Chiral Silver Complex-Catalyzed Diastereoselective and

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Chiral Silver Complex Catalyzed Diastereo- and Enantioselective Michael Addition of 1-Pyrroline-5-Carboxylates to #-Enones Akihiro Koizumi, Masato Harada, Ryosuke Haraguchi, and Shin-ichi Fukuzawa J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01335 • Publication Date (Web): 10 Aug 2017 Downloaded from http://pubs.acs.org on August 10, 2017

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The Journal of Organic Chemistry 1

Chiral Silver Complex Catalyzed Diastereo- and Enantioselective Michael Addition of 1-Pyrroline-5-Carboxylates to α-Enones Akihiro Koizumi, Masato Harada, Ryosuke Haraguchi, and Shin-ichi Fukuzawa* Department of Applied Chemistry, Institute of Science and Engineering, Chuo University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan Email: [email protected]

Abstract: AgOAc/ThioClickFerrophos complex catalyzed the highly diastereo- and enantioselective reaction between 1-pyrroline-5-carboxylates (1) and acyclic α-enones (2) in MeOH, in the presence of DBU, to give the single isomer Michael adducts (3) in high yields (up to 99%) with excellent enantioselectivies (up to 99% ee). Subsequent reduction of the Michael adducts with sodium cyanoborohydride successfully produced the fused pyrrolizidine ester as an almost pure single stereoisomer.

INTRODUCTION Azomethine ylide is a privileged building block for constructing potentially bioactive nitrogen-containing heterocyclic substrates by 1,3-dipolar cycloaddition with activated alkenes.1 Glycine imino ester is a common precursor of azomethine ylide, being activated by a metal complex and an organocatalyst, and can be a useful building block for amino acids by

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alkylation and Michael addition to activated alkenes. Coinciding with the Wang group3, we2 independently proposed 1-pyrroline-5-carboxylates to be a cyclic azomethine ylide capable of undergoing asymmetric 1,3-cycloaddition with a N-substituted maleimide. Then, by using chiral silver complexes, we were able to produce the optically active 7-azanorbornene, a chemical scaffold that has been found in nature. Furthermore, we4 (coinciding with the Deng group5) independently established the asymmetric Michael addition of 1-pyrroline-5-carboxylates to (E)-nitroalkenes with high enantio- and diastereoselectivity (Scheme 1). The diastereoselectivity of the Michael addition step in this reaction was controlled by the choice of the chiral metal (copper or silver)

Scheme 1. Michael Addition of 1-Pyrroline-5-carboxylate to (E))-Nitroalkenes

complex. Opatz and co-workers6 recently reported on the base catalyzed Michael addition of 1-pyrroline-5-nitrile to α-enones. The products of this reaction were transformed to the fused pyrrolizidine derivatives with high diastereoselectivity, following imine reduction and intramolecular reductive amination (reductive cyclization) (Scheme 2). The optically active pyrrolizidine derivatives have been found in many natural substrates and classified as


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Scheme 2. Michael Addition of 1-Pyrroline-5-nitrile to α-Enone and Subsequent Reductive Cyclization

pyrrolizidine alkaloids (Fig. 1). Owing to their diverse biological and pharmaceutical activities, e.g., antibacterial, insecticidal, anti-cancer activity, and trehalase inhibition,7 the efficient synthesis of the pyrrolizidine scaffold and its polysubstituted derivatives have attracted much attention.8 Inspired by the work of Opatz and the biological importance of

Figure 1. Examples of Pyrrolizidine Alkaloid



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pyrrolizidine substrates, we predicted that the application of a chiral catalyst could yield optically active pyrrolizidines.9 We chose a 1-pyrroline-5-carboxylate instead of the corresponding nitrile as a Michael donor because this substrate brought a high stereoselectivity to the asymmetric Michael addition to nitroalkenes.5, 6 It is paramount to control not only the stereochemistry of the asymmetric Michael addition, but also of the imine reduction and reductive cyclization to obtain an optically pure, single pyrrolizidine stereoisomer. We have demonstrated the successful, highly diastereo- and enantioselective Michael addition of 1-pyrroline-5-carboxylates to α-enones by the application of our original Silver/ThioClickFerrophos (chiral ferrocenyl P,S-ligand) complex. Herein, we report the results of the reaction and the successive stereoselective imine reduction and reductive cyclization of the Michael adduct. The proposed method will evaluate the viability of 1-pyrroline-5-carboxylates as a suitable Michael donor for activated alkenes, and provide a versatile synthesis of optically active, polysubstituted pyrrolizidines with potential bioactivity.

RESULTS AND DISCUSSION We first examined some combinations of silver or copper salts and chiral ligands in the model reaction of 1-pyrroline-5-carboxylate (1a) with (E)-benzalacetone (2a). Typically, the reaction

was

carried

out

in

tetrahydrofuran

(THF)

in

the

presence

of

1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature for 15 h, with the addition of 5 mol% metal salt and 5.5 mol% chiral ligand. The results are summarized in Table 1. Every combination of metal salt and ligand tested here (Fig. 2) produced the single diastereomer 3aa (anti-diastereomer) with high selectivity, and a good yield (81–90%).10 The combination of silver salts and ThioClickFerrophos ligands (L1, L2) afforded moderate enantioselectivity in


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Figure 2. Chiral Phosphine Ligands

Table 1. Optimization of Metal Complexesa

entry

metal salt

L

yield (%)b

drc

ee (%)d

1

AgOAc

L1

90

98:2

71

2

AgBF4

L1

83

98:2

67

3

AgOTf

L1

82

98:2

71

4

AgF

L1

87

98:2

10

5

AgOAc

L2

86

97:3

67

6

AgOAc

L3

85

98:2

1

7

AgOAc

L4

93

98:2

2

8

CuOAc

L3

81

98:2

0

9

CuOAc

L4

90

98:2

1

a

Conditions: 1a (0.20 mmol), 2a (0.22 mmol), AgOAc (5.0 mol%), L (5.5 mol%), DBU (0.04

mmol), THF (2.0 mL), rt, 15 h. bCombined isolated yield of diastereomers. cDetermined by 1

H NMR. d Determined by chiral HPLC.



