Synthetic Procedures
General Synthetic Procedure for Intermediate 2
Geraniol (original material 1, 32.41 mmol, 500 mg), phthalimide (35.65 mmol, 525 mg) and triphenylphosphine (PPh3, 35.65 mmol, 9.35 mg) were dissolved in tetrahydrofuran (THF, 30 mL) in a 100 mL round-bottom flask. Diisopropyl azodicarboxylate (DIAD 35.65 mg, 7.21 mmol) was slowly added dropwise (1 mL/min) to the mixture in an ice bath. The mixture was incubated at 25°C for 6 h. Intermediate 2 was purified using column chromatography (petroleum ether/ethyl acetate = 10/1) in yields of 44.9%.
General Synthesis Procedure for Intermediate 3
Intermediate 2 (1.76 mmol, 50 mg) and hydrazine hydrate (110 mg, 2.12 mmol) were dissolved in ethyl alcohol (EtOH, 30 mL) in a 100 mL round-bottom flask. This solution was refluxed for 5 h. The reaction mixture was concentrated under reduced pressure to remove the EtOH. Finally, intermediate 3 was purified using column chromatography (petroleum ether/ethyl acetate = 10/1) in yields of 29.4%.
General Synthesis Procedure for Target Compounds 4a and 4b-4e
The plant germ-resisting compounds 4a-4d were prepared via a crosslinking reaction with different combinations of intermediate 3 and acyl chloride compounds or sulfonyl chloride compounds. Taking the synthetic method of compound 4a-1 as an example, intermediate 3 (700 mg, 4.57 mmol) and triethylamine (920 mg, 9.14 mmol) were dissolved in dichloromethane (DCM, 30 mL), and 2-methylbenzenesulfonyl chloride (1045 mg, 5.48 mmol) was slowly added dropwise (1 mL/min) to the mixture in an ice bath. The mixture was incubated at 25°C for 15 h. Compound 4a-1 was purified using column chromatography (petroleum ether/ethyl acetate = 10/1) to give a yield of 63.2%. All of the other target compounds were prepared using the similar procedures.
Date for 4a-1
Yellow liquid; yield = 51.4%; 1H NMR (300 MHz, Chloroform-d) δ 8.00 (dd, J = 8.2, 1.5 Hz, 1H), 7.47 (td, J = 7.4, 1.4 Hz, 1H), 7.38 – 7.29 (m, 2H), 5.16 – 4.92 (m, 2H), 4.35 (s, 1H), 3.57 (t, J = 6.4 Hz, 2H), 2.66 (s, 3H), 2.08 – 1.84 (m, 4H), 1.68 (s, 3H), 1.59 (s, 3H), 1.54 (s, 3H); 13C NMR (75 MHz, Chloroform-d) δ 140.83, 137.67, 136.65, 132.34, 132.10, 131.50, 129.29, 125.75, 123.27, 118.19, 40.42, 38.96, 25.85, 25.30, 19.94, 17.32, 15.81; ESI-MS: [M+NH4]+: observed: 325.1937; expected: 325.1944.
Date for 4a-2
Yellow liquid; yield = 43.2%; 1H NMR (300 MHz, Chloroform-d) δ 7.74–7.65 (m, 2H), 7.43-7.37 (m, 2H), 5.12–4.98 (m, 2H), 4.33 (d, J = 6.3Hz, 1H), 3.59 (t, J = 6.4Hz, 2H), 2.44 (s, 3H), 2.00-1.92 (m, 4H), 1.68 (s, 3H), 1.58 (s, 3H), 1.55 (s, 3H); 13C NMR (75 MHz, Chloroform-d) δ 140.79, 139.57, 138.87, 133.01, 131.52, 128.55, 127.16, 123.91, 123.26, 118.23, 40.68, 38.97, 25.86, 25.30, 20.98, 17.32, 15.87; ESI-MS: [M-H]-: observed: 306.1537; expected: 306.1533.
