that 1g is the best among all the catalysts studied, we proceeded to check the usefulness of 1g as a catalyst for Michael addition reactions of other nitroalkenes and aldehydes. The reactions were carried out at rt in toluene with 1 equiv of the nitrostyrene and 4 equiv of the aldehyde (Table 2). Reaction of β-nitrostyrene with isobutyraldehyde (entry 1) was slower on reducing the number equivalents of the latter from 6 to 4 and the reaction took 60 h for completion (compare with entry 4 in Table 1). The yield and enantioselectivity was not affected and we decided to continue the studies with 4 equivalents of the aldehydes instead of 6. Reducing the equivalents of aldehyde to 3 or 2 increased the reaction time considerably and was avoided. Entries 1-7 show reactions of various nitroalkenes with isobutyraldehyde. All of the reactions were high yielding and provided the products with high ee ranging from 93-97%. The reactions were generally slower and the reaction with the o-chloro β-nitrostyrene (entry 7) was the slowest and had the lowest enantioselectivity (ee 93%). The high enantioselectivites and fairly good yields for the reactions of isobutyraldehyde, an α,α-disubstituted aldehyde was quite encouraging. Nugent et al. has developed a very efficient three component catalyst system specifically for the reaction of α-branched aldehydes with nitroalkenes.12 Entries 1 and 8-12 show the reactions of β-nitrostyrene with six different aldehydes. The reaction with isobutyraldehyde was the slowest, but it is the most selective (entry 1). Entries 8-10 shows the effect of increasing the alkyl chain length of the aldehydes on the reaction. Interestingly, propanal (entry 8) reacted better than butanal and pentanal. The enantioselectivity for the reaction with pentanal (entry 9) was one of the lowest. Reaction of 3-phenylpropanal was the most sluggish which resulted in a relatively poor enantioselectivity (entry 12). Entries 8-17 list products that contain an additional stereocenter. Moderate to excellent diastereoselectivity was observed for all these reactions and the reaction of β-nitrostyrene with isovaleraldehyde showed the highest diastereoselectivity (entry 11). Entries 8 and 13-17 show reactions of various nitroalkenes with propanal. These reactions were faster than the reactions of corresponding nitroalkenes with isobutyraldehyde. Products were obtained in high yields and with ee ranging from 92-96%. All these reactions produced two diastereomers and the diastereomeric ratios were moderate to good. The examples listed in Table 2 suggest that catalyst 1g is effective in catalyzing the Michael addition reactions between nitroalkenes and aldehydes in very good yields and with high enantioselectivity. Diastereoselectivity can range from moderate to excellent depending on the structure of the reactants. At least 10 mol% of the catalyst is required for the reactions to proceed with useful rates. Most attractive feature of the catalyst is that the best results are obtained at rt which encourages further research in bettering the catalyst. However, in comparison with the catalysts developed by Wennemers’s group based on a carboxylic acid group as the H-bond donors, 1g and its analogues based on an NHTf group require significant improvements to be synthetically useful. Further modification of the catalyst will be required to bring down the number of equivaIents of the aldehydes, catalyst loading and the reaction times. It may be safe to predict that the transition state leading to the major products in these reactions are similar to those proposed for proline-catalyzed Michael addition reactions.13 It is expected that the


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secondary amino group of D-proline activates the aldehyde as an enamine, while the –NHTf group directs the approach of the Michael acceptor through hydrogen bonding.

Conclusion In an effort to develop organocatalysts for the asymmetric Michael addition reaction of nitroalkenes with aldehydes, four 2-(trifluoromethylsulfonamidoalkyl)pyrrolidines and their amides with D-proline were synthesized and screened for the reaction between β-nitrostyrene and isobutyraldehyde in different solvents. It was found that D-prolyl-2(trifluoromethylsulfonamidopropyl)pyrrolidine (1g) was the best among all the catalysts studied and the best result was obtained for reactions in toluene with 10 mol% of the catalyst at rt. Reactions between several nitroalkenes and aldehydes were carried out under these conditions. The reactions were high yielding and provided the products with very high ee ranging from 9297%, while the diastereomeric ratios varied from 72:28 to >99:1. Thus 1g is among the best catalysts for this important reaction, especially at rt. Catalyst loading, time taken for completion of the reactions and number of equivalents of aldehydes required are on the higher side for 1g in comparison with some other peptide catalysts reported. These aspects of 1g need to be improved by structural modification of the catalyst. The other prolinamide catalysts reported for Michael addition reactions use carboxylic acids or phosphonic acid as hydrogen bond donors, while 1g has an NHTf group. A very interesting inference that can be drawn from the results is the requirement of a suitable spacer between the secondary amino group and the hydrogen bond donor in the catalyst, which is in agreement with the reports on other prolinamide catalysts.

Experimental General Information. All the chemicals were purchased from commercial sources. Anhydrous solvents were used for the reactions. Column chromatography was done with silica gel (particle size 60-120 and 100-200 mesh) purchased from Merck. The absolute configuration of the reaction products was confirmed by HPLC, by comparison with reported data. The enantiomeric ratios were estimated by chiral HPLC analysis and diastereomeric ratios were determined from1H NMR analysis. High performance liquid chromatography (HPLC) was performed on an Agilent Technologies chromatograph (1100 Series), using the specified Daicel chiral column and guard columns with a mixture of hexane and 2-propanol as eluents at 25 ºC. Optical rotations were measured using a 5.0 mL cell with a 10 dm path length and are reported as [α]D25 (c in g per 100 mL solvent). Procedure for the preparation of aldehydes 2b and 2d from 2a and 2c, respectively. A solution of (methoxymethyl)triphenylphosphonium chloride (3.42 g, 10.0 mmol, 2.0 equiv) and t-BuOK (1.40 g, 12.5 mmol, 2.5 equiv) were added in dry THF and stirred for 30 min at 0 °C. Aldehydes 2a10 or 2c (5.0 mmol, 1.0 equiv) was added to this solution and was stirred at rt for 3 h. After the complete disappearance of the aldehydes on TLC, the reaction was quenched with saturated NH4Cl solution (15 mL) and the products were extracted with ethyl acetate (2 × 20 mL). Combined organic layers were washed with brine (10 mL) and then dried over Na2SO4 and



filtered. The solvents were removed under reduced pressure and the methyl enol ether waspurified by column chromatography and was dissolved in THF (10 mL). The solution was cooled to 0 ºC and 2N HCl (10 mL) was added. The mixture was allowed to attain rt and the stirring was continued for 2 h. The reaction mixture was then neutralized with saturated NaHCO3 solution (20 mL) and extracted with ethyl acetate (2 × 30 mL). Crude solution of the aldehyde was washed with brine (20 mL), dried over Na2SO4 and filtered. Solvents were removed under reduced pressure and the product was purified by column chromatography. tert-Butyl (S)-2-(2-oxoethyl)pyrrolidine-1-carboxylate (2b). Column chromatography (90:10 petroleum ether/EtOAc); clear oil (0.87 g, 82%); [α]D25 = –13.0 (c 0.33, CH2Cl2) (rotamers) 1H NMR (400 MHz, CDCl3) δ 9.73 (t, J = 2.1 Hz, 1H), 4.20 (s, 1H), 3.30 (t, J = 8 Hz, 2H), 2.88– 2.73 (m, 1H), 2.43 (dd, J = 16.1, 7.1 Hz, 1H), 2.07 (s, 1H), 1.85–1.76 (m, 2H), 1.67–1.56 (m, 1H), 1.41 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 201.0, 200.9, 154.5, 154.1, 123.9, 123.4, 115.8, 114.1, 80.1, 79.5, 52.41, 49.6, 48.9, 46.5, 46.2, 32.1, 31.2, 29.7, 29.6, 28.5, 23.7, 23.0 ppm; FTIR (thin film): ῡ = 2982, 2860, 2756, 2720, 1728, 1658, 1456, 1425, 1391, 1321, 1276, 1249, 1171, 1120 cm-1. HRMS (ESI-TOF) m/z: [M + H]+calcd for C11H20NO3 214.1443, found 214.1448. tert-Butyl (R)-2-(4-oxobutyl)pyrrolidine-1-carboxylate (2d). Column chromatography (80:20 petroleum ether/EtOAc); clear oil (1.02 g, 85%); [α]D25 = –25.0 (c 0.40, CH2Cl2); (rotamers) 1H NMR (500 MHz, CDCl3) δ 9.67 (s, 1H), 3.66 (d, J = 30 Hz, 1H), 3.35-3.21 (m, 2H), 2.38 (t, J = 10 Hz, 2H), 1.70–1.70 (m, 4H), 1.57–1.49 (m, 4H), 1.36 (s, 9H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 202.4 , 202.0 , 154.5 ,79.0, 78.8 , 56.8 , 46.4, 45.9, 43.6,34.0, 33.4, 30.5 , 29.8 , 28.4, 23.6 , 22.9, 18.7 ppm; FTIR (thin film): ῡ = 2972, 2875, 2761, 2718, 1726, 1692, 1478, cm-1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H24NO3 242.1756, found 242.1758. Procedure for the synthesis of aldehyde 2c. Aldehyde 2c was prepared from the ester A, which was prepared according to a reported procedure.11 The ester A was initially reduced to the corresponding primary alcohol and then oxidized to the aldehyde 2c. O N Boc

