Diastereoselective Preparation of Silylated Pyrrolidones
Methyl 3-{(Benzyl)[(2E)-4-hydroxy-2-triethylsilyl-but-2-enyl]- Et2O (3 ϫ 10 mL). The collected organic phases were dried and
FULL PAPER
amino}-3-oxopropanoate (9): NEt3 (0.633 mL, 4.55 mmol) and
Me3SiCl (0.578 mL, 4.55 mmol) were added in that order, under
nitrogen, to a solution of the allyl(benzyl)amine 8b (1.204 g,
4.14 mmol), in dry THF (50 mL), cooled in a water/ice bath. After
the solvent was evaporated under vacuum. Flash chromatography
(hexanes/EtOAc, 75:25) gave the pure compounds (11: 52%; 10:
90%).
10: 1H NMR (CDCl3, 200 MHz): δ ϭ 0.49Ϫ0.63 (6 H), 0.85 (t,
stirring at room temperature for 10 min, a white suspension J ϭ 8 Hz, 9 H), 2.95Ϫ2.99 (m, 1 H), 3.38Ϫ3.54 (3 H), 3.78 (s, 3
formed. Brine (40 mL) was added, and the resulting biphasic sys- H), 4.47 (AB system, 2 H), 5.43 (s, 1 H), 5.72 (s, 1 H), 7.21Ϫ7.34
tem was subjected to a standard extractive workup with Et2O (3 ϫ (m, 5 H) ppm. 13C NMR (CDCl3, 50 MHz): δ ϭ 2.7, 7.1, 40.5,
20 mL). The resulting crude O-silylated amine was then dissolved
46.9, 51.9, 52.7, 54.5, 126.8, 127.8, 128.2, 128.8, 135.8, 147.8, 169.3,
in dry CH2Cl2 (50 mL) and cooled in a water/ice bath. NEt3
170.3 ppm. IR (CDCl3): ν˜ ϭ 2957, 2938, 2912, 2877, 1736, 1686,
(0.633 mL, 4.55 mmol) and methyl 3-chloro-3-oxopropanoate 1431 cmϪ1. MS (EI): m/z (%) ϭ 344 (37) [Mϩ Ϫ Et], 285 (63),
(0.488 mL, 4.55 mmol) were then added in that order. The reaction
mixture was warmed to room temperature while stirring for further
20 min. After addition of brine (40 mL) and a standard extractive
workup with CH2Cl2 (3 ϫ 20 mL), the crude O-silylated amide was
dissolved in THF (50 mL) and treated with 10% HCl solution to
91(100). C21H31NO3Si (373.56): calcd. C 67.52, H 8.36, N 3.75;
found C 67.58, H 8.43, N 3.90.
11: H NMR (CDCl3, 400 MHz): δ ϭ 0.59 (m, 6 H), 0.94 (t, J ϭ
8.0 Hz, 9 H), 3.29 (d, part of AB system, J ϭ 9.6 Hz, 1 H), 3.60
(s, 1 H), 3.63 (d, part of AB system, J ϭ 17.6 Hz, 1 H), 3.68 (s, 3
1
pH ഠ 2. The resulting mixture was stirred at room temperature for H), 4.20 (d, part of AB system, J ϭ 14.6 Hz, 1 H), 4.68 (d, J ϭ
10 min, and then treated at 0 °C with a few drops of a saturated
aqueous NaHCO3 to neutralize the acid. The aqueous phase was
extracted with Et2O (3 ϫ 20 mL), the collected organic layers were
dried, and the solvents were evaporated in vacuo. Flash chromatog-
raphy of the crude product (EtOAc/hexanes, 40:60) gave the pure
17.6 Hz, 1 H), 4.85 (d, part of AB system, J ϭ 14.6 Hz, 1 H), 5.03
