Total Synthesis of [3aS-(3aar,9aa,9bp)]-3a,4,5,9,9a,9b-Hexahydru-3a,6dimethyl-lH-benz[e]indene-3,7(2H,The natural and synthetic glucocorticoids are very important compounds commonly used as drugs against many diseases. Recently, we have reported the synthesis of some of the title compounds and their transformations into 6-methyl-5-androstene-3,11,17-trione 3-ethyleneacctal, a building block for the anti-inflammatory drug 6a-methylprednisolone. We now present a shorter synthesis of the tricyclic systems (title compounds), which can be converted into glucocorticoids and, as reported by Nedelec at aL2), can also be used as antiandrogens. We have also reported3) a stereoselective reductive addition of the hydride anion and some electrophiles to the enedione 1, mediated by tert-bu-L J
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
Thr cliisohutylaluniinium enolate 2. generated in situ from the rnediotie 1 by conjugatc reduction. can be forced to react with itldrhydcs, ally1 bromides. or acyl chlorides by addition of copper(1) iodide to thc reaction mixture.The title compound 1 easily accesible in enantiomerically pure form" is a very handy substrate for total synthesis of natural products, mainly steroids. The transformations of the enedione 1 into steroids described in literature2) are rather long, because till now the selective method of reductive alkylation of the enedione 1 has not been known. This method would enable to obtain in a onestep procedure the trans-hydrindandione derivatives 3 containing the suitable substituent at C-4.Recently3) we have reported the stereoselective conjugate reduction of the enedione 1 which led to trans-hydrindan-1,5-dione by protonation of the intermediate diisobutylaluminium enolate 2. Now, we would like to describe the stereoselective reductive addition of some electrophiles to the title compound 1. During the conjugate reduction3) of the enedione 1 the diisobutylaluminium enolate 2 is produced which could be trapped with electrophiles. It turned out that this enolate 2 does not react directly with many electrophiles except of bromine or N-bromosuccinimide. This unreactivity of the enolate 2 can be rationalized by the withdrawing effect of the electrons from the enol system by the aluminium atom. Lately, Tsuda, Satomi, Hayashi, and Saegusa4' forced similar enolates to react with allyl bromide, methyl iodide, and ethyl bromoacetate by addition of methyllithium to the reaction mixture. Due to the presence of the carbonyl group at C-1 we could not apply their findings. We have found that the addition of an equimolar amount of copper(1) iodide to the reaction mixture contain-593 ing the enolate 2, increases significantly the rate of reaction of 2 with aldehydes, ally1 bromides, or acyl chlorides leading to products 3 in about 70%, 60%, and 20% yield, respectively. We supposed that the substituents at C-4 in the products 3 occupied equatorial position. In the case of compounds 3e, 3f, and 3g it was obvious, because their NMR spectra exhibited signals of the protons at C-4 with the coupling constant equal about 13 Hz. In spite of copper(1) iodide addition the enolate 2 still has not reacted with ketones, esters, acrylates, methyl iodide, tosylates, epichlorohydrin, methyl chloroformate, chloromethyl methyl ether, and methyl vinyl ketone. This unreactivity of the enolate 2 allows to presume that the above described reductive addition can be applied to cc,p-unsaturated compounds possessing various functionalities.Most of the products 3 are very useful for the syntheses of steroids, and this work is in progress.The Authors thank the Polish Academy of Sciences for financial assistance, grant CPBP 01.13.2.25. ExperimentalTetrahydrofuran (THF), hexamethylphosphoric triamide (HMPA), and CuI were anhydrous. All reactions were carried out under argon. The reactions were monitored by thin-layer chromatography. IR spec...
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