148
X. Yu et al. / Tetrahedron 67 (2011) 144e151
48 h, at which point the solvent was removed under reduced
pressure. The residue was dissolved in EtOAc (50 mL), and the
solution was washed with brine. The organic phase was separated
and dried over MgSO4. Flash column chromatography (SiO2: 20%
ꢀ169.12 (c 1.10, DCM). 1H NMR (500 MHz, CDCl3):
8.90 (d, J¼8.0 Hz,
d
1H), 8.72 (d, J¼7.5 Hz,1H), 7.91 (s,1H), 7.74 (dd, J¼3.0 and 6.0 Hz,1H),
7.50 (d, J¼1.5 Hz, 3H), 7.45e7.15 (m, 43H), 7.09 (dd J¼2 and 6.5 Hz,
2H), 7.00e6.98 (m, 3H), 5.29e5.07 (m, 10H), 5.02e4.89 (m, 6H), 4.73
(quint, J¼4.0 Hz, 1H), 4.68e4.57 (m, 2H), 4.48e4.35 (m, 2H), 4.26 (t,
J¼9.0 Hz, 3H), 4.21e4.10 (m, 3H), 4.05 (dd, J¼3.5 and 11.5 Hz, 1H),
3.89e3.74(m, 7H), 3.64(dd,J¼1.5 andJ¼9.0 Hz,1H), 3.50(t,J¼9.5 Hz,
1H), 3.36 (dd, J¼3.0 and 10.0 Hz, 1H), 3.29 (dd, J¼3.0 and 10.0 Hz,
ethyl acetate in hexanes) provided a mixture of diastereomeric 20
24
as a white solid (1.937 g, 2.475 mmol, 83% yield). [
a
]
D
ꢀ111.47 (c
5.20, DCM). 1H NMR (500 MHz, CDCl3):
d
8.84 (d, J¼7.5 Hz, 1H), 8.80
(d, J¼8.0 Hz, 1H), 7.72e7.70 (m, 2H), 7.49e7.16 (m, 39H), 5.43 (d,
J¼9.0 Hz, 1H), 5.29 (d, J¼9.0 Hz, 1H), 5.28 (s, 4H), 5.23 (d, J¼4.0 Hz,
1H), 5.19 (m, 6H), 5.17e5.07 (m, 5H), 4.56 (dd, J¼10.1 and 4.0 Hz,
1H), 4.48e4.47 (m, 1H), 4.47e4.42 (m, 2H), 4.37 (dd, J¼10.1 and
6.5 Hz, 1H), 4.27 (s, 1H), 4.19e4.14 (m, 2H), 3.74e3.72 (m, 2H), 3.59
(dd, J¼10.1 and 3.5 Hz, 1H), 3.48 (td, J¼2.0 and 7 Hz, 1H), 3.42e3.34
(m, 3H), 3.23e3.19 (m, 1H), 1.46 (s, 9H), 1.45 (s, 9H).
1H), 1.40 (s, 9H). 13C NMR (125 MHz, CDCl3):
d 169.0, 168.9, 165.3,
164.6, 155.2, 151.9, 151.5, 147.1, 146.4, 138.7, 138.3, 138.1, 137.6, 137.5,
136.4, 136.3, 136.1, 136.0, 135.1, 129.3, 129.1, 128.7, 128.7, 128.6,
128.6,128.5,128.5,128.5,128.4,128.3,128.3,128.1,128.0,128.0,127.9,
127.8, 127.8, 127.7, 127.7, 127.6, 126.3, 124.5, 123.3, 122.2, 117.6, 116.0,
86.8, 83.8, 81.0, 79.8, 79.4, 78.3, 76.2, 76.1, 75.6, 75.2, 74.9, 73.5,
72.9, 71.4, 71.1, 69.3, 69.2, 67.7, 65.2, 64.4, 53.7, 51.9, 51.7. HRMS
(MALDI): m/z [MþNa]þ found 1736.7006, calcd 1376.7033 for
C104H103N3O20Na.