Date for 4a-3
Yellow liquid; yield = 49.8%; 1H NMR (300 MHz, Chloroform-d) δ 7.75-7.69 (m, 2H), 7.36–7.27 (m, 2H), 5.01 (dd, J = 11.1, 6.3Hz, 2H), 4.45 (t, J = 5.8Hz, 1H), 3.55 (t, J = 6.5Hz, 2H), 2.42 (s, 3H), 1.94 (dt, J = 11.1, 6.0Hz, 4H), 1.65 (s, 3H), 1.56 (s, 3H), 1.52 (s, 3H). 13C NMR (75 MHz, Chloroform-d) δ 142.92, 140.53, 136.84, 131.40, 129.26, 126.85, 123.34, 118.33, 40.64, 38.96, 25.86, 25.28, 21.13, 17.29, 15.86; ESI-MS: [M-H]-: observed: 306.1534; expected: 306.1533.
Date for 4a-4
Yellow liquid; yield = 63.8%; 1H NMR (300 MHz, Chloroform-d) δ 8.28-8.20 (m, 1H), 7.90-7.85 (m, 1H), 7.78–7.67 (m, 2H), 5.07–4.96 (m, 2H), 4.57 (s, 1H), 3.63 (t, J = 6.4Hz, 2H), 1.94 (dt, J = 12.6, 6.9Hz, 4H), 1.68 (s, 3H), 1.58 (s, 3H), 1.55 (s, 3H); 13C NMR (75 MHz, Chloroform-d) δ 140.93, 138.60, 132.28, 131.98, 131.41, 131.33, 128.16, 128.08, 127.99, 127.91, 127.25, 126.81, 123.20, 120.88, 117.91, 40.81, 38.88, 25.78, 25.20, 17.22, 15.75; ESI-MS: [M-H]-: observed: 360.1520; expected: 360.1521.
Date for 4a-5
White solid; yield = 42.1%; 1H NMR (300 MHz, Chloroform-d) δ 8.41–8.30 (m, 2H), 8.14–8.00 (m, 2H), 5.00 (dt, J = 13.1, 6.9Hz, 2H), 4.73 (t, J = 6.4Hz, 1H), 3.65 (t, J = 6.4Hz, 2H), 2.03–1.84 (m, 4H), 1.65 (s, 3H), 1.55 (d, J = 2.9Hz, 6H); 13C NMR (75 MHz, Chloroform-d) δ 149.69, 145.95, 141.58, 131.68, 128.01, 123.94, 123.03, 117.66, 40.78, 38.95, 25.81, 25.27, 17.28, 15.9; ESI-MS: [M+H]-: observed: 339.1368; expected: 339.1373.
Date for 4a-6
Yellow liquid; yield = 56.7%; 1H NMR (300 MHz, Chloroform-d) δ 7.49-7.46 (m, 2H), 7.37-7.32 (m, 1H), 5.32 (t, J = 5.7Hz, 1H), 5.08–4.95 (m, 2H), 3.71 (t, J = 6.6Hz, 2H), 2.03–1.80 (m, 4H), 1.67 (s, 3H), 1.58 (s, 6H); 13C NMR (75 MHz, Chloroform-d) δ 141.46, 135.64, 134.58, 131.89, 131.54, 131.01, 123.20, 117.35, 40.91, 38.96, 25.79, 25.31, 17.34, 15.91; ESI-MS: [M-H]-: observed: 360.0599; expected: 360.0597.
