The Preparation of 21,21-Dimethylprogesterone

Abstract

The introduction of alkyl groups onto the steroid framework has for many years, been a useful strategy in the enhancement of biological activity. This is exemplified by the increased progestational activity shown by 17-methylprogesterone. l In this paper we describe the preparation of 21,21-dimethylprogesterone. There has been relatively little interest in the C-21 alkylation of progesterone since early studies 2 with the homologues of progesterone, 21-methyl and 21-ethylprogesterone, showed that they had little progestational activity on the proliferation of the endometrium of test aninlals. Subsequent studies 3-5 have concentrated on the preparation of 17α-alkyl and 16α, 17α -dialkylpregnanes in which 21-methylated pregnanes were unwanted by-products. However, a 19-nor-steroid promegestone, 17α, 21dimethyl-19-norpregna-4,9-diene-3, 20-dione, 6 has attracted interest because it binds to the progestin receptor.The alkylation at C-17 was achieved by the generation of the intermediate 17-enolate anion through reduction of a 16dehydropregn-20-one 3 or by the conjugate addition of methylmagnesium halide to the unsaturated ketone. 4,5 This was followed by quenching the anion with methyl iodide. The higher homologues of progesterone were prepared 2 by a malonic ester synthesis from the 20-carboxylic acid chloride.The regioselective alkylation in the α-position to a steroidal ketone has been thoroughly studied in the context of the alkylation of ring A. 7 The role of kinetic and thermodynamic control in the alkylation of ketones is well established. In the enolisation of pregn-20-ones, the more heavily-substituted 20(21)-enolate is the thermodynamic enolate whilst the lesshighly substituted 20(21)-enolrate is the kinetic product. Hence if the kinetic enolate is generated in the presence of an excess of methyl iodide, alkylation should take place at C-21. This proved to be the case and it was possible to obtain the 21,21-dimethyl compound 2 from pregnenolone acetate 1 by generation of the anion with sodium hydride and quenching with a large excess of methyl iodide. The product 2 showed two additional methyl group doublets in the 1 H NMR spectrum (δ H 0.92 and 0.94, J 7.1 Hz) The 13 C NMR spectrum of the corresponding alcohol 3 retained the characteristic low field methine signal at δ C 61.0 assigned to C-17 whilst there was a new methine signal at δ C 41.2 assigned to C-21 (see Table 1). Hence the alkylation had taken place at C-21. On occasions the product was contaminated by a trimethyl analogue but this was not obtained pure.Hydrolysis of the 3β-acetate 2 with methanolic potassium carbonate gave the 3β-alcohol 3. Oxidation of this alcohol using the Oppenauer method with aluminium isopropoxide and cyclohexanone, gave the ketone and brought about the isomerisation of the ∆ 5 -double bond to give 21,21-dimethyl-

Steroids: reactions and partial synthesis

“…Aerial oxidation of the corticosteroid side chain in the presence of copper acetate has been shown 89 to lead to dimers based on 17,21-acetals. The preparation of 21,21dimethylprogesterone 90 and the conformation of the side chain of 21-alkylpregnanes 91 have been examined.…”

Counting Individual Trapped Electrons on Liquid Helium

“…In the solid state, electrons have been trapped in a chain of tunnel junctions 3 ; one-electron quantum dots have been made in self-assembled structures 4 , etched vertical pillars 5 and lateral quantum dots 6 ; single 7 and double 8 dots have incorporated a quantum point contact electrometer. Here we show that surface-state electrons can be held in a novel electrostatic trap on a pool of superfluid helium, 5 µm in diameter and 0.8 µm deep.…”