Mimics of Sialyl Lewis X in Selectin Inhibition
J. Am. Chem. Soc., Vol. 119, No. 35, 1997 8157
brine, dried with MgSO4, filtered, and evaporated to yield the
crude aldehyde (1.1090 g).
(t, J ) 3.7 Hz, 1 H), 3.63 (dd, J ) 8.2, 2.9 Hz, 1 H), 3.59 (dd,
J ) 4.4, 3.2 Hz, 1 H), 3.41-3.38 (m, 1 H), 3.38 (t, J ) 6.9 Hz,
2 H), 2.79 (dd, J ) 16.0, 2.3 Hz, 1 H), 2.71 (dd, J ) 16.0, 9.5
Hz, 1 H), 1.39-1.36 (m, 2 H), 1.37 (t, J ) 7.1 Hz, 3 H), 1.26-
1.12 (m, 26 H), 0.88 (t, J ) 7.0 Hz, 3 H); 13C NMR (100 MHz,
CDCl3) δ 169.21, 166.25, 138.35, 137.69, 137.58, 137.44,
130.87, 128.64, 128.46, 128.42, 128.10, 127.90, 127.74, 124.90,
121.40, 75.39, 74.73, 74.55, 73.35, 72.80, 72.41, 71.77, 71.51,
67.75, 66.93, 60.88, 38.43, 31.86, 29.64, 29.60, 29.55, 29.49,
29.35, 29.31, 29.17, 25.82, 22.64, 14.27, 14.08; HRMS (FAB,
M + Cs) calcd for C54H73NO8Cs 996.4391, found 996.4353.
3-{N-[(6-O-Hexadecanyl-r-D-mannopyranosyl)]acetyl]-
amino}benzoic Acid (3a). An ice-cold solution of 0.25 M
LiOH in 75% MeOH(aq) (5.3 mL) was added to a solution of
19 (230 mg, 0.27 mmol) in tetrahydrofuran (5 mL), and the
mixture was vigorously stirred for 2 days at 4 °C. The resulting
solution was acidified with 1 N HCl to pH 1-2 and extracted
with EtOAc (3 × 10 mL). The combined organic layers were
washed with brine, dried with MgSO4, filtered, evaporated, and
purified by a short column chromatography to yield free acid
compound 193 mg (87%): 1H NMR (400 MHz, CDCl3) δ 9.19
(s, 1 H), 8.06 (t, J ) 1.7 Hz, 1 H), 8.02 (ddd, J ) 7.9, 1.7, 1.2
Hz, 1 H), 7.78 (dt, J ) 7.9, 1.2 Hz, 1 H), 7.37-7.23 (m, 16 H),
4.60 (d, J ) 12.0 Hz, 1 H), 4.57-4.49 (m, 5 H), 4.40 (dt, J )
8.8, 2.5 Hz, 1 H), 4.17 (dt, J ) 9.1, 3.4 Hz, 1 H), 4.00 (t, J )
9.9 Hz, 1 H), 3.81 (t, J ) 3.7 Hz, 1 H), 3.65 (dd, J ) 8.1, 2.9
Hz, 1 H), 3.61 (dd, J ) 4.5, 3.2 Hz, 1 H), 3.43-3.41 (m, 1 H),
3.39 (t, J ) 7.0 Hz, 2 H), 2.83 (dd, J ) 16.2, 2.5 Hz, 1 H),
2.70 (dd, J ) 16.2, 9.6 Hz, 1 H), 1.43-1.37 (m, 2 H), 1.31-
1.13 (m, 26 H), 0.87 (t, J ) 7.0 Hz, 3 H); 13C NMR (100 MHz,
CDCl3) δ 170.86, 169.36, 138.60, 137.68, 137.59, 137.39,
129.78, 128.89, 128.48, 128.45, 128.17, 127.95, 127.82, 127.79,
125.60, 125.43, 121.82, 75.41, 74.65, 74.46, 73.48, 72.74, 72.48,
71.81, 71.58, 67.83, 67.12, 38.64, 31.89, 29.68, 29.64, 29.60,
29.54, 29.41, 29.34, 29.20, 25.85, 22.66, 14.11; HRMS (FAB,
M + Cs) calcd for C52H69NO8Cs 968.4078, found 968.4060.
