(+)-Î±-Allokainic Acid and - ACS Publications - American Chemical

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Total Syntheses of (+)-#-Allokainic Acid and (–)-2-epi-#Allokainic Acid Employing Ketopinic Amide as Chiral Auxiliary Yu-Fu Liang, Chuang-Chung Chung, De-Jhong Liao, Woo-Jer Lee, Yu-Wei Tu, and Biing-Jiun Uang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01383 • Publication Date (Web): 30 Jul 2018 Downloaded from http://pubs.acs.org on July 30, 2018

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The Journal of Organic Chemistry

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

ABSTRACT: Asymmetric Michael reaction of iminoglycinate 4 to α,β-unsaturated esters had been developed with >98:98:98:2 to 2:1 between 12 and 7 was observed (Table 4, entry 1). 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 C2 position when the Michael reaction was conducted in the presence of 15-crown-5 (Table 4, entry 3). The replacement of lithium ion with magnesium ion resulted in a reverse of selectivity for Michael reaction at C2. A plausible chelated transition state model was proposed as shown in Scheme 5. Scheme 5 . A Plausible Transition State of Michael Addition with MDA. Cα-si sterically favored

CO2 Me H CO2Me

H H

Me 4

H (Pri)2N

N O

MDA

Ot-Bu Mg

O

O

Mg

t-BuO

N H

N(iPr)2

Cα-re sterically disfavored

Ot-Bu

Me O

Mg

O

4-Mg

O

N

N O

MeO2C

.2

Br−

t-BuO H

x

N

Mg O N

4-Mg

T2

H+

H Me

12

3 ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Based on a previous report,20 magnesium enolate could gather to form dimeric complex. Imagine that dimeric magnesium enolate complex as a box, the less hinder moiety of chiral auxiliary was at the inner part of the box and more hindered gemdimethyl moiety of chiral auxiliary was at the outer part of the box. The attack of magnesium enolate was not easy to happen at re(Cα)-face (the inner part of the metal complex box) of enolate to si(Cβ)-face of α,β-unsaturated ester due to metal ion coordination with the other magnesium enolate. Therefore, the attack of enolate occurred at the more hindered si(Cα)-face of enolate to α,β-unsaturated 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. To extend this methodology further, a total synthesis of (+)-αallokainic acid 1 is illustrated on Scheme 6. With 14b in 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). Scheme 6. Total Synthesis of (+)-α -Allokainic acid 1.

The spectral data of (+)-α-allokainic acid are identical to those reported ones, and 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 auxiliary has been developed with excellent diastereoselectivity. Switching of stereoselectivity at C2 of the Michael adducts could be achieved by replacing lithium enolate with magnesium enolate. Utilization of this methodology for the total syntheses of (−)-2-epi-αallokainic 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. No. 7734 and 9385 silica gels were employed for flash chromatography. 1H NMR spectra were

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obtained and noted at 400 MHz (Bruker DPX-400 or VarianUnity-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 1 H 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 in a spectrophotometer Bomen MB 100 FT-IR and only noteworthy IR absorptions (cm-1) are listed. Optical rotations were measured on Perkin-Elmer 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)-2-(1-(N,N-diisopropylaminocarbonyl)-7,7dimethyl-bicyclo[2.2.1]hept-2-ylideneamino)ethanoate (4). To a 250 mL two-necked round-bottom flask was 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 Dean-Stark apparatus to remove water. After 2 h, tert-butyl glycinate (9 mL, 66.0 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, then was neutralized to pH = 6~7 by the addition of saturated NaHCO3 solution (40 mL). The aqueous layer was extracted with EtOAc (3 x 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 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]D22 – 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 = 6.8Hz, 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 Syntheses of Michael Adducts 7-11 Tert-butyl methyl (2R,3S)-N-2-(((1R,4R)-1-(N,N-diisopropylamino-carbonyl)-7,7-dimethyl-icyclo[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 nhexane, 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 then a 2% H2C2O4 (aq) solution (2 mL) was added to the reaction mixture and the temperature was


