Enantiomerically Pure â-Substituted, â-Amino Acids
J . Org. Chem., Vol. 64, No. 17, 1999 6415
Anal. Calcd for C24H27NO5: C, 70.42; H, 6.60; N, 3.42. Found:
C, 70.27; H, 6.70; N, 3.36.
(R)-4-(ter t-Bu toxy)-2-m eth yl-4-oxobu ta n oic a cid (5a ).
Following the general procedure, a solution of 4.86 g of 3a (8.3
mmol) in 210 mL of THF was treated with 5.7 mL of hydrogen
peroxide (30 wt %, 1.90 g, 56.0 mmol) and a solution of 0.67 g
of LiOH (28.0 mmol) in 70 mL of water at 0 °C. Hydrolysis
proceeded for 2 h. Acidification of the aqueous layer, extraction,
and concentration yielded the carboxylic acid, which was
recrystallized from hexane to afford the product as large white
(4S)-3-((2R)-4-(ter t-Bu toxy)-4-oxo-2-(p h en ylm eth yl)bu -
ta n oyl)-4-(p h en ylm eth yl)-1,3-oxa zolid in -2-on e (3d ). Ac-
cording to the general procedure, 18.1 mL of sodium hexa-
methyldisilazide (0.91 M in THF, 16.4 mmol) was added
dropwise to a stirring solution of 4.65 g of 2e (15.0 mmol) in
40 mL of THF at -78 °C. After 1.5 h, 6.65 mL of tert-butyl
bromoacetate (8.78 g, 45.0 mmol) was added. The solution was
stirred at -78 °C for an additional 2.5 h. Extraction and
concentration yielded a yellow oil that solidified at -20 °C.
The solid (97:3 diastereomeric ratio by HPLC, using conditions
according to the general procedure; tr(major) ) 5.281, tr(minor)
) 4.470) was recrystallized from a minimal volume of hexane/
ether to yield white needles. The mother liquors were concen-
trated and chromatographed on silica gel (2:1 hexane/EtOAc)
to yield additional product for a combined yield of 82% (5.20
g, 12.3 mmol): [R]25D +106.4° (c 0.96, CH2Cl2); mp 111.2-113.4
crystals in 95% yield (2.51 g, 13.4 mmol): [R]25 +3.9° (c 1.00,
D
CH2Cl2); mp 59.3-59.9 °C; IR (neat) 2979, 1721, 1705 cm-1
;
1H NMR (400 MHz, CDCl3) δ 2.92-2.87 (m, 1H), 2.64 (dd, J
) 16.5, 8.2 Hz, 1H), 2.36 (dd, J ) 16.5, 5.8 Hz, 1H), 1.44 (s,
9H), 1.24 (d, J ) 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
181.9, 171.0, 81.0, 38.7, 35.9, 28.0, 16.7. Anal. Calcd for
C9H16O4: C, 57.43; H, 8.57. Found: C, 57.37; H, 8.66. Exact
mass: calcd for C9H20NO4 (M + NH4), 206.1392; found,
206.1384 (CI, NH3).
(S)-4-(ter t-Bu toxy)-2-(1-m eth yleth yl)-4-oxobu tan oic acid
(5b). Following the general procedure, a solution of 3.41 g of
3b (9.1 mmol) in 135 mL of THF was treated with 3.7 mL of
hydrogen peroxide (30 wt %, 1.23 g, 36.3 mmol) and a solution
of 0.44 g of LiOH (18.2 mmol) in 45 mL of water at 0 °C.
Hydrolysis proceeded for 7 h. Acidification of the aqueous layer,
extraction, and concentration afforded the product as an oil
°C; IR (CHCl3) 1779, 1724, 1698 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 7.36-7.20 (m, 10 H), 4.55-4.45 (m, 2H), 4.08 (dd, J
) 8.9, 2.4 Hz, 1H), 3.96-3.92 (m, 1H), 3.31 (dd, J ) 13.3, 3.3
Hz, 1H), 3.01 (dd, J ) 13.1, 6.2 Hz, 1H), 2.85 (dd, J ) 16.9,
10.9 Hz, 1H), 2.73 (dd, J ) 13.5, 10.0 Hz, 1H), 2.64 (dd, J )
13.1, 9.1 Hz, 1H), 2.38 (dd, J ) 16.9, 4.1 Hz, 1H), 1.40 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 175.4, 171.2, 153.0, 138.1, 135.8,
129.6, 129.3, 129.0, 128.5, 127.3, 126.8, 80.9, 65.9, 55.7, 41.3,
38.4, 37.7, 36.9, 28.1; TLC Rf ) 0.57 (2:1 hexane/EtOAc). Anal.