The above aldehyde (1.1090 g) was dissolved in acetone (7
mL), and the solution was cooled to 0 °C. The mixture was
added Celite (0.8 g) in one portion followed by the addition of
Jones reagent drop by drop until a orange color persisted, which
i
indicated the oxidation had gone to completion. PrOH (1 mL)
was added to quench any excess Jones reagent, and the reaction
mixture was then partitioned between EtOAc (50 mL) and 1 N
HCl (50 mL). The aqueous layer was extracted with EtOAc (2
× 50 mL), and the combined organic phases were dried with
(MgSO4), concentrated, and purified by silica gel flash chro-
matography (EtOAc/hexane/AcOH, 3/1/0.01) to yield the car-
boxylic acid 17 (0.904 g, 78% in three steps): HRMS (FAB,
M + Cs) calcd for C45H64O7Cs 849.3706, found 849.3729.
To a solution of carboxylic acid 17 (260 mg, 0.363 mmol)
in CH2Cl2 (3 mL) were added BnO-Glu(OBn)-NH2‚p-TsOH
(200 mg, 0.399 mmol), triethylamine (56 µL, 0.399 mmol),
HOBt (54.0 mg, 0.399 mmol), and EDC (76.4 mg, 0.399 mmol)
at 25 °C under argon. The reaction was allowed to stir for 24
h before being diluted with CH2Cl2 (20 mL) and washed
successively with a 1 N hydrochloric acid solution (15 mL),
saturated NaHCO3 solution (15 mL), and brine (15 mL). The
organic phase was dried with MgSO4, concentrated, and purified
by silica gel chromatography to yield 18 (271 mg, 73%): 1H
NMR (500 MHz, CDCl3) δ 7.33-7.22 (m, 25 H), 7.17 (d, J )
7.9 Hz, 1 H), 5.14 (s, 2 H), 5.07, 5.04 (ABq, J ) 12.3 Hz, 2
H), 4.66 (dt, J ) 7.9, 5.2 Hz, 1 H), 4.54-4.44 (m, 6 H), 4.29
(dt, J ) 8.3, 3.3 Hz, 1 H), 3.98-3.95 (m, 1 H), 3.78-3.71 (m,
3 H), 3.61-3.58 (m, 2 H), 3.39-3.29 (m, 2 H), 2.61 (dd, J )
15.8, 3.2 Hz, 1 H), 2.52 (dd, J ) 15.8, 8.7 Hz, 1 H), 2.43-
2.30 (m, 2 H), 2.23-2.16 (m, 1 H), 1.98-1.91 (m, 1 H), 1.49
(t, J ) 6.1 Hz, 2 H), 1.25 (bs, 26 H), 0.88 (dt, J ) 6.8, 2.7 Hz,
3 H); 13C NMR (100 MHz, CDCl3) δ 172.26, 171.35, 170.49,
137.81, 137.67, 135.70, 135.27, 128.46, 128.40, 128.32, 128.28,
128.22, 128.08, 128.04, 128.02, 127.78, 127.73, 127.69, 75.03,
74.27, 73.94, 73.89, 72.48, 72.28, 71.37, 68.31, 67.49, 66.90,
66.23, 51.37, 37.44, 31.82, 30.13, 29.61, 29.57, 29.45, 29.26,
27.02, 26.00, 22.59, 14.05; HRMS (FAB, M + Cs) calcd for
C64H83NO10Cs 1158.5071, found 1158.5116.
The above acid was hydrogenated by following the previously
1
described method to give compound 3a in 91% yield: H NMR
(400 MHz, CD3OD/CDCl3 ) 1/1) δ 8.16 (s, 1 H), 7.87 (d, J )
7.6 Hz, 1 H), 7.78 (d, J ) 7.6 Hz, 1 H), 7.40 (t, J ) 7.6 Hz, 1
H), 4.39-4.36 (m, 1 H), 4.10 (s, 1 H), 3.82-3.64 (m, 5 H),
3.47 (t, J ) 7.1 Hz, 2 H), 2.81 (dd, J ) 15.1, 9.9 Hz, 1 H),
2.67 (dd, J ) 15.1, 4.6 Hz, 1 H), 1.44-1.18 (m, 28 H), 0.89 (t,
J ) 6.8 Hz, 3 H); HRMS (FAB, M + Cs) calcd for C31H51-
NO8Cs 698.2669, found 698.2684.
