T. Voelker et al. / Bioorg. Med. Chem. 17 (2009) 2047–2068
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(m, 1H), 1.75 (m, 1H), 1.67–1.46 (m, 5H); 1H NMR (CDCl3, 500
4.14.30. cis-2-(N-Phthilimidomethyl)-5-(20-methoxy-50-
fluorobenzyl)tetrahydrofuran (cis 29b)
MHz) trans 28c: d 6.88–6.82 (m, 2H), 6.73 (dd, J = 4.6, 8.6 Hz,
1H), 4.25 (m, 1H), 4.04 (quintet, J = 6.7 Hz, 1H), 3.78 (s, 3H), 3.45
(dd, J = 4.2, 9.5 Hz, 1H), 3.34 (dd, J = 6.4, 9.5 Hz, 1H), 2.70 (m, 1H),
2.6 (m, 1H), 2.13 (m, 1H), 2.05 (m, 1H), 1.87–1.56 (m, 4H).
The product (138 mg, 47% yield) was obtained as a white solid
by chromatography on silica; (Rf = 0.52, EtOAc/hexane, 30:70,
v:v); 1H NMR (CDCl3, 500 MHz): d 7.87–7.85 (m, 2H), 7.71–7.7
(m, 2H), 6.94 (dd, J = 3.1, 9.1 Hz, 1H), 6.8 (dt, J = 3.1, 9.1 Hz. 1H),
6.71 (dd, J = 4.7, 9.1Hz, 1H), 4.25 (m, 1H), 4.11 (p, J = 6.7 Hz, 1H),
3.84 (dd, J = 8.1, 13.8 Hz, 1H), 3.75 (s, 3H), 3.68 (dd, J = 5.2
13.8 Hz, 1H), 2.84 (d, J = 6.3 Hz, 2H), 1.98–1.92 (m, 2H), 1.73–1.67
(m, 2H).
4.14.25. trans-2-(Bromomethyl)-5-(30-(200-methoxy-500-
fluorophenyl)-10-propyl)tetrahydrofuran (trans 28d)
The product (530 mg, 40%) was obtained as an oil by chroma-
tography on silica; (Rf = 0.1, EtOAc/hexane, 5:95, v:v); 1H NMR
(CDCl3, 500 MHz): d 6.86–6.81 (m, 2H), 6.72 (dd, J = 4.6, 8.6 Hz,
1H), 4.22 (m, 1H), 4.03 (m, 1H), 3.78 (s, 3H), 3.44 (dd, J = 4.3,
9.7 Hz, 1H), 3.34 (dd, J = 6.4, 9.7 Hz, 1H), 2.6 (t, J = 7.3 Hz, 2H),
2.13 (m, 1H), 2.05 (m, 1H), 1.75 (m, 1H), 1.67–1.46 (m, 5H).
4.14.31. trans-2-(50-Fluoro-20-methoxyphenethyl)-5-
(phthalimidomethyl)tetrahydrofuran (trans 29c)
The product (0.7 g, 57% yield) was obtained as a white solid by
chromatography on silica; (Rf = 0.2, EtOAc/hexane, 20:80, v:v); 1H
NMR (CDCl3, 500 MHz): d 7.85–7.84 (m, 2H), 7.72–7.71 (m, 2H),
6.86 (dd, J = 3.1, 9.1 Hz, 1H), 6.8 (dt, J = 3.1, 9.1 Hz. 1H), 6.71 (dd,
J = 4.7, 9.1Hz, 1H), 4.38 (m, 1H), 4.05 (quintet, J = 6.6 Hz, 1H),
3.83 (dd, J = 8.0, 13.8 Hz, 1H), 3.76 (s, 3H), 3.62 (dd, J = 5.1
13.8 Hz, 1H), 2.67–2.52 (m, 2H), 2.11–2.04 (m, 2H), 1.79–1.54 (m,
4H).
4.14.26. cis-2-(Bromomethyl)-5-(30-(200-methoxy-500-
fluorophenyl)-10-propyl)tetrahydrofuran (cis 28d)
The product (110 mg, 10%) was obtained as an oil by chroma-
tography on silica; (Rf = 0.1, EtOAc/hexane, 5:95, v:v); 1H NMR
(CDCl3, 500 MHz): d 6.86–6.81 (m, 2H), 6.72 (dd, J = 4.6, 8.6 Hz,
1H), 4.13 (m, 1H), 3.93 (m, 1H), 3.78 (s, 3H), 3.42 (m, 1H), 3.32
(m, 1H), 2.6 (t, J = 7.3 Hz, 2H), 2.06–1.96 (m, 2H), 1.8–1.51 (m, 6H).
