General Procedure for Carbamate Synthesis
In a 250 mL round bottom flask, 1 M NaOH (75 mL) was added and left to cool to 0 °C in an ice bath. After that, the respective amino acid (24 mmol) was added, and the solution was left to stir until it was homogeneous. Then, the respective chloroformate (33 mmol) and 1,4-dioxane (30 mL) were added drop by drop. The reaction mixture was then allowed to stir overnight at room temperature. The solution was extracted with Et2O (3 × 50 mL). The aqueous layer was cooled to 0 °C in an ice bath and concentrated HCl was added dropwise until pH = 2. The aqueous solution was extracted again with Et2O (3 × 100 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a viscous oily product. The compound was used for the next step without further purification.
(Methoxycarbonyl)-L-valine (1C). The compound was synthesized according to the procedure for carbamate synthesis using L-valine amino acid and methyl chloroformate to give a white crystalline product: yield 2.5 g (44%); mp 109–113 °C; CAS no. 74761-42-5; C7H13NO4.
(Methoxycarbonyl)-D-valine (2C). The compound was synthesized according to the procedure for carbamate synthesis using L-valine amino acid and methyl chloroformate to give a white crystalline product: yield 2.4 g (57%); mp 109–113 °C; CAS no. 153575-98-5; C7H13NO4.
(Ethoxycarbonyl)-L-valine (3C). The compound was synthesized according to the procedure for carbamate synthesis using L-valine amino acid and ethyl chloroformate to give a clear oily product: yield 2.4 g (52%); CAS no. 5701-14-4; C8H15NO4.
(Butoxycarbonyl)-L-valine (4C). The compound was synthesized according to the procedure for carbamate synthesis using L-valine amino acid and butyl chloroformate to give a clear oily product: yield 3.1 g (60%); CAS no. 122315-77-9; C10H19NO4.
(Methoxycarbonyl)-L-leucine (5C). The compound was synthesized according to the procedure for carbamate synthesis using L-leucine amino acid and methyl chloroformate to give a clear oily product: yield 2.6 g (58%); CAS no. 74761-37-8; C8H15NO4.
(Methoxycarbonyl)-D-leucine (6C). The compound was synthesized according to the procedure for carbamate synthesis using D-leucine amino acid and methyl chloroformate to give a clear oily product: yield 2.4 g (52%); CAS no. 791635-26-2; C8H15NO4.
(Ethoxycarbonyl)-L-leucine (7C). The compound was synthesized according to the procedure for carbamate synthesis using L-leucine amino acid and ethyl chloroformate to give a clear oily product: yield 2.5 g (51%); CAS no. 19887-30-0; C9H17NO4.
(Ethoxycarbonyl)-D-leucine (8C). The compound was synthesized according to the procedure for carbamate synthesis using D-leucine amino acid and ethyl chloroformate to give a clear oily product: yield 2.7 g (55%); CAS no. 136159-70-1; C9H17NO4.
(Methoxycarbonyl)-L-phenylglycine (9C). The compound was synthesized according to the procedure for carbamate synthesis using L-phenylglycine amino acid and methyl chloroformate to give a clear oily product: yield 2.8 g (58%); CAS no. 60725-19-1; C10H11NO4.
(Methoxycarbonyl)-D-phenylglycine (10C). The compound was synthesized according to the procedure for carbamate synthesis using D-phenylglycine amino acid and methyl chloroformate to give a clear oily product: yield 2.6 g (54%); C10H11NO4.
General Procedure for Alpha Carbon Bromination
N-bromosuccinimide (6.25 mmol, 1.11 g) was added to the appropriate iodoacetophenone (5 mmol, 1.22 g) in acetonitrile (30 mL), the mixture was stirred at room temperature for 10–15 min, then p-toluene sulfonic acid (p-TsOH) (10 mmol, 1.90 g) was added to the mixture and refluxed for 2 h. The reaction mixture was concentrated under reduced pressure, washed with a saturated solution of Na2CO3 and extracted with EtOAc. The organic layer was separated and dried over MgSO4, filtered then concentrated under reduced pressure.
2-Bromo-1-(3-iodophenyl) ethan-1-one (A1). Synthesized according to the method outlined above using 3′-iodoacetophenone; orange oil; yield: 1.5 g (92%); 1H NMR (400 MHz, CDCl3) δ 4.29 (2H, s), 7.32 (1H, ddd, J = 7.8, 1.6, 1.2 Hz), 7.52 (1H, ddd, J = 7.8, 7.7, 0.4 Hz), 7.94 (1H, ddd, J = 7.7, 1.9, 1.2 Hz), 8.12 (1H, ddd, J = 1.9, 1.6, 0.4 Hz); MS (ESI): m/z = 324.8 (M+H+).
2-Bromo-1-(4-iodophenyl) ethan-1-one (A2). Synthesized according to the method outlined above using 4′-iodoacetophenone; orange solid; yield: 1.53 g (94%); mp: 113–115 °C, 1H NMR (400 MHz, CDCl3) δ 4.28 (2H, s), 7.65 (2H, ddd, J = 8.6, 1.4, 0.5 Hz), 7.93 (2H, ddd, J = 8.6, 1.8, 0.5 Hz); MS (ESI): m/z = 324.8 (M+H+).
General Procedure for Pyrrolidine Dicarboxylate Formation. Boc-L-proline (4.6 mmol, 1.5 g) was added to Compound A1 or A2 in Acetonitrile (15 mL)
Following that, TEA (25 mmol, 3.50 mL) was added, and the reaction mixture was left to stir at room temperature for 3 h. Then, it was concentrated under vacuum, washed with distilled water, and extracted with EtOAc (50 mL × 3). The combined organic layers were separated and dried over MgSO4 and filtered then concentrated under vacuum. The compound was confirmed by MS analysis and used in the next step without further purification.
1-(Tert-butyl) 2-(2-(3-iodophenyl)-2-oxoethyl) pyrrolidine-1,2-dicarboxylate (B1). It was synthesized by reacting 2-bromo-1-(3-iodophenyl) ethan-1-one (A1) with Boc-L-proline according to the previous general procedure; reddish-brown oil; yield: 1.9 g (90%); 1H NMR (400 MHz, CDCl3) δ 8.01 (ddd, J = 8.0, 1.9, 1.2 Hz, 1H), 7.75 (ddd, J = 1.9, 1.6, 0.4 Hz, 1H), 7.56 (ddd, J = 8.0, 7.8, 0.4 Hz, 1H), 7.30 (ddd, J = 7.8, 1.6, 1.2 Hz, 1H), 4.54–4.58 (m, 2H), 4.33 (dd, J = 9.3, 5.6 Hz, 1H), 3.20–3.52 (m, 2H), 1.77–2.23 (m, 4H), 1.42 (s, 9H); MS (ESI): m/z = 460.0 (M+H+).
1-(Tert-butyl) 2-(2-(4-iodophenyl)-2-oxoethyl) pyrrolidine-1, 2-dicarboxylate (B2). It was synthesized by reacting 2-bromo-1-(4-iodophenyl) ethan-1-one (A2) with Boc-L-proline according to the previous general procedure; reddish brown semi solid; yield: 2.0 g (95%); 1H NMR (400 MHz, CDCl3) δ 7.94 (ddd, J = 8.6, 1.8, 0.4 Hz, 2H), 7.65 (ddd, J = 8.6, 1.4, 0.4 Hz, 2H), 4.60 (s, 2H), 4.24 (dd, J = 9.3, 5.6 Hz, 1H), 3.35 (ddd, J = 15.6, 6.9, 1.8 Hz, 2H), 1.77–2.23 (m, 4H), 1.42 (s, 9H); MS (ESI): m/z = 460.0 (M+H+)
General Procedure for the Formation of the Imidazole Ring
In a one-pot, multistep transformation, compound B1 or B2 was exposed to ammonium acetate (75 mmol, 5.78 g) in toluene (20 mL) under reflux. The reaction mixture was concentrated under vacuum, washed with distilled water, and extracted with EtOAc (50 × 3). The combined organic layers were separated and dried over MgSO4, filtered then concentrated under vacuum. The product was purified with silica gel column chromatography.
