Structure-activity relationships of phomactin derivatives as platelet activating factor antagonists

Article abstract of DOI:10.1021/jm950640q

Phomactins, natural products isolated from the culture broth of marine fungus Phoma sp., were found to be active as PAF antagonists. This unique carbon skeleton led us to investigate the structure-activity relationship demonstrating that the lipophilicity

Full text of DOI:10.1021/jm950640q

J . Med. Chem. 1996, 39, 5281-5284
5281
Str u ctu r e-Activity Rela tion sh ip s of P h om a ctin Der iva tives a s P la telet
Activa tin g F a ctor An ta gon ists
Michihiro Sugano,† Aiya Sato,*,† Kazuko Saito,† Sachiko Takaishi,‡ Yoichi Matsushita,‡ and Yasuteru Iijima‡
Biomedical Research Laboratories, and Pharmacology and Molecular Biology Research Laboratories, Sankyo Co. Ltd.,
2-58, 1-chome, Hiromachi, Shinagawa-ku, Tokyo 140, J apan
Received September 23, 1996X
Phomactins, natural products isolated from the culture broth of marine fungus Phoma sp.,
were found to be active as PAF antagonists. This unique carbon skeleton led us to investigate
the structure-activity relationship demonstrating that the lipophilicity at C-(7-8), acetoxy,
(methoxycarbonyl)oxy, and 3-isoxazolyloxy substitution at C-20, and 2-â-OH configuration at
C-2 are all required for the enhancement of inhibitor activity.
Platelet activating factor (PAF) is a naturally occur-
ring ether phospholipid [1-O-alkyl-2(R)-acetylglyceryl-
3-phosphorylcholine] that is a mediator of anaphylaxis
released by a number of stimulated cells, such as
basophils, neutrophils, platelets, and macrophages. PAF
also causes platelet aggregation, chemotaxis, and de-
granulation of polymorphonuclear leukocytes, smooth
muscle contraction, vascular permeability, and hypo-
tension. Studies have further shown that PAF may be
involved in many inflammatory, respiratory, and car-
diovascular diseases.1 Intensive efforts to find drugs
which block the effects of PAF have resulted in the
discovery of a number of specific PAF antagonists, some
of which are being tested for their clinical effectiveness.2
During the screening of novel PAF antagonists from
natural sources, we systematically screened lipophilic
extracts of marine fungal isolates for inhibition of PAF-
induced platelet aggregation and binding of PAF to its
receptors and found that a marine fungus Phoma sp.
produced novel PAF antagonists, phomactins.3 They
characteristically bear a unique bicyclo[9.3.1]pentadecane
F igu r e 1. Structure of 1 shown in boxes with fragments of
the molecule subjected to SAR investigation.
carbon skeleton. This led us to prepare derivatives to
examine how each moiety contributes in binding the
substrate to the PAF receptor.
affording 3 through 1,4-reduction and therefore was the
reagent of choice (Scheme 1).
As phomactin D (1) was identified as the most potent
PAF antagonist in the phomactin series (inhibition of
platelet aggregation IC50 0.80 µM, inhibition of binding
IC50 0.12 µM),3b it was initiated as the lead compound
and was dissected into three key fragments shown in
Figure 1. Fragment A concerns the effect of addition
at C-(7-8). Fragments B and C relate to the functional
effect at C-20 and the configuration effect at C-2-O
respectively. In this paper we describe the structure-
activity relationship by virtue of modification in frag-
ments A, B, and C.
F r a gm en t A. MCPBA oxidation of 1 and 3 gave the
respective epoxides 4 and 5, whereas oxidation of 1 and
3 with OsO4 in the presence of N-methylmorpholine
N-oxide provided 6 and 7, respectively. In both reac-
tions a single diastereomer was obtained, suggesting
that oxidation occurred at the less hindered side of the
double bond. In NOE experiments of 1 and 3, irradia-
tion of H-8Me resulted in enhancement of H-15 and
H-20, whereas irradiation of H-7 resulted in enhance-
ment of H-12. These results exemplified that the â-side
of the C-(7-8) double bond is sterically less hindered
than its R-side, thus the MCPBA and OsO4 presumably
attacks the double bond from the less hindered side.
Hence the stereochemistry at C-7 and C-8 of 4, 5, 6, and
7 was supposed as being 7S and 8S, respectively.
