M. Nakamura et al. / Bioorg. Med. Chem. 11 (2003) 5449–5460
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Typical procedure for the preparation of compounds 8a–d
(d, 3H, J=6.6 Hz), 0.90 (d, 3H, J=6.6 Hz), 1.36-1.53
(m, 2H), 1.64-1.84 (m, 3H), 2.46 (m, 1H), 2.60(m, 1H),
3.75-3.97 (m, 6H), 4.80(d, 1H, J=3.3 Hz), 5.47 (d, 1H,
J=6.3 Hz), 7.14–7.19 (m, 3H), 7.25-7.30(m, 2H), 7.41
(d, 1H, J=9.3 Hz). HRMS (MALDI) calcd for
C18H27NO4 (M+Na)+, 344.1838, found, 344.1832.
(1S)-1-(2,5-Dioxolanyl)-2-phenylethylamine (8a). Com-
pound 7a (32 g, 96 mmol) was dissolved in EtOAc (250
mL) and hydrogenated at room temperature under
atmosphere pressure over Pd/C powder (10%) (15 g).
After stirring for 18 h, Pd/C was filtered off, and the
filtrate was concentrated in vacuo to give 8a (19 g, 95%)
(2S)-N-((1S)-1-(2,5-Dioxolanyl)-2-(2-naphthyl)ethyl)-2-
hydroxy-4-methylpentanamide (9c). Yield 54%. Color-
1
as a colorless oil. H NMR (DMSO-d6) d 1.21 (s, 2H),
ꢁ
1
2.44 (dd, 1H, J=13.3, 9.3 Hz), 2.79 (dd, 1H, J=13.3,
4.4 Hz), 2.88 (m, 1H), 3.80–3.97 (m, 4H), 4.61 (d, 1H,
J=3.9 Hz), 7.15–7.31 (m, 5H). HRMS (MALDI) calcd
for C11H15NO2 (M+Na)+, 216.1001, found, 216.1008.
less crystals. Mp 142–143 C. H NMR (DMSO-d6) d
0.61–0.65 (m, 6H), 0.94–1.01 (m, 2H), 1.46 (m, 1H), 2.85
(dd, 1H, J=13.7, 10.4 Hz), 3.05 (dd, 1H, J=14.0, 4.4
Hz), 3.72 (m, 1H), 3.81–3.99 (m, 4H), 4.27 (m, 1H), 4.90
(d, 1H, J=3.6 Hz), 5.41 (d, 1H, J=5.7 Hz), 7.36–7.48
(m, 4H), 7.67 (s, 1H), 7.77–7.86 (m, 3H). Anal. calcd for
C21H27NO4: C, 70.56; H, 7.61; N, 3.92; found: C, 70.21;
H, 7.64; N, 3.80.
(1S)-1-(2,5-Dioxolanyl)-3-phenylpropylamine (8b). Yield
82%. Colorless oil. 1H NMR (DMSO-d6) d 1.32 (s, 2H),
1.45 (m, 1H), 1.73 (m, 1H), 2.54–2.56 (m, 2H), 2.79 (m,
1H), 3.75–3.90(m, 4H), 4.58 (d, 1H, J=4.2 Hz), 7.13–
7.30(m, 5H). HRMS (MALDI) calcd for C 12H17NO2
(M+Na)+, 230.1157, found, 230.1166.
(2S) - N - ((1R) - 1 - (2,5 - Dioxolanyl) - 2 - phenylethyl) - 2 -
hydroxy-4-methylpentanamide (9d). Yield 81%. Color-
less crystals. Mp 121–122 ꢁC. H NMR (DMSO-d6) d
1
(1S)-1-(2,5-Dioxolanyl)-2-(2-naphthyl)ethylamine (8c).
1
0.80 (d, 3H, J=3.9 Hz), 0.83 (d, 3H, J=3.9 Hz), 1.15–
1.34 (m, 2H), 1.62 (m, 1H), 2.70(dd, 1H, J=14.1, 10.1
Hz), 2.86 (dd, 1H, J=14.1, 4.5 Hz), 3.72–3.98 (m, 5H),
4.14 (m, 1H), 4.83 (d, 1H, J=3.3 Hz), 5.28 (d, 1H,
J=6.3 Hz), 7.14–7.27 (m, 5H), 7.44 (d, 1H, J=9.3 Hz).
Anal. calcd for C17H25NO4: C, 66.43; H, 8.20; N, 4.56;
found: C, 66.53; H, 8.24; N, 4.46.
Yield 97%. Colorless oil. H NMR (DMSO-d6) d 1.57
(s, 2H), 2.63 (dd, 1H, J=13.1, 8.9 Hz), 2.94–3.05 (m,
2H), 3.79–4.02 (m, 4H), 4.68 (d, 1H, J=3.6 Hz), 7.41–
7.51 (m, 3H), 7.73 (s, 1H), 7.82–7.88 (m, 3H). HRMS
(MALDI) calcd for C15H17NO2 (M+Na)+, 266.1157,
found, 266.1163.
(1R)-1-(2,5-Dioxolanyl)-2-phenylethylamine (8d). Yield
75%. Colorless oil. 1H NMR (DMSO-d6) d 1.25 (s, 2H),
2.44 (dd, 1H, J=13.2, 9.3 Hz), 2.79 (dd, 1H, J=13.4,
4.4 Hz), 2.88 (m, 1H), 3.79–3.97 (m, 4H), 4.61 (d, 1H,
J=3.9 Hz), 7.15–7.31 (m, 5H). HRMS (MALDI) calcd
for C11H15NO2 (M+Na)+, 216.1001, found, 216.1011.
