P. S. Jones et al.17
synthesized several racemic
bicyclo[3.2.1]octene derivatives and evaluated as inhibitors of
influenza virus sialidases. The 5-acetamido-bicyclo[3.2.1]octenol (9) showed modest activity against
influenza A and B virus sialidases. The [3.2.1] bicyclic nucleus was
constructed from the readily available ester (7) using an extension of the method of Rodrigues et a1.18 This
method involves a base promoted Michael addition followed by an intramolecular
aldol reaction and is typified by the reaction between methyl-2-oxocyclopentanecarboxylate
and crotonaldehyde.18 In his work, Rodrigues18 used an
aldehyde as the aldol component. Jones investigated that the carbonyl group of
an α-keto-b, γ-unsaturated ester might also
undergo this reaction and at the same time introduce carboxyl functionality.
The required α-keto-b,
γ-unsaturated ester (6) was prepared19
in 29% yield by reaction of 3-pentyl vinyl ether20 with t-butyl oxalyl chloride.21
Reaction of the α-keto-b,
γ-unsaturated ester (6) with methyl
2-oxocyclopentanecarboxylate (6) in
a mixture of N,N-dimethylpropylene
urea and dichloromethane with DBU as base gave the product 8 as a racemic mixture of four diastereoisomers (8a-d) (Scheme 2). Jones et al prepared
compound (9) from 8a in a six step. Compound (9) contains four functional group,
alcoholic, carboxylic, amide and ether. Compound (9) and intermediates were tested inhibitory activity against influenza
A and influenza B.
___________________________________
17. P. S. Jones, P. W. Smith, G. W. Hardy P. D. Howes,
and R. C. Bethell, Bioorg. Med. Chem. Lett., 1999, 9, 605.
18. M. Filippini,
R. Faure, and J. Rodriguez, J. Org. Chem., 1995, 60, 6872.
19. L. F. Tietze,
H. Meier, and E. Voss, Synthesis, 1988, 274
20. E. Taskinen, and J. Hellman, Magn. Reson. Chem., 1994, 353.