X. Li et al. / Tetrahedron 57 /2001) 6557±6565
6563
distilled from a drying agent prior to use. Commercially
available reagents were used without further puri®cation.
Proton and Carbon-13 NMR spectra were obtained on a
Bruker Avance 300 multinuclear spectrometer. Chemical
shifts were reported in d scale in parts per million from
Me4Si.
red and the color quickly disappeared. The reaction
appeared complete within 5 min as judged by TLC. The
solution was concentrated and puri®ed by column chroma-
tography to give 22 ,1.68 g, 95%): a20.358 ,EtOAc, c
2.30);mp 115.98C;TLC Rf0.33 ,pentane/EtOAC, 3:1);
1H NMR ,300 MHz, CDCl3) d 7.76 ,s, 4H), 5.49 ,d, 1H,
J7.7 Hz), 4.30 ,m, 1H), 4.24 ,t, 3H, J6.6 Hz), 2.20 ,m,
2H), 1.40 ,s, 9H), 1.38 ,s, 9H); 13C NMR ,75 MHz, CDCl3)
d 171.30, 163.82, 155.90, 134.89, 129.31, 123.97, 82.54,
80.10, 75.50, 51.86, 31.28, 28.71, 28.33;LRMS ,ESI) m/z
419 ,M2H1).
4.1.1. N-,tert-Butoxycarbonyl)-l-tert-butyl-aspartic acid
4-benzyl ester ,19). t-Butanol ,1.7 mL, 18.4 mmol), 1, 3-
dicyclohexylcarbodiimide ,DCC, 3.7 g, 18.0 mmol) and
4-dimethylaminopyridine ,DMAP, 0.19 g, 1.5 mmol) were
added to a solution of N-,tert-butoxycarbonyl)-l-aspartic
acid 4-benzyl ester ,5 g, 15.5 mmol) in dichloromethane
,CH2Cl2, 10 mL). This solution was stirred at room
temperature for 2 h and then ®ltered, concentrated and
subjected to column chromatography ,pentane/EtOAc,
10:1) to give 19 ,5 g, 85%): a2.358 ,EtOAc, c1.95);
4.1.5.
tert-Butyl
l-2-,tert-butoxycarbonyl)amino-4-
aminoxy-butyrate ,17). Hydrazine ,43. mL, 1.37 mmol)
was slowly added to a solution of 21 ,0.56 g, 1.33 mmol)
in EtOH ,2 mL). A white precipitate formed and the mixture
was stirred until the reaction was complete as judged by
TLC. The mixture was ®ltered and the ®ltrate concentrated
and puri®ed by column chromatography ,pentane/EtOAc,
2:1) to afford compound 17 ,0.33 g, 85%): a20.328
,EtOAc, c2.14);TLC Rf0.35 ,pentane/EtOAc, 1.2:1);
1H NMR ,300 MHz, CDCl3) d 5.19 ,d, 1H, J7.5 Hz),
4.30±4.90 ,bs, 2H), 4.20 ,m, 1H), 3.69 ,t, 2H, J5.5 Hz),
1.95 ,m, 2H), 1.40 ,s, 9H), 1.38 ,s, 9H); 13C NMR ,75 MHz,
CDCl3) d 172.05, 155.77, 82.20, 79.99, 72.35, 52.12, 31.74,
28.69, 28.34;Anal. Calcd for C 13H26N2O5: C, 53.78;H,
9.05;N;9.65. Found: C, 53.71;H, 9.05;N, 9.71;LRMS
,ESI) m/z 291 ,M1H1).
mp65.08C;TLC
Rf0.3 ,pentane/EtOAc, 10:1); 1H
NMR ,300 MHz, CDCl3) d 7.36 ,s, 5H), 5.47 ,d, 1H,
J8.2 Hz), 5.14 ,d, 2H, J5.7 Hz), 4.47 ,m, 1H), 3.05
,dd, 1H, J4.5, 6.8 Hz), 2.84 ,dd, 1H, J4.5, 6.8 Hz),
1.45 ,s, 9H), 1.42 ,s, 9H); 13C NMR ,75 MHz, CDCl3) d
171.18, 170.28, 155.79, 135.96, 128.94, 128.71, 128.66,
82.69, 80.21, 67.00, 50.96, 37.46, 28.46, 28.20;LRMS
,ESI) m/z 378 ,M2H1).
4.1.2. N-,tert-Butoxycarbonyl)-l-tert-butyl-aspartic acid
,20). A mixture of 19 ,5 g, 13.2 mmol) and 10% Pd/C ,1 g)
in EtOH was shaken in a Parr Hydrogenator under hydrogen
,50 psi) for 1 h. The catalyst was ®ltered and the ®ltrate
concentrated to give 20 ,3.8 g, 100%): a22.738
,EtOAc, c0.44);mp 104.88C;TLC Rf0.5 ,pentane/
4.1.6. tert-Butyl l-2-,tert-butoxycarbonyl)amino-4-,¯uor-
enyl-methyloxycarbonyl)thioureio-oxy)-buryrate ,23).
Fmoc-NCS ,0.56 g, 2 mmol) was added to a solution of
17 ,0.43 g, 1.48 mmol) in dry dichloromethane ,5 mL).
