Synthesis of Neoglycopeptides
under vacuum at 45 °C for 24 h afforded 1.32 g (2.89 mmol,
93%) of 8 as a viscous oil. H NMR (400 MHz, CDCl3): δ 7.44
dissolved in CH2Cl2 (15 mL). Triphenylphosphine (42 mg, 0.16
mmol) and pyrrolidine (266 µL, 3.18 mmol) were added, and
the flask was flushed with Ar. Tetrakis(triphenylphosphine)-
palladium(0) (92 mg, 0.080 mmol) was then added, and the
mixture was stirred for 90 min. The reaction mixture was
diluted with CH2Cl2 (100 mL) and poured into a separatory
funnel. The organic layer was washed with 0.1 M KHSO4 (3
× 50 mL) and saturated NaCl (50 mL) and then dried. The
solvent was removed, and column chromatography of the
residue (EtOAc/hexanes/AcOH, 40:60:1 to 50:50:1) afforded an
oil that was further purified by size-exclusion chromatography
(LH-20, MeOH:CH2Cl2, 10:90). The resulting residue was dried
under vacuum overnight at 50 °C to yield 1.121 g (2.69 mmol,
85%) of 2b as a viscous oil. 1H NMR (400 MHz, CD3CN, 55
°C): δ 8.6 (bs, 1H), 7.48 (m, 1H) 7.42 (m, 1H), 7.33 (m, 2H),
5.67 (d, 1H, J ) 8.1 Hz), 5.24 (s, 2H), 4.17 (bs, 1H), 3.67 (s,
1
(m, 1H), 7.38 (m, 1H) 7.28 (m, 2H), 5.89 (m, 1H), 5.57 (bs, 1H),
5.22-5.34 (m, 4H), 4.62 (m, 2H), 4.46 (m, 1H), 3.99 (m, 2H),
3.18 (s, 3H), 2.18 (m, 1H), 2.04 (m, 1H), 1.43 (s, 9H). 13C NMR
(100 MHz, CDCl3): δ 172.0, 157.2, 155.6, 133.8, 133.6, 131.7,
129.8, 129.62, 129.60, 127.0, 118.8, 79.9, 70.6, 66.0, 65.2, 51.3,
36.6, 30.6, 28.4. FAB-HRMS: calcd for C21H30ClN2O7 (M + H)+
457.1742, found 457.1739. Anal. Calcd for C21H29ClN2O7: C,
55.20; H, 6.40; N, 6.13. Found: C, 55.17; H, 6.38; N, 6.07.
N-(2-Ch lor oben zyloxyca r bon yl)m eth oxyla m in e (9). A
flask was charged with KOH (1.12 g, 20.0 mmol) and MeOH
(10 mL). Methoxylamine hydrochloride (1.67 g, 20.0 mmol) and
more MeOH (5 mL) were added, and the resulting solution
was stirred for 15 min. The precipitated KCl was removed by
filtration through cotton, and the solids were rinsed with
MeOH (5 mL). To the clear solution was added N-(2-chloroben-
zyloxycarbonyloxy)succinimide (2.84 g, 10.0 mmol), and the
mixture was stirred for 17 h. The solvent was removed, and
the residue was dissolved in EtOAc (100 mL) and poured into
a separatory funnel. The organic layer was washed with 0.1
M KHSO4 (3 × 30 mL) and saturated NaCl (30 mL) and then
dried. Removal of the solvent followed by drying under vacuum
afforded 2.11 g (9.79 mmol, 98%) of 9 as a waxy solid, which
was used without further purification. Mp: 35-38 °C. 1H NMR
(400 MHz, CDCl3): δ 7.93 (s, 1H), 7.42 (m, 1H), 7.36 (m, 1H),
7.26 (m, 2H), 5.28 (s, 2H), 3.73 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 157.4, 133.7, 133.5, 130.0, 129.8, 129.7, 127.0, 64.82,
64.77. Anal. Calcd for C9H10ClNO3: C, 50.13; H, 4.67; N, 6.50.
Found: C, 50.11; H, 4.86; N, 6.26.
