B. Imidazoles and a Pyrrazole
By now, it is well established that “conazole” antifungal agents attack
fungi by inhibiting the synthesis of steroids essential to the fungal life
cycle. Virtually every antifungal agent in this class incorporates an imida-
zole ring into its structure. This moiety is thus, not surprisingly, found in
the form of an enamine in a recent conazole. The starting material for this
agent ( 83 ), could, for example, be prepared by bromination of the propio-
phenone ( 81 ) followed by displacement of halogen with imidazole.
Alkylation of the enolate from the ketone with the side-chain fragment
( 84 ), yields the antifungal agentsomoconazole( 85 ).^14
RClClONNHNNClClO81 ; R = H
82 ; R = Br 83Br O
Cl
84
NaHNNClClOOCl85Histamine H 3 receptors have been found to modulate the release of neuro-
transmitters, such as acetyl choline, dopamine, and serotonin, involved in
alertness and cognitive function. Compounds that act as antagonists at
those sites favor release of those neurotransmitters and result in increased
alertness in animal models. Antagonists would hold promise for treatment
of attention deficit syndrome and related conditions including even poss-
ibly Alzheimer’s disease. The first step in the synthesis toward the antag-
onistcipralisant ( 92 ) comprises separation of the enantiomers of the
carboxylic acid 86. To this end, the acid is reacted with a chiral sultam
derived from camphor. The resulting diastereomers ( 87 ) are then separated
by chromatography. Each of the diastereomerically pure derivatives, only
one of which is shown, is then treated in the cold with DIBAL-H to
afford the corresponding aldehyde ( 88 ). Reaction with the anion from
C-trimethylsilyl diazomethane gives the acetylene ( 89 ) in a single step.
The chain is then extended by reaction of the acetylide anion with the tri-
flate derivative from 3,3-dimethylbutanol. Exposure to strong acid serves to
remove the triphenylmethyl protecting group on nitrogen. This last step
affords 92.^15 The absolute stereochemistry was derived from X-ray struc-
ture determination of one isomer of the sultam ( 87 ).
94 FIVE-MEMBERED HETEROCYCLES