of this aldehyde with the ylide from the difluorinated phosphonate 14 leads
to the addition product 15. The double bond in thef olefin has the expected
trans geometry though the next step, hydrogenation, makes this point moot.
Sodium borohydride then reduces the side-chain ketone function to give 17
as a mixture of isomers. The lactone is then reduced to the key lactol in the
usual fashion by means of diisobutyl aluminum hydride. This compound
is then condensed with the ylide obtained from reaction of the zwitterion
4-triphenylphosphoniumbutyrate to give the chain-extended olefin ( 19 ).
The carboxylic acid in this intermediate is next protected as the benzyl
ester by alkylation of its salt with benzyl chloride. Oxidation of the ring
alcohol by means of chromium trioxide followed by exposure to mild
acid to remove the tetrahydropyranyl group establishes the keto–alcohol
PGE-like function in the five-membered ring ( 21 ). Catalytic hydrogenation
of this last intermediate at the same time reduces the remaining double
bond and removes the benzyl protecting group on the acid to give the
open-chain version ( 22 ) of the product. The electron-withdrawing power
of the fluorine atoms adjacent to the side-chain ketone cause the carbonyl
carbon to become a reasonable electrophile. The electron-rich oxygen on
the ring alcohol thus adds to this to give a cyclic hemiacetal. This form
( 23 ), greatly predominates in product 23.^5
B. Antiviral Agents
The enzyme neuraminidase plays a key role in the replication of influenza
viruses. Newly formed virions form blister-like buds on the inside of the
host cell membrane. This proteolytic enzyme, known as sialidase, facili-
tates scission of the base of the bud and thus release of the new virion.
Research on structurally modified neuraminidase congeners culminated
in the development of a derivative that blocked the action of the
enzyme. This complex dihydropyran, zanamivir ( 24 ), was found to be
effective against influenza viruses and most notably avian influenza A
(H5N1), better known as bird flu. The lengthy complex route to that
drug encouraged the search for alternative structures that would fit the
same site. Two more easily accessible agents based on carbocyclic rings
that have the same activity as the natural product based drugs have been
identified to date.
There has been much recent anxious speculation that the bird flu virus
will mutate to a form that will spread from person to person. A worldwide
influenza epidemic, at worst comparable to that which followed the Great
War, could well be the net result of such an event. The efficacy of the first
carbocyclic neuraminidase inhibitor,oseltamivir( 34 ), known familiarly
- MONOCYCLIC COMPOUNDS 25