Total Synthesis of 6‐Methyl‐5‐androstene‐3,11,17‐trione 3‐Ethylene Acetal, Building Block for 6α‐Methylprednisolone

Abstract

Glucocorticoids are very important substances taking part in biological processes. They are used as drugs against spectrum of biological activity, many glucocorticoids with better therapeutic properties have been synthesized. For example, 6a-methylprednisolone is found to have superior ancortisone. tiinflammatory properties than natural cortisone or hydro-6d-Methylprednisolone 6a-Methylprednisolone is produced by many companies, starting from natural sources, by multistep procedures, including microbial degradation and hydroxylation at the C-11 carbon atom.We present the total synthesis of the title compound 25 which should be readily converted into 6a-methylprednisolone by addition of the corticoid side chain and by introduction of a double bond at 1,2-position, by known',') methods. Our starting material consisted of optically active enedione3) 1 which was transformed into sulfone 2, according to Wiechert et al.4) and Crabbt: et al.5).We found that hydrogenation of sulfone 2 at 2.5 atm in formic acid as compared with acetic acid gave a better yield (5%), and that saturated sulfone 3 fails to be stable on a silica gel column. Therefore, a mixture of 3 and 4 was subjected to the coupling reaction with the potassium salt of tert-butyl a-propionylpropionate, and the resulting mixture of compounds 5 and 6 was separated by column chroma- Ot-Bu + 67 5 R=&-H 6 R = P -H tography, affording compound 5 in 65% yield. Compounds 5 and 6 were mixtures of two diastereoisomers in a 9: 1 and 4: 1 ratio, respectively, which was demonstrated by their NMR spectra. The same compounds 5 and 6 were obtained by the coupling of unsaturated sulfone 2 with tert-butyl upropionylpropionate, yielding compound 7 (900/) as a mixture of diastereomers in a 1.2: 1.0 ratio. Catalytic hydrogenation of 7 over palladium on charcoal in ethanol, followed by chromatography, afforded compounds 5 (70%) and 6 (20%). In contrast with hydrogenation of sulfone 2, when epimerization at C-4 took place in formic acid, in this case analogous epimerization occured already during evaporation of the solvent at about 50°C. As hydrogenation of 7 was carried out in ethanolic solution at atmospheric pressure, this method seems preferable. The reactions of cyclization and decarboxylation of 5 were carried out in one step Liebigs Ann. Chem. 1989, 571 -'576

Preparation of a Functionalized Tetracyclic Intermediate for the Synthesis of Rhodexin A

“…With the functionalized tricyclic system in hand, we set about constructing the correct stereochemistry at both C 9 and C 10 utilizing a reductive alkylation process to provide the necessary functionality for the A-ring annulation sequence. , The reductive C-alkylation of the enedione 13 afforded the desired diastereomer but in generally low yields using various well-known annulation reagents, e.g., Wichterle reagents, vinyl silanes, etc. In addition, various Robinson annulation methods on the saturated dione formed from 13 also failed.…”