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Pregabalin Synthesis Essay

MDPI and ACS Style

Chennuru, L.N.; Choppari, T.; Nandula, R.P.; Zhang, T.; Franco, P. Direct Separation of Pregabalin Enantiomers Using a Zwitterionic Chiral Selector by High Performance Liquid Chromatography Coupled to Mass Spectrometry and Ultraviolet Detection. Molecules2016, 21, 1578.

AMA Style

Chennuru LN, Choppari T, Nandula RP, Zhang T, Franco P. Direct Separation of Pregabalin Enantiomers Using a Zwitterionic Chiral Selector by High Performance Liquid Chromatography Coupled to Mass Spectrometry and Ultraviolet Detection. Molecules. 2016; 21(11):1578.

Chicago/Turabian Style

Chennuru, Lakshmi N.; Choppari, Thirupathi; Nandula, Ramakrishna P.; Zhang, Tong; Franco, Pilar. 2016. "Direct Separation of Pregabalin Enantiomers Using a Zwitterionic Chiral Selector by High Performance Liquid Chromatography Coupled to Mass Spectrometry and Ultraviolet Detection." Molecules 21, no. 11: 1578.

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General Procedure A: Synthesis of Keto Esters

The ketone (1.0 equiv) was added slowly, over 15 min, to a stirred suspension of NaH (60% in mineral oil, 1.2 equiv) in dry THF (500 mL) at 0 °C. After the addition was complete, the cooling bath was removed, and the resulting mixture was stirred at rt for 40 min. The reaction was cooled to 0 °C, and the carbonate ester (1.5 equiv) was added slowly over 1 h. After the addition was complete, the reaction was allowed to slowly warm to rt with stirring (18 h). The reaction was quenched and acidified to pH ∼6 by careful addition of acetic acid (60 mL). Water (400 mL) was added, and the resulting mixture was extracted with Et2O. The organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude β-ketoester.

Ethyl 3-Oxopentanoate32

Using general procedure A, 2-butanone (51.6 mL, 41.5 g, 576 mmol), NaH (60% in mineral oil, 27.6 g, 691 mmol) in dry THF (500 mL), and diethyl carbonate (105 mL, 102 g, 864 mmol) gave the crude product as a clear yellow oil, which was distilled twice under reduced pressure (60 °C, 4 mbar) resulting in a 2:1 mixture of the desired product and the regioisomer ethyl 2-methyl-3-oxobutanoate as a clear colorless oil (31.9 g, 38%): 1H NMR (300 MHz, CDCl3) δ 1.09 (t, J = 7.5 Hz, 3H), 1.28 (t, J = 7.0 Hz, 3H), 2.56 (q, J = 7.5 Hz, 2H), 3.43 (s, 1H), 4.19 (q, J = 7.0 Hz, 2H). Ethyl 2-methyl-3-oxobutanoate: 1H NMR (300 MHz, CDCl3) δ 1.28 (t, J = 7.0 Hz, 3H), 1.34 (d, J = 7.0 Hz, 3H), 2.24 (s, 3H), 3.49 (q, J = 7.0 Hz, 1H), 4.19 (q, J = 7.0 Hz, 2H).

Ethyl 3-Oxohexanoate33

Using general procedure A, 2-pentanone (61.5 mL, 49.6 g, 576 mmol), NaH (60% in mineral oil, 27.6 g, 691 mmol) in dry THF (500 mL), and diethyl carbonate (104.9 mL, 102.1 g, 864 mmol) gave the crude product as a clear yellow oil, which was distilled under reduced pressure (60 °C, 4 mbar) yielding the desired product as a clear colorless oil (39.9 g, 44%): 1H NMR (300 MHz, CDCl3) δ 0.93 (t, J = 7.5 Hz, 3H), 1.28 (t, J = 7.0 Hz, 3H), 1.56–1.70 (m, 2H), 2.51 (t, J = 7.0 Hz, 2H), 3.42 (s, 2H), 4.19 (q, J = 7.0 Hz, 2H).