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yielding the product, except in the case of AgF (see entries 1–5). Whereas FcPHOX ligands (L3, L4) produced almost racemic mixtures (see entries 6 and 7). The combination of CuOAc and FcPHOX ligands afforded the same diastereomer (anti-isomer) as a racemate (see entries 8–9).4a As the combination of AgOAc/L1 gave the highest yield, it was selected as the catalyst prior to optimization of the reaction conditions. Table 2. Optimization of Reaction Conditionsa

entry

solvent

base

yield

drc

ee (%)d

(%)b 1

THF

DBU

90

98:2

71

2

Et2O

DBU

89

99:1

60

3

toluene

DBU

89

98:2

61

4

CH2Cl2

DBU

80

98:2

55

5

MeOH

DBU

99

99:1

87

6e

MeOH

DBU

99

99:1

87

7

MeOH

Et3N

39

99:1

89

8f

MeOH

DBU

99

99:1

94

9

MeOH

DIPEA

29

99:1

88

10

MeOH

DABCO

50

98:1

82

11

MeOH

Cs2CO3

89

98:2

45

a

Conditions: 1a (0.20 mmol), 2a (0.22 mmol), AgOAc (5.0 mol%), L3 (5.5 mol%), DBU

(0.04 mmol), solvent (3.0 mL), rt, 15 h. bCombined isolated yield of diastereomers. c

Determined by 1H NMR. d Determined by chiral HPLC. eReaction was carried out at 0 ˚C.

f

Reaction was carried out at –20 ˚C.


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Table 2 summarizes the various solvents and bases trialed as part of the optimization experiments. The effect of changing the solvent is shown in entries 1–5, with methanol being determined as the optimal solvent11 because it afforded the product quantitatively with excellent diastereoselectivity (>99:1): The use of solvents such as diethyl ether, toluene, and dichloromethane resulted in lower enantioselectivity than that achieved in methanol. The enantioselectivity was dramatically enhanced to 94% when the reaction was carried out in methanol at –20 °C (entry 8). Entries 7–11 detail the reaction in methanol whilst testing various organic and inorganic bases, where DBU was found to be the optimal base, giving both a good yield and a favorable enantiomeric excess (ee%). Diisopropylethylamine (DIPEA) gave a good ee%, but a low yield (entry 9), and so was deselected, while other bases did not surpass the ee% achieved with DBU. We then examined the scope of the substrate under the optimal conditions (5.0 mol% AgOAc, 5.5mol% L1, 20 mol% DBU in MeOH at –20 °C) previously determined. Table 3 summarizes the results of the reaction for a variety of 1-pyrroline-5-carboxylates and acyclic α-enones. Entries 1–4 show the substrate’s influence with respect to the Michael donor (1a– 1d) bearing substituents on the phenyl group, in the reaction with (E)-benzalacetone (2a). Regardless of the electron donating (p-Me), and electron withdrawing (p-Cl and p-Br) substituents, the corresponding products were obtained in good yield with good ee%. Subsequently, we evaluated various acyclic α-enones as Michael acceptors in the reaction with 1a. Entries 5–10 and 11–16 show the reaction of (E)-benzalacetone (2b–2g), and (E)-chalcone derivatives (2h–2m), bearing substituents on the aryl group (R1, R2), respectively. Single diastereomer products were obtained in every case, and the effect of the substituents on product yield and stereoselectivity were hardly observed: all products were



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Table 3. The Scope of Substratesa

entry

Ar in 1

R1, R2 in 2

product

&

yield drc

ee (%)d

(%)b 1

Ph, 1a

Ph, Me, 2a

3aa, 99

99/1

94

2

p-MeOC6H4, 1b

Ph, Me, 2a

3ba, 97

97/3

95

3

p-ClC6H4, 1c

Ph, Me, 2a

3ca, 99

99/1

83

4

p-BrC6H4, 1d

Ph, Me, 2a

3da, 88

99/1

85

5

Ph, 1a

o-MeC6H4, Me, 2b

3ab, 65

99/1

92

6

Ph, 1a

p-MeC6H4, Me, 2c

3ac, 94

99/1

97

7

Ph, 1a

p-MeOC6H4, Me, 2d

3ad, 98

99/1

93

8

Ph, 1a

p-BrC6H4, Me, 2e

3ae, 94

99/1

89

9

Ph, 1a

2-thienyl, Me, 2f

3af, 51

99/1

89

10

Ph, 1a

Fc, Me, 2g

3ag, 89

99/1

99

11

Ph, 1a

Ph, Ph, 2h

3ah, 92

99/1

96

12

Ph, 1a

Ph, p-MeC6H4, 2i

3ai, 99

97/3

96

13

Ph, 1a

Ph, p-MeOC6H4, 2j

3aj, 99

94/6

95

14

Ph, 1a

Ph, p-ClC6H4, 2k

3ak, 84

98/2

84

15

Ph, 1a

Ph, p-BrC6H4, 2l

3al, 95

95/5

88

16

Ph, 1a

Ph, p-NO2C6H4, 2m

3am, 96

99/1

94

17

Ph, 1a

Me, Me, 2n

3an, 42

99/1

97

a

Conditions: 1a (0.20 mmol), 2a (0.22 mmol), AgOAc (5.0 mol%), L3 (5.5 mol%), DBU

(0.04 mmol), MeOH (3.0 mL), –20 ˚C, 15 h. bCombined isolated yield of diastereomers. c

Determined by 1H NMR. d Determined by chiral HPLC.