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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 x 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 white solid. Rf = 0.36 (EtOAc/hexanes, 1/6); mp = 142-145 °C; [α]D28 –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. Tert-butyl methyl (2R,3S)-N-2-(((1R,4R)-1-(N,N-diisopropylaminocarbonyl)-7,7-dimethyl-bicyclo[2.2.1]heptan-2ylidene)amino)-3-propyl-glutamate (8a). Starting with a solution of iminoglycinate 4 (0.2 g, 0.53 mmol) in THF (1.0 mL), and followed the same procedure as in the synthesis of 7 provided 8a (0.24 g, 0.48 mmol, 90 %) as white solid. Rf = 0.41 (EtOAc/hexanes, 1/6); mp = 150-151 °C; [α]D23 –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; HRMS (ESI) m/z: [M + H]+ Calcd for C29H51N2O5 507.3792; Found 507.3796. Tert-butyl methyl (2R,3S)-N-2-(((1R,4R)-1-(N,N-diisopropylaminocarbonyl)-7,7-dimethyl-bicyclo[2.2.1]heptan-2ylidene)amino)-3-isopropyl-glutamate (9). Starting with a solution of iminoglycinate 4 (0.2 g, 0.53 mmol) in THF (1.0 mL), and followed the same procedure as in the synthesis of 7 provided 9 (0.19 g, 0.37 mmol, 71 %) as white solid, and recovered 4 (0.03 g, 0.08 mmol, 15 %). Rf = 0.43 (EtOAc/hexanes, 1/6); mp = 156-158 °C; [α]D27 +32.6 (c 1.0, CH2Cl2); IR (neat) 2966, 2938, 2883, 1739, 1730, 1630, 1474, 1368, 1335 cm-1; 1H NMR (CDCl3, 400 MHz) 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 (CDCl3, 100 MHz) 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. Tert-butyl methyl (2R,3S)-N-2-(((1R,4R)-1-(N,N-diisopropylamino-carbonyl)-7,7-dimethyl-bicyclo[2.2.1]heptan-2ylidene)amino)-3-phenyl- glutamate (10). Starting with a solution of iminoglycinate 4 (0.2 g, 0.53 mmol) in THF (1.0 mL), and followed the same procedure as in the synthesis of 7 provided 10 (0.24 g, 0.45 mmol, 84 %) as white solid. Rf = 0.36 (EtOAc/hexanes, 1/6); mp = 162-163 °C; [α]D23 -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 7.247.12 (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. Tert-butyl 2,3-dimethyl (2R,3S)-N-2-(((1R,4R)-1-(N,N-diisopropylamino-arbonyl)-7,7-imethyl-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 followed 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]D25 -114.3 (c 1.0, CH2Cl2); IR (neat) 2970, 1736, 1676, 1475, 1437, 1368, 1335, 1150 cm1 1 ; H 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), 2.522.45 (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 Tert-butyl methyl (2S,3S)-N-2-(((1R,4R)-1-(N,N-diisopropylamino-carbonyl)-7,7-dimethyl-bicyclo[2.2.1]heptan-2-ylidene)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 (0.2g, 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) was added slowly. The mixture was stirred at –78 °C for 18 h, 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 x 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]D 27 –193.5 (c 1.0, CH2Cl2); IR (neat) 2969, 2935, 2885, 1736, 1728, 1677, 1628, 1436, 1367 cm-1; 1H 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. Tert-butyl methyl (2S,3S)-N-2-(((1R,4R)-1-(N,N-diisopropylamino-carbonyl)-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 followed the same procedure as in the synthesis of 12 provided 8b (0.177 g, 0.35 mmol, 66 %) as white solid and 4 (42 mg, 0.16 mmol, 30 %). Rf = 0.46 (EtOAc/hexanes, 1/6); mp = 153155 °C; [α]D23 –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),1.991.86 (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) ; 13 C 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 o C and stirred for 5 min. A solution of 1,3-propanol (2 mL, 27.78 mmol) in THF (6 mL) was then added at 0 oC and the mixture was warmed to room temperature for 30 min. After 30 min, reaction mixture was again cooled to 0 oC, and pmethoxybenzyl 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 iced water. The aqueous phase was separated and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water, 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 colorless liquid. Rf = 0.36 (EtOAc/hexanes, 1/1); IR (neat)