O A

To a stirred solution of the ester A (0.54 g, 2.0 mmol, 1.0 equiv) in dry THF (10 mL) at 0 °C, LiAlH4 (0.09 g, 2.4 mmol, 1.2 equiv) was added in small portions. The reaction mixture was stirred at rt for 30 min. After the complete disappearance of A on TLC, the reaction was quenched with saturated NH4Cl solution (10 mL) and extracted with ethyl acetate (2 × 30 mL). Combined organic layers were washed with brine (20 mL), dried over Na2SO4 and filtered. The solvents were removed under reduced pressure and the primary alcohol was purified by column chromatography. Column chromatography (75:25 petroleum ether/EtOAc); clear oil (0.42 g, 92%); [α]D25 = –19.0 (c 0.50, CHCl3); (rotamers) 1H NMR (500 MHz, CDCl3) δ 3.91–3.81 (m, 1H), 3.77–3.62 (m, 2H), 3.43–3.29 (m, 2H), 1.91–1.69 (m, 4H), 1.63–1.58 (m, 3H), 1.54–1.49


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(m, 1H), 1.45 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 154.9, 154.8, 79.1, 62.7, 62.5, 57.0, 56.7, 46.5, 46.1, 30.8, 30.2, 29.5, 29.1, 28.6, 23.7, 23.1 ppm; FTIR (thin film): ῡ = 3435, 2959, 2933, 2856, 1693, 1676, 1478, 1454, 1424, 1366,1343, 1337, 1251, 1175,1127, cm-1. HRMS (ESI-TOF) m/z: [M + H]+calcd for C12H24NO3 230.1756, found 230.1753. To a solution of the primary alcohol obtained from A (0.46 g, 2.0 mmol, 1.0 equiv) in DMSO (10 mL), IBX (0.56 g, 2.4 mmol, 1.2 equiv) was added and the reaction mixture was stirred at rt for 10 h. The reaction was quenched with saturated NaHCO3 solution (10 mL) and extracted with ethyl acetate (2 × 20 mL). Combined organic layers were washed with brine (30 mL), dried over Na2SO4 and was filtered. The solvents were removed under reduced pressure and the aldehyde 2c was purified by column chromatography. Column chromatography (90:10 petroleum ether/EtOAc); clear oil (0.40 g, 88%); [α]D25 = –10.0 (c 0.40, CHCl3); (rotamers) 1H NMR (500 MHz, CDCl3) δ 9.65 (s, 1H), 3.84–3.68 (m, 1H), 3.33–3.18 (m, 2H), 2.35 (s, 2H), 1.84–1.69 (m, 4H), 1.62–1.50 (m, 2H), 1.35 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 202.3, 201.8, 155.0, 154.9, 79.5, 79.2, 56.5, 46.6, 46.2, 40.9, 40.8, 30.8, 30.3, 29.7, 28.5, 27.0, 23.7, 23.0 ppm; FTIR (thin film): ῡ = 3061, 3026, 2959, 2930, 2856, 1676, 1472, 1454, 1424, 1393,1376, 1337, 1256, 1175, cm-1. HRMS (ESI-TOF) m/z: [M + H]+calcd for C12H22NO3 228.1600, found 228.1599. General procedure for the reductive amination of aldehydes 2. To a stirred solution of the aldehyde 2 (5.0 mmol, 1.0 equiv) in 1,2-DCE (20 mL) dibenzylamine (1.06 mL, 5.5 mmol, 1.10 equiv) and NaBH(OAc)3 (2.12 g, 10.0 mmol, 2.0 equiv) were added at 0 °C. The reaction mixture was stirred at rtfor 16 h. After the complete disappearance of 2 on TLC, the reaction was quenched with saturated NaHCO3 solution (10 mL) and extracted with ethyl acetate (2 × 15 mL). Combined organic layers were washed with brine (20 mL) and then dried over Na2SO4 and filtered.The solvents were removed under reduced pressure and the crude tertiary amines 3were purified by column chromatography. tert-butyl (S)-2-((dibenzylamino)methyl)pyrrolidine-1-carboxylate (3a). Column chromatography (90:10 petroleum ether/EtOAc); clear oil (1.74 g, 92%); [α]D25 = –40.6 (c 0.33, CH2Cl2); (rotamers) 1H NMR (400 MHz, CDCl3) δ 7.36–1.23 (m, 10H), 4.03–3.85 (m, 3H), 3.30–3.16 (m, 4H), 2.59–2.46 (m, 1H), 2.28 (t, J = 12 Hz, 1H), 1.87–1.60 (m, 4H), 1.47 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 154.6, 154.5, 140.0, 139.8, 129.0, 128.2, 127.0, 126.8, 79.2, 78.9, 59.3, 59.0, 56.1, 55.6, 55.4, 55.1, 46.5, 46.1, 29.1, 28.7, 28.3, 23.2, 22.2 ppm; FTIR (thin film): ῡ = 3061, 3026, 2959, 2930, 2856, 1676, 1472, 1454, 1424, 1393,1376, 1337, 1256, 1175, cm-1. HRMS (ESI-TOF) m/z: [M + H]+calcd for C24H33N2O2 381.2542, found 381.2544. tert-butyl(S)-2-(2-(dibenzylamino)ethyl)pyrrolidine-1-carboxylate(3b).Column chromatography (95:5 petroleum ether/EtOAc); clear oil (1.77 g, 90%); [α]D25 = –4.0 (c 0.25, CH2Cl2); ); 1H NMR (500 MHz, CDCl3) δ 7.37 (d, J = 7.36 Hz, 4H), 7.31 (t, J = 8 Hz, 4H), 7.23 (t, J = 8 Hz, 2H), 3.80–3.27 (m, 9H), 2.50–2.38 (m, 2H), 2.09 (s, 1H), 1.78–1.70 (m, 3H), 1.40 (s, 9H) ppm; 13C{1H} NMR (125 MHz, CDCl ) δ 154.5, 139.7, 128.7, 128.1, 126.8, 79.0, 58.2, 55.5, 50.3, 3 46.0, 31.5, 30.3, 28.5, 22.9 ppm; FTIR (thin film): ῡ = 3065, 3026, 2994, 2876, 2730, 1692,



