N-tert-Butyloxycarbonyl-L-phenylalanyl-L-serine ethyl ester (16)
N-tert-Butyloxycarbonyl-L-phenylalanyl-DL-ꢀ-(tert-butyl-
diphenylsilyloxy)glycine (12)
To a solution of N-tert-butyloxycarbonyl--phenylalanine (2.34
g; 8.84 mmol) in dry dichloromethane (70 cm3) -serine ethyl
ester hydrochloride (1.50 g; 8.84 mmol), BOP reagent (4.69 g;
10.60 mmol) and triethylamine (3.10 cm3; 22.0 mmol) were
added. The mixture was stirred overnight at room temperature.
The solvent was removed and the crude residue was dissolved in
ethyl acetate. After four washes with 5% sodium hydrogen carb-
onate solution, brine, 5% citric acid solution and brine, succes-
sively, the organic layer was dried on MgSO4 and evaporated.
Compound 16 (3.09 g, 92%), mp 113–115 ЊC was purified by
flash column chromatography on silica gel (solvent: n-hexane–
ethyl acetate 2:3) as a white solid.
HMRS calcd for C19H28N2O6: 380.4448. Found: 380.4398.
νmax (film/cmϪ1) 3598, 1702, 1658, 908, 731, 658. δH (250 MHz;
CDCl3) 7.40 (br d, 1H, NH, J = 7.21 Hz), 7.19–7.14 (m, 5H,
CHarom), 5.57 (d, 1H, NH, J = 7.73 Hz), 4.55 (m, 1H, CH-
CH2OH ), 4.45 (m, 1H, CH-CH2Ph), 4.15–4.00 (q, 2H, O-CH2-
CH3, J = 10.65 Hz), 3.91 (d, 2H, CH2-OH, J = 5.70 Hz),
3.81 (br s, 1H, OH), 3.10–2.75 (m, 2H, Ph-CH2-CH), 1.26
(s, 9H, (CH3)3C-O), 1.13 (t, 3H, O-CH2-CH3, J = 7.13 Hz).
δC (62.8 MHz; CDCl3) 172.8 (CO), 170.6 (CO), 156.2 (CO),
137.0 (Cquat.arom), 129.6, 128.6, 126.9 (CHarom), 80.4 (Cquat.t-Bu),
62.7 (CH2-OH), 62.0 (O-CH2-CH3), 56.0 (Ph-CH2-CH), 50.5
(CH-CH2-OH), 38.7 (CH-CH2-Ph), 28.4 ((CH3)3C-O), 14.2
(CH3-CH2). FABMS m/z 381 (MH)ϩ.
To a solution of compound 11 (120 mg; 0.20 mmol) in metha-
nol (5 cm3) 1 M sodium hydroxide solution (0.5 cm3; 0.45
mmol) was slowly added. The mixture was stirred for one
hour then 1 M hydrochloric acid solution (0.20 cm3) was
added before methanol was evaporated. The residue was
cooled to 0 ЊC before slow addition of 1 M hydrochloric acid
solution (0.3 cm3). The mixture was extracted three times with
ethyl acetate. The organic layer was dried and evaporated
to give 12 (0.09 g, 85%) which was used without further
purification.
HMRS calcd for C32H40N2O6Si: 576.7714. Found: 576.7742.
νmax (film/cmϪ1) 2358, 1698, 1662, 913, 737, 650. δH (250 MHz;
CDCl3) 7.50–7.47 (m, 5H, CHarom-Si), 7.16–7.07 (m, 5H,
CHarom-CH2), 7.03–6.89 (m, 5H, CHarom-Si), 5.52 (2d, 1H, CH-
OSi, J = 9.42 Hz), 4.93 (br s, 1H, NH), 4.59 (br s, 1H, NH),
4.07 (m, 1H, CH-CH2Ph), 2.79–2.47 (m, 2H, Ph-CH2-CH), 1.16
(2s, 9H, (CH3)3C-O), 0.86 (2s, 9H, (CH3)3C-Si).
N-Benzyl-[N-tert-butyloxycarbonyl-L-phenylalanyl-DL-ꢀ-(tert-
butyldiphenylsilyloxy)]glycinamide (13)
Compound 12 (770 mg; 1.33 mmol) was dissolved in dry
dichloromethane (10 cm3) then benzylamine (0.15 cm3; 1.33
mmol), BOP reagent (710 mg; 1.60 mmol) and triethylamine
(0.46 cm3; 3.32 mmol) were added. The mixture was stirred
overnight before the solvent was evaporated. The crude residue
was dissolved in ethyl acetate and the organic layer was succes-
sively washed with 5% sodium hydrogen carbonate solution,
brine, dried on MgSO4 and evaporated. The crude residue was
purified by flash column chromatography on silica gel (solvent:
n-hexane–ethyl acetate 7:3) to give 13 (0.39 g, 45% ) as a yellow
oil.
HMRS calcd for C39H47N3O5Si: 665.9125. Found: 665.9128.
νmax (film/cmϪ1) 2359, 1683, 1558, 973, 737, 650. δH (250 MHz;
CDCl3) 7.42–6.92 (m, 20H, CHarom), 6.76 (d, 1H, NH, J = 8.09
Hz), 6.65 (d, 1H, NH, J = 8.43 Hz), 6.37 ϩ 6.29 (2br m, 2H,
2NH), 5.34 (2s, 1H, CH-OSi, J = 8.47 Hz), 4.54 (br m, 1H, NH),
4.54 ϩ 4.45 (2br s, 2H, NH), 4.20–4.08 (m, 2H, Ph-CH2-NH),
4.08–3.90 (m, 1H, CH-CH2Ph), 2.84–2.40 (m, 2H, Ph-CH2-
CH), 1.12 (2s, 9H, (CH3)3C-O), 0.80 (2s, 9H, (CH3)3C-Si).