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obtained in good yields with excellent enantioselectivities for the para-substituted electron donating and electron withdrawing groups. For the o-methyl substituents, the yield decreased relative to the original substrate, although a high ee% was maintained (entry 5). Heteroaryl substrates, such as the thienyl substituted α-enone, were also capable of delivering a single diastereomer product with a moderate yield and high enantioselectivity (entry 9). The Michael adducts with an aliphatic α-enones such as (E)-3-penten-2-one was also obtained as a single diastereomer in high enantioselectivity in a moderate yield (entry 17). It should be noted that diastereomeric ratios of the products were determined by 1H NMR integration of the methyl ester signal, and the relative and absolute configurations of the major product were determined by X-ray crystallography of the ferrocenyl-substituted substrate (3ag) (see Supporting Information). Stereochemistry of the chiral quaternary center and the ferrocenyl-substituted carbon were defined as S and S, respectively; the phenyl-substituted carbon was assigned R. The stereochemistry assigned was consistent with that from the nitroalkene reaction that afforded the anti-diastereomer.4a The gram-scale synthesis of the Michael adduct 3aa was accomplished with no influence in a yield, diastereo- and enantioselectivity: the reaction was carried out by using 1.0 g (4.9 mmol) of 1a, 0.73 g (5.0 mmol) of 2a, and 5.0 mol% of AgOAc/L1 in the presence of 20 mol% of DBU in methanol (75 mL) at –20 °C for 15 h, and 1.53 g (4.4 mmol, 90% yield) of 3aa was obtained with 92% ee. In the final step, we transformed the product into the pyrrolizidine, following the modified reductive cyclization protocol described by Opatz.6 Stereoselective reduction of 3aa with sodium cyanoborohydride (NaBH3CN) in THF was accomplished, affording the corresponding pyrrolizidine 4aa as an almost single diastereomer (Scheme 3) without loss of



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the ester group. Stereochemistry of the product was assigned as (1R,3S,5S,7aS) following NOESY measurement (see Supporting Information). The resultant stereochemistry of the pyrroline reduction was consistent with that of the pyrroline reduction (also by NaBH3CN) detailed in previous work.4a

Scheme 3. Conversion of Pyrroline 3aa to Pyrrolizidine 4aa

CONCLUSION We have successfully demonstrated the silver-catalyzed asymmetric Michael addition of 1-pyrroline-5-carboxylate to acyclic α-enones, such as (E)-banzalacetone and (E)-chalcone derivatives, to yield the α-substituted α-aminoester (δ-keto pyrroline derivatives bearing chiral quaternary centers). The Silver/ThioClickFerrophos (L1) complex was shown to be highly effective, allowing single stereoisomers to be obtained in high yields, with high diastereo- and enatioselectivity. Practical synthetic value of the reaction was demonstrated by the gram-scale synthesis and subsequent transformation of the product to the potentially biological active fused pyrrolizidine, by stereoselective reduction and reductive cyclization in the presence of NaBH3CN.


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EXPERIMENTAL SECTION General procedure for the Michael addition reaction of 1a to 2a: All reactions were carried out under nitrogen atmosphere with oven-dried glassware. In a 20 mL Schlenk tube containing a stirrer bar, AgOAc (1.7 mg, 0.01 mmol) and (R,Sp)-ThioClickFerrophos (L1) (6.9 mg, 0.011 mmol) were dissolved in MeOH (3.0 mL) and stirred at –20 ˚C for 30 min. Then, 1a (40.6 mg, 0.20 mmol), 2a (32.2 mg, 0.22 mmol) and DBU (6.0 µL) were added successively. The resulting mixture was stirred at –20 ˚C for 15 h, after which it was filtered through Celite and concentrated by rotary evaporation. The 1H NMR spectrum of the crude product showed the presence of 3aa isomer (anti-isomer) as the major product, and its diastereomer as the corresponding minor product. Pure 3aa was isolated by PTLC on silica gel as a white solid and the enantiomeric excess determined by HPLC: racemates of all products for HPLC analyses were prepared by AgOAc/PPh3. (S)-methyl

2-((R)-3-oxo-1-phenylbutyl)-5-phenyl-3,4-dihydro-2H-pyrrole-2-

carboxylate 3aa: White solid; 70.0 mg, 99% yield; mp = 111—113 °C; 1H NMR (300 MHz, CDCl3) δ 7.83-7.80 (m, 2H), 7.49-7.38 (m, 3H), 7.20-7.12 (m, 5H), 4.06 (dd, J = 4.1, 10.3 Hz, 1H), 3.77 (s, 3H), 3.27 (dd, J = 10.3, 17.2 Hz, 1H), 3.03 (dd, J = 4.1, 17.2 Hz, 1H), 2.72 (ddd, J = 5.2, 9.5, 16.9 Hz, 1H), 2.23-2.03 (m, 2H), 2.03 (s, 3H), 1.87 (ddd, J = 6.9, 9.5, 16.9 Hz, 1H);

13

C NMR (75 MHz, CDCl3) δ 206.8, 176.5, 175.0, 139.1, 134.0, 131.0, 129.9, 128.5,

128.1, 127.1, 86.5, 52.6, 47.8, 46.1, 35.3, 31.1, 30.5; HPLC (Daicel Chiralpak AS-3, hexane/2-propanol = 95/5, flow rate = 1.0 mL/min) tR = 17.9 min (major), 23.4 min (minor); [α]D22 = –152 (c = 0.125, CHCl3); HRMS (ESI-TOF) calcd for C22H23NNaO3 [M+Na]+ 372.1576, found: 372.1570.



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(S)-methyl 5-(4-methoxyphenyl)-2-((R)-3-oxo-1-phenylbutyl)-3,4-dihydro-2H-pyrrole2-carboxylate 3ba: White solid; 73.4 mg, 97% yield; mp = 94—96 °C; 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J = 8.9 Hz, 2H), 7.19-7.11 (m, 5H), 6.92 (d, J = 8.9 Hz, 2H), 4.05 (dd, J = 4.0, 10.3 Hz, 1H), 3.85 (s, 3H), 3.76 (s, 3H), 3.26 (dd, J = 10.3, 17.3 Hz, 1H), 3.01 (dd, J = 4.0, 17.3 Hz, 1H), 2.67 (ddd, J = 5.2, 9.5, 16.8 Hz, 1H), 2.21-2.02 (m, 2H), 2.02 (s, 3H), 1.83 (ddd, J = 7.0, 9.5, 16.8 Hz, 1H);

13

C NMR (75 MHz, CDCl3) δ 206.9, 175.7, 175.2, 161.9,

139.2, 129.9, 129.8, 128.0, 127.1, 126.8, 113.8, 86.3, 55.5, 52.6, 47.8, 46.1, 35.2, 31.1, 30.4; HPLC (Daicel Chiralpak ID-3, hexane/2-propanol = 90/10, flow rate = 0.5 mL/min, at 10 ˚C) tR = 122.1 min (minor), 126.7 min (major); [α]D23 = –175 (c = 0.056, CHCl3); HRMS (ESI-TOF) calcd for C23H26NO4 [M+H]+ 380.1862, found: 380.1846. (S)-methyl

