7
ACCEPTED MANUSCRIPT
requires 318].
J = 9.7, 18.2 Hz, 1 H), 3.04 (dd, J = 4.6, 18.2 Hz, 1 H), 2.77-2.86
(m, 1 H), 1.55-1.72 (comp, 2 H), 0.92 (t, J = 7.4 Hz, 3 H); 13C
NMR (75 Hz) δ 174.9, 171.2, 153.7, 138.6, 129.1, 128.5, 125.7,
70.1, 57.4, 51.5, 41.9, 37.1, 24.9, 11.4; IR (neat) 1782, 1733,
1707 1386, 1197 cm-1; mass spectrum (CI) m/z 306.1340
[C16H20NO5 (M + 1) requires 306.1340].
(R,E)-Methyl 4-oxo-4-(2-oxo-4-phenyloxazolidin-3-yl)but-
2-enoate (30).
A solution of methyl fumarate (29) (2.66 g, 20.4 mmol) and
pivaloyl chloride (2.70 g, 2.76 mL, 22.5 mmol) in THF (40 mL)
was cooled to –20 °C. Triethylamine (4.13 g, 5.68 mL, 40.8
mmol) was added dropwise, and the mixture was stirred 1.5 h at
–20 °C. The cooling bath was removed, and the solution was
allowed to warm to room temperature. Solid LiCl (0.953 g, 22.5
mmol) and (R)-phenyl-oxazolidone 13 (5.00 g, 30.6 mmol) were
added portionwise, and the reaction was stirred 12 h. H2O (10
mL) and ethyl acetate (50 mL) were added. The layers were
separated, and the aqueous layer was extracted with ethyl acetate
(2 x 10 mL). The combined organic layers were washed with 1
M HCl (1 x 25 mL), saturated Na2CO3 (2 x 50 mL), saturated
brine (1 x 50 mL), dried (Na2SO4), and concentrated under
reduced pressure. The crude product was purified by flash
chromatography, eluting with hexanes/ethyl acetate (3:1) to
provide 4.38 g (78%) of the chiral methyl fumarate 30 as a white
(S)-methyl
yl)ethyl)hexanoate (31c).
2-(2-oxo-2-((R)-2-oxo-4-phenyloxazolidin-3-
Compound 11c was prepared on 1 mmol via the same method
as 31a, employing n-BuLi in place of MeLi. Isolated 0.275 g
(83%) of 31c as a clear oil. 1H NMR (300 MHz) δ 7.43-7.29 (m,
5 H), 5.44 (dd, J = 8.8, 4.3 Hz, 1 H), 4.72 (t, J = 8.8 Hz, 1 H),
4.31-4.26 (m, 1 H), 3.54 (s, 3 H), 3.43 (dd, J = 18.0, 9.6 Hz, 1 H),
3.06 (dd, J = 18.0, 4.3 Hz, 1 H), 2.92-2.82 (m, 1 H), 1.67-1.48
(m, 3 H), 1.30-1.28 (m, 3 H), 0.89-0.87 (m, 3 H); 13C NMR (75
MHz): δ 175.4, 171.5, 154.0, 138.9, 129.1, 126.0, 77.7, 70.4,
57.8, 51.9, 40.8, 37.8, 31.8, 29.4, 22.7, 14.1; IR (neat) 2957,
2861, 1785, 1733, 1704, 1386 cm-1; mass spectrum (CI) m/z
334.1656 [C16H20NO5 (M + 1) requires 336.1654].