Tert-butyl (S)-2-(5-(3-iodophenyl)-1H-imidazol-2-yl) pyrrolidine-1-carboxylate (C1). It was synthesized by reacting 1-(tert-butyl) 2-(2-(3-iodophenyl)-2-oxoethyl) pyrrolidine-1,2-dicarboxylate (B1) with ammonium acetate, as mentioned in the general procedure for imidazole formation. The product was purified using hexane/EtOAc 2:1 with 1% TEA; brown solid; yield: 1.2 g (70%); mp: 161–164 °C; 1H NMR (400 MHz, CDCl3) δ 7.84 (ddd, J = 8.2, 7.7, 0.5 Hz, 1H), 7.56 (ddd, J = 1.7, 1.5, 0.5 Hz, 1H), 7.51 (s, 1H), 7.30–7.39 (m, 2H), 5.38 (dd, J = 7.4, 7.1 Hz, 1H), 3.38–3.59 (m, 2H), 1.73–2.33 (m, 4H), 1.35 (s, 9H); MS (ESI): m/z = 440.0 (M+H)+.
Tert-butyl (S)-2-(5-(4-iodophenyl)-1H-imidazol-2-yl) pyrrolidine-1-carboxylate (C2). It was synthesized by reacting 1-(Tert-butyl) 2-(2-(4-iodophenyl)-2-oxoethyl) pyrrolidine-1, 2-dicarboxylate (B2) with ammonium acetate as in the general procedure for imidazole formation; the product was purified using hexane: EtOAc 2:1 with 1% TEA; buff solid; yield: 1.1 g (69%); mp: 156–158 °C; 1H NMR (400 MHz, CDCl3) 7.93 (ddd, J = 8.6, 1.7, 0.5 Hz, 2H), 7.62-7.68 (m, 3H), 5.29 (dd, J = 7.4, 7.1 Hz, 1H), 3.51 (m, 2H), 2.25 (m, 1H),1.82-2.15 (m, 3H), 1.41 (s, 9H); MS (ESI): m/z = 440.0 (M+H)+.
General Procedure for Boc Deprotection
Trifluoroacetic acid (2 mL) was added to compound C1 or C2 in dichloromethane (15 mL) at room temperature, and the reaction was left for 3 h. The reaction mixture was concentrated under reduced pressure, neutralized with 5 M NaOH, and extracted with EtOAc. The organic layer was separated, dried over MgSO4, and filtered then concentrated under reduced pressure.
(S)-5-(3-Iodophenyl)-2-(pyrrolidin-2-yl)-1H-imidazole (D1). It was deprotected as mentioned in the general procedure above; yellow semisolid; yield: 0.8 g (88%); 1H NMR (400 MHz, CDCl3) δ 7.81 (ddd, J = 8.2, 7.7, 0.5 Hz, 1H), 7.70 (ddd, J = 1.7, 1.5, 0.5 Hz, 1H), 7.28–7.64 (m, 3H), 4.61 (dd, J = 7.7, 6.9 Hz, 1H), 3.22 (ddd, J = 6.9, 3.2, 1.7 Hz, 1H), 3.01 (ddd, J = 7.7, 6.9, 3.2 Hz, 1H), 1.43–2.12 (m, 4H); MS (ESI): m/z = 340.0 (M+H)+.
(S)-5-(4-Iodophenyl)-2-(pyrrolidin-2-yl)-1H-imidazole (D2). It was deprotected as mentioned in the general procedure above; light brown semisolid; 0.8 g (88%); 1H-NMR (400 MHz, CDCl3) δ 7.93 (ddd, J = 8.6, 1.7, 0.5 Hz, 2H), 7.61-7.68 (m, 2H), 7.60 (s, 1H), 4.33 (dd, J = 7.7, 6.9 Hz, 1H), 3.15 (ddd, J = 6.9, 3.2, 1.7 Hz, 1H), 2.91 (ddd, J = 7.7, 6.9, 3.2 Hz, 1H), 1.98–2.19 (m, 2H), 1.62–1.95 (m, 2H); MS (ESI) m/z = 340.0 (M+H)+.
General Procedure for Amide Coupling, Compounds 1–20
To a suspension of compound D1 or D2 (2.35 mmol, 0.8 g), the corresponding carbamate (3 equiv.) and TEA (2 mL) in DCM (50 mL), HBTU (8.82 mmol, 3.34 g) were added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum, washed with distilled water, and extracted with DCM (50 × 3). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum. The product was purified using silica gel column chromatography.
Methyl ((S)-1-((S)-2-(5-(3-iodophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (1). It was prepared by coupling compound (D1) with methyl-L-valine carbamate using the previous general procedure, and it was purified using DCM: MeOH with a ratio 20:1; yellow semisolid; 1.0 g (77%); 1H-NMR (400 MHz, CDCl3) δ 8.07 (d, J = 37.2 Hz, 1H), 7.71–7.50 (m, 2H), 7.18–7.01 (m, 2H), 5.62 (t, J = 9.9 Hz, 1H), 5.21 (dt, J = 8.9, 4.5 Hz, 1H), 4.23 (ddd, J = 35.0, 11.9, 7.2 Hz, 1H), 3.94–3.70 (m, 2H), 3.60 (s, 3H), 2.37–1.92 (m, 5H), 0.98–0.82 (m, 6H); 13C-NMR (101 MHz, CDCl3) δ 172.64, 165.73, 157.10, 148.38, 140.22, 135.44, 133.53, 130.24, 127.41, 123.76, 94.73, 57.65, 54.35, 52.36, 47.89, 31.16, 27.46, 25.36, 17.58; MS (ESI) m/z = 497.0 [M+H]+.
Methyl ((S)-1-((S)-2-(5-(4-iodophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl) carbamate (2). It was prepared by coupling compound (D2) with methyl-L-valine carbamate using the previous general procedure, and it was purified using DCM: MeOH 100:3; light brown semisolid; yield: 0.7 g (53%); 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.4 Hz, 2H), 7.52–7.34 (m, 2H), 7.18 (s, 1H), 5.52 (d, J = 9.1 Hz, 1H), 5.22 (dd, J = 8.1, 3.7 Hz, 1H), 4.31 (dd, J = 9.0, 6.8Hz, 1H), 3.67 (s, 3H), 3.65–3.43 (m, 2H), 2.22–1.90 (m, 5H), 0.86 (dd, J = 6.6, 3.6 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 172.53, 157.22, 148.62, 136.66, 135.34, 132.87, 124.65, 119.56, 118.72, 82.35, 74.31, 58.29, 57.83, 52.47, 48.03, 31.32, 25.35, 19.32, 17.77; MS (ESI) m/z = 497.0 [M+H]+.
Methyl ((R)-1-((S)-2-(5-(3-iodophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (3). It was prepared by coupling compound (D1) with methyl-D-valine carbamate using the previous general procedure, and it was purified using DCM: MeOH 20:1; yellow semisolid; yield: 0.8 g (61%); 1H NMR (400 MHz, CDCl3) δ 7.99 (dd, J = 8.3, 1.7 Hz, 1H), 7.56 (dd, J = 10.3, 3.4 Hz, 2H), 7.13–7.04 (m, 2H), 5.71 (d, J = 6.9 Hz, 1H), 5.35 (d, J = 8.5 Hz, 1H), 4.30–4.27 (m, 1H), 3.67 (s, 3H), 3.62 (s, 2H), 2.23–2.04 (m, 5H), 1.03–0.99 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 174.77, 172.27, 165.86, 158.06, 157.05, 148.54, 136.20, 133.75, 130.34, 124.32, 94.62, 58.95, 58.73, 52.79, 47.52, 31.13, 30.46, 24.42, 19.05; MS (ESI) m/z = 497.0 [M+H]+.