4.14.32. cis-2-(50-Fluoro-20-methoxyphenethyl)-5-
(phthalimidomethyl)tetrahydrofuran (cis 29c)
4.14.27. trans-2-(Bromomethyl)-5-(40-(200-methoxy-500-
fluorophenyl)-10-butyl)tetrahydrofuran (trans 28e)
The product (0.26 g, 63% yield) was obtained as a white solid by
chromatography on silica; (Rf = 0.2, EtOAc/hexane, 20:80, v:v); 1H
NMR (CDCl3, 500 MHz): d 7.86–7.85 (m, 2H), 7.72–7.7 (m, 2H),
6.86 (dd, J = 3.1, 9.1 Hz, 1H), 6.81 (dt, J = 3.1, 9.1 Hz. 1H), 6.71
(dd, J = 4.7, 9.1 Hz, 1H), 4.27 (quintet J = 6.1 Hz, 1H), 3.88 (quintet,
J = 6.6 Hz, 1H), 3.82 (dd, J = 8.0, 13.8 Hz, 1H), 3.77 (s, 3H), 3.72 (dd,
J = 5.1 13.8 Hz, 1H), 2.65–2.58 (m, 2H), 2.04–1.97 (m, 2H), 1.83–
1.58 (m, 4H).
The product (80 mg, 32%) was obtained as an oil by chromatog-
raphy on silica; (Rf = 0.1, EtOAc/hexane, 4:96, v:v); 1H NMR (CDCl3,
500 MHz): d 6.84–6.8 (m, 2H), 6.73 (dd, J = 4.6, 8.6 Hz, 1H), 4.22 (m,
1H), 4.01 (m, 1H), 3.78 (s, 3H), 3.44 (dd, J = 5.1, 10.3 Hz, 1H), 3.34
(dd, J = 7.1, 10.3 Hz, 1H), 2.58 (t, J = 7.7 Hz, 2H), 2.15 (m, 1H),
2.06 (m, 1H), 1.75 (m, 1H), 1.65–1.37 (m, 7H).
4.14.28. 2-(N-Phthilimidomethyl)-5-(20-methoxy-50-
fluorophenyl)tetrahydrofuran (29a)
4.14.33. trans-2-(30-(200-Methoxy-500-fluorophenyl)-10-propyl)-
5-(N-phthilimidomethyl) tetrahydrofuran (trans 29d)
To a vial under Ar was added 2-(bromomethyl)-5-(20-methoxy-
50-fluorophenyl)tetrahydrofuran (1.28 g, 4.44 mmol), NaI (100 mg),
potassium phthalimide (2.05 g, 11.1 mmol), and dry DMSO (10
mL). The reaction was heated to 70 °C and stirred under Ar for 12
h. After it was cooled to room temperature, the reaction mixture
was poured into a separatory funnel containing sodium bicarbon-
ate aqueous solution (satd NaHCO3/H2O = 1:1, 70 mL). The organic
material was extracted with EtOAc (3 ꢂ 60 mL) and the combined
organic layer was washed with brine (50 mL) and dried over
Na2SO4. The solvent was removed in vacuo to afford crude product
that was purified by flash column chromatography (Rf = 0.12,
EtOAc/hexane, 20:80, v:v) to yield pure product (a 2:1 mixture of
trans:cis isomers, 1.14 g, 72%) as an oil; 1H NMR (CDCl3, 500
MHz): d 7.88–7.84 (m, 2H), 7.73–7.69 (m, 2H), 7.36 (dd, J = 3.1,
9.4 Hz, 0.35H), 7.07 (dd, J = 3.1, 9.4 Hz, 0.65H), 6.85 (dt, J = 3.1,
8.5 Hz. 0.35H), 6.83 (dt, J = 3.1, 8.5 Hz. 0.65H), 6.72 (dd, J = 4.2,
9.1 Hz, 1H), 5.31 (t, J = 6.8 Hz, 0.65H), 5.09 (t, J = 7.2 Hz, 0.35H),
4.63 (m, 0.65H), 4.39 (m, 0.35H), 4.02 (dd, J = 7.4, 13.7 Hz, 0.35H),
3.92 (dd, J = 8.1 13.7 Hz, 0.65H), 3.87 (dd, J = 7.4, 13.7 Hz, 0.35H),
3.85 (s, 1.95H), 3.78 (s, 1.05H), 3.7 (dd, J = 8.1 13.7 Hz, 0.65H), 2.5
(m, 0.65H), 2.41 (m, 0.35H), 2.11–2.04 (m, 1H), 1.84–1.68 (m, 2H).
