19-Nortestosterone synthesis

The method was applied to the synthesis of (-t-)-l9-nortestosterone by the following sequence of reactions. Michael addition of the bisannulation reagent 124 to the optically active keto ester 129 and decarboxylation afforded 130, and subsequent aldol condensation gave 131. Selective Pd-catalyzed oxidation of the terminal double bond afforded the diketone 132 in 78% yield. Reduction of the double bond and aldol condensation gave ( + )-19-nortestosterone (133)[114]. 

The Roussel group has described recently a novel method for the synthesis of 2,2-dimethyl-A" -3-keto steroids. Thus addition of potassium t-butoxide to a solution of 19-nortestosterone (25) in tetrahydrofuran containing methyl iodide and hexamethylphosphorous triamide at —70° affords the 2,2-dimethyl compound (26) in good yield.Methylation of A" -3-ketone by the classical conditions, namely addition of methyl iodide to a solution of the steroid and potassium /-butoxide, leads to the 4,4-dimethyl product. 

The A -double bond can also be introduced in saturated A-nor-2-ketones by bromination-dehydrobromination. This has been used in an alternate preparation of A-norprogesterone" and in a recent synthesis of A-nor-19-nortestosterone. ... 

For internal olefins, the Wacker oxidation is sometimes surprisingly regioselective. By using aqueous dioxane or THF, oxidation of P,y-unsaturated esters can be achieved selectively to generate y-keto-esters (Eq. 3.18).86 Under appropriate conditions, Wacker oxidation can be used very efficiently in transforming an olefin to a carbonyl compound. Thus, olefins become masked ketones. An example is its application in the synthesis of (+)-19-nortestosterone (3.11) carried out by Tsuji (Scheme 3.5).87... 

The synthesis of ( f)-19-nortestosterone (73) was carried out starting from the optically active keto ester (72 equation 13). 

The reagent 1 also reacts with stabilized carbanions, as in the synthesis of ( + )-19-nortestosterone (8) from optically active 5. 

Similar treatment of the oxime (133b) with benzenesulphonyl chloride in the presence of potassium hydroxide furnished the methylbenzisoxazole (139). Several reports on the synthesis of new analogues of 19-nortestosterone have appeared. The 6a- and 6j8-methyl derivatives have been prepared by a classical alkylation reaction via the 5a,6a-epoxide. ... 

Synthesis of NCA 17ci[2-(E)-[ l]-iodovinyf -19-nortestosterone This I-labelled steroid hormone VNNT), 212, needed for human breast... 

The research team of D.F. Covey developed a synthetic route to convert 5p-methyl-3-ketosteroids into 7(S)-methyl substituted analogues of neuroactive benz[e]indenes. The synthesis began with 19-nortestosterone, in which the a,p-unsaturated cyclic ketone moiety was degraded to afford a tricyclic aldehyde. This aldehyde was unstable and could not be stored. For this reason it was immediately subjected to the Tsuji-Wllkinson decarbonylation to afford the decarbonylated product in high yield. 

The important intermediate 66 of the steroid synthesis has been prepared by the application of the same reaction sequence to 2-methyl-1,3-cyclohexanedione (65) (Scheme 22). A synthesis of (+) 19-nortestosterone (69) starts with the Michael addition of the optically active oxo ester 67 to 1,7-octadien-3-one (59) catalyzed by sodium hydride, the ester group being removed by heating in aqueous HMPA with sodium iodide to give the dione 68. The aldol condensation catalyzed by sodium hydroxide proceeds in 90% yield. The terminal double bond is oxidized with PdCl2/CuCl to the methyl ketone and the internal olefinic double bond subsequently hydrogenated. The final reaction step involves aldol condensation in refluxing... 

In a similar fashion, it is evident that the estrogen screen described above, could be modified to include enzymes required for the synthesis or degradation of estradiol. An alternative therapeutic objective for estradiol inhibition might be to prevent its synthesis. Thus, a yeast strain already built to be sensitive to estradiol could be supplied instead with the precursor to estradiol, 19-nortestosterone, and the enzyme, aromatase, required for its conversion to estradiol. An inhibitor of the enzyme would, therefore, lead to the inability to synthesize estradiol and the loss of production of 3-galactosidase. 

Full details have now appeared of two total syntheses of optically active 8a- and 8a,10a,19-nortestosterone. Application of a Roussel-type synthesis by... 

The most recent step in the study of 19-nortestosterone has been introduction of the series of 19-nor-7a-methylsteroids (31), which have substantially increased androgenic and anabolic properties. Introduction of the 7a-methyl group in the 19-nor series entailed some difficulties, but these were overcome in the synthesis as outlined, and this has made available an entire series of these compounds (9). 

The total synthesis of the highly progestationally active 6,6-difluoro-18-homo-17a-ethynyl-19-nortestosterone (85) has been reported. The approach of the Russian school was used/ appropriately modified in order to introduce the 18-ethyl group. The gern-difluoro-moiety was prepared from the 5a-fluoro-6-ketone (84) by a procedure described previously. 

Yoshioka K, et al. Studies on antiandrogenic agents. Synthesis of 16p-ethyl-19-nortestosterone. Chem Pharm Bull (Tokyo) 1975 23 3203-3207. 

Although ethisterone never attained greater medicinal importance, this compound provided the crucial hint, which led to the synthesis of norethister-one. Carl Djerassi (Fig. 6.16) at Syntex oxidised 19-nortestosterone with chromium trioxide to 19-norandrostene-3,17-dione. Treatment with triethyl orthoformate in presence of pyridinium chloride gave an enol ether, which was reacted with acetylene and potassium t-amyloxide, and could subsequently undergo acid hydrolysis to the desired product. [38]... 

Rearrangements of cyclopropanes. Cyclopropanes are interesting not only by themselves, but also because they are easily converted into important synthons in organic chemistry. Recently, rearrangements of cyclopropanes have appeared in the synthesis of, namely, steroids (pregn-4-en-one) [58], 19-norsteroids (estrone, 19-norandrost-4-en-3-17-dione, estradiol-17,8)and 19-nortestosterone [59], insect juvenile hormone analogs [60]. 

Tsuji and co-workers completed a total synthesis of (+)-19-nortestosterone by using a key intermediate prepared using the Hajos-Wiechert reaction of 40 with stoichiometric (S)-phenylalanine following the Wiechert protocol. This approach was the best among approximately twenty conditions that were tried the resulting product 41 was oxidized to the known crystalline compound 42 to determine that the Hajos-Wiechert reaction occurred in 76% ee. A series of alkylation and annulation reactions was used to convert 42 into (+)-19-nortestosterone (43). 

Norbiotinyl p-nitrophenyl ester, 615 Norepinephrine, 336, 591, 592 Norelevorphanol, synthesis of, 605 19-Nortestosterone, 476 19-Nortestosterone acetate, 89, 476-478 Nuclear-cytoplasmic interactions, 644 Nucleases, 175, 368-362... 

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