Date for 4a-7
Yellow liquid; yield = 45.7%; 1H NMR (300 MHz, Chloroform-d) δ 8.07–7.95 (m, 2H), 7.90-7.75 (m, 2H), 5.03 (q, J = 7.0Hz, 2H), 4.64 (t, J = 5.8Hz, 1H), 3.64 (t, J = 6.4Hz, 2H), 1.95 (qd, J = 8.6, 7.7, 4.5Hz, 4H), 1.68 (s, 3H), 1.58 (s, 3H), 1.57 (s, 3H); 13C NMR (75 MHz, Chloroform-d) δ 144.40, 141.41, 132.50, 131.65, 127.40, 123.07, 117.73, 115.93, 40.72, 38.95, 25.82, 25.28, 17.32, 15.91; ESI-MS: [M-H]-: observed: 317.1327; expected: 317.1329.
Date for 4a-8
Yellow liquid; yield = 55.9%; 1H NMR (300 MHz, Chloroform-d) δ 7.91–7.69 (m, 2H), 7.11–6.83 (m, 2H), 5.10–4.95 (m, 2H), 3.85 (s, 3H), 4.48 (s, 1H), 3.53 (t, J = 6.4Hz, 2H), 2.02–1.85 (m, 4H), 1.65 (s, 3H), 1.55 (s, 3H), 1.52 (s, 3H); 13C NMR (75 MHz, Chloroform-d) δ 162.47, 140.56, 131.44, 131.35, 128.95, 123.31, 118.33, 113.82, 55.25, 40.61, 38.98, 25.87, 25.29, 17.31, 15.88; ESI-MS: [M+H]-: observed: 324.1623; expected: 324.1628.
Date for 4a-9
Yellow liquid; yield = 46.9%; 1H NMR (300 MHz, Chloroform-d) δ 7.48 (dd, J = 8.4, 2.2Hz, 1H), 7.34 (d, J = 2.2Hz, 1H), 6.93 (d, J = 8.4Hz, 1H), 5.11–4.95 (m, 2H), 4.11 (d, J = 7.1Hz, 1H), 3.92 (d, J = 5.7Hz, 6H), 3.54 (t, J = 6.4Hz, 2H), 1.97-1.91 (m, 4H), 1.65 (s, 3H), 1.56 (s, 3H), 1.53 (s, 3H); 13C NMR (75 MHz, Chloroform-d) δ 152.16, 148.80, 140.67, 131.47, 123.26, 120.77, 118.27, 110.17, 109.42, 69.69, 55.89, 40.66, 39.00, 25.89, 25.27, 21.58, 17.29, 15.88; ESI-MS: [M-H]-: observed: 352.1592; expected: 352.1588.
Date for 4a-10
Yellow liquid; yield = 61.0%; 1H NMR (300 MHz, Chloroform-d) δ 8.05–7.86 (m, 2H), 7.43–7.31 (m, 2H), 5.14–4.95 (m, 2H), 4.41 (t, J = 5.7Hz, 1H), 3.62 (t, J = 6.4Hz, 2H), 1.96 (dt, 4H), 1.68 (s, 3H), 1.58 (s, 3H), 1.56 (s, 3H); 13C NMR (75 MHz, Chloroform-d) δ 151.74, 141.20, 138.34, 131.60, 128.93, 123.14, 120.57, 117.94, 40.67, 38.96, 25.82, 25.28, 17.28, 15.88; ESI-MS: [M-H]-: observed: 376.1202; expected: 376.1200.
Date for 4b-1
Yellow solid; yield = 63.2%; 1H NMR (300 MHz, Chloroform-d) δ 7.81 - 7.49 (m, 4H), 5.08 - 4.98 (m, 2H), 4.44 (t, J = 5.73, 5.73 Hz, 1H), 3.58 (t, J = 6.93, 7.19 Hz, 2H), 1.99 – 1.87 (m, 4H), 1.66 (s, 3H), 1.56 (s, 3H), 1.53 (s, 3H), 1.24 (s, 9H); 13C NMR (75 MHz, Chloroform-d) δ 155.31, 139.91, 136.08, 130.77, 126.03, 126.03, 124.98, 124.98, 122.65, 117.70, 39.99, 38.32, 34.10, 30.07, 30.07, 30.07, 25.20, 24.63, 16.66, 15.20; ESI-MS: [M + Na+]: observed: 372.1971; expected: 372.1968.