F r a gm en t B. To clarify the substitution effects in
the portion defined by fragment B, C-20-O derivatives
were prepared. While 8 was prepared by condensation
of 3 and acetic anhydride in pyridine, 9 and 10 were
prepared by the condensation of 3 and n-propionyl
chloride, phenyl chloroformate, respectively. Treatment
of 10 with dimethylamine at -10 °C gave 12. In a
similar manner treatment of 10 with MeOH under basic
conditions afforded methyl carbonate 11.
Ch em istr y
On the basis of the structure of phomactin D (1), a
series of analogues was prepared from a common
intermediate 3, prepared by DIBALH reduction of Sch
47918 (2) (phomactin C) (yield 56%).3b Efforts to afford
3 in higher yield by trying several reducing agents
(namely K-, L-Selectride, LAH, LiBHEt3, NaBH4) were
all unsuccessful and generated a 1,2-reduced product
at C-2 only. Only DIBALH was chemoselective in
† Biomedical Research Laboratories.
‡ Pharmacology and Molecular Biology Research Laboratories.
X Abstract published in Advance ACS Abstracts, November 15, 1996.
S0022-2623(95)00640-6 CCC: $12.00 © 1996 American Chemical Society

5282 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26
Notes
Ta ble 1. SAR of Fragment A
Sch em e 1
compd
R1 ) R2
R3
IC50 (µM)
Attempted condensation of 3 and 3-hydroxyisoxazole
under Mitsunobu conditions was unyielding and re-
sulted in recovery of the starting materials due to the
strong hydrogen bond between C-20-OH and C-2-car-
bonyl. After unsuccessful attempts we found that the
condensation of diol derivative 14 with 3-hydroxy-
isoxazole under the same condition gave isoxazole
derivative 19. Subsequent oxidation with PDC in the
presence of 4A molecular sieves furnished the desired
2-keto derivative 13.
4
5
6
7
-O-
-O-
OH
CHO
17.0
30.0
>280
>280
0.12
CH2OH
CH2OH
CH2OH
OH
phomactin D (1)
3
L-652731
1.3
0.024
Ta ble 2. SAR of Fragment B
F r a gm en t C. Reduction of all ketone derivatives 3,
8, 9, and 12 with NaBH4 proceeded efficiently with
delivery of the hydride onto the R-face to give the
corresponding 2-â-OH derivatives 14, 15, 16, and 18. The
proton NMR revealed a coupling constant of 2.3-2.5 Hz
between H-2 and H-3, confirming the â-orientation of
the C-2 hydroxy. This selectivity is due to the steric
hindrance at C-4Me and chelation between C-20-O and
the boron atom.
Compound 17 was prepared by acylation of 14 with
phenyl chloroformate followed by treatment with MeOH
under basic conditions. Formation of 19 is explained
in fragment B.
Resu lts a n d Discu ssion
In this study a radioreceptor binding assay using
rabbit platelets as the receptor source and [3H]PAF as
a ligand was employed to evaluate new compounds as
potential PAF antagonists. L-652731 (Merck) was
prepared as the reference compound.4
We have recently reported phomactin E (20) and F
(21) as PAF antagonists.5 Although 21 differs structur-
ally to 20 only by the functionality present in fragment
A, the former is less active than the latter (inhibition
of binding phomactin E (20) IC50 5.3 µM, phomactin F
(21) IC50 35.9 µM).
The derivatives acetoxy (8), n-propionyloxy (9), (di-
methylcarbamoyl)oxy (12), (methoxycarbonyl)oxy (11),
and isoxazolyloxy (13) (Table 2) were found to be more
potent than the parent compound (3). Study of the SAR
of PAF analogues shows that substitution at the C-2
6
In order to determine whether the hydrophilic func-
tion in this fragment would have a negative effect on
binding to the receptor, hydrophilic functions were
introduced into phomactin D (1) and 3. Inspection of
the activities of compounds listed in Table 1 reveals that
for a decrease in lipophilicity at C-7-8 there is a
corresponding decrease in activity. These results sug-
gest that a hydrophobicity in the vicinity of fragment A
is essential to the binding.
position by acetoxy, n-propionyloxy,6 (dimethylcar-
bamoyl)oxy,7 (methylcarbonyl)oxy,8 and 3-isoxazolyloxy9
have a strong affinity to the PAF receptor, while lyso-
PAF (2-OH-PAF)6 has no affinity. These results indi-
cate that aforementioned functions in fragment B
facilitate the binding.