1
solid: mp 92-94 °C; H NMR (400 MHz) δ 8.17 (d, J = 15.7 Hz,
1 H), 7.43 (comp, 5 H), 6.87 (d, J = 15.7, 1 H), 5.50 (dd, J = 4.0,
8.9 Hz, 1 H), 4.76 (t, J = 8.9 Hz, 1 H), 4.36 (dd, J = 4.0, 8.9 Hz, 1
H), 3.81 (s, 3 H); 13C NMR (100 MHz) δ 165.1, 163.1, 153.2,
138.2, 133.8, 132.2, 129.1, 128.8, 125.9, 70.2, 57.7, 52.2; IR
(neat) 1780, 1727, 1690, 1387, 1341, 1306, 1279, 1196 cm-1;
mass spectrum (CI) m/z 275.0869 [C14H13NO5 (M+1) requires
275.0794].
(R)-methyl 4-oxo-4-((R)-2-oxo-4-phenyloxazolidin-3-yl)-2-
phenylbutanoate (31d).
Compound 31d was prepared on 1 mmol via the same method
as 31a, employing PhLi in place of MeLi. The reaction was run
on 1 mmol scale and 0.290 g (82%) of compound 31d was
isolated as a clear oil. 1H NMR (300 MHz) δ 7.46-7.29 (m, 9 H),
7.27-7.26 (m, 1 H), 5.58 (dd, J = 11.2, 4.4 Hz, 1 H), 5.37 (dd, J =
8.8, 3.5 Hz, 1 H), 4.58 (t, J = 8.8 Hz, 1 H), 4.21 (dd, J = 8.8, 3.4
Hz, 1H), 3.53 (s, 3 H), 3.27 (dd, J = 17.3, 11.2 Hz, 1 H), 2.62
(dd, J = 17.3, 4.4 Hz, 1 H); 13C NMR (125 MHz) δ 172.5, 171.5,
153.0, 138.9, 136.9, 129.9, 129.1, 128.8, 128.6, 128.5, 128.3,
128.1, 127.8, 125.7, 70.0, 58.1, 51.7, 44.8, 38.6, 29.7; IR (neat)
2922, 2852, 1781, 1735, 1699, 1383, 1192 cm1; mass spectrum
(CI) m/z 354.1336 [C20H20NO5 (M + 1) requires 354.1341].
(S)-Methyl
2-methyl-4-oxo-4-((R)-2-oxo-4-
phenyloxazolidin-3-yl) butanoate (31a).
A suspension of (CuI)4(DMS)3 (0.405 g, 1.71 mmol) in THF
(8.6 mL) was prepared and cooled to –78 °C, whereupon MeLi
(1.31 M in hexanes, 1.2 mL, 1.59 mmol) was added dropwise.
The resulting orange solution was stirred for 40 min at –78 °C.
Iodotrimethylsilane (0.33 g, 0.25 mL, 1.65 mmol) was added
dropwise, and stirring was continued for 30 min. A solution of
chiral fumarate 30 (0.337 g, 1.22 mmol) in THF (1.75 mL) was
added dropwise, and the reaction was stirred for 6 h at –78 °C.
Triethylamine (0.620 g, 0.836 mL, 6.12 mmol) was added, and
the reaction was stirred 1 h. Saturated NH4Cl (10 mL) was added,
and the cooling bath was removed. Upon reaching room
temperature, the septum was removed, and the solution was
stirred until a homogeneous blue solution was obtained. The
reaction mixture was poured into H2O (10 mL) and ethyl acetate
(10 mL), and the layers were separated. The aqueous phase was
extracted with ethyl acetate (3 x 15 mL). The combined organic
layers were washed with brine (1 x 30 mL), dried (Na2SO4), and
concentrated under reduced pressure. The crude product was
purified via flash chromatography, eluting with hexanes/ethyl
acetate (5:1) to provide 0.521 g (86%) of 31a as a white solid:
mp 77-78 °C; 1H NMR (400 MHz) δ 7.40-7.27 (comp, 5 H), 5.42
(dd, J = 3.9, 8.7 Hz, 1 H), 4.70 (t, J = 8.7 Hz, 1 H), 4.27 (dd, J =
3.9, 8.7 Hz, 1 H), 3.55 (s, 3 H), 3.44 (dd, J = 7.5, 17.8 Hz, 1 H),
3.04-2.90 (comp, 2 H), 1.21 (d, J = 7.5 Hz, 3 H); 13C NMR (100
MHz) δ 175.5, 170. 8, 153.6, 138.6, 128.9, 128.4, 125.5, 70.0,
57.3, 51.6, 38.9, 34.9, 16.8; IR (neat) 1781,1733, 1707, 1386 cm-
1; mass spectrum (CI) m/z 291.1107 [C15H17NO5 (M+1) requires
291.1107].
