Total Syntheses of (+)-α-Allokainic Acid and (−)-2-epi-α-Allokainic Acid

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Cite This: J. Org. Chem. 2018, 83, 10564−10572

Total Syntheses of (+)-α-Allokainic Acid and (−)-2-epi-α-Allokainic Acid Employing Ketopinic Amide as a Chiral Auxiliary Yu-Fu Liang, Chuang-Chung Chung, De-Jhong Liao, Woo-Jer Lee, Yu-Wei Tu, and Biing-Jiun Uang* Department of Chemistry, National Tsing Hua University, 101 Sec. 2, Kuang Fu Road, Hsinchu 30013, Taiwan

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S Supporting Information *

ABSTRACT: Asymmetric Michael reaction of iminoglycinate 4 to α,β-unsaturated esters had been developed with >98:98:2a >98:2 >98:2 >98:2 >98:2

a

No second isomer was detected by 400 MHz 1H NMR spectroscopy. bWith a recovery of 15% unreacted 4.

was confirmed by X-ray crystallographic analysis.14 The newly formed stereogenic centers at C2 and C3 are R and S configurations, respectively, which correspond to the stereochemistry at C2 and C3 of (−)-2-epi-α-allokainic acid 6. Hexamethylphosphoramide (HMPA) and crown ethers were known to coordinate a metal cation and break metal ion chelation between the enolate and Michael acceptor. When the Michael addition reaction of enolate 4-Li to methyl crotonate was conducted in the presence of 2 equiv or 4 equiv of HMPA, or 12-crown-4 (Table 2, entries 2−4), it gave a poor

Scheme 2. Plausible Transition State of Michael Addition with Lithium Enolate

Table 2. Additive Influence on Diastereoselective Michael Addition of 4-Li Enolate with Methyl Crotonate

entry

base

1 2 3 4

LDA LDA LDA LDA

additive

t (h)

yield (%)

ratio (7:12)

HMPA (2 equiv) HMPA (6 equiv) 12-crown-4 (2 equiv)

3 3 3 3

87 70 68 76

>98:2 3:2a 3:2 3:2

Scheme 3. Total Synthesis of (−)-2-epi-α-Allokainic Acid 6

a Determined by 400 MHz 1HNMR spectroscopy of the crude mixture.

stereoselectivity. A decrease of product ratio from >98:98:2a >98:2 >98:2 >98:2

base

additive

t (h)

yield (%)

ratio (12/7)

1 2 3

MDA MDA MDA

HMPA (2 equiv) HMPA (6 equiv) 15-crown-5 (2 equiv)

18 18 18

65a 60b 60c

2:1 1:1 1:1

a

With a recovery of 76% unreacted 4. bWith a recovery of 10% unreacted 4. cWith a recovery of 11% unreacted 4. dWith a recovery of 5% unreacted 4.

reacted with methyl crotonate at −78 °C for 18 h in the presence of 2 equiv of HMPA, a decrease of product ratio from >98:2 to 2:1 between 12 and 7 was observed (Table 4, entry 1). A further increase with the amount of HMPA from 2 equiv to 6 equiv gave no selectivity (Table 4, entry 2). It gave no selectivity at the C2 position when the Michael reaction was conducted in the presence of 15-crown-5 (Table 4, entry 3). The replacement of the lithium ion with the magnesium ion resulted in a reverse of selectivity for the Michael reaction at C2. A plausible chelated transition state model was proposed as shown in Scheme 5. Scheme 5. Plausible Transition State of Michael Addition with MDA

Based on a previous report,20 magnesium enolate could gather to form the dimeric complex. Imagine that the dimeric magnesium enolate complex as a box, the less hindered moiety of chiral auxiliary was at the inner part of the box, and the more hindered gem-dimethyl moiety of chiral auxiliary was at the outer part of the box. The attack of magnesium enolate did not easily happen at the re(Cα)-face (the inner part of the metal complex box) of enolate to si(Cβ)-face of α,β-unsaturated ester due to the metal ion coordination with the other magnesium enolate. Therefore, the attack of enolate occurred at the more hindered si(Cα)-face of enolate to the α,βunsaturated ester (shown as T2 in Scheme 5). The reactivity of magnesium enolate is lower, and it required a prolonged reaction time to achieve a reasonable yield (Table 3, entry 2) due to the above-mentioned steric hindrance. Through this magnesium ion chelation pathway, compound 12 was produced as the major product in the reaction of magnesium enolate 4-Mg with methyl crotonate.

Table 3. Diastereoselective Michael Addition of 4Mg Enolate with α,β-Unsaturated Esters

entry

entry

a

No second isomer was detected by 400 MHz 1H NMR spectroscopy. With a recovery of 76% unreacted 4. cWith a recovery of 30% unreacted 4. dWith a recovery of 20% unreacted 4.