The inhibitory activities of derivatives with the 2-â-
OH configuration in fragment C were 1.0-8.1 times
higher than those of the corresponding 2-keto deriva-

Notes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5283
Ta ble 3. SAR of Fragment C
500µL) at room temperature. After 1.5 h, the reaction mixture
was diluted with saturated NaHCO3 solution (20.0 mL) and
extracted with EtOAc (30.0 mL) twice. The residue was
subjected to silica gel column chromatography (hexane-
EtOAc, 2:8) to give 6 (20.6 mg): colorless oil; HREIMS [m/ z
352.2234; ∆ -1.6 mmu (M)+]; 1H NMR (CDCl3) δ 9.97 (1H, s),
5.30 (1H, s), 3.72 (1H, brd, J ) 10.1 Hz), 3.68 (1H, s), 2.92
(1H, d, J ) 3.4 Hz), 2.71 (1H, d, J ) 2.1 Hz), 2.26-2.45 (3H,
m), 1.32-2.04 (11H, m), 1.29 (3H, s), 1.20 (3H, s), 1.19 (3H,
s), 0.90 (3H, d, J ) 7.2 Hz).
7. 7 was prepared in a manner similar to the procedure for
6 above. With 3 (100.5 mg) as starting material and using
OsO4 (2%, 500 µL) and N-methylmorpholine N-oxide (49.1 mg),
7 (85.0 mg) was obtained: colorless oil; HREIMS [m/ z 354.2385;
∆ -2.1 mmu (M)+]; 1H NMR (CD3OD) δ 3.88 (1H, s), 3.83 (1H,
d, J ) 10.4 Hz), 3.82 (1H, dd, J ) 10.7, 2.0 Hz), 3.43 (1H, dd,
J ) 13.4, 10.7 Hz), 3.08 (1H, brd, J ) 7.0 Hz), 2.56 (1H, brd,
J ) 10.8 Hz), 2.37-2.42 (1H, m), 2.34 (1H, dt, J ) 2.0, 13.4
Hz), 1.86 (1H, dt, J ) 2.4, 14.0 Hz), 1.54 (3H, s), 1.31-1.71
(7H, m), 1.25-1.29 (1H, m), 1.13 (3H, s), 0.78-1.09 (2H, m),
0.73 (3H, d, J ) 6.7 Hz), 0.69 (3H, s).
8. To a solution of 3 (80.6 mg) in pyridine (2.0 mL) was
added Ac2O (0.5 mL) at room temperature. After 4 h the
solvent was removed by evaporation, and the residue was
subjected to silica gel column (hexane-EtOAc, 8:2) to give 8
(82.4 mg): colorless crystal; mp 108 °C; HREIMS [m/ z
1
362.2479; ∆ +2.2 mmu (M)+]; H NMR (CD3OD) δ 5.28 (1H,
brd, J ) 9.0 Hz), 4.33 (1H, dd, J ) 11.0, 3.3 Hz), 4.04 (1H, dd,
J ) 11.0, 10.9 Hz), 3.97 (1H, s), 3.34 (1H, dt, J ) 3.3, 10.9
Hz), 2.52 (1H, dt, J ) 2.4, 13.9 Hz), 2.29-2.38 (1H, m), 1.84-
2.11 (7H, m), 1.93 (3H, s), 1.67 (3H, s), 1.27-1.62 (5H, m), 1.18
(3H, s), 0.89 (3H, d, J ) 6.9 Hz), 0.70 (3H, s). Anal. (C22H34O4)
C, H.
9. To a solution of 3 (185.0 mg) in pyridine (3.0 mL) was
added n-propionyl chloride (100 µL) at room temperature. After
15 min the reaction mixture was diluted with EtOAc (20.0 mL)
and saturated CuSO4 solution (20.0 mL). The organic layer
was concentrated, and the residue was subjected to silica gel
column chromatography (hexane-EtOAc, 8:2) to give 9 (139.9
mg): colorless crystal; mp 108 °C; HREIMS [m/ z 376.2635; ∆
tives. These results reveal that the 2-â-OH configura-
tion is preferable in binding the substrate to the PAF
receptor (Table 3).