Ethyl 5-Methyl-3-oxohexanoate34

Using general procedure A, 4-methyl-2-pentanone (608.0 mL, 487.0 g, 4.86 mol), NaH (60% in mineral oil, 256.7 g, 1.32 equiv) in dry THF (4.87 L), and diethyl carbonate (884.0 mL, 1.5 equiv) gave the crude product as an orange oil. The crude product was distilled under reduced pressure (64–82 °C, 7–10 mbar) the desired product as a pale yellow oil (661.2 g, 79% isolated yield): 1H NMR (300 MHz, CDCl3) δ 0.86 (d, J = 6.4 Hz, 6H), 1.21 (t, J = 7.2 Hz, 3H), 2.09 (J = 6.7 Hz, 1H), 2.35 (d, J = 6.9 Hz, 2H), 3.34 (s, 2H), 4.12 (q, J = 7.2 Hz, 2H).

Methyl 5-Methyl-3-oxohexanoate35

Using general procedure A, 4-methyl-2-pentanone (72.1 mL, 57.7 g, 576 mmol), NaH (60% in mineral oil, 27.6 g, 691 mmol) in dry THF (500 mL), and dimethyl carbonate (72.8 mL, 77.8 g, 864 mmol) gave the crude product as a cloudy yellow oil. The crude product was distilled under reduced pressure (60 °C, 4 mbar) to give the desired product as a clear colorless oil (61.9 g, 68%): 1H NMR (300 MHz, CDCl3) δ 0.93 (d, J = 6.5 Hz, 6H), 2.09–2.22 (m, 1H), 2.41 (d, J = 7.0 Hz, 2H), 3.42 (s, 2H), 3.73 (s, 3H).

General Procedure B: Synthesis of (Z)-Triflates

Lithium triflate (2.0 equiv) was added to a stirred solution of the keto ester (1.0 equiv) in dry CH2Cl2 (150 mL). The resulting mixture was cooled to 0 °C, and diisopropylethylamine (1.1 equiv) was added dropwise over 10 min. After the addition was complete the mixture was stirred at 0 °C for 20 min before triflic anhydride (1.1 equiv) was added slowly over 30 min. The resulting mixture was stirred at 0 °C for 1 h before carefully being quenched by addition of saturated aqueous NH4Cl (60 mL). The reaction was allowed to warm to rt and an additional portion of CH2Cl2 (30 mL) was added. The layers were separated, and the organic layer was washed with aqueous HCl (1 M, 2 × 30 mL), water (30 mL), and brine (30 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Et2O (60 mL) was added to the resulting semisolid, and the mixture was filtered. The solids were extracted with more Et2O (2 × 20 mL), and the combined ether extracts were concentrated under reduced pressure to give the crude product.

(Z)-Ethyl 3-(Trifluoromethylsulfonyloxy)but-2-enoate13

Using general procedure B, lithium triflate (24.0 g, 154 mmol), ethyl acetoacetate (9.7 mL, 10.0 g, 76.8 mmol) in dry CH2Cl2 (150 mL), diisopropylethylamine (14.7 mL, 10.9 g, 84.5 mmol) and triflic anhydride (14.22 mL, 23.9 g, 84.5 mmol) gave the crude product as a clear yellow oil (18.6 g, 92%) which was used without further purification: 1H NMR (300 MHz, CDCl3) δ 1.30 (t, J = 7.0 Hz), 2.16 (s, 3H), 4.24 (q, J = 7.0 Hz, 2H), 5.75 (q, J = 1.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.2, 21.1, 61.4, 113.0, 118.5 (q, J = 319.8 Hz, CF3), 155.2, 162.5.

(Z)-Ethyl 3-(Trifluoromethylsulfonyloxy)pent-2-enoate13

Using general procedure B, lithium triflate (21.6 g, 139 mmol), ethyl 3-oxopentanoate (10.0 g, 69.4 mmol) in dry CH2Cl2 (150 mL), diisopropylethylamine (13.3 mL, 9.9 g, 76.3 mmol), and triflic anhydride (12.8 mL, 21.5 g, 76.3 mmol) gave the crude product as a clear dark orange oil. Purification by flash chromatography (silica gel, cyclohexane/EtOAc, 9:1) afforded the desired product as a clear pale yellow oil (17.7 g, 92% yield): 1H NMR (300 MHz, CDCl3) δ 1.18 (t, J = 7.5 Hz, 3H), 1.31 (t, J = 7.0 Hz, 3H), 2.44 (qd, J = 7.5, 1.0 Hz, 2H), 4.25 (q, J = 7.0 Hz, 2H), 5.75 (t, J = 1.0 Hz, 1H).

