Ephedrine enantiomers

Ephedrine has not been extensively studied in humans despite its long history of use. Its ability to activate 3 receptors probably accounted for its earlier use in asthma. Because it gains access to the central nervous system, it is a mild stimulant. Ingestion of ephedrine alkaloids contained in ma huang has raised important safety concerns. Pseudoephedrine, one of four ephedrine enantiomers, has been available over the counter as a component of many decongestant mixtures. However, the use of pseudoephedrine as a precursor in the illicit manufacture of methamphetamine has led to restrictions on its sale. 

Reports of ephedra-related stroke on file with the FDA have not yet been published in the peer reviewed literature. In some of the FDA cases, massive doses of ephedrine were consumed (as with products intended for abuse, such as "herbal ecstasy," now withdrawn from the market). In other cases, toxicology testing was not performed, and it is not known with any certainty whether ephedrine was even taken. In still other cases, the drug identified was not ephedrine Many adverse events attributed to ephedrine have actually been due to ephedrine enantiomers, pseudoephedrine (Loizou et al., 1982 Stoessl et al., 1985) and phenylpropanolamine (Johnson et al., 1983 Glick et al., 1987 Lake et al.,... 

More often than not, psychosis occurs in individuals taking ephedrinebased products for asthma and other respiratory conditions. Ephedrine s usefulness as a bronchodilator is somewhat limited by the fact that chronic use leads to a predictable, and fairly rapid, down regulation of 3-receptors and decreased bronchial responsiveness (Neve and Molinoff, 1986). As the medication becomes less and less effective, patients tend to increase the dose. If they take enough, psychosis can occur. Of course, ephedrine, and products containing ephedrine enantiomers, can also be taken specifically with the intent of becoming intoxicated. 

Legge, C., and Turner, A. P. F. (2001). Recognition of ephedrine enantiomers by molecularly imprinted polymers designed using a computational approach, 126,1826-1830. 

The modeling results clearly indicate that the formation of monomer-template complexes is dependent upon the temperature. It was anticipated that polymers synthesized at higher temperatures (> 283 K or 10°C) would be inferior to those prepared at lower temperatures due to the lack of template binding to the second monomer. In order to prove this hypothesis, a series of polymers were synthesized at different temperatures ( 30°C, 20°C, 10°C, 0°C, 20°C, and 80°C) and tested in HPLC studies. The details of this work are published elsewhere [76]. The chromatographic evaluations were performed at temperatures varying from 10°C to 55°C. The results of this evaluation, expressed in terms of temperature dependence of separation factors for ephedrine enantiomers, are presented in Fig. 13. As expected, a clear decrease in separation factors (a) from a = 4.04 (for polymers made at 30°C... 

In conclusion, Snyder and Benson s approach allows the synthesis of enantiomerically pure dialkyl and alkyl aryl sulfoxides in good yields and with excellent enantioselectivities. Both enantiomers are accessible by reversing the order of organometallic displacement or by employing the (15,2J )-(+)-ephedrine enantiomer. The only limitations are observed in the synthesis of t-butyl phenyl and aryl phenyl sulfoxides. However aryl phenyl sulfoxides are accessible by the Andersen procedure, and t-butyl phenyl sulfoxides by an approach to chiral sulfoxides developed by Kagan, described below. 

A variety of substituents have been introduced in good yields with high stereoselectivity (>92% de), proving the versatility of the synthetic scheme. It has to be kept in mind that the absolute configuration of each of the stereogenic centres of the molecules 67 and 68 can be individually selected simply by changing the ephedrine enantiomer used in the preparation of 7 and/or 31. This... 

Whereas (—)-ephedrine was harmed for use as a dietary supplement by the FDA, it was reported in a patent by Warner Lambert in 1999 that (+ )-ephedrine may be useful as a decongestant and appetite suppressant without the side effects on the central nervous system (CNS) that is seen for the natural (-)-ephedrine enantiomer. Of course, Pseudoephedrine (Sudafed) is an over-the-counter medication in the United States widely used to treat nasal congestion associated with colds or the flu. The enantiomer (+ )-pseudoephedrine has also been patented by Warner Lambert as a decongestant with fewer... 

Paris et al. [15] in 1967 used plates constituted by a mixture of silica gel and D-galacturonic acid as impregnating agent. They obtained an excellent separation of ephedrine enantiomers, with an a-value of 2.37, employing an aqueous alcohohc eluent containing D-galacturonic acid (see Table 5.6). A successful separation of... 

Progress has been made toward enantioselective and highly regioselective Michael type alkylations of 2-cyclohexen-l -one using alkylcuprates with chiral auxiliary ligands, e. g., anions of either enantiomer of N-[2-(dimethylamino)ethyl]ephedrine (E. J. Corey, 1986), of (S)-2-(methoxymethyl)pyrrolidine (from L-proline R. K. EHeter, 1987) or of chiramt (= (R,R)-N-(l-phenylethyl)-7-[(l-phenylethyl)iinino]-l,3,5-cycloheptatrien-l-amine, a chiral aminotro-ponimine G. M. Villacorta, 1988). Enantioselectivities of up to 95% have been reported. 