5-(4-chlorophenyl)-2-((R)-3-oxo-1-phenylbutyl)-3,4-dihydro-2H-pyrrole-

2-carboxylate 3ca: White solid; 76.0 mg, 99% yield; mp = 89—91 °C; 1H NMR (300 MHz, CDCl3) δ 7.75 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.14 (m, 5H), 4.05 (dd, J = 4.0, 10.3 Hz, 1H), 3.77 (s, 3H), 3.25 (dd, J = 10.3, 17.2 Hz, 1H), 3.02 (dd, J = 4.0, 17.2 Hz, 1H), 2.66 (ddd, J = 5.2, 9.4, 16.9 Hz, 1H), 2.23-1.96 (m, 2H), 2.03 (s, 3H), 1.78 (ddd, J = 7.4, 9.4, 16.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ206.7, 175.4, 174.9, 138.9, 137.2, 132.5, 129.9, 129.4, 128.8, 128.1, 127.2, 86.5, 52.7, 47.9, 46.1, 35.2, 31.2, 30.5; HPLC (Daicel Chiralpak ID-3, hexane/2-propanol = 95/5, flow rate = 1.0 mL/min) tR = 12.0 min (minor), 13.5 min (major); [α]D22 = –160 (c = 0.126, CHCl3); HRMS (ESI-TOF) calcd for C22H23ClNO3 [M+H]+ 384.1367, found: 384.1347. (S)-methyl

5-(4-bromophenyl)-2-((R)-3-oxo-1-phenylbutyl)-3,4-dihydro-2H-pyrrole-

2-carboxylate 3da: White solid; 75.4 mg, 88% yield; mp = 103—105 °C; 1H NMR (300 MHz, CDCl3) δ 7.75 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.14 (m, 5H), 4.05 (dd, J = 4.0,


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10.3 Hz, 1H), 3.77 (s, 3H), 3.25 (dd, J = 10.3, 17.2 Hz, 1H), 3.02 (dd, J = 4.0, 17.2 Hz, 1H), 2.66 (ddd, J = 5.2, 9.5, 16.9 Hz, 1H), 2.23-1.96 (m, 2H), 2.03 (s, 3H), 1.78 (ddd, J = 7.3, 9.4, 16.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 206.7, 175.5, 174.8, 138.9, 132.8, 131.8, 129.9, 129.6, 128.1, 127.2, 125.7, 86.5, 52.7, 47.8, 46.1, 35.2, 31.2, 30.5; HPLC (Daicel Chiralpak ID-3, hexane/2-propanol = 95/5, flow rate = 1.0 mL/min) tR = 31.1 min (minor), 37.1 min (major); [α]D26 = –167 (c = 0.075, CHCl3); HRMS (ESI-TOF) calcd for C22H23BrNO3 [M+H]+ 428.0861, found: 428.0861. (S)-methyl

2-((R)-1-(2-methylphenyl)-3-oxobutyl)-5-phenyl-3,4-dihydro-2H-pyrrole-

2-carboxylate 3ab: Brown oil; 47.2 mg, 65% yield; 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J = 6.6 Hz, 2H), 7.43-7.41 (m, 3H), 7.16-7.11 (m, 1H), 7.03-6.99 (m, 2H), 6.88-6.83 (m, 1H), 4.41 (dd, J = 3.4, 10.4 Hz, 1H), 3.77 (s, 3H), 3.41 (dd, J = 10.4, 17.3 Hz, 1H), 3.05 (dd, J = 3.4, 17.3 Hz, 1H), 2.74 (ddd, J = 5.3, 9.7, 15.8 Hz, 1H), 2.55 (s, 3H), 2.20-1.96 (m, 2H), 2.00 (s, 3H), 1.83 (ddd, J = 5.9, 9.7, 15.8 Hz, 1H);

13

C NMR (75 MHz, CDCl3) δ 207.0, 176.6,

175.4, 138.0, 134.1, 131.0, 130.4, 128.5, 128.1, 128.0, 126.6, 125.6, 86.5, 52.7, 47.2, 41.3, 35.4, 31.1, 30.6, 20.8; HPLC (Daicel Chiralpak ID-3, hexane/2-propanol = 95/5, flow rate = 1.0 mL/min) tR = 14.9 min (major), 21.3 min (minor); [α]D24 = –168 (c = 0.086, CHCl3); HRMS (ESI-TOF) calcd for C23H25NNaO3 [M+Na]+ 386.1732, found: 386.1713. (S)-methyl

2-((R)-1-(4-methylphenyl)-3-oxobutyl)-5-phenyl-3,4-dihydro-2H-pyrrole-

2-carboxylate 3ac: White solid; 68.3 mg, 94% yield; mp = 138—140 °C; 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J = 7.1 Hz, 2H), 7.46-7.39 (m, 3H), 7.06 (d, J = 7.8 Hz, 1H), 6.95 (d, J = 7.8 Hz, 2H), 4.03 (d, J = 3.3, 10.2 Hz, 1H), 3.76 (s, 3H), 3.25 (dd, J = 10.2, 16.7 Hz, 1H), 2.99 (dd, J = 3.3, 16.7 Hz, 1H), 2.74 (m, 1H), 2.31-1.94 (m, 3H), 2.23 (s, 3H), 1.97 (s, 3H); 13

C NMR (75 MHz, CDCl3) δ 207.0, 176.5, 175.0, 136.6, 135.8, 134.0, 131.0, 129.7, 128.8,



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Page 14 of 22 14

128.5, 128.1, 86.5, 52.6, 47.4, 35.3, 30.9, 30.4, 21.1; HPLC (Daicel Chiralpak AS-3, hexane/2-propanol = 95/5, flow rate = 1.0 mL/min) tR = 9.7 min (minor), 13.2 min (major); [α]D24 = –173 (c = 0.143, CHCl3); HRMS (ESI-TOF) calcd for C23H25NNaO3 [M+Na]+ 386.1732, found: 386.1749. (S)-methyl

