7006 J . Org. Chem., Vol. 66, No. 21, 2001
Di Gioia et al.
were dried (Na2SO4) and evaporated to dryness to give pure
2-amino-3-methyl-1-(p-methylphenyl)-1-butanone (3) (0.125 g,
87% yield). GC/MS (EI): m/z (%) 148 (3.2), 119 (6.2), 91 (12),
72 (100), 65 (7), 55 (25).
CH3), 5.62 (d, J ) 8.7 Hz, 1 H, FmocNHCH), 6.93 (d, J ) 8.8
Hz, 1H, CONHCHCOC6H4CH3), 7.24-7.89 (m, 12 H, Ar-H).
FAB+ MS: m/z (%) 527 (14) [(M + H)+], 407 (2), 331 (17), 305
(13), 192 (64), 165 (100). [R]28 -110.4° (c 11.0, CHCl3). Anal.
D
A solution of the latter compound 3 (0.125 g, 0.65 mmol) in
ethanol-free chloroform (5 mL) was treated with acetic anhy-
dride (0.12 mL, 1.30 mmol) at room temperature for 30 min.
The mixture was basified with saturated aqueous Na2CO3 (pH
9) and then extracted with chloroform (3 × 8 mL). The organic
phase was washed with distilled water (2 × 6 mL), dried, and
evaporated to dryness to afford 5 (0.135 g, 89% yield) as a
white solid, mp 120-124 °C. IR (KBr): ν 3287 cm-1, 2965,
Calcd for C33H38N2O4: C, 75.26; H, 7.27; N, 5.32. Found: C,
75.22; H, 7.29; N, 5.29.
Da ta for 16: 92% yield, white solid, mp 114-118 °C. IR
(KBr): ν 3285 cm-1, 2965, 1714, 1686, 1651, 1530, 1250, 1032,
758, 739. 1H NMR: δ 0.75 ppm [d, J ) 6.8 Hz, 3 H, (CH3)2-
CH], 0.99 [d, J ) 6.8 Hz, 3 H, (CH3)2CH], 1.40 [d, J ) 6.9 Hz,
3 H, CH3CHCONH], 2.19 [m, 1 H, (CH3)2CH], 2.39 (s, 3 H,
CH3C6H4), 4.22 (m, 1 H, CHCH2O), 4.34 (m, 1 H, CHCONH),
4.40 (d, J ) 6.8 Hz, 2 H, CHCH2O), 5.55 (dd, J 1 ) 4.3 Hz,
J 2 ) 8.8 Hz, 1 H, CHCOC6H4CH3), 5.68 (d, J ) 7.6 Hz, 1 H,
FmocNHCH), 6.99 (d, J ) 8.8 Hz, 1H, CONHCHCOC6H4CH3),
7.26-7.90 (m, 12 H, Ar-H). FAB+ MS: m/z (%) 485 (23)
[(M + H)+], 365 (5), 263 (18), 192 (34), 179 (100), 178 (99), 165
1
1677, 1636, 1542, 1088, 1017, 782. H NMR: δ 0.77 ppm [d,
J ) 6.8 Hz, 3 H, (CH3)2CH)], 1.01 [d, J ) 6.8 Hz, 3 H, (CH3)2-
CH)], 2.10 (s, 3 H, CH3CO), 2.18 (m, 1 H, 3-H), 2.43 (s, 3 H,
CH3C6H4), 5.58 (dd, J 1 ) 4.3 Hz, J 2 ) 8.8 Hz, 1 H, 2-H), 6.45
(d, J ) 8.8 Hz, 1 H, NH), 7.28 (d, J ) 8.4 Hz, 2 H, Ar-H) 7.90
(d, J ) 8.4 Hz, 2 H, Ar-H). GC-MS: m/z (%) 233 (1) [M+],
(40). [R]28 -308.5° (c 2.9, CHCl3). Anal. Calcd for C30H32N2-
D
148 (5), 119 (28), 114 (69), 91 (16), 72 (100), 43 (11). [R]28
O4: C, 74.36; H, 6.65; N, 5.78. Found: C, 74.33; H, 6.68; N,
5.75.
D
-145.1° (c 4.5, CHCl3). Anal. Calcd for C14H19NO2: C, 72.07;
H, 8.21; N, 6.00. Found: C, 72.09; H, 8.18; N, 6.04.
Da ta for 17: 86% yield, white solid, mp 117-120 °C. IR
(KBr): ν 3289 cm-1, 2975, 1691, 1648, 1540, 1230, 760, 725.
