Threonine- and Azathreonine N-Carboxy Anhydrides
J . Org. Chem., Vol. 61, No. 13, 1996 4403
(C)O). 1H NMR (DMSO-d6, 90 °C, δ) 7.37-7.11 (m, 5H); 5.99
(d, 1H, J ) 6.5 Hz); 4.84 (t, 1H, J ) 5.8 Hz); 4.67 (d, 1H, J )
15.4 Hz); 4.48 (m, 1H); 3.96 (dd, 1H, J ) 4.7 Hz, J ′ ) 10.7
Hz); 3.82 (m, 1H); 4.74 (d, 1H, J ) 15.4 Hz); 2.5 (m, 1H); 1.7
(m, 1H); 1.61-1.35 (m, 4H); 1.45 (s, 9H); 1.26 (m, 1H). 13C
NMR (DMSO-d6, 90 °C, δ) 168.6, 153.6, 135.6, 128.0, 127.1,
126.8, 78.3, 74.9, 53.9, 50.7, 43.5, 39.4, 27.7, 24.8, 24.5, 18.4.
Anal. Calcd for C20H28N2O4 (360.45): C, 66.64 H, 7.83; N, 7.77.
Found: C, 66.76; H, 7.65; N, 7.59.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of r-Am in o
Acid N-Ca r boxy An h yd r id es. To a magnetically stirred
solution of 3-hydroxyazetidin-2-one (3 mmol) in 15 mL of
dichloromethane were added 2,2,6,6-tetramethylpiperidin-1-
oxyl (TEMPO) (6 mg, 0.03 mmol) and a solution of potassium
bromide (36 mg, 0.3 mmol) in water (0.15 mL) at room
temperature. The solution was cooled to -5-0 °C (ice-salt
bath) and aqueous sodium hypochlorite (Aldrich, 23,930-5) (30
mL) buffered at pH 6.9 (1.8 g of sodium hydrogen carbonate
for 84 mL of a 0.25 M buffer solution phosphate) was added,
keeping the temperature of the reaction mixture between 10
and 15 °C. The mixture was stirred for a further 10 min.
Workup8c afforded the corresponding R-amino acid N-carboxy
anhydrides.
(DMSO-d6, 90 °C, δ) 167.3, 152.4, 135.2, 128.6, 127.9, 127.8,
78.7, 62.7, 46.4, 46.1, 28.1, 15.6.
(4R)-3-Ben zyl-4-[(1S)-1-[N-(ter t-bu toxycar bon yl)am in o]-
2-m eth ylp r op yl]oxa zolid in e-2,5-d ion e (16b). The general
procedure was followed starting from 15b. Yield 92%. Oil.
[R]25D ) -41.4° (c ) 1.2, CH2Cl2). IR (KBr) υ 3355 cm-1 (CdO),
1795 cm-1 (CdO), 1730 cm-1 (CdO). 1H NMR (DMSO-d6, 90
°C, δ) 7.44-7.39 (m, 5H); 6.84 (sb, 1H); 4.70 (d, 1H, J ) -15.8
Hz); 4.56 (d, 1H, J ) -15.8 Hz); 4.39 (d, 1H, J ) 3.2 Hz); 3.94-
3.89 (m, 1H); 1.62-1.53 (m, 1H); 1.45 (s, 9H); 0.85 (d, 3H, J )
6.6 Hz); 0.67 (d, 3H, J ) 6.4 Hz). 13C NMR (DMSO-d6, 90 °C,
δ) 167.5, 152.6, 135.3, 128.9, 128.4, 128.0, 127.8, 78.7, 63.0,
46.8, 38.2, 28.1, 24.2, 22.7, 20.7.
