CHCOCOC 5 H 11 Na furnishing alkene 64. Under Luche’s conditions, 64 is reduced
into a mixture of allylic alcohols that are then converted into their silyl ethers.
Methanolysis of the acetate liberates an alcohol that is oxidized (Collins) into
aldehyde 65. On treatment with MeONa in MeOH 65 epimerizes its endocarbaldehyde moiety into the more stable exo-carbaldehyde. Subsequent homologation by Wittig olefination with Ph 3 P¼CH–OMe and subsequent alkenyl methyl
ether hydrolysis provides 66. Another Wittig olefination of 66, followed by esterification with CH 2 N 2 , then desilylation, saponification, and chromatographic separation, produces (+)-58 [122] (Scheme 9). Compound (À)-59 has been derived
from exo-anhydride 5 in a similar way.
The prostaglandin analogue (+)-67 was also derived from 5. It is a potent
inhibitor of fatty acid cyclooxygenase [118], the enzyme catalyzing the formation
of PGH 2 from arachidonic acid. Among the numerous 7-oxanorbornane-like prostaglandin analogues made, (+)-68 which incorporates an oxazole carboxamide
moiety was found to be potent, selective, and orally active TXA 2 antagonist with
a long duration of action. In human platelet-rich plasma, (+)-68 inhibits arachidonic
acid-induced aggregation with an IC 50 value of 7 nM [123–128] (for further
analogues incorporating an exo-5,6-epoxy-7-oxanorbornane moiety, see [129])
(Fig. 9).
O
H
H
H
O
OTBS
O
AcO
O
O
AcO
H
NNMe 2
O
HO O
O
HO O
O
O O
O
HOOC
O
H
H OTBS
H
O
N
Me 2 N
60
(i-Bu) 2 AlH
DMAP:
THF
HO
O
COOH
H
H
1)
DMAP, DCC, CH 2 Cl 2
2) LiOH, H 2 O 2 , THF, H 2 O
(+)-62 (ee = 99%)
1) H 2 NNMe 2
2) Ac 2 O, Et 3 N
DMAP
3) H 2 , Pd/C
1) CuCl 2 /THF, H 2 O
2) (MeO) 2 P(O)CH
- COC 5 H 11 Na
+
63
64
1) NaBH 4 ×CeCl 3
2) t-BuMe 2 SiCl
imidazole, DMF
3) Na 3 CO 3 /MeOH
4) CrO 3 ×Py
1) MeONa, MeOH
2) Ph 3 P=CHOMe
3) Hg(OAc) 2 /KI/H 2 O
1) Ph 3 P=CH(CH 2 ) 3 COONa
2) CH 2 N 2
3) HF/MeCN
4) LiOH, H 2 O, THF
5) Separation
65
(+)-58
1) Ac 2 O/Py
2) NaBH 4 /THF
66
75% (from 60)
82% (from 65)
99%
62%
86%
O
COOH
HOOC
(+)-61 _
( + ) - 62
_
Scheme 9 Synthesis of a thromboxane mimetic incorporating a 7-oxabicyclo[2.2.1]heptane
moiety
152
A.J. Moreno-Vargas and P. Vogel
into a mixture of allylic alcohols that are then converted into their silyl ethers.
Methanolysis of the acetate liberates an alcohol that is oxidized (Collins) into
aldehyde 65. On treatment with MeONa in MeOH 65 epimerizes its endocarbaldehyde moiety into the more stable exo-carbaldehyde. Subsequent homologation by Wittig olefination with Ph 3 P¼CH–OMe and subsequent alkenyl methyl
ether hydrolysis provides 66. Another Wittig olefination of 66, followed by esterification with CH 2 N 2 , then desilylation, saponification, and chromatographic separation, produces (+)-58 [122] (Scheme 9). Compound (À)-59 has been derived
from exo-anhydride 5 in a similar way.
The prostaglandin analogue (+)-67 was also derived from 5. It is a potent
inhibitor of fatty acid cyclooxygenase [118], the enzyme catalyzing the formation
of PGH 2 from arachidonic acid. Among the numerous 7-oxanorbornane-like prostaglandin analogues made, (+)-68 which incorporates an oxazole carboxamide
moiety was found to be potent, selective, and orally active TXA 2 antagonist with
a long duration of action. In human platelet-rich plasma, (+)-68 inhibits arachidonic
acid-induced aggregation with an IC 50 value of 7 nM [123–128] (for further
analogues incorporating an exo-5,6-epoxy-7-oxanorbornane moiety, see [129])
(Fig. 9).
O
H
H
H
O
OTBS
O
AcO
O
O
AcO
H
NNMe 2
O
HO O
O
HO O
O
O O
O
HOOC
O
H
H OTBS
H
O
N
Me 2 N
60
(i-Bu) 2 AlH
DMAP:
THF
HO
O
COOH
H
H
1)
DMAP, DCC, CH 2 Cl 2
2) LiOH, H 2 O 2 , THF, H 2 O
(+)-62 (ee = 99%)
1) H 2 NNMe 2
2) Ac 2 O, Et 3 N
DMAP
3) H 2 , Pd/C
1) CuCl 2 /THF, H 2 O
2) (MeO) 2 P(O)CH
- COC 5 H 11 Na
+
63
64
1) NaBH 4 ×CeCl 3
2) t-BuMe 2 SiCl
imidazole, DMF
3) Na 3 CO 3 /MeOH
4) CrO 3 ×Py
1) MeONa, MeOH
2) Ph 3 P=CHOMe
3) Hg(OAc) 2 /KI/H 2 O
1) Ph 3 P=CH(CH 2 ) 3 COONa
2) CH 2 N 2
3) HF/MeCN
4) LiOH, H 2 O, THF
5) Separation
65
(+)-58
1) Ac 2 O/Py
2) NaBH 4 /THF
66
75% (from 60)
82% (from 65)
99%
62%
86%
O
COOH
HOOC
(+)-61 _
( + ) - 62
_
Scheme 9 Synthesis of a thromboxane mimetic incorporating a 7-oxabicyclo[2.2.1]heptane
moiety
152
A.J. Moreno-Vargas and P. Vogel