Nor Steroids

A simple sequence for the preparation of 18-nor steroids which may be related to the biosynthesis of fukujusonorone, the first isolated naturally occurring 

18-nor steroid, has been described The synthesis d starts with the 3-acetate of (329 R = 0,R = Me) readily prepared from hecogenin, which with iodine and lead tetra-acetate affords the lactone (330). Decarboxylation by treatment with base (the lactone was stable to acid) then gave the c/o-trans-18-nor-12-ketone (329 R = O, = H) as sole product This, and also the subsequent Wolff-Kishner reduction to the 12-desoxy-compound (329 R = Hj, = H) which left the c/d ring junction unaffected, is in contrast to 18-nor-l7-ketones which equilibrate with base. 

Unlike 12)S-sulphonyloxy-derivatives of conanine which afford rearranged c-nor-D-homosteroids, the 12a-epimers undergo reductive fragmentation d with dichloroaluminium hydride to give the 18-nor-l2-ene (331). 

The purified isomer (84) is currently used in the clinic as a treatment for endometriosis, as well as other conditions related to excess progesterone stimulation. 

Topically applied corticosteroids have proven very effective in treating asthma. The amount of drug from the inhaled dose that reaches the small airways has a critical effect on relieving asthmatic episodes. The acetal at positions 16,17 of the diol (97) with acetone,desonide, has 

Reduction of this intermediate by hydrogen transfer from 1,4-cyclohexa-diene in the presence of platinum leads to loss of the carbobenzoxy group and formation of the transient primary amine 119. The terminal primary amino group in that product then participates in a second addition-elimination sequence to form an eight-membered ring (120). Treatment of this intermediate with trimethylsilyl bromide then cleaves the ethyl ethers on phosphorus to give the free phosphonic acid and thus perzinfotel (121).  

Lednicer, The Organic Chemistry of Drug Synthesis, Vol. 6, John Wiley Sons, Inc., NY 1999, p. 98. 

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The Simmons-Smith reaction has been used to great advantage in the conversion of 19-nor steroids to the naturally occurring 10)5-methyl steroids as well as the unnatural lOa-methyl steroids. Thus methylenation of androst-5(10)-ene-3a,17 -diol (9) proceeds in an autoclave at elevated temperatures with stereospecific a-face addition to give the 5a,10a-methylene compound (10) in 85% yield. 

Elaboration of a commercially viable route for total synthesis of 19-nor steroids led to the introduction of the totally synthetic product norgestrel (71) as the progestational component of an oral contraceptive. As was observed in the "natural" 19-nor-compounds, reduction of the 17-ethynyl group to 17-ethyl affords compounds with androgenic/anabolic... 

The clinical success of the progestational gonanes engendered a corresponding effort toward finding potent orally active androgens in the 19-nor steroid series. The... 

The chemical steps involved in this synthetic scheme are somewhat similar to the ones described in a previous synthesis of 19-nor steroids.9... 

The figures in parentheses indicate the ratio of the rate for 19-nor steroid to that for the corresponding... 

Schubert, G., Schbnecker, B.. Wunderwald, M.. and Ponsold, K.. Synthesis of 17P-configurated acrylic acid derivatives of 19-nor steroids, Pharmazie. 41, 469, 1986. 

A carbonyl transposition based on enamine hydroboration has been described by Gore and coworkers . The same reaction attempted on enamines of 5a-3-keto-steroids resulted in an unusual reactivity of diborane, leading to reduction of the enamine double bond. The 3 a-derivative prevailed over the 3jS-derivative as a consequence of the presence of the 19-methyl group, as demonstrated successively for the 19-nor-steroids (Scheme 117). 

Garda, C.R., Pincus, G. and Rock, J. (1958) Effects of three 19-nor steroids on human ovulation and menstruation. American Journal of Obstetrics and Gynecology, 75, 82—97. 

D-homosteroid (15) in 24% yield together with some of a double-bond isomer. Ozonolysis to a triketoaldehyde followed by acid cyclization gave the 19-nor-steroid. 

Other elimination reactions reported include the formation of the l(10),5-diene from a 5,6-dibromo-19-nor-steroid, and also from a 6j -methoxyoestr-5(10)-... 

The stereochemistry of hydrogenation of the 19-nor-steroidal 4,9-dien-3-one system (212) depends upon substitution at C-17. 17a-Substituents lead to major... 

Catalytic hydrogenation of the 1-methyl-11-oxo-oestrogen derivative (222) gave the fully-reduced l/3-methyl-5a,10a-19-nor-steroid (223), which, because of its 11-oxo-group, could be isomerised by base with inversion at C-9, to afford the novel l)S-methyl retro structure (224). ... 

Methylation of the ethyleneketal of 11-oxo-oestrone methyl ether with methyl magnesium bromide gives the 1 la-methyl compound which has been further transformed into the 11 -methyl-19-nor steroids (356 = O, R = H) and... 

Functionalisation of both 4a- and 4j -methyl groups in 10-methyl and 19-nor steroids has been achieved by photolysis of the 6a- or 6)S-nitrites (602) or (603). 

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