Steroid malonic ester

The Bucherer-Bergs synthesis has been successfully applied to a great variety of cyclic ketones, ranging from cyclopropanone to steroidal ketones. However, the difficulty of preparing small-ring ketones has led to the development of alternative methods to obtain the corresponding spirohy-dantoins. Isocyanate intermediate 27 may be prepared in several steps from malonic ester typical Bucherer-Bergs chemistry follows.51... 

Chiral malonate esters have been used successfully in asymmetric cyclopropanations, as shown by the example in Scheme 6.39, part of a total synthesis of steroids such as estrone [143,144]. The key step in this sequence is an intramolecular Sn2 alkylation of the monosubstituted malonate. The rationale for the diastereoselec-tivity is shown in the illustrated transition structure. Note that the enolate has C2 symmetry, so it doesn t matter which face of the enolate is considered. The illustrated conformation has the ester residues syn to the enolate oxygens to relieve Al>3 strain, with the enolate oxygens and the carbinol methines eclipsed. The allyl halide moiety is oriented away from the dimethylphenyl substituent, exposing the alkene Re face to the enolate. The crude selectivity is about 90% as determined by conversion to the dimethyl ester and comparison of optical rotations [143], but a single diastereomer may be isolated in 67% yield by preparative HPLC [144], This reaction deserves special note because it was conducted on a reasonably large scale ... 

Almost 10 years after and independent of Inhoffens pioneering research, Karl Miescher (1892-1974) and George Anner from Ciba AG in Basel published in 1948 the first total synthesis of enantiopure (+)-oestrone. [32] Their approach was based on earlier work from Robert Robinson (1886-1975) in Oxford and Werner Emmanuel Bachmann (1901-1951) in Ann Arbor, Michigan. As another highlight in steroid chemistry, their synthesis stands out as one of the earliest attempts to circumvent the challenging demethylation step. Key reaction sequences are a malonic ester synthesis, a Dieckmarm cychsation, a Reformatzky reaction and the application of the Arndt-Eistert reaction. Remarkable is here as well the high art of crystallisation In the first fractional crystallisation, three racemic diastereomers were separated and in the second one two. Finally, enantiopure (+)-oestrone is obtained by stereoselective crystallisation of the desired diastereomer of the ((-)-menthyloxy) acetate. 

The synthesis of 6a-methyldigitoxigenin acetate (394) has been reported according to Scheme 19.198 Pregn-4-en-21-ol-3,20-dione was converted into its 6a-methyl derivative (387) using a previously described five-step reaction sequence biological hydroxylation furnished the 14a,12-diol (388) and reduction of the derived 21-acetate gave the 5/3-dihydro-steroid (389). Dehydration furnished the A14-olefin (390) which was converted into the 21-mesylate and thence into the lactone (391) by reaction with the monoethyl ester of malonic acid. The crude lactone was decarbox-ylated, reduced to the 3/3-alcohol (392), and converted into the bromohydrin (393) via its 3/3-acetate and thence by debromination into 6a-methyldigitoxigen 3-acetate... 

This sequence illustrates the use of enolates from 1,3-dicarbonyl compounds in Michael reactions they are useful too in alkylations, aldol condensations (Knoevenagel conditions), and reactions with epoxides, as in the synthesis3 of 20. Nowadays they tend to be used if they are readily available, or if the disconnections suggest their use, as in the building of 11 into 18. Examples include the diketone 11 and the six-membered equivalent both used in steroid synthesis, acetoacetates 16 and 19 and the keto-lactones 20, malonic acid 21 and its esters, "Meldrum s acid 22, a very enolisable malonate derivative,4 and the keto-ester 25 formed via its stable enolate 24, by the cyclisation of the diester 23, an intermediate in nylon manufacture. The compounds 11,16, 19, 20 R=H, 21, 22, and 25 are all available commercially. 

Based on this reaction, allylic alkylation of alkenes is possible. Active methylene compounds, such as malonates and /8-keto esters, can be introduced to a steroid skeleton by the reaction of the steroidal jr-allylpalladium complex in DMSO (eq 20). 4 Jijg reaction of carbon nucleophiles also proceeds in the presence of an excess of triphenylphosphine (eq 21). ... 

---