Macrocycle 2. Sodium hydride (0.72 g, 30.0 mmol) was added to a DMF solution (600 mL) of the diol 4 (0.83 g, 6.0 mmol) and then the mixture was stirred at room temperature for 20 min. A solution of the dichloride 3[1] (2.32 g, 6 mmol) in DMF (60 mL) was slowly added over 2 h and then the mixture was stirred at room temperature for 10 days. The organic solvent was evaporated under reduced pressure and the yellow residue was then partitioned between ethyl acetate (300 mL) and water (100 mL). The organic layer was washed with water (2 × 100 mL), dried (MgSO4), and concentrated. The crude product was purified (SiO2; hexane/ethyl acetate, 6/4) to afford the macrocycle 2 as a yellow solid (0.19 g, 7%). M.p. 131–133 °C; 1H NMR (400 MHz, CDCl3) δ 4.41 (s, 4 H), 4.51 (s, 4 H), 5.18 (s, 4 H), 6.73 (d, J = 8.1 Hz, 4 H), 7.12 (d, J = 8.1 Hz, 4 H), 7.28 (d, J = 7.7 Hz, 2 H), 7.30 (s, 4 H), 7.64 (t, J = 7.7 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 69.2, 71.3, 71.6, 115.4, 120.3, 126.8, 129.6, 136.9, 136.9, 157.4, 157.5 (one carbon signal is missing, possibly because of signal overlapping); HRMS (ESI): m/z [M + Na]+ C29H27NO4Na calcd. 476.1838, found 476.1812.
NC PPh3Br
NaHMDS
K2CO3
MeOH
LAH
79 %from II
7
OO
83 %
NaHMDS
CH3PPh3Br
67 %
quant.
I II III
IVV
PCC
O
O
OCN
NC
NC
NCH2N O
HO
R
S
Scheme S1. Synthesis of the amine 7
(1S,2R)-cis-2-Butyryloxymethyl-1-[(Z)-4-cyanobut-1-enyl]cyclopropane (II). A solution of (3-cyanopropyl)triphenylphosphonium bromide (53.1 g, 130 mmol) in THF (650 mL) was cooled to 0 °C; NaHMDS (2 M in THF, 69 mL, 138 mmol) was added and then the mixture was stirred for 10 min. A solution of the aldehyde I[2] (14.7 g, 86.3 mmol) in THF (130 mL) was added and then the mixture was stirred at 0 °C for 3.5 h before being poured into petroleum ether (1 L). The precipitate was filtered off, and the filtrate was concentrated and purified (SiO2; hexane/ethyl acetate, 7:3 then 6:4) to afford the alkene II as a yellow oil (15.9 g, 83%). [α]D
14.2, 17.1, 17.4, 18.5, 23.6, 36.1, 64.6, 119.1, 126.6, 131.1, 173.3; HRMS (ESI) m/z [M + Na]+ C13H19NaNO2 calcd. 244.1314, found 244.1318. (1S,2R)-cis-1-[(Z)-4-Cyanobut-1-enyl]-2-hydroxymethylcyclopropane (III). Alkene II (15.9 g, 71.8 mmol) and K2CO3 (29.8 g, 216 mmol) were stirred in MeOH (72 mL) at room temperature for 1.5 h. The mixture was then partitioned between CH2Cl2 (300 mL) and H2O (200 mL) and the organic layer was dried (MgSO4) and concentrated to give the crude alcohol III as a colorless oil (10.9 g, quant.). [α]D
C9H13NaNO calcd. 174.0895, found 174.0920. (1R,2S)-cis-1-Formyl-2-[(Z)-4-cyanobut-1-enyl]cyclopropane (IV). A solution of the alcohol III (15 g, 87.2 mmol) in CH2Cl2 (45 mL) was added to a mixture of PCC (37.6 g, 174 mmol), NaOAc (4.3 g, 52.3 mmol), 4 Å molecular sieves (15.0 g), and Celite (15 g) in CH2Cl2 (45 mL) and then the mélange was stirred at room temperature for 2 h. After additional Celite (90 g) and ethyl ether (300 mL) had been added, the mixture was filtered through a pad of silica gel; the filtrate was concentrated and purified (SiO2; hexane/ethyl acetate, 7:3) to afford the desired aldehyde IV as a colorless oil (11.8 g, 79% from II). [α]D