1601, 1494, 1477, 1452, 1394, 1364, 1236, 1170, 1107, cm-1. HRMS (ESI-TOF) m/z: [M + H]+calcd for C25H35N2O2 395.2699, found 395.2692. tert-butyl (R)-2-(3-(dibenzylamino)propyl)pyrrolidine-1-carboxylate (3c).Column 25 chromatography (90:10 petroleum ether/EtOAc); clear oil (1.75 g, 86%); [α]D = –5.0 (c 0.30, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 7.4 Hz, 4H), 7.30 (t, J = 7.3 Hz, 4H), 7.22 (t, J = 7.0 Hz, 2H), 3.75–3.56 (m, 5H), 3.38–3.28 (m, 2H), 2.44 (s, 2H), 1.89–1.73 (m, 4H), 1.58– 1.44 (m, 12H), 1.33–1.24 (m, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 154.7, 139.9, 128.8, 128.2, 126.8, 78.9, 58.4, 57.3, 53.6, 46.5, 46.1, 32.6, 30.8, 28.6, 24.0 ppm; FTIR (thin film): ῡ = 3063, 3026, 2970, 2872, 2794, 1693, 1478, 1464, 1453, 1393, 1364, 1252, 1170, 1108, cm-1. HRMS (ESI-TOF) m/z: [M + H]+calcd for C26H37N2O2 409.2855, found 409.2857. tert-butyl(R)-2-(4-(dibenzylamino)butyl)pyrrolidine-1-carboxylate (3d).Column chromatography (90:10 petroleum ether/EtOAc); clear oil (1.77 g, 84%); [α]D25 = –28.0 (c 0.33, CH2Cl2); (rotamers) 1H NMR (500 MHz, CDCl3) δ 7.29 (d, J = 7.8 Hz, 4H), 7.22 (t, J = 10 Hz, 4H), 7.14 (t, J = 10 Hz, 2H), 3.68–3.59 (m, 1H), 3.51–3.47 (m, 4H), 3.21 (s, 2H), 2.35 (t, J = 7.5 Hz, 2H), 1.78–1.64 (m, 4H), 1.51–1.48 (m, 3H), 1.39 (s, 9H), 1.19 (d, J = 18.3 Hz, 3H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 154.6 , 140.0 , 128.7 , 128.1 , 126.7 , 78.83 , 58.3, 57.2, 53.4 , 46.4 , 46.0 , 34.6 , 34.3, 30.6, 29.8, 28.6, 27.1, 24.0, 23.4.ppm; FTIR (thin film): ῡ = 3084, 3061, 3026, 2970, 2932, 2794, 2860, 1693, 1602, 1494, 1477, 1454, 1426, 1393, 1365, 1248, 1171, 1130, cm1. HRMS (ESI-TOF) m/z: [M + H]+calcd for C H N O 423.3012, found 423.3014. 27 39 2 2 General procedure for the debenzylation followed by trifluromethylsulfonylation of 3. To a solution of 3 (3.0 mmol) in methanol Pd/C (30.00 mg) was added and the mixture was stirred under a hydrogen atmosphere at rtfor 24 h. The reaction mixture was filtered through a celite pad and the solvents were removed under reduced pressure to get the corresponding primary amines, which were dissolved in DCM(20 mL) and used without further purification. The solution of the amine was cooled to 0 ºC and triethylamine (1.04 mL, 7.5 mmol, 2.5 equiv) and DMAP (0.1 g, 0.9 mmol, 0.3 equiv) were added to this cold solution. This was followed by a slow addition of trifluoromethanesulfonic anhydride (0.63 mL, 3.6 mmol, 1.2 equiv) over a period of 15 min and the mixture was stirred for 3 h at 0 °C. Reaction was quenched with saturated NaHCO3 solution (10 mL) and was extracted with DCM (2 × 30 mL). Combined organic layers were washed with brine (25 mL), dried over Na2SO4 and was filtered. Solvents were removed under reduced pressure and the crude amino triflates 4 were purified by column chromatography. tert-butyl (S)-2-(((trifluoromethyl)sulfonamido)methyl)pyrrolidine-1-carboxylate (4a).Column chromatography (85:15 petroleum ether/EtOAc); White wax(0.69 g, 70%); [α]D25 = –24.0 (c 0.25, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 4.05–3.91 (m, 1H), 3.45–3.28 (m, 3H), 3.19 (t, J = 12 Hz, 1H), 2.08–1.98 (m, 1H), 1.84–1.79 (m, 2H), 1.65–1.57 (m, 1H), 1.42 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 157.0, 119.9 (q, J = 321.7Hz), 80.9, 56.8, 49.2, 47.3, 29.1, 28.2, 23.6 ppm; FTIR (thin film): ῡ = 3142, 2976, 1666, 1478, 1454, 1408, 1369, 1336, 1230, 1211, 1151, 1109, cm-1. HRMS (ESI-TOF) m/z: [M + Na]+calcd for C11H19F3 N2NaO4S 355.0915, found 355.0910.


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tert-butyl (S)-2-(2-((trifluoromethyl)sulfonamido)ethyl)pyrrolidine-1-carboxylate (4b).Column chromatography (85:15 petroleum ether/EtOAc); White solid, mp 90-92 °C (0.75 g, 73%); [α]D25 = –5.3 (c 0.3, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.81 (s, 1H), 4.01 (t, J = 10 Hz, 1H), 3.40–3.34 (m, 1H), 3.32–3.26 (m, 2H), 3.07 (t, J = 10 Hz, 1H), 2.01–1.93 (m 1H), 1.89–1.82 (m, 2H), 1.67–1.64 (m, 1H), 1.59–1.49 (m, 2H), 1.42 (s, 9H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 156.6, 119.8 (q, J = 321.5 Hz), 80.3, 53.7, 46.5, 41.3, 36.0, 31.1, 28.1, 23.3 ppm; FTIR (thin film): ῡ = 3156, 2975, 2888, 2756, 1666, 1648, 1478, 1455, 1417, 1369, 1233, 1186, 1151, 1109, cm-1. HRMS (ESI-TOF) m/z: [M + H]+calcd for C12H21F3N2O4S 347.1252, found 347.1250. tert-butyl (S)-2-(3-((trifluoromethyl)sulfonamido)propyl)pyrrolidine-1-carboxylate (4c).Column chromatography (85:15 petroleum ether/EtOAc); clear oil (0.83 g, 77%); [α]D25 = –14.0 (c 0.40, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.62 (s, 1H), 3.81 (s, 1H), 3.33 (d, J = 31.5 Hz, 4H), 2.00–1.83 (m, 4H), 1.65–151 (m, 4H), 1.44 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 155.4, 121.5 (q, J = 322.4 Hz), 80.1, 55.5, 46.4, 43.5, 31.7, 30.8, 28.5, 25.6, 23.6 ppm; FTIR (thin film): ῡ = 3139, 2975, 2936, 2882, 1693, 1666, 1478, 1457, 1415, 1389, 1252, 1229, 1182, 1151, 1134, cm-1. HRMS (ESI-TOF) m/z: [M + H]+calcd for C13H24F3N2O4S 361.1409, found 361.1418. tert-butyl (R)-2-(4-((trifluoromethyl)sulfonamido)butyl)pyrrolidine-1-carboxylate (4d). Column chromatography (85:15 petroleum ether/EtOAc); clear oil (0.80 g, 72%); [α]D25 = –18.0 (c 0.25, CH2Cl2); (rotamers) 1H NMR (400 MHz, CDCl3) δ 6.94 (s, 0.7H), 6.19 (s, 0.3H), 3.81–3.68 (m, 1H), 3.28–3.23 (m, 4H), 1.93–1.79 (m, 3H), 1.68–1.58 (m, 4H), 1.41–1.25 (m, 12H) ppm; 13C{1H} NMR (100 MHz, CDCl ) δ 155.4, 154.8, 119.9 (q, J = 321.5 Hz), 79.7, 79.5, 57.0, 56.2, 3 46.6, 46.1, 44.1, 34.0, 33.5, 30.4, 29.7, 28.5, 23.6, 23.0 ppm; FTIR (thin film): ῡ = 3141, 2985, 2938, 2882, 2847, 1683, 1665, 1455, 1457, 1428, 1379, 1355, 1260, 1229, 1176, 1141, 1127, 1121, cm-1. HRMS (ESI-TOF) m/z: [M + H]+calcd for C14H25F3N2O4S 375.1565, found 375.1565. General procedure for the N-Boc deprotection of 4 to get 1a-d. To a stirred solution of 4 (2.0 mmol) in dry DCM (5 mL), TFA (5 mL) was added at 0 °C and the solution was stirred at rt for 6 h. Reaction was monitored through TLC and after the complete disappearance of 4, the reaction mixture was concentrated under reduced pressure and 2N NaOH solution was added to get a solution of pH 12. This mixture was extracted with ethyl acetate (3 × 20 mL) and dried over Na2SO4 and filtered. Solvents were removed under reduced pressure to get the alkylamino triflates (1a-d). (S)-1,1,1-trifluoro-N-(pyrrolidin-2-ylmethyl)methanesulfonamide (1a).White solid, mp 162-164 °C (0.41 g, 90%); [α]D25 = +32.0 (c 0.25, CHCl3:MeOH); 1H NMR (500 MHz, D2O) δ 3.70–3.64 (m, 1H), 3.60 (dd, J = 15.0, 4.7 Hz, 1H), 3.50 (dd, J = 14.9, 5 Hz, 1H), 3.35–3.23 (m, 2H), 2.18– 2.11 (m, 1H), 2.02–1.95 (m, 2H), 1.69–1.61 (m, 1H) ppm; 13C{1H} NMR (100 MHz, D2O) δ 119.5(q, J = 320.1 Hz), 60.1, 45.6, 43.6, 26.8, 22.4 ppm; FTIR (thin film): ῡ = 3440, 3036, 2976, 2880, 2755, 1673, 1632, 1468, 1452, 1398, 1229, 1184, 1122, 1110, cm-1. HRMS (ESI-TOF) m/z: [M + H]+calcd for C6H12F3N2O2S 233.0572, found 233.0577.