(Z)-Ethyl 3-(Trifluoromethylsulfonyloxy)hex-2-enoate

Using general procedure B, lithium triflate (19.7 g, 126 mmol), ethyl 3-oxohexanoate (10.0g, 63.2 mmol) in dry CH2Cl2 (150 mL), diisopropylethylamine (12.1 mL, 9.0 g, 69.5 mmol), and triflic anhydride (11.7 mL, 19.6 g, 69.5 mmol) gave the crude product as a clear dark red oil (17.0 g, 93% yield) which was used without further purification: 1H NMR (300 MHz, CDCl3) δ 0.99 (t, J = 7.5 Hz, 3H), 1.30 (t, J = 7.0 Hz, 3H), 1.55–1.69 (m, 2H), 2.37 (t, J = 7.5 Hz, 2H), 4.25 (q, J = 7.0 Hz, 2H), 5.74 (t, J = 1.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.3, 14.2, 19.5, 36.5, 61.5, 112.1, 118.6 (q, J = 319.8 Hz, CF3), 158.9, 162.7; HRMS (EI+) m/z calcd for C9H13F3O5S [M]+ 290.0439, found 290.0436.

(Z)-Ethyl 5-Methyl-3-(trifluoromethylsulfonyloxy)hex-2-enoate34

A 20 L jacketed reactor was charged with CH2Cl2 (2.45 L), ethyl 3-oxo-5-methylhexanoate (163.3 g; 1 equiv), and lithium triflate (295.86 g; 2 equiv) under an inert atmosphere. The resulting white suspension was stirred and cooled to 0 °C. N,N-Diisopropylethylamine (134.8 g; 182 mL; 1.1 equiv) was added over 10 min at <10 °C. The suspension was stirred for 20 min at 0 °C, and then triflic anhydride (294.28 g; 175 mL; 1.1 equiv) was added slowly to the mixture over 30 min at <10 °C. The suspension was stirred at 0 °C for 1 h. The mixture then was allowed to warm from 0 to 25 °C over 1 h while quenching with satd NH4Cl solution (980 mL). Dichloromethane (490 mL) was added, and the mixture was stirred for 5 min and then allowed to settle, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (490 mL). The combined organic phases were then washed with 1 M HCl (2 × 490 mL), water (490 mL), and 20% brine (490 mL) and then stirred for 30 min with MgSO4 (∼165 g) for 15–30 min. The solids were removed by filtration and washed with CH2Cl2 (165 mL). The filtrate was concentrated under vacuum at ≤40 °C to give an orange/brown oil containing crystalline solids. The crude product was triturated with MTBE (980 mL). The mixture was filtered and the solids were washed with MTBE (2 × 165 mL). The filtrate was concentrated under vacuum at ≤40 °C to give the title product as an orange/brown oil: overall yield 271 g (94%; corrected for 2.1% w/w MTBE content); 87.7% area purity by GC; 1H NMR (400 MHz, CDCl3): δ 0.94 (6H, d, J = 6.7 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.89 (1H, hept, J = 6.8 Hz), 2.17 (2H, d, J = 7.2 Hz), 4.18 (2H, q, J = 7.2 Hz), 5.67 (1H, s).

(Z)-Methyl 5-Methyl-3-(trifluoromethylsulfonyloxy)hex-2-enoate

Using general procedure B, lithium triflate (19.7 g, 126 mmol), methyl 5-methyl-3-oxohexanoate (10.0 g, 63.2 mmol) in dry CH2Cl2 (150 mL), diisopropylethylamine (12.1 mL, 9.0 g, 69.5 mmol), and triflic anhydride (11.7 mL, 19.6 g, 69.5 mmol) gave the crude product as a clear orange oil. Purification by flash chromatography (silica gel, cyclohexane/EtOAc, 9:1) afforded the desired product as a clear pale yellow oil (14.7 g, 80%): 1H NMR (300 MHz, CDCl3) δ 0.99 (d, J = 6.6 Hz, 6H), 1.98 (dp, J = 13.6, 6.8, 1H), 2.27 (d, J = 7.2 Hz, 2H), 3.80 (s, 3H), 5.76 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 21.9, 25.8, 43.7, 51.9, 112.4, 118.4 (q, J = 318.0 Hz, CF3), 158.3, 162.8; HRMS (ES+) m/z calcd for C9H14F3O5S [M + H]+ 291.0514, found 291.0519.