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3412, 2937, 2864, 1613, 1513, 1464, 1442, 1365, 1302, 1248, 1174, 1090, 1084 cm-1; 1H NMR (CDCl3, 400 MHz) 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 (CDCl3, 100 MHz) 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 oC. 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 stirring for 1 h, the mixture was added triethylamine (6.7 mL, 47.48 mmol) and slowly warmed to 0 oC for 1 h. The reaction mixture was quenched by the addition of saturated sodium bicarbonate solution (10 mL), then organic layer was washed with brine (3×20 mL). Aqueous layer was extracted with EtOAc (2×20 mL). 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 oC. 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 saturated aqueous ammonium chloride solution (10 mL) and brine (10 mL). The aqueous phase was extracted with EtOAc (3×20 mL). 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 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 (CDCl3, 400 MHz) 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 (CDCl3, 100 MHz) 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-αAllokainic acid 6 Tert-butyl Ethyl (2R,3S)-N-2-(((1R,4R)-1-(N,N-diisopropylamino-carbonyl)-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 oC. After stirring for 30 min, the solution was cooled to –78 oC 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, 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 oC, then a solution of 2% H2C2O4(aq) (10 mL) was added. The reaction mixture was warmed to 0 oC then was neutralized with addi-


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tional 2% H2C2O4 (aq) to pH=6~7. The aqueous layer was extracted with EtOAc (3 x 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 colorless liquid. Rf = 0.22 (EtOAc/hexanes, 1/6); [α]D21 –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), 2.682.39 (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. Tert-butyl Ethyl (2S,3S)-N-2-(((1R,4R)-1-(N,N-diisopropylamino-carbonyl)-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 oC. After stirring for 30 min, the solution was cooled to –78 oC 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, 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 oC, 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 oC then neutralized with additional 2% H2C2O4(aq) to pH=7~8. The aqueous layer was extracted with EtOAc (3 x 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 pale yellow liquid and 6 (0.2 g, 0.53 mmol, 20 %). Rf = 0.23 (EtOAc/hexanes, 1/6); [α]D 21 –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-oxopyrrolidine-2-carboxylate (15a). To a 25 mL flask was charged with 14a (1.0 g, 1.55 mmol) in THF ( 5.2 mL) and an aqeous solution of 15% citric acid ( 3.4 mL, 1.63 mmol). The mixture was stirred at room temperature for 9 day, 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 saturated Na2CO3 solution then extracted with dichloromethane (2 x 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 colorless liquid and auxiliary 16 (393 mg, 1.48 mmol, 95 %). Rf = 0.16 (EtOAc/hexanes, 1/1); [α]D23 –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 (CDCl3, 400 MHz) 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 (CDCl3, 100 MHz) 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-oxopyrrolidine-2-carboxylate (15b). Starting with 14b (1.0 g, 1.55 mmol) and followed the same procedure as in the synthesis of 15 a provided 15b (381 mg, 1.09 mmol, 70 %) as colorless liquid and recovered auxiliary 16 (379 mg, 1.43 mmol, 92 %). Rf = 0.11 (EtOAc/hexanes, 1/1); [α]D 23 +17.8 (c 1.0, CH2Cl2); IR (neat) 3246, 2972, 2928, 2858, 1734, 1700, 1514, 1457, 1369, 1290, 1247,1156,1100, 1034 cm-1; 1H NMR (CDCl3, 400 MHz) 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 (CDCl3, 100 MHz) 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)-5oxo-pyrrole- dine-1,2-dicarboxylate (17a). To a 10 mL roundbottom flask containing a solution of 15a (0.59 g, 1.67 mmol) in MeCN (5.5 mL) was added Boc2O (0.77 mL, 3.35 mmol) and DMAP (0.02 g, 0.17 mmol). The reaction mixture was cooled to 0 oC for 10 min, 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 x 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 colorless liquid. Rf = 0.44 (EtOAc/hexanes, 1/1);



[α]D27 –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 (CDCl3, 400 MHz) 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 (CDCl3, 100 MHz) 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)-5oxo-pyrrolidine-1,2-dicarboxylate (17b). Starting with 15b (423 mg, 1.2 mmol) and followed the same procedure as in the synthesis of 17a provided 17b (510 mg, 1.14 mmol, 95 %) as pale yellow liquid. Rf = 0.49 (EtOAc/hexanes, 1/1); [α]D26 –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; 1 H NMR (CDCl3, 400 MHz) 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 (CDCl3, 100 MHz) 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((-4-methoxybenzyl)-oxy)ethyl)-5-oxopyrrolidine-1,2dicarboxylate (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 o C. After 7 h, the reaction mixture was quenched with the addition of 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 colorless liquid. Rf = 0.42 (EtOAc/hexanes, 1/1); [α]D27 –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 (CDCl3, 400 MHz) 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 (CDCl3, 100 MHz) 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((4-methoxybenzyl)oxy)-ethyl)-5-oxopyrrolidine-1,2dicarboxylate (18b). Starting with 17b (373 mg, 0.83 mmol), and followed the same procedure as in the synthesis of 18a

