D. Mori, et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
C16H23N2O5+). [α]D20 = − 60.28 (c = 1.01, CHCl3).
dipicolylamine (0.83 g, 4.5 mmol), potassium carbonate (0.62 g,
4.5 mmol), and potassium iodide (0.74 g, 4.5 mmol) were added. Under
N2 stream, the mixture was stirred at 80 °C for 95 hr. After the reaction,
a saturated aqueous ammonium chloride solution was added to the
mixture. Compounds were extracted with ethyl acetate, and the organic
layer was dried with sodium sulfate. The solvent was removed under
reduced pressure. Purification by silica gel flash-chromatography
(hexane/ethyl acetate = 4/1) yielded 6 (0.77 g, 1.6 mmol, 54%) as a
colorless oil. 1H NMR (500 MHz, CDCl3) δ; 8.56–8.53 (m, 2H), 8.27 (s,
1H), 8.22 (d, J = 2.9 Hz, 1H), 7.71–7.65 (m, 2H), 7.54 (d, J = 8.0 Hz,
2H), 7.35 (s, 1H), 7.19–7.14 (m, 2H), 4.55–4.50 (m, 1H), 4.31 (broad s,
1H), 4.15 (dd, J = 6.9, 2.9 Hz, 1H), 3.92–3.89 (m, 2H), 3.85 (s, 4H),
3.73 (s, 2H), 2.27–2.38 (m, 2H), 1.41 (s, 9H). 13C NMR (125 MHz,
CDCl3) δ; 159.0, 156.2, 155.1, 149.0, 142.6, 136.6, 135.3, 133.8, 123.0,
122.2, 121.9, 79.6, 68.8, 59.9, 58.3, 55.6, 28.4, 19.2. MS (EI+) m/z;
475 ([M]+, 3.0), 383 (94), 327 (1 0 0). HRMS (EI+) m/z; 475.2592
2.2.3. (S)-tert-Butyl
2-[(5-(hydroxymethyl)pyridine-3-yloxy)methyl]
azetidine-1-]carboxylate (3)
Under N2 stream, lithium aluminum hydride (121 mg, 3.2 mmol) at
0 °C was added to a solution of 2 (0.86 g, 2.7 mmol) in THF (25 mL).
The mixture was stirred at 0 °C for 1 hr. After the reaction, saturated
aqueous sodium sulfate solution was added to the mixture at 0 °C to
eliminate excessive lithium aluminum hydride. The reaction mixture
was dried with magnesium sulfate, followed by filtration through celite.
The solvent was removed under reduced pressure. Purification by silica
gel flash-chromatography (chloroform/methanol = 20/1) yielded 3
(0.63 g, 2.5 mmol, 94%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ;
8.24 (d, J = 1.3 Hz, 1H), 8.17 (d, J = 2.8 Hz, 1H), 7.31 (dd, J = 2.8,
1.3 Hz, 1H), 4.71 (s, 2H), 4.52–4.48 (m, 1H), 4.36–4.31 (m, 1H), 4.13
(dd, J = 9.9, 2.6 Hz, 1H), 3.89 (t, J = 7.7 Hz, 2H), 2.41–2.34 (m, 1H),
2.31–2.26 (m, 1H), 1.75 (broad s, 1H), 1.41 (s, 9H). 13C NMR (75 MHz,
CDCl3) δ; 156.2, 155.2, 140.5, 137.7, 136.9, 119.9, 79.8, 68.6, 61.9,
(Calcd: 475.2583 for
CHCl3).
C
27H33N5O3). [α]D20 = −40.50 (c = 0.49,
60.1, 47.1, 28.3, 19.0. MS (FAB+) m/z; 295 ([M + H]+). HRMS (FAB+
)
m/z; 295.1653 (Calcd: 295.1658 for C15H23N2O4+). [α]D20 = − 68.52
(c = 1.08, CHCl3).
2.2.7. 5-Bis(methoxycarbonylmethyl)aminomethyl-3-[(S)-1-(tert-
butoxycarbonyl)-2-azetidinyl-methoxy]pyridine (7)
To a solution of 4 (1.7 g, 5.5 mmol) in DMF (20 mL), dimethyl
iminodiacetate hydrochloride (1.6 g, 8.2 mmol), potassium carbonate
(1.1 g, 8.2 mmol), and potassium iodide (1.4 g, 8.2 mmol) were added.