2-((R)-1-(4-methoxylphenyl)-3-oxobutyl)-5-phenyl-3,4-dihydro-

2H-carboxylate 3ad: White solid; 74.2 mg, 98% yield; mp = 125—128 °C; 1H NMR (300 MHz, CDCl3) δ 7.83-7.80 (m, 2H), 7.49-7.38 (m, 3H), 7.10-7.06 (m, 2H), 6.70-6.65 (m, 2H), 4.00 (dd, J = 3.7, 10.4 Hz, 1H), 3.83-3.77 (m, 4H), 3.71 (s, 3H), 3.23 (dd, J = 10.4, 17.1 Hz, 1H), 2.98 (dd, J = 3.7, 17.1 Hz, 1H), 2.73 (ddd, J = 5.0, 9.6, 16.5 Hz, 1H), 2.22-2.04 (m, 2H), 2.02 (s, 3H), 1.93 (ddd, J = 6.9, 9.6, 16.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 207.1, 176.6, 175.1, 158.6, 133.9, 131.1, 130.8, 130.8, 128.6, 128.2, 113.5, 86.5, 55.2, 52.7, 47.1, 46.3, 35.4, 31.1, 30.5; HPLC (Daicel Chiralpak AS-3, hexane/2-propanol = 95/5, flow rate = 1.0 mL/min) tR = 42.4 min (minor), 63.7 min (major); [α]D22 = –159 (c = 0.124, CHCl3); HRMS (ESI-TOF) calcd for C23H25NNaO4 [M+Na]+ 402.1681, found: 402.1694. (S)-methyl

2-((R)-1-(4-bromophenyl)-3-oxobutyl)-5-phenyl-3,4-dihydro-2H-pyrrole-

2-carboxylate 3ae: White solid; 80.3 mg, 94% yield; mp = 154—155 °C; 1H NMR (300 MHz, CDCl3) δ 7.84-7.81 (m, 2H), 7.51-7.39 (m, 3H), 7.29-7.26 (m, 2H), 7.08-7.05 (m, 2H), 4.03 (dd, J = 3.7, 10.3 Hz, 1H), 3.76 (s, 3H), 3.25 (dd, J = 10.3, 17.3 Hz, 1H), 3.02 (dd, J = 3.7, 17.3 Hz, 1H), 2.83-2.71 (m, 1H), 2.26-2.15 (m, 1H), 2.10-1.95 (m, 2H), 2.03 (s, 3H);

13

C

NMR (75 MHz, CDCl3) δ 206.4, 176.6, 174.7, 138.4, 133.7, 131.5, 131.1, 131.1, 128.6, 128.0, 121.1, 86.1, 52.7, 47.0, 46.1, 35.3, 31.0, 30.4; HPLC (Daicel Chiralpak AS-3, hexane/2-propanol = 98/2, flow rate = 0.7 mL/min) tR = 50.4 min (major), 56.4 min (minor); [α]D22 = –155 (c = 0.069, CHCl3); HRMS (ESI-TOF) calcd for C22H23BrNO3 [M+H]+


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428.0861, found: 428.0865. (S)-methyl

2-((S)-3-oxo-1-(2-thiophenyl)butyl)-5-phenyl-3,4-dihydro-2H-pyrrole-

2-carboxylate 3af: White solid; 36.2 mg, 51% yield; mp = 74—76 °C; 1H NMR (300 MHz, CDCl3) δ 7.89-7.86 (m, 2H), 7.51-7.40 (m, 3H), 7.09 (d, J = 0.8, 5.0 Hz, 1H), 6.88-6.82 (m, 2H), 4.47 (dd, J = 3.6, 10.4 Hz, 1H), 3.77 (s, 3H), 3.25 (dd, J = 10.4, 16.7 Hz, 1H), 2.96 (dd, J = 3.6, 16.7 Hz, 1H), 2.96-2.85 (m, 1H), 2.36-2.02 (m, 3H), 2.05 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 206.5, 177.4, 174.6, 142.0, 134.1, 131.2, 128.6, 128.3, 127.5, 126.4, 125.2, 86.5, 52.8, 47.8, 43.4, 35.8, 30.9, 30.6; HPLC (Daicel Chiralpak AS-3, hexane/2-propanol = 95/5, flow rate = 1.0 mL/min) tR = 20.8 min (major), 25.6 min (minor); [α]D24 = –158 (c = 0.033, CHCl3); HRMS (ESI-TOF) calcd for C20H22NO3S [M+H]+ 356.1320, found: 356.1303. (S)-methyl

2-((S)-3-oxo-1-(ferrocenyl)butyl)-5-phenyl-3,4-dihydro-2H-pyrrole-

2-carboxylate 3ag: Yellow solid; 81.4 mg, 89% yield; mp = 124—127 °C; 1H NMR (300 MHz, CDCl3) δ 7.75-7.72 (m, 2H), 7.41-7.27 (m, 3H), 4.23 (s, 1H), 4.07 (s, 5H), 4.04-4.00 (m, 3H), 3.77 (s, 1H), 3.70 (s, 3H), 3.34 (dd, J = 7.8, 17.8 Hz, 1H), 3.04 (dd, J = 2.4, 17.8 Hz, 1H), 2.75 (ddd, J = 4.0, 9.6, 16.6 Hz, 1H), 2.27 (s, 3H), 2.22-2.03 (m, 3H);

13

C NMR (75

MHz, CDCl3) δ 207.0, 175.6, 174.5, 134.0, 130.8, 128.4, 128.1, 89.3, 86.7, 70.1, 68.7, 68.2, 67.9, 67.3, 52.3, 46.5, 41.2, 35.6, 30.3, 29.4; HPLC (Daicel Chiralpak ID-3, hexane/2-propanol = 95/5, flow rate = 1.0 mL/min) tR = 38.5 min (major), 46.4 min (minor); [α]D25 = +54.9 (c = 0.041, CHCl3); HRMS (ESI-TOF) calcd for C26H28FeNO3 [M+H]+ 458.1419, found: 458.1409. CCDC1535169. (S)-methyl

2-((R)-3-oxo-1,3-diphenylpropyl)-5-phenyl-3,4-dihydro-2H-pyrrole-

2-carboxylate 3ah: White solid; 75.6 mg, 92% yield; mp = 162–164 °C;