b

10566

DOI: 10.1021/acs.joc.8b01383 J. Org. Chem. 2018, 83, 10564−10572

Note

The Journal of Organic Chemistry

mmol) was added by means of a syringe pump over 24 h, and the resulting brown solution was stirred for 12 h at 140 °C. After that, the reaction mixture was cooled to room temperature and then was neutralized to pH = 6−7 by the addition of a saturated NaHCO3 solution (40 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (eluent EtOAc/hexanes, 1:10 + 1% Et3N) to provide 4 (8.29 g, 21.9 mmol, 65%) as a white solid and recover 16 (2.25 g, 8.5 mmol, 25%): Rf = 0.42 (EtOAc/hexanes, 1:6); mp = 98.0−98.8 °C; [α]22 D −106.0 (c 1.5, CHCl3); IR (neat) 2972, 1717, 1681, 1625, 1437, 1366 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.25 (septet, J = 6.8 Hz, 1H), 4.04 (d, J = 15.6 Hz, 1H), 3.80 (d, J = 15.6 Hz, 1H), 3.28 (septet, J = 6.8 Hz, 1H), 2.39 (ddd, J = 16.8, 4.4, 2.8 Hz, 1H), 2.14−1.87 (m, 4H), 1.77−1.69 (m, 1H), 1.43 (d, J = 6.8 Hz, 3H), 1.42 (s, 9H), 1.32 (d, J = 6.8 Hz, 3H), 1.30−1.22 (m, 1H), 1.16 (d, J = 6.8 Hz, 3H), 1.14 (s, 3H), 1.13 (s, 3H), 1.05 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 181.2, 170.2, 169.3, 80.8, 65.2, 54.9, 50.9, 48.3, 46.1, 44.0, 35.3, 28.6, 28.0, 27.2, 21.5, 21.0, 20.6, 20.3, 20.2; HRMS (HRFI) m/z [M]+ calcd for C22H38N2O3 378.2882, found 378.2888. General Procedures for the Syntheses of Michael Adducts 7−11. 1-tert-Butyl Methyl (2R,3S)-N-2-(((1S,4R)-1-(N,N-Diisopropylamino-carbonyl)-7,7-dimethyl-bicyclo[2.2.1]heptan-2-ylidene)amino)-3-methyl-glutamate (7). A solution of LDA in THF was prepared under argon with diisopropylamine (0.1 mL, 0.69 mmol), THF (1 mL), and n-BuLi (2.3 M solution in n-hexane, 0.28 mL, 0.64 mmol) at 0 °C. After stirring for 30 min, the solution was cooled to −78 °C with a dry ice−acetone bath. A solution of iminoglycinate 4 (0.2 g, 0.53 mmol) in THF (1.0 mL) was added over 20 min, and the mixture was stirred for 30 min; then a solution of methyl crotonate (0.07 mL, 0.69 mmol) in THF (1 mL) was added slowly. The mixture was stirred at −78 °C for 3 h, and then a 2% H2C2O4 (aq) solution (2 mL) was added to the reaction mixture; the temperature was raised to 0 °C. The mixture was neutralized to pH = 6−7 with additional 2% H2C2O4 (aq). The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography (eluent EtOAc/hexanes, 1:8 + 1% Et3N) to provide 7 (0.22 g, 0.46 mmol, 87%) as a white solid: Rf = 0.36 (EtOAc/hexanes, 1:6); mp = 142−145 °C; [α]28 D −9.9 (c 1.0, CHCl3); IR (neat) 2969, 2940, 2889, 1738, 1728, 1679, 1630, 1474, 1436, 1335 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.16 (septet, J = 6.4 Hz, 1H), 3.64 (d, J = 6.4 Hz, 1H), 3.60 (s, 3H), 3.24 (septet, J = 6.4 Hz, 1H), 2.53−2.45 (m, 3H), 2.15−2.02 (m, 2H), 1.95−1.81 (m, 2H), 1.74−1.64 (m, 2H), 1.37 (d, J = 6.4 Hz, 3H), 1.33 (s, 9H), 1.29 (d, J = 6.8 Hz, 3H), 1.15 (d, J = 6.4 Hz, 3H), 1.12 (s, 3H), 1.09−1.05 (m, 1H), 1.06 (s, 3H), 1.00 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 180.7, 172.9, 169.8, 169.6, 81.0, 69.9, 65.4, 51.5, 51.3, 48.0, 45.9, 43.9, 37.6, 36.4, 32.9, 29.2, 27.8, 27.2, 21.7, 20.8, 20.6, 20.4, 20.3, 16.0; HRMS (ESI) m/z [M + H]+ calcd for C27H47N2O5 479.3479, found 479.3472. 1-tert-Butyl Methyl (2R,3S)-N-2-(((1S,4R)-1-(N,N-Diisopropylaminocarbonyl)-7,7-dimethyl-bicyclo[2.2.1]heptan-2-ylidene)amino)3-propyl-glutamate (8a). Starting with a solution of iminoglycinate 4 (0.2 g, 0.53 mmol) in THF (1.0 mL) and following the same procedure as in the synthesis of 7 provided 8a (0.24 g, 0.48 mmol, 90%) as a white solid: Rf = 0.41 (EtOAc/hexanes, 1:6); mp = 150− 151 °C; [α]23 D −5.3 (c 1.0, CH2Cl2); IR (neat) 2964, 2928, 2868, 1738, 1722, 1626, 1434, 1370 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.18 (septet, J = 6.8 Hz, 1H), 3.84 (d, J = 6.8 Hz, 1H), 3.60 (s, 3H), 3.27 (septet, J = 6.8 Hz, 1H), 2.58 (dd, J = 15.6, 4.8 Hz, 1H), 2.54− 2.46 (m, 1H), 2.43−2.35 (m, 1H), 2.25 (dd, J = 15.6, 7.6 Hz, 1H), 2.20−2.11 (m, 1H), 1.97−1.85 (m, 2H), 1.77 (s, 1H), 1.70 (t, J = 4.5 Hz, 1H), 1.43−1.36 (m, 2H), 1.39 (d, J = 6.8 Hz, 3H), 1.36 (s, 9H), 1.31 (d, J = 6.8 Hz, 3H), 1.30−1.21 (m, 2H), 1.17 (d, J = 6.4 Hz, 3H), 1.16−1.12 (m, 1H), 1.16 (s, 3H), 1.09 (s, 3H), 1.02 (d, J = 6.4 Hz, 3H), 0.84 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 180.8, 173.5, 170.0, 169.7, 81.0, 67.8, 65.6, 51.6, 51.3, 48.0, 46.0, 44.0, 37.9, 36.6, 34.9, 32.7, 29.3, 27.8, 27.2, 21.9, 20.8, 20.7, 20.4, 20.3, 19.8, 14.3;

To extend this methodology further, a total synthesis of (+)-α-allokainic acid 1 is illustrated on Scheme 6. With 14b in Scheme 6. Total Synthesis of (+)-α-Allokainic Acid 1

hand, one could follow the same synthetic protocol as for the synthesis of (−)-2-epi-α-allokainic acid to accomplish the synthesis of (+)-α-allokainic acid 1 in 11 steps with 17.8% overall yield (Scheme 6). The spectral data of (+)-α-allokainic acid are identical to those of the reported ones, and the specific rotation [α]D +7.8 (c 0.2, H2O) is in agreement with the literature value (lit.7 [α]D +7.1 (c 0.1, H2O)). In conclusion, an asymmetric Michael reaction of iminoglycinate bearing ketopinic amide as an auxiliary has been developed with an excellent diastereoselectivity. Switching of stereoselectivity at C2 of the Michael adducts could be achieved by replacing the lithium enolate with magnesium enolate. Utilization of this methodology for the total syntheses of (−)-2-epi-α-allokainic acid and (+)-α-allokainic acid from chiral iminoglycinate 4 in 11 synthetic steps with 18% and 17.8% overall yields, respectively, had been demonstrated.

■

EXPERIMENTAL SECTION

General Information. Reagents were obtained from commercial sources and used without further purification. Most reactions were performed under an argon atmosphere in anhydrous solvents, which were dried prior to use following standard procedures. Merck Art. 7734 and 9385 silica gels were employed for flash chromatography. 1 H NMR spectra were obtained and noted at 400 MHz (Bruker DPX400 or Varian-Unity-400). 13C NMR spectra were obtained at 100 MHz. Chemical shifts are reported in values in parts per million (ppm) relative to relative to residual chloroform (7.26 ppm for 1H NMR, 77.00 ppm for 13C NMR) or H2O (4.80 ppm for 1H NMR) as an internal standard. The multiplicities of the signals are described using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet, br = broad band. The melting point was recorded on a melting point apparatus (Buchi512 melting point system) and is uncorrected. IR spectra were performed on a spectrophotometer, Bomen MB 100 FT-IR, and only noteworthy IR absorptions (cm−1) are listed. Optical rotations were measured on a PerkinElmer 241 polarimeter. Mass spectrometric analyses were performed by the Center for Advanced Instrumentation and Department of Applied Chemistry at National Chiao Tung University, Hsinchu, Taiwan. tert-Butyl (1S,4R)-2-(1-(N,N-Diisopropylaminocarbonyl)-7,7-dimethyl-bicyclo[2.2.1]hept-2-ylideneamino)ethanoate (4). To a 250 mL two-necked round-bottom flask were added 1621 (9.0 g, 33.9 mmol), toluene (70 mL), and benzoic acid (12.36 g, 101.7 mmol). The mixture was heated to reflux for 2 h with a Dean−Stark apparatus to remove water. After 2 h, tert-butyl glycinate (9 mL, 66.0 10567

