T. Golakoti et al. / Tetrahedron 56 (2000) 9093±9102
9101
was washed with brine, dried over mgSO4 and evaporated.
The residue was subjected to ¯ash chromatography on silica
gel using eluants starting from 10% EtOAc to 50% EtOAc
in hexane to obtain N-Boc-l-leucylacetic acid (0.35 g). The
Boc protected acid was dissolved in TFA (2 mL) and stirred
at room temperature. After 1 h, the solvent was evaporated
and the residue was analyzed by HPLC (see Table 3 for
conditions). Only l-Leu was observed in the HPLC chro-
matogram. Using the same procedure compound 8 was
converted to d-Leu.
E. a-tert-Butyl (2S,4S)-5-hydroxy-4-methyl-2-N-(9-(9-
phenyl¯uorenyl))amino)pentanoate (19) and a-tert-
butyl (2S,4R)-5-hydroxy-4-methyl-2-N-(9-(9-phenyl¯uor-
enyl))amino)pentanoate (20). The diastereomeric mixture
of 15 and 16 (1.35 g, 2.86 mmol) was converted and sepa-
rated into 19 (0.81 g, 64%) and 20 (0.26 g, 21%) as
previously described.13 1H NMR (CDCl3, 300 MHz) of 19
d 1.16 (a-tert-butyl ester, 9H, s), 2.49 (H-2, dd; J10.2 and
3.7 Hz), 1.20±1.28 (H-3, m), 1.48±1.58 (H-3, m), 1.70±
1.84 (H-4, m), 0.61 (4-CH3, d; J6.8 Hz), 3.32
(5-CH2OH, dd; J10.5 and 8.0 Hz), 3.48 (5-CH2OH, dd;
J10.5 and 4.9 Hz), 7.17±7.71 (N-PhFl, 13 H, m). 1H
NMR (CDCl3, 300 MHz) of 20 d 1.25 (a-tert-butyl ester,
9H, s), 2.60 (H-2, dd; J5.0 and 5.0 Hz), 1.28±1.37 (H-3,
m), 1.43±1.50 (H-3, m), 1.65±1.77 (H-4, m), 0.80 (4-CH3,
d; J6.8 Hz), 3.23 (5-CH2OH, dd; J10.7 and 7.1 Hz), 3.47
(5-CH2OH, dd; J10.7 and 4.6 Hz), 7.15±7.73 (N-PhFl,
13H, m).
Synthesis of 4-methylprolines. A. Glutamic acid g-
methylester. A pre-cooled solution of 2.9 mL of acetyl
chloride (40.8 mmol) in 20 mL of methanol was added
dropwise to a suspension of l- or d-glutamic acid (5 g,
34 mmol) in 20 mL of methanol at 58C. After 4 h the
mixture was allowed to warm to RT and stirring was con-
tinued for 12 h. Pyridine (4 mL) was added and after 48 h,
the product, a white solid, was collected and washed with
ethanol and ether (4.65 g, 85%). 1H NMR (CD3OD,
300 MHz) of l- (9) or d-glutamic acid g-methylester (10)
d 3.57 (H-2, t; J6.5 Hz), 2.01±2.20 (H2-3, m), 2.60 (H2-4,
t; J7.4 Hz), 3.68 (g-COOCH3, s).
a-tert-Butyl (2R,4R)-5-hydroxy-4-methyl-2-N-(9-(9-phenyl-
¯uorenyl))amino)pentanoate (21) and a-tert-butyl-(2R,4S)-
5-hydroxy-4-methyl-2-N-(9-(9-phenyl¯uorenyl))amino)-
pentanoate (22). As described above the mixture 17 and 18
(1.893 g, 4.01 mmol) was converted and separated into 21
1
B. N-(9-(9-Phenyl¯uorenyl))glutamic acid g-methyl
ester. Compound 9 or 10 was converted to l- (11) or d-N-
(9-(9-phenyl¯uorenyl))glutamic acid g-methyl ester (12) as
previously described.13 1H NMR (CDCl3, 300 MHz) of 11
or 12 d 2.64 (H-2, dd; J7.2 and 4.8 Hz), 1.66±1.76 (H-3,
m), 1.79±1.91 (H-3, m), 2.25±2.45 (H2-4, m), 3.67
(g-COOCH3, s), 7.19±7.73 (N-PhFl, 13H, m).
(1.16 g, 65%) and 22 (0.38 g, 21%). The H NMR spectra
of 21 and 22 were identical with those of 19 and 20,
respectively.
