Adrenosterone synthesis

This intramolecular Michael addition has been used to obtain the C/D ring in a short synthesis of adrenosterone (6).2 Thus cyclization of 3 with zirconium tetra-n-propoxide results in the desired 4 and the corresponding cw-isomer in a 25 1 ratio. The B ring was added to give 5 in 62% yield by reaction of the anion of 4 with 2-(trimethylsilyl)-l-pentene-3-one (5, 462). The last ring was then added to obtain 6 by a method developed previously by Stork and Logusch (10,234-235). 

Inter- and intramolecular cycloaddition reactions of furans followed by transformation of adducts were employed in the synthesis of complex natural products <02T9903>. As shown below, an intramolecular Diels-AIder reaction served as a key step to set up the D-homo- 10-epi-adrenosterone with non-natural configuration at C-10 <02CEJ1051>. 

Stoik et al. have shown that heteroannular extended dienolates such as (73), which contain substituents at both the a- and y-positions, undergo predominantly equatorial alkylation (Scheme 35). The dienolate (73) was product by lithium-ammonia reduction of the tricyclic dienone (72) and the product of its alkylation wiA I-bromo-3-chloro-2-butene and hydrolysis of the resulting enol ether, i.e. (74), was a key intermediate in a short, highly stereoselective synthesis of ( )-adrenosterone. It was pointed out that equatorial alkylation is obtained with dienolates such as (73) and related compounds brcause a peri interaction (Me OMe) of the a- and y-substituents forces the ring a to adopt a half-boat conformation in which the a-face of the ir-system is accessible to attack. 

This reaction was used for a synthesis of the corticosteroid adrenosterone (1), the latter stages of which are shown in equation (II).2... 

Intramolecular Diels-AUer reaction. For tethering a diene/dienophile pair to control the Diels-Alder reaction, the use of PhjSiCI, is illustrated in a synthesis of I+)-adrenosterone. The first step is enolsilylation, which is followed immediately by tfeatment of an alcohol bearing the dienophile. 

A method for the reductive alkylation of enediones was developed by Stork for incorporation in the synthesis of corticosteroids such as ( )-D-homoadrenosterone (48) and ( )-adrenosterone (50). Attempted reductive alkylation of 46 by aprotic Michael addition using silyl enones was found to be ineffective thus equatorial alkylation with the modified Wichterle reagent was found to proceed stereoselectively to afford the dione 47. Subsequent elaboration through a Wichterle sequence and hydrolysis/Jones oxidation of the Cl 7a formate provided ( )-D-homoadrenosterone (48). 

Van Royen, L.A. Mijngheer, R. De Clercq, P.J., Intramolecular Diels-Alder reaction with furan-diene. Total synthesis of ( )-l 1-ketotestosterone and ( )-adrenosterone. Tetrahedron, 1985,41,4667-80. 

Stork has continued his monumental work on the use of the intramolecular Michael addition to control vicinal stereochemistry in the construction of /ran -fused hydrindanes, and this year he has extended the study to a short stereoselective synthesis of adrenosterone (66) (Scheme 6). ... 

Stork investigated a sequence involving intramolecular Michael addition followed by aldol condensation to access trans-fused hydroindan 10 (Scheme 12.1) [51, 52]. Zr(On-Pr)4 proved effective in the generation of an aldehyde enolate, which underwent Michael addition to furnish 9. Formation of the cyclopentane ring was followed by aldol condensation to give 10 in 63% overall yield (dr=25 l). The product enone was a key intermediate in a total synthesis of ( )-Adrenosterone (11) [52]. 

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