DOI: 10.1021/acs.joc.8b01383 J. Org. Chem. 2018, 83, 10564−10572

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The Journal of Organic Chemistry

was added slowly. The mixture was stirred at −78 °C for 18 h, and then a 2% H2C2O4 (aq) solution (2 mL) was added. The reaction mixture was warmed to 0 °C and neutralized with additional 2% H2C2O4 (aq) to pH = 7−8. The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography (eluent EtOAc/hexanes, 1:10 + 1% Et3N) to provide 12 (235 mg, 0.49 mmol, 92%): Rf = 0.38 (EtOAc/hexanes, 1:6); mp = 143−145 °C; [α]27 D −193.5 (c 1.0, CH2Cl2); IR (neat) 2969, 2935, 2885, 1736, 1728, −1 1 1677, 1628, 1436, 1367 cm ; H NMR (400 MHz, CDCl3) δ 4.17 (septet, J = 6.8 Hz, 1H), 3.62 (d, J = 7.2 Hz, 1H), 3.56 (s, 3H), 3.25 (septet, J = 6.8 Hz, 1H), 2.62−2.39 (m, 3H), 2.17−2.01 (m, 2H), 1.96−1.85 (m, 2H), 1.81−1.69 (m, 2H), 1.37 (s, 9H), 1.35 (d, J = 6.8 Hz, 3H), 1.29 (d, J = 6.8 Hz, 3H), 1.23−1.15 (m, 1H), 1.12 (d, J = 6.8 Hz, 3H), 1.09 (s, 3H), 1.06 (s, 3H), 0.99 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 180.8, 173.4, 169.8, 169.7, 80.6, 69.0, 65.3, 51.2, 50.4, 48.0, 45.9, 43.9, 37.0, 35.6, 33.0, 28.5, 27.9, 27.3, 21.6, 21.5, 20.8, 20.3, 20.2, 16.7; HRMS (ESI) m/z [M + H]+ calcd for C27H47N2O5 479.3479, found 479.3488. 1-tert-Butyl Methyl (2S,3S)-N-2-(((1S,4R)-1-(N,N-Diisopropylaminocarbonyl)-7,7-dimethyl-bicyclo[2.2.1]heptan-2-ylidene)amino)3-propyl-glutamate (8b). Starting with a solution of iminoglycinate 4 (0.2 g, 0.53 mmol) in THF (1.0 mL) and following the same procedure as in the synthesis of 12 provided 8b (0.177 g, 0.35 mmol, 66%) as a white solid and 4 (42 mg, 0.16 mmol, 30%): Rf = 0.46 (EtOAc/hexanes, 1:6); mp = 153−155 °C; [α]23 D −175.3 (c 1.0, CH2Cl2); IR (neat) 2960, 2935, 2878, 1735, 1720, 1629, 1435, 1375 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.23 (septet, J = 6.8 Hz, 1H), 3.86 (d, J = 6.8 Hz, 1H), 3.59 (s, 3H), 3.31 (septet, J = 6.8 Hz, 1H), 2.52−2.40 (m, 2H), 2.37−2.29 (m, 1H), 2.22−2.14 (m, 1H), 2.10− 2.02 (m, 1H), 1.99−1.86 (m, 3H), 1.76−1.71 (m, 1H), 1.41 (d, J = 6.8 Hz, 3H), 1.41 (s, 9H), 1.33 (d, J = 6.8 Hz, 3H), 1.25 (d, J = 6.4 Hz, 3H), 1.30−1.21 (m, 1H), 1.18 (s, 3H), 1.17 (s, 3H), 1.16−1.12 (m, 1H), 1.10 (d, J = 6.6 Hz, 3H), 1.06 (d, J = 6.6 Hz, 3H), 0.83 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 180.8, 173.7, 170.3, 167.9, 80.7, 68.5, 66.7, 51.2, 50.8, 48.4, 46.3, 43.7, 37.5, 35.6, 35.1, 33.4, 28.0, 27.8, 27.5, 21.5, 21.3, 21.0, 20.8, 20.7, 20.2, 14.1; HRMS (ESI) m/z [M + H]+ calcd for C29H51N2O5 507.3792, found 507.3796. Synthesis of Michael Acceptor 13. 3-((4-Methoxybenzyl)oxy)propan-1-ol (22). To a suspension of sodium hydride (60% in mineral oil, 1.22 g, 30.6 mmol) in dry THF (50 mL) was added TBAI (1.028 g, 2.78 mmol) at 0 °C, and the mixture was stirred for 5 min. A solution of 1,3-propanol (2 mL, 27.78 mmol) in THF (6 mL) was then added at 0 °C, and the mixture was warmed to room temperature for 30 min. After 30 min, the reaction mixture was again cooled to 0 °C, and p-methoxybenzyl chloride (3.76 mL, 27.85 mmol) was added slowly with additional stirring for 12 h. Finally, the reaction was quenched by the addition of ice water. The aqueous phase was separated and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (eluent EtOAc/hexanes, 2:1) to provide 22 (4.74 g, 24.17 mmol, 87%) as a colorless liquid: Rf = 0.36 (EtOAc/hexanes, 1:1); IR (neat) 3412, 2937, 2864, 1613, 1513, 1464, 1442, 1365, 1302, 1248, 1174, 1090, 1084 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 4.42 (s, 2H), 3.77 (s, 3H), 3.72 (t, J = 5.6 Hz, 2H), 3.60 (t, J = 5.8 Hz, 2H), 2.56 (br, 1H), 1.89−1.77 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 159.1, 130.1, 129.2, 113.7, 72.8, 68.9, 61.6, 55.2, 32.0; HRMS (ESI) m/z [M + Na]+ calcd for C11H16O3Na 219.0992, found 219.0995. Ethyl (E)-5-((4-Methoxybenzyl)oxy)pent-2-enoate (13). To a 100 mL round-bottom flask containing DMSO (2.52 mL, 35.61 mmol) and DCM (30 mL) was slowly added oxalyl chloride (1.52 mL, 17.80 mmol) at −78 °C. After the reaction mixture was stirred for 30 min, a solution of 22 (2.33 g, 11.87 mmol) in DCM (9 mL) was added. After the mixture was stirred for 1 h, triethylamine (6.7 mL, 47.48 mmol) was added, and the solution was slowly warmed to 0 °C for 1 h. The reaction mixture was quenched by the addition of a saturated