3H), 3.61 (m, 2H), 2.15 (m, 1H), 1.93 (m, 1H), 1.40 (s, 9H). 13
C
NMR (100 MHz, CD3CN, 55 °C): δ 173.2, 156.4, 155.8, 134.0,
133.1, 130.0, 129.9, 129.5, 127.3, 79.4, 64.8, 61.9, 51.4, 45.6,
29.1, 27.7. FAB-HRMS: calcd for C18H26ClN2O7 (M + H)+
417.1429, found 417.1425. Anal. Calcd for C18H25ClN2O7: C,
51.86; H, 6.05; N, 6.72. Found: C, 51.92; H, 6.20; N, 6.58.
2-(N-ter t-Bu toxyca r bon yl)-3-(N-2-ch lor oben zyloxyca r -
bon yl-N-m et h oxy)d ia m in op r op a n oic Acid (3b ). A flask
was charged with 1111 (544 mg, 2.52 mmol), LiOH‚H2O (211
mg, 5.02 mmol), H2O (5 mL), and THF (10 mL), and the
mixture was stirred for 20 h. NaHCO3 (250 mg) and N-(2-
chlorobenzyloxycarbonyloxy)succinimide (1.43 g, 5.04 mmol)
were added, and the contents were stirred for an additional
21 h. The THF was removed, and the resulting aqueous
mixture was diluted with brine (25 mL) and acidified to pH
4-5 with 0.1 M KHSO4. The aqueous layer was extracted with
EtOAc (4 × 40 mL), and the combined organic layers were
then washed with 0.1 M KHSO4 (2 × 50 mL) and brine (50
mL) and then dried. Removal of the solvent gave a residue
that was purified by column chromatography (acetone/CH2-
Cl2/AcOH, 10:90:0.5 to 20:80:0.5) and then size-exclusion
chromatography (LH-20, MeOH/CH2Cl2, 10:90) to yield 790 mg
2-(N -t er t -Bu t oxyca r b on yl)a m in o-4-[O-[N -(2-ch lor o-
ben zyloxyca r bon yl)-N-m eth yl]a m in o]h yd r oxybu ta n oic
Acid (1b). A flask was charged with 8 (1.28 g, 2.80 mmol)
and CH2Cl2 (10 mL). Triphenylphosphine (38 mg, 0.14 mmol)
and pyrrolidine (246 µL, 2.94 mmol) were added, and the flask
was flushed with N2. Tetrakis(triphenylphosphine)palladium-
(0) (81 mg, 0.070 mmol) was then added, and the mixture was
stirred for 40 min. The solvents were removed by rotary
evaporation, and the residue was dissolved in EtOAc (125 mL)
and poured into a separatory funnel. The organic layer was
washed with 0.1 M KHSO4 (3 × 50 mL) and saturated NaCl
(50 mL), and then dried. The solvent was removed, and column
chromatography of the residue (EtOAc/hexanes/AcOH, 40:60:
0.5 to 50:50:0.5) afforded an oil that was further purified by
size-exclusion chromatography (LH-20, CHCl3). The resulting
residue was dried under vacuum overnight at 55 °C to yield
1
of 3b (1.96 mmol, 78%). H NMR (400 MHz, CD3CN, 55 °C):
δ 8.6 (bs, 1H), 7.48 (m, 1H), 7.43 (m, 1H), 7.34 (m, 2H), 5.63
(d, 1H, J ) 8.0 Hz), 5.25 (s, 2H), 4.42 (bs, 1H), 3.97 (dd, 1H, J
) 4.9, 14.8 Hz), 3.89 (dd, 1H, J ) 7.2, 14.8 Hz), 3.66 (s, 3H),
1.40 (s, 9H). 13C NMR (100 MHz, CD3CN, 55 °C): δ 171.5,
156.4, 155.5, 133.8, 133.1, 130.0, 129.9, 129.5, 127.3, 79.6, 65.0,
61.8, 51.8, 49.5, 27.6. Anal. Calcd for C18H25ClN2O7: C, 50.69;
H, 5.75; N, 6.95. Found: C, 50.62; H, 5.87; N, 6.59.
1
1.16 g (2.79 mmol, 100%) of 1b as a viscous oil. H NMR (400
2-(N-ter t-Bu toxyca r bon yl)-3-(N-2-ch lor oben zyloxyca r -
bon yl-N-m eth oxy)d ia m in obu ta n oic Acid (4b). A flask was
charged with 1211 (435 mg, 1.89 mmol), LiOH‚H2O (159 mg,
3.78 mmol), H2O (4 mL), and CH3CN (8 mL), and the mixture
was stirred for 90 min. NaHCO3 (200 mg) and N-(2-chloro-
benzyloxycarbonyloxy)succinimide (2.68 g, 9.45 mmol) were
added, and the contents were stirred for an additional 68 h.