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provided 18b (323 mg, 0.64 mmol, 77%). Rf = 0.35 (EtOAc/ hexanes, 1/1); [α]D 26 – 4.0 (c 1.0, CHCl3); IR (neat) 2976, 2930, 2861, 1784, 1734, 1700, 1515, 1457, 1369, 1307, 1249, 1156 cm-1; 1H NMR (CDCl3, 400 MHz) 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 (CDCl3, 100 MHz) 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)-5-oxo-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 then cooled to room temperature. After cooling, 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 colorless liquid. Rf = 0.56 (EtOAc/hexanes, 1/1); [α]D 24 –25.0 (c 1.0, CH2Cl2); IR (neat) 2978, 2936, 1793, 1735, 1514, 1457, 1369, 1313, 1250, 1157 cm-1; 1H NMR (CDCl3, 400 MHz) 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 (CDCl3, 100 MHz) 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)5-oxo-4-(prop-1-en-2-yl)pyrrolidine-1,2-dicarboxylate (19b). Starting with 18b (303 mg, 0.60 mmol), and followed the same procedure as in the synthesis of 19a provided 19b (254 mg, 0.52 mmol, 87%) as colorless liquid. Rf = 0.51 (EtOAc/ hexanes, 1/1); [α]D 25 –9.2 (c 1.0, CH2Cl2); IR (neat) 2978, 2936, 1792, 1742, 1514, 1369, 1311, 1249, 1157 cm-1; 1H NMR (CDCl3, 400 MHz) 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 (CDCl3, 100 MHz) 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 a 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 two phases were separated. The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over


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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 2 h at -78 °C, and quenched with saturated NaHCO3(aq) solution. The aqueous layer was separated and extracted with CH2Cl2 (3 x 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 colorless liquid. Rf = 0.70 (EtOAc/hexanes, 1/3); [α]D 26 –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 (CDCl3, 400 MHz) 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 (CDCl3, 100 MHz) 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, 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 followed the same procedure as in the synthesis of 20a provided 20b (110 mg, 0.23 mmol, 2 steps for 82%) as colorless liquid. Rf = 0.66 (EtOAc/hexanes, 1/1); [α]D25 –27.2 (c 1.0, CH2Cl2); IR (neat) 2976, 2935, 1736, 1701, 1514, 1394, 1366, 1248, 1172, 1157, 1135, 1092 cm-1; 1H NMR (CDCl3, 400 MHz) 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), 3.623.43 (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 (CDCl3, 100 MHz) 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-en2-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 oC. The mixture was stirred at room temperature for 2 h, then quenched with saturated NaHCO3 solution (5 mL), 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 pale yellow liquid. Rf = 0.45 (EtOAc/ hexanes, 1/1); [α]D27 –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 (CDCl3, 400 MHz) δ 4.77 (s, 2H), 4.23 (dd, J = 17.8, 8.1 Hz, 1H), 3.703.50 (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); 13C NMR (CDCl3, 100

MHz) 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-en2-yl)pyro-lidine-1,2-dicarboxylate (21b). Starting with 20b (74 mg, 0.15 mmol), and followed the same procedure as in the synthesis of 21a provided 21b (46 mg, 0.13 mmol, 85 %) as pale yellow liquid. Rf = 0.44 (EtOAc/hexanes, 1/1); [α]D19 – 14.0 (c 1.0, CH2Cl2); IR (neat) 3474, 2978, 2933, 2886, 1739, 1702, 1404, 1368, 1255, 1171,1156, 1133 cm-1; 1H NMR (CDCl3, 400 MHz) 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 (CDCl3, 100 MHz) 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 freshprepared 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. The filtrate was added water (1 mL) and the mixture was extracted with EtOAc (3 x 10mL). 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 oC 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 white solid. [α]D24 –15.8 (c 0.8, D2O); 1H NMR (D2O, 400 MHz) 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), 2.872.75 (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 (D2O, 100 MHz) 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 freshprepared 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. The filtrate was added water (1 mL) and the mixture extracted with EtOAc (3 x 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 oC 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 colorless oil. [α]D24 +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 (D2O, 400 MHz) 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.

ASSOCIATED CONTENT Supporting Information Copies of the 1H and 13C NMR spectra for all new compounds, and X-ray crystallographic data (CIF) for compounds 6, 10, and 12. The Supporting Information is available free of charge on the ACS Publications website.