General Procedure C: Synthesis of (E)-Triflates

A mixture of Me4N+OH (25% in H2O, 5.0 equiv) and water (72.5 mL) was added dropwise over 30 min to a vigorously stirred solution of the keto ester (1.0 equiv) in heptane (300 mL) at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 15 min before triflic anhydride (2.5 equiv) was added dropwise over 1 h. After the addition was complete, the reaction was stirred for another 1 h at 0 °C before being quenched by careful addition of water (75 mL). The mixture was allowed to warm to rt, and the layers were separated. The aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with water (75 mL) and brine (75 mL), dried over Na2SO4, and concentrated under reduced pressure to yield the crude product.

(E)-Ethyl 3-(Trifluoromethylsulfonyloxy)but-2-enoate13

Using general procedure C, Me4N+OH (25% in H2O, 137 mL, 140 g, 384 mmol), water (72.5 mL), ethyl acetoacetate (9.7 mL, 10.0 g, 76.8 mmol) in heptanes (300 mL), and triflic anhydride (32.3 mL, 54.2 g, 192.1 mmol) gave the crude product as a clear colorless oil (14.4 g, 71%), which was used without further purification: 1H NMR (400 MHz, CDCl3) δ 1.31 (t, J = 7.0 Hz, 3H), 2.51 (s, 3H), 4.22 (q, J = 7.0 Hz, 2H), 5.95 (s, 1H).

(E)-Ethyl 3-(Trifluoromethylsulfonyloxy)pent-2-enoate13

Using general procedure C, Me4N+OH (25% in H2O, 124 mL, 26.4 g, 347 mmol), water (72.5 mL), ethyl 3-oxopentanoate (10.0 g, 69.4 mmol) in heptanes (300 mL), and triflic anhydride (29.2 mL, 48.9 g, 173.4 mmol) gave the crude product as a clear pale yellow oil. Purification by flash chromatography (silica gel, cyclohexane/EtOAc, 19:1) afforded the desired product as a clear colorless oil (10.6 g, 55%): 1H NMR (400 MHz, CDCl3) δ 1.21 (t, J = 7.5 Hz, 3H), 1.31 (t, J = 7.0 Hz, 3H), 2.94 (q, J = 7.5 Hz, 2H), 4.22 (q, J = 7.0 Hz, 2H), 5.92 (s, 1H).

(E)-Ethyl 3-(Trifluoromethylsulfonyloxy)hex-2-enoate36

Using general procedure C, Me4N+OH (25% in H2O, 113 mL, 115 g, 316.1 mmol), water (72.5 mL), ethyl 3-oxohexanoate (10.0 g, 63.2 mmol) in heptanes (300 mL), and triflic anhydride (26.6 mL, 44.6 g, 158.0 mmol) gave the crude product as a clear yellow oil (13.8 g, 75% yield), which was used without further purification: 1H NMR (300 MHz, CDCl3) δ 0.99 (t, J = 7.5 Hz, 3H), 1.30 (t, J = 7.0 Hz, 3H), 1.59–1.73 (m, 2H), 2.90 (t, J = 7.5 Hz, 2H), 4.22 (q, J = 7.0 Hz, 2H), 5.95 (s, 1H).

