6920 J . Org. Chem., Vol. 62, No. 20, 1997
Zhang et al.
Nr-t-Boc-â-a m in o-L-a la n in e (4).6 A slurry of NR-t-Boc-L-
asparagine (5.0 g, 21.5 mmol), ethyl acetate (24 mL), aceto-
nitrile (24 mL), water (12 mL), and PIDA (8.32 g, 25.8 mmol)
was cooled and stirred at 16 °C for 30 min. The temperature
was allowed to reach 20 °C, and the reaction was stirred until
completion (4 h). The mixture was cooled to 0 °C and filtered.
The filter cake was washed with ethyl acetate (10 mL) and
dried in vacuo at 65 °C to give 4 (2.73 g, 62% yield): mp 216
°C; 1H NMR (DMSO/TFA) δ 7.92 (bs, 3H), 7.23 (d, 1H), 4.27-
4.14 (m, 1H), 3.27-3.11 (m, 1H), 3.06 -2.89 (m, 1H), 2.52-
2.46 (m, 9H). Anal. Calcd for C8H16N2O4: C, 47.05; H, 7.90;
N, 13.72. Found: C, 46.94; H, 7.87; N, 13.46.
Nr-Ca r beth oxy-â-a m in o-L-a la n in e (5). A solution of NR-
carbethoxy-n-L-asparagine (5.0 g, 24.5 mmol), ethyl acetate (24
mL), acetonitrile (24 mL), water (6 mL), and PIDA (9.9 g, 30.6
mmol) was stirred at 15 °C for 30 min. The temperature was
allowed to reach 20 °C, and the reaction was stirred until
completion (4 h). Water (10 mL) was added, and the mixture
was heated to 60 °C. After phase separation, the oily product
was solidified by addition of ethyl acetate. Product was dried
in vacuo at 50 °C to give 5 as off-white solids (4.0 g, 93%
yield): 1H NMR (DMSO/TFA) δ 8.03 (bs, 3H), 7.54 (d, 1H),
4.32-4.22 (m, 1H), 4.03 (q, 2H), 3.32-3.17 (m, 1H), 3.10-2.95
(m, 1H), 1.19 (t, 3H); 13C NMR δ 171.30, 156.72, 60.75, 52.80,
52.11, 14.83; HRMS (NH3-CI) m/z calcd for C6H12N2O4 (MH+)
177.0875, found 177.0867.
Nr-F m oc-â-a m in o-L-a la n in e (6). A slurry of NR-Fmoc-L-
asparagine (5.0 g, 14.1 mmol), methyl acetate (50 mL),
n-propanol (50 mL), water (5 mL), and PIDA (6.0 g, 18.6 mmol)
was stirred at 25 °C for 1 h followed by 5 h at 32 °C. The
mixture was filtered and the solid washed with 2-propanol (2
× 20 mL), methanol (2 × 20 mL), and methyl acetate (2 × 20
mL). The resulting white solids were dried in vacuo to give
product 6 (2.7 g, 59% yield): mp 146 °C (decomposed); 1H NMR
(DMSO/TFA) δ 14.50-14.00 (m, 1H), 8.00 (s, 2H), 7.90-7.10
(m, 8H), 4.50-4.20 (m, 4H), 3.30-3.20 (m, 1H), 3.15-3.00 (m,
1H). Anal. Calcd for C18H18N2O4: C, 66.24; H, 5.56; N, 8.58.
Found: C, 65.91; H, 5.81; N, 8.38.
Nr-DDZ-â-a m in o-L-a la n in e (7). A solution of NR-DDZ-L-
asparagine (5.0 g, 14.1 mmol), acetonitrile (50 mL), water (50
mL), and PIDA (5.7 g, 17.7 mmol) was stirred from 10 to 25
°C for 8 h. The lower layer of iodobenzene was separated, and
the aqueous solution was concentrated in vacuo to give the
acetate of product 7 (5.3 g, 97% yield). An analytical sample
was prepared by slurrying the product with heptane and then
drying to give the acetate of 7: mp 45 °C (dec); 1H NMR
(DMSO/TFA) δ 7.95 (bs, 1H), 7.56 (bs, 1H), 6.55-6.42 (m, 2H),
6.40-6.25 (m, 1H), 4.30-4.10 (m, 1H), 3.72 (br, 6H), 3.30-
3.15 (m, 1H), 3.10-2.90 (m, 1H), 1.90 (s, 3H), 1.68-1.62 (br,
6H); 13C NMR δ 172.1, 171.4, 160.2, 154.4, 149.4, 102.6, 98.0,
79.7, 55.1, 51.3, 29.0, 28.9, 21.2; HRMS (NH3-CI) m/ z calcd
for C15H22N2O6 (MH+) 327.1556, found 327.1552. Anal. Calcd
for C17H26N2O8: C, 52.84; H, 6.78; N, 7.25. Found: C, 53.06;
H, 6.52; N, 7.36.
