Quaternary ammonium steroids

M. Gazdag, M. Babjak, P. Kemenes-Bakos, and S. Gorog, XLI. Ion-pair high-performance liquid chromatographic separation of quaternary ammonium steroids on silica, J. Chromatogr., 550 639... 

The reaction of bromosteroid 14 and DBU in refluxing hexane under a nitrogen atmosphere gave an isomeric mixture of quaternary ammonium steroids (15) (71USP3553211). 

The amino functional group is not commonly encountered in steroid synthesis except perhaps in steroidal alkaloids. However, certain elimination reactions have been shown to have theoretical and limited preparative importance, largely due to the efforts of McKenna and co-workers. The Hofmann rule for 2 elimination predicts that alkaline elimination of quaternary ammonium salts will occur towards the carbon carrying the most hydrogen atoms cf. the converse Saytzeff orientation, above). In cyclohexyl systems, the requirement for diaxial elimination appears to be important, as in other 2 eliminations, and the Hofmann rule frequently is not obeyed [e.g., (116) (117)]. 

Cholestyramine (Cuemid, Dowex 1-X2-C1, Questran) is a quaternary ammonium cationic resin used primarily to bind, in the gut, bile salts which appear to be the main cause of pruritis in obstructive hepatic disease. Again, many unexpected facets of steroid and lipid metabolism are becoming clear following studies of the drug s effects [451.452]. 

Steroidal aminomethyl derivatives have been subjected to some of the reactions typical of Mannich bases, described in Chap. II, usually with the aim of introducing structural modifications of the molecule by means, in particular, of deamination and hydrogen-olysis. The formation of a quaternary ammonium salt (mainly iodomethylatc) by N-alkylation of the base - is also performed to the same end in order to obtain unsaturated deaminated products. ... 

The Hofmann fission of quaternary ammonium salts displays some unusual features in the steroid field. The elimination is normally of E2 character, and in acyclic structures gives olefinic products according to the familiar Hofmann rule [ 14]. The behaviour of 3-trimethylammonium steroidal salts is unexceptional [32, 3 ] the axial 3u compounds in the 5a-series giving A -olefins (5), or in the case of compounds already unsaturated at C-C 6) (6), the A -dienes (7). The 3j8-trimethylammonium-5a compounds are stable to bases, or... 

In order to enhance the sensitivity in steroid analysis, a number of derivatization procedures have been proposed. In most cases, the aim of the derivatization is an increase of the proton affinity of the compound, although the introduction of a fixed charge on a quaternary ammonium or a group with high electron affinity has been described as well. An overview of the derivatives generated is given in Figme 13.4. Most derivatization procedures are applied in combination with ESI-MS. 

Orally administered corticosteroids are effective in the treatment of chronic bronchial asthma. The inhalation route has been widely used in attempts to avoid systemic side-effects, such as adrenal suppression, but evidence suggests that inhaled steroids are absorbed systemically to a significant extent. The respiratory tract epithelium has permeability characteristics similar to those of the classical biological membrane, so lipid-soluble compounds are absorbed more rapidly than lipid-insoluble molecules. Cortisone, hydrocortisone and dexamethasone are absorbed rapidly by a nonsaturable diffusion process from the lung, the half-time of absorption being of the order of 1-1.7 min. Quaternary ammonium compounds, hippurates and mannitol have absorption half-times, in contrast, of between 45 and 70 min. 

Use. A solution of this oil-soluble quaternary ammonium salt in chloroform or ethyl acetate quantitatively extracts polar, anionic lipids such as steroid conjugates from aqueous solution by a process of anion exchange. 

Hofmann degradation of 5of-cholestan-4a- and -4/3-yI trimethylammonium salts closely resembled that of the C-6 quaternary ammonium salts the 4j -compound producing solely the 4-ene by Saytzeff elimination whilst the 4a-epimer gives largely demethylated 4a-dimethylamino-steroid, with some 3-ene. ... 

Paravallaridine (1) has been utilised as the starting point for the preparation of a number of steroidal quaternary ammonium salts which are exemplified by the bis-methiodides (2a) to (2d). These... 

The tightly bonded inclusion complexes in aqueous solution, between aromatic and aliphatic guests (steroids, among others) and cyclophane receptors with tetra-oxa[ .l.n.l]paracyclophanes and quaternary ammonium cyclophanes is entropically unfavorable and strongly enthalpically driven. The thermodynamic characteristics of tight inclusion complexes differ from those measured for weak apolar association processes, which are characterized by small enthalpic changes and favorable entropic terms. This is the usual interpretation of the so-called hydrophobic effect. 

Carboxylic acid methyl esters. A methanolic soln. of oleanolic acid containing phenolphthalein as indicator titrated with a soln. of tetramethylammonium hydroxide in the same solvent, which is then removed by distillation, and the residual tetramethylammonium salt heated under reduced pressure with distillation of the resulting trimethylamine -> methyl oleanolate. Y 83%. F. e. s. V. Prelog and M. Piantanida, H. 244, 56 (1936) by gas-diromatography s. A. S. Hyman, J. Chromatogr. 45, 132 (1969) ethers from quaternary ammonium hydroxides and acetates cf. J. MacGee and K. G. Allen, Steroids 16, 19 (1970). 

Some of the innumerable reagents used in TEC are based on reactions with more or less well-established mechanism. Eor example, sodium iodobismuthate (Dragendorff reagent) is widely used among others for alkaloids and quaternary ammonium compounds, 4-dimethylaminobenzaldehyde for primary amines and amino acids, 2,4-dinitrophenylhydrazine for aldehydes and ketones, ninhydrin for amino acids and some antibiotics, fluorescamine for primary and secondary amines, phosphomolybdic acid for lipids, various steroids, and other compounds, chlorine vapor followed by Kl/starch for amines and amides. More complex is the mechanism of the reactions with some other reagents, containing high concentrations of sulfuric acid, vanillin/sulfuric acid, phosphoric acid, aluminum chloride, antimony(III)... 

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