Methyl ((R)-1-((S)-2-(5-(4-iodophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1 oxobutan-2-yl)carbamate (4). It was prepared by coupling compound (D2) with methyl-D-valine carbamate using the previous general procedure, and it was purified using DCM: MeOH 100:5; yellow semisolid; yield: 0.6 g (46%); 1H NMR (400 MHz, CDCl3) δ 7.66–7.60 (m, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 4.7 Hz, 1H), 5.47 (d, J = 7.8 Hz, 1H), 5.28 (d, J = 6.3 Hz, 1H), 4.20 (t, J = 7.6 Hz, 1H), 3.89 (t, J = 7.9 Hz, 1H), 3.63 (s, 3H), 3.59 (dd, J = 13.1, 5.7 Hz, 2H), 2.10 (dd, J = 20.6, 13.7, 11.5 Hz, 4H), 1.02 (dd, J = 6.6, 3.3 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 172.30, 157.59, 148.48, 147.32, 137.69, 130.56, 126.68, 117.96, 91.65, 58.47, 55.25, 52.64, 47.69, 30.93, 29.35, 24.81, 18.20; MS (ESI) m/z = 497.0 [M+H]+.
Ethyl ((S)-1-((S)-2-(5-(3-iodophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (5). It was prepared by coupling compound (D1) with ethyl-L-valine carbamate using the previous general procedure, and it was purified using DCM: MeOH 20:1; yellow semisolid; yield: 0.6 g (50%); 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.57–7.50 (m, 2H), 7.20–7.01 (m, 2H), 5.61 (t, J = 47.2 Hz, 1H), 5.22 (dd, J = 8.1,4.0 Hz, 1H), 4.32–4.27 (m, 1H), 4.10 (dd, J = 8.0, 3.9 Hz, 2H), 3.87–3.63 (m, 2H), 2.35–1.94 (m, 5H), 1.07–0.97 (m, 3H), 0.91–0.84 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 172.59, 165.59, 156.54, 148.19, 135.38, 133.32, 130.08, 123.88, 123.56, 118.80, 94.53, 61.02, 57.39, 54.18, 47.71, 30.86, 25.14, 18.91, 17.41, 14.36; MS (ESI) m/z = 511 [M+H]+.
Ethyl ((S)-1-((S)-2-(5-(4-iodophenyl)-1H-imidazol-2-yl) pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl) carbamate (6). It was prepared by coupling compound (D2) with ethyl-L-valine carbamate using the previous general procedure, and it was purified using DCM: MeOH 100:3; yellow semisolid; yield: 0.9 g (75%); 1H NMR (400 MHz, CDCl3) δ 7.77–7.29 (m, 4H), 7.18 (d, J = 22.4 Hz, 1H), 5.46 (d, J = 9.0 Hz, 1H), 5.23 (dd, J = 7.7, 3.7 Hz, 1H), 4.20 (ddd, J = 11.1,10.0,5.7 Hz, 3H), 3.81 (dd, J = 38.3, 31.6 Hz, 2H), 2.36–1.94 (m, 5H), 1.25 (t, J = 7.0 Hz, 3H), 0.91 (dd, J = 27.1, 16.0 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 172.93, 156.84, 148.55, 143.57, 137.76, 126.70, 126.54, 118.65, 96.46, 61.35, 57.63, 54.52, 48.05, 31.26, 27.54, 25.50, 19.40, 14.69; MS (ESI) m/z = 511.0 [M+H]+.
Butyl ((S)-1-((S)-2-(5-(3-iodophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (7). It was prepared by coupling compound (D1) with butyl-L-valine carbamate using the previous general procedure, and it was purified using DCM: MeOH 25:1; yellow semisolid; yield: 1.0 g (78%); 1H NMR (400 MHz, CDCl3) δ 8.00–7.80 (m, 1H), 7.57 (ddd, J =26.3, 23.6, 7.9 Hz, 2H), 7.36 (ddd, J = 33.7, 17.4, 6.9 Hz, 1H), 7.06 (dd, J = 16.0, 8.0 Hz, 1H), 5.90–5.33 (m, 1H),5.24 (d, J = 4.4 Hz, 1H), 4.31–4.28 (m, 1H), 4.05 (d, J = 6.6 Hz, 3H), 3.93–3.48 (m, 1H), 2.40–1.89 (m, 4H), 1.57 (d, J = 6.4 Hz, 3H), 1.36 (s, 2H), 0.91 (d, J = 6.4 Hz, 9H); 13C NMR (101 MHz, CDCl3) δ 175.52, 156.63, 154.49, 148.03, 135.87, 134.97, 133.44, 130.19, 128.59, 123.71, 94.54, 64.99, 58.65, 54.17, 53.25, 47.82, 38.47, 30.92, 25.15, 18.85, 17.22, 13.55; MS (ESI) m/z = 539.0 [M+H]+.
Butyl ((S)-1-((S)-2-(5-(4-iodophenyl)-1H-imidazol-2-yl) pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl) carbamate (8). It was prepared by coupling compound (D2) with butyl-L-valine carbamate using the previous general procedure, and it was purified using EtOAc: hexane 2:1; yellow semisolid; yield: 0.9 g (71%), 1H NMR (400 MHz, CDCl3) δ 7.64 (t, J = 8.3 Hz, 2H), 7.55–7.27 (m, 2H), 7.18 (s, 1H), 5.44 (d, J = 9.1 Hz, 1H), 5.23 (dd, J = 8.1, 3.9 Hz, 1H), 4.35–4.12 (m, 1H),4.06 (td, J = 10.8, 3.9 Hz, 2H), 3.89–3.60 (m, 2H), 2.44–1.86 (m, 4H), 1.59 (dd, J = 14.2, 6.4 Hz, 2H), 1.37 (dd, J = 15.0, 7.4 Hz, 2H), 1.25 (dd, J = 8.1, 6.2 Hz, 1H), 0.95–0.83 (m, 9H); 13C NMR (101 MHz, CDCl3) δ 172.97, 156.98, 148.52, 143.24, 137.77, 126.77, 126.52, 115.63, 65.31, 57.69, 54.55, 48.07, 31.25, 31.14, 27.67, 25.48, 19.18, 17.63, 13.88; MS (ESI) m/z = 539.0 [M+H]+.
Methyl ((S)-1-((S)-2-(5-(3-iodophenyl)-1H-imidazol-2-yl)pyrrolidin- 1-yl)-4-methyl-1-oxopentan-2-yl)carbamate (9). It was prepared by coupling compound (D1) with methyl-L-leucine carbamate using the previous general procedure, and it was purified using DCM: MeOH 20:1; yield: 0.7 g (58%), yellow semisolid; 1H NMR (400 MHz, CDCl3) δ 8.13–7.95 (m, 1H), 7.54 (dt, J = 8.2,4.1 Hz, 2H), 7.22–7.02 (m, 2H), 5.48 (d, J = 8.8 Hz, 1H),5.22 (dd, J = 8.0, 3.4 Hz, 1H), 4.53 (td, J = 9.8, 3.8 Hz, 1H),3.67 (s, 3H), 3.65–3.47 (m, 2H), 1.87–1.54 (m, 4H), 1.53– 1.37 (m, 2H), 1.36–1.23 (m, 1H), 0.94 (dd, J = 5.6, 3.2Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.38, 165.63, 156.79, 156.58, 148.06, 146.87, 135.52, 133.34, 130.11, 123.64, 94.55, 54.30, 52.19, 50.90, 47.35, 41.37, 27.68, 25.16, 24.44, 23.14; MS (ESI) m/z = 511.0 [M+H]+.
Methyl ((S)-1-((S)-2-(5-(4-iodophenyl)-1H-imidazol-2-yl) pyrrolidin-1-yl)-4-methyl-1-oxopentan-2-yl) carbamate (10). It was prepared by coupling compound (D2) with methyl-L-leucine carbamate using the previous general procedure, and it was purified using DCM: MeOH 100:3; yellow semisolid; yield: 0.8 g (66%); 1H NMR (400 MHz, CDCl3) δ 7.65 (t, J = 8.9 Hz, 2H), 7.40 (dt, J = 14.0, 7.0 Hz, 2H), 7.18 (s, 1H), 5.46 (d, J = 8.7 Hz, 1H), 5.22 (dd, J = 7.9, 2.8 Hz, 1H), 4.53 (td, J = 9.9, 3.6 Hz, 1H), 3.69 (s, 3H), 3.63–3.46 (m, 2H), 2.61 (ddd, J = 18.3, 10.4, 3.1 Hz, 2H), 2.13–1.02 (m, 5H),0.98–0.87 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 173.71, 157.08, 151.73, 148.36, 137.79, 126.76, 126.57, 111.35, 91.92, 54.64, 52.51, 51.20, 47.66, 41.79, 27.84, 24.74, 23.45, 21.65; MS (ESI) m/z = 511.0 [M+H]+.