4.6.6. (R)-Benzyl3-((S)-2-(2,3-bis(benzyloxy)-5-((2S,3S,4S,5S,6R)-
3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)
benzamido)-3-hydroxypropanoyloxy)-2-(2,3-bis(benzyloxy)benza-
mido)propanoate (21). This compound was prepared according to
the general procedure C by deprotection of the Boc and THP groups
of 20 (0.100 g,100 mol %, 0.128 mmol) with HCl (1 M, 2.3 mL) in THF
(3.7 mL). After the solvent and excess HCl was removed, the dry
residue was dissolved in THF (5 mL) at 0 ꢁC, followed by the addi-
tion of Ar1COOH (0.110 g, 100 mol %, 0.128 mmol), HOBT
(0.170 g, 100 mol %, 0.110 mmol), and EDC$HCl (0.280 g, 110 mol %,
0.141 mmol) under nitrogen. After the reaction mixture become
4.6.8. (S)-Benzyl 3-((S)-3-((S)-3-(benzyloxy)-2-(2,3-bis(benzyloxy)-
5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetra-
hydro-2H-pyran-2-yl)benzamido)propanoyloxy)-2-(2,3-bis(benzy-
loxy)-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)
tetrahydro-2H-pyran-2-yl)benzamido)propanoyloxy)-2-(2,3-bis(ben-
zyloxy)benzamido)propanoate (18, per-Bn-S2). According to the
general procedures C, deprotection of 22 (0.050 g, 100 mol %,
0.029 mmol) was performed using HCl (1 M in 0.7 mL MeOH) in
THF (1 mL). After the solvent and excess HCl were removed, DCM
homogenous, 4-methyl morpholine (28 mL, 200 mol %, 0.230 mmol)
was added. The resulting mixture was stirred at 0 ꢁC for 2 h, then at
20 ꢁC overnight. Upon evaporation of the solvent under reduced
pressure, the residue was dissolved in EtOAc (5 mL). The solution
was washed with brine, and the organic phase was separated and
dried over MgSO4. Flash column chromatography (SiO2: 20% ethyl
(1.0 mL) and Et3N (32
the resulting solution was added a solution of 1 in DCM (1 mL) at
mL, 800 mol %, 0.232 mmol) were added. To
0
ꢁC, which was prepared according to the general procedures A
using Ar1COOH (0.025 g, 100 mol %, 0.029 mmol). The reaction
mixture was allowed to warm to 20 ꢁC, and stir for 0.5 h, at which
point it was concentrated over silica gel. Flash column chroma-
tography (SiO2: 20% EtOAc in hexanes) gave the product as a white
acetate in hexanes) gave the title product as a white foam (0.110 g,
24
0.077 mmol, 60% yield). [
a
]
ꢀ342.24 (c 0.80, DCM). 1H NMR
D
(500 MHz, CDCl3):
d
8.89 (t, J¼7.0 Hz, 2H), 7.89 (d, J¼2.0 Hz, 1H),
foam (0.038 g, 0.016 mol, 54% yield). [
NMR (500 MHz, CDCl3):
a
]
24 þ79.36 (c 0.10, DCM). 1H
D
7.70 (dd, J¼7.0 and 2.0 Hz,1H), 7.48 (d, J¼13.0 Hz, 2H), 7.42e7.14 (m,
45H), 6.97e6.95 (m, 2H), 5.28 (t, J¼6.0 Hz, 2H), 5.22 (q, J¼5.0 Hz,
3H), 5.16 (s, 3H), 5.01 (t, J¼9.0 Hz, 2H), 4.97e4.86 (m, 5H), 4.73 (dd,
J¼4.0 and 10.5 Hz, 1H), 4.65e4.54 (m, 2H), 4.42 (d, J¼10.5 Hz, 1H),
4.23 (d, J¼4.5 Hz, 1H), 3.98 (q, J¼6.5 Hz, 1H), 3.82e3.71 (m, 5H),
3.63e3.61 (m, 2H), 3.53 (dd, J¼10.5 and 3.5 Hz, 1H), 3.48 (t,
d
7.93 (d, J¼2.0 Hz, 1H), 7.86 (d, J¼2.0 Hz,
1H), 7.70 (dd, J¼7.0 and 2.0 Hz, 1H), 7.42e6.91 (m, 77H), 5.21e5,17
(m, 5H), 5.13e5.11 (m, 3H), 5.10 (d, J¼3.5 Hz, 1H), 5.04 (s, 3H),
4.98e4.87 (m, 14H), 4.74 (td, J¼4.0 and 8.0 Hz, 1H), 4.68e4.56 (m,
8H), 4.40 (dd, J¼10.5 and 2.0 Hz, 2H), 4.36 (dd, J¼12.0 and 4.0 Hz,
1H), 4.20e4.15 (m, 3H), 4.11 (q, J¼15.0 Hz, 3H), 3.85e3.74 (m, 13H),
3.64e3.60 (m, 3H), 3.52e3.46 (m, 3H), 3.34 (dd, J¼10.0 and 3.5 Hz,
1H), 3.25 (dd, J¼10.0 and 3.5 Hz, 1H). 13C NMR (125 MHz, CDCl3):
J¼9.0 Hz, 1H). 13C NMR (125 MHz, CDCl3):
d 170.3, 168.9, 165.8,
165.0, 151.8, 151.6, 147.0, 146.7, 138.7, 138. 3, 138.2, 137.6, 136.3,
136.2, 136.0, 135.4, 135.0, 129.5, 129.2, 128.8, 128.7, 128.7, 128.5,
128.5,128.4,128.3,128.3,128.1,128.0,127.9,127.8,127.7,127.6,127.6,
126.7, 126.1, 124.6, 123.3, 122.1, 117.6, 116.4, 86.8, 83.9, 81.1, 79.4,
78.3, 76.4, 76.2, 75.6, 75.2, 74.9, 73.5, 71.4, 71.2, 69.2, 67.8, 65.1, 62.4,
55.1, 51.7. HRMS (MALDI): m/z [MþNa]þ found 1459.5724, calcd
1459.5719 for C89H84N2O16Na.
