Chiral Silver Complex-Catalyzed Diastereoselective and

Article pubs.acs.org/joc

Chiral Silver Complex-Catalyzed Diastereoselective 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 S Supporting Information *

ABSTRACT: A AgOAc/ThioClickFerrophos complex-catalyzed the highly diastereo- and enantioselective reaction between 1pyrroline-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.

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INTRODUCTION An 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 an azomethine ylide, being activated by a metal complex and an organocatalyst, and can be a useful building block for amino acids by alkylation and Michael addition to activated alkenes. Coinciding with the Wang group,3 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 7azanorbornene, 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) complex. Opatz and co-workers6 recently reported on the basecatalyzed 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

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

pyrrolizidine derivatives have been found in many natural substrates and classified as pyrrolizidine alkaloids (Figure 1). Owing to their diverse biological and pharmaceutical activities, e.g., antibacterial, insecticidal, anticancer, 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 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

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

Received: May 31, 2017 Published: August 10, 2017 © 2017 American Chemical Society

8927

DOI: 10.1021/acs.joc.7b01335 J. Org. Chem. 2017, 82, 8927−8932

Article

The Journal of Organic Chemistry Table 1. Optimization of Metal Complexesa

Figure 1. Examples of pyrrolizidine alkaloid.

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 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.

entry

metal salt

L

yield (%)b

drc

ee (%)d

1 2 3 4 5 6 7 8 9

AgOAc AgBF4 AgOTf AgF AgOAc AgOAc AgOAc CuOAc CuOAc

L1 L1 L1 L1 L2 L3 L4 L3 L4

90 83 82 87 86 85 93 81 90

98:2 98:2 98:2 98:2 97:3 98:2 98:2 98:2 98:2

71 67 71 10 67 1 2 0 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. c Determined by 1 H NMR. d Determined by chiral HPLC.

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Figure 2. Chiral phosphine ligands.

RESULTS AND DISCUSSION We first examined some combinations of silver or copper salts and chiral ligands in the model reaction of 1-pyrroline-5carboxylate (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 (Figure 2) produced the single diastereomer 3aa (antidiastereomer) with high selectivity and a good yield (81− 90%).10 The combination of silver salts and ThioClickFerrophos ligands (L1 and L2) afforded moderate enantioselectivity in yielding the product, except in the case of AgF (see entries 1−5), whereas FcPHOX ligands (L3 and 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 and 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 summarizes the various solvents and bases used 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

Table 2. Optimization of Reaction Conditionsa

entry

solvent

base

yield (%)b

drc

ee (%)d

1 2 3 4 5 6e 7 8f 9 10 11

THF Et2O toluene CH2Cl2 MeOH MeOH MeOH MeOH MeOH MeOH MeOH

DBU DBU DBU DBU DBU DBU Et3N DBU DIPEA DABCO Cs2CO3

90 89 89 80 99 99 39 99 29 50 89

98:2 99:1 98:2 98:2 99:1 99:1 99:1 99:1 99:1 98:1 98:2

71 60 61 55 87 87 89 94 88 82 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. b Combined isolated yield of diastereomers. cDetermined by 1H NMR. d Determined by chiral HPLC. eReaction was carried out at 0 °C. f Reaction was carried out at −20 °C.

reaction in methanol, while testing various organic and inorganic bases, where DBU was found to be the optimal 8928


Article

The Journal of Organic Chemistry

product and yield (%)b

drc

ee (%)d

Ph, Me, 2a Ph, Me, 2a

3aa, 99 3ba, 97

99:1 97:3

94 95

Ph, Me, 2a Ph, Me, 2a o-MeC6H4, Me, 2b p-MeC6H4, Me, 2c p-MeOC6H4, Me, 2d p-BrC6H4, Me, 2e 2-thienyl, Me, 2f Fc, Me, 2g Ph, Ph, 2h Ph, p-MeC6H4, 2i Ph, p-MeOC6H4, 2j Ph, p-ClC6H4, 2k Ph, p-BrC6H4, 2l Ph, p-NO2C6H4, 2m Me, Me, 2n

3ca, 99 3da, 88 3ab, 65

99:1 99:1 99:1

83 85 92

3ac, 94

99:1

97

3ad, 98

99:1

93

3ae, 94

99:1

89

3af, 51 3ag, 89 3ah, 92 3ai, 99

99:1 99:1 99:1 97:3

89 99 96 96

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 thienylsubstituted 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-enone such as (E)-3-penten-2-one were 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 the Supporting Information). Stereochemistries 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 on the yield and 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 % AgOAc/L1 in the presence of 20 mol % 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 by 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 the loss of

3aj, 99

94:6

95

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

3ak, 84

98:2

84

3al, 95 3am, 96

95:5 99:1

88 94

3an, 42

99:1

97

base, giving both a good yield and a favorable enantiomeric excess (ee%). Diisopropylethylamine (DIPEA) gave a good ee % but gave a low yield (entry 9), so it 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, 5.5 mol % L1, 20 mol % DBU in MeOH at −20 °C) previously determined. Table 3 Table 3. Scope of Substratesa

entry

Ar in 1

1 2 3 4 5

Ph, 1a p-MeOC6H4, 1b p-ClC6H4, 1c p-BrC6H4, 1d Ph, 1a

6

Ph, 1a

7

Ph, 1a

8

Ph, 1a

9 10 11 12

Ph, Ph, Ph, Ph,

13

Ph, 1a

14

Ph, 1a

15 16

Ph, 1a Ph, 1a

17

Ph, 1a

1a 1a 1a 1a

R1, R2 in 2

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. b Combined isolated yield of diastereomers. cDetermined by 1H NMR. d Determined by chiral HPLC.

