Isomers of ephedrine

Pseudoephedrine is an isomer of ephedrine in which the hydroxyl group is on the other side of the molecule. 

Chen, . K. 1929. Relationship between the pharmacological action and the chemical constitution and configuration of the optical isomers of ephedrine and related compounds. J. Pharmacol. 36 363-400. 

D-isomer of ephedrine) (phenylpropanoid amino alcohol) E. sinica, E. spp. (Ephedraceae) [bronchodilator, hypertensive, respiratory stimulant, sympathomimetic, vasoconstrictive]... 

TABLE 16-1 Relative Pressor Activity of the Isomers of Ephedrine... 

Epinephrine (adrenaline) was one of the first hormones for which differential effects on blood pressure were reported for the two epimers in the early 20th century [58]. A reassessment of epinephrine activity was made by analyzing the effects of optical isomers of ephedrine and methylephedrine on the spontaneous beating rate of the isolated right atrium of normal and reserpinized rats by investigating direct and indirect actions on al-adrenoceptors. L-ephedrine, and to a lesser extent D-ephedrine, markedly increased the beating rate of rat right atrium [59]. 

Kawasuji,T., Koike, K., Saito, H., Chronotropic effects of optical isomers of ephedrine and methylephedrine in the isolated rat right atria and in vitro assessment of direct and indirect actions on al-adrenoceptors, Biol. Pharm. Bull. 

One of these is Ephedrine where the carbon chain plus aminic tail is CH(0H)CH(CH3)NH(CH3), looking like a close brother of PEA. Ephedrine is a natural product extracted from a plant called Ephedra and used in traditional Chinese medicine. It can also be made in the laboratory. Ephedrine is administered as a stimulant, appetite suppressant, and concentration aid. It seems to work by increasing the activity of norepinephrine. It is used, for example, by professional weightlifters and athletes. Another close brother of PEA is pseudoephedrine, which is a chiral isomer of ephedrine, and it causes vasoconstriction (constriction of blood vessels) and relaxation of smooth muscles, thus leading to bronchial dilation. It is administered for nasal/sinus congestion and difficulty in breathing. Methamphetamine is another... 

Considering the chemical characteristics, ephedrine has two chiral centers, and therefore four isomers can be identified ( )-ephedrine and ( )-pseudoephedrine [39]. (lR,2S)-(—)-ephedrine is the major isomer found in Ephedra sp., and pharmacological studies have shown it as responsible for the pharmacological activities of ephedra. Not only (—)-ephedrine has the widespread use but also (+)-pseudoephedrine is added in over-the-counter decongestant preparations [40]. The four isomers of ephedrine may be naturally present in Ephedra species, and they are usually used as a hydrochloride form, being the classical purification method for ephedrine hydrochloride a combination of conventional infusion and organic solvent extraction or adsorption [41]. Other alkaloids are also present in smaller amounts, and the minor ephedrine alkaloids include (+)-pseudoephedrine and the demethyl analogues (—)-norephedrine and (+)-norpseudoephedrine [40]. 

Analytical strategies including GC-NPD [45], GC-FID [46], GCxGC [47], GC-MS [48-50], LC-UV [6,51], and LC-MS/MS [6,52-55] have been employed in the routine laboratories to normal and chiral analysis. The use of mass spectrometry detection is mandatory to the confirmatory steps of the analyses. Methods by CE have been successfully used to separate chiral isomers of ephedrine and related compounds [56, 57]. Chromatographic techniques can easily distinguish (—)-ephedrine from other phenylethylamine derivatives and diastereoisomers. 

Treatment of (-)-ephedrine (42) with methylthiophosphonic dichloride afforded a mixture of the isomeric 2-methyl-l,3,2 oxazaphospholidine-2-thiones 120a,b, from which the pure isomers could be separated in approximately equal quantities by chromatography over silica (Scheme 34) [32],... 

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. 

Rh-H / -elimination step in step E gives the vinyl-borane which then dissociates to generate the first intermediate. This cycle explains the production of equimolar quantities of alkane and -vinylborane with unreactive R2BH derived from ephedrines with catecholborane there is an additional shunt pathway — step C in competition with step E leading to the primary regio-isomer of alkylborane. 

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. 

Since its discovery by Pasteur in 1853,5 classical resolution by selective crystallization of diastereo-isomers, despite wide and frequent use, remains to a large degree a method of trial and error. Various attempts to rationalize classical resolutions and predict a successful combination of race-mate and resolving agent by computational approaches so far have not been crowned with remarkable success.6 Even when the crystal structures of both diastereoisomeric salts are known, molecular modeling calculations do not provide a basis for a reliable prediction. Only recently has some progress been made in the calculation of the relative thermodynamic stability of ephedrine-cyclic phosphoric acid 4 diastereoisomers,7 a diastereoisomeric salt frequently used as a model system (vide infra). 

In the presence of (+)-ephedrine, ( )-l-acetylcyclo-octene 59dE photoisomerizes to enantiomeric (Z)-isomer, which is trapped by cyclo-pentadiene to give the Diels-Alder adduct 62d in 22% ee (Sch. 21) [118]. Direct irradiation at >280 nm of doubly bridged (Z)-l(10)-bicyclo[8.8.0] octadecen-2-one 87Z in diethyl (+)-tartrate as a solvent affords the (E)-isomer 87E in favor of the levorotatory enantiomer where the EjZ ratio is 7 (Sch. 31) [162]. 

