P. Merino et al. / Tetrahedron: Asymmetry 16 (2005) 3865–3876
3871
135.7. Anal. Calcd for C16H20N2O3 (288.34): C, 66.65;
H, 6.99; N, 9.72. Found: C, 66.73, H, 6.80, N, 9.91.
66.8, 67.8, 77.9, 109.2, 127.8, 128.5 (2C), 129.3 (2C),
136.2, 170.5, 176.4.
4.1.3. (3R,5R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxo-
lan-4-yl]-5-cyanoisoxazolidine 8c. Eluted third (0.231
g, 10%), sticky foam; [a]D = + 11 (c 0.37, CHCl3); dH
(400 MHz, CDCl3): 1.30 (s, 3H), 1.37 (s, 3H), 2.52
(ddd, 1H, J = 5.9, 8.8, 13.2 Hz), 2.75 (ddd, 1H,
J = 4.4, 8.1, 13.2 Hz), 3.50 (pseudo q, 1H, J = 5.9 Hz),
3.69 (dd, 1H, J = 5.9, 8.8 Hz), 3.94 (dd, 1H, J = 6.6,
8.1 Hz), 4.07 (pseudo q, 1H, J = 5.9 Hz), 4.19 (d, 1H,
J = 13.2 Hz), 4.28 (d, 1H, J = 13.2 Hz), 4.70 (dd, 1H,
J = 4.4, 8.8 Hz), 7.32 (m, 5H); dC (100 MHz, CDCl3):
25.5, 26.5, 36.9, 61.5, 64.6, 66.9, 67.3, 76.1, 110.3,
118.9, 127.9, 128.7 (2C), 129.0 (2C), 136.1. Anal. Calcd
for C16H20N2O3 (288.34): C, 66.65; H, 6.99; N, 9.72.
Found: C, 66.41; H, 6.84; N, 9.83.
4.2.2. (3S,5R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxo-
lan-4-yl]-5-[(4S)-4-(methoxycarbonyl)-2-thiazolin-2-yl]-
isoxazolidine 9b. 76 mg (6%), oil; [a]D = À4 (c 0.10,
CHCl3); dH (400 MHz, CDCl3): 1.28 (s, 3H), 1.30 (s,
3H), 2.50 (dddd, 1H, J = 4.1, 6.5, 7.6, 13.0 Hz), 2.88
(ddt, 1H, J = 3.5, 8.8, 13.0 Hz), 3.20 (ddt, 1H, J = 3.5,
7.0, 8.2 Hz), 3.40–3.56 (m, 3H), 3.79 (s, 3H), 3.83 (d,
1H, J = 12.9 Hz), 3.90 (ddd, 1H, J = 3.5, 6.5, 9.4 Hz),
4.10 (d, 1H, J = 12.9 Hz), 4.16 (dt, 1H, J = 5.9,
8.2 Hz), 5.08 (dt, 1H, J = 4.7, 9.4 Hz), 5.17 (ddd, 1H,
J = 3.5, 5.8, 9.4 Hz), 7.30–7.38 (m, 5H); dC (100 MHz,
CDCl3): 25.2, 26.8, 34.1, 34.4, 37.2, 52.8, 61.5, 66.6,
66.8, 67.8, 77.9, 109.2, 127.8, 128.5 (2C), 129.3 (2C),
136.2, 171.0, 176.5. Anal. Calcd for C20H26N2O5S
(406.50): C, 59.09; H, 6.45; N, 6.89. Found: C, 59.25;
H, 6.27; N, 7.02.
4.1.4. (3R,5S)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxo-
8d. Eluted
lan-4-yl]-5-cyanoisoxazolidine
fourth
(0.115 g, 5%), white solid; mp 115–117 ꢁC; [a]D = À32
(c 0.25, CHCl3); dH (400 MHz, CDCl3): 1.34 (s, 3H),
1.43 (s, 3H), 2.29 (ddd, 1H, J = 3.5, 7.0, 13.1 Hz),
2.70 (dt, 1H, J = 9.2, 13.1 Hz), 3.05 (pseudo q,
1H, J = 7.4 Hz), 3.79 (dd, 1H, J = 7.4, 9.3 Hz), 3.95
(d, 1H, J = 15.0 Hz), 4.09 (dd, 1H, J = 7.6, 9.4 Hz),
4.26 (pseudo q, 1H, J = 6.7 Hz), 4.50 (d, 1H,
J = 15.0 Hz), 4.73 (dd, 1H, J = 3.5, 9.0 Hz), 7.38 (m,
5H); dC (100 MHz, CDCl3): 25.4, 26.9, 37.7, 60.9, 63.9,
66.5, 66.9, 76.6, 110.5, 119.0, 127.7, 128.6 (2C), 128.8
(2C), 136.7. Anal. Calcd for C16H20N2O3 (288.34): C,
66.65; H, 6.99; N, 9.72. Found: C, 66.80, H, 6.73, N,
9.59.