the ester group. Stereochemistry of the product was assigned as (1R,3S,5S,7aS) by following the NOESY measurement (see the 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

summarizes the results of the reaction for a variety of 1pyrroline-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 yields 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 effects of the substituents on product yield and stereoselectivity were hardly observed; all products were

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CONCLUSION We have successfully demonstrated the silver-catalyzed asymmetric Michael addition of 1-pyrroline-5-carboxylate to acyclic α-enones, such as (E)-benzalacetone 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 gramscale synthesis and subsequent transformation of the product to the potentially biologically active fused pyrrolizidine, by 8929


Article


(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-3,4dihydro-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); 13C 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]24 D = −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-3,4dihydro-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); 13C NMR (75 MHz, CDCl3) δ 207.0, 176.5, 175.0, 136.6, 135.8, 134.0, 131.0, 129.7, 128.8, 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]24 D = −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-phenyl3,4-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]22 D = −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-3,4dihydro-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); 13C 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]22 D = −155 (c = 0.069, CHCl3); HRMS (ESI-TOF) calcd for C22H23BrNO3 [M + H]+ 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]24 D = −158 (c = 0.033, CHCl3); HRMS (ESI-TOF) calcd for C20H22NO3S [M + H]+ 356.1320, found 356.1303.

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 a nitrogen atmosphere with oven-dried glassware. In a 20 mL Schlenk tube containing a stir 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 the mixture was 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 the 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 was 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-2Hpyrrole-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); 13C 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]22 D = −152 (c = 0.125, CHCl3); HRMS (ESI-TOF) calcd for C22H23NNaO3 [M + Na]+ 372.1576, found 372.1570. (S)-Methyl 5-(4-Methoxyphenyl)-2-((R)-3-oxo-1-phenylbutyl)-3,4dihydro-2H-pyrrole-2-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); 13C 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/2propanol = 90:10, flow rate = 0.5 mL/min, at 10 °C) tR = 122.1 min (minor), 126.7 min (major); [α]23 D = −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)-3,4dihydro-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]22 D = −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)-3,4dihydro-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, 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]26 D = −167 8930


Article


(S)-Methyl 2-((R)-3-(4-Bromophenyl)-3-oxo-1-phenylpropyl)-5phenyl-3,4-dihydro-2H-pyrrole-2-carboxylate (3al): white solid; 92.9 mg, 95% yield; mp = 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); 13C 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, 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]22 D = −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-2H-pyrrole-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]22 D = −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-2Hpyrrole-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/2propanol = 98:2, flow rate = 0.7 mL/min) tR = 37.0 min (major), 40.5 min (minor); [α]27 D = −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. To a capped 4 mL vial containing a stir bar were added 3aa (70.0 mg, 0.2 mmol) and dry THF (2 mL). To this solution were added NaBH3CN (75.4 mg, 1.2 mmol) and acetic acid (72 μL, 1.2 mmol) successively at room temperature, and the mixture was 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), washed with water and brine, and then dried by the addition of Na2SO4. The solution was filtered, and the filtrate was 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 the 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]24 D = −108.3 (c = 0.066, CHCl3); HRMS (ESI-TOF) calcd for C22H25NNaO2 [M + Na]+ 358.1783, found 358.1794.

(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); 13C 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]25 D = +54.9 (c = 0.041, CHCl3); HRMS (ESI-TOF) calcd for C26H28FeNO3 [M + H]+ 458.1419, found 458.1409. CCDC 1535169. (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; 1H 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), 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]22 D = −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)-5phenyl-3,4-dihydro-2H-pyrrole-2- carboxylate (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]22 D = −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)-5phenyl-3,4-dihydro-2H-pyrrole-2-carboxylate (3aj): white solid; 87.4 mg, 99% yield; mp = 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), 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]22 D = −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)-5phenyl-3,4-dihydro-2H-pyrrole-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]22 D = −42.8 (c = 0.085, CHCl3); HRMS (ESI-TOF) calcd for C27H25ClNO3 [M + H]+ 446.1523, found 446.1533.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01335. 8931


Article

The Journal of Organic Chemistry 1

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H and 13C NMR spectra of compounds 3aa−3da, 3ab− 3an, and 4aa; NOE spectra of 4aa; X-ray structure of 3ag; and HPLC analytical data of compounds 3aa−3da, 3ab−3an, and 4aa (PDF) X-ray crystallography of compound 3ag (CIF)

2012, 14, 2556. (e) Oura, I.; Shimizu, K.; Ogata, K.; Fukuzawa, S.-i. Org. Lett. 2010, 12, 1752. (10) We define anti-stereochemistry as the imino nitrogen group and the phenyl group from α-enone are placed anti to each other. (11) An 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.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Ryosuke Haraguchi: 0000-0001-6703-8036 Shin-ichi Fukuzawa: 0000-0001-8108-3829 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS 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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REFERENCES

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