The mixture was stirred for 30 min and concentrated
under reduced pressure to give an oil that was puri®ed by
column chromatography ,pentane/EtOAc 4:1) to afford 23
,0.72 g, 85%): a20.288 ,EtOAc, c2.53);TLC Rf0.35
,pentane/EtOAc, 2.5:1); 1H NMR ,300 MHz, CDCl3) d 11.8
,s, 1H), 8.32 ,s, 1H), 7.78 ,d, 2H, J7.5 Hz), 7.57 ,d, 2H,
J7.5 Hz), 7.44 ,t, 2H, J7.4 Hz), 7.34 ,t, 2H, J7.4 Hz),
5.52 ,d, 1H, J7.5 Hz), 4.49 ,d, 2H, J6.5 Hz), 4.40 ,m,
1H), 4.18 ,m, 3H), 2.10 ,m, 2H), 1.45 ,s, 9H), 1.43 ,s, 9H);
13C NMR ,75 MHz, CDCl3) d 177.39, 171.70, 155.95,
152.28, 143.72, 143.20, 141.72, 128.49, 128.28, 127.66,
125.40, 125.19, 120.61, 120.44, 82.75, 80.20, 72.84,
69.01, 51.79, 46.92, 31.26, 28.71, 28.34;Anal. Calcd for
C29H37N3O7S: C, 60.93;H, 6.52;N, 7.35;S, 5.61. Found:
1
EtOAc, 1:1.5); H NMR ,300 MHz, CDCl3) d 8.18 ,bs, 1
H), 5.51 ,d, 1H, J8.2 Hz), 4.43 ,m, 1H), 2.98 ,dd, 1H,
J4.0, 7.1 Hz), 2.78 ,dd, 1H, J4.0, 7.1 Hz), 1.45 ,s,
9H), 1.42 ,s, 9H); 13C NMR ,75 MHz, CDCl3) d 176.05,
170.28, 155.96, 82.83, 80.46, 50.74, 37.20, 28.64, 28.18;
LRMS ,ESI) m/z 288 ,M2H1).
4.1.3. tert-Butyl l-2-,tert-butoxycarbonyl)amino-4-hy-
droxy-butyrate ,21). Borane ,BH3)±THF complex ,1 M,
6 mL) was added dropwise to a solution of 20 ,1.7 g,
5.9 mmol) in anhydrous THF ,4 mL) under argon at
2158C in an ice-salt bath. Hydrogen evolution occurred
during the addition of BH3±THF. The mixture was stirred
for 1 h, allowed to warm to room temperature, and quenched
with saturated NaHCO3. The liquid solution was extracted
with EtOAc ,3£10 mL). The organic layers were combined,
dried over MgSO4, and concentrated to give an oil that was
puri®ed by column chromatography ,pentane/EtOAc, 2:1)
to give 21 ,1.3 g, 80%): a20.348 ,EtOAc, c3.56);TLC
Rf0.34 ,pentane/EtOAc, 1.5:1); 1H NMR ,300 MHz,
CDCl3) d 5.32 ,d, 1H, J6.9 Hz), 3.62 ,m, 2H), 2.06 ,m,
1H), 1.50 ,m, 1H), 1.40 ,s, 9H), 1.38 ,s, 9H); 13C NMR
,75 MHz, CDCl3) d 172.23, 156.80, 82.46, 80.49, 58.54,
51.26, 36.66, 28.50, 28.21;LRMS ,ESI) m/z 298 ,M1Na1).
C, 60.90;H, 6.55;N, 7.31;S, 5.62;LRMS ,ESI)
,M2H1).
m/z 571
4.1.7. tert-Butyl l-2-,tert-butoxycarbonyl)amino-4-,thio-
ureidooxy)-butyrate ,24). A solution of 20% piperidine in
methanol ,3.4 mL) was added to a solution of 23 ,1.08 g,
1.9 mmol) in dry dichloromethane ,10 mL). After 10 h, the
reaction was judged complete by TLC and the solution
concentrated and puri®ed by column chromatography ,pen-
tane/EtOAc 3:1) to yield 24 ,0.50 g, 75%): a22.548
,EtOAc, c1.18);TLC Rf0.35 ,pentane/EtOAc, 1.2:1);
1H NMR ,300 MHz, CDCl3) d 9.47 ,s, 1H), 7.38 ,bs, 1H),
7.28 ,bs, 1H), 6.11 ,d, 1H, J6.8 Hz), 4.15 ,m, 1H), 4.12 ,t,
2H, J5.3 Hz), 2.21 ,m, 2H), 1.40 ,s, 9H), 1.38 ,s, 9H); 13C
NMR ,75 MHz, CDCl3) d 183.78, 172.65, 157.12, 82.35,
80.03, 73.17, 52.65, 31.87, 28.93, 28.49;Anal. Calcd for
4.1.4.
tert-Butyl
l-2-,tert-butoxycarbonyl)amino-4-
phthalimidooxy-butyrate ,22). Diethyl azodicarboxylate
,DEAD, 0.72 mL, 4.6 mmol) was added to a solution of
21 ,1.16 g, 4.2 mmol), N-hydroxyphthalimide ,0.75 g,
4.6 mmol) and triphenylphosphine ,1.22 g, 4.6 mmol) in
CH2Cl2 ,10 mL) at 08C. The solution immediately turned