(4R)-3-Ben zyl-4-[(1S)-1-[(N-(ter t-bu toxyca r bon yl)a m i-
n o]ben zyl]oxa zolid in e-2,5-d ion e (16c). The general pro-
cedure was followed starting from 15c. Yield 97%. Oil. [R]25
D
) -29.8° (c ) 1.2, CH2Cl2). IR (KBr) υ 3150 cm-1 (N-H), 1825
cm-1 (CdO), 1750 cm-1 (CdO). 1H NMR (DMSO-d6, 90 °C, δ)
7.41-6.96 (m, 10H); 6.85 (sb, 1H); 4.76 (d, 1H, J ) -15.9 Hz);
4.60 (d, 1H, J ) -15.9 Hz); 4.43 (d, 1H, J ) 2.9 Hz); 4.19-
4.02 (m, 1H); 2.76-2.50 (m, 2H); 1.32 (s, 9H). 13C NMR
(DMSO-d6, 90 °C, δ) 167.6, 152.6, 137.3, 135.3, 128.9, 128.8,
128.4, 128.3, 128.0, 127.9, 126.3, 78.7, 62.2, 52.6, 46.8, 36.1,
28.0.
(4S)-3-Ben zyl-4-[(1R)-1-[(ter t-bu tyld ip h en ylsilyl)oxy]-
2-m eth ylp r op yl]oxa zolid in e-3,5-d ion e (5a ). The general
procedure was followed starting from 3a . Yield: 95%. Mp:
168-170 °C (EtOH). [R]25D ) +31.8° (c ) 1, CH2Cl2). IR (KBr)
υ 1839 cm-1 (CdO), 1764 cm-1 (CdO). 1H NMR (CDCl3, δ)
7.72-7.66 (m, 4H); 7.51-7.26 (m, 2H); 7.04-7.01 (m, 9H); 4.58
(d, 1H, J ) -15.6 Hz); 4.23 (d, 2H, J ) -15.6 Hz); 4.07 (d,
1H, J ) 3.6 Hz); 3.83 (dd, 1H, J ) 3.7 Hz, J ) 4.8 Hz); 1.77-
1.71 (m, 1H); 1.05 (s, 9H); 0.77 (d, 3H, J ) 6.6 Hz); 0.52 (d,
3H, J ) 6.8 Hz). 13C NMR (CDCl3, δ) 167.0, 152.7, 136.1,
136.0, 134.4, 132.8, 132.4, 130.2, 130.0, 129.0, 128.4, 127.9,
127.8, 127.7, 75.6, 61.5, 46.8, 30.5, 26.8, 20.1, 19.6, 18.0. Anal.
Calcd for C30H35NO4Si (501.60): C, 71.83; H, 7.05; N, 2.72.
Found: C, 72.08; H, 7.16; N, 2.67.
Gen er a l P r oced u r e for th e P r ep a r a tion of P ep tid es
fr om r-Am in o Acid N-Ca r boxy An h yd r id es. To a solution
of the NCA (1 mmol) and the ω-amino ester (1 mmol) in
dimethylformamide (5 mL) was added NaN3 (65mg, 1 mmol),
and the mixture was stirred at room temperature for 15 h.
Then, diethyl ether (10 mL) was added and the organic layer
was washed with a satured solution of NaHCO3 (3 × 8 mL).
Drying and evaporation afforded the corresponding peptide
which was purified by column chromatography.