1

H NMR (300

MHz, CDCl3) δ 7.95-7.92 (m, 2H), 7.86-7.82 (m, 2H), 7.51-7.37 (m, 6H), 7.25-7.20 (m, 2H),



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Page 16 of 22 16

7.10-7.08 (m, 3H), 4.28 (dd, J = 3.4, 10.4 Hz, 1H), 3.90 (d, J = 10.4, 17.3), 3.75 (s, 3H), 3.55 (dd, J = 3.4, 17.3 Hz, 1H), 2.72 (ddd, J = 5.6, 9.4, 16.9 Hz, 1H), 2.25-2.09 (m, 2H), 1.84 (ddd, J = 7.1, 9.4, 16.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 198.1, 176.6, 175.1, 139.2, 137.1, 134.0, 132.9, 130.9, 130.0, 128.5, 128.5, 128.8, 128.0, 127.9, 126.9, 86.5, 52.6, 48.0, 41.2, 35.3, 31.5; HPLC (Daicel Chiralpak AS-3, hexane/2-propanol = 95/5, flow rate = 1.0 mL/min) tR = 14.5 min (major), 21.4 min (minor); [α]D22 = –81.5 (c = 0.056, CHCl3); HRMS (ESI-TOF) calcd for C27H26NO3 [M+H]+ 412.1913, found: 412.1895. (S)-methyl

2-((R)-3-(4-methylphenyl)-3-oxo-1-phenylpropyl)-5-phenyl-3,4-dihydro-

-2H-pyrrole-2carboxylate 3ai: White solid; 84.2 mg, 99% yield; mp = 135—137 °C; 1H NMR (300 MHz, CDCl3) δ 7.86-7.82 (m, 4H), 7.48-7.37 (m, 3H), 7.23-7.18 (m, 4H), 7.10-7.07 (m, 3H), 4.27 (dd, J = 3.6, 10.5 Hz, 1H), 3.83 (d, J = 10.5, 17.2 Hz, 1H), 3.75 (s, 3H), 3.51 (d, J = 3.6, 17.2 Hz, 1H), 2.72 (ddd, J = 5.6, 9.4, 16.9 Hz, 1H), 2.36 (s, 3H), 2.25-2.09 (m, 2H), 1.83 (ddd, J = 7.2, 9.4, 16.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 197.7, 176.6, 175.2, 143.6, 139.2, 134.6, 134.1, 130.9, 130.0, 129.1, 128.5, 128.3, 128.1, 127.9, 126.8, 86.6, 52.6, 48.1, 41.1, 35.3, 31.5, 21.6; HPLC (Daicel Chiralpak ID-3, hexane/2-propanol = 95/5, flow rate = 1.0 mL/min) tR = 52.6 min (major), 69.0 min (minor); [α]D22 = –48.7 (c = 0.138, CHCl3); HRMS (ESI-TOF) calcd for C28H28NO3 [M+H]+ 426.2069, found: 426.2069. (S)-methyl 2-((R)-3-(4-methoxyphenyl)-3-oxo-1-phenylpropyl)-5-phenyl-3,4-dihydro2H-pyrrole-2carboxylate 3aj: White solid; 87.4 mg, 99% yield; 83—85 °C; 1H NMR (300 MHz, CDCl3) δ 7.95-7.91 (m, 2H), 7.86-7.82 (m, 2H), 7.49-7.39 (m, 3H), 7.23-7.20 (m, 2H), 7.11-7.08 (m, 3H), 6.91-6.87 (m, 2H), 4.26 (dd, J = 3.2, 10.3 Hz, 1H), 3.89-3.80 (m, 3H), 3.84 (s, 3H), 3.76 (s, 3H), 3.47 (d, J = 3.2, 16.9 Hz, 1H), 2.73 (ddd, J = 5.6, 9.4, 16.9 Hz, 1H),


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2.25-2.09 (m, 2H), 1.83 (ddd, J = 7.3, 9.4, 16.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 196.7, 176.7, 175.3, 163.4, 139.2, 134.1, 131.0, 130.5, 130.3, 130.1, 128.5, 128.1, 127.9, 126.9, 113.6, 86.6, 55.5, 52.7, 48.3, 40.9, 35.3, 31.6; HPLC (Daicel Chiralpak ID-3, hexane/2-propanol = 95/5, flow rate = 1.0 mL/min) tR = 100.6 min (major), 128.9 min (minor); [α]D22 = –36.0 (c = 0.041, CHCl3); HRMS (ESI-TOF) calcd for C28H28NO4 [M+H]+ 442.2018, found: 442.2039. (S)-methyl 2-((R)-3-(4-chlorophenyl)-3-oxo-1-phenylpropyl)-5-phenyl-3,4-dihydro-2Hpyrrole-2-carboxylate 3ak: White solid; 74.8 mg, 84% yield; mp = 84—86 °C; 1H NMR (300 MHz, CDCl3) δ 7.90-7.82 (m, 4H), 7.51-7.36 (m, 5H), 7.21-7.18 (m, 2H), 7.13-7.09 (m, 3H), 4.24 (dd, J = 3.5, 10.5 Hz, 1H), 3.85 (d, J = 10.5, 17.3, 1H), 3.76 (s, 3H), 3.52 (d, J = 3.5, 17.3 Hz, 1H)), 2.74 (ddd, J = 5.4, 9.4, 16.8 Hz, 1H), 2.25-2.08 (m, 2H), 1.85 (ddd, J = 7.4, 9.4, 16.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 197.1, 176.9, 175.2, 139.4, 139.0, 135.4, 134.0, 131.1, 130.0, 129.7, 128.9, 128.6, 128.1, 128.0, 127.1, 86.5, 52.8, 48.1, 41.4, 35.4, 31.6; HPLC (Daicel Chiralpak ID-3, hexane/2-propanol = 95/5, flow rate = 1.0 mL/min) tR = 27.1 min (major), 34.4 min (minor); [α]D22 = –42.8 (c = 0.085, CHCl3); HRMS (ESI-TOF) calcd for C27H25ClNO3 [M+H]+ 446.1523, found: 446.1533. (S)-methyl