Kcurentjes et al. (1996) have also reported the separation of racemic mixtures. Two liquids are made oppositely chiral by the addition of R- or S-enantiomers of a chiral selector, respectively. These liquids are miscible, but are kept separated by a non-miscible liquid contained in a porous membrane. These authors have used different types of hollow-fibre modules and optimization of shell-side flow distribution was carried out. The liquid membrane should be permeable to the enantiomers to be separated but non-permeable to the chiral selector molecules. Separation of racemic mixtures like norephedrine, ephedrine, phenyl glycine, salbutanol, etc. was attempted and both enantiomers of 99.3 to 99.8% purity were realized. 

The use of dissociable diastereomers for enantiomer resolution may be illustrated by the case where racemic mandelic acid is resolved using en-antiomerically pure a-methylbenzylamine. The n and p salts of a-methylbenzyl-amine mandelate have aqueous solubilities of 49.1 and 180 g/L, respectively, at 25°C [153], A more recent example, which focuses on the crystallographic origin of the solubility differences, is provided by the resolution of ( )-mandelic acid with (-)-ephedrine in water or methanol solution [154], In general, the relative solubilities of the n and p salt pairs are strongly influenced by the choice of solvent medium and temperature, which provide considerable flexiblity in optimizing the crystallization conditions and the efficiency of resolution. This process may be facilitated by the development of a full solubility phase diagram. 

BINAP Ru catalyst and (lR,25 )-ephedrine (Scheme 8-53). This result is similar to that obtained when catalyzed by pure (R)-BINAP. In pure (R)-BINAP complex-catalyzed hydrogenation, (S )-2-cyclohexenol can also be obtained with over 95% ee. This means that in the presence of (R)-BINAP-Ru catalyst, (R)-cyclohexenol is hydrogenated much faster than its (S )-enantiomer. When ephedrine is present, (R)-BINAP-Ru will be selectively deactivated, and the action of (S -BINAP-Ru leads to the selective hydrogenation of (S)-2-cyclohexenol, leaving the intact (R)-2-cyclohexenol in high ee. 

The most successful modifier is cinchonidine and its enantiomer cinchonine, but some work in expanding the repertoire of substrate/modifier/catalyst combinations has been reported (S)-(-)-l-(l-naphthyl)ethylamine or (//)-1 -(I -naphth T)eth Tamine for Pt/alumina [108,231], derivatives of cinchona alkaloid such as 10,11-dihydrocinchonidine [36,71], 2-phenyl-9-deoxy-10, 11-dihydrocinchonidine [55], and O-methyl-cinchonidine for Pt/alumina [133], ephedrine for Pd/alumina [107], (-)-dihydroapovincaminic acid ethyl ester (-)-DHVIN for Pd/TiOz [122], (-)-dihydrovinpocetine for Pt/alumina [42], chiral amines such as 1 -(1 -naphtln I)-2-(I -pyrro 1 idiny 1) ethanol, l-(9-anthracenyl)-2-(l-pyrrolidinyl)ethanol, l-(9-triptycenyl)-2-(l-pyrrol idi nyl)cthanol, (Z )-2-(l-pyrrolidinyl)-l-(l-naphthyl)ethanol for Pt/alumina [37,116], D- and L-histidine and methyl esters of d- and L-tryptophan for Pt/alumina [35], morphine alkaloids [113],... 

Miller, J. H. McB., and Rose, U. (2001). Comparison of chiral liquid chromatographic methods and capillary electrophoresis, separation of the enantiomers of ephedrine hydrochloride. Pharmeuropa 13(1), 3-7. 

Now the other three of the possible four stereoisomers are the (15,25), (l/f,2/f), and (15,2/f) versions. These are also shown, and mirror image relationships are emphasized. The (15,2/f) isomer is the mirror image of (—)-ephedrine, which has the (l/f,25) configuration. Therefore, it is the enantiomer of (—)-ephedrine, and can be designated (+)-ephedrine. Note that the enantiomeric form has the opposite configuration at both chiral centres. 

Both enantiomers of 2-methylamino-l-phenylpropanol (ephedrine, 1), which are commercially available and relatively inexpensive, have been used as auxiliaries in many syntheses of chiral compounds. Ephedrine can be used for amide alkylations both directly1-3, or as derived heterocyclic compounds (see Sections 1.1.1.3.3.4.2.1. and 1.1.1.3.3.4.2.2.). Acyclic derivatives of ephedrine are discussed in this section. For example, either enantiomer of ephedrine gives A-acylephedrines 2 in good yield without epimerization if treated with an anhydride at 65 °C for 10 minutes2. 

Notice that ephedrine has two chiral carbons. This would give rise to four possible optical isomers- two pairs of enantiomers and four sets of diastereomers. One of the diastereomers is called pseudoephedrine. 

Even if some of the optically active spirophosphoranes mentioned above can exist as single species in the solid state, all of them are more or less rapidly transformed, when dissolved, into binary mixtures of diastereoisomers114-129 such as 12 and T3. However, a third type of synthesis yielded pure, optically active phosphoranes not subject to change when dissolved129. This was obtained by the stereospecific synthesis of the oxazaphos-pholidine 53130 (Scheme 5) derived from the —(1R, 2S)enantiomer of ephedrine by means... 

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