Methyl ((R)-1-((S)-2-(5-(3-iodophenyl)-1H-imidazol-2-yl)pyrrolidin- 1-yl)-4-methyl-1-oxopentan-2-yl)carbamate (11). It was prepared by coupling compound (D1) with methyl-D-leucine carbamate using the previous general procedure, and it was purified using DCM: MeOH 20:1; yellow semisolid; yield: 0.8 g (66%); 1H NMR (δ) (400 MHz, CDCl3) δ 8.17–7.95 (m, 1H), 7.69–7.56 (m, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.17–7.03 (m, 2H), 5.47 (dd, J = 26.5, 8.6 Hz, 1H), 5.22 (dd, J = 8.0, 2.9 Hz, 1H), 4.54 (td, J = 9.8, 3.8 Hz, 1H), 3.68 (s, 3H), 3.55 (ddd, J = 24.6,11.7, 5.8 Hz, 2H), 2.43–2.06 (m, 4H), 1.75 (ddd, J = 20.4,13.7, 10.1 Hz, 2H), 1.39–1.31 (m, 1H), 0.94–0.87 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 173.44, 156.92, 155.65, 148.31, 139.30, 135.49, 133.52, 130.25, 123.79, 115.96, 94.75, 54.47, 52.34, 51.00, 47.50, 41.80, 27.50, 25.38, 24.60, 23.34, 21.55; MS (ESI) m/z= 511.0 [M+H]+.
Methyl ((R)-1-((S)-2-(5-(4-iodophenyl)-1H-imidazol-2-yl) pyrrolidin-1-yl)-4-methyl-1-oxopentan-2-yl) carbamate (12). It was prepared by coupling compound (D2) with methyl-D-leucine carbamate using the previous general procedure, and it was purified using DCM: MeOH 100:3; yellow semisolid; yield: 0.55 g (45%); 1H NMR (400 MHz, CDCl3) δ 7.65 (t, J = 8.9 Hz, 2H), 7.40 (dt, J = 14.0, 7.0 Hz, 2H), 7.18 (s, 1H), 5.46 (d, J = 8.7 Hz, 1H), 5.22 (dd, J = 7.9, 2.8 Hz, 1H), 4.53 (td, J = 9.9, 3.6 Hz, 1H), 3.69 (s, 3H), 3.63–3.46 (m, 2H), 2.61 (ddd, J = 18.3, 10.4, 3.1 Hz, 2H), 2.13–1.02 (m, 5H),0.98–0.87 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 173.71, 157.08, 151.73, 148.36, 137.79, 126.76, 126.57, 111.35, 91.92, 54.64, 52.51, 51.20, 47.66, 41.79, 27.84, 24.74, 23.45, 21.65; MS (ESI) m/z = 511.0 [M+H]+.
Ethyl ((S)-1-((S)-2-(5-(3-iodophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-4-methyl-1oxopentan-2-yl)carbamate (13). It was prepared by coupling compound (D1) with ethyl-L-leucine carbamate using the previous general procedure, and it was purified using DCM: MeOH 20:1; yellow semisolid; yield: 0.75 g (62%); 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.28 (d, J = 6.0 Hz, 1H), 7.08 (dt, J = 15.8, 8.0 Hz, 2H), 5.24 (dd, J = 13.0, 7.5 Hz, 1H), 5.13 (s, 1H), 4.54–4.46 (m, 1H), 4.10 (s, 2H), 3.91–3.79 (m, 2H), 2.50–2.11 (m, 4H), 1.73–1.70 (m, 2H), 1.54 (s, 1H), 1.23 (s, 3H), 0.95 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 173.79, 156.52, 156.27, 148.10, 145.99, 141.50, 137.03, 133.40, 130.45, 123.95, 94.56, 61.03, 52.15, 51.34, 47.43, 41.47, 24.60, 22.74, 21.57, 21.09, 14.34; MS (ESI) m/z = 525.0 [M+H]+.
Ethyl ((S)-1-((S)-2-(5-(4-iodophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-4-methyl-1-oxopentan-2-yl)carbamate (14). It was prepared by coupling compound (D2) with ethyl-L-leucine carbamate using the previous general procedure, and it was purified using DCM: MeOH 100: 4.5; dark yellow oil; yield: 0.65 g (52%); 1H NMR (δ) (400 MHz, CDCl3) δ 7.79–7.29 (m, 4H), 7.19 (s, 1H), 5.59–5.31 (m, 1H), 5.30–5.05 (m, 1H), 4.21 (dd, J = 91.9, 85.2 Hz, 3H), 3.87–3.53 (m, 2H), 1.92 (ddd, J = 261.2, 54.6, 6.4 Hz, 7H), 1.24 (d, J = 7.1 Hz, 3H), 0.97–0.89 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 177.25, 156.64, 155.31, 143.30, 138.04, 128.61, 126.80, 119.15, 102.58, 61.40, 52.50, 51.37, 47.74, 41.68, 24.91, 23.36, 23.03, 21.84, 14.64; MS (ESI) m/z = 525.0 [M+H]+.
Ethyl ((R)-1-((S)-2-(5-(3-iodophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-4-methyl-1-oxopentan-2-yl)carbamate (15). It was prepared by coupling compound (D1) with ethyl-D-leucine carbamate using the previous general procedure, and it was purified using DCM: MeOH; 20:1; yellow semisolid; yield: 0.76 g (60%); 1H NMR (400 MHz, CDCl3) δ 8.15–7.91 (m, 1H), 7.62 (dd, J = 42.8, 11.8 Hz, 1H), 7.54–7.50 (m, 1H), 7.18–7.04 (m, 2H), 5.43–5.28 (m, 1H), 5.28–5.17 (m, 1H), 4.53 (td, J = 9.9, 3.8 Hz, 1H), 4.15–4.07 (m, 2H), 3.82–3.55 (m, 2H), 2.47–1.98 (m, 4H), 1.88–1.63 (m, 2H), 1.49 (m 1H), 1.27–1.23 (m, 3H), 0.91 (m, 6H);13C NMR (δ) (101 MHz, CDCl3) δ 173.36, 156.77, 156.34, 148.16, 147.17, 135.32, 133.35, 130.07, 123.61, 122.59, 94.58, 61.01, 54.29, 50.70, 47.31, 41.66, 25.21, 24.43, 23.18, 21.39, 14.37; MS (ESI) m/z = 525.0 [M+H]+.
Ethyl ((R)-1-((S)-2-(5-(4-iodophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-4-methyl-1-oxopentan-2-yl) carbamate (16). It was prepared by coupling compound (D2) with ethyl-D-leucine carbamate using the previous general procedure, and it was purified using EtOAc; yellow semisolid; yield: 1.0 g (80%); 1H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 8.4, 3.7 Hz, 2H), 7.51–7.30 (m, 2H), 7.20 (s, 1H), 5.36 (d, J = 8.8 Hz, 1H), 5.24–5.16 (m, 1H), 4.54–4.33 (m, 1H), 4.10 (d, J = 7.0 Hz, 2H), 3.85–3.63 (m, 2H), 1.67 (ddd, J = 91.9, 49.0, 43.6 Hz, 4H), 1.23 (td, J = 7.2, 5.0 Hz, 6H), 0.93–0.86 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 165.92, 156.69, 148.42, 142.31, 137.80, 126.77, 126.61, 119.22, 103.53, 61.34, 54.58, 51.08, 47.64, 38.74, 27.87, 23.45, 23.09, 21.65, 14.67; MS (ESI) m/z = 525.0 [M+H]+.