23 –231.9°; 1H NMR (400 MHz, CDCl3) δ 1.48 (t, J = 7.2 Hz, 2 H), 2.17–2.30 (m, 2 H), 2.37–2.47 (m, 2 H), 2.47–2.60 (m, 2 H), 5.43–5.55 (m, 2 H), 9.36 (d, J = 5.2 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 15.5, 17.2, 21.5, 23.5, 30.0, 119.0, 128.0, 128.9, 200.0; HRMS (ESI): m/z [M + Na]+ C9H11NaNO calcd. 172.0738, found 172.0762. (1S,2R)-cis-1-[(Z)-4-Cyanobut-1-enyl]-2-ethenylcyclopropane (V). NaHMDS (2 M in THF, 24.3 mL, 48.6 mmol) was added to a THF solution (320 mL) of methyltriphenylphosphonium bromide (17.4 g, 48.6 mmol) at –78 °C and then the mixture was stirred for 10 min. A solution of the aldehyde IV (6.04 g, 40.5 mmol) in THF (80.0 mL) was added and then the mixture was stirred at –78 °C for 0.5 h and then warmed to 0 °C for 3.5 h. The mixture was poured into petroleum ether (500 mL) and filtered. The filtrate was concentrated and the residue purified (SiO2; hexane/ethyl acetate, 9:1) to afford the desired product V as a yellow oil (4.0 g, 67%). [α]D
J = 10.4 Hz, 1 H), 5.12 (d, J = 17.2 Hz, 1 H), 5.19–5.30 (m, 1 H), 5.40–5.50 (m, 1 H), 5.50–5.60 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 14.8, 17.1, 17.5, 22.6, 23.7, 114.8, 119.3, 125.7, 132.1, 137.2; HRMS (ESI): m/z [M + Na]+ C10H13NaN calcd. 170.0945, found 170.0924. (1S,2R)-cis-1-[(Z)-5-Aminopent-1-enyl]-2-ethenylcyclopropane (7). Lithium aluminum hydride (2.51 g, 66.0 mmol) was added in small portions to a THF solution (200 mL) of the nitrile V (2.0 g, 13.2 mmol) at 0 °C. The mixture was stirred at 0 °C for 5 h and then wet THF (100 mL), water (2 mL), and MgSO4 (20 g) were added sequentially. The suspension was filtered and the filtrate concentrated to afford the crude amine 7 as a yellow oil (2.05 g, quant.), which was used in the next reaction without further purification. [α]D
2,6-Bis(methanol)-4-[4-(1,3-dioxolanyl)phenyl)]pyridine (X). Sodium methoxide (0.28 g, 5.2 mmol) was added to a MeOH solution (65 mL) of the acetal IX (4.82 g, 13.0 mmol) and then the mixture was heated under reflux for 4 h. After cooling to room temperature, IR-120 (H+) resin was added to the mixture until the pH reached 6.0–7.0. The suspension was filtered and the filtrate concentrated to afford the diol X as a white solid (3.16 g, quant.). M.p. 123–125 °C; 1H NMR (400 MHz, CDCl3/CD3CN, 1:1) δ 3.62 (br s, 2 H), 3.73–3.95 (m, 4 H), 4.48 (s, 4 H), 5.56 (s, 1 H), 7.26 (s, 2 H), 7.33 (d, J = 8.2 Hz, 2 H), 7.46 (d, J = 8.2 Hz, 2 H); 13C NMR (100 MHz, CDCl3/CD3CN, 1:1) δ 63.6, 64.5, 102.3, 115.8, 126.2, 126.5, 138.2, 138.4, 148.2, 159.4; HRMS (ESI): m/z [M + H]+ C16H18NO4 calcd. 288.1236, found 288.1228. Macrocycle XI. Sodium hydride (1.3 g, 54.0 mmol) was added to a solution of diol X (4.18 g, 10.8 mmol) in DMF (1.08 L) and then the mixture was stirred at room temperature for 20 min. A solution of the dichloride 3[1] (2.63 g, 10.8 mmol) in DMF (150 mL) was added slowly to the alkoxide solution over 2 h and then the mixture was stirred at room temperature for 10 d. After evaporating the organic solvent under reduced pressure, the yellow residue was suspended in ethyl acetate (300 mL) and washed with water (3 × 100 mL); the solution was dried (MgSO4) and concentrated. The crude product was purified (SiO2; CH2Cl2/MeOH, 98:2) to afford the macrocycle XI as a white solid (0.44 g, 7%). M.p. 180–182 °C; 1H NMR (400 MHz, CDCl3) δ 4.00–4.23 (m, 4 H), 4.45 (s, 4 H), 4.53 (s, 4 H), 5.18 (s, 4 H), 5.86 (s, 1 H), 6.73 (d, J = 8.6 Hz, 4 H), 7.12 (d, J = 8.6 Hz, 4 H), 7.28 (s, 4 H), 7.49 (s, 2 H), 7.57 (d, J = 8.3 Hz, 2 H), 7.67 (d, J = 8.3 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 65.4, 69.3, 71.4, 71.8, 103.3, 115.4, 118.4, 126.9, 127.1, 127.2, 129.7, 129.8, 137.0, 138.7, 139.3, 149.1, 157.6, 158.3; HRMS (ESI): m/z [M+H]+ C38H36NO6 calcd. 