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R. Ettari et al. / Bioorg. Med. Chem. 23 (2015) 7053–7060
(m, 2H), 5.32–5.45 (m, 2H), 5.83–6.01 (m, 1H); MS: m/z 388.1 [M
+H]+; Anal. calcd for C15H22BrN3O4: C, 46.40; H, 5.71; N, 10.82;
found: C, 46.73; H, 5.62; N, 10.69.
4.4.2. Allyl (S)-1-((3aS,6aS)-3-bromo-3a,4,6,6a-tetrahydropyrro-
lo[3,4-d]isoxazol-5-yl)-1-oxo-3-phenylpropan-2-ylcarbamate
[(S,S,S)-1b]
Yield 92%; Rf = 0.40 (EtOAc/light petroleum, 6:4); [a]
20 = +42.7
D
4.3.10. Benzyl (S)-1-((3aR,6aR)-3-bromo-3a,4,6,6a-tetrahydropyr-
rolo[3,4-d]isoxazol-5-yl)-4-methyl-1-oxopentan-2-ylcarbamate
(10a) and benzyl (S)-1-((3aS,6aS)-3-bromo-3a,4,6,6a-tetrahydro-
pyrrolo[3,4-d]isoxazol-5-yl)-4-methyl-1-oxopentan-2-
ylcarbamate (10b)
(c = 0.18, CH2Cl2); 1H NMR (300 MHz, CDCl3): d = 2.83–3.16 (m,
2H), 3.34 (d, J = 12.30 Hz, 1H), 3.54 (m, 1H), 3.73–3.96 (m, 2H),
4.07 (d, J = 12.30 Hz, 1H), 4.51–4.72 (m, 3H), 5.19–5.37 (m, 3H),
5.51 (d, J = 7.6 Hz, 1H), 5.82–6.00 (m, 1H), 7.13–7.36 (m, 5H); 13C
(75 MHz, CDCl3): d = 40.42, 48.71, 53.41, 55.82, 57.50, 66.79,
85.38, 118.40, 128.78, 129.10, 129.51, 134.08, 136.08, 137.20,
155.78, 171.77; MS: m/z 422.2 [M+H]+; Anal. calcd for
Yield 83%; Rf = 0.56 (EtOAc/light petroleum, 6:4); 1H NMR
(300 MHz, CDCl3): d = 0.96 (d, J = 6.5 Hz, 3H), 1.01 (d, J = 6.7 Hz,
3H), 1.46–1.59 (m, 2H), 1.66–1.80 (m, 1H), 3.42–3.54 (m, 0.5H),
3.55–3.68 (m, 0.5H), 3.71–3.84 (m, 1H), 3.86–4.13 (m, 2H), 4.21
(d, J = 13.8 Hz, 1H), 4.42–4.63 (m, 1H), 5.11 (s, 2H), 5.27–5.52 (m,
2H), 7.30–7.47 (m, 5H); MS: m/z 438.1 [M+H]+; Anal. calcd for
C18H20BrN3O4: C, 51.20; H, 4.77; N, 9.95; found: C, 51.33; H,
4.59; N, 10.07.
4.4.3. Allyl (S)-1-((3aR,6aR)-3-bromo-3a,4,6,6a-tetrahydropyrro-
lo[3,4-d]isoxazol-5-yl)-1-oxo-4-phenylbutan-2-ylcarbamate [(S,
R,R)-5a]
C19H24BrN3O4: C, 52.06; H, 5.52; N, 9.59; found: C, 51.72; H,
5.39; N, 9.76.
