Legeay and Langlois
over MgSO4, and concentrated under vacuum. The residue was
without further purification. To a solution of this product in dry
THF (3.0 mL) was added under Ar MeI (0.69 mL, 11.0 mmol).
The solution was stirred at rt for 24 h. Then MeI (0.69 mL, 11.0
mmol) and NaHCO3 (66.9 mg, 0.80 mmol) were added to the
mixture. The reaction medium was stirred at rt for 3 days. After
elimination of the solvent under reduced pressure, the crude product
was purified by filtration over silica gel (eluent Et2O) to give
filtered on silica gel (eluent heptane-Et2O, 1:9) to give (S)-12 as
27
a colorless oil (373.5 mg, 89%). [R]D +56 (c 1.36, CHCl3). IR
(cm-1): 1782, 1739, 1711, 1319, 1254, 1158, 1102, 1049, 821.
MS (ESI, MeCN, m/z): 745 (2MNa)+, 384 [(MNa)+, 100]. 1H (500
MHz, CDCl3): δ 7.37-7.24 (m, 5H), 6.99 (d, 1H, J ) 6.1 Hz,),
6.24 (d, 1H, J ) 6.1 Hz), 4.53 (d, 1H, J ) 12.2 Hz), 4.51 (d, 1H,
J ) 12.2 Hz), 4.17 (d, 1H, J ) 10.4 Hz), 4.14 (d, 1H, J ) 10.4
Hz), 3.73 (s, 3H), 1.47 (s, 9H). 13C NMR (75 MHz, CDCl3): δ
169.0, 167.8, 148.6, 147.0, 137.5, 128.6, 128.4, 128.0, 127.7, 83.8,
73.8, 73.2, 68.6, 53.0, 28.0. Anal. Calcd for C19H23NO6: C, 63.15;
H, 6.41, N, 3.88. Found: C, 63.21; H, 6.41, N, 3.71.
27
(2R,3S)-22 as a clear oil (136.7 mg, 89% for three steps). [R]D
-32.6 (c 1.13, CHCl3). IR (cm-1): 3448, 2943, 1772, 1746, 1454,
1369, 1304, 1248, 1151, 1116, 1048. MS (ESI, MeCN + CH2Cl2,
1
m/z): 414 (MNa)+, 314 [[(M - Boc)Na]+, 100]. H NMR (500
MHz, CDCl3): δ 7.38-7.25 (m, 5H), 6.41 (d, 1H, J ) 2.7 Hz),
5.83 (d, 1H, J ) 2.1 Hz), 4.95 (m, 1H), 4.57 (d, 1H, J ) 12.2 Hz),
4.54 (d, 1H, J ) 12.2 Hz), 4.10 (d, 1H, J ) 10.0 Hz), 4.07 (d, 1H,
J ) 10.0 Hz), 3.75 (s, 3H), 2.57 (br m, 1H), 1.47). 13C NMR (75
MHz, CDCl3): δ 168.9, 165.0, 149.8, 140.6, 137.5, 128.7, 128.1,
127.8, 123.5, 84.3, 73.7, 71.5, 70.3, 69.3, 52.7, 28.0. HRMS (ESI,
MeCN + CH2Cl2, m/z): calcd for C20H25NO7Na (MNa)+ 414.1529,
found 414.1536.
Cycloaddition of N-Methylnitrone to (()-14: Methyl 6-[(Ben-
zyloxy)methyl]-5-(4-methoxybenzyl)-2-methyl-4-oxohexahydro-
2H-pyrrolo[3,4-d]isoxazole-6-carboxylates (()-15 and (()-16. A
solution of N-methylnitrone (44.3 mg, 0.75 mmol) in dry toluene
(2.5 mL) was added to (()-14 (111.7 mg, 0.29 mmol) placed under
Ar. The mixture was stirred at 110 °C for 3 h. The solvent was
evaporated under reduced pressure and the crude material purified
by chromatography (eluent EtOAc) to give a mixture of isomers
(127.7 mg, 99%). The diastereomeric ratio (58:28:8:5) was deter-
mined by HPLC (SunFire, 3 × 150 mm; eluent MeCN-H2O, 1:1).
The two main diastereomers were separated by preparative TLC
(eluent CH2Cl2-EtOAc, 9:1) to afford (3aR*,6R*,6aS*)-15 (75.0
mg, 58%) and (3aS*,6R*,6aR*)-16 (35 mg, 27%), described in the
Supporting Information). (()-15 was obtained as a colorless gum.