Date for 4b-2
Yellow solid; yield = 55.3%; 1H NMR (300 MHz, Chloroform-d) δ 7.17 (s, 2H), 5.15-4.99 (m, 2H), 4.22-4.12 (m, 1H), 3.58 (t, J = 7.02, 5.94 Hz, 2H), 2.00 – 1.91 (m, 4H), 1.66 (s, 3H), 1.56 (s, 3H),1.53 (s, 3H), 1.28-1.24(q, J = 6.22, 5.92 Hz, 18H), 1.15-1.13 (d, J = 6.74 Hz, 3H); 13C NMR (75 MHz, Chloroform-d) δ 168.13, 140.62, 133.80, 132.37, 131.70, 123.82, 123.14, 118.04, 39.50, 35.82, 30.92, 26.33, 25.63, 25.63, 17.66, 17.66, 17.66, 17.66, 17.66, 17.66, 16.37, 16.37, 16.37; ESI-MS: [M + Na+]: observed: 442.2752; expected: 442.2750.
Date for 4b-3
Yellow solid; yield = 39.8%; 1H NMR (300 MHz, Chloroform-d) δ 8.03 - 7.77 (m, 4H), 5.06-4.98 (m, 2H), 4.74 (t, J = 5.96, 5.53 Hz, 1H), 3.62 (t, J = 6.22, 5.92 Hz, 2H), 1.99 – 1.87 (m, 4H), 1.66 (s, 3H), 1.56 (s, 6H); 13C NMR (75 MHz, Chloroform-d) δ 144.00, 141.65, 131.98, 127.69, 126.29, 126.24, 126.19, 126.14, 123.51, 118.22, 41.08, 39.32, 26.19, 25.64, 17.64, 16.27; ESI-MS: [M + Na+]: observed: 384.1219 ; expected: 384.1216.
Date for 4c-1
Yellow solid; yield = 44.5%; 1H NMR (300 MHz, Chloroform-d) δ 9.16 – 8.21 (m, 7H), 5.21 (t, J = 7.08, 1.21 Hz, 1H), 5.02 – 4.94 (m, 2H), 3.27 (m, 2H), 2.17 – 2.05 (m, 4H), 1.68 (s, 3H),1.25 (s, 3H) 1.27 (s, 3H); 13C NMR (75 MHz, Chloroform-d) δ 141.15, 140.85, 131.83, 131.53, 131.41, 126.98, 123.29, 117.90, 40.93, 39.01, 25.88, 25.29, 17.32, 15.88; ESI-MS: [M + Na+]: observed: 366.1498; expected: 366.1498.
Date for 4c-2
Yellow solid; yield = 47.2%; 1H NMR (300 MHz, Chloroform-d) δ 8.56– 7.49 (m, 6H), 4.96 – 4.87 (m, 2H), 4.56 (d, J = 5.49, 5.67 Hz, 1H), 3.51 (t, J = 6.42, 6.48 Hz, 2H), 2.88 (s, 6H), 1.90 – 1.75 (m, 4H), 1.64 (s, 3H), 1.52 (s, 3H), 1.39 (s, 3H); 13C NMR (75 MHz, Chloroform-d) δ 152.05, 140.91, 134.93, 131.73, 130.39, 129.93, 129.75, 128.35, 128.35, 123.65, 123.17, 118.81, 118.57, 115.16, 45.40, 41.13, 39.20, 30.90, 26.10, 25.62, 17.64, 16.0; ESI-MS: [M + Na+]: observed: 387.2103; expected: 387.2101.