Yield 81%; Rf = 0.46 (EtOAc/light petroleum, 6:4); [
a
]
20 = ꢀ70.5
D
4.3.11. n-Propyl (S)-1-((3aR,6aR)-3-bromo-3a,4,6,6a-tetrahydro-
pyrrolo[3,4-d]isoxazol-5-yl)-4-methyl-1-oxopentan-2-ylcar-
bamate (11a) and n-propyl (S)-1-((3aS,6aS)-3-bromo-3a,4,6,6a-
tetrahydropyrrolo[3,4-d]isoxazol-5-yl)-4-methyl-1-oxopentan-
2-ylcarbamate (11b)
(c = 0.39, CH2Cl2); 1H NMR (300 MHz, CDCl3): d = 1.87–2.06 (m,
2H), 2.60–2.82 (m, 2H), 3.42 (m, 1H), 3.57–3.77 (m, 1H), 3.68 (d,
J = 13.4 Hz, 1H), 3.88–4.05 (m, 1H), 4.13 (d, J = 13.4 Hz, 1H), 4.39–
4.55 (m, 1H), 4.54–4.66 (m, 2H), 5.20–5.32 (m, 1H), 5.28 (m, 2H),
5.62 (d, J = 8.1 Hz, 1H), 5.85–6.01 (m, 1H), 7.17–7.38 (m, 5H); 13C
(75 MHz, CDCl3): d = 29.50, 31.74, 47.91, 51.40, 53.09, 55.63,
66.11, 84.43, 117.22, 125.89, 128.68, 129.35, 133.11, 139.21,
141.28, 156.58, 171.78; MS: m/z 436.1 [M+H]+; Anal. calcd for
Yield 86%; Rf = 0.50 (EtOAc/light petroleum, 6:4); 1H NMR
(300 MHz, CDCl3): d = 0.91 (d, J = 7.5 Hz, 3H), 0.96 (d, J = 7.3 Hz,
3H), 1.02 (t, J = 7.4 Hz, 3H), 1.48–1.80 (m, 5H), 3.47–3.84 (m, 2H),
3.87–4.15 (m, 4H), 4.21 (d, J = 13.4 Hz, 1H), 4.39–4.61 (m, 1H),
5.19–5.44 (m, 2H); MS: m/z 390.1 [M+H]+; Anal. calcd for
C19H22BrN3O4: C, 52.30; H, 5.08; N, 9.63; found: C, 52.56; H,
5.42; N, 9.55.
C15H24BrN3O4: C, 46.16; H, 6.20; N, 10.77; found: C, 46.02; H,
6.43; N, 10.62.
4.4.4. Allyl (S)-1-((3aS,6aS)-3-bromo-3a,4,6,6a-tetrahydropyrro-
lo[3,4-d]isoxazol-5-yl)-1-oxo-4-phenylbutan-2-ylcarbamate [(S,
S,S)-5b]
4.3.12. tert-Butyl (S)-1-((3aR,6aR)-3-bromo-3a,4,6,6a-tetrahydro-
pyrrolo[3,4-d]isoxazol-5-yl)-4-methyl-1-oxopentan-2-ylcarba-
mate (12a) and tert-butyl (S)-1-((3aS,6aS)-3-bromo-3a,4,6,6a-
tetrahydropyrrolo[3,4-d]isoxazol-5-yl)-4-methyl-1-oxopentan-
2-ylcarbamate(12b)
Yield 85%; Rf = 0.46 (EtOAc/light petroleum, 6:4); [a]
20 = +60.4
D
(c = 0.22, CH2Cl2); 1H NMR (300 MHz, CDCl3): d = 1.88–2.13 (m,
2H), 2.63–2.78 (m, 2H), 3.46 (m, 1H), 3.60–3.72 (m, 2H), 3.94
(m, 1H), 4.21 (d, J = 13.0 Hz, 1H), 4.33–4.45 (m, 1H), 4.55–4.63
(m, 2H), 5.20–5.39 (m, 3H), 5.60 (d, J = 7.7 Hz, 1H), 5.85–6.01 (m,
1H), 7.15–7.38 (m, 5H); 13C (75 MHz, CDCl3): d = 29.57, 31.77,
47.93, 51.45, 53.15, 55.69, 66.08, 84.48, 117.28, 125.85, 128.62,
129.37, 133.09, 139.24, 141.26, 156.60, 171.80; MS: m/z 436.1 [M
+H]+;Anal. calcd for C19H22BrN3O4: C, 52.30; H, 5.08; N, 9.63;
found: C, 52.44; H, 5.33; N, 9.47.
Yield 93%; Rf = 0.58 (EtOAc/light petroleum, 6:4); 1H NMR
(300 MHz, CDCl3): d = 0.96 (d, J = 6.7 Hz, 3H), 1.00 (d, J = 7.4 Hz,
3H), 1.45 (s, 9H), 1.54–1.67 (m, 2H), 1.66–1.79 (m, 1H),
3.46–3.59 (m, 0.5H), 3.59–3.69 (m, 0.5H), 3.91–4.12 (m, 3H), 4.21
(d, J = 14.9 Hz, 1H), 4.36–4.55 (m, 1H), 5.06–5.20 (m, 1H), 5.20 (d,
J = 7.9 Hz, 1H); MS: m/z 404.1 [M+H]+; Anal. calcd for
C16H26BrN3O4: C, 47.53; H, 6.48; N, 10.39; found: C, 47.21; H,
6.32; N, 10.58.