d
169.1, 165.3, 151.8, 151.6, 147.0, 146.5, 146.4, 138.7, 138.3, 138.2,
137.6, 137.5, 136.4, 136.3, 136.1, 136.0, 135.9, 135.6, 135.4, 135.2,
129.5, 129.4, 129.1, 128.6, 128.4, 128.2, 128.1, 127.9, 127.8, 127.7,
127.6, 127.5, 126.5, 126.2, 124.4,123.2, 122.2, 122.1, 117.5, 116.2, 116.0,
86.8, 83.9, 83.8, 81.1, 81.0, 79.4, 78.3, 76.1, 76.0, 75.6, 75.2, 74.9, 73.5,
72.7, 71.3, 71.1, 69.2, 68.9, 67.7, 65.2, 64.6, 53.0, 51.9, 51.6. HRMS
(MALDI): m/z [MþNa]þ found 2475.0044, calcd 2475.0014 for
C154H145N3O26Na.
4.6.7. (2R)-Benzyl 3-((3S,7S)-7-(benzyloxymethyl)-1-(2,3-bis(benzy-
loxy)-5-((2S,5S,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetra-
hydro-2H-pyran-2-yl)phenyl)-11,11-dimethyl-1,6,9-trioxo-5,10-di-
oxa-2,8-diazadodecanecarbonyloxy)-2-(2,3-bis(benzyloxy)benza-
mido)propanoate (22). A mixture of 21 (0.100 g, 100 mol %,
0.070 mmol), Boc-Ser (Bzl)-OH (11) (0.300 g,150 mol %, 0.100 mmol),
and HOBT (0.014 g, 150 mol %, 0.100 mmol) was dissolved dry ace-
tonitrile at 0 ꢁC, to which was added EDC$HCl (0.027 g, 200 mol %,
0.140 mmol) under N2. The mixture was stirred for 1 h at 0 ꢁC and an
4.6.9. (S)-3-((S)-2-(2,3-Dihydroxy-5-((2S,3R,4R,5S,6R)-3,4,5-tri-
hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzamido)-
3-((S)-2-(2,3-dihydroxy-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-
(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzamido)-3-hydrox-
ypropanoyloxy)propanoyloxy)-2-(2,3-dihydroxybenzamido)
propanoic acid (salmochelin S2). This compound was prepared
according to the general procedures C using Per-Bn-S2 18 (0.050 g,
100 mol %, 0.020 mmol) and Pd (OH)2 (0.050 g, 20% weight on
carbon). Filtration and removal of the solvent gave the title com-
pound as a white solid (0.019 g, 0.018 mmol, 90% yield), which was
additional 1 h at 20 ꢁC, at which point pyridine (14
mL, 250 mol %,
0.170 mmol) was added. The resulting mixture was stirred for 48 h.
After removal of the solvent under reduced pressure, the residue was
dissolved in EtOAc (5 mL). The solution was washed with brine, and
the organic phase was collected, dried over MgSO4. Flash column
further purified using RP-preparative HPLC using a gradient of
24
0e50% CH3CN in 0.1% TFA/H2O over 45 min [
MeOH). 1H NMR (500 MHz, CD3OD):
and 1.0 Hz, 1H), 7.05 (s, 2H), 6.95 (dd, J¼8.0 and 1.5 Hz, 1H), 6.76 (t,
a
]
ꢀ70.14 (c 0.70,
D
chromatography (SiO2: 20% ethyl acetate in hexanes) gave the title
d
7.42 (s, 2H), 7.34 (dd, J¼8.0
24
product as a white foam (0.055 g, 0.039 mmol, 43% yield). [
a
]
D