N-[(6-O-Hexadecanyl-r-D-mannopyranosyl)acetyl]-L-
glutamic Acid (3). To a mixture of benzyl ether 18 (250 mg,
0.24 mmol) in HOAc/THF/H2O (12 mL, 4/1/1) was added a
catalytic amount of Pd/C (Degussa type, 10% by wt). The
solution was flushed with hydrogen for 30 min, then stirred for
24 h under a H2 atmosphere. The reaction mixture was filtered
and coevaporated with toluene under reduced pressure. The
crude produce was recrystallized from chloroform and hexane
to yield mimetic 3 as a white solid (130 mg, 93%): 1H NMR
(400 MHz, CD3OD/CDCl3, 1/1) δ 4.52-4.48 (m, 1 H), 4.30-
4.26 (m, 1 H), 3.76-3.69 (m, 6 H), 3.50 (t, J ) 7.0 Hz, 2 H),
2.67 (dd, J ) 14.9, 8.2 Hz, 1 H), 2.57 (dd, J ) 14.9, 5.8 Hz, 1
H), 2.44-2.40 (m, 2 H), 2.26-2.22 (m, 1 H), 2.05-1.98 (m, 1
H), 1.59-1.56 (m, 2 H), 1.27 (bs, 26 H), 0.89 (t, J ) 6.9 Hz,
3 H); HRMS (FAB, M + Na) calcd for C29H53NO10Na
598.3567, found 598.3576.
Compound 20. D-Mannose (1500 mg, 8.3 mmol) was added
to 10 mL of allyl alcohol together with a catalytic amount (10
mg) of camphorsulfonic acid. The mixture was heated to 90
°C overnight, and then the excess allyl alcohol was evaporated
in Vacuo. Flash chromatography of the residue (EtOAc:MeOH,
6:1 to 4:1) gave 1400 mg (76%) of R-O-allylmannopyrano-
side: 13C NMR (CD3OD, δ, ppm) 136.31, 118.28, 101.48,
75.47, 73.55, 72.94, 69.67, 69.36, 63.68.
To a solution of the above compound (482 mg, 2.2 mmol) in
CH2Cl2:MeOH (1:4) was bubbled ozone at -78 °C in the
presence of a catalytic amount of NaHCO3. After the blue color
appeared, indicating that the solution was saturated with ozone,
an excess (3 equiv) of Ph3P was added. After stirring overnight,
an extractive workup was performed (CH2Cl2/water), the
aqueous portion was evaporated, and the residue showed the
presence of only one aldehyde as the dihydrate as judged by
13C NMR (CD3OD, δ, ppm): 100.13, 88.22, 72.73, 70.36, 69.84,
66.66, 60.85.
Ethyl 3-{N-[(6-O-Hexadecanyl-2,3,4-tri-O-benzyl-r-D-
mannopyranosyl)acetyl]amino}benzoate (19). The prepara-
tion for the coupling of 17 and ethyl 3-aminobenzoate was
followed by the above procedure to afford 19 in 63% yield:
1H NMR (500 MHz, CDCl3) δ 9.09 (s, 1 H), 8.05 (t, J ) 1.5
Hz, 1 H), 7.84 (d, J ) 6.5 Hz, 1 H), 7.75 (dt, J ) 6.5, 1.5 Hz,
1 H), 7.34-7.22 (m, 16 H), 4.60 (d, J ) 12.1 Hz, 1 H), 4.56-
4.48 (m, 5 H), 4.39-4.35 (m, 1 H), 4.35 (q, J ) 7.1 Hz, 2 H),
4.16 (dt, J ) 9.0, 3.5 Hz, 1 H), 4.00 (t, J ) 10.0 Hz, 1 H), 3.80
Compound 20a. The ozonolysis of 9a was performed as
described above. The aldehyde product (2 mmol, 1.1 g) was