Methyl (2S,3R)-2-ethyl-3-((R)-2-oxo-4-phenyloxazolidine-
3-carbonyl)hex-5-enoate (36)
n-Butyllithium (2.5 M solution in hexanes, 0.7 mL, 1.8
mmol,) was added to a solution of hexamethyldisilazane (0.31 g,
1.9 mmol) in THF (1.9 M) at –78 °C. The solution was stirred for
15 min at –78 °C, 30 min at 0 °C, and then again at –78 °C.
Hexamethylphosphoramide (0.47 g, 2.6 mmol) was added to the
solution, and succinate 31b (0.360 g, 0.85 mmol) in THF (1.6
mL) was added dropwise. The solution was stirred for 1 h at –78
°C, whereupon allyl iodide (0.44 g, 2.6 mmol) was added. The
reaction was stirred for 6 h at which time 1 M HCl (2.5 mL) was
added and the reaction allowed to warm to room temperature.
The mixture was extracted with EtOAc (3 x 5 mL). The
combined organic extracts were washed with brine (1 x 20 mL),
dried (MgSO4), and concentrated under reduced pressure. The
resulting crude reaction mixture purified via column
chromatography eluting with hexanes/ethyl acetate (8:1 ꢀ 6:1) to
provide 0.10 g (34%) of 36 as a clear colorless oil: 1H NMR (600
MHz, CDCl3) δ 7.35-7.26 (m, 5H), 5.48 (dddd, J = 17.0, 10.2,
7.6, 6.7 Hz, 1 H), 5.42 (dd, J = 8.7, 3.7 Hz, 1 H), 4.77 (ddt, J =
10.2, 1.8, 0.9 Hz, 1 H), 4.72 (dq, J = 17.0, 1.5 Hz, 1 H), 4.67 (t, J
= 8.9 Hz, 1 H), 4.30 (td, J = 8.5, 4.7 Hz, 1 H), 4.26 (dd, J = 8.9,
3.8 H, 1 H), 2.65 (ddd, J = 10.7, 8.5, 3.8 Hz, 1 H), 2.32-2.27 (m,
1 H), 2.23-2.19 (m, 1 H), 1.67-1.60 (m, 1 H), 1.55-1.48 (m, 1 H),
0.85 (t, J = 7.4 Hz, 3 H); 13C NMR (150 MHz; CDCl3): δ 174.4,
173.4, 153.3, 138.9, 133.7, 129.0 (2C), 128.7, 126.2 (2C), 117.7,
69.6, 57.9, 51.6, 49.0, 44.1, 34.9, 23.5, 11.9; IR (film, NaCl)
2968, 1779, 1733, 1701, 1384, 1195, 1168 cm-1; HRMS (ESI)
(S)-Methyl 2-ethyl-4-oxo-4-((R)-2-oxo-4-phenyloxazolidin-
3-yl)butanoate (31b).
Compound 31b was prepared on 1 mmol scale via the same
method as 31a, employing EtLi in place of MeLi. Isolated 0.210
1
g (72 %) of 31b as a white solid: mp 80-81 °C; H NMR (300
MHz) δ 7.26-7.41 (comp, 5 H), 5.42 (dd, J = 3.8, 8.7 Hz, 1 H),
4.70 (t, J = 8.9 Hz, 1 H), 4.26 (dd, J = 4.1, 8.9 Hz, 1 H), 3.42 (dd,