1H NMR: δ 0.74 ppm [t, J ) 6.8 Hz, 3 H, CH3CH2(CH3)CH],
0.86-1.02 [m, 9 H, (CH3)2CH and CH3CH2(CH3)CH], 1.24-
1.35 [m, 2 H, CH3CH2(CH3)CH], 1.93 [m, 1 H, CH3CH2(CH3)-
CH], 2.07 [m, 1 H, (CH3)2CH], 2.40 (s, 3 H, CH3C6H4), 4.14
(dd, J 1 ) 6.8 Hz, J 1 ) 8.8 Hz, 1 H, CHCONH), 4.23 (m, 1 H,
Syn th esis of Dip ep tid es 13-19. Gen er a l P r oced u r e. To
a magnetically stirred solution of the appropriate N-Fmoc-R-
amino acid chloride 1, 9-11 (1 mmol) in dry toluene (16 mL)
was added AlCl3 (3 mmol). The resulting mixture was main-
tained at room temperature and under inert atmosphere (N2)
for 1-3 h. HCl (1 N) was then added, and the acidified solution
(pH 2) was extracted with diethyl ether (3 × 15 mL). The
aqueous phase was basified with saturated aqueous Na2CO3
(pH 9). The basic liquors, containing the respective R-ami-
noalkyl p-methylphenyl ketones 3, 6-8, were then treated
with a solution of N-Fmoc-R-amino acid chloride 1, 9-12 (1
mmol) in ethanol-free chloroform (10 mL). The reaction
mixture was stirred at room temperature for 1 h, and then
the chloroform layer was separated. The aqueous phase was
extracted with three additional portions of chloroform (3 × 10
mL). The combined chloroform extracts were dried over Na2-
SO4 and evaporated under vacuum to afford dipeptides 13-
19 (80-96% overall yields).
CHCH2O), 4.39 (m 2 H, CHCH2O), 5.56 (dd, J 1 ) 4.9 Hz, J 2
)
8.8 Hz, 1 H, CHCOC6H4CH3), 5.79 (d, J ) 8.8 Hz, 1 H,
FmocNHCH), 6.90 (d, J ) 8.8 Hz, 1H, CONHCHCOC6H4CH3),
7.23-7.95 (m, 12 H, Ar-H). FAB+ MS: m/z (%) 527 (8) [(M +
H)+], 407 (1), 331 (1), 305 (3), 206 (10), 179 (100), 178 (48),
165 (16). [R]28 -31.4° (c 25.8, CHCl3). Anal. Calcd for
D
C
33H38N2O4: C, 75.26; H, 7.27; N, 5.32. Found: C, 75.28; H,
7.24; N, 5.30.
Da ta for 18: 80% yield, white solid, mp 116-118 °C. IR
(KBr): ν 3294 cm-1, 3060, 2982, 1689, 1648, 1541, 1260, 738.
1H NMR: δ 1.42 ppm [d, J ) 7.4 Hz, 6 H, CH3CHCONH and
CH3CHCOC6H4CH3], 2.41 (s, 3 H, CH3C6H4), 4.22 (m, 1 H,
CHCH2O), 4.37-4.42 (m, 3 H, CHCH2O and CHCONH), 5.51
(m, 1 H, CHCOC6H4CH3), 5.63 (d, J ) 7.4 Hz, 1 H, FmocN-
HCH), 7.15 (d, J ) 6.9 Hz, 1H, CONHCHCOC6H4CH3), 7.25-
7.98 (m, 12 H, Ar-H). FAB+ MS: m/z (%) 457 (44) [(M + H)+],
337 (3), 294 (2), 279 (3), 261 (7), 235 (15), 178 (100), 165 (25),
Da ta for 13: 90% yield, white solid, mp 160-164 °C. IR
(KBr): ν 3316 cm-1, 3060, 2954, 1714, 1686, 1656, 1254, 760,
739. 1H NMR: δ 0.82 ppm [d, J ) 6.3 Hz, 3 H, (CH3)2CHCH2)],
1.02 [d, J ) 6.3 Hz, 3 H, (CH3)2CHCH2)], 1.30[ m, 1 H,
(CH3)2CHCH2], 1.39 (d, J ) 6.8 Hz, 3 H, CH3CHCONH), 1.47
[m, 1 H, (CH3)2CHCH2], 1.61 [m, 1 H, (CH3)2CHCH2], 2.40 (s,
3 H, CH3C6H4), 4.18-4.26 (m, 2 H, CHCH2O and CHCONH),
4.37 (d, J ) 6.8 Hz, 2 H, CHCH2O), 5.62 (m, 1 H, CHCOC6H4-
CH3), 5.75 (d, J ) 7.8 Hz, 1 H, FmocNHCH), 6.93 (d, J ) 7.8
Hz, 1H, CONHCHCOC6H4CH3), 7.25-7.75 (m, 12 H, Ar-H).
FAB+ MS: m/z (%) 499 (11) [(M + H)+], 379 (2), 303 (2), 277
164 (29). [R]28 -117.2° (c 22.0, CHCl3). Anal. Calcd for
D
C
28H28N2O4: C, 73.66; H, 6.18; N, 6.14. Found: C, 73.64; H,
6.20; N, 6.17.