(S)-1,1,1-trifluoro-N-(2-(pyrrolidin-2-yl)ethyl)methanesulfonamide (1b). White solid, mp 96-98 °C (0.43 g, 88%); [α]D25 = –11.0 (c 0.2, CHCl3:MeOH); 1H NMR (400 MHz, D2O) δ 3.59–3.52 (m,1H), 3.32–3.20 (m, 4H), 2.21–2.13 (m, 1H), 2.01–1.84 (m, 4H), 1.64–1.54 (m, 1H) ppm; 13C{1H} NMR (100 MHz, D O) δ 122.1 (q, J = 320.7 Hz),, 60.2, 47.8, 43.3, 34.6, 31.9, 25.5 2 ppm; FTIR (thin film): ῡ = 3421, 3055, 2976, 2926, 2880, 2762, 2722, 1676, 1646, 1642, 1472, 1455, 1378, 1359, 1352, 1346, 1276, 1236, 1230, 1180, 1178,cm-1. HRMS(ESI-TOF)m/z: [M + H]+ calcd for C7H14F3N2O2S 247.0728, found 247.0720. (S)-1,1,1-trifluoro-N-(3-(pyrrolidin-2-yl)propyl)methanesulfonamide (1c).White solid, mp 76-79 °C (0.48 g, 93%); [α]D25 = +22.0 (c 0.40, CHCl3:MeOH); 1H NMR (400 MHz, D2O) δ 3.46–3.39 (m, 1H), 3.23–3.12 (m, 4H), 2.15–2.07 (m, 1H), 1.94–1.85 (m, 2H), 1.73–1.48 (m, 5H) ppm; 13C{1H} NMR (100 MHz, D O) δ 119.8 (q, J = 321.5 Hz), 60.2, 45.1, 43.3, 29.5, 28.5, 26.9, 23.0 2 ppm; FTIR (thin film): ῡ = 3421, 2955, 2942, 2845, 1645, 1478, 1456, 1421, 1371, 1321, 1310, 1178, 1122, 1112, cm-1. HRMS (ESI-TOF) m/z: [M + H]+calcd for C8H15F3N2O2S 261.0885, found 261.0887. (R)-1,1,1-trifluoro-N-(4-(pyrrolidin-2-yl)butyl)methanesulfonamide (1d).White solid, mp 74-76 °C (0.47 g, 86%); [α]D25 = +24.0 (c 0.30, CHCl3:MeOH);1H NMR (400 MHz, D2O) δ 3.47 (t, J = 4 Hz, 1H), 3.23 (s, 4H), 2.15 (d, J = 4 Hz, 1H), 1.99–1.88 (m, 2H), 1.72–1.57 (m, 5H), 1.40 (d, J = 8 Hz, 2H) ppm; 13C{1H} NMR (100 MHz, D2O) δ 120.0 (q, J = 322.0 Hz), 60.6, 45.0, 43.6, 30.9, 29.5, 29.3, 23.0, 22.9 ppm; FTIR (thin film): ῡ = 3421, 2951, 2887, 2845, 2761, 1645, 1478, 1450, 1371, 1322, 1210, 1174, 1122, cm-1. HRMS (ESI-TOF) m/z: [M + H]+calcd for C9H18F3N2O2S 275.1041, found 275.1040. General procedure for the preparation of prolinamides 1e-i. A solution of the N-Boc derivative (0.21 g, 1.0 mmol, 1.0 equiv) of D-proline (for 1e-h) or of L-proline (for 1i) in DCM (20 mL) was cooled to 0 ºC. To this solution,EDC·HCl (0.28 g, 1.5 mmol, 1.5 equiv), HOBt (0.20 g, 1.5 mmol, 1.5 equiv) and DIPEA (0.43 mL, 2.5 mmol, 2.5 equiv) were added and was stirred for 15 min. To the cold mixture, the secondary amine 1a-d (1.0 mmol, 1.0 equiv) was added as a solution in DCM (3 mL) and the solution was stirred at rt for 16 h. Reaction was monitored through TLC and after the complete disappearance of the amine, the reaction mixture was diluted with DCM (30 mL) and was washed with saturated NaHCO3 solution (10 mL) and then with 1N KHSO4 solution (10 mL). Crude solution of the prolinamide 1e-i was washed with brine (20 mL), dried over Na2SO4 and was filtered. Solvents were removed under reduced pressure and the products were purified by column chromatography to get the N-Boc derivatives of 1e-i. tert-butyl(R)-2-((S)-2-(((trifluoromethyl)sulfonamido)methyl)pyrrolidine-1-carbonyl)pyrrolidine1-carboxylate (N-Boc-1e). Column chromatography (60:40 petroleum ether/EtOAc); White wax (0.37 g, 88%); [α]D25 = –12.0 (c 0.25, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.42 (s, 1H), 4.29 (t, J = 7.5 Hz, 1H), 4.09–4.05 (m, 2H), 3.73–3.68 (m, 1H), 3.53–3.42 (m, 3H), 3.18 (d, J = 8 Hz,1H), 2.15–2.05 (m, 4H), 1.99–1.91 (m, 2H), 1.86–1.79 (m, 2H), 1.41 (s, 9H) ppm;13C{1H} NMR (100 MHz, CDCl3) δ 171.7, 155.0, 119.9 (q, J = 321.5 Hz), 80.8, 58.1, 57.3, 48.2, 47.2,


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44.6, 29.0, 28.3, 28.0, 24.9, 24.4 ppm; FTIR (thin film): ῡ = 3129, 2975, 2976, 2927, 2885, 2856, 2248, 1698, 1659, 1655, 1634, 1478, 1417, 1377, 1331, 1229, 1162, 1151, cm-1.HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H26F3N3NaO5S 452.1443, found 452.1445. tert-butyl (R)-2-((S)-2-(2-((trifluoromethyl)sulfonamido)ethyl)pyrrolidine-1carbonyl)pyrrolidine-1-carboxylate (N-Boc-1f). Column chromatography (50:50 petroleum ether/EtOAc); clear oil (0.40 g, 92 %); [α]D25 = +27.0 (c 0.20, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.73 (s, 1H), 4.43–4.34 (m, 2H), 3.76–3.72 (m, 1H), 3.55–3.50 (m, 1H), 3.42–3.35 (m, 3H), 3.23 (dd, J = 15.3, 6.9 Hz, 1H), 2.16–2.11 (m, 1H), 2.05–1.96 (m, 4H), 1.87–1.78 (m, 2H), 1.75–1.69 (m, 1H), 1.65–1.62 (m, 1H), 1.56–1.50 (m,1H), 1.43–1.36 (m, 9H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 173.2, 154.7, 119.8 (q, J = 321.4 Hz), 80.0, 58.2, 53.6, 47.0, 46.1, 40.9, 35.8, 30.3, 28.8, 28.3, 24.6, 23.4 ppm; FTIR thin film): ῡ = 3129, 2975, 2976, 2927, 2884, 2856, 2248, 1698, 1659, 1655, 1634, 1478, 1417, 1377, 1331, 1229, 1162, 1151, cm-1. HRMS (ESI-TOF) m/z: [M + Na]+calcd for C17H28F3N3Na O5S 466.1599, found 466.1605. tert-butyl (R)-2-((S)-2-(3-((trifluoromethyl)sulfonamido)propyl)pyrrolidine-1carbonyl)pyrrolidine-1-carboxylate (N-Boc-1g). Column chromatography (60:40 petroleum ether/EtOAc); clear oil (0.39 g, 87%); [α]D25 = +12.0 (c 0.25, CHCl3); (rotamers) 1H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 11.1, 5.7 Hz, 1H), 4.36–4.29 (m, 1H), 4.22–4.01 (m, 1H), 3.76– 3.61 (m, 1H), 3.54–3.21 (m, 5H), 2.13–1.77 (m, 8H), 1.68–1.53 (m, 4H), 1.39–1.34 (m, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 171.9, 171.5, 154.5, 153.8, 120.0 (q, J = 321.8 Hz), 79.7, 79.6, 58.2, 57.5, 57.0, 47.0, 46.7, 46.4, 46.3, 44.0, 32.8, 32.3, 30.1, 29.6, 29.2, 28.4, 24.2, 24.0, 23.9, 23.5, 22.0 ppm; FTIR (thin film): ῡ = 3109, 2976, 2880, 1697, 1673, 1632, 1478, 1452, 1398, 1376, 1258, 1229, 1188, 1184, 1175, 1142, cm-1. HRMS (ESI-TOF) m/z: [M + H]+calcd for C18H30F3N3O5S 458.1937, found 458.1933. tert-butyl (R)-2-((R)-2-(4-((trifluoromethyl)sulfonamido)butyl)pyrrolidine-1carbonyl)pyrrolidine-1-carboxylate (N-Boc-1h). Column chromatography (55:45 petroleum ether/EtOAc); clear oil (0.39 g, 83%); [α]D25 = +6.0 (c 0.20, CH2Cl2);(rotamers) 1H NMR (400 MHz, CDCl3) δ 7.57 (dd, J = 4.0, 4.0 Hz, 1H), 4.37–4.28 (m, 1H), 4.11–3.96 (m, 1H), 3.54–3.48 (m, 2H), 3.42–3.32 (m, 2H), 3.24–3.12 (m, 2H), 2.13–1.78 (m, 8H), 1.64–1.51 (m, 4H), 1.38– 1.32 (m, 11H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 171.9, 171.5, 154.5, 153.8, 120.0 (q, J = 320.9 Hz), 79.7, 79.6, 77.4, 77.1, 76.8, 58.2, 57.5, 57.0, 47.0, 46.7, 46.4, 46.3, 44.0, 32.8, 32.3, 30.1, 29.6, 29.2, 28.4, 24.2, 24.0, 23.9, 23.5, 22.0 ppm; FTIR (thin film): ῡ = 3119, 2976, 2955, 2880, 2815, 1697, 1673, 1655, 1478, 1422, 1412, 1398, 1375, 1260, 1235, 1184, 1141, 1125, cm1. HRMS (ESI-TOF) m/z: [M + H]+calcd for C H F N O S 472.2093, found 472.2102. 19 33 3 3 5 tert-butyl (S)-2-((S)-2-(3-((trifluoromethyl)sulfonamido)propyl)pyrrolidine-1carbonyl)pyrrolidine-1-carboxylate (N-Boc-1i). Column chromatography (55:45 petroleum ether/EtOAc); clear oil (0.41 g, 90%); [α]D25 = –26.0 (c 0.40, CHCl3); (rotamers) 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 9.7, 4.9 Hz, 1H), 4.48–4.27 (m, 1H), 4.06–3.89 (m, 1H), 3.67–3.29 (m, 6H), 2.0–1.55 (m, 12H), 1.40–1.33 (m, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 172.2, 171.8, 154.7, 153.9, 119.9 (q, J = 322.2 Hz,), 79.7, 79.6, 77.4, 58.0, 57.9, 56.4, 55.9, 46.9, 46.7,