4.3. (3S,5R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-
4-yl]-5-[4-(ethoxycarbonyl)-2-thiazolyl]isoxazolidine 10a
To a well-stirred solution of 9a (0.841 g, 2 mmol) in ben-
zene (40 mL) at room temperature was added activated
MnO2 (2.0 g). The resulting suspension was refluxed for
12 h and then filtered. The solid was washed with
CH2Cl2 and the filtrate evaporated to dryness. The
crude product was purified by radial chromatography
(hexane/EtOAc, 85:15) to afford 0.753 g (90%) of pure
10a as an oil. [a]D = À16 (c 0.39, CHCl3); dH
(400 MHz, CDCl3): 1.20 (s, 3H), 1.23 (s, 3H), 1.33 (t,
3H, J = 7.0 Hz), 2.48 (ddd, 1H, J = 4.0, 5.8, 13.4 Hz),
3.00 (dt, 1H, J = 8.8, 13.4 Hz), 3.24 (ddd, 1H, J = 4.0,
7.6, 8.8 Hz), 3.47 (dd, 1H, J = 5.8, 8.3 Hz), 3.93 (dd,
1H, J = 6.3, 8.3 Hz), 3.94 (d, 1H, J = 13.2 Hz), 4.04
(q, 1H, J = 6.2 Hz), 4.05 (d, 1H, J = 13.2 Hz), 4.35 (q,
2H, J = 7.0 Hz), 5.56 (dd, 1H, J = 5.8, 9.1 Hz), 7.22–
7.34 (m, 5H), 8.05 (s, 1H); dC (100 MHz, CDCl3):
14.3, 25.1, 26.6, 38.7, 61.4, 61.7, 67.1, 67.5, 76.8, 78.0,
109.3, 127.8, 127.9, 128.5 (2C), 129.3 (2C), 136.2,
146.9, 161.3, 172.6. Anal. Calcd for C21H26N2O5S
(418.51): C, 60.27; H, 6.26; N, 6.69. Found: C, 60.09;
H, 6.17; N, 6.81.
4.2. Condensation between 8b and L-cysteine
To a well-stirred solution of 8b (0.865 g, 3 mmol) in dry
methanol (50 mL) at room temperature under an argon
atmosphere was added (S)-cysteine ethyl ester hydro-
chloride (0.835 g, 4.5 mmol) and triethylamine
(0.455 g, 4.5 mmol). The resulting mixture was stirred
for 3 h and evaporated to dryness. The residue was
taken up in CH2Cl2 and washed with water, 5% NaHCO3
solution and brine. The organic extract was dried over
MgSO4, filtered, and evaporated to dryness. The crude
product, containing 6% of the corresponding methyl
ester, can be used as such for the next reaction. It can
also be purified by radial chromatography (hexane/
EtOAc, 90:10) to give pure products.
4.4. (3S,5R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-
4-yl]-5-[4-(methoxycarbonyl)-2-thiazolyl]isoxazolidine
10b
Treatment of 9b (80 mg, 0.2 mmol) under the same
conditions described above for the preparation of 10a
provided after radial chromatography (hexane/EtOAc,
85:15) 71 mg (88%) of pure 10b as an oil [a]D = À23
(c 0.12, CHCl3); dH (400 MHz, CDCl3): 1.20 (s, 3H),
1.23 (s, 3H), 2.48 (ddd, 1H, J = 4.0, 5.6, 13.2 Hz),
3.02 (dt, 1H, J = 8.8, 13.2 Hz), 3.24 (ddd, 1H,
J = 4.0, 7.6, 8.8 Hz), 3.47 (dd, 1H, J = 5.6, 8.3 Hz),
3.90 (dd, 1H, J = 6.3, 8.3 Hz), 3.94 (d, 1H, J =
13.2 Hz), 3.99 (s, 3H), 4.06 (m, 1H), 4.05 (d, 1H,
J = 13.2 Hz), 5.56 (dd, 1H, J = 5.8, 9.1 Hz), 7.22–7.34
(m, 5H), 8.05 (s, 1H); dC (100 MHz, CDCl3): 25.1,
26.6, 38.8, 61.3, 61.7, 67.4 (2C), 76.6, 77.6, 109.3,
127.8, 127.9, 128.5 (2C), 129.3 (2C), 136.2, 146.9,
4.2.1. (3S,5R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxo-
lan-4-yl]-5-[(4RS)-4-(ethoxycarbonyl)-2-thiazolin-2-yl]-
isoxazolidine 9a (mixture of epimers). 0.883 g (70%),
oil; dH (400 MHz, CDCl3): 1.27 (s, 3H), 1.28 (t, 3H,
J = 7.0 Hz), 1.29 (s, 3H), 2.50 (ddt, 1H, J = 3.3, 6.3,
13.2 Hz), 2.86 (ddt, 1H, J = 5.3, 8.8, 13.2 Hz), 3.19
(ddt, 1H, J = 3.3, 7.0, 8.1 Hz), 3.40–3.50 (m, 3H),
3.82 (d, 1H, J = 12.9 Hz), 3.95 (dd, 1H, J = 5.9,
9.1 Hz), 4.02 (d, 1H, J = 12.9 Hz), 4.11 (dt, 1H,
J = 5.9, 9.1 Hz), 4.22 (dq, 2H, J = 1.8, 7.0 Hz), 5.06
(dt, 1H, J = 7.0, 9.1 Hz), 5.18 (ddt, 1H, J = 3.5, 6.3,
8.8 Hz), 7.26–7.32 (m, 5H); dC (100 MHz, CDCl3):
14.2, 25.3, 26.9, 34.2, 34.5, 37.2, 61.5, 61.8, 66.5,