Methyl ((S)-2-((S)-2-(5-(3-iodophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethyl)carbamate (17). It was prepared by coupling compound (D1) with methyl-L-phenylglycine carbamate using the previous general procedure, and it was purified using DCM: MeOH 20:1; yellow semisolid; yield: 0.8 g (64%); 1H NMR (400 MHz, CDCl3) δ 7.67 (ddd, J = 24.0, 10.9, 5.6 Hz, 1H), 7.57–7.45 (m, 1H), 7.44–7.29 (m, 8H), 5.98–5.82 (m, 1H), 5.33–5.21 (m, 1H), 3.65 (s, 3H), 3.17 (s, 2H), 1.33 (d, J = 5.7 Hz, 5H); MS (ESI) m/z = 531.0 [M+H]+.
Methyl ((S)-2-((S)-2-(5-(4-iodophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethyl) carbamate (18). It was prepared by coupling compound (D2) with methyl-L-phenylglycine carbamate using the previous general procedure, and it was purified using DCM: MeOH 100:4; yellow semisolid; yield: 0.9 g (72%); 1H NMR (400 MHz, CDCl3) δ 7.64 (dd, J = 19.9, 8.4 Hz, 2H), 7.36 (ddd, J = 30.7, 17.8, 5.5 Hz, 6H), 7.24–7.12 (m, 2H), 6.11 (t, J = 13.6 Hz, 1H), 5.48 (d, J = 7.9 Hz, 1H), 5.29–5.24 (m, 1H), 3.75–3.65 (m, 2H), 3.64 (s, 3H), 2.19–1.85 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 170.49, 157.94, 156.40, 147.58, 137.72, 136.40, 129.30, 128.78, 128.19, 127.69, 126.50, 114.36, 91.81, 58.31, 56.94, 52.49, 47.33, 27.95, 25.22; MS (ESI) m/z = 531.0 [M+H]+.
Methyl ((R)-2-((S)-2-(5-(3-iodophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethyl)carbamate (19). It was prepared by coupling compound (D1) with methyl-D-phenylglycine carbamate using the previous general procedure, and it was purified using DCM: MeOH; 20:1; yellow semisolid; yield: 0.5 g (40%); 1H NMR (400 MHz, CDCl3) δ 7.90 (t, J = 36.0 Hz, 1H), 7.55 (dd, J = 26.6, 9.3 Hz, 1H), 7.39–7.28 (m, 8H), 6.06–6.00 (m, 1H), 5.39–5.31 (m, 1H), 5.18 (s, 1H), 3.62 (s, 3H), 3.23–2.87 (m, 2H), 2.57–1.68 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 173.57, 157.16, 156.01, 137.33, 133.80, 132.45, 130.46, 129.88, 129.23, 128.54, 127.92, 126.98 124.51, 116.06, 94.43, 58.09, 57.70, 52.79, 52.15, 38.45, 36.65; MS (ESI) m/z = 531.0 [M+H]+.
Methyl ((R)-2-((S)-2-(5-(4-iodophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethyl) carbamate (20). It was prepared by coupling compound (D2) with methyl-D-phenylglycine carbamate using the previous general procedure, and it was purified using DCM: MeOH 100: 4; brown semisolid; yield: 0.9 g (72%); 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.1 Hz, 2H), 7.40–7.34 (m, 8H), 5.86 (d, J = 4.8 Hz, 1H), 5.38 (d, J = 5.3 Hz, 1H), 5.33 (d, J = 7.0 Hz, 1H), 3.64 (s, 3H), 3.57 (m, 2H), 2.38–1.88 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 168.37, 157.31, 151.80, 148.41, 138.47, 132.98, 129.71, 129.05, 128.27, 127.35, 125.66, 118.94, 95.82, 58.11, 53.21, 52.60, 47.33, 31.16, 24.72; MS (ESI) m/z = 531.0 [M+H]+.
Procedures of Sonogashira Reaction Followed by Desilylation and Dimerization, Compounds (1a–10a) and Compounds (1b–10b)
Compounds (1–20) were mixed with bis-(triphenylphosphine) palladium II chloride (5% mmol) and copper (I) iodide (10% mmol) in DMF (5 mL). TEA was added (1.5 equiv.), followed by trimethylsilylacetylene (TMS) (1.15 equiv.). The mixture was left to stir at 70 °C for 4 h under argon. Afterwards, the reaction mixture was left to cool, concentrated under vacuum, washed with saturated aqueous NaCl solution, and extracted with EtOAc (50 mL × 3). The organic layer was separated and dried over MgSO4, filtered then concentrated under reduced pressure to be used in the next step without further purification.
To the resulting compounds from the Sonogashira reaction step, distilled water (2 mL), methanol (10 mL), and potassium carbonate (4 mmol, 0.55 g) were added. The reaction mixture was stirred at 55 °C overnight. Then, it was concentrated under vacuum, washed with distilled water, and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over MgSO4, filtered then concentrated under vacuum. The final product was later purified using silica gel in column chromatography.
Dimethyl ((2S,2′S)-((2S,2′S)-((buta-1,3-diyne-1,4-diylbis(3,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2diyl))dicarbamate (1a). It was prepared using a Sonogashira reaction, followed by dimerization of compound 1, and it was purified using DCM: MeOH 20:1; yellow semisolid; yield: 11%; 1H NMR (400 MHz, CDCl3) δ 7.57–7.52 (m, 2H), 7.46 (ddd, J = 5.7, 3.8, 2.1 Hz, 2H), 7.34–7.28 (m, 4H), 7.23–7.19 (m, 2H), 5.60 (d, J = 9.1 Hz, 2H), 5.24–5.21 (m, 2H), 4.31 (dd, J = 9.0, 6.9 Hz, 2H), 3.68 (s, 6H), 3.63 (d, J = 14.1 Hz, 4H), 2.21–2.12 (m, 3H), 2.09–2.04 (m, 3H), 2.03–1.92 (m, 4H), 0.86 (d, J = 6.7 Hz, 12H); 13C NMR (101 MHz, CDCl3) δ 172.47, 158.29, 156.94, 148.12, 132.68, 131.94, 130.08, 128.39, 128.08, 125.04, 122.18, 115.33, 82.22, 74.81, 57.47, 54.18, 52.18, 47.71, 30.96, 27.25, 25.19, 19.04; MS (ESI) m/z = 787.0 [M+H]+.
Dimethyl ((2S,2′S)-((2S,2′S)-((buta-1,3-diyne-1,4-diylbis(4,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate (1b). It was prepared using a Sonogashira reaction, followed by dimerization of compound 2, and it was purified using EtOAc: MeOH 100:3; light brown solid; yield: 12%; mp = 116–118 °C; 1H NMR (400 MHz, CDCl3) δ 7.77–7.28 (m, 8H), 7.21–6.95 (m, 2H), 5.66 (d, J = 7.4 Hz, 2H), 5.29–5.19 (m, 2H), 4.37–3.98 (m, 2H), 3.67 (s, 6H), 3.22–2.74 (m, 4H), 2.44–2.11 (m, 5H), 2.11–1.87 (m, 5H), 0.92 (t, J = 26.6 Hz, 12H); 13C NMR (101 MHz, CDCl3) δ 172.53, 157.22, 148.62, 136.66, 135.34, 132.87, 124.65, 119.56, 118.72, 82.35, 74.31, 58.29, 57.83, 52.47, 48.03, 31.32, 25.35, 19.32, 17.77; MS (ESI) m/z = 787.0 [M+H]+; HRMS m/z = 785.3783 (calculated = 785.3781) (M-H)−.
