Ephedrine stereoisomers

The drug acts as a direct and indirect agonist i.e., it helps in the release of norepinephrine. Besides, it also exerts CNS-stimulatory actions. It has been observed that the ephedrine stereoisomer having essentially the (IR, 2S) absolute configuration exhibits direct activity on the receptors, both a and P, as well as an indirect component. It is worthwhile to state here that the (1S, 2R) entantiomer has primarily an indirect activity. 

Starting with two chiral centres, there should, therefore, be four stereoisomers, and this is nicely exemplified by the natural alkaloid (-)-ephedrine, which is employed as a bronchodilator drug and decongestant. Ephedrine is (li ,25)-2-methylamino-l-phenylpropan-l-ol, so has the structure and stereochemistry shown. 

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. 

Now for a rather unexpected twist. We have seen that if there are n chiral centres there should be 2" configurational isomers, and we have considered each of these for n = 2 (e.g. ephedrine, pseudoephedrine). It transpires that if the groups around chiral centres are the same, then the number of stereoisomers is less than 2". Thus, when n = 2, there are only three stereoisomers, not four. As one of the simplest examples, let us consider in detail tartaric acid, a component of grape juice and many other fruits. This fits the requirement, since each of the two chiral centres has the same substituents. 

Ephedrine is an alkaloid that is present in various forms of the ephedrine family, and which is still extracted from Ephedra sinica and Ephedra equisetina. Because of the presence of two asymmetric atoms, there are four isomeric forms. Pseudoepinephrine (d-isoephrine) is a stereoisomer with pharmacological action that differs slightly from ephedrine. The pharmacological action of ephedrine is typical of noncatecholamine sympathomimetics of mixed action. It stimulates both a- and 8-adrenoreceptors, and simultaneously causes a release of norepinephrine from synaptic neurons. Its vasoconstrictive ability is approximately 100 times weaker than that of epinephrine however, the duration of action is approximately 10 times longer. It is much less toxic than epinephrine, which allows it to be used widely in medicine. 

R)-( - )-3-Benzyloxy-2-methylpropionaldehyde (2), obtained from N-methyl-ephedrine, reacts with the ketene f-butylthio trialkylsilyl acetal 3 in CH2C12 in the presence of TiCl4 to give 4 in >99% de. Use of BF3 etherate as the Lewis acid catalyst results in three stereoisomers.13... 

Analogous to the use of chiral enoates (see previous section), a, -unsaturated carboxylic amides, prepared from chiral amines, may be utilized in asymmetric 1,4-additions. When Grignard reagents are added to unsaturated amides (21), derived from (-)-ephedrine (20),25 highly optically active fi-sub-stituted alkanoic acids (22 R and R = alkyl or phenyl) are obtained in a variety of cases, after hydrolysis of the initially formed adducts (Scheme 7). This method was used for the synthesis of the antibiotic (-) malyngolide and its stereoisomers.26 Recrystallization of the intermediate (saturated) amide was necess-... 

EXTENSIONS AND COMMENT ARY Here is another example of the presentation of a compound for which there has not yet been an effective level determined. Why For a very good reason. This is an example of a whole class of compounds that I have called the pseudos, or the -compounds. Pseudo- as a prefix in the literary world generally stands for false. A pseudopod is a thing that looks like a foot, but isn t one. A pseudonym is a fictitious name. But in chemistry, it has quite a different meaning. If something has a common name, and there is a second form (or isomer, or shape, or orientation) that is possible and it doesn t have a common name, it can be given the name of the first form with a pseudo- attached. Ephedrine is the erythro-isomer of N-methyl-13-hydroxyamphetamine. There is a second stereoisomer, the threo- isomer, but it has no trivial name. So it is called pseudoephedrine, or the Sudafed of sinus decongestant fame. 

The thought that transmethylation of noradrenaline may be an initial step in its deactivation in the body makes one wonder whether further transmethylation of adrenaline is also not a common biological process. As a result of studies of the various alkaloids of plants of the Ephedra species, it was noted that not only Z-ephedrine and its stereoisomer d-pseudoephedrine are present but also that -norephedrine, d-norpseudoephedrine, l-methylephedrine, and d-methylpseudoephedrine (8) are present. The quaternary tri-methylammonium compounds corresponding to these were not reported but very... 

There are two chirality centers, so the formula predicts a total of four stereoisomers. However, each of the chirality centers has identical groups attached to the carbon, so fewer than four stereoisomers actually exist. The analysis can be conducted in the same manner as was done previously for ephedrine. We start by drawing one of the stereoisomers, the (2/ ,37 )-isomer for example. Then the mirror image of this, the (25,35 )-stereoisomer is drawn. These two compounds are nonsuperimposable mirror images—enantiomers. 

Ephedrine and pseudoephedrine are stereoisomers that are clearly not mirror images of each other—only one of the two stereogenic centres in ephedrine is inverted in pseudoephedrine—so they must be diastereoisomers. Thinking in terms of stereogenic centres is useful, because, just as this compound has two stereogenic centres and can exist as two diastereoisomers, any compound with more than one stereogenic centre can exist in more than one diastereoisomeric form. 