Calcd for C25H29NO5: C, 70.92; H, 6.86; N, 3.31. Found: C,
70.81; H, 6.93; N, 3.26.
in 84% yield (1.65 g, 7.66 mmol): [R]25 +7.86° (c 1.00, CH2-
D
Cl2); IR (neat) 2966, 1734, 1708 cm-1
;
1H NMR (400 MHz,
CDCl3) δ 2.72-2.57 (m, 2H), 2.35 (dd, J ) 16.3, 3.6 Hz, 1H),
2.06-1.97 (m, 1H), 1.42 (s, 9H), 0.97 (d, J ) 6.8 Hz, 3H), 0.94
(d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 180.6, 171.5,
80.8, 47.4, 34.0, 29.8, 27.9, 20.0, 19.4; TLC Rf ) 0.37 (50%
EtOAc/hexanes); exact mass calcd for C11H24NO4 (M + NH4)
234.1705, found 234.1700 (CI, NH3).
(4S)-3-((2S)-4-(ter t-Bu toxy)-2-(1,1-d im eth yleth yl)-4-ox-
obu ta n oyl)-4-(p h en ylm eth yl)-1,3-oxa zolid in -2-on e (3e).
According to the general procedure, 2.40 mL of sodium
hexamethyldisilazide (0.84 M in THF, 2.0 mmol) was added
dropwise to a stirring solution of 0.50 g of 2e (1.82 mmol) in 9
mL of THF at -78 °C. After 2.5 h, 0.81 mL of tert-butyl
bromoacetate (1.06 g, 5.45 mmol) was added. The solution was
stirred at -78 °C for an additional 15 h. Extraction and
concentration yielded a solid residue (128:1 diastereomeric
ratio by HPLC, 1.3% isopropyl alcohol/hexanes; tr(major) )
5.290, tr(minor) ) 6.413). Flash chromatography (20% EtOAc/
hexane) afforded a white solid, which was recrystallized from
a minimal amount of hexane to provide the major isomer as
(S)-4-(ter t-Bu toxy)-4-oxo-2-p h en ylbu ta n oic a cid (5c).
Following the general procedure, a solution of 2.64 g of 3c (6.4
mmol) in 96 mL of THF was treated with 2.28 mL of hydrogen
peroxide (35 wt %, 1.13 g, 33.2 mmol) and a solution of 0.31 g
of LiOH (12.8 mmol) in 32 mL of water at 0 °C. Hydrolysis
proceeded for 1.5 h. Acidification of the aqueous layer, extrac-
tion, and concentration yielded the carboxylic acid, which was
recrystallized from hexane to afford the product as white
needles in 89% yield (1.44 g, 5.7 mmol): [R]25 +106° (c 0.95,
D
CH2Cl2); mp 76.0-78.5 °C; IR (CHCl3) 2980, 1729, 1710 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.34-7.25 (m, 5H), 4.03 (dd, J
) 10.1, 5.5 Hz, 1H), 3.08 (dd, J ) 16.7, 10.1 Hz, 1H), 2.61 (dd,
J ) 16.7, 5.6 Hz, 1H), 1.39 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 178.9, 170.5, 137.2, 128.9, 127.9, 127.9, 81.3, 47.4, 38.7, 27.9;
TLC Rf ) 0.32 (2:1 hexane/EtOAc). Anal. Calcd for C14H18O4:
C, 67.20; H, 7.20. Found: C, 67.09; H, 7.21.
white needles in 84% yield (0.59 g, 1.52 mmol): [R]25 +51.4°
D
(c 1.00, CH2Cl2); mp 117.5-118.6 °C; IR (neat) 1782, 1729,
1
1693 cm-1; H NMR (400 MHz, CDCl3) δ 7.36-7.24 (m, 5H),
4.69-4.63 (m, 1H), 4.36 (dd, J ) 12.2, 3.2 Hz, 1H), 4.15-4.07
(m, 2H), 3.38 (dd, J ) 13.4, 3.1 Hz, 1H), 2.90 (dd, J ) 16.9,
12.2 Hz, 1H), 2.68 (dd, J ) 13.4, 10.6 Hz, 1H), 2.51 (dd, J )
16.9, 3.2 Hz, 1H), 1.41 (s, 9H), 1.00 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 175.6, 171.9, 153.4, 136.3, 129.6, 128.9, 127.1, 80.7,
65.5, 56.2, 46.0, 37.1, 35.0, 33.3, 28.1, 27.5; TLC Rf ) 0.58 (30%
EtOAc/hexane); exact mass calcd for C22H35N2O5 (M + NH4)
407.2546, found 407.2541 (CI, NH3).