4.4.5. Allyl (S)-1-((3aR,6aR)-3-bromo-3a,4,6,6a-tetrahydropyrro-
lo[3,4-d]isoxazol-5-yl)-4-methyl-1-oxopentan-2-ylcarbamate
[(S,R,R)-9a]
4.4. General procedure for the synthesis of compounds 1a, 1b,
5a, 5b, 9a, 9b, 13b and 14b
Yield 93%; Rf = 0.48 (EtOAc/light petroleum, 6:4); [
a
]
20 = ꢀ79.3
D
(c = 0.75, CH2Cl2); 1H NMR (300 MHz, CDCl3): d = 0.94 (d,
J = 6.5 Hz, 3H), 1.01 (d, J = 6.7 Hz, 3H), 1.31–1.45 (m, 1H),
1.44–1.62 (m, 1H), 1.64–1.81 (m, 1H), 3.58 (m, 1H), 3.67–3.82
(m, 1H), 3.96–4.11 (m, 1H), 4.00 (d, J = 14.1 Hz, 1H), 4.17 (d,
J = 14.1 Hz, 1H), 4.41–4.50 (m, 1H), 4.50–4.62 (m, 2H), 5.24
(m, 2H), 5.24–5.42 (m, 1H), 5.49 (d, J = 8.1 Hz, 1H), 5.82–5.98 (m,
1H); 13C (75 MHz, CDCl3): d = 21.75, 23.82, 26.50, 44.22, 47.91,
51.63, 53.73, 57.96, 65.93, 84.15, 119.09, 134.91, 139.68, 157.45,
172.23; MS: m/z 388.3 [M+H]+; Anal. calcd for C15H22BrN3O4: C,
46.40; H, 5.71; N, 10.82; found: C, 46.65; H, 5.43; N, 10.67.
According to the procedure described for the synthesis of
1–12a,b, the carboxylic acid 30, 34, 38, 43 or 44 was reacted with
the enantiopure amines (R,R)-4211a or (S,S)-4211a to give the
desired compounds.
4.4.1. Allyl (S)-1-((3aR,6aR)-3-bromo-3a,4,6,6a-tetrahydropyrr-
olo[3,4-d]isoxazol-5-yl)-1-oxo-3-phenylpropan-2-ylcarbamate
[(S,R,R)-1a]
Yield 89%; Rf = 0.40 (EtOAc/light petroleum, 6:4); [
a
]
20 = ꢀ51.2
D
(c = 0.40, CH2Cl2); 1H NMR (300 MHz, CDCl3): d = 2.86–3.19 (m,
2H), 3.27 (m, 1H), 3.38 (d, J = 11.8 Hz, 1H), 3.67–3.85 (m, 1H),
3.88–4.03 (m, 1H), 4.19 (d, J = 11.8 Hz, 1H), 4.51–4.69 (m, 3H),
5.22 (m, 2H), 5.30 (m, 1H), 5.58 (d, J = 8.8 Hz, 1H), 5.81–6.00 (m,
1H), 7.13–7.38 (m, 5H); 13C (75 MHz, CDCl3): d = 40.40, 48.73,
53.38, 55.87, 57.54, 66.82, 85.43, 118.42, 128.80, 129.05, 129.47,
134.02, 136.05, 137.24, 155.80, 171.82; MS: m/z 422.2 [M+H]+;
Anal. calcd for C18H20BrN3O4: C, 51.20; H, 4.77; N, 9.95; found: C,
51.39; H, 4.62; N, 10.24.
4.4.6. Allyl (S)-1-((3aS,6aS)-3-bromo-3a,4,6,6a-tetrahydropyrro-
lo[3,4-d]isoxazol-5-yl)-4-methyl-1-oxopentan-2-ylcarbamate
[(S,S,S)-9b]
Yield 87%; Rf = 0.48 (EtOAc/light petroleum, 6:4): [a]
20 = + 62.2
D
(c = 0.36, CH2Cl2); 1H NMR (300 MHz, CDCl3): d = 0.94 (d, J = 6.5 Hz,
3H), 0.99 (d, J = 6.1 Hz, 3H), 1.38–1.62 (m, 2H), 1.63–1.77 (m, 1H),
3.51 (m, 1H), 3.90–4.03 (m, 1H), 3.99 (d, J = 12.2 Hz, 1H), 4.15–4.28
(m, 1H), 4.19 (d, J = 12.2 Hz, 1H), 4.39–4.50 (m, 1H), 4.51–4.63