Under N2 stream, the mixture was stirred at 80 °C for 95 hr. After the
reaction, a saturated aqueous ammonium chloride solution was added
to the mixture. Compounds were extracted with ethyl acetate, and the
organic layer was dried with sodium sulfate. Solvent was removed
under reduced pressure. Purification by silica gel flash-chromatography
(hexane/ethyl acetate = 4/1) yielded 7 (1.4 g, 3.2 mmol, 60%) as a
colorless oil. 1H NMR (500 MHz, CDCl3) δ; 8.28 (d, J = 2.6 Hz, 1H),
8.19 (d, J = 1.7 Hz, 1H), 7.50–7.48 (m, 1H), 4.54 (broad s, 1H), 4.33
(broad s, 1H), 4.15 (dd, J = 9.7, 2.9 Hz, 1H), 3.95 (s, 2H), 3.93–3.88
2.2.4. (S)-tert-Butyl 2-[(5-(chloromethyl)pyridine-3-yloxy)methyl]azeti-
dine-1-carboxylate (4)
Under N2 stream, 1-chloro-N,N,2-trimethyl-1-propenylamine
(0.23 g, 1.7 mmol) at 0 °C was added to a solution of 3 (0.43 g,
1.5 mmol) in DCM (14 mL). The mixture was stirred at room tempera-
ture for 6 hr. The solvent was removed under reduced pressure.
Purification by silica gel chromatography (chloroform/methanol = 30/
1) yielded 4 (0.36 g, 1.2 mmol, 80%) as a colorless oil. 1H NMR
(300 MHz, CDCl3) δ; 8.31 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 2.4 Hz, 1H),
6.85 (dd, J = 2.4, 1.6 Hz, 1H), 4.57 (s, 2H), 4.55–4.49 (m, 1H),
4.38–4.33 (m, 1H), 4.16 (dd, J = 10.1, 2.9 Hz, 1H), 3.90 (t, J = 7.7 Hz,
2H), 2.43–2.34 (m, 1H), 2.31–2.26 (m, 1H), 1.41 (s, 9H). 13C NMR
(75 MHz, CDCl3) δ; 155.8, 154.8, 141.5, 138.1, 133.5, 120.9, 79.7,
68.5, 59.8, 46.9, 42.7, 28.1, 18.8. MS (FAB+) m/z; 313 ([M + H]+).
HRMS (FAB+) m/z; 313.1324 (Calcd: 313.1319 for C15H22N2O3Cl).
[α]D20 = −63.07 (c = 1.42, CHCl3).
(m, 2H), 3.71 (s, 6H), 3.56 (s, 4H), 2.38–2.28 (m, 2H), 1.42 (s, 9H). 13
C
NMR (125 MHz, CDCl3) δ; 171.3, 156.1, 155.4, 142.1, 137.2, 134.8,
122.0, 79.6, 68.7, 60.1, 54.9, 54.0, 51.6, 48.2, 28.4, 19.1. MS (EI+) m/
z; 437 ([M]+, 0.03), 378 (17), 322 (24). HRMS (EI+) m/z; 437.2164
(Calcd: 437.2162 for
CHCl3).
C
21H31N3O7). [α]D20 = − 31.45 (c = 2.61,
2.2.5. 5-[(2-Pyridylmethyl)-(ethoxycarbonylmethyl)aminomethyl]-3-[(S)-
1-(tert-butoxycarbonyl)-2-azetidinyl-methoxy]pyridine (5)
2.2.8. Triaquatricarbonylrhenium(I) bromide ([Re(CO)3(H2O)3]Br)
[Re(CO)3(H2O)3]Br was prepared as previously reported.14 Briefly,
rhenium pentacarbonyl bromide (5.0 g, 12.3 mmol) was suspended in
water. The suspension was refluxed for 72 hr. The reaction mixture was
lyophilized to afford [Re(CO)3(H2O)3]Br (4.4 g, 10.9 mmol, 89%).