Dimethyl ((2R,2′R)-((2S,2′S)-((buta-1,3-diyne-1,4-diylbis(3,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate (2a). It was prepared using a Sonogashira reaction, followed by dimerization of compound 3, and it was purified using DCM: MeOH 20:1; light brown solid; yield: 10%; mp = 103.0–105.0 °C; 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 2H), 7.66 (t, J = 11.4 Hz, 2H), 7.37 (ddd, J = 7.7, 4.6, 1.4 Hz, 2H), 7.30 (t, J = 7.7 Hz, 2H), 7.21 (d, J = 9.7 Hz, 2H), 5.53 (d, J = 7.7 Hz, 2H), 5.31–5.28 (m, 2H), 4.21 (t, J = 7.6 Hz, 2H), 3.72–3.63 (m, 6H), 3.63–3.44 (m, 4H), 2.25–2.01 (m, 9H), 1.97 (d, J = 16.4 Hz, 1H), 1.02 (dd, J = 6.6, 2.0 Hz, 12H); 13C NMR (101 MHz, CDCl3) δ 171.99, 157.36, 151.33, 148.28, 135.03, 133.28, 130.38, 128.55, 125.45, 121.81, 119.07, 117.31, 81.50, 73.68, 58.21, 54.97, 52.38, 47.35, 30.57, 29.13, 24.47, 19.24; MS (ESI) m/z = 787.0 [M+H]+; HRMS m/z = 785.3777 (calculated = 785.3781) (M-H)−.
Dimethyl ((2R,2′R)-((2S,2′S)-((buta-1,3-diyne-1,4-diylbis(4,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate (2b). It was prepared using a Sonogashira reaction, followed by dimerization of compound 4, and it was purified using DCM: MeOH 100:5; light brown solid; yield: 14%; mp: 120–122 °C; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.7 Hz, 4H), 7.47 (d, J = 8.2 Hz, 4H), 7.18 (s, 2H), 5.56 (d, J = 7.3 Hz, 2H), 5.30 (d, J = 4.5 Hz, 2H), 4.21 (t, J = 7.5 Hz, 2H), 3.79 (d, J = 91.2 Hz, 2H), 3.63 (s, 6H), 3.58 (d, J = 9.0 Hz, 2H), 2.34–2.09 (m, 5H), 2.09–1.86 (m, 5H), 1.06–0.97 (m, 12H); 13C NMR (101 MHz, CDCl3) δ 172.17, 157.49, 149.27, 148.57, 136.92, 132.81, 124.49, 119.58, 115.89, 82.13, 74.31, 58.38, 55.16, 52.52, 47.55, 30.76, 29.35, 24.65, 18.08; MS (ESI) m/z = 787.0 [M+H]+; HRMS m/z = 785.3784 (calculated = 785.3781) (M-H)−.
Diethyl ((2S,2′S)-((2S,2′S)-((buta-1,3-diyne-1,4-diylbis(3,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate (3a). It was prepared using a Sonogashira reaction, followed by dimerization of compound 5, and it was purified using DCM: MeOH 20:1; yellow solid; yield: 14%; mp: 124 –126.7 °C; 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 2H), 7.57–7.50 (m, 4H), 7.20–7.01 (m, 4H), 5.61 (t, J = 47.2 Hz, 2H), 5.22 (dd, J = 8.1, 4.0 Hz, 2H), 4.32–4.27 (m, 2H), 4.10 (dd, J = 8.0, 3.9 Hz, 4H), 3.87–3.63 (m, 4H), 2.35–1.94 (m, 10H), 1.07–0.97 (m, 6H), 0.91–0.84 (m, 12H); 13C NMR (101 MHz, CDCl3) δ 172.59, 165.59, 156.54, 148.19, 147.36, 135.38, 133.32, 130.08, 123.88, 123.56, 118.80, 82.61, 74.65, 61.02, 57.39, 54.18, 47.71, 30.86, 25.14, 18.91, 17.41, 14.36; MS (ESI) m/z = 815.0 [M+H]+.
Diethyl ((2S,2′S)-((2S,2′S)-((buta-1,3-diyne-1,4-diylbis(4,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate (3b). It was prepared using a Sonogashira reaction, followed by dimerization of compound 6, and it was purified using EtOAc: MeOH 100:2.5; dark brown solid; yield: 17%; mp =139–141 °C; 1H NMR (400 MHz, CDCl3) δ 7.77–7.29 (m, 8H), 7.18 (d, J = 22.4 Hz, 2H), 5.46 (d, J = 9.0 Hz, 2H), 5.23 (dd, J = 7.7, 3.7 Hz, 2H), 4.28 (dd, J = 42.7, 35.9 Hz, 2H), 4.13–4.04 (m, 4H), 3.81 (dd, J = 38.3, 31.6 Hz, 4H), 2.36–1.95 (m, 10H), 1.25 (t, J = 7.0 Hz, 6H), 0.91 (dd, J = 27.1, 16.0 Hz, 12H); 13C NMR (101 MHz, CDCl3) δ 172.74, 156.85, 150.04, 141.81, 132.93, 127.58, 125.65, 124.50, 110.69, 82.64, 74.22, 61.33, 57.70, 54.66, 48.06, 31.30, 25.41, 19.39, 17.74, 14.70; MS (ESI) m/z = 815.0 [M+H]+; HRMS m/z = 813.4100 (calculated = 813.4094) (M-H)−.
Dibutyl ((2S,2′S)-((2S,2′S)-((buta-1,3-diyne-1,4-diylbis(3,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate (4a). It was prepared using a Sonogashira reaction, followed by dimerization of compound 7, and it was purified using DCM: MeOH 20:1; light brown semisolid; yield: 15%; 1H NMR (400 MHz, CDCl3) δ 7.79–7.66 (m, 5H), 7.61–7.47 (m, 5H), 5.44 (d, J = 9.1 Hz, 2H), 5.29– 5.09 (m, 2H), 4.21 (t, J = 6.0 Hz, 6H), 4.04 (d, J = 8.6 Hz, 4H), 2.37–1.81 (m, 10H), 1.67 (dd, J = 12.0, 5.9 Hz, 4H), 1.60–1.50 (m, 4H), 0.93–0.89 (m, 18H); 13C NMR (101 MHz, CDCl3) δ 167.58, 160.22, 154.81, 141.70, 133.68, 132.24, 131.95, 130.70, 128.60, 126.47, 125.68, 124.16, 81.60, 74.10, 67.96, 65.03, 60.00, 45.90, 38.52, 30.16, 28.73, 23.54, 22.80, 13.88, 10.78; MS (ESI) m/z = 871.0 [M+H]+.
Dibutyl ((2S,2′S)-((2S,2′S)-((buta-1,3-diyne-1,4-diylbis(4,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate (4b). It was prepared using a Sonogashira reaction, followed by dimerization of compound 8, and it was purified using EtOAc: MeOH 100:2; light brown solid; yield: 21%; mp =136–138 °C; 1H NMR (400 MHz, CDCl3) δ 7.74–7.28 (m, 8H), 7.21–7.07 (m, 2H), 5.50 (t, J = 9.7 Hz, 2H) 5.29–5.20 (m, 2H), 4.36–4.13 (m, 2H), 4.04 (dt, J = 8.7, 6.0 Hz, 4H), 3.82 (dd, J = 35.8, 28.6 Hz, 4H), 2.39–2.15 (m, 5H), 2.13–1.98 (m, 5H), 1.61–1.56 (m, 4H), 1.40–1.34 (m, 4H), 0.90 (dd, J = 15.3, 7.6 Hz, 18H); 13C NMR (101 MHz, CDCl3) δ 172.87, 157.21, 152.52, 149.10, 133.12, 127.17, 124.89, 124.58, 119.92, 82.57, 74.79, 65.51, 57.97, 54.95, 48.31, 31.55, 31.38, 25.60, 19.62, 19.41, 18.04, 14.12; MS (ESI) m/z = 871.0 [M+H]+; HRMS m/z = 869.4715 (calculated = 869.4720) (M-H)−.