Date for 4d-1
Yellow solid; yield = 37.4%; 1H NMR (300 MHz, Chloroform-d) δ 7.61 – 7.07 (m, 3H), 5.09 – 5.07 (m, 1H), 5.03 - 5.01 (m, 1H), 4.58 (d, J = 7.1 Hz, 1H), 3.65 (m, 2H), 1.98 – 1.94 (m, 4H), 1.65 (s, 3H), 1.55 (s, 6H); 13C NMR (75 MHz, Chloroform-d) δ 141.15, 140.85, 131.83, 131.53, 131.41, 126.98, 123.29, 117.90, 40.93, 39.01, 25.88, 25.29, 17.32, 15.88; ESI-MS: [M + Na+]: observed: 322.0910; expected: 322.0906.
Date for 4d-2
Yellow solid; yield = 51.6%; 1H NMR (300 MHz, Chloroform-d): δ 7.40 - 6.92 (m, 2H), 5.11 (t, J = 7.1, 1.2 Hz, 1H), 5.03 (d, J = 6.7, 4.0 Hz, 1H), 4.70 (t, J = 5.6, 5.6 Hz, 1H), 3.66 (t, J = 6.4, 6.4 Hz, 2H), 2.08 – 1.92 (m, 4H), 1.67 (d, J = 0.8 Hz, 3H), 1.59 (s, 6H); 13C NMR (75 MHz, Chloroform-d) δ 142.37, 139.45, 136.67, 132.70, 130.99, 126.22, 124.67, 117.56, 40.91, 39.11, 25.88, 25.30, 17.32, 15.94; ESI-MS: [M + Na+]: observed: 356.0517; expected: 356.0516.
Date for 4d-3
Yellow solid; yield = 47.7%; 1H NMR (300 MHz, Chloroform-d) δ 7.36 - 7.04 (m, 2H), 5.09 (t, J = 7.0, 1.1 Hz, 1H), 5.02 (m, J = 5.8 Hz, 2H), 3.64 (t, J = 6.4 Hz, 2H), 2.06 – 1.89 (m, 4H), 1.65 (s, 3H), 1.57 (s, 6H); 13C NMR (75 MHz, Chloroform-d) δ 141.83, 141.11, 131.86, 131.47, 130.02, 123.33, 119.25, 117.80, 40.91, 39.01, 25.90, 25.31, 17.34, 15.95; ESI-MS: [M + Na+]: observed: 400.0014; expected: 400.0011.
Date for 4d-4
Yellow solid; yield = 55.5%; 1H NMR (300 MHz, Chloroform-d) δ 7.59 - 7.53 (m, 2H), 6.19 (t, J = 5.84, 5.94 Hz, 1H), 5.03-4.98 (m, 2H), 3.94 (s, 3H), 3.64 (t, J = 7.14, 6.78 Hz, 2H), 1.97 – 1.82 (m, 4H), 1.66 (s, 3H), 1.58 (s, 3H),1.53 (s, 3H); 13C NMR (75 MHz, Chloroform-d) δ 161.14, 146.05, 140.96, 131.31, 131.15, 130.53, 130.20, 123.65, 118.39, 53.14, 52.92, 41.39, 39.33, 25.65, 17.67, 16.19; ESI-MS: [M + Na+]: observed: 356.0998; expected: 356.0996.
Date for 4e-1
Yellow solid; yield = 43.7%; 1H NMR (300 MHz, Chloroform-d) δ 8.69 – 7.32 (m, 4H), 5.08 – 5.01 (m, 2H), 4.88 (s, 1H), 3.57 (t, J = 6.39, 6.42 Hz, 2H), 2.15 – 2.07 (m, 4H), 1.69 (s, 3H), 1.53 (s, 6H); 13C NMR (75 MHz, Chloroform-d) δ 155.88, 142.25, 141.16, 131.03, 130.94, 130.90, 130.87, 127.57, 127.41, 40.09, 38.30, 25.27, 24.90, 16.98, 15.31; ESI-MS: [M + Na+]: observed: 295.1471; expected: 295.1475.
