Cycloaddition-fragmentation mediated pathways to ring D modified 19-norsteroids

An efficient strategy for the synthesis of 14β-3'-oxobutyl 19-norsteroids has been developed and the intramolecular reactivity of the derived compounds has been investigated. The approach is based on cycloaddition of methyl vinyl ketone to 3-methoxyestra-1,3,5(10),14,16-pentaen-17-yl acetate which proceeded with a high degree of regio- and stereoselectivity to give 16α-acetyl-3-methoxy-14, 17α-ethenoestra-1 ,3,5(1 O)-trien-17β-yl acetate. The cycloadduct underwent base mediated fragmentation, affording an efficient and stereocontrolled synthesis of 3-methoxy-14β-3'-oxobutylestra-1,3,5(10),15-tetraen-17-one which in turn gave 3-methoxy-5',6'-dihydro-15αH-benzo[14,15]-14β-estra-1,3,5(1O)-trien-4'(3'H), 17-dione via an intramolecular Michael reaction. Regioselective deoxygenation of the dione at C-4', followed by standard functional group modifications provided the parent 14β-perhydrobenzo[14,15]-estradiol analogues. An alternative, more expedient, route to this novel steroidal ring system was developed which relied on an anionic oxy-Cope rearrangement as the key step. Thus methylenation of the cycloadducts derived from reaction of the dienyl acetate and selected dienophiles (acrolein and methyl vinyl ketone) gave after hydrolysis of the bridgehead ester, substrates which underwent [3,3]sigmatropic rearrangement to generate a series of 14β-perhydrobenzo[14,15]-17-ketones.

Grantor dc:publisher.institution

Department of Chemistry

Year dc:date.issued

1997

Author dc:creator

• Sickle, Eugene Stanford

Advisor dc:contributor.advisor

• Bull, James R

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/11427/17967

OAI identifier oai:identifier

oai:open.uct.ac.za:11427/17967