1
+2.1 mmu (M)+]; H NMR (CD3OD) δ 5.28 (1H, brd, J ) 7.3
In conclusion, the lipophilicity at C-(7-8), acetoxy,
(methoxycarbonyl)oxy, and 3-isoxazolyloxy at C-20, and
the 2-â-OH configuration at C-2 all enhance inhibitory
activity over that of the lead compound 1. The result
obtained in this study will provide useful information
for the interaction between the PAF receptor and its
ligands. Further pharmacological characterizations of
these compounds are in progress.
Hz), 4.35 (1H, dd, J ) 10.9, 3.2 Hz), 4.03 (1H, t, J ) 10.9 Hz),
3.98 (1H, s), 3.35 (1H, dt, J ) 3.2, 10.9 Hz), 2.52 (1H, dt, J )
2.5, 13.7 Hz), 2.19-2.36 (3H, m), 1.85-2.11 (7H, m), 1.66 (3H,
s), 1.27-1.62 (5H, m), 1.18 (3H, s), 1.07 (3H, t, J ) 7.6 Hz),
0.90 (3H, d, J ) 6.9 Hz), 0.71 (3H, s). Anal. (C23H36O4) C, H.
10. To a solution of 3 (233.0 mg) and pyridine (2.0 mL) in
CH2Cl2 (10.0 mL) was added phenyl chloroformate (220 µL)
at room temperature. After 30 min the reaction mixture was
diluted with EtOAc (20.0 mL) and washed with saturated
CuSO4 solution (20.0 mL). The organic layer was concen-
trated, and the residue was subjected to silica gel column
(hexane-EtOAc, 9:1) to give 10 (266.0 mg): colorless crystal;
Exp er im en ta l Section
4. To a solution of 1 (40.7 mg) in CH2Cl2 (5.0 mL) was added
MCPBA (80-85%, 30 mg) at 0 °C. After 10 min the reaction
mixture was diluted with saturated NaHCO3 solution (30.0
mL) and CH2Cl2 (30.0 mL). The dichloromethane layer was
concentrated, and the residue was subjected to silica gel
column chromatography (hexane-EtOAc, 7:3) to give 4 (16.0
mg): colorless oil; HREIMS [m/ z 334.2137; ∆ -0.7 mmu (M)+];
1H NMR (CD3OD) δ 10.15 (1H, s), 3.54 (1H, s), 3.26 (1H, d, J
) 12.6 Hz), 3.03 (1H, dd, J ) 5.7, 3.2 Hz), 2.73 (1H, dt, J )
5.0, 12.6 Hz), 2.10-2.20 (3H, m), 1.55-1.94 (6H, m), 1.44-
1.54 (2H, m), 1.39 (3H, s), 1.26-1.43 (2H, m), 1.25 (3H, s), 0.84
(3H, s), 0.82 (3H, d, J ) 6.8 Hz).
1
mp 127 °C; HREIMS [m/ z 440.2554; ∆ -0.8 mmu (M)+]; H
NMR (CD3OD) δ 7.39 (2H, dd, J ) 7.4, 7.6 Hz), 7.25 (1H, t, J
) 7.4 Hz), 7.16 (2H, d, J ) 7.6 Hz), 5.31 (1H, brd, J ) 8.6 Hz),
4.53 (1H, dd, J ) 10.8, 3.4 Hz), 4.29 (1H, dd, J ) 10.8, 10.5
Hz), 3.94 (1H, s), 3.41 (1H, td, J ) 10.5, 3.4 Hz), 2.40-2.54
(2H, m), 1.88-2.12 (7H, m), 1.71 (3H, s), 1.31-1.65 (5H, m),
1.19 (3H, s), 0.90 (3H, d, J ) 6.9 Hz), 0.72 (3H, s). Anal.
(C27H36O5) C, H.
11. To a solution of 10 (46.1 mg) in MeOH (3.0 mL) was
added one drop of 1 N NaOH at room temperature. After 45
min the mixture was concentrated, and the residue was
subjected to silica gel column chromatography (hexane-
EtOAc, 8:2) to give 11 (36.5 mg): colorless oil; HREIMS [m/ z
5. 5 was prepared similarly to the procedure for 4 above.