Date for 4e-2
Yellow solid; yield = 40.6%; 1H NMR (300 MHz, Chloroform-d) δ 8.86 – 7.47 (m, 3H), 5.06 – 4.99 (m, 2H), 4.92 (s, 1H, NH), 3.66 (t, J = 6.39, 6.42 Hz, 2H), 2.01 – 1.90 (m, 4H), 1.67 (s, 3H), 1.58 (s, 6H); 13C NMR (75 MHz, Chloroform-d) δ 154.32, 147.45, 140.86, 136.34, 135.15, 130.99, 123.61, 122.45, 117.02, 40.04, 38.30, 25.16, 24.64, 16.67, 15.31; ESI-MS: [M + Na+]: observed: 329.1083; expected: 329.1085.
General Synthesis Procedure for Target Compounds 5a.
Taking the synthetic method of compound 5a-1 as an example. 4a-1 (300 mg, 0.98 mmol) was dissolved in alcohol (10 mL) followed by adding sodium ethoxide (20% v/v, 180 mg, 1.50 mmol) and then the mixture was stirred for 0.5 h at room temperature. Iodomethane (1 mL) was dripped into the mixture and then it was stirred for 3 h at room temperature. After the reaction was completed, the mixture was concentrated under vacuum and was extracted using ethyl acetate and saturated NaCl solution. Finally, the organic phase was washed by Na2SO4, and then was concentrated to give pure 5a-1 in a yield of 73.4%. All of the other target compounds were prepared using the similar procedures.
Date for 5a-1
Yellow liquid; yield = 73.4%; 1H NMR (300 MHz, Chloroform-d) δ 7.77–7.63 (m, 2H), 7.32-7.28 (m, 2H), 5.06 (dd, J = 14.7, 7.3Hz, 2H), 3.61 (d, J = 7.1Hz, 2H), 2.62 (s, 3H), 2.43 (s, 3H), 2.04-1.98 (m, 4H), 1.66 (s, 3H), 1.57 (s, 6H); 13C NMR (75 MHz, Methylene Chloride-d2) δ 140.90, 138.93, 132.36, 129.49, 127.31, 125.27, 124.92, 121.47, 115.95, 45.33, 37.27, 31.60, 23.93, 23.40, 19.22, 15.39, 13.87; ESI-MS: [M+H]-: observed: 322.1834; expected: 322.1835.
Date for 5a-2
Yellow solid; yield = 78.1%; 1H NMR (300 MHz, Chloroform-d) δ 8.54–8.24 (m, 2H), 7.99-7.95 (m, 2H), 5.15–4.91 (m, 2H), 3.70 (d, J = 7.2Hz, 2H), 2.71 (s, 3H), 2.04-1.96 (m, 4H), 1.65 (s, 3H), 1.60 (s, 3H), 1.56 (s, 3H); 13C NMR (75 MHz, Methylene Chloride-d2) δ 147.72, 141.73,141.73, 139.92, 129.67, 126.29, 121.99, 121.24, 115.05, 45.36, 37.25, 31.55, 23.88, 23.39, 15.37, 13.89; ESI-MS: [M+H]-: observed: 353.1533; expected: 353.1530.
Date for 5a-3
Yellow liquid; yield = 69.2%; 1H NMR (300 MHz, Chloroform-d) δ 7.75–7.66 (m, 2H), 7.03–6.92 (m, 2H), 5.11–4.97 (m, 2H), 3.85 (s, 3H), 3.58 (d, J = 7.1Hz, 2H), 2.60 (s, 3H), 2.03-1.95 (m, 4H), 1.64 (s, 3H), 1.56 (d, J = 3.7Hz, 6H); 13C NMR (75 MHz, Chloroform-d) δ 162.43, 140.81, 131.39, 129.22, 128.87, 123.39, 117.90, 113.79, 55.22, 47.25, 39.20, 33.52, 25.85, 25.31, 17.30, 15.78; ESI-MS: [M+H]-: observed: 338.1784; expected: 338.1784.