δC (62.8 MHz; CDCl3) 171.3, 170.2 (CO), 158.4 (CO), 136.7,
136.2, 136.1, 135.5, 135.4, 135.3, 132.9, 132.7, 132.3, 130.6,
130.3, 129.6, 128.9, 127.8, 127.1 (CHarom), 73.5 (NH-CH-OSi),
47.5 (NH-CH2-Ph), 38.2 (CH-CH2-Ph), 28.3 ((CH3)3C-O), 27.1
((CH3)3C-Si).
N-Benzyl-(N-tert-butyloxycarbonyl-L-phenylalanyl)-L-serin-
amide (17)
Compound 16 (1.50 g; 3.94 mmol) was dissolved in methanol
(10 cm3), then 1 M sodium hydroxide solution (8.70 cm3; 8.67
mmol) was added slowly. After 3 hours, 1 M hydrochloric acid
solution (4 cm3) was added and methanol was removed, then
1 M hydrochloric acid solution (4.7 cm3) was added slowly at
0 ЊC. The aqueous layer was extracted twice with ethyl acetate,
and the organic layer was dried on MgSO4. The crude carb-
oxylic acid intermediate, obtained in a quantitative yield (3.05
g; 8.67 mmol), was dissolved in dry dichloromethane (30 cm3)
then benzylamine (0.94 cm3; 8.67 mmol), BOP reagent (4.60 g;
10.40 mmol) and triethylamine (3.01 cm3; 21.67 mmol) were
added. After one night’s stirring at room temperature, the
solvent was removed and the residue dissolved in ethyl acetate.
The organic layer was washed successively with 5% sodium
hydrogen carbonate solution, 5% citric acid solution and brine,
and then dried and evaporated. The crude residue was purified
by flash column chromatography on silica gel (solvent: ethyl
acetate) to afford 17 (1.66 g, 96%), mp 150–154 ЊC as a white
solid.
N-Benzyl-(N-tert-butyloxycarbonyl-L-phenylalanyl-DL-ꢀ-
HMRS calcd for C24H31N3O5: 441.5317. Found:
441.5220. νmax (film/cmϪ1) 3573, 1705, 1662, 1562, 910, 736, 660.
δH (250 MHz; CDCl3) 7.40 (br m, 1H, NH), 7.20–6.95 (m, 10H,
CHarom), 6.82 (d, 1H, NH, J = 7.78 Hz), 5.00 (br m, 1H, NH,
J = 7.21 Hz), 4.39 (m, 1H, CH-CH2OH), 4.31–4.25 (m, 3H,
CH-CH2Ph ϩ NH-CH2Ph), 4.16–3.97 (m, 2H, CH2-OH), 2.97
(m, 2H, Ph-CH2-CH), 1.26 (s, 9H, (CH3)3C-O). δC (62.8 MHz;
CDCl3) 172.8, 170.5 (CO), 137.1 (Cquat.arom), 129.6, 128.6, 128.4,
127.3, 127.2, 127.0 (CHarom), 80.3 (Cquat.t-Bu), 62.6 (CH2-OH),
56.0 (Ph-CH2-CH), 43.2 (Ph-CH2-NH), 38.5 (CH-CH2-Ph),
28.3 ((CH3)3C-O). FABMS m/z 442(MH)ϩ.
hydroxy)glycinamide (14)
To a solution of compound 17 (400 mg; 0.60 mmol) in dry
tetrahydrofuran (5 cm3) tetrabutylammonium fluoride (0.60
cm3; 0.62 mmol) was added. The mixture was stirred for 30
minutes, then tetrahydrofuran was evaporated and the crude
residue was dissolved in dichloromethane. The organic layer
was washed twice with water, dried on MgSO4 and evaporated.
Compound 14 (0.17 g, 66%), mp 135–137 ЊC was obtained after
purification by flash column chromatography on silica gel
(solvent: n-hexane–ethyl acetate 2:3) as a white solid.
HMRS calcd for C23H29N3O5: 427.5046. Found: 427.5120.
νmax (film/cmϪ1) 2360, 1694, 1592, 909, 737, 668. δH (250 MHz;
CDCl3) 7.25–7.12 (m, 10H, CHarom), 6.07 (br s, 1H, NH), 5.86
(br m, 2H, NH ϩ OH), 5.16 (br m, 1H, NH), 5.00 (2d, 1H,
CH-OH, J = 8.08 Hz), 4.31 (m, 2H, Ph-CH2-NH), 4.06 (m, 1H,
CH-CH2Ph), 2.96 (m, 2H, Ph-CH2-CH), 1.31 (s, 9H, (CH3)3-
C-O). δC (62.8 MHz; CDCl3) 136.8, 135.2, 129.5, 129.1, 128.9,
128.7, 128.3, 127.2 (CHarom), 78.6 (NH-CH-OH), 47.4 (NH-
CH2-Ph), 38.7 (CH-CH2-Ph), 28.5 ((CH3)3C-O). FABMS m/z
428 (MH)ϩ.
N-Benzyl-(N-tert-butyloxycarbonyl-L-phenylalanyl-DL-ꢀ-
acetoxy)glycinamide (18)
Compound 17 (750 mg; 1.51 mmol) was dissolved in dry ethyl
acetate (30 cm3) then lead tetraacetate (2.00 g; 4.53 mmol) and
molecular sieves 4 Å (3 g) were added. The mixture was refluxed
under nitrogen for 2 hours. The precipitate was filtrated on
Celite and the organic layer was stirred with 10% citric acid
solution during 20 minutes. The organic layer was washed with
J. Chem. Soc., Perkin Trans. 1, 2000, 819–824
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