2-((R)-3-(4-bromophenyl)-3-oxo-1-phenylpropyl)-5-phenyl-3,4-dihydro-

2H-pyrrole-2carboxylate 3al: White solid; 92.9 mg, 95% yield; 74—77 °C; 1H NMR (300 MHz, CDCl3) δ 7.84-7.78 (m, 4H), 7.55-7.52 (m, 2H), 7.49-7.38 (m, 3H), 7.21-7.18 (m, 2H), 7.11-7.09 (m, 2H), 4.25 (dd, J = 3.2, 10.3 Hz, 1H), 3.85 (d, J = 10.3, 17.0, 1H), 3.76 (s, 3H), 3.53 (d, J = 3.2, 17.0 Hz, 1H), 2.74 (ddd, J = 5.3, 9.4, 16.8 Hz, 1H), 2.25-2.07 (m, 2H), 1.86 (ddd, J = 7.2, 9.4, 16.8 Hz, 1H);

13

C NMR (75 MHz, CDCl3) δ 197.2, 176.8, 175.1, 139.0,

135.8, 133.9, 131.8, 131.0, 130.0, 129.8, 128.5, 128.1, 128.0, 127.0, 86.4, 52.7, 48.0, 41.3,



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Page 18 of 22 18

35.3, 31.5; HPLC (Daicel Chiralpak ID-3, hexane/2-propanol = 95/5, flow rate = 1.0 mL/min) tR = 28.3 min (major), 36.8 min (minor); [α]D22 = –38.2 (c = 0.182, CHCl3); HRMS (ESI-TOF) calcd for C27H25BrNO3 [M+H]+ 490.1018, found: 490.1043. (S)-methyl 2-((R)-3-(4-nitrophenyl)-3-oxo-1-phenylpropyl)-5-phenyl-3,4-dihydro-2Hpyrrole-2-carboxylate 3am: White solid; 87.6 mg, 96% yield; mp = 161—164 °C; 1H NMR (300 MHz, CDCl3) δ 8.27-8.24 (m, 2H), 8.09-8.06 (m, 2H), 7.86-7.82 (m, 2H), 7.51-7.40 (m, 3H), 7.21-7.18 (m, 2H), 7.13-7.11 (m, 3H), 4.25 (dd, J = 3.6, 10.4 Hz, 1H), 3.89 (d, J = 10.4, 17.4, 1H), 3.78 (s, 3H), 3.63 (d, J = 3.6, 17.4 Hz, 1H), 2.76 (ddd, J = 5.2, 9.6, 16.9 Hz, 1H), 2.26-2.07 (m, 2H), 1.87 (ddd, J = 7.0, 9.6, 16.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 197.0, 177.2, 175.1, 150.3, 141.5, 138.7, 133.8, 131.2, 130.0, 129.3, 128.6, 128.1, 127.3, 123.8, 86.3, 52.9, 47.9, 42.1, 35.4, 31.5; HPLC (Daicel Chiralpak ID-3, hexane/2-propanol = 95/5, flow rate = 1.0 mL/min) tR = 46.3 min (major), 62.1 min (minor); [α]D22 = –51.7 (c = 0.096, CHCl3); HRMS (ESI-TOF) calcd for C27H25N2O5 [M+H]+ 457.1764, found: 457.1777. (S)-methyl-2-((R)-4-oxopentan-2-yl)-5-phenyl-3,4-dihydro-2H-pyrrole-2-carboxylate 3an: Colorless oil; 22.9 mg, 42% yield; 1H NMR (300 MHz, CDCl3) δ 7.89-7.85 (m, 2H), 7.46-7.38 (m, 3H), 3.74 (s, 3H), 3.15-2.94 (m, 3H), 2.57 (dd, J = 3.3, 16.4 Hz, 1H), 2.53-2.43 (m, 1H), 2.30 (dd, J = 10.2, 16.4 Hz, 1H), 2.15 (s, 3H), 2.05-1.92 (m, 1H), 0.90 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 208.1, 175.1, 174.6, 133.9, 131.2, 128.6, 128.3, 87.2, 52.6, 46.4, 36.0, 30.4, 28.1, 15.1; HPLC (Daicel Chiralpak AD-H, hexane/2-propanol = 98/2, flow rate = 0.7 mL/min) tR = 37.0 min (major), 40.5 min (minor); [α]D27 = –48.7 (c = 0.053, + CHCl3); HRMS calcd for C17H21NNaO3 [M+Na] 310.1419, found: 310.1434. Reduction of 3aa by NaBH3CN: Synthesis of pyrrolizidine 4aa


Page 19 of 22

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To a capped 4 mL vial containing a stirrer bar, 3aa (70.0 mg, 0.2 mmol) and dry THF (2 mL) were added. To this solution, NaBH3CN (75.4 mg, 1.2 mmol) and acetic acid (72 L, 1.2 mmol) were added successively at room temperature, and stirred for a further 6 h at room temperature. Ethanolamine (0.5 mL) was then added and the mixture stirred overnight at room temperature. The solution was diluted with ethyl acetate (20 mL) and washed with water, brine, and then dried by the addition of Na2SO4. The solution was filtered and the filtrate concentrated by rotary evaporation. Short silica gel column chromatography (5 cm × 10 cm) gave the crude product and revealed the presence of the single product by 1H NMR measurement. The crude product was purified by PTLC (silica gel, hexane/ethyl acetate = 2/1) to yield 4aa (63.6 mg, 91% yield) as a brown oil. (1R,3S,5S,7aS)-methyl 3-methyl-1,5-diphenylpyrrolizidine-7a-carboxylate 4aa: Yellow oil; 63.6 mg, 91% yield; 1H NMR (300 MHz, CDCl3) δ 7.50-7.47 (m, 2H), 7.41-7.36 (m, 4H), 7.31-7.18 (m, 4H), 4.12 (dd, J = 4.1, 9.4 Hz, 1H), 3.79 (s, 3H), 3.51 (dd, J = 2.7, 9.4 Hz, 1H), 3.36 (sext, J = 6.7 Hz, 1H), 2.77 (td, J = 8.8, 13.8 Hz, 1H), 2.60-2.46 (m, 1H), 1.89 (ddd, J = 2.7, 6.7, 13.8 Hz, 1H), 1.82-1.74 (m, 1H), 1.51-1.45 (m, 1H), 1.17-1.06 (m, 1H), 0.70 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 176.9, 147.8, 143.8, 129.2, 128.2, 128.1, 127.7, 126.8, 126.5, 83.5, 58.2, 51.5, 50.0, 45.2, 40.0, 28.1, 20.7; [α]D24 = –108.3 (c = 0.066, CHCl3); HRMS (ESI-TOF) calcd for C22H25NNaO2 [M+Na]+ 358.1783, found: 358.1794.

