Organic Chemistry of Drug Synthesis. Volume 7

bromine by the basic nitrogen on the eneamine; conjugate addition of the
active methylene group to the quinone then closes the ring to afford the
observed product ( 131 ). Treatment with DDQ next oxidizes the exocyclic
methoxymethylene group to the corresponding aldehyde ( 132 ).
Condensation of this product with the phosphorane from Emmon’s
reagent results in the homologated product 133 ; the added salt assures
the trans configuration of the newly introduced double bond. In the next
step, reduction with DIBAL converts both esters to the corresponding
alcohols ( 134 ). Reaction of this last intermediate with aziridine results in
displacement (or again, addition–elimination) of the ring methoxy
group. Thus, the antitumor agent 135 is obtained.^18
In yet another illustration of the breadth of the SAR of estrogen
antagonists, the carbonyl group in the estrogen antagonist raloxifene
can be replaced by ether oxygen. Reaction of the benzothiophene
( 136 ) with bromine leads to the derivative ( 136 ) halogenated at the
3 position ( 137 ). The ring sulfur atom is next oxidized with hydrogen
peroxide in order to activate that bromine toward displacement ( 138 ).
Reaction of this intermediate with the anion from treatment of the
phenol ( 139 ) with sodium hydride displaces bromine, and in a single
step introduces the ring that carries the requite basic ether. The sulfox-
ide function is next reduced to the sulfide oxidation state by means of
lithium aluminum hydride ( 140 ). Scission of the methyl ethers with
boron tribromide completes the synthesis of the estrogen antagonist
arzoxifene( 141 ).^19

CH 3 O S

OCH 3

136

Br

CH 3 O S

OCH 3

137

Br

H 2 O 2

CH 3 O

OCH 3

OCH 3

Br

SO

138

N O OH

139

NaH

CH 3 O

O

S

O

N O

140

1. LiAlH 4

HO OH 2. BBr^3

O

S

N O

141

1. COMPOUNDS WITH ONE HETEROATOM 155