Estradiol-3-methyl ether synthesis from

Catalytic hydrogenation of the 14—15 double bond from the face opposite to the C18 substituent yields (196). Compound (196) contains the natural steroid stereochemistry around the D-ring. A metal-ammonia reduction of (196) forms the most stable product (197) thermodynamically. When R is equal to methyl, this process comprises an efficient total synthesis of estradiol methyl ester. Birch reduction of the A-ring of (197) followed by acid hydrolysis of the resultant enol ether allows access into the 19-norsteroids (198) (204). 

An enantioselective synthesis of (+)-estradiol has been accomplished from 1,3-dihy-drobenzo[c]thiophene 2,2-dioxide (306) by successive thermal S02-extrusion and cycloaddition (80HCA1703). Treatment of the optically active iodide (307) with two mole equivalents of the masked quinodimethane (306) in the presence of two mole equivalents of sodium hydride gave (308) as a 1 1 mixture of diastereoisomers. Thermolysis of this alkenic sulfone in 1,2,4-trichlorobenzene furnished the trans-anti-trans steroid (309) in 80% yield. Treatment of (309) with methyllithium gave the methyl ketone, which was subjected to a Baeyer-Villiger oxidation and then silyl ether-acetate cleavage to afford (-l-)-estradiol (310 Scheme 66). 

The Birch reduction of the methyl ether of rfZ-estradiol (407) has permitted the preparation of 19-nortestosterone (406), also synthesized independently from the -dehydro derivative (404). In the second case, however, the reduction of the A )-bond takes place nonselectively and with the (406) is formed its 9j8, lOa-isomer, amounting to about l/3 of the mixture of products. The third variant of the synthesis, from the A ( )-ketone (403), proved to be the most suitable, enabling (406) to be obtained in a single stage with an over-all yield of 55% [95, 489, 496]. Passage to derivatives of 19-norandrostane has also been effected by the Birch reduction of the ketals (393) and (401) [95,496] of the 17o -alkyl derivatives obtained from the ketone (403) and its 13-alkyl homologs [442, 488, 503, 504, 518-520] and also of the methyl ether of 8-isoestrone (368) and its 17 -dihydro and 13-alkyl derivatives. J... 

---