HRMS (ESI) m/z [M + H]+ calcd for C29H51N2O5 507.3792, found 507.3796. 1-tert-Butyl Methyl (2R,3S)-N-2-(((1S,4R)-1-(N,N-Diisopropylaminocarbonyl)-7,7-dimethyl-bicyclo[2.2.1]heptan-2-ylidene)amino)3-isopropyl-glutamate (9). Starting with a solution of iminoglycinate 4 (0.2 g, 0.53 mmol) in THF (1.0 mL) and following the same procedure as in the synthesis of 7 provided 9 (0.19 g, 0.37 mmol, 71%) as a white solid and recovered 4 (0.03 g, 0.08 mmol, 15%): Rf = 0.43 (EtOAc/hexanes, 1:6); mp = 156−158 °C; [α]27 D +32.6 (c 1.0, CH2Cl2); IR (neat) 2966, 2938, 2883, 1739, 1730, 1630, 1474, 1368, 1335 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.17 (septet, J = 6.8 Hz, 1H), 3.87 (d, J = 6.8 Hz, 1H), 3.59 (s, 3H), 3.24 (septet, J = 6.8 Hz, 1H), 2.53 (dd, J = 16.0, 4.0 Hz, 1H), 2.50−2.30 (m, 2H), 2.23 (dd, J = 16.0, 6.8 Hz, 1H), 2.18−2.04 (m, 1H), 1.99−1.83 (m, 2H), 1.77 (d, J = 16.8 Hz, 1H), 1.73−1.64 (m, 1H), 1.38 (d, J = 6.8 Hz, 3H), 1.34 (s, 9H), 1.29 (d, J = 6.8 Hz, 3H), 1.26−1.24 (m, 2H), 1.22 (d, J = 6.8 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H), 1.13 (s, 3H), 1.06 (s, 3H), 1.00 (d, J = 6.8 Hz, 3H), 0.82 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 180.8, 173.5, 170.0, 169.8, 81.0, 67.8, 65.6, 51.6, 51.3, 48.0, 46.0, 44.0, 43.0, 37.9, 36.6, 34.9, 32.7, 27.8, 21.9, 21.8, 20.8, 20.7, 20.6, 20.4, 20.3, 19.8, 14.3; HRMS (ESI) m/z [M + H]+ calcd for C29H51N2O5 507.3792, found 507.3799. 1-tert-Butyl Methyl (2R,3S)-N-2-(((1S,4R)-1-(N,N-Diisopropylaminocarbonyl)-7,7-dimethyl-bicyclo[2.2.1]heptan-2-ylidene)amino)3-phenyl-glutamate (10). Starting with a solution of iminoglycinate 4 (0.2 g, 0.53 mmol) in THF (1.0 mL) and following the same procedure as in the synthesis of 7 provided 10 (0.24 g, 0.45 mmol, 84%) as a white solid: Rf = 0.36 (EtOAc/hexanes, 1:6); mp = 162− 163 °C; [α]23 D −6.3 (c 1.0, CH2Cl2); IR (neat) 2994, 2971, 2932, 1742, 1728, 1686, 1436, 1425, 1365, 1334 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.24−7.12 (m, 5H), 3.98 (d, J = 10.4 Hz, 1H), 3.94 (septet, J = 6.8 Hz, 1H), 3.64 (dt, J = 10.4, 4.0 Hz, 1H), 3.46 (s, 3H), 3.26 (septet, J = 6.8 Hz, 1H), 2.84 (dd, J = 15.6, 4.4 Hz, 1H), 2.70 (dd, J = 15.6, 10.8 Hz, 1H), 2.40−2.32 (m, 1H), 1.77−1.73 (m, 1H), 1.63− 1.58 (m, 1H), 1.48−1.44 (m, 1H), 1.34 (s, 9H), 1.32 (d, J = 8.8 Hz, 3H), 1.30 (d, J = 8.8 Hz, 3H), 1.25 (d, J = 6.8 Hz, 3H), 1.15−1.11 (m, 3H), 1.05 (s, 3H), 0.96 (s, 3H), 0.94 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 180.7, 172.0, 170.0, 169.7, 140.7, 128.8, 127.9, 127.0, 81.5, 71.0, 65.6, 51.5, 51.2, 47.8, 46.1, 44.0, 43.6, 37.4, 36.1, 28.6, 27.9, 26.8, 22.0, 21.9, 20.7, 20.6, 20.2; HRMS (ESI) m/z [M + H]+ calcd for C32H49N2O5 541.3644, found 541.3636. 1-tert-Butyl 2,3-Dimethyl (2R,3S)-N-2-(((1S,4R)-1-(N,N-Diisopropylaminocarbonyl)-7,7-dimethyl-bicyclo[2.2.1]heptan-2-ylidene)amino)propane-1,2,3-tricarboxylate (11). Starting with a solution of iminoglycinate 4 (0.2 g, 0.53 mmol) in THF (1.0 mL) and following the same procedure as in the synthesis of 7 provided 11 (0.23 g, 0.44 mmol, 83%): Rf = 0.24 (EtOAc/hexanes, 1:6); mp = 160−162 °C; [α]25 D −114.3 (c 1.0, CH2Cl2); IR (neat) 2970, 1736, 1676, 1475, 1437, 1368, 1335, 1150 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.14 (d, J = 8.0 Hz, 1H), 4.13 (septet, J = 6.4 Hz, 1H), 3.64 (s, 6H), 3.39− 3.20 (m, 1H), 3.27 (septet, J = 6.4 Hz, 1H), 2.72 (dd, J = 6.0, 2.0 Hz, 1H), 2.52−2.45 (m, 1H), 2.12 (dt, J = 12.0, 4.0 Hz, 1H), 1.98−1.88 (m, 1H), 1.87−1.78 (m, 1H), 1.84 (d, J = 16.8 Hz, 1H), 1.75−1.70 (m, 1H), 1.36 (s, 9H), 1.35 (d, J = 6.4 Hz, 3H), 1.31 (d, J = 6.8 Hz, 3H), 1.28−1.19 (m, 2H), 1.18 (s, 3H), 1.16 (d, J = 6.4 Hz, 3H), 1.11 (s, 3H), 1.02 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 182.5, 173.2, 172.1, 169.5, 168.4, 82.0, 66.3, 65.5, 51.8, 51.7, 51.6, 48.0, 46.0, 44.2, 43.9, 36.1, 32.8, 29.0, 27.8, 27.1, 21.8, 21.6, 20.7, 20.6, 20.4, 20.3; HRMS (ESI) m/z [M + H]+ calcd for C28H47N2O7 523.3378, found 523.3378. General Procedures for the Synthesis of Michael Adduct 12 Using MDA. 1-tert-Butyl Methyl (2S,3S)-N-2-(((1S,4R)-1-(N,NDiisopropylaminocarbonyl)-7,7-dimethyl-bicyclo[2.2.1]heptan-2ylidene)amino)-3-methyl-glutamate (12). A solution of MDA in THF was prepared under argon with diisopropylamine (0.1 mL, 0.69 mmol), THF (1.3 mL), and methylmagnesium bromide (3.0 M solution in THF, 0.21 mL, 0.64 mmol) at 0 °C. After stirring for 30 min, the solution was cooled to −78 °C with a dry ice−acetone bath. A solution of iminoglycinate 4 (0.2 g, 0.53 mmol) in THF (1.0 mL) was added over 20 min, and the mixture was stirred for 1 h; then a solution of methyl crotonate (0.07 mL, 0.69 mmol) in THF (1 mL) 10568