IR (cm-1): 2953, 2848, 1753, 1692, 1512. MS (ESI, MeOH +
(2R,3S)-Methyl 2-[(Benzyloxy)methyl]-3-hydroxy-4-methyl-
ene-5-oxopyrrolidine-2-carboxylate (25). To a solution of com-
pound 22 (133.9 mg, 0.34 mmol) in CH2Cl2 (1.3 mL) was added
TFA (250 µL, 3.37 mmol) at rt, and the mixture was stirred for 50
min. After dilution with CH2Cl2 and addition of saturated aqueous
Na2CO3, the aqueous phase was extracted with CH2Cl2. The organic
phases were dried over MgSO4, and the solvent was evaporated to
afford (2R,3S)-25 (100.1 mg, 100%) as a colorless oil. [R]D25 -7.0
(c 1.10, CHCl3). IR (cm-1): 3290, 2866, 1737, 1694, 1666, 1433,
1314, 1233. MS (ESI, MeOH + CH2Cl2, m/z): 605 [(2MNa)+, 100],
1
CH2Cl2, m/z): 463 [(MNa)+, 100]. H NMR (500 MHz, CDCl3):
δ 7.30-7.24 (m, 5H), 7.08 (d, 2H, J ) 7.4 Hz), 6.75 (2H, d, 2H,
J ) 8.5 Hz), 5.19 (br d, 1H, J ) 15.7 Hz), 4.66 (br d, 1H, J ) 6.3
Hz), 4.12 (d, 1H, J ) 15.7 Hz), 3.94 (d, H, J ) 11.4 Hz), 3.86 (d,
H, J ) 11.4 Hz), 3.81 (masked d, 1H), 3.79 (s, 3H), 3.74 (s, 3H),
3.63 (m, 1H), 3.52 (m, 1H), 3.25 (d, 1H, J ) 9.8 Hz), 2.65 (s, 3H),
2.56 (m, 1H). 13C NMR (125 MHz, CDCl3): δ 175.0, 168.2, 159.0,
137.6, 130.1, 129.9, 128.5, 127.8, 127.3, 113.7, 79.8, 76.0, 72.9,
70.3, 60.1, 55.4, 52.5, 51.9, 45.3, 44.9. HRMS (ESI, MeOH + CH2-
Cl2, m/z): calcd for C24H28N2O6Na (MNa)+ 463.1845, found
463.1882.
1
314 (MNa)+. H NMR (500 MHz, CDCl3): δ 7.36-7.26 (2 m,
5H), 6.47 (br d, 1H exch., J ) 7.9 Hz), 6.26 (d, 1H, J ) 2.1 Hz),
5.75 (br s, 1H), 4.59 (m, 1H), 4.56 (d, 1H, J ) 12.2 Hz), 4.53 (d,
1H, J ) 12.2 Hz), 4.01 (d, 1H, J ) 9.1 Hz,), 3.81 (s, 3H), 3.41 (d,
1H, J ) 9.1 Hz), 2.71 (m, 1H exch.). 13C NMR (75.0 MHz,
CDCl3,): δ 170.6, 168.3, 141.2, 137.3, 128.6, 128.0, 127.7, 122.0,
73.7, 73.2, 71.9, 70.8, 53.1. HRMS (ESI, MeOH + CH2Cl2, m/z):
calcd for C15H17NO5Na (MNa)+ 314.1004, found 314.1000.
(2R,3S)-Methyl 2-[(Benzyloxy)methyl]-3-[(tert-butyldimeth-
ylsilyl)oxy]-4-methylene-5-oxopyrrolidine-2-carboxylate (26). To
a stirred solution of 25 (97.5 mg, 0.33 mmol) in CH2Cl2 (2.0 mL)
were successively added under argon at rt 2,6-lutidine (218 µL,
1.87 mmol) and (TBS)OTf (285 µL, 1.22 mmol). The mixture was
stirred at rt for 24 h. Then a solution of Na2CO3 (10% w/v) was
added until pH 8, and the product was extracted with CH2Cl2.
Drying on MgSO4 and evaporation of the organic phase under
reduced pressure afforded (2R,3S)-26 as a white solid (131.9 mg,
97%). Mp: 99 °C. [R]D25 +15.0 (c 1.28, CHCl3). IR (cm-1): 3192,
2926, 2854, 1741, 1702, 1674, 1452, 1428, 1359, 1343, 1250, 1235,
1109, 835. MS (ESI, MeOH + CH2Cl2 m/z): 428 [(MNa)+, 100].