46.6, 46.5, 43.8, 43.4, 30.8, 30.5, 30.4, 29.8, 29.7, 29.4, 29.3, 28.5, 28.3, 26.3, 26.2, 24.2, 24.2, 23.7 ppm; FTIR (thin film): ῡ = 3110, 2978, 2955, 2885, 1688, 1676, 1673, 1632, 1478, 1453, 1397, 1355, 1326, 1258, 1249, 1184, 1178, 1172, 1141, cm-1. HRMS (ESI-TOF) m/z: [M + H]+calcd for C18H30F3N3O5S 458.1937, found 458.1937. The N-Boc derivatives were converted to 1e-i by removing the Boc group as described for the synthesis of 1a-d. The reactions were done with whole of the products formed in the previous step. N-(((S)-1-(D-prolyl)pyrrolidin-2-yl)methyl)-1,1,1-trifluoromethanesulfonamide (1e).Colorless 25 1 wax(0.26 g, 90%); [α]D = –29.1 (c 0.33, CHCl3:MeOH); white semi solid; H NMR (400 MHz, D2O) δ 4.44–4.39 (m, 1H), 4.04 (d, J = 2.7 Hz, 1H), 3.53-3.49 (m, 1H), 3.44–3.31 (m, 3H), 3.29– 3.23 (m, 2H), 2.47–2.39 (m, 1H), 1.91–1.78 (m, 7H) ppm; 13C{1H} NMR (125 MHz, D2O) δ 167.8, 120.1 (q, J = 322.3 Hz), 59.4, 58.5, 47.3, 46.7, 44.5, 28.1, 27.0, 24.0, 23.2 ppm; FTIR(thin film): ῡ = 3452, 3062, 2976, 2956, 2880, 2762, 1674, 1656, 1646, 1478, 1452, 1358, 1352, 1322, 1276, 1230, 1190, 1178, cm-1. HRMS (ESI-TOF) m/z: [M + H]+calcd for C11H19N3F3O3S 330.1099, found 330.1098. N-(2-((S)-1-(D-prolyl)pyrrolidin-2-yl)ethyl)-1,1,1-trifluoromethanesulfonamide (1f). White wax (0.28 g, 88%) [α]D25 = –18.0 (c 0.30, CHCl3:MeOH);(rotamers) 1H NMR (400 MHz, D2O) δ 4.51–4.41 (m, 1H), 4.10–4.04 (m, 1H), 3.56–3.20 (m, 6H), 2.51–2.42 (m, 1H), 2.03–1.83 (m, 7H), 1.78–1.60 (m, 2H) ppm; 13C{1H} NMR (100 MHz, D2O) δ 167.8, 167.3, 119.6 (q, J = 319.7 Hz),, 59.3, 59.2, 56.2, 55.8, 46.6, 41.2, 41.0, 32.9, 32.5, 28.8, 28.7, 28.2, 24.0, 23.9, 23.4, 23.0 ppm; FTIR (thin film): ῡ = 3431, 2955, 2951, 2845, 2761, 1678, 1645, 1478, 1456, 1421, 1371, 1322, 1310, 1178, 1126, 1112, cm-1. HRMS (ESI-TOF) m/z: [M + H]+calcd for C12H21F3N3O3S 344.1256, found 344.1251. N-(3-((S)-1-(D-prolyl)pyrrolidin-2-yl)propyl)-1,1,1-trifluoromethanesulfonamide (1g). White wax (0.29 g, 93%); [α]D25 = +11.0 (c 0.40, CHCl3:MeOH); 1H NMR (400 MHz, D2O) δ 4.42 (t, J = 8.0 Hz, 1H), 3.93 (d, J = 2 Hz, 1H), 3.54–3.49 (m, 1H), 3.41–3.26 (m, 3H), 3.20–3.09 (m, 2H), 2.50–2.41 (m, 1H), 2.00–1.83 (m, 6H), 1.72–1.68 (m, 2H), 1.51–1.34 (m, 3H) ppm; 13C{1H} NMR (100 MHz, D O) δ 167.0, 120.1 (q, J = 322.3 Hz), 59.3, 58.6, 58.5, 46.7, 44.0, 2 29.0, 28.5, 28.2, 26.8, 24.0, 23.1 ppm; FTIR (thin film): ῡ = 3421, 3041, 2955, 2941, 2845, 2761, 2750, 1668, 1645, 1478, 1422, 1410, 1371, 1322, 1310, 1156, 1125, cm-1. HRMS (ESI-TOF) m/z: [M + H]+calcd for C13H22F3N3O3S 358.1412, found 358.1418. N-(4-((R)-1-(D-prolyl)pyrrolidin-2-yl)butyl)-1,1,1-trifluoromethanesulfonamide (1h):White wax (0.26 g, 84%); [α]D25 = +21.0 (c 0.50, CHCl3:MeOH); 1H NMR (400 MHz, D2O) δ 4.42 (t, J = 8.0 Hz, 1H), 3.92 (s, 1H), 3.54–3.49 (m, 1H), 3.43–3.28 (m, 3H), 3.19 (t, J = 4 Hz, 2H), 2.51– 2.42 (m, 1H), 2.03–1.82 (m, 6H), 1.73–1.49 (m, 4H), 1.35–1.26 (m, 3H) ppm; 13C{1H} NMR (100 MHz, D2O) δ 166.8, 119.7 (q, J = 320.7 Hz), 59.3, 58.8, 46.7, 46.6, 43.5, 31.2, 29.1, 28.4, 28.2, 24.0, 23.1, 22.3 ppm; FTIR (thin film): ῡ = 3422, 2942, 2921, 2845, 2761, 1672, 1648, 1471, 1456, 1421, 1371, 1230, 1178, 1149, cm-1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H25F3N3O3S 372.1569, found 372.1563.