â(R)-[(ter t-Bu t yld ip h en ylsilyl)oxy]-(R)-Leu -(S)-Leu -
(OMe) (7). The general procedure was followed starting from
NCA 5a and (S)-leucine methyl ester to afford N-benzyl-â(R)-
[(tert-butyldiphenylsilyl)oxy]-(R)-Leu-(S)-Leu-(OMe) (6) which
was purified by column chromatography (silica, eluant: AcOEt/
(4S)-3-Ben zyl-4-[(1R)-1-[(ter t-bu tyld im eth ylsilyl)oxy]-
ben zyl]oxa zolid in e-3,5-d ion e (5b). The general procedure
hexanes 1/30). Yield 90%. Oil. [R]25 ) -7.5° (c ) 1, CH2-
D
Cl2). IR (KBr) υ 3350 cm-1 (NH), 1743 cm-1 (CdO), 1676 cm-1
(CdO). 1H NMR (CDCl3, δ) 7.69-7.61 (m, 4H); 7.43-7.21 (m,
6H); 7.15-7.11 (m, 5H); 4.51-4.45 (m, 1H); 3.56 (t, 1H, J )
4.9 Hz); 3.70 (d, 1H, J ) -12.5 Hz); 3.67 (s, 3H); 3.23 (d, 1H,
J ) 4.9 Hz); 1.82-1.77 (m, 1H); 1.55-1.40 (m, 3H); 1.00 (s,
9H); 0.85 (d, 6H, J ) 7.0 Hz). 13C NMR (CDCl3, δ) 173.1, 136.0,
135.8, 133.4, 133.0, 129.7, 128.2, 128.1, 127.5, 127.4, 126.9,
79.0, 64.8, 52.7, 52.1, 50.4, 41.2, 32.2, 27.2, 24.8, 22.8, 22.0,
18.9, 18.8, 17.8. Compound 6 was hydrogenolyzed following
the General Procedure for the synthesis of 3-hydroxy â-lac-
was followed starting from 3b. Yield 96%. Oil. [R]25
)
D
-53.2° (c ) 1, CH2Cl2). IR (KBr) υ 1810 cm-1 (CdO), 1763
cm-1 (CdO). 1H NMR (CDCl3, δ) 7.45-7.12 (m, 9H); 6.52-
6.49 (m, 1H); 5.28 (d, 1H, J ) 1.7 Hz); 4.90 (d, 1H, J ) -14.9
Hz); 4.11 (d, 1H, J ) 1.7 Hz); 3.42 (d, 1H, J ) -14.9 Hz); 0.99
(s, 9H); -0.02 (s, 3H); -0.05 (s, 3H). 13C NMR (CDCl3, δ)
167.5, 152.9, 139.1, 133.7, 128.7, 128.6, 128.4, 128.2, 128.0,
125.8, 72.9, 65.1, 46.7, 25.7, -4.4, -5.8.
(4R)-3-Ben zyl-4-[(2S)-N-(ter t-bu toxyca r bon yl)p yr r oli-
d in -2-yl]oxa zolid in e-2,5-d ion e (13a ). The general proce-
tams, to afford the title compound 7. Yield 82%. Oil. [R]25
D
dure was followed starting from 12a . Yield 98%. Oil. [R]25
) -52.8° (c ) 1, CH2Cl2). IR (KBr) υ 3850 cm-1 (NH), 1743
cm-1 (CdO), 1672 cm-1 (CdO). 1H NMR (CDCl3, δ) 7.63-7.52
(m, 4H); 7.31-7.20 (m, 6H); 4.38-4.33 (m, 1H); 3.99 (dd, 1H,
J ) 2.6 Hz, J ) 5.6 Hz); 3.53 (s, 3H); 3.69-3.36 (m, 1H); 1.55-
1.40 (m, 4H); 1.00 (s, 9H); 0.94 (d, 3H, J ) 6.6 Hz); 0.94 (d,
3H, J ) 6.6 Hz); 0.91 (d, 3H, J ) 6.8 Hz); 0.86 (d, 3H, J ) 7.1
Hz); 0.69 (d, 3H, J ) 6.6 Hz). 13C NMR (CDCl3, δ) 173, 172,
135, 135, 133, 132, 129, 129, 127, 127, 76.9, 55.1, 52.1, 51.1,
41.2, 32.5, 27.1, 24.8, 22.7, 22.3, 19.7, 19.3, 18.3.
D
) -33.4° (c ) 0.9, CH2Cl2). IR (KBr) υ 1840 cm-1 (CdO), 1776
cm-1 (CdO), 1691 cm-1 (CdO). 1H NMR (CDCl3, δ) 7.37-7.29
(m, 5H); 4.73 (d, 1H, J ) 4.1 Hz); 4.57 (d, 1H, J ) -15.8 Hz);
4.47 (d, 1H, J ) -15.8 Hz); 4.06 (m, 1H); 3.35 (m, 1H); 1.99
(m, 1H); 1.71-1.51 (m, 3H); 1.37 (s, 9H). 13C NMR (CDCl3, δ)
167.3, 153.6, 151.8, 134.8, 128.1, 128.0, 127.3, 79.0, 60.2, 55.5,
46.5, 45.9.