Da ta for 19: 85% yield, white solid, mp 176-178 °C. IR
(KBr): ν 3302 cm-1, 3060, 2926, 1718, 1690, 1654, 1540, 1259,
1033, 739, 700. 1H NMR: δ 1.37 ppm [d, J ) 6.9 Hz, 3 H, CH3-
CHCOC6H4CH3], 2.41 (s, 3 H, CH3C6H4), 3.04 (dd, J 1 ) 6.4
(7), 206 (16), 179 (100), 178 (55), 165 (19). [R]28 -106.3° (c
D
10.0, CHCl3). Anal. Calcd for C31H34N2O4: C, 74.67; H, 6.87;
N, 5.62. Found: C, 74.58; H, 6.82; N, 5.63.
Hz, J 2) 13.3 Hz, 1 H, PhCH2CH), 3.14 (dd,, J 1 ) 6.3 Hz, J 2 )
13.3 Hz, 1 H, PhCH2CH), 4.18 (m, 1 H, CHCH2O), 4.37 (m, 2
H, CHCH2O), 4.54 (m, 1 H, CHCONH), 5.43 (m, 1 H,
CHCOC6H4CH3), 5.53 (d, J ) 8.3 Hz, 1 H, FmocNHCH), 6.98
(d, J ) 6.9 Hz, 1H, CONHCHCOC6H4CH3), 7.15-7.90 (m, 17
H, Ar-H). FAB+ MS: m/z (%) 533 (23) [(M + H)+], 413 (2),
370 (1), 337 (6), 311 (11), 179 (100), 178 (59), 165 (19), 164
Da ta for 14: 96% yield, white solid, mp 184-187 °C. IR
(KBr): ν 3288 cm-1, 3060, 2961, 1718, 1691, 1646, 1540, 1234,
1
1032, 757, 739. H NMR: δ 0.85-0.98 ppm [m, 6 H, CH3CH2-
(CH3)CH], 1.22 [m, 1 H, CH3CH2(CH3)CH], 1.41(d, J ) 6.9 Hz,
3 H, CH3CHCOC6H4CH3), 1.50 [m, 1 H, CH3CH2(CH3)CH],
1.88 [m, 1 H, CH3CH2(CH3)CH], 2.40 (s, 3 H, CH3C6H4), 4.16-
4.24 (m, 2 H, CHCH2O and CHCONH), 4.39 (m, 2 H,
CHCH2O), 5.51 (m, 1 H, CHCOC6H4CH3), 5.75 (d, J ) 8.6 Hz,
1 H, FmocNHCH), 7.11 (d, J ) 7.7 Hz, 1H, CONHCHCOC6H4-
CH3), 7.25-7.90 (m, 12 H, Ar-H). FAB+ MS: m/z (%) 499 (10)
[(M + H)+], 303 (4), 287 (12), 277 (7), 273 (16), 259 (18), 245
(15), 179 (100), 178 (61), 165 (37). [R]28D -347.5° (c 2.8, CHCl3).
Anal. Calcd for C31H34N2O4: C, 74.67; H, 6.87; N, 5.62.
Found: C, 74.61; H, 6.84; N, 5.59.
(12). [R]28 -112.1° (c 8.6, CHCl3). Anal. Calcd for C34H32N2-
D
O4: C, 76.67; H, 6.06; N, 5.26. Found: C, 76.65; H, 6.03; N,
5.28.
Syn th esis of N-F m oc-L-Va l-L-Ile-L-Ala -C6H4CH3 (21).
AlCl3 (0.27 g, 2 mmol) was added to a solution of the dipeptide
14 (0.25 g, 0.50 mmol) in dry toluene (10 mL). The resulting
mixture was stirred at room temperature for 2 h until complete
conversion of the protected precursor. The mixture was then
acidified with a solution of HCl (1 N), extracted with diethyl
ether (3 × 10 mL), and basified with saturated aqueous Na2-
CO3. The basic liquors containing the unblocked dipeptide 20
were treated with N-Fmoc-L-valine chloride 1 (0.18 g, 0.50
mmol) dissolved in ethanol-free chloroform (10 mL). After 50
min at room temperature, the chloroform layer was separated,
and the aqueous phase was extracted with three additional
portions of chloroform (3 × 10 mL). The combined chloroform
extracts were then dried over Na2SO4 and evaporated under
Da ta for 15: 95% yield, white solid, mp 130-134 °C. IR
(KBr): ν 3304 cm-1, 2959, 2954, 1707, 1684, 1653, 1534, 1261,
758, 738. 1H NMR: δ 0.74 ppm [d, J ) 6.8 Hz, 3 H, (CH3)2-
CHCH2], 0.91-0.98 [m, 9 H, (CH3)2CHCH2) and (CH3)2CH],
1.31 [m, 1 H, (CH3)2CHCH2], 1.54-1.74 [m, 2 H, (CH3)2-
CHCH2], 2.19 [m, 1 H, (CH3)2CH], 2.40 (s, 3 H, CH3C6H4), 4.22
(m, 1 H, CHCH2O), 4.33 (m, 1 H, CHCONH), 4.40 (m 2 H,
CHCH2O), 5.50 (dd, J 1 ) 4.4 Hz, J 2 ) 8.8 Hz, 1 H, CHCOC6H4-