With 3 (50.0 mg) as starting material and using MCPBA (80-
85%, 40.0 mg) and CH2Cl2 (5.0 mL), 5 (21.3 mg) was ob-
tained: colorless oil; HREIMS [m/ z 336.2314; ∆ +1.3 mmu
1
378.2397; ∆ -0.9 mmu (M)+]; H NMR (CD3OD) δ 5.30 (1H,
brd, J ) 8.4 Hz), 4.36 (1H, dd, J ) 10.7, 3.4 Hz), 4.10 (1H, dd,
J ) 10.7, 10.6 Hz), 3.90 (1H, s), 3.71 (3H, s), 3.33 (1H, dt, J )
3.4, 10.6 Hz), 2.52 (1H, dt, J ) 2.3, 13.7 Hz), 1.85-2.41 (8H,
m), 1.67 (3H, s), 1.23-1.62 (5H, m), 1.17 (3H, s), 0.89 (3H, d,
J ) 6.9 Hz), 0.70 (3H, s).
1
(M)+]; H NMR (CDCl3) δ 4.46 (1H,s), 4.11 (1H, dd, J ) 10.2,
3.2 Hz), 3.47 (1H, dd, J ) 10.2, 10.8 Hz), 2.93-2.95 (1H, m),
2.86 (1H, s), 2.60 (1H, dt, J ) 3.2, 10.8 Hz), 2.35-2.43 (1H,
m), 2.16-2.17 (2H, m), 1.97-2.15 (1H, m), 1.91 (1H, brt, J )
14.1 Hz), 1.59-1.66 (4H, m), 1.47-1.58 (2H, m), 1.42 (3H, s),
1.30-1.40 (3H, m), 1.23 (3H, s), 0.81 (3H, d, J ) 6.8 Hz), 0.65
(3H, s).
12. To a solution of 10 (122.1 mg) in CH2Cl2 (3.0 mL) was
added dimethylamine (100 µL) at -10 °C. After 30 min the
mixture was concentrated, and the residue was subjected to
silica gel column chromatography (hexane-EtOAc, 8:2) to give
12 (107.4 mg): colorless crystal; mp 133 °C; HREIMS [m/ z
6. To a solution of 1 (57.8 mg) in CH3CN-H2O (3:1, 4mL)
was added N-methylmorpholine N-oxide and OsO4 (2% in H2O,

5284 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26
Notes
1
391.2701; ∆ -2.1 mmu (M)+]; H NMR (CD3OD) δ 5.28 (1H,
) 11.6, 4.7 Hz), 2.95 (3H, s), 2.92 (4H, s), 2.60 (1H, ddd, J )
11.0, 4.7, 3.3 Hz), 2.44 (1H, dt, J ) 2.4, 13.8 Hz), 1.76-2.07
(9H, m), 1.54 (6H, s), 1.43-1.48 (1H, m), 1.04-1.32 (3H, m),
0.86 (3H, d, J ) 6.9 Hz), 0.70 (3H, s). Anal. (C23H39O4) C, H,
N.
brd, J ) 6.9 Hz), 4.38 (1H, dd, J ) 10.7, 3.0 Hz), 3.98 (1H, s),
3.98 (1H, t, J ) 10.7 Hz), 3.30 (1H, dt, J ) 3.0, 10.7 Hz), 2.88
(3H, s), 2.80 (3H, s), 2.51 (1H, dt, J ) 2.6, 13.7 Hz), 2.34-2.42
(1H, m), 1.86-2.12 (7H, m), 1.67 (3H, s), 1.50-1.62 (1H, m),
1.47-1.49 (1H, m), 1.28-1.42 (3H, m), 1.17 (3H, s), 0.90 (3H,
d, J ) 6.9 Hz), 0.70 (3H, s). Anal. (C23H37NO4) C, H, N.
