60CH 3+ClOCCO 2 CH 357AlCl 3
CH 3OCO 2 CH 3
61(C 6 H 5 )PCH 3 +CH 3 CO 2 H CH 3 CO 2 CH 3NaOH63 62The saga of estrogen antagonists had its start in the mid-1960s when
several series of compound related to diethylstilbestrol were investigated
as nonsteroidal antifertility agents. The early work culminated in the devel-
opment of tamoxifen, an estrogen antagonist that was and still is widely
used as adjuvant treatment for breast cancer. The benzothiophene-based
analogue raloxifene, which retains some estrogenic activity, was intro-
duced more recently as a drug for treating osteoporosis. Other more
recent examples will be found scattered throughout this volume. A tetralin
ring forms the nucleus of another recent entry,lasofoxifene( 74 ). One syn-
thesis for the penultimate intermediate starts with the formylation of the
desoxybenzoin ( 64 ) with ethyl formate and sodium ethoxide to its
sodium salt ( 65 ). In a convergent step, the benzyl chloride ( 66 )is
allowed to react with triphenylphosphine to give the corresponding phos-
phonium salt ( 67 ). Reaction of 67 with the salt ( 65 ) leads directly to the
product from coupling with the ylide as a mixture of isomers. This
mixture is then hydrogenated to give the ketone ( 68 ). Treatment of 68
with 3 equiv of aluminum chloride results in scission of the methyl
ether on the most electron-deficient ether to give the phenol ( 69 ). This
compound is then cyclized to the corresponding dihydronaphthalene
with toluenesulfonic acid (TSA). The basic ether side chain required for
antagonist activity is added by alkylation with 2-chloroethyl pyrrolidine
to afford, nafoxidine ( 72 ). Catalytic hydrogenation of this product gives
the tetralin ( 73 ).^11 Reaction of 73 with boron tribromide results in cleavage
of the methyl ether in the fused ring to give ( 74 ).^12
- TETRAHYDRONAPHTHALENES 77