The product (0.15 g, 62% yield) was obtained as an oil by chro-
matography on silica; (Rf = 0.1, EtOAc/hexane, 15:85, v:v); 1H NMR
(CDCl3, 500 MHz): d 7.84 (m, 2H), 7.7 (m, 2H), 6.84–6.79 (m, 2H),
6.72 (dd, J = 4.6, 8.6 Hz, 1H), 4.37 (m, 1H), 4.05 (m, 1H), 3.82 (dd,
J = 8.3, 13.5 Hz, 1H), 3.76 (s, 3H), 3.59 (dd, J = 5.0, 13.5 Hz, 1H),
2.57 (t, J = 7.1 Hz, 2H), 2.06 (m, 2H), 1.68–1.45 (m, 6H).
4.14.34. cis-2-(30-(200-Methoxy-500-fluorophenyl)-10-propyl)-5-
(N-phthilimidomethyl) tetrahydrofuran (cis 29d)
The product (95 mg, 73% yield) was obtained as an oil by chro-
matography on silica; (Rf = 0.1, EtOAc/hexane, 15:85, v:v); 1H NMR
(CDCl3, 500 MHz): d 7.84 (m, 2H), 7.7 (m, 2H), 6.84–6.8 (m, 2H),
6.72 (dd, J = 4.6, 8.6 Hz, 1H), 4.25 (m, 1H), 3.86 (m, 1H), 3.81 (dd,
J = 8.3, 13.5 Hz, 1H), 3.77 (s, 3H), 3.68 (dd, J = 5.0, 13.5 Hz, 1H),
2.58 (t, J = 7.1 Hz, 2H), 2.0–1.95 (m, 2H), 1.74–1.49 (m, 6H).
4.14.35. trans-2-(30-(200-Methoxy-500-fluorophenyl)-10-butyl)-5-
(N-phthilimidomethyl) tetrahydrofuran (trans 29e)
The product (67 mg, 69% yield) was obtained as an oil by chro-
matography on silica; (Rf = 0.15, EtOAc/hexane, 20:80, v:v); 1H
NMR (CDCl3, 500 MHz): d 7.84 (m, 2H), 7.7 (m, 2H), 6.83–6.79
(m, 2H), 6.72 (dd, J = 4.3, 8.3 Hz, 1H), 4.36 (m, 1H), 4.01 (m, 1H),
3.81 (dd, J = 8.3, 13.5 Hz, 1H), 3.77 (s, 3H), 2.55 (,J = 7.8 Hz, 2H),
2.07 (m, 2H), 1.68–1.39 (m, 8H).
4.14.29. trans-2-(N-phthilimidomethyl)-5-(20-methoxy-50-
fluorobenzyl)tetrahydrofuran (trans 29b)
The product (385 mg, 70% yield) was obtained as a white solid
by chromatography on silica; (Rf = 0.5, EtOAc/hexane, 30:70, v:v);
1H NMR (CDCl3, 500 MHz): d 7.85–7.84 (m, 2H), 7.72–7.7 (m, 2H),
6.91 (dd, J = 3.1, 9.1 Hz, 1H), 6.82 (dt, J = 3.1, 9.1 Hz. 1H), 6.72
(dd, J = 4.7, 9.1 Hz, 1H), 4.41 (m, 1H), 4.34 (p, J = 6.7 Hz, 1H), 3.83
(dd, J = 8.1, 13.5 Hz, 1H), 3.77 (s, 3H), 3.62 (dd, J = 5.3 13.5 Hz,
1H), 2.85 (dd, J = 6.4, 13.7 Hz, 1H), 2.7 (dd, J = 6.4, 13.7 Hz, 1H),
2.03 (m, 2H), 1.64 (m, 2H).
4.14.36. 2-Aminomethyl-5-(20-methoxy-50-fluorophenyl)
tetrahydrofuran (30a)
To a vial under Ar was added 2-(N-phthalimidomethyl)-5-(20-
methoxy-50-fluorophenyl)tetrahydrofuran (225 mg, 0.63 mmol),
hydrazine hydrate (150 mg, 4.9 mmol), and methanol (10 mL).
The mixture was stirred at room temperature for 12 h. The solvent