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N-(3-((S)-1-(L-prolyl)pyrrolidin-2-yl)propyl)-1,1,1-trifluoromethanesulfonamide (1i): White wax (0.28 g, 88%); [α]D25 = +17.0 (c 0.25, CHCl3:MeOH); 1H NMR (400 MHz, D2O) δ 4.44 (dd, J = 8.8, 6.6 Hz, 1H), 3.98–3.96 (m, 1H), 3.45–3.25 (m, 4H), 3.16–3.13 (m, 2H), 2.45–2.40 (m, 1H), 1.98–1.80 (m, 6H), 1.66–1.38 (m, 5H) ppm; 13C{1H} NMR (100 MHz, D2O) δ 167.6, 119.7 (q, J = 321.6 Hz), 59.2, 58.0, 46.9, 46.7, 43.8, 29.1, 28.8, 28.6, 26.1, 23.9, 23.5 ppm; FTIR (thin film); ῡ = 3412, 3048, 2962, 2951, 2841, 2761, 2755, 1675, 1640, 1478, 1421, 1355, 1322, 1221, 1178, 1136, cm-1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H22F3N3O3S 358.1412, found 358.1416. General procedure for the Michael addition of aldehydes to nitroalkenes. To a solution of the aldehydes (2.0 mmol, 4.0 equiv) in 2 mL of the solvent, the nitroalkenes (0.5 mmol, 1.0 equiv) and the catalyst 1 (0.02 g, 0.05 mmol, 0.1 equiv) were added and stirred at rt. The reactions were continued until the complete disappearance of the nitroalkenes on TLC. The solvent was removed under reduced pressure and the γ-nitro aldehydes 5 formed were purified by column chromatography. 1H NMR of the crude reaction mixtures were taken to determine the diastereomeric ratios, wherever applicable. Purified compounds were subjected to HPLC analysis for the determination of enantiomeric ratios. Racemic mixtures of the γ-nitro aldehydes were prepared as references for HPLC analysis by carrying out each of the reactions listed in Table 2 in the presence of 20 mol% of DL-proline as the catalyst. (S)-2,2-dimethyl-4-nitro-3-phenylbutanal (5a). Column chromatography (90:10 petroleum ether/EtOAc); Pale yellow oil (0.09 g, 86% Yield); 1H NMR (400 MHz, CDCl3) δ 9.50 (s, 1H), 7.33–7.25 (m, 3H), 7.19–7.17 (m, 2H), 4.84 (dd, J = 12.0, 11.0 Hz, 1H), 4.67 (dd, J = 12.0, 4.3 Hz, 1H), 3.77 (dd, J = 11.2, 4.2 Hz, 1H), 1.11 (s, 3H), 0.98 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 204.3, 135.4, 129.1, 128.7, 128.2, 76.4, 48.5, 48.3, 21.7, 18.9 ppm; HRMS (ESITOF) m/z: [M −H]− calcd for C12H14NO3 220.0974, found 220.0977; HPLC (Chiralpak OD-H column, Hexane:2-propanol = 90:10, flow rate: 0.9 mL/min, λ= 254 nm), tR minor= 11.00, tR major= 16.91, 97% ee. (S)-2,2-dimethyl-4-nitro-3-(p-tolyl)butanal (5b). Column chromatography (90:10 petroleum ether/EtOAc); Pale yellow oil (0.10 g, 88% Yield); 1H NMR (400 MHz, CDCl3) δ 9.51 (s, 1H), 7.11 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8 Hz, 2H), 4.81 (dd, J = 12.8, 11.4 Hz, 1H), 4.65 (dd, J = 13.0, 4.2 Hz, 1H), 3.72 (dd, J = 11.3, 4.2 Hz, 1H), 2.30 (s, 3H), 1.11 (s, 3H), 0.98 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl ) δ 204.4, 137.9, 132.2, 129.4, 128.9, 76.4, 48.3, 48.2, 21.6, 3 21.1, 18.9 ppm; HRMS (ESI-TOF) m/z: [M−H]− calcd for C13H16NO3 234.1130, found 234.1147; HPLC (Chiralpak OD-H column, Hexane:2-Propanol = 90:10, flow rate: 0.9 mL/min, λ= 254 nm), tR minor= 12.49, tR major= 17.97, 95% ee. (S)-3-(4-methoxyphenyl)-2,2-dimethyl-4-nitrobutanal (5c). Column chromatography (90:10 petroleum ether/EtOAc); Pale yellow oil (0.11 g, 90% Yield); 1H NMR (400 MHz, CDCl3) δ 9.50 (d, J = 1.5 Hz, 1H), 7.09 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.0 Hz, 2H), 4.78 (dd, J = 12.6, 11.7 Hz, 1H), 4.64 (dd, J = 12.9, 4.2 Hz, 1H), 3.77 (s, 3H), 3.71 (dd, J = 11.4, 4.3 Hz, 1H), 1.10



(s, 3H), 0.98 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 204.5, 159.3, 130.1, 127.1, 114.1, 76.5, 55.3, 48.4, 47.9, 21.6, 18.9 ppm; HRMS (ESI-TOF) m/z: [M−H]− calcd for C13H16NO4 250.1079, found 250.1089; HPLC (Chiralpak OD-H column, Hexane:2-Propanol = 90:10, flow rate: 0.9 mL/min, λ = 254 nm), tR minor= 18.62, tR major= 27.68, 95% ee. (S)-3-(4-fluorophenyl)-2,2-dimethyl-4-nitrobutanal (5d). Column chromatography (88:12 petroleum ether/EtOAc); Pale yellow oil (0.10 g, 85% Yield); 1H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 7.20–7.13 (m, 2H), 7.01 (t, J = 8.3 Hz, 2H), 4.80 (t, J = 12.2 Hz, 1H), 4.67 (dd, J = 13.0, 3.9 Hz, 1H), 3.76 (dd, J = 11.3, 3.7 Hz, 1H), 1.10 (s, 3H), 0.99 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 204.0, 162.5 (d, J = 248.1 Hz), 131.2 (d, J = 3.4 Hz), 130.7 (d, J = 7.2 Hz), 115.8 (d, J = 21.5 Hz), 76.4, 48.3, 47.9, 21.8, 19.0 ppm; HRMS (ESI-TOF) m/z: [M −H]− calcd for C12H13FNO3 238.0879, found 238.0877; HPLC (Chiralpak OD-H column, Hexane:2Propanol = 90:10, flow rate: 0.9 mL/min, λ = 254 nm), tR minor= 13.86, tR major= 25.61, 96% ee. (S)-3-(furan-2-yl)-2,2-dimethyl-4-nitrobutanal (5e). Column chromatography (85:15 petroleum ether/EtOAc); Pale yellow oil (0.10 g, 92% Yield); 1H NMR (400 MHz, CDCl3) δ 9.51 (s, 1H), 7.35 (dd, J = 1.7, 0.6 Hz, 1H), 6.30 (dd, J = 3.3, 1.9 Hz, 1H), 6.20 (d, J = 3.1 Hz, 1H), 4.76 – 4.70 (m, 1H), 4.57 (dd, J = 12.9, 3.9 Hz, 1H), 3.90 (dd, J = 11.0, 3.9 Hz, 1H), 1.16 (s, 3H), 1.03 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 203.5, 149.8, 142.8, 110.5, 109.7, 74.9, 48.2, 42.3, 21.2, 19.1 ppm; HRMS (ESI-TOF) m/z: [M−H]− calcd for C10H12NO4 210.0766, found 210.0760; HPLC (Chiralpak OD-H column, Hexane:2-Propanol = 90:10, flow rate: 0.9 mL/min, λ = 254 nm), tR minor= 11.06, tR major= 18.77, 96% ee. (S)-3-(3-chlorophenyl)-2,2-dimethyl-4-nitrobutanal (5f). Column chromatography (90:10 petroleum ether/EtOAc); Pale yellow oil (0.10 g, 84% Yield); 1H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 7.28 – 7.26 (m, 2H), 7.19 (m, 1H), 7.10 – 7.07 (m, 1H), 4.84 – 4.78 (m, 1H), 4.68 (dd, J = 13.3, 4.1 Hz, 1H), 3.75 (dd, J = 11.3, 4.1 Hz, 1H), 1.12 (s, 3H), 1.00 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl ) δ 203.8, 137.7, 134.7, 130.0, 129.3, 128.5, 127.3, 76.1, 48.2, 3 48.1, 21.9, 19.0 ppm; HRMS (ESI-TOF) m/z: [M−H]− calcd for C12H13ClNO3 254.0584, found 254.0583; HPLC (Chiralpak OD-H column, Hexane:2-Propanol = 90:10, flow rate: 0.8 mL/min, λ = 254 nm), tR 14.21, tR major= 19.77, 95% ee. (R)-3-(2-chlorophenyl)-2,2-dimethyl-4-nitrobutanal (5g). Column chromatography (90:10 petroleum ether/EtOAc); Pale yellow oil (0.10 g, 80% Yield); 1H NMR (400 MHz, CDCl3) δ 9.54 (s, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.29 – 7.20 (m, 3H), 4.83 (dd, J = 15.8, 8.8 Hz, 1H), 4.71 (dd, J = 13.3, 4.0 Hz, 1H), 4.62 (dd, J = 11.2, 3.3 Hz, 1H), 1.15 (s, 3H), 1.06 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl ) δ 203.9, 135.9, 133.8, 130.5, 129.2, 128.3, 127.2, 76.2, 49.1, 3 42.5, 21.0, 18.7 ppm; HRMS (ESI-TOF) m/z: [M−H]− calcd for C12H13ClNO3 254.0584, found 254.0581; HPLC (Chiralpak OD–H column, Hexane:2–Propanol = 90:10, flow rate: 0.7 mL/min, λ = 254 nm), tR minor= 16.28, tR major= 29.53, 93% ee. (2S,3R)-2-methyl-4-nitro-3-phenylbutanal (5h). Column chromatography (85:15 petroleum ether/EtOAc); Pale yellow oil (0.09 g, 95% Yield); 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H),


