Design And Synthesis Of Ring D Modified Steroidal Hormones

Abstract

Cycloadditions of steroidal 14,16-dienes with ketene equivalents were investigated,

as routes to estradiol and estriol analogues. The cycloadduct of 3-methoxyestra-

1,3,5(10), 14,16-pentaen-17-yl acetate and 2-chloroacrylonitrile underwent an

unprecedented tandem rearrangement, on attempted alkaline hydrolysis to the

corresponding ketone. This product, obtained in ca. 90% yield, was formulated as

(161R)-3-methoxy-17-oxo-158,161-cyclo-14,168-ethano-148-estra-1,3,5(10)-triene-16L

carbonitrile. The chemistry of the 16Lcarbonitrile was extensively studied and, in

addition, the derived estradiol analogues were prepared and evaluated for receptorbinding

affinity. The 161-carbonitrile, and its derivatives, could be transformed into

14,15-dihydrocyclobutano or 148,168-bridged compounds by cleavage of a cyclopropyl

bond. Indeed, a 14,15-dihydrocyclobutano estradiol analogue was synthesised and

submitted for biological evaluation.

The cycloadduct of 3-methoxyestra-1,3,5(10),14,16-pentaen-17-yl acetate and 2-

acetoxyacrylonitrile afforded the corresponding 17-hydroxy 16-oxo compound on

alkaline hydrolysis. The 17-hydroxy 16-oxo compound was efficiently converted to the

14a,17a-ethano 15,16-etheno compound by the Shapiro reaction. Reduction of the 17-

hydroxy 16-oxo compound led to the formation of the corresponding 16,17-diols, which

gave the derived 148-compounds on glycol cleavage. Furthermore, under acidic

conditions the 16,17-diols were found to undergo high yield 16(17 -+ l 71)abeo

rearrangements, to afford 14,16-etheno compounds.

Read Download