Exp er im en ta l Section
1
Gen er a l. All melting points are uncorrected. The H and
13C NMR spectra were recorded at 300 and 75.4 MHz,
respectively, and reported in DMSO-d6 (except where noted).
The coupling constants (J ) of NMR spectra are reported in
hertz. Mass spectra were recorded by the analytical labora-
tory, Chemical Process R&D, DuPont Merck Research Labo-
ratories. The elemental analyses were determined by Quan-
titative Technologies Inc., Whitehouse, NJ . Solvents, protected
amino acids, and reagents were used as purchased without
further purification.
Nr-n -Boc-â-a m in o-L-a la n in e (2). Meth od A. A solution
of NR-n-Boc-L-asparagine (2.65 kg, 11.4 mol), ethyl acetate
(12.0 L), acetonitrile (12.0 L), water (6.0 L), and PIDA (4.4
kg, 13.7 mol) was cooled and stirred at 10 °C for 30 min. The
temperature was allowed to reach 20 °C, and the reaction was
stirred until completion (3-4 h). The mixture was heated to
70 °C until completely dissolved and then slowly cooled to
ambient temperature over a 3 h period. The solid was filtered,
washed with ethyl acetate (2 L), and dried in vacuo at 50 °C
1
to give 2 (1.70 kg, 73%): mp 215 °C (dec); H NMR (DMSO/
TFA) δ 7.95 (s, 3H), 7.54 (d, 1H), 4.31-4.05 (m, 1H), 3.99 (t,
2H), 3.28-3.19 (m, 1H), 3.07-2.96 (m, 1H), 1.61-1.50 (m, 2H),
1.42-1.28 (m, 2H), 0.90 (t, 3H); 13C NMR (DMSO/TFA) δ
171.31, 156.83, 64.47, 52.84, 52.16, 31.03, 18.96, 13.97. Anal.
Calcd for C8H16N2O4: C, 47.05; H, 7.90; N, 13.72. Found: C,
47.28; H, 7.86; N, 13.75.
Nr-n -Boc-â-a m in o-L-a la n in e (2). Meth od B. A mixture
of NR-n-Boc-L-asparagine (15.0 g, 64.5 mmol), methyl acetate
(50 mL), n-propanol (50 mL), water (6.0 mL), and PIDA (27.4
g, 85.1 mmol) was stirred below 32 °C for 50 min. The mixture
was warmed to 40 °C over 15 min and then cooled to 15 °C
over 45 min. The solids were collected by filtration, washed
with n-propanol, and dried in vacuo to give product 2 which
has the same spectroscopic data as the one from method A.
Nr-Cbz-â-a m in o-L-a la n in e (3).8a A slurry of NR-Cbz-â-
amino-L-alanine (5.0 g, 18.8 mmol), ethyl acetate (24 mL),
acetonitrile (24 mL), water (12 mL), and PIDA (7.26 g, 22.5
mmol) was cooled and stirred at 16 °C for 30 min. The
temperature was allowed to reach 20 °C, and the reaction was
stirred until completion (4 h). The mixture was cooled to 5
°C, and the product was filtered, washed with ethyl acetate
(10 mL), and dried in vacuo at 50 °C to give 3 (3.9 g, 87%
yield): mp 210 °C (dec); 1H NMR (DMSO/TFA) δ 7.99 (bs, 3H),
7.74 (d, 1H), 7.42-7.30 (m, 5H), 5.09 (s, 2H), 4.36-4.26 (m,
1H), 3.34 -3.18 (m, 1H), 3.12-2.96 (m, 1H); 13C NMR δ 171.23,
156.65, 137.08, 128.76, 128.32, 128.21, 66.27, 52.27. Anal.
Calcd for C11H14N2O4: C, 55.50; H, 5.92; N, 11.80. Found: C,
55.53; H, 6.04; N, 11.72.
J O9702756