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7.34–7.27 (m, 3H), 7.18–7.14 (m, 2H), 4.78 (dd, J = 10.9, 6.0 Hz, 1H), 4.67 (dd, J = 12.6,10.0 Hz, 1H), 3.79 (dd, J = 12.2, 8.1 Hz, 1H), 2.81–2.72 (m, 1H), 0.99 (d, J = 6.9 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl ) δ 202.3, 136.6, 129.1, 128.2, 128.1, 78.1, 48.5, 44.1, 12.2 3 ppm; HRMS (ESI-TOF) m/z: [M−H]− calcd for C11H12NO3 206.0817, found 206.0827; HPLC (Chiralpak IC–column, Hexane:2–Propanol = 90:10, flow rate: 0.9 mL/min, λ = 254 nm), tR major = 26.92,tR minor = 31.79, 95% ee and 85:15 dr. (2S,3R)-2-ethyl-4-nitro-3-phenylbutanal (5i). Column chromatography (85:15 petroleum ether/EtOAc); Pale yellow oil (0.10 g, 93% Yield); 1H NMR (400 MHz, CDCl3) δ 9.71 (d, J = 2.5 Hz, 1H), 7.35 – 7.27 (m, 3H), 7.17 (dd, J = 5.3, 3.1 Hz, 2H), 4.71 (dd, J = 12.7, 5.0 Hz, 1H), 4.62 (dd, J = 12.7, 9.6 Hz, 1H), 3.78 (td, J = 9.8, 5.0 Hz, 1H), 2.67 (dddd, J = 10.1, 7.6, 5.0, 2.6 Hz, 1H), 1.52-1.46 (m, 2H), 0.82 (t, J = 7.5 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 203.2, 136.8, 129.2, 128.3, 128.0, 78.6, 55.0, 42.7, 20.4, 10.7 ppm; HRMS (ESI-TOF) m/z: [M−H]− calcd for C12H14NO3 220.0974, found 220.0977; HPLC (Chiralpak IC– column, Hexane:2–Propanol = 90:10, flow rate: 1 mL/min, λ = 254 nm), tR major= 21.46, tR minor= 24.91, 92% ee and 91:9 dr. (S)-2-((R)-2-nitro-1-phenylethyl)pentanal (5j). Column chromatography (92:08 petroleum ether/EtOAc); Pale yellow oil (0.10 g, 86% Yield); 1H NMR (400 MHz, CDCl3) δ 9.69 (d, J = 2.9 Hz, 1H), 7.35 – 7.27 (m, 3H), 7.16 (dd, J = 8.0, 1.2 Hz, 2H), 4.71–4.63 (m, 2H), 3.80–3.73 (m, 1H), 2.72–2.66 (m, 1H), 1.45–1.25 (m, 4H), 0.78 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 203.3, 136.8, 129.2, 128.2, 128.0, 78.5, 53.8, 43.2, 29.5, 19.8, 14.0 ppm; HRMS (ESI-TOF) m/z: [M−H]− calcd for C13H16NO3 234.1130, found 234.1134; HPLC (Chiralpak IC–column, Hexane:2–Propanol = 90:10, flow rate: 0.7 mL/min, λ = 254 nm), tR major = 19.04,tR minor = 21.94, 88% ee and 86:14 dr. (2S,3R)-2-isopropyl-4-nitro-3-phenylbutanal (5k). Column chromatography (85:15 petroleum ether/EtOAc); Pale yellow oil (0.09 g, 84% Yield); 1H NMR (400 MHz, CDCl3) δ 9.91 (d, J = 2.2 Hz, 1H), 7.37–7.26 (m, 3H), 7.20–7.16 (m, 2H), 4.66 (dd, J = 12.5, 4.4 Hz, 1H), 4.56 (dd, J = 12.4, 10.1 Hz, 1H), 3.89 (td, J = 10.3, 4.4 Hz, 1H), 2.76 (ddd, J = 10.7, 3.9, 2.1 Hz, 1H), 1.75– 1.66 (m, 1H), 1.08 (d, J = 7.2 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 204.4, 137.1, 129.2, 128.1, 128.0, 79.0, 58.8, 42.0, 27.9, 21.7, 17.0 ppm; HRMS (ESITOF) m/z: [M−H]− calcd for C13H16NO3 234.1130, found 234.1135; HPLC (Chiralpak IC– column, Hexane:2–Propanol = 90:10, flow rate: 0.6 mL/min, λ = 254 nm), tR major= 22.22, tR minor= 25.57, 94% ee and >99% dr. (2S,3R)-2-benzyl-4-nitro-3-phenylbutanal (5l) .Column chromatography (95:5 petroleum ether/EtOAc); Pale yellow oil (0.11 g, 83% Yield); 1H NMR (400 MHz, CDCl3) δ 9.70 (d, J = 2.3 Hz, 1H), 7.35–7.20 (m, 8H), 7.02 (d, J = 6.9 Hz, 2H), 4.89–4.78 (m, 1H), 4.71 (dd, J = 7.3, 2.5 Hz, 1H), 3.85–3.79 (m, 1H), 3.14–3.08 (m, 1H), 2.77–2.74 (m, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 203.1, 137.2, 136.7, 129.3, 128.9, 128.8, 128.4, 128.1, 127.0, 78.1, 55.4, 43.5, 34.3 ppm; HRMS (ESI-TOF) m/z: [M−H]−calcd for C17H16NO3 282.1130, found 282.1131;



HPLC (Chiralpak IC–column, Hexane:2–Propanol = 90:10, flow rate: 0.7 mL/min, λ = 254 nm), tR major = 30.70,tR minor = 39.17, 80% ee and 73:27 dr. (2S,3R)-2-methyl-4-nitro-3-(p-tolyl)butanal (5m). Column chromatography (85:15 petroleum ether/EtOAc); Pale yellow oil (0.10 g, 94% Yield); 1H NMR (400 MHz, CDCl3) δ 9.69 (d, J = 1.8 Hz, 1H), 7.13 (d, J = 7.9 Hz, 2H), 7.04–7.02 (m, 2H), 4.78–4.72 (m, 1H), 4.64 (dd, J = 12.6, 9.3 Hz, 1H), 3.76 (td, J = 9.1, 5.7 Hz, 1H), 2.75–2.71 (m, 1H), 2.30 (s, 3H), 0.99 (d, J = 7.2 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 202.4, 137.9, 133.4, 129.8, 127.9, 78.3, 48.5, 43.7, 21.1, 12.1 ppm; HRMS (ESI-TOF) m/z: [M−H]− calcd for C12H14NO3 220.0974, found 220.0987; HPLC (Chiralpak IC–column, Hexane:2–Propanol = 90:10, flow rate: 0.7 mL/min, λ = 254 nm), tR major = 29.31, tR minor = 34.18, 96% ee and 83:17 dr. (2S,3R)-3-(4-fluorophenyl)-2-methyl-4-nitrobutanal (5n). Column chromatography (80:20 petroleum ether/EtOAc); Pale yellow oil (0.10 g, 90% Yield); 1H NMR (400 MHz, CDCl3) δ 9.68 (d, J = 1.6 Hz, 1H ), 7.19–7.12 (m, 2H), 7.04–6.99 (m, 2H), 4.79–4.73 (m, 1H), 4.62 (dd, J = 12.7, 9.6 Hz, 1H), 3.82–3.77 (m, 1H), 2.80–2.71 (m, 1H), 0.98 (d, J = 7.3 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl ) δ 202.1, 162.4 (d, J = 247.5Hz), 132.4 (d, J = 3.0 Hz), 129.7 3 (d, J = 8.0 Hz), 116.1 (d, J = 21.5 Hz), 78.2, 48.4, 43.4, 12.2 ppm; HRMS (ESI-TOF) m/z: [M−H]− calcd for C11H11FNO3 224.0723, found 224.0723; HPLC (Chiralpak IC–column, Hexane:2–Propanol = 90:10, flow rate: 0.8 mL/min, λ = 254 nm), tR major= 23.83, tR minor = 27.75, 94% ee and 72:28 dr. (2S,3R)-3-(4-methoxyphenyl)-2-methyl-4-nitrobutanal (5o). Column chromatography (80:20 petroleum ether/EtOAc); Pale yellow oil (0.11 g, 91% Yield); 1H NMR (400 MHz, CDCl3) δ 9.69 (d, J = 1.6 Hz, 1H), 7.06 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 4.77–4.72 (m, 1H), 4.61 (dd, J = 12.4, 9.2 Hz, 1H), 3.77 (s, 3H), 3.74–3.72 (m, 1H), 2.75–2.67 (m, 1H), 0.98 (d, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 202.5, 159.3, 129.1, 128.3, 114.5, 78.4, 55.3, 48.6, 43.4, 12.1 ppm; HRMS (ESI-TOF) m/z: [M−H]− calcd for C12H14NO4 236.0923, found 236.0920; HPLC (Chiralpak IC–column, Hexane:2–Propanol = 90:10, flow rate: 0.9 mL/min, λ = 254 nm), tR major= 35.09, tR minor = 40.42, 94% ee and 85:15 dr. (2S,3R)-3-(3-chlorophenyl)-2-methyl-4-nitrobutanal (5p). Column chromatography (85:15 petroleum ether/EtOAc); Pale yellow oil (0.10 g, 90% Yield); 1H NMR (400 MHz, CDCl3) δ 9.68 (d, J = 1.5 Hz, 1H), 7.27 – 7.25 (m, 2H), 7.17 – 7.15 (m, 1H), 7.07 – 7.04 (m, 1H), 4.76 (t, J = 5.6 Hz, 1H), 4.64 (dd, J = 12.9, 9.6 Hz, 1H), 3.81 – 3.74 (m, 1H), 2.81 – 2.73 (m, 1H), 1.00 (d, J = 7.3 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 201.8, 138.8, 135.0, 130.4, 128.5, 128.3, 126.4, 77.8, 48.2, 43.7, 12.3 ppm; HRMS (ESI-TOF) m/z: [M−H]− calcd for C11H11ClNO3 240.0427, found 240.0426; HPLC (Chiralpak– IC column, Hexane:2–Propanol = 90:10, flow rate: 0.8 mL/min, λ = 254 nm), tR major= 21.30, tR minor = 24.44, 96% ee and 76:24 dr. (2S,3S)-3-(furan-2-yl)-2-methyl-4-nitrobutanal (5q). Column chromatography (85:15 petroleum ether/EtOAc); Pale yellow oil (0.09 g, 95% Yield); 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 7.34 (dd, J = 3.0, 1.6 Hz, 1H), 6.29 (dd, J = 3.4, 1.8 Hz, 1H), 6.19 – 6.16 (m, 1H), 4.74–4.66 (m, 2H), 4.11 – 4.03 (m, 1H), 2.79 (dd, J = 7.6, 6.7 Hz, 1H), 1.06 (d, J = 7.2 Hz, 3H) ppm; 13C{1H}