13. To a solution of 19 (20.0 mg) in CH2Cl2 (3.0 mL) was
added 4A molecular sieves (500 mg) and PDC (48.2 mg) at
room temperature. After 3 h the solution was filtered, and
the filtrate was subjected to silica gel column (dichloromethane-
acetone, 98:2) to give 13 (29.1 mg): colorless crystal; mp 143
°C; HREIMS [m/ z 387.2426; ∆ +1.7 mmu (M)+]; UV; 1H NMR
(CD3OD) δ 8.41 (1H, d, J ) 1.8 Hz), 6.04 (1H, d, J ) 1.8 Hz),
5.38 (1H, brd, J ) 7.9 Hz), 4.64 (1H, dd, J ) 10.1, 3.2 Hz),
4.14 (1H, t, J ) 10.1 Hz), 4.06 (1H, s), 3.54 (1H, dt, J ) 3.2,
10.1 Hz), 2.58 (1H, dt, J ) 2.6, 13.8 Hz), 2.44-2.53 (1H, m),
1.93-2.17 (7H, m), 1.70 (3H, s), 1.26-1.68 (5H, m), 1.23 (3H,
s), 0.94 (3H, d, J ) 6.9 Hz), 0.77 (3H, s). Anal. (C23H33NO4)
C, H, N.
19. To a solution of 14 (60.0 mg), 3-hydroxyisoxazole (79.5
mg), and triphenylphosphine (244.2 mg) was added DEAE (146
µL) at room temperature. After 2.0 h solvent was removed
by evaporation, and the residue was subjected to silica gel
column (hexane-EtOAc, 7:3) to give 19 (50.0 mg): colorless
crystal; mp 178 °C; HRFABMS [m/ z 390.1654 ∆ +0.9 mmu
(M + H)+]; 1H NMR (CD3OD) δ 8.41 (1H, d, J ) 1.8 Hz), 6.16
(1H, d, J ) 1.8 Hz), 5.21 (1H, brd, J ) 9.3 Hz), 4.56 (1H, dd,
J ) 4.6, 2.5 Hz), 4.43 (1H, dd, J ) 11.0, 3.6 Hz), 4.29 (1H, dd,
J ) 11.0, 4.3 Hz), 2.99 (1H, d, J ) 2.5 Hz), 2.75 (1H, ddd, J )
11.7, 4.3, 3.6 Hz), 2.48 (1H, dt, J ) 2.6, 13.5 Hz), 1.84-2.22
(9H, m), 1.59 (3H, s), 1.58 (3H, s), 1.48-1.53 (1H, m), 1.09-
1.40 (3H, m), 0.90 (3H, d, J ) 6.9 Hz), 0.74 (3H, s). Anal.
(C23H35NO4) C, H, N.
14. To a solution of 3 (50.0 mg) in dry EtOH (5.0 mL) was
added NaBH4 (20.0 mg) at room temperature. After 3 h the
solvent was removed by evaporation, and the residue was
subjected to silica gel to give 14 (45.5 mg): colorless crystal;
mp 112-113 °C; HREIMS [m/ z 322.2488; ∆ -2.0 mmu (M)+];
1H NMR (CD3OD) δ 5.13 (1H, brd, J ) 9.0 Hz), 4.70 (1H, dd,
J ) 4.7, 2.5 Hz), 3.76 (1H, dd, J ) 11.5, 4.1 Hz), 3.67 (1H, dd,
J ) 11.5, 3.7 Hz), 2.96 (1H, d, J ) 2.5 Hz), 2.41 (1H, dt, J )
2.6, 13.5 Hz), 2.28 (1H, ddd, J ) 11.7, 4.1, 3.7 Hz), 1.78-2.12
(9H, m), 1.57 (3H, s), 1.54 (3H, s), 1.40-1.45 (1H, m), 0.87-
1.27 (3H, m), 0.84 (3H, d, J ) 6.9 Hz), 0.70 (3H, s). Anal.
(C20H34O3) C, H.
15. 15 was prepared similarly to the procedure for 14 above.
With 8 (62.4 mg) as starting material and using NaBH4 (30.0
mg) and EtOH (5.0 mL), 15 (59.4 mg) was obtained: colorless
crystal; mp 117 °C; HREIMS [m/ z 364.2599; ∆ -1.4 mmu
(M)+]; 1H NMR (CD3OD) δ 5.16 (1H, brd, J ) 9.2 Hz), 4.46
(1H, dd, J ) 4.5, 2.5 Hz), 4.29 (1H, dd, J ) 12.1, 3.8 Hz), 4.10
(1H, dd, J ) 12.1, 4.2 Hz), 2.88 (1H, d, J ) 2.5 Hz), 2.57 (1H,
ddd, J ) 11.4, 4.2, 3.8 Hz), 2.43 (1H, dt, J ) 2.6, 13.6 Hz),
1.73-2.08 (9H, m), 2.05 (3H, s), 1.55 (3H, s), 1.55 (3H, s), 1.43-
1.48 (1H, m), 1.03-1.31 (3H, m), 0.86 (3H, d, J ) 6.9 Hz), 0.68
(3H, s). Anal. (C22H36O4) C, H.