Backscattered dual circular polarization results on ephedrine and its stereoisomers are reported by Yu et al. (1993). All four stereoisomers examined show very similar Raman spectra, but their ROA spectra nicely show the sensitivity of ROA to the configurations and conformations of the molecules. As the features observed seem to be connected to the local stereochemistry, it seems to be possible that in the near future, with some more experimental data at hand, to deduce the absolute configuration of molecules of unknown stereochemistry directly from the ROA spectra. 

Leusen et al. studied the crystal packing of ephedrine with several phosphoric acid stereoisomers to verify whether a relationship between enthalpy of formation and separation of enantiomers via diastereomeric salt formation exists.They considered four different force fields and determined that the CHARMM program, as implemented in QUANTA, was the best for their application. Their decision was based mainly on the knowledge that non-bonded cutoff distances are larger in CHARMM. A larger cutoff distance is necessary to account for the interaction between different hydrophobic layers in the crystal (interlayer distances of 14—16 A). These authors were unable to quantitatively determine the validity of their hypothesis, although qualitative explanations were derived for their observations. 

A clockwise rotation of a beam of plane-polarized light by a stereoisomer, usually used to denote a specific enantiomer of a chiral molecule, that is d- or (-1-)-ephedrine... 

Pseudoephedrine is a stereoisomer of ephedrine, in which two of three chiral centers are different. 

Despite being a stereoisomer of atropine, hyoscine tends to have central depressant effects in conditions where atropine might be expected to cause excitation however, excitation can occur (1). Hyoscine hydrobromide produces somnolence and dryness of the mouth in a high proportion of patients, and when ephedrine is not given the somnolence is likely to be present in the majority some individuals also have headache, giddiness, and blurred vision. 

Ephedrine erythro- ) and pseudoephed-rine threo-(5) are diastereomers with ephedrine, a racemic mixture of the R,S and S,R stereoisomers, and pseudoephedrine, a race-... 

For example, ephedrine erythro-(S) and pseudoephedrinethreo-(5)have the same substitution pattern and two asymmetric centers, so there are four possible stereoisomers. The drug ephedrine is a mixture of the erythro enantiomers (li ,2S) and (1S,2R) the threo pair... 

The Chinese drug ma huang (Ephedra sinica Stapf) has been used in China for more than SOOOyears. The alkaloid that is responsible for the CNS stimulant effects is ephedrine. The levorotatory erythro isomer ( l)is the most active of the four possible stereoisomers with that structural formula. Khat (kat, or qat) or Abyssinian tea Catha edulis Forskal) is the product from a small tree or shrub indigenous to tropical East Afiica. Khat leaves are chewed habitually by peoples in East Africa and certain other Arabian countries, and produce a mild CNS stimulant effect (2). The principal... 

Since there are two possible configurations for an asymmetrically substituted carbon atom, a structure containing n such centres will, in theory, possess 2 stereoisomers. The actual number of stereoisomers that exist may be less than this due to steric effects. Compounds that have the same stereochemistry at one chiral centre but different stereochemistry at the others are known as diastereoisomers (diastereomers) a good example is given by the alkaloids ephedrine and pseudoephedrine. Ephedrine (the (1R, 2S) diastereoisomer) is a natural product isolated from Ephedra (the Ma Huang plant) and known to Chinese medicine for over 3000 years. It was used in the last century for the treatment of asthma. Pseudoephedrine (the (IS, 2S) diastereoisomer) is a decongestant and a constituent of several over-the-counter cold and flu remedies (Figure 4.12). 

Reliable techniques exist for liquid-liquid extraction of ephedrine from alkaline tissue samples. Gas chromatography-mass spectrometry measurement requires pentafluoropropionic acid derivatization. Blood and tissue measurements have been reported in several ephedrine-related deaths, and in clinical trials with therapeutic doses of the drug (Backer et al., 1997). More recently capillary electrophoresis has been used to separate and identify all 10 stereoisomers of the ephedrine family found in nutritional supplements. Chiral discrimination is effected by using hydroxypropyl-P-cyclodextrin (Flurer et al., 1995). 

A molecule with two nonidentical asymmetric centers can exist as four stereoisomers (i.e., as two different racemates). Enantiomers from either of the racemates cannot exist in a mirror-image relationship. Such enantiomers are referred to as diastereoisomers, which are illustrated by the drug ephedrine. 

Many of the functionalized phosphonic acids and their derivatives described so far in this and the preceding chapter are capable of resolution into enantiomeric forms, through chirality at the carbon atom which carries the functional group. In the case of functionalized phosphonic acids, diastereoisomeric forms become possible as a result of any additional chirality at phosphorus. In practice, few resolutions have been carried out amongst the many types of functionalized acids considered so far, even for those classes of acids in which there is potential biological interest, e.g. the (hydroxyalkyl)phosphonic acids. Two examples of the latter are (l-hydroxy-3-methylbutyl)phosphonic acid, in the form of its monobenzyl ester, and (a-hydroxybenzyl)phosphonic acid , each of which has been resolved with stereoisomers of ephedrine. Nor have many syntheses been devised in the course of which one stereoisomer is obtained preferentially. 

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