(R)-4-(ter t-Bu t oxy)-4-oxo-2-(1-p h en ylm et h yl)b u t a n o-
ic a cid (5d ). Following the general procedure, a solution of
3.50 g of 3d (8.3 mmol) in 125 mL of THF was treated with
3.0 mL of hydrogen peroxide (35 wt %, 25.6 mmol) and a
solution of 0.40 g of LiOH (16.6 mmol) in 42 mL of water at 0
°C. Hydrolysis proceeded for 1 h. Acidification of the aqueous
layer, extraction, and concentration yielded the carboxylic acid,
which was recrystallized from hexane to afford the product
Gen er a l P r oced u r e for Lith iu m Hyd r oxid e/Hyd r ogen
P er oxid e Hyd r olysis. To a solution of 3 (6.4 mmol) in 96
mL of THF at 0 °C was added 4 equiv of H2O2 (35 wt %)
dropwise via syringe, followed by the addition of a solution of
2 equiv of anhydrous LiOH in 32 mL of H2O. The solution was
stirred at 0 °C for 1-2 h. After TLC indicated completion of
the hydrolysis, 20 mL of saturated Na2SO3 and 20 mL of
saturated NaHCO3 were added at 0 °C. The contents were
partially concentrated in vacuo and diluted with 50 mL of H2O.
The aqueous solution was extracted with four 50 mL portions
of dichloromethane. The dichloromethane extracts were com-
bined, dried (MgSO4), filtered through cotton, and concentrated
in vacuo to yield free oxazolidinone 1 as a white solid, which
was recrystallized from hexane/ethyl acetate. At 0 °C, the
aqueous layer was acidified to pH ∼1.5 with 6 M HCl and
extracted with four 50 mL portions of ethyl acetate. The
combined organic extracts were dried (MgSO4), filtered through
cotton, and concentrated in vacuo to yield an oil, which
solidified at -20 °C. The residue was recrystallized or chro-
matographed on silica gel, using an appropriate solvent
mixture, to yield the carboxylic acid.
as large white crystals in 91% yield (1.99 g, 7.5 mmol): [R]25
D
+7.1° (c 1.00, CH2Cl2); mp 57.0-59.8 °C; IR (CHCl3) 2979,
1730, 1709 cm-1;1H NMR (400 MHz, CDCl3) δ 7.32-7.18 (m,
5H), 3.13-3.06 (m, 2H), 2.76 (dd, J ) 15.4, 10.3 Hz, 1H), 2.56
(dd, J ) 16.7, 8.9 Hz, 1H), 2.34 (dd, J ) 16.9, 4.8 Hz, 1H),
1.41 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 180.5, 170.9, 138.1,
129.1, 128.6, 126.8, 81.1, 43.2, 37.4, 36.1, 28.0; TLC Rf ) 0.17
(2:1 hexanes/EtOAc). Anal. Calcd for C15H20O4: C, 68.18; H,
7.58. Found: C, 68.24; H, 7.63.
S-Eth yl (S)-4-(ter t-Bu toxy)-2-(1,1-d im eth yleth yl)-4-ox-
obu ta n th ioa te (4). To a solution of 0.45 mL of ethanethiol
(0.36 g, 5.8 mmol, 3.4 equiv) in 10 mL of THF at -78 °C was
added 1.7 mL of n-butyllithium (2.5 M in hexanes, 0.27 g, 4.2
mmol, 2.5 equiv) via syringe. The solution was allowed to warm
to 0 °C. The cloudy solution was stirred for 15 min before a
precooled (-78 °C) solution of 0.66 g of 3e (1.7 mmol, 1.0 equiv)
in 10 mL of THF was added via cannula. The reaction was
stirred at 0 °C for 9 h before being partitioned between 40 mL
of 1 M aqueous NaOH and 30 mL of ethyl ether. The layers