ACKNOWLEDGEMENT We acknowledge financial support from the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid No.16K05704 for scientific research.



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Page 20 of 22 20

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

H and 13C NMR spectra of compounds, 3aa–3da, 3ab–3an, 4aa (PDF).

X-ray crystallography of compound 3ag (CIF). HPLC analytical data of compounds, 3aa–3da, 3ab–3an, 4aa (PDF).

REFRENCES

1. For reviews, a) Meyrer, A. G.; Ryan, J. H. Molecules, 2016, 21, 935. b) Narayan, R.; Potowski, M.; Jia, Z.-J.; Antonchick, A. P.; Waldmann, H. Acc. Chem. Res. 2014, 47, 1296. c) Ryan, J. H. Arkivoc, 2015, 160. d) Adrio, J.; Carretero, J. C. Chem. Comm. 2014, 50, 12434. e) Adrio, J.; Carretero, J. C. Chem. Comm. 2011, 47, 6784. f) Xing, Y.; Wang, N.-X. Coord. Chem. Rev. 2012, 256, 938. g) Nájera, C.; Sansano, J. M. J. Organomet. Chem. 2014, 771, 78. h) Nájera, C.; Sansano, J. Monatsh Chem. 2011, 142, 659. i) Nájera, C.; Sansano, J. Org. Biomol. Chem. 2009, 7, 4567. j) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765. 2. Tada, A.; Watanabe, S.; Kimura, M.; Tokoro, Y.; Fukuzawa, S.-i. Tetrahedron Lett. 2014, 55, 6224. 3. Xue, Z.-Y.; Xiong, Y.; Wang, C.-J. Synlett 2014, 2733 – 2737. 4. a) Koizumi, A.; Kimura, M.; Arai, Y.; Tokoro, Y.; Fukuzawa, S.-i. J. Org. Chem. 2015, 80, 10883. b) Matsuda, Y.; Koizumi, A.; Haraguchi, R.; Fukuzawa, S.-i. J. Org. Chem. 2016, 81, 7939. 5. Li, C.-Y.; Yang, W.-L.; Luo, X.; Deng, W.-P. Chem.-Eur. J. 2015, 21, 19048. 6. a) Bergner, I.; Wiebe, C.; Meyer, N.; Opatz, T. J. Org. Chem. 2009, 74, 8243. b) Nebe, M. M.; Kucukdisli, M; Opatz, T. J. Org. Chem. 2016, 81, 4112.


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7. For selected examples, a) Robertson, J.; Stevens, K. Nat. Prod. Rep. 2017, 34, 62. b) Desvergnes, V.; Landais, Y. Studies in Natural Products Chemistry 2014, 42, 373. c) Tasso, B.; Novelli, F.; Sparatore, F.; Fasolo, F.; Gotti, C. J. Nat. Prod. 2013, 76, 727, d) Robertson, J.; Stevens, K. Nat. Prod. Rep. 2014, 31, 1721, and references are cited therein. 8. For recent examples for synthetic works of pyrrolizidine, a) Bhat, C.; Tilve, S. G. RSC Adv. 2014, 4, 5405. b) Mancebo-Aracil, J.; Nájera, C.; Castelló, L. M.; Sansano, J. M.; Larrañaga O.; de Cózar, A.; Cossío, F. P. Tetrahedron, 2015, 71, 9645. c) Kim, J. H.; Lee, S.; Kim, S. Angew. Chem., Int. Ed. 2015, 54, 10875, d) Brambilla, M.; Davies, S. G. Fletcher, A. M.; Thomson, J. E. Tetrahedron: Asymmetry 2014, 25, 387. e) Lim, A. D.; Codelli, J. A.; Reisman, S. E. Chem. Sci. 2013, 4, 650, f) Ritthiwigrom, T.; Willis, A. C.; Pyne, S. G. J. Org. Chem. 2010, 75, 815. g) Brandi, A.; Cardona, F.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem. Eur.-J. 2009, 15, 7808. h) Griesbeck, A. G.; Hoffmann, N.; Warzecha, K.-D. Acc. Chem. Res. 2007, 40, 128. 9. Successful asymmetric cycloaddition and conjugate addition of glycine imino esters with α-enones have been reported. a) Li, J.-Y.; Kim, H. Y.; Oh, K. Adv. Synth. Catal. 2016, 358, 984. b) Strohmeier, M.; Leach, K.; Zajac, M. A. Angew. Chem., Int. Ed. 2011, 50, 12335. c) Hernández-Toribio, J.; Arrayás, R. G.; Martín-Matute, B.; Carretero, J. C. Org. Lett. 2009, 11, 393. d) Sarotti, A. M.; Spanevello, R. A.; Suárez, A. G.; Echeverría, G. A.; Piro, O. E. Org. Lett. 2012, 14, 2556. e) Oura, I.; Shimizu, K.; Ogata, K.; Fukuzawa, S.-i. Org. Lett. 2010, 12, 1752. 10. We define anti-stereochemistry is as that the imino nitrogen group and the phenyl group from α-enone is placed in anti each other.



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11. A alcohol solvent is effective for silver-catalyzed asymmetric reactions. a) Bai, X.-F.; Xu, Z.; Xia, C.-G.; Zheng, Z.-J.; Xu. L.-W. ACS Catal. 2015, 5, 6016. b) Bai, X.-F.; Li, L.; Xu, Z.; Zheng, Z.-J.; Xia, C.-G.; Cui, Y.-M.; Xu. L.-W. Chem. Eur. J. 2016, 22, 10399. c) Yanagisawa, A.; Lin, Y.; Miyake, R.; Yoshida, K. Org. Lett. 2014, 16, 86.


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