3.2. General Procedure for the Synthesis of GABA Esters 1–6
To a stirred solution of terpene (3.2 mmol) in CH
2Cl
2 (20 mL) at room temperature Boc-protected glycine (0.662 g, 3.26 mmol) and 4-dimethylaminopyridine (DMAP) (0.097 g, 0.794 mmol) were added. The reaction mixture was cooled to 0 °C, stirred for 10 min, and
N,
N′-dicyclohexylcarbodiimide (DCC) was added dropwise (0.727 g, 3.53 mmol). Stirring was continued for 30 min, the flask was then gradually warmed to room temperature, and the stirring continued for additional 10 h. Reaction completion was monitored by TLC. The reaction mixture was filtered, and the filtrate was diluted to 100 mL and washed with 1 M aqueous HCl, 10% aqueous NaHCO
3, and water. Deprotection of the N-Boc group was carried out using HCl/CH
3COOH according to the literature procedure [
12]. The crude products were purified by recrystallization from methanol.
(1R,2S,5R)-2-Isopropyl-5-methylcuclohexyl aminoacetate hydrochloride (1): White solid (84%). IR νmax (cm−1): 3460, 2953–2869, 1757, 1512, 1406, 1255. 1H-NMR (DMSO-d6, δ, ppm): 4.87–4.92 (td, 1H), 3.48 (s, 2H), 1.59 (m, 1H), 1,56–160 (m, 3H), 1.43–1.49 (m, 3H), 1.40 (m, 1H), 1.23–1.28 (m, 1H), 0.93 (d, J = 6.18 Hz, 3H), 0.86 (d, J = 6.71 Hz, 6H). MS (FAB) m/z: 214 [M + H]+. HRMS (ESI-TOF) calculated for C12H24NO2 [M + H]+ 214.3166, found 214.1446.
2-Isopropyl-5-methylphenyl aminoacetate hydrochloride (2): White solid (82%). IR νmax (cm−1): 3326, 2933–2855, 1766, 1510, 1205, 1088, 815. 1H-NMR (DMSO-d6, δ, ppm): 7.25 (d, J = 7.03 Hz, 1H, Ar-H), 7.05 (d, J = 7.28 Hz, 1H, Ar-H), 6.92 (s, 1H, Ar-H), 3.63 (s, 2H, CH2NH2), 2.99–3.05 (m, 1H, CH), 2.28 (s, 3H, CH3), 1.13 (d, J = 6.98 Hz, 6H, CH3). MS (FAB) m/z: 208 [M + H]+. HRMS (ESI-TOF) calculated for C12H18NO2 [M + H]+ 208.2689, found 208.0986.
5-Isopropyl-2-methylphenyl aminoacetate hydrochloride (3): White solid (80%). IR νmax (cm−1): 3439, 2957–2875, 1768, 1508, 1247, 1215, 908. 1H-NMR (DMSO-d6, δ, ppm): 7.10 (d, 2H, Ar-H), 6.98 (s, 1H, Ar-H), 3.32 (s, 2H, CH2NH2), 2.83–2.88 (m, 1H, CH), 2.11 (s, 3H, CH3), 1.17 (d, J = 6.72 Hz, 6H, CH3). MS (FAB) m/z: 208 [M + H]+. HRMS (ESI-TOF) calculated for C12H18NO2 [M + H]+ 208.2689, found 208.0986.
2-Methoxyphenyl aminoacetate hydrochloride (4): Brownish solid (74%). IR νmax (cm−1): 3434, 3146–2935, 1734, 1500, 1413, 1178, 956. 1H-NMR (DMSO-d6, δ, ppm): 7.31 (t, 1H, Ar-H), 7.17 (t, 1H, Ar-H), 7.06 (d, J = 10.20 Hz, 1H, Ar-H), 6.70 (d, J = 8.60 Hz, 1H, Ar-H), 3.78 (s, 3H, CH3), 3.45 (s, 2H, CH2NH2). MS (FAB) m/z: 182 [M + H]+. HRMS (ESI-TOF) calculated for C9H12NO3 [M + H]+ 182.1886, found 182.0098.
1,7,7-Trimethyl-bicyclo[2.2.1]heptan-2-yl aminoacetate hydrochloride (5): White solid (80%). IR νmax (cm−1): 3330, 2934–2854,1748, 1501, 1246, 1114, 1054. 1H-NMR (DMSO-d6, δ, ppm): 5.32–5.35 (dd, J1 = 4.30 Hz, J2 = 4.30 Hz, 1H, CH), 3.65 (s, 2H, CH2NH2), 2.24-2.31 (m, 1H, CH), 2.04-2.10 (m, 1H, CH), 1.88-192 (m, 1H, CH), 1.67–1.71 (m, 2H, CH), 1.38–1.44 (m, 2H, CH), 1.03 (s, 3H, CH3), 0.89 (s, 6H, CH3). MS (FAB) m/z: 212 [M + H]+. HRMS (ESI-TOF) calculated for C12H22NO2 [M + H]+ 212.3007, found 212.1006.
4-Allyl-2-methoxyphenol aminoacetate hydrochloride (6): Yellowish solid (83%). IR νmax (cm−1): 3426, 2929–2851, 1783, 1511, 1206, 1026, 902. 1H-NMR (DMSO-d6, δ, ppm): 7.06 (d, J = 6.28 Hz, 1H, Ar-H), 6.70 (s, 1H, Ar-H), 6.00 (d, J = 6.28 Hz, 1H, Ar-H), 5.88–5.97 (m, 1H, –CH=), 4.98 (d, J = 4.30 Hz, 2H, =CH2), 3.76 (s, 3H, CH3), 3.22 (d, J = 6.18 Hz, 2H, –CH2–), 3.65 (s, 2H, CH2NH2). MS (FAB) m/z: 222 [M + H]+. HRMS (ESI-TOF) calculated for C12H16NO3 [M + H]+ 222.2524, found 222.0986.