602.2543, found 602.2528. Aldehyde 6. TsOH·H2O (0.13 g, 0.66 mmol) was added to a solution of the macrocycle XI (0.4 g, 0.66 mmol) in acetone/water (10:1, 4.4 mL) and then the mixture was stirred at room temperature for 16 h before being partitioned between CH2Cl2 (30 mL) and water (10 mL). The organic layer was washed with water (2 × 10 mL), dried (MgSO4), and concentrated. The crude product was purified (SiO2; CH2Cl2/MeOH, 98:2) to afford the aldehyde 6 as a white solid (0.33 g, 90%). M.p. 67–69 °C; 1H NMR (400 MHz, CDCl3) δ 4.46 (s, 4 H), 4.54 (s, 4 H), 5.18 (s, 4 H), 6.73 (d, J = 8.1 Hz, 4 H), 7.12 (d, J = 8.1 Hz, 4 H), 7.28 (s, 4 H), 7.52 (s, 2 H), 7.81 (d, J = 8.0 Hz, 2 H), 7.97 (d, J = 8.0 Hz, 2 H), 10.1 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ 69.2, 71.2, 71.9, 115.4, 118.4, 126.9, 127.8, 129.5, 129.8, 130.3, 136.4, 137.0, 144.4, 148.1, 157.6, 158.6, 191.7; HRMS (ESI): m/z [M + H]+ C36H32NO5 calcd. 558.2280,
found 558.2275. Hermaphroditic Monomer 5-H·PF6. Macrocycle 6 (0.33 g, 0.59 mmol), the amine 7 (0.11 g, 0.71 mmol), and potassium carbonate (49 mg, 0.35 mmol) were stirred in CH2Cl2 (10 mL) at 0 °C and then slowly warmed to room temperature over 16 h. The mixture was then filtered and the filtrate concentrated to give a solid residue. The residue was dissolved in MeOH/CH2Cl2 (10:3, 13 mL) at 0 °C and then NaBH4
(45 mg, 1.18 mmol) was added; the mixture was then stirred for 4 h at 0 °C. The mixture was then partitioned between CH2Cl2 (30 mL) and water (10 mL); the organic layer was washed with water (2 × 10 mL), dried (MgSO4), and concentrated. The crude product was purified (SiO2; CH2Cl2/MeOH, 96:4) to afford the amine 5 as a yellow residue (90.0 mg, 23%). [α]D
25 –36.0 °; 1H NMR (400 MHz, CDCl3) δ 0.55 (q, J = 5.2 Hz, 1 H), 1.13 (td, J = 8.2, 5.2 Hz, 1 H), 1.63 (quintet, J = 7.2 Hz, 2 H), 1.65–1.80 (m, 1 H), 1.80–1.92 (m, 1 H), 2.20 (q, J = 7.2 Hz, 2 H), 2.67 (t, J = 7.2 Hz, 2 H), 3.84 (s, 2 H), 4.45 (s, 4 H), 4.53 (s, 4 H), 4.98 (d, J = 10.5 Hz, 1 H), 5.02–5.15 (m, 2 H), 5.18 (s, 4 H), 5.44 (dt, J = 10.5, 7.3 Hz, 1 H), 5.48–5.60 (m, 1 H), 6.72 (d, J = 8.6 Hz, 4 H), 7.12 (d, J = 8.6 Hz, 4 H), 7.28 (s, 4 H), 7.42 (d, J = 8.0 Hz, 2 H), 7.49 (s, 2 H), 7.62 (d, J = 8.0 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 14.7, 17.1, 22.4, 25.3, 29.8, 48.9, 53.5, 69.2, 71.4, 71.7, 114.4, 115.4, 118.2, 126.9, 127.1, 128.7, 129.1, 129.7, 130.2, 137.0, 138.0, 141.4, 149.2, 157.5, 158.1 (two carbon signals are missing, possibly because of signal overlapping); HRMS (ESI): m/z [M + Na]+ C46H48N2O4Na calcd. 715.3512, found 715.3501. 1 N HCl (57 µL) was added to a solution of the amine 5 (40 mg, 57 µmol) in CH2Cl2 (1 mL) and CH3CN (10 mL) and then saturated aqueous KPF6 solution (20 mL) was added. The organic solvent was evaporated under reduced pressure and the precipitate was filtered off to give the monomer 5-H·PF6 as a white solid (40 mg, 84%). M.p. >230 °C; [α]D
Figure 1. Partial 1H NMR spectra (400 MHz, CD3CN, 298 K) of (a) macrocycle 2, (b) an equimolar mixture of 2 and DBA·PF6 (10 mM), and (c) DBA·PF6. The descriptors “UC” and “C” refer to the uncomplexed and complexed states, respectively.
