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drous sodium sulfate, the solution was filtered and
evaporated to provide an off white solid. Silica gel
chromatography (eluted with 6:3:1 CH2Cl2:hexanes:
EtOAc) provided 1.37 g (93%) of pure (+)-5 as a white
solid.
1H NMR (300 MHz) (DMSO-d6, 393K) l DMSO: 3.50
(3H, bs); 3.51 (3H, s); 4.87 (1H, d, J=2.9 Hz); 5.02
(2H, broad m); 5.14 (1H, d, J=2.9 Hz); 5.28 (1H, d,
J=3.3 Hz); 6.28 (1H, d, J=3.3 Hz); 6.61 (2H, d, J=7.0
Hz); 7.01–7.29 (13H, m). IR (NaCl, neat) 3031, 2940,
2837, 1753, 1706, 1454, 1401, 1348, 1288, 1267, 1250,
1207, 1189, 1109, 1081 cm−1. HRMS (FAB+) calcd for
C27H28NO6 (MH+) 462.1917; found 462.1917. (+)-5.
[h]D25=+1.7 (c=1.0, CH2Cl2). (−)-5. [h]2D5=−1.8 (c=1.0,
CH2Cl2).
Figure 2.
Compound (−)-1: A solution of (+)-5 (472 mg, 1.02
mmol, 1 equiv.) in 3:1 THF:MeOH (32 mL) was purged
with argon for 10 min. To this solution in a pressure
tube, 20% Pd(OH)2 on activated carbon (360 mg, 0.51
mmol, 0.5 equiv.) was added, and the tube filled with
hydrogen gas to 95 psi. The pressure was released, and
the tube refilled. This was repeated 4 times more. The
pressurized tube was then stirred for 2 days at room
temperature. After the 2 days, the pressure was
released, the solution purged with argon, and the 20%
Pd(OH)2 on activated carbon removed by filtration
through Celite. Evaporation of the filtrate and tritura-
tion of the residue with ether provided 152 mg (99%) of
(−)-1 as an oily solid.
Scheme 1.
Scheme 2.
1H NMR (400 MHz) (DMSO-d6) l DMSO: 3.35 (3H,
s); 3.36 (3H, s); 3.39 (1H, d, J=2.1 Hz); 4.71 (1H, d,
J=2.1 Hz); 6.80–8.40 (3H, bs). 13C NMR (100 MHz)
(DMSO-d6) l DMSO: 55.0, 55.6, 56.8, 103.7, 166.3. IR
(NaCl, neat): 2939, 1641, 1506, 1406, 1342, 1272, 1218,
1194, 1067 cm−1. HRMS (FAB+) calcd for C5H12NO4
(MH+) 150.0766; found 150.0768. (−)-1. [h]2D5=−7.4
(c=0.50, MeOH). (+)-1. [h]2D5=+7.6 (c=0.67, MeOH).
accomplished in excellent yield. This has served as the
key step in the first asymmetric synthesis of (2S)- and
(2R)-amino-3,3-dimethoxypropanoic acid. This work
constitutes the first example of the successful deploy-
ment of a titanium enolate generated from 4 that may
find other useful applications in amino acid synthesis.
In addition, the condensation product 5 is a potentially
useful chiral building block, and studies are currently
underway to explore other uses for this substance.
Compound (+)-6: A stirred solution of MeOH (10 mL)
at 0°C was treated with acetyl chloride (2 mL, 30
mmol). This mixture was warmed to room temperature
and stirred for 20 min. The resulting methanolic HCl
solution was added to a round bottomed flask contain-
ing (−)-1 (95 mg, 0.64 mmol, 1 equiv.). After stirring
the reaction at reflux for 2.5 h, the solvent was removed
in vacuo to provide 126 mg (99%) of (+)-6 as a clear oil.
Experimental
1H NMR (400 MHz) (CD3OD) l CD3OD: 3.49 (3H, s);
3.54 (3H, s); 3.86 (3H, s); 4.33 (1H, d, J=2.8 Hz); 4.86
(1H, d, J=2.8 Hz). 13C NMR (100 MHz) (CD3OD) l:
53.9; 56.4; 57.2; 57.7; 103.2; 167.8. IR (NaCl, neat):
3583, 3408, 2956, 2843, 1749, 1643, 1591, 1503, 1443,
1378, 1306, 1241, 1195, 1111, 1070 cm−1. HRMS (FAB+)
calcd for C6H14NO4 (MH+) 164.0923; found 164.0922.
(+)-6. [h]2D5=+2.7 (c=0.66, MeOH). (−)-6. [h]2D5=−2.7
(c=0.66, MeOH). The enantiomeric purity of (+)-6 was
found to be >95% ee by formation of the Mosher’s
amide via both the optically pure and racemic Mosher’s
acid chlorides and comparison of the resulting
diastereomers by 1H NMR. None of the minor
Compound (+)-5: A solution of (−)-4 (1.24 g, 3.2 mmol,
1 equiv.) is dissolved in CH2Cl2 (50 mL) and cooled to
−78°C. While stirring, TiCl4 (700 mL, 6.4 mmol, 2
equiv.) was added, followed by triethylamine (900 mL,
6.4 mmol, 2 equiv.) to provide a dark blue enolate
solution. After stirring for 15 min, trimethyl orthofor-
mate (2.1 mL, 19.2 mmol, 6 equiv.) was added, and the
solution warmed slowly to 0°C. After stirring 45 min at
0°C, 0.025 M pH 7 phosphate buffer was added and
stirred 30 min. The quenched reaction was filtered
through Celite, diluted with CH2Cl2, and washed twice
with brine. Upon drying the organic layer over anhy-