To a solution of 4 (1.1 g, 3.4 mmol) in DMF (10 mL), N-(2-pyr-
idylmethyl)glycine ethyl (1.0 g, 5.2 mmol), potassium carbonate
(0.71 g, 5.2 mmol), and potassium iodide (0.86 g, 5.2 mmol) were
added. Under N2 stream, the mixture was stirred at 80 °C for 95 hr.
After the reaction, a saturated aqueous ammonium chloride solution
was added to the mixture. Compounds were extracted with ethyl
acetate, and the organic layer was dried with sodium sulfate. The sol-
vent was removed under reduced pressure. Purification by silica gel
flash-chromatography (hexane/ethyl acetate = 4/1) yielded 5 (0.17 g,
0.4 mmol, 11%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ;
8.56–8.53 (m, 1H), 8.24 (d, J = 2.6 Hz, 1H), 8.21 (d, J = 1.1 Hz, 1H),
7.68 (dt, J = 7.7, 1.7 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H),
7.18 (dd, J = 6.4, 5.0 Hz, 1H), 4.56–4.50 (m, 1H), 4.31 (broad s, 1H),
4.17 (q, J = 7.2 Hz, 2H), 4.14 (dd, J = 9.9, 3.0 Hz, 1H), 3.98 (s, 2H),
3.94–3.89 (m, 2H), 3.86 (s, 2H), 3.40 (s, 2H), 2.39–2.24 (m, 2H), 1.41
(s, 9H), 1.27 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ; 170.1,
158.8, 156.2, 155.3, 148.9, 142.2, 142.0, 136.8, 135.3, 123.1, 122.3,
122.2, 79.7, 68.4, 60.5, 60.0, 59.6, 58.4, 55.1, 54.4, 28.4, 16.1, 14.2.
MS (EI+) m/z; 470 ([M]+, 2.2), 397 (19), 378 (80), 322 (1 0 0). HRMS
2.2.9. 5-{Tricarbonyl rhenium(I)-[pyridine–2-ylmethyl(methoxycarbonyl)
aminomethyl]}–3-(S)- (2-azetidinylmethoxy)pyridine (Re-A-PAMA)
5 (13.4 mg, 0.03 mmol) was incubated with 10% HCl-MeOH (1 mL)
at 60 °C for 15 min. After the reaction, 1 N aqueous solution of sodium
hydroxide was added to the mixture to adjust pH to 8. [Re(CO)3(H2O)3]
Br (13.8 mg, 0.03 mmol) was added to the mixture. The reaction vial
was crimp-sealed prior to microwave heating at 110 °C for 5 min.
Compounds were extracted with chloroform, and the organic layer was
dried with sodium sulfate. The solvent was removed under reduced
pressure. Purification by recycle-HPLC (GPC-column) yielded Re-A-
PAMA (4.3 mg, 25%). Re-A-PAMA was analyzed by reverse-phase
HPLC (tR; 42.1 min); Cosmosil 5C18-AR-II 10 × 250 mm, methanol:-
water (0.1% TFA) = 15:85 (0 min) to 70:30 (60 min), 2 mL/min. MS
(APCI+) m/z; 613 ([M + H]+).
(EI+
)
m/z; 470.2533 (Calcd: 470.2529 for C25H34N4O5).
[α]D20 = −18.21 (c = 1.04, CHCl3).
2.2.10. 5-(Tricarbonyl rhenium(I)-6-{8-[bis(pyridine-2-ylmethyl)]amino-
methyl})-3-[(S)-2-azetidinyl- methoxy]pyridine (Re-A-DPA)
2.2.6. 5-[Bis(2-pyridylmethyl)aminomethyl]-3-[(S)-1-tert-
butoxycarbonyl)-2-azetidinylmethoxy] pyridine (6)
6 (0.12 g, 0.24 mmol) was incubated with 10% HCl-MeOH (1 mL) at
60 °C for 15 min. After the reaction, 1 N aqueous solution of sodium
hydroxide was added to the mixture to adjust pH to 8. To the mixture
To a solution of 4 (0.93 g, 3.0 mmol) in DMF (20 mL), 2,2′-
3