Steroids 1,5-diketone cyclization

Danishefsky examined the regiochemistry of 1,5-diketone cyclization in the context of a steroid syn-thesis. Diketone (71) cyclizes in aqueous ethanolic base to give a mixture of isomeric cyclohexenones (72) and (73) (equation 123). If the reaction is carried out at room temperature, the (72) (73) ratio is 77 23 after refluxing for 50 h, the ratio is 21 79. Furthermore, pure (72) is converted into (73) under the latter reaction conditions. With diketone (74), cyclohexenone (75) is the only product seen under either conditions (equation 124). 

Carbonyl condensation reactions are widely used in synthesis. One example of their versatility is the Robinson anuulation reaction, which leads to the formation of an substituted cyclohexenone. Treatment of a /3-diketone or /3-keto ester with an a,/3-unsaturated ketone leads first to a Michael addition, which is followed by intramolecular aldol cyclization. Condensation reactions are also used widely in nature for the biosynthesis of such molecules as fats and steroids. 

Attempts by Fish and Johnson to effect a steroid synthesis using a standard epoxide-initiated pentacyclization of a polyene afforded complex mixtures [69]. Alternatively, the allyl alcohol 326 was synthesized and treated with TFA (Scheme 19.60). Protonation affords a symmetrical tetramethylallyl cation that undergoes cyclization to give pentacycle 327 in 31% yield. Simultaneous cleavage of the isopropylidene and vinylidene groups was carried out to furnish the diketone 328 in 88% yield, which was then converted to sophoradiol (329). 

Dyker and Grundt [92] used the Mizoroki-Heck reaction of232for the synthesis diketone 233, which provides access to the steroid skeleton via double transannular cyclization (232 233, Scheme 5.40). The 13-membered macrocycle was formed in 61% yield along with 17% of a dimer (not shown). 

During their enantiocontrolled total synthesis of 18,18,18-trifluoro-steroid 26, Fukumoto and co-workers used a five-step Wichterle sequence to install the A-ring beginning from a previously prepared enantiopure precursor. Alkylation of the enamine of ketone 25 was followed by subsequent reprotection and hydrolysis of the vinylic chloride to afford the diketone intermediate 26, which underwent cyclization and acetylative isomerization to afford 18,18,18-trifluorosteroid 27 in 24% yield over the five-step sequence. 

Fukumoto and co-workers also used the Wichterle sequence to construct the A-ring in their total synthesis of 19-norcanrenone (55), constituting a formal total synthesis of the spiro steroid 19-norspironolactone. The enone 53 was reductively alkylated using the method developed by Stork to afford the enone 54 following a Pd-mediated dehydrogenation. Jones oxidation of 54 followed by hydrolysis and cyclization provides the pentacyclic diketone 55 in 22% overall yield over 5 steps. 

Total syntheses of steroids by the allgrlation of cyclic 1,3-diketones with bicyclic bromides are illustrated in Scheme 34. The product of the Birch reduction of resorcinol dimethyl ether (350), which is in the dienol ether of the diketone (338) gives, on alkylation with the bromide (3) and hydrolysis, the tricyclic ABD diketone (351), the cyclization of which with polyphosphoric acid leads to the 18-nor-D-homo derivative (352) [447]. 

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