■ AUTHOR INFORMATION Corresponding Author * E-mail: [email protected]

ORCID Biing-Jiun Uang: 0000-0003-4304-0064 Notes The authors declare no competing financial interest.

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

■ REFERENCES (1). (a) Murakami, S.; Takemoto, T.; Shimizu, Z. Studies on the Effective Principles of Digenea simplex Aq. I. Separation of the Effective Fraction by Liquid Chromatography. J. Pharm. Soc. Jpn. 1953, 73, 1026. (b) Nitta, I.; Watase, H.; Tomiie, Y. Structure of Kainic Acid and Its Isomer, Allokainic Acid. Nature 1958, 181, 761. (2) For previous syntheses see: Tian, Z.; Menard, F. Synthesis of Kainoids and C4 Derivatives. J. Org. Chem. 2018, 83, 6162. (3). Burns, J. M.; Schock, T. B.; Hsia, M. H.; Moeller, P. D. R.; Ferry, J. L. Photostability of Kainic Acid in Seawater. J. Agric. Food Chem. 2007, 55, 9951. (4). (a) Parsons, A. F. Recent Developments in Kainoid Amino Acid Chemistry. Tetrahedron 1996, 52, 4149. (b) Schwarcz, R.; Scholz, D.; Coyle, J. T. Structure-Activity Relations for the Neurotoxicity of Kainic Acid Derivatives and Glutamate Analogues. Neuropharmacology. 1978, 17, 145. (5). (a) Coyle, J. T.; Schwarcz, R. Lesion of Striatal Neurones with Kainic Acid Provides a Model for Huntington's Chorea. Nature 1976, 263, 244. (b) McGeer, E. G.; McGeer, P. L. Duplication of Biochemical Changes of Huntington's Chorea by Intrastriatal Injections of Glutamic and Kainic Acids. Nature 1976, 263, 517. (6). Sperk, G. Kainic Acid Seizures in the Rat. Prog. Neurobiol. 1994, 42, 1. (7). For previous syntheses see: Suzuki, J.; Miyano, N.; Yashiro, S.; Umezawa, T.; Matsuda, F. Total Synthesis of (−)-Kainic Acid and (+)-allo-Kainic Acid through SmI2-Mediated Intramolecular Coupling between Allyl Chloride and An α, β -Unsaturated Ester. Org. Biomol. Chem. 2017, 15, 6557, and references cited therein. (8). For previous syntheses, see : (a) Kraus, G. A.; Nagy, J. O. The Synthesis of Amino Acids by 1,3-Dipolar Cycloadditions of Azomethine Ylides. Tetrahedron 1985, 41, 3537. (b) DeShong, P.; Kell, D. A. A Total Synthesis of (±)-allo-Kainic Acid. Tetrahedron Lett. 1986, 27, 3979. (c) Yoo, S.-E.; Lee, S.-H.; Yi, K.-Y.; Jeong, N. Synthesis of