(E)-Ethyl 5-Methyl-3-(trifluoromethylsulfonyloxy)hex-2-enoate34

A 20 L jacketed reactor was charged with hexane (7.83 L) and ethyl 3-oxo-5-methylhexanoate (261.0 g, 1 equiv) under an inert atmosphere. The solution was cooled to 5 °C and stirred vigorously while a mixture of 25% aq tetramethylammonium hydroxide (2.76 kg, 2.76 L, 5 equiv) and water (1.89 L) was added over 30 min at 15 °C. The biphasic mixture was stirred vigorously for 10 min at 5–10 °C, and then triflic anhydride (1.07 kg, 637 mL, 2.5 equiv) was added dropwise to the mixture over 1.5 h at <10 °C. The mixture was stirred vigorously at 5 °C for a further 1 h, agitation was stopped, and the layers were allowed to settle before the upper organic layer was sampled. The mixture was then allowed to warm from 5 to 25 °C over 1 h while being quenched with water (1.97 L) and then stirred for 5 min. The mixture was allowed to settle, and layers were separated. The aqueous layer was extracted with EtOAc (3.92 L). The combined organic layers were washed with water (1.97 L) and then 20% brine (1.97 L), stirred with MgSO4 (∼300g) for 15–30 min, and then filtered. The residue was washed with EtOAc (260 mL), and the filtrate was concentrated under vacuum at ≤40 °C to give the E-vinyl triflate as a brown oil (overall yield of 378 g, 82%; corrected for 8.4% w/w EtOAc content, 75.5% area purity by GC). NMR analysis indicated that the isomeric ratio was 6:1: 1H NMR (400 MHz, CDCl3): δ 0.92 (6H, d, J = 6.7 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.95 (1H, hept, J = 6.8 Hz), 2.17 (0.33H, d, J = 7.2 Hz), 2.76 (2H, d, J = 7.3 Hz), 4.14 (2H, q, J = 7.2 Hz), 4.18 (0.28H, q, J = 7.2 Hz), 5.66 (0.14H, s), 5.91 (1H, s).

(E)-Methyl 5-Methyl-3-(trifluoromethylsulfonyloxy)hex-2-enoate

Using general procedure C, Me4N+OH (25% in H2O, 113 mL, 115 g, 316 mmol), water (72.5 mL), ethyl 3-oxo-5-methylhexanoate (10.0 g, 63.2 mmol) in heptane (300 mL), and triflic anhydride (26.6 mL, 44.6 g, 158 mmol) gave the crude product as a clear pale yellow oil. Purification by flash chromatography (silica gel, cyclohexane–EtOAc, 19:1) afforded the desired product as a clear colorless oil (10.0 g, 54%): 1H NMR (400 MHz, CDCl3) δ 0.99 (d, J = 6.5 Hz, 6H), 2.02 (m, 1H), 2.83 (d, J = 7.5 Hz, 2H), 3.76 (s, 3H), 5.99 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 21.8, 22.1, 26.5, 39.8, 51.9, 112.9, 118.4 (q, J = 319.8 Hz, CF3), 164.5, 165.1; HRMS (ES+) m/z calcd for C9H14F3O5S [M + H]+ 291.0514, found 291.0516.

General Procedure D: Synthesis of α,β-Dehydro Cyanoesters

The triflate (1.0 equiv) and Zn(CN)2 (0.6 equiv) were added to dry DMF (75 mL). The mixture was purged with N2 for 15 min before Pd(PPh3)4 (0.01 equiv) was added, and the mixture was heated at 70 °C for 15 h. The reaction mixture was allowed to cool to rt, and toluene (125 mL) was added. The mixture was washed with aqueous ammonium hydroxide (20%, 2 × 50 mL), and the aqueous washings were extracted with toluene (50 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product.

(Z)-Ethyl 3-Cyanobut-2-enoate [(Z)-1a]37

Using general procedure D, (Z)-ethyl 3-(trifluoromethylsulfonyloxy)but-2-enoate (12.3 g, 46.8 mmol), Zn(CN)2 (3.30 g, 28.1 mmol) in DMF (75 mL), and Pd(PPh3)4 (0.54 g, 0.47 mmol) gave the crude product as a clear yellow oil. Purification by flash chromatography (silica gel, cyclohexane/EtOAc 9:1) afforded the desired product as a clear pale yellow oil (4.23 g, 65%): 1H NMR (400 MHz, CDCl3) δ 1.33 (t, J = 7.0 Hz, 3H), 2.16 (s, 3H), 4.28 (q, J = 7.0 Hz, 2H), 6.32 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 14.0, 22.0, 61.5, 116.4, 122.8, 133.1, 162.7.

(E)-Ethyl 3-Cyanobut-2-enoate [(E)-1a]37

Using general procedure D, (E)-ethyl 3-(trifluoromethylsulfonyloxy)but-2-enoate (12.3 g, 46.8 mmol), Zn(CN)2 (3.30 g, 28.1 mmol) in dry DMF (75 mL), and Pd(PPh3)4 (0.54 g, 0.47 mmol) gave the crude product as a clear red oil. Purification by flash chromatography (silica gel, cyclohexane/EtOAc, 9:1) afforded the desired product as a clear pale yellow oil (4.52 g, 69%): 1H NMR (400 MHz, CDCl3): δ 1.31 (t, J = 7.0 Hz, 3H), 2.35 (s, 3H), 4.23 (q, J = 7.0 Hz, 2H), 6.41 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 14.1, 17.3, 61.2, 118.8, 125.9, 132.7, 163.8.