DOI: 10.1021/acs.joc.8b01383 J. Org. Chem. 2018, 83, 10564−10572

Note

The Journal of Organic Chemistry sodium bicarbonate solution (10 mL); then the organic layer was washed with brine (3 × 20 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was used without purification. To a 50 mL round-bottom flask containing NaH (60% in mineral oil, 522 mg, 13.06 mmol) and THF (20 mL) was added triethylphosphonoacetate (2.8 mL, 14.24 mmol) at 0 °C. The mixture was stirred for 30 min; then a solution of crude aldehyde in THF (5.7 mL) was added. After stirring for additional 30 min, the reaction mixture was quenched by the addition of a saturated aqueous ammonium chloride solution (10 mL) and brine (10 mL). The aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (eluent EtOAc/hexanes, 1:3) to provide 13 (2.38 g, 9.02 mmol, 76%) as a colorless liquid: Rf = 0.56 (EtOAc/ hexanes, 1:2); IR (neat) 2937, 2905, 2859, 1718, 1655, 1612, 1513, 1248, 1175, 1096, 1037 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.6 Hz, 2H), 6.94 (dt, J = 15.7, 7.0 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 5.86 (dt, J = 15.7, 1.5 Hz, 1H), 4.42 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 3.77 (s, 3H), 3.52 (t, J = 6.5 Hz, 2H), 2.46 (qd, J = 6.6, 1.6 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.4, 159.1, 145.6, 130.1, 129.2, 122.8, 113.7, 72.6, 67.9, 60.1, 55.2, 32.5, 14.2; HRMS (ESI) m/z [M + Na]+ calcd for C15H20O4Na 287.1254, found 287.1250. Syntheses of (+)-α-Allokainic Acid 1 and (−)-2-epi-α-Allokainic Acid 6 1-tert-Butyl Ethyl (2R,3S)-N-2-(((1S,4R)-1-(N,N-Diisopropylaminocarbonyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-ylidene)amino)-3-(2-((4-methoxy-benzyl)oxy)ethyl)glutamate (14a). A solution of LDA in THF was prepared under argon with diisopropylamine (0.55 mL, 3.96 mmol), THF (4.2 mL), and n-BuLi solution (2.3 M solution in hexane, 1.61 mL, 3.70 mmol) at 0 °C. After stirring for 30 min, the solution was cooled to −78 °C with a dry ice−acetone bath, and a solution of iminoglycinate 4 (1.0 g, 2.64 mmol) in THF (1.8 mL) was added over 20 min. The mixture was stirred for 30 min, and then the solution of 13 (0.84 g, 3.17 mmol) in THF (0.8 mL) was added slowly. The mixture was stirred for 4 h at −78 °C, and then a solution of 2% H2C2O4 (aq) (10 mL) was added. The reaction mixture was warmed to 0 °C and then was neutralized with additional 2% H2C2O4 (aq) to pH = 6−7. The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography (eluent EtOAc/hexanes, 1:8 + 1% Et3N) to provide 14a (1.42 g, 2.21 mmol, 84%) as a colorless liquid: Rf = 0.22 (EtOAc/hexanes, 1:6); [α]21 D −4.8 (c 1.0, CH2Cl2); IR (neat) 2969, 2936, 1734, 1628, 1513, 1438, 1367, 1335, 1248, 1160 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 7.7 Hz, 2H), 6.82 (d, J = 7.7 Hz, 2H), 4.39−4.35 (m, 2H), 4.16 (septet, J = 6.4 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.90 (d, J = 6.4 Hz, 1H), 3.76 (s, 3H), 3.55−3.38 (m, 2H), 3.35−3.20 (m, 1H), 2.68−2.39 (m, 3H), 2.31 (dd, J = 15.9, 4.0 Hz, 1H), 2.21−2.06 (m, 1H), 2.02−1.82 (m, 3H), 1.80−1.58 (m, 4H), 1.43 (d, J = 6.8 Hz, 2H), 1.39−1.35 (m, 2H), 1.37 (s, 9H), 1.32 (d, J = 6.4 Hz, 3H), 1.21 (d, J = 6.4 Hz, 3H), 1.25−1.15 (m, 2H), 1.16 (s, 3H), 1.09 (s, 3H), 1.01 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 181.2, 172.8, 169.9, 169.7, 159.0, 130.4, 129.1, 113.6, 81.1, 72.3, 67.8, 67.7, 65.5, 60.1, 55.1, 51.7, 48.0, 46.0, 44.0, 36.5, 35.7, 35.1, 30.2, 29.3, 27.8, 27.4, 27.1, 21.8, 20.8, 20.7, 20.4, 20.3, 14.2; HRMS (ESI) m/z [M + H]+ calcd for C37H59N2O7 643.4317, found 643.4331. 1-tert-Butyl Ethyl (2S,3S)-N-2-(((1S,4R)-1-(N,N-Diisopropylaminocarbonyl)-7,7-dimethyl-bicyclo[2.2.1]heptan-2-ylidene)amino)3-(2-((4-methoxy-benzyl)oxy)ethyl)glutamate (14b). A solution of MDA in THF was prepared under argon with diisopropylamine (0.56 mL, 3.96 mmol), THF (6.7 mL), and methylmagnesium bromide solution (1.0 M solution in THF, 3.7 mL, 3.70 mmol) at 0 °C. After stirring for 30 min, the solution was cooled to −78 °C with a dry ice− acetone bath, and a solution of iminoglycinate 4 (1.0 g, 2.64 mmol) in THF (1.8 mL) was added over 20 min. The mixture was stirred for 1 h, and then a solution of 13 (0.7 g, 2.64 mmol) in THF (2.6 mL) was added slowly. The mixture was warmed to −60 °C and stirred for an

additional 18 h; then a solution of 2% H2C2O4 (aq) (10 mL) was added. The reaction mixture was warmed to 0 °C and then neutralized with additional 2% H2C2O4 (aq) to pH = 7−8. The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (eluent EtOAc/hexanes, 1:8 + 1% Et3N) to provide 14b (1.19 g, 1.85 mmol, 70%) as a pale yellow liquid and 6 (0.2 g, 0.53 mmol, 20%): Rf = 0.23 (EtOAc/hexanes, 1:6); [α]21 D − 39.6 (c 1.0, CH2Cl2); IR (neat) 2969, 2935, 2885, 1732, 1627, 1513, 1367, 1365, 1247, 1155 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 4.45− 4.31 (m, 3H), 4.23 (septet, J = 6.8 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H), 3.96 (d, J = 6.2 Hz, 1H), 3.80 (s, 3H), 3.44 (t, J = 6.5 Hz, 1H), 3.34− 3.24 (m, 1H), 2.82−2.62 (m, 1H), 2.50 (dd, J = 16.0, 4.0 Hz, 1H), 2.45−2.30 (m, 2H), 2.15−2.05 (m, 1H), 2.03−1.87 (m, 1H), 1.79− 1.60 (m, 3H), 1.42 (s, 9H), 1.41 (d, J = 6.8 Hz, 3H), 1.34 (d, J = 6.8 Hz, 3H), 1.29−1.20 (m, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H), 1.12 (s, 3H), 1.09 (s, 3H), 1.04 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 181.2, 173.1, 170.1, 169.6, 159.0, 130.6, 129.3, 113.6, 80.7, 72.3, 68.1, 66.7, 65.4, 60.0, 55.2, 50.5, 48.1, 46.0, 44.0, 35.7, 35.7, 35.5, 35.2, 30.7, 28.6, 28.0, 27.4, 21.9, 21.6, 20.9, 20.3, 14.1; HRMS (HRFI) m/z [M] calcd for C37H58N2O7 642.4244, found 642.4239. tert-Butyl (2R,3S)-3-(2-((4-Methoxybenzyl)oxy)ethyl)-5-oxo-pyrrolidine-2-carboxylate (15a). A 25 mL flask was charged with 14a (1.0 g, 1.55 mmol) in THF (5.2 mL) and an aqueous solution of 15% citric acid (3.4 mL, 1.63 mmol). The mixture was stirred at room temperature for 9 days and then concentrated under reduced pressure to remove THF. The residue was dissolved in H2O (5 mL). The aqueous phase was adjusted to pH 7 using a saturated Na2CO3 solution then extracted with dichloromethane (2 × 30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude amino ester was dissolved in MeOH (7.8 mL) and refluxed for 6 h. Finally, MeOH was evaporated in vacuo, and the residue was purified by flash chromatography (eluent EtOAC/hexanes, 1:2 to DCM/MeOH, 10:1) to provide 15a (368 mg, 1.05 mmol, 68%) as a colorless liquid and auxiliary 16 (393 mg, 1.48 mmol, 95%): Rf = 0.16 (EtOAc/hexanes, 1:1); [α]23 D −8.1 (c 1.0, CH2Cl2); IR (neat) 3252, 2979, 2936, 2863, 2290, 1732, 1682, 1515, 1456, 1422, 1369, 1301, 1249, 1156, 1095, 1034 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 6.00 (br, 1H), 4.43 (d, J = 11.5 Hz, 1H), 4.40 (d, J = 11.5 Hz, 1H), 4.04 (d, J = 8.0 Hz, 1H), 3.80 (s, 3H), 3.56−3.41 (m, 2H), 2.92−2.79 (m, 1H), 2.33 (dd, J = 16.4, 8.2 Hz, 1H), 2.17 (dd, J = 16.4, 9.9 Hz, 1H), 1.93−1.82 (m, 1H), 1.63−1.52 (m, 1H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 178.3, 170.3, 159.2, 130.1, 129.2, 113.8, 82.5, 72.7, 67.4, 59.8, 55.2, 35.7, 34.9, 30.3, 28.0; HRMS (ESI) m/z [M + Na]+ calcd for C19H27NO5 Na 372.1781, found 372.1785. tert-Butyl (2S,3S)-3-(2-((4-Methoxybenzyl)oxy)ethyl)-5-oxo-pyrrolidine-2-carboxylate (15b). Starting with 14b (1.0 g, 1.55 mmol) and following the same procedure as in the synthesis of 15a provided 15b (381 mg, 1.09 mmol, 70%) as a colorless liquid and recovered auxiliary 16 (379 mg, 1.43 mmol, 92%): Rf = 0.11 (EtOAc/hexanes, 1:1); [α]23 D +17.8 (c 1.0, CH2Cl2); IR (neat) 3246, 2972, 2928, 2858, 1734, 1700, 1514, 1457, 1369, 1290, 1247, 1156, 1100, 1034 cm−1; 1 H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.35 (br, 1H), 4.42 (d, J = 11.5 Hz, 1H), 4.40 (d, J = 11.5 Hz, 1H), 3.82 (d, J = 5.6 Hz, 1H), 3.80 (s, 3H), 3.53−3.46 (m, 2H), 2.68−2.56 (m, 1H), 2.51 (dd, J = 16.6, 9.0 Hz, 1H), 2.02 (dd, J = 16.5, 6.6 Hz, 1H), 2.02−1.99 (m, 1H), 1.76−1.67 (m, 1H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 176.9, 170.7, 159.1, 130.2, 129.1, 113.7, 82.4, 72.6, 67.6, 61.4, 55.2, 36.5, 36.1, 34.6, 27.9; HRMS (ESI) m/z [M + Na]+ calcd for C19H27NO5Na 372.1786, found 372.1780. Di(tert-butyl) (2R,3S)-3-(2-((4-Methoxybenzyl)oxy)ethyl)-5-oxopyrrole-dine-1,2-dicarboxylate (17a). To a 10 mL round-bottom flask containing a solution of 15a (0.59 g, 1.67 mmol) in MeCN (5.5 mL) were added Boc2O (0.77 mL, 3.35 mmol) and DMAP (0.02 g, 10569