(2S) - N - ((1S) - 1 - (2,5 - Dioxolanyl) - 2 - phenylethyl) - 2 -
hydroxy-3-methylbutanamide (11a). Yield 92%. Color-
less crystals. Mp 91–92 ꢁC. 1H NMR (DMSO-d6) d 0.46
(d, 3H, J=6.9 Hz), 0.74 (d, 3H, J=7.2 Hz), 1.79 (m,
1H), 2.70(dd, 1H, J=13.9, 10.5 Hz), 2.87 (dd, 1H,
J=13.9, 4.4 Hz), 3.60(dd, 1H, J=6.0, 3.6 Hz), 3.79–
3.97 (m, 4H), 4.22 (m, 1H), 4.83 (d, 1H, J=3.6 Hz), 5.31
(d, 1H, J=5.7 Hz), 7.13–7.26 (m, 5H), 7.33 (d, 1H,
J=9.3 Hz). Anal. calcd for C16H23NO4: C, 65.51; H,
7.90; N, 4.77; found: C, 65.36; H, 7.84; N, 4.54.
Typical procedure for the preparation of compounds 9a–
d, 11a–b and 13a
(2S) - N - ((1S) - 1 - (2,5 - Dioxolanyl) - 2 - phenylethyl) - 2 -
hydroxy-4-methylpentanamide (9a). Compound 8a (15
g, 78 mmol), l-leucic acid (10g, 78 mmol), HOBt (12 g,
85 mmol) and Et3N (8.6 g, 85 mmol) were dissolved in
DMF (120mL). A suspension of EDC (16 g, 85 mmol)
in CH2Cl2 (40mL) was added to the mixture under the
ice cool condition. The mixture was stirred at room
temperature for 18 h and concentrated in vacuo. The
mixture was diluted with EtOAc, and the solution was
washed with 1 M HCl, saturated NaHCO3 and satu-
rated NaCl, dried over MgSO4 and concentrated in
vacuo. The residue was crystallized from EtOAc to give
9a (18 g, 75%) as colorless crystals. Mp 104–107 ꢁC. 1H
NMR (DMSO-d6) d 0.78 (d, 6H, J=6.6 Hz), 1.05–1.20
(m, 2H), 1.59 (m, 1H), 2.69 (dd, 1H, J=14.1, 10.2 Hz),
2.86 (dd, 1H, J=14.1, 4.5 Hz), 3.74-3.97 (m, 5H), 4.16
(m, 1H), 4.83 (d, 1H, J=3.3 Hz), 5.40(d, 1H, J=5.7
Hz), 7.13–7.27 (m, 5H), 7.34 (d, 1H, J=9.6 Hz). Anal.
calcd for C17H25NO4: C, 66.43; H, 8.20; N, 4.56; found:
C, 66.60; H, 8.30; N, 4.27.
(2S) - N - ((1S) - 1- (2,5 - Dioxolanyl) - 3- phenylpropyl) -2 -
hydroxy-3-methylbutanamide (11b). Yield 84%. Color-
less crystals. Mp 104–111 ꢁC. H NMR (DMSO-d6) d
1
0.82 (d, 3H, J=6.9 Hz), 0.93 (d, 3H, J=6.9 Hz), 1.62–
1.86 (m, 2H), 2.02 (m, 1H), 2.47 (m, 1H), 2.62 (m, 1H),
3.73–4.00 (m, 6H), 4.81 (d, 1H, J=3.6 Hz), 5.41 (d, 1H,
J=6.3 Hz), 7.14–7.19 (m, 3H), 7.25–7.27 (m, 2H), 7.42
(d, 1H, J=9.3 Hz). Anal. calcd for C17H25NO4: C, 66.43;
H, 8.20; N, 4.56; found: C, 66.73; H, 8.18; N, 5.00.
(2S) - N - ((1S) - 1 - (2,5 - Dioxolanyl) - 2 - phenylethyl) - 2 -
hydroxy-3-phenylpropanamide (13a). Yield 82%. Color-
less crystals. Mp 119–121 ꢁC. H NMR (DMSO-d6) d
1
2.43 (dd, 1H, J=13.7, 8.9 Hz), 2.65–2.85 (m, 3H), 3.77–
4.01 (m, 5H), 4.17 (m, 1H), 4.81 (d, 1H, J=3.6 Hz), 5.55
(d, 1H, J=6.0Hz), 7.12-7.29 (m, 10H), 7.45 (d, 1H,
J=9.6 Hz). Anal. calcd for C20H23NO4: C, 70.36; H,
6.79; N, 4.10; found: C, 70.23; H, 6.71; N, 4.01.
Typical procedure for the preparation of compounds
10a–d, 12a–b and 14a
(2S) - N - ((1S)- 1 - (2,5-Dioxolanyl) -3 -phenylpropyl) - 2-
hydroxy-4-methylpentanamide (9b). Yield 82%. Color-
less crystals. Mp 87–88 ꢁC. 1H NMR (DMSO-d6) d 0.89
(2S,5S)-5-Benzyl-6-hydroxy-2-(2-methylpropyl)-3-mor-