Su p p or tin g In for m a tion Ava ila ble: The data of 13C
NMR, IR, and mass spectra (4 pages). Ordering information
is given on any current masthead page.
Refer en ces
(1) Braquet, P.; Touqui, L.; Shen, T. Y.; Vargaftig, B. B. Perspectives
in platelet-activating factor research. Pharm. Rev. 1987, 39, 97-
145.
(2) (a) Casals-Stenzel, J .; Muacevic, G.; Weber, K.-H. Pharmacologi-
cal Actions of WEB 2086, A new specific antagonist of platelet
activating factor. J . Pharmacol. Exp. Ther. 1987, 241, 974-981.
(b) Takahara, S.; Mikashima, H.; Muramoto, Y.; Terasawa, M.;
Setoguchi, M.; Tahara, T. Pharmacological actions of Y-24180,
a new specific antagonist of platelet activating factor (PAF): II.
Interactions with PAF and benzodiazepine receptors. Prosta-
glandins 1990, 40, 571-583. (c) Tsunoda, H.; Sakuma, Y.;
Harada, K.; Muramoto, K.; Katayama, S.; Horie, T.; Shimomura,
N.; Clark, R.; Miyazawa, S.; Okano, K. Pharmacological activities
of a novel thienodiazepine derivative as a platelet-activating
factor antagonist. Arzneim.-Forsch. 1990, 40, 1201-1205. (d)
Sahoo, S. P.; Graham, D. W.; Acton, J . J .; Bitfu, T.; Bugianes,
R. L.; Girotra, N. N.; Kuo, C.-H.; Ponpipom, M. M.; Doebber, T.
W.; Wu, M. S.; Hwang, S-B.; Lam, M-H.; MacIntyre, D. E.; Bach,
T. J .; Luell, S.; Meurer, R.; Davis, P.; Alberts, A. W. Synthesis
and Biological Activity of MK 287 (L-680,573) a Potent, Specific
and Orally Active PAF Receptor Antagonist. Bioorg. Med. Chem.
Lett. 1991, 1, 327-332.
(3) (a) Sugano, M.; Sato, A.; Oshima, T.; Furuya, K.; Kuwano, H.;
Hata, T.; Hanzawa, H. Phomactin A: A Novel PAF Antagonist
from a Marine Fungus Phoma sp. J . Am. Chem. Soc. 1991, 113,
5463-5464. (b) Sugano, M.; Sato, A.; Iijima, Y.; Furuya, K.;
Haruyama, H.; Yoda, K.; Hata, T. Phomactins, Novel PAF
antagonists from Marine Fungus Phoma sp. J . Org. Chem. 1994,
59, 564-569.
(4) Biftu, T.; Gamble, N. F.; Doebber, T.; Hwang, S.-B.; Shen, T.-
Y.; Snyder, J .; Springer, J . P.; Stevenson, R. Conformation and
Activity of Tetrahydrofuran Lignans and Analogues as Specific
Platelet Activating Factor Antagonists. J . Med. Chem. 1986, 29,
1917-1921.
(5) Sugano, M.; Sato, A.; Iijima, Y.; Furuya, K.; Hata, T.; Kuwano,
H. Phomactin E, F, and G: New Phomactin-Group PAF An-
tagonists from a Marine Fungus Phoma sp. J . Antibiot. 1995,
48, 1188-1190.
(6) Demopoulos, C. A.; Pinckard, R. N.; Hanahan, D. J . Platelet-
Activating Factor; Evidence for 1-O-alkyl-2-acetyl-sn-glyceryl-
3-phoshorylcholine as the Active Component (A New Class of
Lipid Chemical Mediators). J . Biol. Chem. 1979, 254, 9355-
9358.