DOI: 10.1021/acs.joc.8b01383 J. Org. Chem. 2018, 83, 10564−10572

Note

The Journal of Organic Chemistry 0.17 mmol). The reaction mixture was cooled to 0 °C for 10 min, and then triethylamine (0.7 mL, 5.01 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 12 h. A saturated NaHCO3(aq) solution was added to the reaction mixture with stirring. The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (eluent EtOAc/hexanes, 1:2) to provide 17a (741 mg, 1.65 mmol, 99%) as a colorless liquid: Rf = 0.44 (EtOAc/hexanes, 1:1); [α]27 D −5.4 (c 1.0, CHCl3); IR (neat) 3521, 2980, 2934, 2877, 1790, 1761, 1696, 1583, 1542, 1515, 1456, 1372, 1316, 1160, 1030 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 4.43 (d, J = 11.5 Hz, 1H), 4.39 (d, J = 11.5 Hz, 1H), 4.37 (d, J = 8.4 Hz, 1H), 3.79 (s, 3H), 3.56−3.42 (m, 2H), 2.73−2.60 (m, 1H), 2.48 (dd, J = 16.9, 8.0 Hz, 1H), 2.36 (dd, J = 16.8, 12.7 Hz, 1H), 1.93−1.81 (m, 1H), 1.73−1.63 (m, 1H), 1.49 (s, 9H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 173.3, 170.0, 159.2, 149.2, 130.0, 129.3, 113.8, 83.3, 82.6, 72.7, 67.2, 63.3, 55.2, 37.3, 31.6, 30.4, 28.0, 27.9; HRMS (ESI) m/z [M + Na]+ calcd for C24H35NO7Na 472.2306, found 472.2313. Di(tert-butyl) (2S,3S)-3-(2-((4-Methoxybenzyl)oxy)ethyl)-5-oxopyrrolidine-1,2-dicarboxylate (17b). Starting with 15b (423 mg, 1.2 mmol) and following the same procedure as in the synthesis of 17a provided 17b (510 mg, 1.14 mmol, 95%) as a pale yellow liquid: Rf = 0.49 (EtOAc/hexanes, 1:1); [α]26 D −2.3 (c 1.0, CHCl3); IR (neat) 2979, 2927, 2853, 1792, 1734, 1717, 1700, 1559, 1508, 1457, 1369, 1313, 1249, 1155, 1034 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 4.42 (d, J = 11.5 Hz, 1H), 4.36 (d, J = 11.5 Hz, 1H), 4.19 (d, J = 3.2 Hz, 1H), 3.76 (s, 3H), 3.54−3.44 (m, 2H), 2.69 (dd, J = 17.5, 8.9 Hz, 1H), 2.42−2.33 (m, 1H), 2.18 (dd, J = 17.5, 3.8 Hz, 1H), 1.93−1.83 (m, 1H), 1.72−1.61 (m, 1H), 1.46 (s, 9H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.9, 169.8, 159.1, 149.2, 129.9, 129.0, 113.6, 83.2, 82.0, 72.6, 66.9, 64.7, 55.1, 37.5, 34.6, 32.0, 27.8, 27.7; HRMS (ESI) m/z [M + Na]+ calcd for C24H35NO7Na 472.2311, found 472.2303. Di(tert-butyl) (2R,3S,4R)-4-(2-Hydroxypropan-2-yl)-3-(2-((4methoxybenzyl)oxy)ethyl)-5-oxopyrrolidine-1,2-dicarboxylate (18a). To a 25 mL round-bottom flask containing 17a (624 mg, 1.39 mmol) in THF (3.6 mL) was dropwise added LHMDS (1.06 M solution in THF, 1.7 mL, 1.81 mmol) at −78 °C. The resulting mixture was stirred for 1 h before the solution of BF3·OEt2 (0.34 mL, 2.78 mmol) and acetone (0.2 mL, 2.78 mmol) in THF (1.0 mL) was added dropwise at −78 °C. After 7 h, the reaction mixture was quenched with the addition of a saturated NH4Cl solution (5 mL), and the aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (eluent DCM/EtOAc, 7:2) to give 18a (605 mg, 1.14 mmol, 82%) as a colorless liquid: Rf = 0.42 (EtOAc/hexanes, 1:1); [α]27 D −18.0 (c 0.9, CHCl3); IR (neat) 3491, 2978, 2936, 2871, 1789, 1736, 1696, 1613, 1514, 1459, 1370, 1305, 1254, 1158 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 4.46 (d, J = 11.5 Hz, 1H), 4.40 (d, J = 11.5 Hz, 1H), 4.35 (d, J = 8.3 Hz, 1H), 3.79 (s, 3H), 3.57 (dd, J = 7.6, 4.5 Hz, 2H), 2.59−2.42 (m, 2H), 2.19−2.07 (m, 1H), 1.64−1.54 (m, 1H), 1.50 (s, 9H), 1.45 (s, 9H), 1.26 (s, 3H), 1.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.9, 169.0, 159.2, 149.0, 130.1, 129.2, 113.8, 83.9, 82.9, 72.7, 72.2, 66.9, 61.8, 55.9, 55.2, 33.5, 30.6, 28.2, 27.9, 27.8, 25.9; HRMS (ESI) m/z [M + Na]+ calcd for C27H41NO8 Na 530.2724, found 530.2722. Di(tert-butyl) (2S,3S,4R)-4-(2-Hydroxypropan-2-yl)-3-(2-((4methoxybenzyl)oxy)ethyl)-5-oxopyrrolidine-1,2-dicarboxylate (18b). Starting with 17b (373 mg, 0.83 mmol) and following the same procedure as in the synthesis of 18a provided 18b (323 mg, 0.64 mmol, 77%): Rf = 0.35 (EtOAc/hexanes, 1:1); [α]26 D −4.0 (c 1.0, CHCl3); IR (neat) 2976, 2930, 2861, 1784, 1734, 1700, 1515, 1457, 1369, 1307, 1249, 1156 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 4.42 (d, J = 11.2 Hz, 1H), 4.38(d, J = 11.2 Hz, 1H), 4.14 (d, J = 4.4 Hz, 1H), 4.01 (br, 1H), 3.77 (s, 3H), 3.60 (t, J = 5.3 Hz, 2H), 2.45 (d, J = 6.1 Hz, 1H),