Dimethyl ((2S,2′S)-((2S,2′S)-((buta-1,3-diyne-1,4-diylbis(3,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(4-methyl-1-oxopentane-1,2-diyl))dicarbamate (5a). It was prepared using a Sonogashira reaction, followed by dimerization of compound 9, and it was purified using DCM: MeOH; 20:1; light brown solid; yield: 14%; mp= 103.1–105.3 °C; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.3 Hz, 1H), 7.65 (s, 1H), 7.31 (ddd, J = 11.8, 10.9, 6.0 Hz, 6H), 7.21 (d, J = 7.6 Hz, 2H), 5.54 (t, J = 9.8 Hz, 2H), 5.25–5.17 (m, 2H), 4.53 (dd, J = 12.5, 6.2 Hz, 2H), 3.67 (s, 6H), 3.47 (d, J = 2.8 Hz, 4H), 1.81–1.48 (m, 8H), 1.47–1.33 (m, 4H), 1.31–1.21 (m, 2H), 0.91 (dd, J = 14.7, 5.1 Hz, 12H);13C NMR (101 MHz, CDCl3) δ 173.21, 158.39, 156.78, 148.16, 131.08, 130.38, 128.54, 125.24, 121.86, 120.35, 119.49, 117.42, 81.46, 74.39, 54.31, 52.14, 50.85, 47.29, 41.52, 25.16, 24.41, 23.14, 21.32; MS (ESI) m/z = 815.0 [M+H]+; HRMS m/z = 813.4089 (calculated = 813.4094) (M-H)−.
Dimethyl ((2S,2′S)-((2S,2′S)-((buta-1,3-diyne-1,4-diylbis(4,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(4-methyl-1-oxopentane-1,2-diyl))dicarbamate (5b). It was prepared using a Sonogashira reaction, followed by dimerization of compound 10, and it was purified using EtOAc: MeOH 100:4.5; light brown solid; yield: 21%; mp = 124–126 °C; 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 88.4 Hz, 4H), 7.48 (s, 4H), 7.21 (d, J = 5.2 Hz, 2H), 5.47 (d, J = 7.8 Hz, 2H), 5.22 (d, J = 7.2 Hz, 2H), 4.60–4.50 (m, 2H), 3.68 (s, 6H), 3.64–3.54 (m, 4H), 2.15 (ddd, J = 28.9, 15.1, 5.8 Hz, 8H), 1.70 (m, 4H), 1.53–1.47 (m, 2H), 0.94–0.87 (m, 12H); 13C NMR (101 MHz, CDCl3) δ 173.87, 157.08, 152.56, 146.80, 139.02, 132.93, 127.18, 124.71, 119.45, 82.54, 74.99, 54.70, 52.49, 51.14, 47.63, 38.74, 25.47, 24.73, 23.49, 21.70; MS (ESI) m/z = 815.0 [M+H]+; HRMS m/z = 813.4101 (calculated = 813.4094) (M-H)−.
Dimethyl ((2R,2′R)-((2S,2′S)-((buta-1,3-diyne-1,4-diylbis(3,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(4-methyl-1-oxopentane-1,2-diyl))dicarbamate (6a). It was prepared using a Sonogashira reaction, followed by dimerization of compound 11, and it was purified using DCM: MeOH 20:1; yellow solid; yield: 12%; mp =111–113 °C; 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 2H), 7.35 (t, J = 5.8 Hz, 3H), 7.29 (dd, J = 12.6, 5.0 Hz, 3H), 7.20 (d, J = 6.4 Hz, 2H), 5.52 (d, J = 8.7 Hz, 2H), 5.26–5.21 (m, 2H), 4.54 (td, J = 9.8, 3.7 Hz, 2H), 3.68 (s, 6H), 3.56 (dd, J = 49.1, 14.3 Hz, 4H), 2.20–1.96 (m, 8H), 1.83–1.64 (m, 4H), 1.49 (td, J = 10.1, 5.3 Hz, 2H), 0.95–0.88 (m, 12H); 13C NMR (101 MHz, CDCl3) δ 171.59, 156.76, 151.03, 148.10, 130.39, 128.83, 128.55, 126.74, 125.26, 121.81, 120.99, 115.14, 81.54, 73.86, 54.32, 52.15, 50.84, 47.31, 41.62, 27.38, 25.19, 24.43, 21.37; MS (ESI) m/z = 815.0 [M+H]+; HRMS m/z = 813.4088 (calculated = 813.4094) (M-H)−.
Dimethyl ((2R,2′R)-((2S,2′S)-((buta-1,3-diyne-1,4-diylbis(4,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(4-methyl-1-oxopentane-1,2-diyl))dicarbamate (6b). It was prepared using a Sonogashira reaction, followed by dimerization of compound 12, and it was purified using EtOAc: MeOH 100:2.5; brown solid; MP = 129–131 °C; yield: 25%; 1H NMR (400 MHz, CDCl3) δ 7.63 (dd, J = 71.0, 14.1 Hz, 4H), 7.46 (dd, J = 15.5, 4.4 Hz, 4H), 7.18 (d, J = 17.3 Hz, 2H), 5.55 (d, J = 8.6 Hz, 2H), 5.24 (dd, J = 17.3, 12.1 Hz, 2H), 4.55 (td, J = 9.6, 3.8 Hz, 2H), 3.89–3.69 (m, 4H), 3.69–3.65 (s, 6H), 3.13–2.86 (m, 2H), 2.21–2.09 (m, 6H), 1.70–1.43 (m, 4H), 1.35 (dd, J = 12.4, 5.0 Hz, 2H), 0.92 (dd, J = 20.5, 6.3 Hz, 12H); 13C NMR (101 MHz, CDCl3) δ 173.48, 158.59, 157.07, 148.63, 132.94, 127.54, 124.68, 124.48, 119.77, 116.97, 81.89, 74.50, 54.72, 52.47, 51.17, 47.63, 41.88, 25.41, 24.73, 23.48, 21.68; MS (ESI) m/z = 815.0 [M+H]+; HRMS m/z = 813.4091 (calculated = 813.4094) (M-H)−.
Diethyl ((2S,2′S)-((2S,2′S)-((buta-1,3-diyne-1,4-diylbis(3,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(4-methyl-1-oxopentane-1,2-diyl))dicarbamate (7a). It was prepared using a Sonogashira reaction, followed by dimerization of compound 13, and it was purified using DCM: MeOH 20:1; light brown semi-solid; yield: 14%; 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.65 (d, J = 7.0 Hz, 2H), 7.37–7.29 (m, 5H), 7.20 (s, 2H), 5.42 (d, J = 8.0 Hz, 2H), 5.24 (s, 2H), 4.53 (s, 2H), 4.11 (d, J = 6.4 Hz, 4H), 3.56 (d, J = 24.2 Hz, 4H), 2.25 (d, J = 85.1 Hz, 8H), 1.70 (s, 4H), 1.48 (d, J = 10.1 Hz, 2H), 1.24 (s, 6H), 0.95–0.89 (m, 12H); 13C NMR (101 MHz, CDCl3) δ 173.30, 156.34, 155.62, 148.17, 134.71, 133.38, 130.37, 129.94, 128.56, 125.27, 121.83, 118.01, 81.50, 73.68, 61.00, 54.31, 50.73, 47.29, 41.63, 25.19, 24.43, 23.16, 21.37, 14.37; MS (ESI) m/z = 843.0 [M+H]+; HRMS m/z = 841.4398 (calculated = 841.4407) (M-H)−.
Diethyl ((2S,2′S)-((2S,2′S)-((buta-1,3-diyne-1,4-diylbis(4,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(4-methyl-1-oxopentane-1,2-diyl))dicarbamate (7b). It was prepared using a Sonogashira reaction, followed by dimerization of compound 14, and it was purified using DCM: MeOH 100: 2.5; brown solid; yield: 13%; mp = 118–120 °C; 1H NMR (400 MHz, CDCl3) δ 7.79–7.29 (m, 8H), 7.19 (s, 2H), 5.62–5.48 (m, 2H), 5.30–4.99 (m, 2H), 4.21 (dd, J = 91.9, 85.2 Hz, 6H), 3.87–3.53 (m, 4H), 2.40–1.93 (m, 7H), 1.80–1.37 (m, 7H), 1.24 (d, J = 7.1 Hz, 6H), 0.97–0.89 (m, 12H); 13C NMR (101 MHz, CDCl3) δ 169.07, 156.69, 151.88, 141.95, 132.98, 132.07, 124.51, 121.70, 117.21, 82.14, 72.30, 61.35, 54.73, 51.11, 47.70, 41.92, 24.79, 23.51, 23.12, 21.71, 14.71; MS (ESI) m/z: 843.0 [M+H]+.
