potassium channels showed early promise as an agent for treating
migraine.^2 Lack of recent references suggest that this activity did not
hold up in the clinic. The synthesis that follows^3 is somewhat conjectural
as it depends on a sketchy description in a patent. Thus stereoselective
epoxidation of the benzopyran ( 10 ), using, for example, Sharpless con-
ditions, affords the chiral oxirane ( 11 ). Ring opening that intermediate
with ammonia or an equivalent would then afford the trans aminoalcohol
( 12 ). Acylation with 3,5-difluoro-benzoyl chloride would give 13 as a
single diastreomer.
OO10OO11OOO12NH 2
OH
OO13NH
OHOF FEvery cell in a living organism incorporates a time clock that marks its
longevity. The cell then dies at the end of its prescribed lifetime. This
process, called apoptosis, is disrupted in cancer cells and results in their
immortality. One of the approaches to treating neoplasms involves restor-
ing this process. The benzopyranalvocidib( 20 ), perhaps better known by
its previous nameflavoperidol, has shown promising activity as an agent
that restores apoptosis. The scheme below is based on that for the com-
pound in which methyl replaces the pendant chlorobenzene ring.^4 The
sequence starts with addition of diborane to the olefin in the tetrahydro-
pyridine ( 14 ), itself available by addition of an organometallic reagent to
N-methyl-4-piperidone followed by dehydration of the tertiary alcohol.
Oxidation of the hydroborane adduct with a peroxide then affords the
hydration product as its cis isomer ( 15 ). The stereochemistry at that
center is then reversed by oxidation to the corresponding ketone followed
by reduction with sodium borohydride ( 16 ). This intermediate is acylated
with acetic anhydride in the presence of boron trifluoride. Use of an excess
of the latter leads to selective demethylation of the ether adjacent to the
newly introduce acyl function ( 17 ). Claisen condensation of this product
with methyl 2-chlorobenzoate gives theb-diketone ( 18 ). Treatment with
acid causes the phenolic oxygen to add to the enone, thus forming the
pyran ring by an addition–elimination sequence ( 19 ). Demethylation of
the remaining phenolic ethers, for example, with boron tribromide,
would then afford 20.^5
- COMPOUNDS WITH ONE HETEROATOM 165