2.22−2.13 (m, 1H), 2.01−1.91 (m, 1H), 1.87−1.76 (m, 1H), 1.48 (s, 9H), 1.44 (s, 9H), 1.21 (s, 3H), 1.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.0, 169.9, 159.1, 148.9, 129.9, 129.0, 113.6, 83.7, 82.2, 72.6, 72.0, 66.8, 63.6, 58.3, 55.1, 36.8, 34.1, 27.7, 27.0, 26.1; HRMS (ESI) m/z [M + Na]+ calcd for C27H41NO8 Na 530.2729, found 530.2722. Di(tert-butyl) (2R,3S,4R)-3-(2-((4-Methoxybenzyl)oxy)ethyl)-5oxo-4-(prop-1-en-2-yl)pyrrolidine-1,2-dicarboxylate (19a). To a stirred solution of alcohol 18a (283 mg, 0.56 mmol) in toluene (6 mL) was added Burgess reagent18a (405 mg, 1.70 mmol). The mixture was stirred at 110 °C for 10 min and then cooled to room temperature. After the mixture cooled, the solvent was evaporated and the residue was purified by flash chromatography (EtOAc/hexanes, 1:1) to give 19a (233 mg, 0.48 mmol, 85%) as a colorless liquid: Rf = 0.56 (EtOAc/hexanes, 1:1); [α]24 D −25.0 (c 1.0, CH2Cl2); IR (neat) 2978, 2936, 1793, 1735, 1514, 1457, 1369, 1313, 1250, 1157 cm−1; 1 H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.04 (s, 1H), 4.90 (s, 1H), 4.46−4.33 (m, 3H), 3.79 (s, 3H), 3.57 (t, J = 6.0 Hz, 2H), 3.12 (d, J = 12.7 Hz, 1H), 2.73−2.60 (m, 1H), 1.81−1.72 (m, 1H), 1.71 (s, 3H), 1.69−1.56 (m, 1H), 1.49 (s, 9H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.9, 169.0, 159.2, 149.3, 139.2, 130.2, 129.2, 117.6, 113.7, 83.3, 82.6, 72.5, 66.5, 61.4, 56.0, 55.2, 34.4, 29.4, 28.0, 18.9; HRMS (ESI) m/z [M + Na]+ calcd for C27H39NO7Na 5 12.2619, found 512.2631. Di(tert-butyl) (2S,3S,4R)-3-(2-((4-Methoxybenzyl)oxy)ethyl)-5oxo-4-(prop-1-en-2-yl)pyrrolidine-1,2-dicarboxylate (19b). Starting with 18b (303 mg, 0.60 mmol) and following the same procedure as in the synthesis of 19a provided 19b (254 mg, 0.52 mmol, 87%) as a colorless liquid: Rf = 0.51 (EtOAc/hexanes, 1:1); [α]25 D −9.2 (c 1.0, CH2Cl2); IR (neat) 2978, 2936, 1792, 1742, 1514, 1369, 1311, 1249, 1157 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 4.96 (s, 1H), 4.87 (s, 1H), 4.40 (d, J = 11.5 Hz, 1H), 4.36 (d, J = 11.2 Hz, 1H), 4.10 (d, J = 6.4 Hz, 1H), 3.77 (s, 3H), 3.53 (t, J = 6.2 Hz, 2H), 2.98 (d, J = 8.3 Hz, 1H), 2.41−2.31 (m, 1H), 2.02−1.91 (m, 1H), 1.88−1.79 (m, 1H), 1.71 (s, 3H), 1.49 (s, 9H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.4, 169.8, 159.1, 149.3, 140.0, 130.1, 129.1, 116.3, 113.6, 83.4, 82.0, 72.4, 66.4, 63.5, 57.4, 55.0, 35.8, 34.1, 27.7, 19.4; HRMS (ESI) m/z [M + Na]+ calcd for C27H39NO7Na 512.2619, found 512.2630. Di(tert-butyl) (2R,3S,4R)-3-(2-((4-Methoxybenzyl)oxy)ethyl)-4(prop-1-en-2-yl)-pyrrolidine-1,2-dicarboxylate (20a). To a solution of 19a (0.20 g, 0.41 mmol) in THF (4.1 mL) was added DIBAL-H (1.0 M solution in toluene, 3.28 mL, 3.28 mmol) at −78 °C under an argon atmosphere. After 90 min, the reaction mixture was quenched with saturated potassium sodium tartrate (aq) and warmed to room temperature. The reaction mixture was stirred vigorously for 1 h, and the two phases were separated. The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was used without purification. The above crude product (0.20 g) was dissolved in DCM (3.1 mL), and Et3SiH (0.13 mL, 0.82 mmol) was added at −78 °C. After 15 min, a solution of BF3·OEt2 (0.1 mL, 0.82 mmol) in CH2Cl2 (1.0 mL) was added dropwise under an argon atmosphere. The resulting mixture was stirred for 2 h at −78 °C and quenched with a saturated NaHCO3 (aq) solution. The aqueous layer was separated and extracted with CH2Cl2 (3 × 10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (eluent EtOAc/hexanes, 1:3) to give 20a (176 mg, 0.37 mmol, 2 steps for 90%) as a colorless liquid: Rf = 0.70 (EtOAc/ hexanes, 1:3); [α]26 D − 33.1 (c 1.30, CH2Cl2); IR (neat) 2976, 2933, 2857, 1738, 1730, 1614, 1515, 1456, 1394, 1367, 1301, 1249, 1172, 1158, 1135 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 4.85 (s, 2H), 4.46−4.35 (m, 2H), 4.25 and 4.16 (d, J = 8.2 Hz, 1H), 3.78 (s, 3H), 3.75−3.48 (m, 3H), 3.26− 3.06 (m, 1H), 2.86−2.70 (m, 1H), 2.55−2.39 (m, 1H), 1.83−1.71 (m, 2H), 1.67 (s, 3H), 1.45 (s, 9H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.0, 159.1, 153.7, 142.2, 130.5, 129.2, 114.1, 113.8, 81.4, 79.8, 72.5, 67.8, 62.9, 55.3, 49.7, 48.9, 41.4, 28.7, 28.4, 28.1, 10570

