bromide proceeds to the allyl ether ( 24 ). Heating compound 24 leads to a
Claisen rearrangement to theC-allyl derivative ( 25 ); bromine at the other
ortho position prevents formation of the alternate undesired isomer. Ozoniza-
tion followed by reductive workup leads to 26 ; treatment of the aldehyde
with sodium borohydride reduces that function to an alcohol providing
27. The blocking bromine atom is then replaced by hydrogen by means of
hydrogenation over palladium to yield 27. Construction of the furan ring
starts by conversion of the primary alcohol to its mesylate with methane-
sulfonyl chloride. Treatment of the product with triethylamine (TEA)
forms the phenoxide, which then displaces the mesylate group. This internal
displacement forms the furan ring. Thus, ramelteon ( 29 ) is obtained.^5
2. NAPHTHALENES
The parathyroid glands comprise one of the principal centers for regulation
of calcium levels. The parathyroid hormone secreted by those glands into
the bloodstream directly controls levels of calcium and phosphorus. In the
normal course of events, low levels of calcium will result in release of the
hormone and vice versa. Patients with kidney disease who are on dialysis, as
well as those with parathyroid gland neoplasms, tend to have significantly
elevated calcium levels, a condition that can lead to hypertension and conges-
tive heart failure. A structurally relativelysimple naphthalene derivative lowers
parathyroid levels by binding to calcium receptors on the gland. Reaction of
commercially available (R)-ethyl-a-naphthyl amine ( 31 ) with the aldehyde
( 32 ) affords the Schiff base ( 33 ). Reduction of intermediate 33 with cyano-
borohydride leads to the calcium mimetic compoundcinalcet( 34 ).^6
NH 231+O=HCCF 3
32CF 333 34NaCNBH 3NCF 3
HNIt is now recognized that protein kinases play an important role in intra-
and intercellular communications. These enzymes are consequently
directly involved in cell proliferation. The p38 kinase, for example, regu-
lates the production of key inflammatory mediators. Excess expression
of this factor is involved in the pathology of rheumatoid arthritis, psoriasis,
and Crohn’s disease. A rather complex protein kinase inhibitor, which
- NAPHTHALENES 73