(Z)-Ethyl 3-Cyanopent-2-enoate [(Z)-2a)]

Using general procedure D, (Z)-ethyl 3-(trifluoromethylsulfonyloxy)pent-2-enoate (17.66 g, 63.9 mmol), Zn(CN)2 (4.50 g, 38.4 mmol) in dry DMF (75 mL), and Pd(PPh3)4 (0.74 g, 0.64 mmol) gave the crude product as a clear yellow oil. Purification by flash chromatography (silica gel, cyclohexane/EtOAc 9:1 afforded the desired product as a clear pale yellow oil (7.27 g, 74%): 1H NMR (400 MHz, CDCl3) δ 1.24 (t, J = 7.5 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H), 2.45 (qd, J = 7.4, 1.5 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H), 6.33 (t, J = 1.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 12.0, 14.0, 29.3, 61.5, 115.9, 129.2, 131.4, 162.9; HRMS (ESI) m/z calcd for C8H11NO2Na (M + Na+) 176.0682, found 176.0680.

(E)-Ethyl 3-Cyanopent-2-enoate [(E)-2a]

Using general procedure D, (E)-ethyl 3-(trifluoromethyl sulfonyloxy)pent-2-enoate (10.62 g, 38.4 mmol), Zn(CN)2 (2.71 g, 23.1 mmol) in dry DMF (75 mL), and Pd(PPh3)4 (0.44 g, 0.38 mmol) gave the crude product as a clear yellow oil. Purification by flash chromatography (silica gel, cyclohexane/EtOAc 9:1) afforded the desired product as a clear pale yellow oil (4.9 g, 84%): 1H NMR (400 MHz, CDCl3) δ 1.23 (t, J = 7.6 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H), 2.81 (qd, J = 7.6, 1.2 Hz, 2H), 4.24 (q, J = 7.1 Hz, 2H) 6.39 (t, J = 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 12.4, 14.1, 23.6, 61.2, 118.0, 131.8, 132.6, 163.7; HRMS (EI) m/z calcd for C8H11NO2 (M+) 153.0790, found 153.0798.

(Z)-Ethyl 3-Cyanohex-2-enoate [(Z)-3a]

Using general procedure D, (Z)-ethyl 3-(trifluoromethylsulfonyloxy)hex-2-enoate (13.6 g, 46.8 mmol), Zn(CN)2 (3.30 g, 28.1 mmol) in dry DMF (75 mL), and Pd(PPh3)4 (0.54 g, 0.47 mmol) gave the crude product as a clear yellow oil. Purification by flash chromatography (silica gel, cyclohexane/EtOAc 9:1, product from first column was repurified on a second silica column) afforded the desired product as a clear pale yellow oil (4.56 g, 58%): 1H NMR (300 MHz, CDCl3) δ 0.98 (t, J = 7.4 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H), 1.68 (m, 2H), 2.37 (td, J = 7.5, 1.5 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H), 6.32 (t, J = 1.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.1, 14.0, 20.8, 37.7, 61.5, 115.9, 127.8, 132.3, 162.9; HRMS (ESI) m/z calcd for C9H13NO2Na (M + Na+) 190.0839, found 190.0838.

(E)-Ethyl 3-Cyanohex-2-enoate [(E)-3a]

Using general procedure D, (E)-ethyl 3-(trifluoromethylsulfonyloxy)hex-2-enoate (13.6 g, 46.8 mmol), Zn(CN)2 (3.30 g, 28.1 mmol) in dry DMF (75 mL), and Pd(PPh3)4 (0.54 g, 0.47 mmol) gave the crude product as a clear yellow oil. Purification by flash chromatography (silica gel, cyclohexane/EtOAc, 19:1, product from first column was repurified on second silica column) afforded the desired product as a clear pale yellow oil (4.02 g, 51%): 1H NMR (400 MHz, CDCl3) δ 1.00 (t, J = 7.4 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H), 1.67 (dq, J = 14.8, 7.4 2H), 2.77 (td, J = 7.6, 1.1 Hz, 2H), 4.23 (q, J = 7.0 Hz, 2H), 6.42 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 13.3, 14.1, 21.3, 31.8, 61.2, 118.2, 131.2, 132.4, 163.7; HRMS (EI) m/z calcd for C9H13NO2 (M+) 167.0946, found 167.0952.