(d, J ϭ 11.0 Hz, 1 H), 5.85 (dd, J ϭ 17.6, 11.0 Hz, 1 H), 7.26Ϫ7.39
(m, 5 H) ppm. 13C NMR (CDCl3, 100 MHz): δ ϭ 1.6, 7.9, 47.1,
51.8, 52.0, 52.7, 55.7, 113.3, 127.8, 128.5, 128.7, 135.6, 137.4, 169.6,
170.5 ppm. H NMR (C6D6, 400 MHz): δ ϭ 0.53 (q, J ϭ 8 Hz, 6
H), 0.94 (t, J ϭ 8 Hz, 9 H), 3.16 (d, J ϭ 9.4 Hz, 1 H), 3.39 (s, 3
1
1
amide 9 (82%). H NMR (CDCl3, 200 MHz): δ ϭ 0.51Ϫ0.62 (m,
6 H), 0.84Ϫ0.91 (m, 9 H), 2.52 (br. s, 1 H), 3.72Ϫ3.39 (m, 5 H), H), 3.71 (d, J ϭ 9.4 Hz, 1 H), 3.89 (s, 1 H), 4.16 (d, J ϭ 14.6 Hz,
3.89Ϫ4.19 (m, 4 H), 4.45Ϫ4.55 (m, 2 H), 6.05Ϫ6.15 (m, 1 H), 1 H), 4.56 (d, J ϭ 17.5 Hz, 1 H), 4.89 (d, J ϭ 14 Hz, 1 H), 4.92
7.08Ϫ7.37 (m, 5 H) ppm. 13C NMR (CDCl3, 50 MHz): δ ϭ 2.6, (d, J ϭ 10.9 Hz, 1 H), 5.91 (dd, J ϭ 17.5, 10.9 Hz, 1 H), 7.17Ϫ7.42
2.9, 7.2, 41.3, 43.1, 47.4, 47.7, 49.6, 52.3, 58.8, 59.0, 125.5, 127.2,
(m, 5 H) ppm. 13C NMR (C6D6, 50 MHz): δ ϭ 1.7, 7.8, 36.6, 46.9,
127.4, 127.6, 128.5, 129.0, 134.2, 135.5, 145.0, 145.9, 166.4, 51.3, 51.6, 56.7, 112.8, 127.8, 128.7, 128.8, 136.4, 138.0, 169.5,
167.5 ppm. IR (CH2Cl2): ν˜ ϭ 3056, 2987, 2876, 1739, 1644, 1420, 169.7 ppm. IR (CHCl3): ν˜ ϭ 3064, 3041, 2956, 2931, 2880, 1737,
1255 cmϪ1. MS (EI): m/z (%) ϭ 362 (10) [Mϩ Ϫ Et], 158 (22),
1688, 1649 cmϪ1. MS (EI): m/z (%) ϭ 373 (1.5) [Mϩ], 315 (19), 314
91 (100).
(99), 91 (100), 59 (71).
Methyl 3-((Benzyl){(2E)-2-triethylsilyl-4-[(methoxycarbonyl)oxy]-
Methyl trans-1-Benzyl-4-ethyl-2-oxo-4-(triethylsilyl)pyrrolidine-3-
but-2-enyl}amino)-3-oxopropanoate (4): Pyridine (0.100 mL, carboxylate (12): Pd(OH)2 (10 mol %) was added to a solution of
1.25 mmol), methyl chloroformate (0.096 mL, 1.25 mmol) and 4-
DMAP (6 mg, 0.05 mmol), were added in that order, under nitro-
pyrrolidone 11 (17 mg, 0.046 mmol) in EtOH (1 mL), and the sys-
tem was purged three times with hydrogen and evacuated. The het-
gen at 0 °C, to a solution of the amide 9 (0.406 g, 1.04 mmol) in erogeneous solution was stirred overnight under hydrogen and was
dry CH2Cl2 (10 mL). After stirring at room temperature for 6 h, then filtered through Celite. The solvent was removed under re-
brine (10 mL) was added and the reaction mixture was extracted
with CH2Cl2 (3 ϫ 6 mL). The collected organic layers were dried
and the solvents were evaporated in vacuo. Flash chromatography
of the crude product (EtOAc/hexanes, 40:60) afforded the expected
carbonate 4 (Ͼ 98%). 1H NMR (CDCl3, 200 MHz): δ ϭ 0.48Ϫ0.59
duced pressure and the residue was purified on silica (EtOH) to
give 14 mg (82% yield) of the expected product 12 as a clear oil.