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NMR (100 MHz, CDCl3) δ 201.7 , 149.9 , 142.7 , 110.4 , 108.8 , 100.1 , 99.6 (s), 75.8 , 47.1 , 37.7 , 11.0 ppm; HRMS (ESI-TOF) m/z: [M−H]− calcd for C9H10NO4 196.0610, found 196.0625; HPLC (Chiralpak IC–3 column, Hexane:2–Propanol = 90:10, flow rate: 1 mL/min, λ = 254 nm), tR major= 15.29, tR minor = 20.91, 92% ee and 75:25 dr.

Supporting Information The Supporting Information is available free of charge on the ACS Publications website. 1H

and 13C spectra for all of the compounds and HPLC data (PDF)

Acknowledgements We thank Prof. J. K. Bera, Prof. M. K. Ghorai and Prof. D.H. Dethe for helping us with HPLC analysis.

References (1) Selected recent examples: (a) Keller, M.; Perrier, A.; Linhardt, R.; Travers, L.; Wittmann, S.; Caminade, A.-M.; Majoral, J.-P.; Reiser, O.; Ouali, A. Dendrimers or Nanoparticles as Supports for the Design of Efficient and Recoverable Organocatalysts? Adv. Synth. Catal. 2013, 355, 1748–1754. (b) Wang, C. A.; Zhang, Z. K.; Yue, T.; Sun, Y. L.; Wang, L.; Wang, W. D.; Zhang, Y.; Liu, C.; Wang, W. “Bottom-Up” Embedding of the Jørgensen–Hayashi Catalyst into a Chiral Porous Polymer for Highly Efficient Heterogeneous Asymmetric Organocatalysis. Chem. - Eur. J. 2012, 18, 6718–6723. (c) Wang, Y.; Ji, S.; Wei, K.; Lin, J. Epiandrosteronederived prolinamide as an efficient asymmetric catalyst for Michael addition reactions of aldehydes to nitroalkenes. RSC Adv. 2014, 4, 30850–30856. (d) Tuchman–Shukron, L.; Miller, S. J.; Portnoy, M. Polymer-Supported Enantioselective Bifunctional Catalysts for Nitro-Michael Addition of Ketones and Aldehydes. Chem. - Eur. J. 2012, 18, 2290–2296. (e) Sagamanova, I.; Rodríguez-Escrich, C.; Molnar, I. G.; Sayalero, S.; Gilmour, R.; Pericas, M. A. Translating the Enantioselective Michael Reaction to a Continuous Flow Paradigm with an Immobilized, Fluorinated Organocatalyst. ACS Catal. 2015, 5, 6241–6248. (f) Chandrasekhar, S.; Kumar, C. P.; Kumar, T. P.; Haribabu, K.; Jagadeesh, B.; Lakshmib, J. K.; Mainkar, P. S. Peptidomimetic organocatalysts: efficient Michael addition of ketones onto nitroolefins with very low catalyst loading. RSC Adv. 2014, 4, 30325–30331. (2) (a) List, B.; Pojarliev, P.; Martin, H. J. Efficient Proline-Catalyzed Michael Additions of Unmodified Ketones to Nitro Olefins. Org. Lett. 2001, 3, 2423–2425. (b) Betancort, J. M.; Barbas III, C. F. Catalytic Direct Asymmetric Michael Reactions: Taming Naked Aldehyde Donors. Org. Lett. 2001, 3, 3737–3740. (c) Yang, H.; Wong, M. W. (S)-Proline-catalyzed nitroMichael reactions: towards a better understanding of the catalytic mechanism and enantioselectivity. Org. Biomol. Chem. 2012, 10, 3229–3235. (3) (a) Wang, W.; Wang, J.; Li, H. Direct, Highly Enantioselective Pyrrolidine Sulfonamide Catalyzed Michael Addition of Aldehydes to Nitrostyrenes. Angew. Chem., Int. Ed. 2005, 44, 1369–1371. (b) Wang, J.; Li, H.; Lou, B.; Zu, L.; Guo, H.; Wang, W. Enantio- and



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Revell, J. D.; Wennemers, H. Investigating Sequence Space: How Important is the Spatial Arrangement of Functional Groups in the Asymmetric Aldol Reaction Catalyst H-Pro-Pro-AspNH2?.Adv. Synth. Catal. 2008, 350, 1046–1052. (d) Revell, J. D.; Gantenbein, D.; Krattiger, P.; Wennemers, H. Solid-supported and pegylated H–Pro–Pro–Asp–NHR as catalysts for asymmetric aldol reactions. Biopolymers 2006, 84, 105–113. (e) Revell, J. D.; Wennemers, H. Functional group requirements within the peptide H-Pro-Pro-Asp-NH2 as a catalyst for aldol reactions. Tetrahedron 2007, 63, 8420–8424. (8) (a) Cortes-Clerget, M.; Gager, O.; Monteil, M.; Pirat, J.-L.; Migianu–Griffoni, E.; Deschamp, J.; Lecouvey, M. Novel Easily Recyclable Bifunctional Phosphonic Acid Carrying Tripeptides for the Stereoselective Michael Addition of Aldehydes with Nitroalkenes. Adv. Synth. Catal. 2016, 358, 34–40. (b) Cortes-Clerget, M.; Jover, J.; Dussart, J.; Kolodziej, E.; Monteil, M.; Migianu-Griffoni, E.; Gager, O.; Deschamp, J.; Lecouvey, M. Bifunctional Tripeptide with a Phosphonic Acid as a Brønsted Acid for Michael Addition: Mechanistic Insights. Chem. - Eur. J. 2017, 23, 6654–6662. (9) Borges-González, J.; Feher-Voelger, A.; Crisóstomo, F. P.; Morales, E. Q.; Martín, T. Tetrahydropyran-Based Hybrid Dipeptides as Asymmetric Catalysts for Michael Addition of Aldehydes to β-Nitrostyrenes. Adv. Synth. Catal. 2017, 359, 576–583. (10) Aldehyde 2a was prepared using a known procedure: Zhang, Y.-L.; Wang, Y.–Q. Enantioselective biomimetic cyclization of 2'-hydroxychalcones to flavanones. Tetrahedron Lett. 2014, 55, 3255–3258. (11) Aldehydes 2b and 2dwere prepared by homologation of 2a and 2c, respectively. The aldehyde 2c was prepared from an ester derivative of a bis-homo derivative of L-proline, which was prepared using a procedure given in Siegrist, R.; Baumgartner, C.; Seiler, P.; Diederich, F. Facile Synthesis of Diastereoisomerically and Optically Pure 2-Substituted Hexahydro-1Hpyrrolizin-3-ones. Helv.Chim. Acta. 2005, 88, 2250–2261. Detailed procedures are given in the experimental section. (12) Nugent, T. C.; Shoaib, M.; Shoaib, A. Practical access to highly enantioenriched quaternary carbon Michael adducts using simple organocatalysts. Org. Biomol. Chem. 2011, 9, 52–56. (13) Patil, M. P.; Sunoj, R. B. The Role of Noninnocent Solvent Molecules in Organocatalyzed Asymmetric Michael Addition Reactions. Chem. - Eur. J. 2008, 14, 10472– 10485.


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