(Z)-Ethyl 5-Methyl-3-cyanohex-2-enoate [(Z)-4a]34

Using general procedure D, (Z)-ethyl 5-methyl-3-(trifluoromethylsulfonyloxy)hex-2-enoate (271.38 g, 1 equiv), Zn(CN)2 (62.8 g, 0.6 equiv) in dry DMF (1.63 L), and Pd(PPh3)4 (10.31 g, 0.01 equiv) gave the crude product as a yellow oil. Purification by chromatography on a Biotage apparatus (25.3g per run using a 65i cartridge (350 g silica) and 1–6% EtOAc in cyclohexane) gave the product as a yellow oil (67 g, 60% yield): 1H NMR (400 MHz, CDCl3) δ 0.90 (d, J = 6.6 Hz, 6H), 1.27 (t, J = 7.2 Hz, 3H), 1.99 (hept, J = 6.8 Hz, 1H), 2.19 (dd, J = 7.2 Hz, 1.2 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 6.21 (t, J = 1.2 Hz, 1H).

(E)-Ethyl 5-Methyl-3-cyanohex-2-enoate [(E)-4a]34

Using general procedure D, (E)-ethyl 5-methyl-3-(trifluoromethylsulfonyloxy)hex-2-enoate (378 g, 1 equiv), Zn(CN)2 (87.6 g, 0.6 equiv) in dry DMF (2.27 L), and Pd(PPh3)4 (14.4g; 0.01 equiv) gave the crude product as a red oil (244 g, 108%). A portion of the crude product (111 g) was purified by chromatography on a Biotage apparatus using a 65i cartridge (350 g silica) and 1–6% EtOAc in cyclohexane to give the product as an yellow-orange oil (55 g, 53%): 1H NMR (400 MHz, CDCl3) δ 0.91 (d, J = 6.7 Hz, 6H), 1.24 (t, J = 7.1 Hz, 3H), 1.95 (hept, J = 6.8 Hz, 1H), 2.61 (dd, J = 7.3, 1.1 Hz, 2H), 4.15 (q, J = 7.1 Hz, 2H), 6.37 (t, J = 1.1 Hz, 1H).

(Z)-Methyl 5-Methyl-3-cyanohex-2-enoate [(Z)-5a]38

Using general procedure D, (Z)-methyl 5-methyl-3-(trifluoromethylsulfonyloxy)hex-2-enoate (14.7 g, 50.8 mmol) and Zn(CN)2 (3.58 g, 30.5 mmol) in dry DMF (75 mL) and Pd(PPh3)4 (0.59 g, 0.51 mmol) gave the crude product as a clear yellow oil. Purification by flash chromatography (silica gel, cyclohexane/EtOAc 9:1) afforded the desired product as a clear pale yellow oil (7.32 g, 86%): 1H NMR (400 MHz, CDCl3) δ 0.96 (d, J = 6.5 Hz, 6H), 2.05 (m, 1H), 2.20 (dd, J = 7.0, 1.0 Hz, 2H), 3.82 (s, 3H), 6.29 (t, J = 1.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.9, 27.1, 44.8, 52.3, 116.0, 127.5, 132.6, 163.2.

(E)-Methyl 5-Methyl-3-cyanohex-2-enoate [(E)-5a]34

Using general procedure D, (E)-methyl 5-methyl-3-(trifluoromethylsulfonyloxy)hex-2-enoate (9.96 g, 34.3 mmol), Zn(CN)2 (2.42 g, 20.6 mmol) in dry DMF (75 mL) and Pd(PPh3)4 (0.40 g, 0.34 mmol) gave the crude product as a clear red oil. Purification by flash chromatography (silica gel, cyclohexane/EtOAc 9:1, product from first column was repurified on a second silica column) afforded the desired product as a clear pale yellow oil (4.24 g, 74%): 1H NMR (400 MHz, CDCl3) δ 0.98 (d, J = 6.5 Hz, 6H), 2.02 (m, 1H), 2.69 (dd, J = 7.5, 1.0 Hz, 2H), 3.77 (s, 3H), 6.45 (t, J = 1.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 22.0, 28.0, 38.5, 52.0, 118.3, 131.1, 132.5, 164.2.

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