(7) Hayashi, H.; Kudo, I.; Inoue, K.; Onozaki, K.; Tsushima, S.;
Nomura, H.; Nojima, S. Activation of Gunia Pig Peritoneal
Macrophages by Platelet Activationg Factor (PAF) and Its
Agonists. J . Biochem. 1985, 97, 1737-1745.
(8) Terachi, T.; Toudou, E.; Shimazaki, A.; Oku, T.; Namiki, T. J pn.
Kokai Tokkyo Koho J p. 58-13592.
16. 16 was prepared similarly to the procedure for 14. With
9 (90.8 mg) as starting material and using NaBH4 (30.0 mg)
and EtOH (4.0 mL), 16 (85.8 mg) was obtained: colorless
crystal; mp 118 °C; HREIMS [m/ z 378.2773; ∆ +0.3 mmu
(M)+]; 1H NMR (CD3OD) δ 5.16 (1H, brd, J ) 8.3 Hz), 4.46
(1H, dd, J ) 4.4, 2.4 Hz), 4.31 (1H, dd, J ) 12.1, 3.6 Hz), 4.09
(1H, dd, J ) 12.1, 4.5 Hz), 2.90 (1H, d, J ) 2.4 Hz), 2.59 (1H,
ddd, J ) 11.4, 3.6, 4.5 Hz), 2.40-2.57 (1H, m), 2.36 (2H, q, J
) 7.6 Hz), 1.74-2.06 (9H, m), 1.55 (3H, s), 1.54 (3H, s), 1.43-
1.48 (1H, m), 1.03-1.32 (3H, m), 1.14 (3H, t, J ) 7.6 Hz), 0.86
(3H, d, J ) 6.9 Hz), 0.69 (3H, s). Anal. (C23H38O4) C, H.
17. To a solution of 4 (130.0 mg) and pyridine (200 µL) in
CH2Cl2 (10.0 mL) was added phenyl chloroformate (60.7 µL)
at room temperature. After 30 min the reaction mixture was
diluted with EtOAc (20.0 mL) and washed with CuSO4 solution
(20.0 mL). The organic layer was concentrated to give an oil
(137.1 mg). To a solution of this oil (52.0 mg) in MeOH (3.0
mL) was added 1 drop of NaOH at room temperature. After
3 h the mixture was concentrated, and the residue was
subjected to silica gel column chromatography (hexane-
EtOAc, 8:2) to give 17 (45.8 mg): colorless oil; HREIMS [m/ z
1
380.2589; ∆ +2.7 mmu (M)+]; H NMR (CD3OD) δ 5.13 (1H,
brd, J ) 9.2 Hz), 4.45-4.81 (1H, m), 4.32 (1H, dd, J ) 11.6,
3.9 Hz), 4.16 (1H, dd, J ) 11.6, 4.1 Hz), 3.72 (3H, s), 2.82 (1H,
d, J ) 2.5 Hz), 2.53 (1H, ddd, J ) 11.4, 4.1, 3.9 Hz), 2.40 (1H,
dt, J ) 2.7, 13.5 Hz), 1.71-2.04 (9H, m), 1.51 (3H, s), 1.51
(3H, s), 1.40-1.45 (1H, m), 1.01-1.29 (3H, m), 0.83 (3H, d, J
) 6.7 Hz), 0.65 (3H, s).
(9) Nakamura, N.; Miyazaki, H.; Ohkawa, N.; Oshima, T.; Koike,
H. An Efficient Synthesis of Platelet-Activating Factor (PAF)
via 1-O-Alkyl-2-O-(3-isoxazolyl)-sn-glycero-3-phosphocholine, A
New PAF Agonist. Utilization of the 3-Isoxazolyloxy Group as a
Protected Hydroxyl. Tetrahedron Lett. 1990, 31, 699-702.
18. 18 was prepared similarly to the procedure for 14. With
12 (44.0 mg) as starting material and using NaBH4 (20.0 mg)
and EtOH (4.0 mL), 18 (35.6 mg) was obtained: colorless
crystal; mp 126-127 °C; HREIMS [m/ z 393.2887; ∆ +0.8 mmu
1
(M)+]; H NMR (CD3OD) δ 5.15 (1H, brd, J ) 9.3 Hz), 4.52-
4.96 (1H, m), 4.34 (1H, dd, J ) 11.6, 3.3 Hz), 4.05 (1H, dd, J
J M950640Q