(4R)-3-Ben zyl-4-[(2S)-N-(ter t-bu toxycar bon yl)piper idin -
2-yl]oxa zolid in e-2,5-d ion e (13b). The general procedure
N-(ter t-Bu toxyca r bon yl)-â(R)-[(ter t-bu tyld im eth ylsily-
l)oxy]-(R)-P h e-(â(R)-[(ter t-b u t yld ip h en ylsilyl)oxy]-Leu -
(S)-Leu -(OMe) (9). The general procedure was followed
starting from NCA 5b and dipeptide 7 to afford N-benzyl-â-
(R)-[(tert-butyldimethylsilyl)oxy]-(R)-Phe-â(R)-[(tert-butyldiphe-
nylsilyl)oxy]-Leu-(S)-Leu-(OMe) (8) which was purified by
column chromatography (silica, eluant: AcOEt/hexanes 1/8).
was followed starting from 12b. Yield 96%. Oil. [R]25
)
D
-19.3° (c ) 1, CH2Cl2). IR (KBr) υ 1840 cm-1 (CdO), 1774
cm-1 (CdO), 1687 cm-1 (CdO). 1H NMR (CDCl3, δ) 7.38-7.28
(m, 5H); 4.65 (d, 1H, J ) 6.6 Hz); 4.64 (d, 1H, J ) -15.8 Hz);
4.36 (m, 1H); 4.35 (d, 1H, J ) -15.8 Hz); 3.77 (m, 1H); 2.83
(m, 1H); 1.73 (m, 1H); 1.53-1.30 (m, 5H); 1.41 (s, 9H). 13C
NMR (CDCl3, δ) 167.5, 153.7, 151.7, 134.7, 128.0, 127.2, 127.1,
79.4, 59.7, 51.3, 45.9, 40.3, 38.9, 27.5, 22.8, 17.8.
Yield 65%. Oil. [R]25 ) -26.9° (c ) 1, CH2Cl2). IR (KBr) υ
D
3481-3349 cm-1 (NH), 1743 cm-1 (CdO), 1662 cm-1 (CdO).
1H NMR (CDCl3, δ) 7.76 (d, 1H, J ) 6.9 Hz); 7.85-7.79 (m,
4H); 7.77-7.08 (m, 16H); 5.41 (d, 1H, J ) 3.2 Hz); 4.68-4.63
(m, 2H); 4.23 (dd, 1H, J ) 2.5 Hz, J ) 6.3 Hz); 3.76 (s, 3H);
3.44 (d, 1H, J ) 12.2 Hz); 3.32 (d, 1H, J ) 12.2 Hz); 3.28 (d,
1H, J ) 3.2 Hz); 1.99-1.90 (m, 1H); 1.64-1.49 (m, 3H); 1.22
(s, 9H); 0.93 (d, 3H, J ) 5.9 Hz); 0.91 (d, 3H, J ) 5.9 Hz); 0.86
(s, 9H); 0.76 (d, 3H, J ) 6.8 Hz); 0.67 (d, 3H, J ) 6.9 Hz);
-0.06 (s, 3H); -0.18 (s, 3H). 13C NMR (CDCl3, δ) 172.9, 172.3,
(4R)-3-Ben zyl-4-[(1S)-1-[N-(ter t-bu toxycar bon yl)am in o]-
eth yl]oxa zolid in e-2,5-d ion e (16a ). The general procedure
was followed starting from 15a . Yield 96%. Oil. [R]25
)
D
-24.3° (c ) 0.8, CH2Cl2). IR (KBr) υ 3160 cm-1 (CdO), 1788
cm-1 (CdO), 1725 cm-1 (CdO). 1H NMR (DMSO-d6, 90 °C, δ)
7.41-7.38 (m, 5H); 6.75 (sb, 1H); 4.70 (d, 1H, J ) -15.8 Hz);
4.51 (d, 1H, J ) -15.8 Hz); 4.41 (d, 1H, J ) 3.6 Hz); 4.02-
3.93 (m, 1H); 1.41 (s, 9H); 1.07 (d, 3H, J ) 7.1 Hz). 13C NMR