Novel Synthetic Routes To 14,17 Propano And Cyclopenta[14,15] 19-Norsteroids

ABSTRACT

Novel Synthetic Routes to 14(3,17(3-Propano and Cyclopenta[14,15] 19-Norsteroids

Pia Gail Mountford, Chemistry Department, University of Cape Town, Rondebosch 7700,

February 1995

An efficient synthetic strategy for the stereoselective introduction of a 14(3-allyl

group to estrone 3-methyl ether has been developed. The approach involves regio- and

stereoselective Diets-Alder cycloaddition of acrolein to 3-methoxyestra-1,3,5(10),14,16-

pentaen-17-yl acetate. Hydride reduction of the formyl group of the cycloadduct,

followed by tosylation of the resultant primary hydroxy group, gave rise to a 17(3-alkoxy

161-tosylate. Base-mediated Wharton fragmentation of the 1,3-removed diol derivative

produced the 14(3-allyl .! _17-ketone. Chemoselective conjugate reduction of the ring

enone gave rise to 14-allyl-3-methoxy-14(3-estra-1,3,5(10)-trien-17-one in 51% overall

yield for five steps.

Regioselective oxidation of the 14(3-allyl group furnished precursors for

intramolecular coupling reactions with the 17-oxo group, providing access to a series of

14(3,17(3-propanoestradiol and 'estriol' analogues.

Wacker oxidation of the 14-allyl-3-methoxy-14(3-estra-1,3,5(10),15-tetraen-17-

one gave rise to both the 14(3-acetonyl and 14(3-formylethyl derivatives. The acetonyl

enone underwent cerium(III)-mediated aldol condensation with the 17-oxo group to yield

the 14(3,17(3-propano .! -estradiol analogue. This series of (3-face propano bridged

estradiols displayed no competitive binding affinity for the estradiol receptor. The

enolisable 14(3-acetonyl group was also shown to undergo smooth Michael addition to

C(15). The product, 3-methoxy-3'H,l5aH-cyclopenta[14,15]-14f3-estra-1,3,5(1 0)-triene-

4'(5'11),17-dione, was regioselectively deoxygenated and reduced to yield the 3,17-

estradiol analogues. The 3,17(3-estradiol displayed promising binding affinity for the

estradiol receptor site, whereas the 17a-epimer was biologically inactive.

The 14(3-formylethyl enone underwent vinylogous reductive cyclisation with

C(lS), to yield the 3'-hydroxy cyclopenta[14,15] 17-ketone. No regioselective coupling

with the 17-oxo group was observed.

Various attempts to homologate ring D of the 14f3-allyl17-ketone or its .! _

analogue are described, none of which were successful. However, the silyl enol ether

derivative of estrone 3-methyl ether underwent facile cyclopropanation of the .! 16-bond.

Iron(III) chloride-mediated cleavage of the zero bridge of the resultant bicyclo[3.1.0]

hexanoid intermediate gave rise to the D-homo .! 16_17a-ketone. Conversion of the en one

into the derived 14,16-dienyl 17a-ketone furnished an intermediate for conjugate addition

studies.