Diethyl ((2R,2′R)-((2S,2′S)-((buta-1,3-diyne-1,4-diylbis(3,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(4-methyl-1-oxopentane-1,2-diyl))dicarbamate (8a). It was prepared using a Sonogashira reaction, followed by dimerization of compound 15, and it was purified using DCM: MeOH; 20:1; yellow solid; yield: 13%; mp = 109.0–111.0 °C; 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.68–7.64 (m, 1H), 7.35 (t, J = 6.8 Hz, 4H), 7.30 (d, J = 7.5 Hz, 2H), 7.21 (d, J = 6.4 Hz, 2H), 5.40 (d, J = 8.7 Hz, 2H), 5.26–5.22 (m, 2H), 4.54 (td, J = 9.8, 3.5 Hz, 2H), 4.13–4.09 (m, 4H), 3.58 (d, J = 26.5 Hz, 4H), 2.24–2.06 (m, 8H), 2.04–1.81 (m, 4H), 1.80–1.53 (m, 6H), 1.52–1.47 (m, 2H), 0.92 (dd, J = 15.4, 5.6 Hz, 12H); 13C NMR (101 MHz, CDCl3) δ 173.30, 162.65, 156.36, 134.58, 130.43, 128.57, 127.40, 125.38, 124.06, 121.84, 116.25, 114.57, 81.41, 73.53, 61.01, 54.30, 50.72, 47.31, 41.68, 25.20, 24.44, 23.18, 21.38, 14.37; MS (ESI) m/z = 843.0 [M+H]+; HRMS m/z = 841.4401 (calculated = 841.4407) (M-H)−.
Diethyl ((2R,2′R)-((2S,2′S)-((buta-1,3-diyne-1,4-diylbis(4,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(4-methyl-1-oxopentane-1,2-diyl))dicarbamate (8b). It was prepared using a Sonogashira reaction, followed by dimerization on compound 16, and it was purified using DCM: MeOH 100:5; light brown solid; yield: 17%; mp = 129–132 °C; 1H NMR (400 MHz, CDCl3) δ 7.75–7.39 (m, 8H), 7.20 (d, J = 15.0 Hz, 2H), 5.65–5.51 (m, 2H), 5.39–5.01 (m, 2H), 4.55 (d, J = 9.1 Hz, 2H), 4.11 (dd, J = 13.2, 6.5 Hz, 4H), 3.85–3.47 (m, 4H), 2.41–1.94 (m, 8H), 1.70–1.44 (m, 4H), 1.41–1.32 (m, 2H), 1.24 (t, J = 7.0 Hz, 6H), 0.96–0.87 (m, 12H); 13C NMR (101 MHz, CDCl3) δ 173.60, 156.67, 155.52, 140.75, 132.95, 124.67, 124.51, 122.70, 117.63, 81.99, 74.50, 61.33, 54.71, 51.05, 47.65, 41.99, 25.45, 24.76, 23.50, 21.71, 14.69; MS (ESI) m/z = 843.0 [M+H]+.
Dimethyl ((1S,1′S)-((2S,2′S)-((buta-1,3-diyne-1,4-diylbis(3,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate (9a). It was prepared using a Sonogashira reaction, followed by dimerization of compound 17, and it was purified using DCM: MeOH 20:1; light brown solid; yield: 10%; mp = 125–127 °C; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 18.0 Hz, 1H), 7.78–7.60 (m, 4H), 7.54 (dd, J = 11.2, 5.1 Hz, 1H), 7.49–7.33 (m, 12H), 7.31–7.29 (m, 2H), 6.25–6.05 (m, 2H), 5.44 (dd, J = 30.4, 7.3 Hz, 2H), 5.29 (d, J = 2.8 Hz, 2H), 3.65 (d, J = 9.2 Hz, 6H), 3.42–3.11 (m, 4H), 2.24–1.95 (m, 8H); 13C NMR (101 MHz, CDCl3) δ 170.16, 156.11, 155.42, 136.19, 131.84, 130.37, 129.02, 128.50, 127.91, 127.39, 125.32, 121.85, 115.71, 114.80, 83.07, 73.71, 56.63, 574.76, 52.19, 47.01, 29.11, 24.96; MS (ESI) m/z = 855.0 [M+H]+; HRMS m/z = 853.3474 (calculated = 853.3468) (M-H)−.
Dimethyl ((1S,1′S)-((2S,2′S)-((buta-1,3-diyne-1,4-diylbis(4,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate (9b). It was prepared using a Sonogashira reaction, followed by dimerization of compound 18, and it was purified using DCM: MeOH 100:4; brown semisolid; yield: 15%; 1H NMR (400 MHz, CDCl3) δ 7.64 (dd, J = 19.9, 8.4 Hz, 4H), 7.36 (ddd, J = 30.7, 17.8, 5.5 Hz, 12H), 7.24–7.08 (m, 4H), 6.11 (t, J = 13.6 Hz, 2H), 5.48 (d, J = 7.9 Hz, 2H), 5.29–5.24 (m, 2H), 3.75–3.65 (m, 4H), 3.64 (s, 6H), 2.14 (dd, J = 11.7, 5.9 Hz, 3H), 2.11–1.83 (m, 5H);13C NMR (101 MHz, CDCl3) δ 156.55, 147.45, 142.77, 141.65, 132.82, 129.26, 128.00, 124.52, 123.81, 119.42, 116.76, 84.51, 74.36, 57.61, 47.12, 29.30, 22.96; MS (ESI) m/z = 855.0 [M+H]+; HRMS m/z = 853.3470 (calculated = 853.3468) (M-H)−.
Dimethyl ((1R,1′R)-((2S,2′S)-((buta-1,3-diyne-1,4-diylbis(3,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate (10a). It was prepared using a Sonogashira reaction, followed by dimerization of compound 19, and it was purified using DCM: MeOH 20:1; light brown solid; mp =126–128 °C; yield: 10%; 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 15.4, 8.4 Hz, 6H), 7.50 (d, J = 8.4 Hz, 1H), 7.40–7.27 (m, 12H), 7.15 (s, 3H), 6.13 (d, J = 7.8 Hz, 1H), 5.48 (d, J = 7.9 Hz, 2H), 5.31–5.19 (m, 3H), 3.72–3.68 (m, 2H), 3.61 (s, 6H), 3.25 (t, J = 8.5 Hz, 2H), 2.21–2.07 (m, 4H), 2.07–1.84 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 173.57, 156.01, 148.13, 137.33, 133.90, 133.80, 130.46, 129.88, 129.23, 129.12, 128.54, 128.01, 127.92, 126.98, 124.51, 82.61, 72.59, 57.70, 52.79, 52.15, 46.86, 38.45, 24.31; MS (ESI) m/z = 855.0 [M+H]+; HRMS m/z = 853.3472 (calculated = 853.3468) (M-H)−.
Dimethyl ((1R,1′R)-((2S,2′S)-((buta-1,3-diyne-1,4-diylbis(4,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate (10b). It was prepared using a Sonogashira reaction, followed by dimerization of compound 20, and it was purified using DCM: MeOH 100:4; brown solid; yield: 15%; mp = 125–127 °C; δ 7.80 (s, 2H), 7.68 (d, J = 8.1 Hz, 4H), 7.40–7.34 (m, 14H), 5.86 (d, J = 4.8 Hz, 2H), 5.38 (d, J = 5.3 Hz, 2H), 5.33 (d, J = 7.0 Hz, 2H), 3.64 (s, 6H), 3.57 (m, 4H), 2.16 (s, 5H), 1.99–1.84 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 169.34, 156.55, 147.45, 142.77, 141.65, 132.82, 129.26, 128.00, 124.52, 123.81, 119.42, 116.76, 84.51, 74.36, 60.34, 57.61, 51.13, 47.12, 29.30, 22.96; MS (ESI) m/z = 855.0 [M+H]+; HRMS m/z = 853.3472 (calculated = 853.3468) (M-H)−.