DOI: 10.1021/acs.joc.8b01383 J. Org. Chem. 2018, 83, 10564−10572

Note

The Journal of Organic Chemistry 18.5; HRMS (ESI) m/z [M + Na]+ calcd for C27H41NO6 Na 498.2826, found 498.2836. Di(tert-butyl) (2S,3S,4R)-3-(2-((4-Methoxybenzyl)oxy)ethyl)-4(prop-1-en-2-yl)pyrrolidine-1,2-dicarboxylate (20b). Starting with 19b (137 mg, 0.28 mmol) and following the same procedure as in the synthesis of 20a provided 20b (110 mg, 0.23 mmol, 2 steps for 82%) as a colorless liquid: Rf = 0.66 (EtOAc/hexanes, 1:1); [α]25 D −27.2 (c 1.0, CH2Cl2); IR (neat) 2976, 2935, 1736, 1701, 1514, 1394, 1366, 1248, 1172, 1157, 1135, 1092 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 4.83 (s, 2H), 4.37 (s, 2H), 3.86−3.78 (m, 1H), 3.76 (s, 3H), 3.75−3.68 (m, 1H), 3.62− 3.43 (m, 2H), 3.22 (td, J = 10.8, 3.6 Hz, 1H), 2.55−2.42 (m, 1H), 2.34−2.19 (m, 1H), 1.91−1.70 (m, 2H), 1.67 (s, 3H), 1.43 (s, 9H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.1, 158.9, 153.5, 142.0, 130.4, 128.9, 113.6, 113.6, 80.9, 79.8, 72.2, 67.4, 65.4, 55.1, 51.4, 50.3, 43.9, 32.8, 28.2, 27.9, 19.1; HRMS (ESI) m/z [M + Na]+ calcd for C27H41NO6Na 498.2826, found 498.2829. Di(tert-butyl) (2R,3S,4R)-3-(2-Hydroxyethyl)-4-(prop-1-en-2-yl)pyrrolidine-1,2-dicarboxylate (21a). To a mixed solution containing 20a (58 mg, 0.12 mmol), DCM (1.1 mL), and H2O (0.06 mL) was added DDQ (40 mg, 0.18 mmol) at 0 °C. The mixture was stirred at room temperature for 2 h and then quenched with a saturated NaHCO3 solution (5 mL) and filtered, and the collected solids were washed with CH2Cl2 (20 mL). The filtrate was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent EtOAc/hexanes, 1:2) to give 21a (39 mg, 0.11 mmol, 90%) as a pale yellow liquid: Rf = 0.45 (EtOAc/ hexanes, 1:1); [α]27 D −31.9 (c 0.3, CH2Cl2); IR (neat) 3460, 2977, 2931, 2857, 1733, 1704, 1479, 1455, 1394, 1368, 1299, 1259, 1221, 1172, 1159, 1136 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.77 (s, 2H), 4.23 (dd, J = 17.8, 8.1 Hz, 1H), 3.70−3.50 (m, 3H), 3.09 (t, J = 10.2 Hz, 1H), 2.96−2.74 (br, 1H), 2.73−2.59 (m, 1H), 2.49−2.29 (m, 1H), 1.59 (s, 3H), 1.65−1.53 (m, 2H), 1.39 (s, 9H), 1.33 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 171.1, 153.6, 141.8, 114.1, 81.6, 79.7, 62.9, 60.5, 49.3, 48.8, 41.5, 31.1, 28.1, 27.9, 18.2; HRMS (ESI) m/z [M + Na]+ calcd for C19H33NO5Na 378.2251, found 378.2261. Di(tert-butyl) (2S,3S,4R)-3-(2-Hydroxyethyl)-4-(prop-1-en-2-yl)pyrrolidine-1,2-dicarboxylate (21b). Starting with 20b (74 mg, 0.15 mmol) and following the same procedure as in the synthesis of 21a provided 21b (46 mg, 0.13 mmol, 85%) as a pale yellow liquid: Rf = 0.44 (EtOAc/hexanes, 1:1); [α]19 D −14.0 (c 1.0, CH2Cl2); IR (neat) 3474, 2978, 2933, 2886, 1739, 1702, 1404, 1368, 1255, 1171, 1156, 1133 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.85 (m, 2H), 3.93 (dd, J = 14.8, 7.7 Hz, 1H), 3.82−3.57 (m, 3H), 3.23−3.13 (m, 1H), 2.54− 2.41 (m, 1H), 2.22−2.12 (m, 1H), 1.88−1.76 (m, 1H), 1.73−1.53 (m, 2H), 1.69 (s, 3H), 1.46 (s, 9H), 1.41 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 173.2, 153.6, 142.0, 113.8, 81.7, 80.1, 65.0, 60.8, 52.0, 50.0, 45.1, 36.4, 28.3, 28.0, 19.3; HRMS (ESI) m/z [M + Na]+ calcd for C19H33NO5Na 378.2251, found 378.2255. (−)-2-epi-α-Allokainic Acid (6). To a solution of 21a (52 mg, 0.15 mmol) in acetone (1.50 mL) was dropwise added a freshly prepared Jones reagent (2.50 M in H2O, 0.11 mL, 0.28 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h, then quenched with 2-propanol, and filtered through a plug of Celite. To the filtrate was added water (1 mL), and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude carboxylic acid, which was directly employed in the next step. To a solution of the crude dicarboxylic acid in DCM (2.9 mL) was added TFA (0.14 mL, 1.73 mmol) at room temperature. The mixture was heated for 2 h at 40 °C and concentrated in vacuo to give crude allokainic acid. The residue was purified using Dowex-50 H+ (100− 200 wet mesh) column chromatography (elution with 1 N NH4OH) to give 6 (26 mg, 0.12 mmol, 80% for 2 steps) as a white solid: [α]24 D −15.8 (c 0.8, D2O); 1H NMR (400 MHz, D2O) δ 4.99 (s, 1H), 4.94 (s, 1H), 4.28 (d, J = 8.0 Hz, 1H), 3.66 (dd, J = 12.0, 8.4 Hz, 1H), 3.29 (t, J = 10.0 Hz, 1H), 2.87−2.75 (m, 2H), 2.43 (dd, J = 16.0, 6.8 Hz, 1H), 2.33 (dd, J = 16.0, 7.6 Hz, 1H), 1.74 (s, 3H); 13C NMR (100 MHz, D2O) δ 175.5, 170.1, 139.5, 114.7, 61.3, 48.4, 47.8, 39.5, 32.8,

17.3; HRMS (ESI) m/z [M + H]+ calcd for C10H16NO4 214.1079, found 214.1076. (+)-α-Allokainic Acid (1). To a solution of 21b (65 mg, 0.18 mmol) in acetone (1.80 mL) was dropwise added a freshly prepared Jones reagent (2.50 M in H2O, 0.14 mL, 0.36 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h, then quenched with 2-propanol, and filtered through a plug of Celite. To the filtrate was added water (1 mL), and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude carboxylic acid, which was directly employed in the next step. To a solution of the crude dicarboxylic acid in DCM (3.60 mL) was added TFA (0.17 mL, 2.16 mmol) at room temperature. The mixture was heated for 2 h at 40 °C and evaporated in vacuo to give crude allokainic acid. The residue was purified using Dowex-50 H+ (100− 200 wet mesh) column chromatography (elution with 1 N NH4OH) to give 1 (31 mg, 0.15 mmol, 82% for 2 steps) as a colorless oil: [α]24 D +7.8 (c 1.0, H2O) {lit.7 [α]D +7.7 (c, 0.2, H2O) or lit.7 [α]D +7.1 (c, 0.1, H2O)}; 1H NMR (400 MHz, D2O) δ 4.93 (s, 1H), 4.91 (s, 1H), 3.88 (d, J = 8.6 Hz, 1H), 3.52−3.45 (m, 1H), 3.30 (t, J = 11.0 Hz, 1H), 2.83 (dt, J = 10.0, 8.1 Hz, 1H), 2.71−2.56 (m, 2H), 2.35 (dd, J = 14.7, 7.8 Hz, 1H), 1.70 (s, 3H); 13C NMR (125 MHz, D2O) δ 179.0, 173.7, 140.6, 114.7, 64.9, 51.5, 48.2, 42.6, 39.4, 17.7; HRMS (ESI) m/ z [M + H]+ calcd for C10H16NO4 214.1079, found 214.1076.

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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.8b01383. Crystal data for 6 (CIF) Crystal data for 10 (CIF) Crystal data for 12 (CIF) Copies of the 1H and 13C NMR spectra for all new compounds and X-ray crystallographic data for compounds 6, 10, and 12 (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Yu-Fu Liang: 0000-0001-9116-9239 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Ministry of Science and Technology, Taiwan for financial support (MOST 106-2113-M-007-003). REFERENCES

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DOI: 10.1021/acs.joc.8b01383 J. Org. Chem. 2018, 83, 10564−10572

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The Journal of Organic Chemistry

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DOI: 10.1021/acs.joc.8b01383 J. Org. Chem. 2018, 83, 10564−10572