A stereoselective synthesis of ( )-ephedrine and ( )-methylephedrine has been described (318). The method utilizes a carbanion, in which the negative charge is located a to the nitrogen, formed by deprotonation of 1. Subsequent reaction with benzaldehyde yields the 2-oxazolidone 2, and thermal removal of the diphenylphosphinyl group gives the 2-oxazolone 3. Hydrogenation of 3 proceeds with perfect stereoselectivity to yield the erythro isomer 4, which is easily converted to ( )-ephedrine or ( )-W-methylephedrine. 

Chiral [160, l70, l80]phosphomonoesters and ATPy[l60, l70, lsO] have been synthesized by Knowles and associates, who devised the procedure outlined in Fig. 19 [51-55], The procedure has been used to synthesize phenyl[160, l70, l80]phos-phate and 2-[160,170,180]phospho-D-glycerate as well as the propylene glycol ester shown. The starting cyclic adduct was prepared by reaction of (— )-ephedrine with P17OCl3, giving a separable mixture of 2-chloro-l,3,2-oxazaphospholidin-2-ones whose chemistry had been described [56], The major isomer was converted to (/ p)-l-[160, nO,180]phospho-1,2-propanediol and (Sp)-ATPy[l60, nO, lsO] by the reactions shown. The stereochemistry at each step of the synthesis was well prece-dented in the literature nevertheless, the configurations were verified by independent methods described in the next section. 

The most promising result was obtained when (S)-tropolone 2-methylbutyl ether (chiral ether) was irradiated within an ephedrine included NaY (Fig. 15) [295,306]. In the absence of ephedrine, diastereomer A is obtained in 53% diaste-reomeric excess. When (— )ephedrine was used as the chiral inductor, the same isomer was enhanced to the extent of 90%. The importance of this result becomes more apparent when one recognizes that irradiation in solution of the same com-... 

The reaction is also convenient for synthesis of acyclic -amino alcohols. Thus reaction of 1 with benzaldehyde followed by reduction gives a mixture of ( )-ephedrine (2,erylhro) and ( )-i -ephedrine (3, threo) in the ratio 3.3 1. The opposite stereoselectivity obtains when the reaction is used to prepare a tertiary amino alcohol. Thus the same sequence applied to 4 leads mainly to the threo-isomer (5, N-methyl-i r-ephedrine). 

The pharmacokinetic and toxicokinetic behavior of any isomer cannot be used to predict that of any other ephedrine isomer. The (+) isomer of meth-amphetamine, for example, is a potent CNS stimulant, but the (-)-isomer is merely a decongestant. There is a tendency in the literature to lump together all ephedrine alkaloids and use the term class effect to assume that all the different drugs in that class exert the same effects on the same biological targets. In fact, some of the drugs in the class will be similar in some regards and different in others. 

Vansal SS, Feller DR. Direct effects of ephedrine isomers on human beta-adrenergic receptor subtypes. Biochem Pharmacol 1999 58(5) 807—810. 

The two ketones (28) and (29) are known to undergo the Norrish Type II hydrogen abstraction process, and their photochemical reactivities have now been studied in chirally modified zeolites. The zeolites were modified by stirring them with known amounts of ( —)-ephedrine. Irradiation of the ketones in the zeolites brought about some enantiomeric enhancement. However, the various zeolites studied behaved differently and the NaX zeolite favoured the (+)-isomer of the product (30) while the NaY favoured the ( —)-isomer. The other ketone (29) showed only low enantiomeric enhancement and gave both the cis and the trans cyclobutanols (31) and (32) in a ratio of 4 1. ... 

The pure trans-isomer (106) was obtained by distillation from the reaction of (—)-ephedrine with phosphorus trichloride in the presence of base, although some cis-isomer was present in the crude reaction mixture. ... 

As early as 1904, Willstatter attempted to separate optical isomers on the optically active natural polymers wool and silk [10]. About 35 years later, the first partial chromatographic resolution of the enantiomers ofp-phenylene-bis-imino-cam-phor on lactose was achieved by Henderson and Rule [11], and a few years later by Lecoq for the enantiomers of ephedrine [12], and by Prelog and Wieland for the enantiomers ofTroeger s base [13]. 

Kier, L. B. The preferred conformations of ephedrine isomers and the nature of the alpha adrenergic receptor. J. Pharmacol. Exp. Then 1968,164, 75-81. 

Portoghese, P. S. Stereochemical studies on medicinal agents. IV Conformational analysis of ephedrine isomers and related compounds. J. Med. Chem. 1967,10, 1057-1063. 

Ketene silylacetals also react with a- or P-alkoxy- or -aminoaldehydes. Chelation control may take place in the reaction of ephedrine-derived ketene silylacetal 6.121 with p-benzyloxyaldehydes. Under TiCl4 catalysis, syn isomers are favored (Figure 6.98), but the reaction is highly selective only if the aldehyde is a-alkylated and the reagents are matched [1295], The results are interpreted through the intervention of a six-coordinate titanium complex 6.122 (Figure 6.98). 

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