1H NMR (400 MHz, CDCl3): δ ϭ 0.63 (q, J ϭ 8 Hz, 6 H), 0.84 (t,
J ϭ 7 Hz, 3 H), 0.96 (t, J ϭ 7.6 Hz, 9 H), 1.44Ϫ1.62 (m, AB system,
2 H), 3.14 (d, J ϭ 10.2 Hz, 1 H), 3.26 (d, J ϭ 10.2 Hz, 1 H), 3.54
(6 H), 0.80Ϫ0.87 (9 H), 3.37Ϫ3.90 (9 H), 4.19Ϫ4.52 (5 H), 5.97 (s, 1 H), 3.75 (s, 3 H), 4.23 (d, J ϭ 14.2 Hz, 1 H), 4.72 (d, J ϭ
(m, 1 H), 7.03Ϫ7.28 (5 H) ppm. 13C NMR (CDCl3, 50 MHz): δ ϭ 14.8 Hz, 1 H), 7.28Ϫ7.36 (m, 5 H) ppm. 13C NMR (CDCl3,
2.3, 2.7, 7.0, 41.1, 42.3, 47.1, 47.4, 48.9, 52.1, 54.5, 63.7, 63.9, 125.4, 50 MHz): δ ϭ 2.6, 7.9, 10.8, 26.7, 51.9, 53.2, 55.5, 127.7, 128.4,
127.1, 127.3, 127.4, 128.3, 128.8, 135.1, 135.9, 137.7, 138.3, 139.4,
128.6, 135.6, 169.6, 170.7. IR (neat): ν˜ ϭ 2953, 1737, 1694, 1500,
155.0, 166.1, 167.2 ppm. IR (CHCl3): ν˜ ϭ 2955, 2912, 2876, 1745,
1450, 1433, 1164, 729, 702 cmϪ1. MS (EI): m/z (%) ϭ 375 (5), 347
1645, 1422 cmϪ1. MS (EI): m/z (%) ϭ 420 (14) [Mϩ Ϫ Et], 374 (4), (25), 317 (100), 91 (25), 59 (13). C21H33NO3Si (375.58): calcd. C
91 (100).
67.16, H 8.85, N 3.73; found C 67.52, H 9.19, N 3.28.
General Procedure for the Synthesis of Methyl trans-1-Benzyl-2-oxo-
4-[1-(triethylsilyl)vinyl]pyrrolidine-3-carboxylate (10) and Methyl
Methyl cis-1-Benzyl-3-methyl-2-oxo-4-(triethylsilyl)-4-vinylpyrroli-
dine-3-carboxylate (15): Solid NaH (60% dispersion in mineral oil)
trans-1-Benzyl-2-oxo-4-(triethylsilyl)-4-vinylpyrrolidine-3-carb- (4 mg, 1.1 equiv.) was slowly added at 0 °C to a solution of pyrroli-
oxylate (11): NaH (60% dispersion in mineral oil, 0.22 mmol) was
added under argon to a solution of the appropriate acyclic precur-
sor (3 or 4, 0.20 mmol) in dry DMF (2 mL), cooled in a water/ice
done 11 (34 mg, 0.09 mmol) in DMF (1 mL). After the reaction
mixture had been stirred for 20 min, CH3I (0.05 mL, 9 equiv.) was
added and the reaction mixture was allowed to reach room tem-
bath, and the solution was stirred at room temperature for 10 min. perature and stirred for 1 h. Water (5 mL) and saturated aqueous
The enolate generated was cannulated under positive argon press-
NH4Cl solution (1 mL) were then added, and the aqueous phase
was subjected to standard extractive workup with Et2O (3 ϫ
ure into a Pd0 complex solution, previously prepared in a separate
flask by dissolution of Pd(OAc)2 (2.5 mg, 0.01 mmol) and dppe 10 mL). Flash chromatography (hexanes/EtOAc, 80:20) gave the
(8 mg, 0.02 mmol) in dry DMF (2 mL). After stirring at 100 °C for
pure methylated compound 15 in quantitative yield. 1H NMR
30 min, the reaction mixture was treated with a 25 wt.% aqueous (400 MHz, CDCl3): δ ϭ 0.61 (q, J ϭ 8 Hz, 6 H,), 0.92 (t, J ϭ
NH4Cl solution (20 mL) and the aqueous phase was extracted with 7.6 Hz, 9 H), 1.39 (s, 3 H), 3.29 (d, AB system, J ϭ 11 Hz, 1 H),
Eur. J. Org. Chem. 2003, 2702Ϫ2708
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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