The mixture was diluted with 0.1 M KHSO4 (40 mL) and
extracted with EtOAc (4 × 35 mL). The combined organic
layers were washed with brine (25 mL) and then dried.
Removal of the solvent gave a residue that was purified by
column chromatography (acetone/CH2Cl2/AcOH, 5:95:0.5 to 10:
90:0.5), additional chromatography (EtOAc/hexanes/AcOH, 40:
60:0.5 to 50:50:0.5), and then size-exclusion chromatography
(LH-20, MeOH:CH2Cl2, 10:90) to yield 288 mg of 4b (0.691
mmol, 37%). 1H NMR (400 MHz, CD3CN, 55 °C): δ 7.50-7.56
(m, 2H), 7.41 (m, 2H), 5.74 (bs, 1H), 5.35 (d, 1H, J ) 12.8 Hz),
5.30 (d, 1H, J ) 13.0 Hz), 4.50 (m, 1H), 4.38 (m, 1H), 3.77 (s,
3H), 1.47 (s, 9H), 1.35 (d, 3H, J ) 6.7 Hz). 13C NMR (100 MHz,
CD3CN): δ 171.6, 157.0, 155.6, 133.6, 133.1, 130.1, 130.0,
129.4, 127.3, 79.4, 65.0, 63.4, 56.6, 56.2, 27.5, 14.1. FAB-
HRMS: calcd for C18H26ClN2O7 (M + H)+ 417.1429, found
417.1421. Anal. Calcd for C18H25ClN2O7: C, 51.86; H, 6.05; N,
6.72. Found: C, 51.91; H, 6.22; N, 6.60.
MHz, CDCl3, 55 °C): δ 8.60 (bs, 1H), 7.39 (m, 2H), 7.26 (m,
2H), 5.63 (bs, 1H), 5.29 (s, 2H), 4.43 (bs, 1H), 4.01 (m, 2H),
3.18 (s, 3H), 2.17 (m, 1H), 2.05 (m, 1H), 1.43 (s, 9H). 13C NMR
(100 MHz, CDCl3, 55 °C): δ 175.7, 157.6, 156.2, 133.93, 133.90,
130.1, 129.82, 129.80, 127.2, 80.6, 71.0, 65.5, 51.8, 36.7, 30.7,
28.5. FAB-HRMS: calcd for C18H26ClN2O7 (M + H)+ 417.1429,
found 417.1421. Anal. Calcd for C18H25ClN2O7: C, 51.86; H,
6.05; N, 6.72. Found: C, 52.03; H, 6.16; N, 6.67.
2-(N-ter t-Bu t oxyca r b on yl)-4-[N-[2-ch lor ob en zyloxy-
ca r bon yl]-N-m eth oxy]d ia m in obu ta n oic Acid (2b). A flask
was charged with 9 (856 mg, 3.97 mmol) and anhydrous DMF
(5 mL). Sodium hydride (60% dispersion in mineral oil, 152
mg, 3.81 mmol) was added, and the mixture was stirred for
30 min and then cooled to 0 °C. Compound 6 (1.02 g, 3.18
mmol) was added, the sides of the flask were rinsed with
additional DMF (5 mL), and the resulting solution was stirred
for 30 min at 0 °C. The ice bath was removed, and the reaction
was allowed to warm to rt and stirred for an additional 3.5 h.
The reaction mixture was poured into a separatory funnel and
diluted with EtOAc (125 mL). The organic layer was washed
with 0.1 M KHSO4 (3 × 50 mL) and saturated NaCl (50 mL)
and then dried. The solvent was removed, and column chro-
matography of the residue (EtOAc/hexanes, 20:80 to 25:75 to
30:70) afforded 1.48 g of a residue identified by 1H NMR as
an approximately 3:1 mixture of 9 and 10. This residue was
Rep r esen ta tive Glycosyla tion Rea ction . Lyophilized
powder of 14 (0.65 mg) was dissolved in 0.1 M NaOAc, pH 4.0
J . Org. Chem, Vol. 68, No. 23, 2003 8857