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α-Kainic Acid and α-alloKainic Acid by Pd(0) Mediated Olefin Insertion-Carbonylation Reaction. Tetrahedron Lett. 1990, 31, 6877. (d) Murakami, M.; Hasegawa, N.; Hayashi, M.; Ito, Y. Synthesis of (±)α-Allokainic Acid via the Zinc Acetate Catalyzed Cyclization of γIsocyano Silyl Enolates. J. Org. Chem. 1991, 56, 7356. (e) Mooiweer, H. H.; Hiemstra, H.; Specamp, W. N. Total Synthesis of (±)-αalloKainic Acid via Two Allylsilane N-acyliminium Ion Reactions. Tetrahedron 1991, 47, 3451. (9). Rossiter, B. E.; Swingle, N. M. Asymmetric Conjugate Addition. Chem. Rev. 1992, 92, 771. (10). (a) Zhang, F.-Y.; Corey, E. J. Highly Enantioselective Michael Reactions Catalyzed by a Chiral Quaternary Ammonium Salt. Illustrationby Asymmetric Syntheses of (S)-Ornithine and Chiral 2Cyclohexenones. Org. Lett. 2000, 2, 1097. (b) Arai, S.; Tsuji, R.; Nishida, A. Phase-Transfer-Catalyzed Asymmetric Michael Reaction Using Newly-Prepared Chiral Quaternary Ammonium Salts Derived from L-Tartrate. Tetrahedron Lett. 2002, 43, 9535. (c) Shibuguchi, T.; Fukuta, Y.; Akachi, Y.; Sekine, A.; Ohshima, T.; Shibasaki, M. Development of New Asymmetric Two-Center Catalysts in PhaseTransfer Reactions. Tetrahedron Lett. 2002, 43, 9539. (d) Kobayashi, S.; Yamashita, Y. Alkaline Earth Metal Catalysts for Asymmetric Reactions. Acc.Chem. Res. 2011, 44, 58. (11). (a) Yang, T. K.; Chen, R. Y.; Lee, D. S.; Peng, W. S.; Jiang, Y. Z.; Mi, A. Q.; Jong, T. T. Application of New Camphor-Derived Mercapto Chiral Auxiliaries to the Synthesis of Optically Active Primary Amines. J. Org. Chem. 1994, 59, 914. (b) Achqar, A. E.; Boumzebra, M.; Roumestant, M. L.; Viallefont, P. 2-Hydroxy-3Pinamone As Chiral Auxiliary in the Asymmetric Synthesis of αAmino Acids. Tetrahedron 1998, 44, 5319. (c) Yamamoto, H.; Kanemasa, S.; Wada E. Asymmetric Michael Addition of the NAlkylidene Derivative of an α-Amino Ester to Methyl (E)-3[(3R,7aS)-2-Phenylperhydropyrro lo[1,2-c]imidazol-3-yl]propenoate. Bull. Chem. Soc. Jpn. 1991, 64, 2739. (d) Kanemasa, S.; Tatsukawa, A.; Wada, E. Highly Diastereoselective Michael Addition of Lithiated Camphor Imines of Glycine Esters to α,β-Unsaturated Esters. Synthesis of Optically Pure 5-Oxo2,4-pyrrolidinedicarboxylates of Unnatural Stereochemistry. J. Org. Chem. 1991, 56, 2875. (e) Kanemasa, S.; Tatsukawa, A.; Wada, E.; Tsuge, O. Absolutely Diastereoselective Asymmetric Michael Addition of the Camphor Imine of t-Butyl Aminoacetate with 2Alkylidenemalonates. Chem. Lett. 1989, 1301. (f) Liang, B.; Carroll, P. J.; Joullie, M. M. Progress toward the Total Synthesis of Callipeltin A (I): Asymmetric Synthesis of (3S,4R)-3,4-Dimethylglutamine. Org. Lett. 2000, 2, 4157. (g) Chavan, S. P.; Sharma, P.; Sivappa, R.; Bhadbhade, M. M.; Gronnade, R. C.; Kalkote, U. R. Enantioselective Synthesis of L-CCG-I. J. Org. Chem. 2003, 68, 6817. (12). Casella, L.; Jommi, G.; Montanari, S.; Sisti, M. Metal-Directed Asymmetric Synthesis of Diastereoisomeric β-Phenyl Serines Using (+)- Ketopinic Acid as a Chiral Auxiliary. Tetrahedron Lett. 1988, 29, 2067. (13). (a) Lu, S. S.; Uang, B. J. Asymmetric Synthesis of α-Amino Acids from Glycine. J. Chin. Chem. Soc. 1992, 39, 245.(b) Yeh, T. L.; Liao, C. C.; Uang, B. J. Enantioselective Synthesis of α-Amino Acids from Glycine t-Butyl Ester. Tetrahedron. 1997, 53, 11141. (14). For X-ray crystallographic analysis of 10, see Supporting Information. (15). For X-ray crystallographic analysis of 12, see Supporting Information. (16). Rolland, J. W.; Roumestant, M. L.; Martinez, J. Glutamate Transporter Blockers: Enantiomerically Pure (2S,3S)-and (2S,3R)-3Methyl Glutamic Acids. Tetrahedron: Asymmetry 2003, 14, 1123. (17). Ezquerra, J.; Pedregal, C.; Yruretagoyena, B.; Rubio, A. Synthesis of Enantiomerically Pure 4-Substituted Glutamic Acids and Prolines: General Aldol Reaction of Pyroglutamate Lactam Lithium Enolate Mediated by Et2O‧BF3. J. Org. Chem. 1995, 60, 2925. (18). (a) Burgess, E. M.; Penton, H. R.; Taylor, E. A. Thermal Reactions of Alkyl N-Carbomethoxysulfamate Esters. J. Org. Chem. 1973, 38, 26. (b) Ushakov, D. B.; Navickas, V.; Strobele, M.; Mossmer, C.


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(+)-Î±-Allokainic Acid and - ACS Publications - American Chemical

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