Abstract:
A PGE1 analog, namely (±)-trans-2-(6'-carbomethoxyhexyl)-3-
(E-3"-thia-1 "-octene)-4-hydroxycyclopentanone 71, has been
prepared for the first time. Towards the synthesis of this compound,
several synthetic approaches aimed at the preparation of the
required acetylenic and E-halovinylic sulfides as building blocks
were investigated.
Among all the methods examined, it appeared evident that the
best route to ethynyl n.pentyl sulfide 81 is via a double
dehydrohalogenation of the corresponding 1,2-dibromoethyl sulfide
with sodium amide in liquid ammonia. In addition, the isomerically
pure E-2-iodoethenyl n.pentyl sulfide 85 is conveniently prepared in
high yield and stereoselectivity by hydrozirconation-iodination of
the terminal ethynyl sulfide 81. The classical hydroalumination and
hydroboration reactions for the preparation of vinyl halides from
alkynes gave only small yields when applied as methods towards the
synthesis of 85 .
The building block 2-(6'-carbomethoxyhexyl)-4-hydroxy-2-
cyclopentenone (±)-1 carrying the upper side-chain of prostaglandin
E 1 was prepared by a step-wise synthesis involving transformations
of compounds possessing the required carbocyclic framework (see
scheme 27). The synthesis proved to be convenient and gave a good
overall yield of (±)-1 which was protected as the TH P-derivative 37
or the siloxy derivative 38.
With the required building blocks 81 and 37 in hand, the target
1S-thia-PGE1 analog (±)-71 was prepared via the in situ higher cuprate formation-conjugate addition reaction. This method proved
to be convenient and stereospecific. The standard cuprate method,
involving an organocuprate reagent generated from an isolated vinyl
iodide, did not work well in our case and gave a complicated mixture
of products.
The target compound will be submitted for assessment of
bio log ical activity.
