M. Salvati et al. / Tetrahedron 61 (2005) 8836–8847
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Compound 9b. RfZ0.32 (CH2Cl2:–MeOHZ15:1); mp 100–
102 8C (iPr2O); 1H NMR (200 MHz) d 6.26 (br s, 1H; NH),
5.87 (br s, 1H; NH), 4.50 (dd, JZ9.2, 7.4 Hz, 1H; 2-H),
3.39–3.30 (m, 1H; 6-Ha), 3.22–3.12 (m, 1H; 6-Hb), 3.19 (dd,
JZ13.0, 7.5 Hz, 1H; 3-Ha), 2.27–2.06 (m, 1H; 4-Ha), 2.23
(dd, JZ12.8, 9.6 Hz, 1H; 3-Hb), 1.98–1.83 (m, 3H; 4-Hb,
5-H), 1.46 (s, 9H; CMe3); 13C NMR (50 MHz) d 172.7,
171.4 (s; CO2tBu, CONH2), 82.0, 78.4 (s; C-3a, CMe3), 77.5
(d; C-2), 57.4 (t; C-6), 43.9, 35.0 (t; C-3, C-4), 27.8 (q, 3C;
CMe3), 24.2 (t; C-5); IR (CDCl3) nZ3519, 3402, 2981,
1725, 1693, 1573, 1370, 1159, 1117 cmK1; MS (EI): m/zZ
257 (0.4, MHC), 255 [1, (MKH)C], 155 (100), 138 (53),
110 (57), 82 (55), 57 (100); C12H20N2O4 (256.30): Calcd C
56.23, H 7.87, N 10.93; found: C 55.98, H 7.64, N 11.21.
Compound 11a. RfZ0.32 (AcOEt); mp 125–126 8C (iPr2O);
1H NMR (200 MHz) d 4.69 (t, JZ8.9 Hz, 1H; 2-H), 3.70
(dt, JZ11.7, 7.7 Hz, 1H; 5-Ha), 3.53 (br s, 1H; OH), 3.15
(dt, JZ11.7, 5.8 Hz, 1H; 5-Hb), 3.00 (dd, JZ12.6, 7.5 Hz,
1H; 1-Ha), 2.49–2.37 (m, 1H; 6-Ha), 2.14–1.98 (m, 1H;
6-Hb), 1.90 (dd, JZ12.6, 10.4 Hz, 1H; 1-Hb), 1.78–1.60 (m,
2H; 7-H), 1.46 (s, 9H; CMe3); 13C NMR (50 MHz) d 174.6,
171.9 (s; C-3, CO2tBu), 82.4 (s; CMe3), 72.5 (d; C-2), 70.0
(s; C-7a), 42.0 (t; C-5), 41.7 (t; C-1), 36.0 (t; C-7), 27.8 (q,
3C; CMe3), 25.2 (t; C-6); IR (KBr) nZ3351, 2982, 1732,
1674, 1428, 1149, 1110, 624 cmK1; MS (EI): m/zZ242 (2,
MHC), 140 (100), 112 (98), 105 (16), 97 (12), 84 (60), 57
(84); C12H19NO4 (241.28): Calcd C 59.73, H 7.94, N 5.81;
found: C 60.12, H 7.89, N 6.08.
Compound 10. RfZ0.58 (CH2Cl2–MeOHZ15:1); mp 98–
100 8C (Et2O); 1H NMR (200 MHz) d 6.85 (br s, 1H; NH),
5.49 (br s, 1H; NH), 4.31 (t, JZ9.1 Hz, 1H; 3-H), 4.06
(dd, JZ9.0, 7.7 Hz, 1H; 2-Ha), 3.81 (dd, JZ9.2, 7.7 Hz, 1H;
2-Hb), 3.46–3.37 (m, 1H; 6-Ha), 3.25–3.12 (m, 1H; 6-Hb),
2.09–1.92 (m, 4H; 4-H, 5-H), 1.50 (s, 9H; CMe3); 13C NMR
(50 MHz) d 174.0, 171.3 (s; CO2tBu, CONH2), 83.2, 78.5
(s; C-3a, CMe3), 67.0 (t; C-2), 56.8 (t; C-6), 33.9 (d; C-3),
32.6 (t; C-4), 27.8 (q, 3C; CMe3), 24.7 (t; C-5); IR (KBr) nZ
3641, 3123, 2985, 1740, 1685, 1604, 1396, 1257, 1119, 838,
658 cmK1; MS (EI): m/zZ255 [1, (MKH)C], 167 (40), 156
(5), 110 (14), 91 (100), 83 (17), 77 (16), 57 (96);
C12H20N2O4 (256.30): Calcd C 56.23, H 7.87, N 10.93;
found: C 56.33, H 8.02, N 10.87.
4.1.5. tert-Butyl (2S*,7aR*)-2-[(methoxysulfonyl)oxy]-3-
oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (13).
Procedure A. Freshly distilled triethylamine (1.3 mL,
9.54 mmol) and methanesulfonyl chloride (0.37 mL,
4.77 mmol) were added to a solution of alcohol 11a
(766 mg, 3.18 mmol) in CH2Cl2 under nitrogen atmosphere,
at 0 8C. After 1 h, the solution was diluted with CH2Cl2,
washed in turn with water and brine and dried over Na2SO4.
The filtrate was concentrated under reduced pressure to give
crude mesylate 13 (931 mg, 92%) as a white solid, which
was used in the next step without further purification.