1H NMR (500 MHz, CDCl3): δ 7.38-7.28 (m, 5H), 6.18 (br s,
1H, NH), 6.16 (d, 1H, J ) 2.2 Hz), 5.51 (br s, 1H), 4.63 (m, 1H,
J ) 2.2 Hz), 4.56 (d, 1H, J ) 12.2 Hz), 4.54 (d, 1H, J ) 12.2 Hz),
4.06 (d, 1H, J ) 9.2 Hz), 3.73 (s, 3H), 3.42 (d, 1H, J ) 9.2 Hz),
0.87 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 169.5, 167.9, 141.9, 137.3, 128.6, 128.1, 127.9, 119.4,
73.8, 73.0, 72.2, 69.6, 52.6, 25.7, 17.9, -4.2, -4.6. HRMS (ESI,
MeOH + CH2Cl2, m/z): calcd for C21H31NO5SiNa (MNa)+
428.1869, found 428.1858.
Cycloaddition of N-Methylnitrone to (S)-12: 5-tert-Butyl
6-Methyl 6-[(Benzyloxy)methyl]-2-methyl-4-oxohexahydro-5H-
pyrrolo[3,4-d]isoxazole-5,6-dicarboxylates (3aR,6R,6aS)-20 and
(3aS,6R,6aR)-21. A solution of N-methylnitrone (58.0 mg, 0.98
mmol) in dry toluene (2.0 mL) was added to (S)-12 (167.4 mg,
0.46 mmol) placed under Ar. The mixture was stirred at 110 °C
for 2.2 h. The solvent was evaporated under reduced pressure, and
the crude material was purified by chromatography (eluent hep-
tane-EtOAc, 4:6) to give the main cycloadduct (3aR,6R,6aS)-20
(173.3 mg, 89%) as a colorless gum and diastereomer (3aS,6R,-
6aR)-21 (4.3 mg, 2.2% described in the Supporting Information).
24
The following are data for (3aR,6R,6aS)-20. [R]D +5.6 (c 1.55,
CHCl3). IR (cm-1): 2922, 1787, 1718, 1454, 1368, 1298, 1233,
1152, 1124, 1076. MS (ESI, MeOH), m/z): 443 (MNa)+, 343 [[(M
- Boc)Na]+, 100], 321 [M - Boc)H]+. 1H NMR (500 MHz,
CDCl3): δ 7.36-7.23 (m, 5H), 4.64 (d, 1H, J ) 6.4 Hz), 4.53 (d,
1H, J ) 12.2 Hz), 4.49 (d, 1H, J ) 12.2 Hz), 4.12 (d, 1H, J ) 9.8
Hz), 4.03 (d, 1H, J ) 9.8 Hz), 3.77 (s, 3H), 3.62 (m, 1H), 3.56 (m,
1H), 2.63 (s, 3H), 2.58 (m, 1H), 1.44 (s, 9H). 13C NMR (75 MHz,
CDCl3): δ 174.0, 167.5, 148.7, 137.4, 128.7, 128.1, 127.7, 83.8,
78.7, 74.2, 73.7, 70.8, 60.7, 53.2, 52.4, 44.8, 28.0. Anal. Calcd for
C21H28N2O7: C, 59.99, H, 6.71; N, 6.66. Found: C, 59.71; H, 6.58;
N, 6.27.
(2R,3S)-Methyl 2-[(Benzyloxy)methyl]-3-[(tert-butyldimethyl-
silyl)oxy]-1-(4-methoxybenzyl)-4-methylene-5-oxopyrrolidine-2-car-
boxylate [(2R,3S)-18]. Cs2CO3 (151.5 mg, 0.46 mmol) was added
to a solution of 26 (123.4 mg, 0.30 mmol) in anhydrous DMF (1.5
mL) under Ar. The mixture was stirred for 10 min at rt and cooled
to 0 °C before dropwise addition of (PMB)Br (67.0 µL, 0.46 mmol).
The reaction mixture was stirred for 0.5 h at 0 °C and then 16 h at
rt. After addition of H2O and extraction with EtOAc, the organic
solution was dried on MgSO4, filtered, and evapored under reduced
pressure. The crude product was purified by preparative TLC (eluent
heptane-EtOAc, 7:3) to give (2R,3S)-18 (146.7 mg, 92%) as a
(2R,3S)-1-tert-Butyl 2-Methyl 2-[(Benzyloxy)methyl]-3-hy-
droxy-4-methylene-5-oxopyrrolidine-1,2-dicarboxylate (22). Pd-
(OH)2 (22.4 mg) was added to a stirred solution of (3aR,6R,6aS)-
20 (165.1 mg, 0.39 mmol) in EtOAc (3.0 mL) placed under N2.
The mixture was stirred under H2 at rt for 8 h. The catalyst was
filtered through Celite and washed with EtOAc. Evaporation under
reduced pressure afforded the crude product as a colorless foam
(163.5 mg), which was directly engaged in the following step
10112 J. Org. Chem., Vol. 72, No. 26, 2007