CO 2 H62CO 2 CH 3
63- LiAlH 4
2. MnO 2 CH=O
64
CO 2 C 2 H 5(C 2 H 5 O) 2 PO66 ; R = C 2 H 5
67 ; R = HCO 2 R65
NaH2. POLYCYCLIC COMPOUNDS: STEROIDS
The first five volumes in this series each feature a separate chapter that
bears the title Steroids. The steady diminution of research on this structural
class is illustrated by the regularly decreasing extent of those chapters. By
the time Volume 6 appeared, the discussion of steroid-based drugs takes up
but a section in the chapter on Carbocyclic Compounds. The relatively
small amount of research devoted to this area is reflected in the present
volume as well. The compounds that follow are organized by structural
class as they each display quite different biological activities from one
another.
A. 19-Nor Steroids
Virtually all known antiestrogens comprise non-steroidal compounds
based more or less closely on triphenyl ethylene (see ospemifene,
Chapter 3). Tamoxifen ranks as the success story in this class of drugs
having found widespread use in the treatment of women suffering from
estrogen receptor positive breast cancer. It is thus notable that a derivative
of estradiol itself, which carries a very unusual substituent, also acts as an
estrogen antagonist. Unlike its non-steroid forerunners, all of which show
some measure of agonist activity, this agent is devoid of any estrogenic
activity. Conjugate 1,4 addition of the Grignard reagent from long-chain
bromide 69 to the dienone 68 affords the 7-alkylated product 70 as a
mixture of epimers at the new linkage. The 7-aisomer is separated from
the mixture before proceeding; the hydroxyl group at the end of the long
chain is then unmasked by hydrolytic removal of the silyl protecting
group. Reaction with cupric bromide serves to aromatize ring A; saponifi-
cation with mild base preferentially removes the less sterically hindered
acetate at the end of the long chain. Acylation by means of benzoyl
chloride converts the phenol to the corresponding ester 72.^13 The synthetic
- POLYCYCLIC COMPOUNDS: STEROIDS 31