Procedure B. Methanesulfonic acid (24 mL, 0.36 mmol) was
added to a solution of alcohol 11b (44 mg, 0.18 mmol) and
triphenylphosphine (144 mg, 0.55 mmol) in dry THF
(0.5 mL) under nitrogen atmosphere and the reaction flask
was dipped in an oil bath at 40 8C. After diethylazodicarb-
oxylate (86 mL, 0.55 mmol) was added, the reaction mixture
was stirred at 40 8C under nitrogen overnight. Purification
of the crude product by chromatography on silica gel
(petroleum ether–AcOEtZ2:1) afforded pure 13 (29 mg,
50%) as a white solid along with recovered starting material
11b (5 mg, 89% conversion).
4.1.3. tert-Butyl (2R*,7aR*)-2-hydroxy-3-oxotetrahydro-
1H-pyrrolizine-7a(5H)-carboxylate (11b). A mixture of
the isoxazolidine 9b (529 mg, 2.07 mmol) and acetic acid
(1.2 mL, 20.66 mmol) in MeOH (21.0 mL) was hydro-
genated over 20% Pd(OH)2/C (108 mg, 10% mol) overnight
at atmospheric pressure. The reaction mixture was then
filtered and concentrated. The resulting colorless oil was
dissolved in CH2Cl2, stirred in the presence of K2CO3 and
Na2SO4 and filtered, yielding the alcohol 11b (465 mg,
93%) as a white solid, which was used in the next step
without further purification.
Compound 13. RfZ0.40 (petroleum ether–AcOEtZ1:1);
mp 125–127 8C (iPr2O); 1H NMR (400 MHz) d 5.55 (t, JZ
9.1 Hz, 1H; 2-H), 3.70 (dt, JZ11.7, 7.8 Hz, 1H; 5-Ha),
3.22–3.13 (m, 1H; 5-Hb), 3.09 (dd, JZ13.0, 7.9 Hz, 1H;
1-Ha), 2.50 (ddd, JZ12.7, 7.0, 3.3 Hz, 1H; 7-Ha), 2.16 (dd,
JZ13.1, 10.2 Hz, 1H; 1-Hb), 2.15–2.03 (m, 2H; 6-H), 1.68
(dt, JZ12.7, 9.6 Hz, 1H; 7-Hb), 1.47 (s, 9H; CMe3); 13C
NMR (100 MHz) d 170.9, 168.0 (s; C-3, CO2tBu), 83.1 (s;
CMe3), 79.5 (d; C-2), 69.8 (s; C-7a), 41.9 (t; C-5), 39.9 (tC
q, 2C; C-1, SCH3), 35.8 (t; C-7), 27.8 (q, 3C; CMe3), 25.1 (t;
C-6); IR (KBr) nZ2977, 1727 (br), 1376, 1359, 1219, 1173,
1154, 980, 844, 766 cmK1; MS (EI): m/zZ320 (3, MHC),
218 (32), 122 (100), 112 (19), 94 (10), 79 (27), 58 (76);
C13H21NO6S (319.37): Calcd C 48.89, H 6.63, N 4.39;
found: C 48.47, H 6.27, N 4.57.
Compound 11b. RfZ0.33 (CH2Cl2–MeOHZ15:1); mp
1
128–130 8C (iPr2O); H NMR (400 MHz) d 4.39 (dd, JZ
7.0, 1.4 Hz, 1H; 2-H), 3.64 (dt, JZ11.7, 8.0 Hz, 1H; 5-Ha),
3.30 (ddd, JZ11.7, 9.0, 4.3 Hz, 1H; 5-Hb), 2.52 (dd, JZ
14.3, 1.4 Hz, 1H; 1-Ha), 2.42 (ddd, JZ12.7, 7.0, 2.7 Hz, 1H;
7-Ha), 2.24 (dd, JZ14.4, 7.0 Hz, 1H; 1-Hb), 2.20–2.12
(m, 2H; 6-H), 1.70 (br s, 1H; OH), 1.59 (dm, JZ12.7 Hz,
1H; 7-Hb), 1.52 (s, 9H; CMe3); 13C NMR (100 MHz) d
173.6, 173.1 (s; CO2tBu, C-3), 82.7 (s; CMe3), 75.1 (d; C-2),
72.9 (s; C-7a), 41.3 (t; C-5), 40.0 (t; C-1), 35.7 (t; C-7), 27.8
(q, 3C; CMe3), 26.0 (t; C-6); IR (KBr) nZ3256, 2978, 1742,
1703, 1450, 1367, 1155, 1122, 852, 645 cmK1; MS (EI):
m/zZ239 (1), 140 (14), 111 (15), 100 (19), 86 (45), 72 (80),
58 (100); C12H19NO4 (241.28): Calcd C 59.73, H 7.94, N
5.81; found: C 59.38, H 7.49, N 5.66.
4.1.6. tert-Butyl (2R*,7aR*)-2-azido-3-oxotetrahydro-
1H-pyrrolizine-7a(5H)-carboxylate (14). Compound 13
(365 mg, 1.14 mmol) was dissolved in DMF (3.8 mL) and
the solution was added with NaN3 (112 mg, 1.72 mmol).
The reaction mixture was stirred overnight at 40 8C, then it
was allowed to cool to rt, diluted with CH2Cl2, treated
dropwise with 10% aqueous HCl solution and vigorously
stirred for 15 min. The separated organic phase was washed
4.1.4. tert-Butyl (2S*,7aR*)-2-hydroxy-3-oxotetrahydro-
1H-pyrrolizine-7a(5H)-carboxylate (11a). Following the
previous procedure, alcohol 11a (564 mg, 95%) was
obtained from isoxazolidine 9a (629 mg, 2.46 mmol) as a
white solid.