F. (2S,4S)-4-Methyl-N-(9-(9-phenyl¯uorenyl))proline tert-
butyl ester (23). Compound 19 (0.47 g, 1.06 mmol) was
converted into 23 (0.41 g, 90%) as previously described.13
1H NMR (CDCl3, 300 MHz) d 1.21 (a-tert-butyl ester, 9H,
s), 2.98 (H-2, dd; J8.3 and 8.3), 1.30 (H-3, m), 2.04 (H-3,
m), 1.97 (H-4, m), 0.94 (4-CH3, d; J6.3 Hz), 3.01 (H-5, dd;
J11.2 and 9.4 Hz), 3.31 (H-5, dd; J11.2 and 7.0 Hz),
7.10±7.71 (N-PhFl, 13H, m).
C. a-tert-Butyl g-methyl N-(9-(9-phenyl¯uorenyl))gluta-
mate. Compound 11 or 12 was converted to l- (13) or d-a-
tert-butyl g-methyl N-(9-(9-phenyl¯uorenyl))glutamate
(14) as previously described.13 1H NMR (CDCl3,
300 MHz) of 13 or 14 d 1.17 (a-tert-butyl ester, 9H, s),
2.51 (H-2, m), 1.65±1.73 (H2-3, m), 2.27±2.51 (H2-4, m),
3.67 (g-COOCH3, s), 7.18±7.71 (N-PhFl, 13H, m).
(2S,4R)-4-Methyl-N-(9-(9-phenyl¯uorenyl))proline tert-
butyl ester (24). As described above for 19, 130 mg
(0.29 mmol) of 20 was transformed into 107 mg (86%) of
1
D. (2S,4S)-a-tert-Butyl g-methyl N-(9-(9-phenyl¯uor-
enyl))-4-methylglutamate (15) and (2S,4R)-a-tert-butyl
g-methyl N-(9-(9-phenyl¯uorenyl))-4-methylglutamate
(16). Compound 13 (2.62 g, 5.74 mmol) was converted to
a 3:1 mixture of 15 and 16 (2.63 g, 97%) as previously
described.13 1H NMR (CDCl3, 300 MHz) of 15 d 1.14
(a-tert-butyl ester, 9H, s), 2.47 (2, dd; J10.5 and
3.9 Hz), 1.28±1.37 (H-3, m), 1.83±1.93 (H-3, m), 2.66±
2.77 (H-4, m), 0.79 (4-CH3, d; J7.2 Hz), 3.69
24. H NMR (CDCl3, 300 MHz) d 1.28 (a-tert-butyl ester,
9H, s), 3.25 (H-2, m), 1.22±1.40 (H-3, m), 1.66 (H-3, m),
2.32±2.46 (H-4, m), 0.86 (4-CH3, d; J6.1 Hz), 3.16 (H-5,
dd; J10.0 and 1.0 Hz), 3.26 (H-5, m), 7.10±7.71 (N-PhFl,
13H, m).
(2R,4R)-4-Methyl-N-(9-(9-phenyl¯uorenyl))proline tert-
butyl ester (25). As described above for 19, 0.7 g
(1.58 mmol) of 21 was transformed into 0.593 g (88%) of
25. The 1H NMR spectrum of 25 was identical with the one
for 23.
1
(g-COOCH3, s), 7.16±7.71 (N-PhFl, 13H, m). H NMR
(CDCl3, 300 MHz) of 16 d 1.18 (a-tert-butyl ester, 9H, s),
2.56 (H-2, dd; J7.6 and 5.1 Hz), 1.35±1.44 (H-3, m),
1.81±1.91 (H-3, m), 2.69±2.80 (H-4, m), 1.07 (4-CH3,
d; J7.1 Hz), 3.57 (g-COOCH3, s), 7.16±7.71 (N-PhFl,
13H, m).
(2R,4S)-4-Methyl-N-(9-(9-phenyl¯uorenyl))proline tert-
butyl ester (26). As described above for 19, 177 mg
(0.4 mmol) of 22 was transformed into 146 mg (86%) of
1
26. The H NMR spectrum of 26 was identical with the
one for 24.
(2R,4R)-a-tert-Butyl g-methyl N-(9-(9-phenyl¯uor-
enyl))-4-methylglutamate (17) and (2R,4S)-a-tert-butyl
g-methyl N-(9-(9-phenyl¯uorenyl))-4-methylglutamate
(18). Using the same procedure compound 14 (2.07 g,
4.52 mmol) was converted to a 3:1 mixture of 17 and 18
G. (2S,4S)-4-Methylproline (4). Compound 23 (0.40 g,
0.94 mmol) was converted into 0.11 g, of 4 (91%) as
previously described.13 1H NMR (CD3OD 300 MHz) d
4.40 (H-2, dd; J9.8 and 8.0 Hz), 1.69 (H-3, dt; J212.7
and 9.8 Hz), 2.60 (H-3, m), 2.49 (H-4, m), 1.12 (4-CH3, d;
1
(2.03 g, 95%). The H NMR spectra of 17 and 18 were
identical with those of 15 and 16, respectively.