Ephedrine stereochemistry

Another chiral auxiliary for controlling the absolute stereochemistry in Mukaiyama aldol reactions of chiral silyl ketene acetals has been derived from TV-methyl ephedrine.18 This has been successfully applied to the enantioselec-tive synthesis of various natural products19 such as a-methyl-/ -hydroxy esters (ee 91-94%),18,20 a-methyl-/Miydroxy aldehydes (91% ee),21 a-hydrazino and a-amino acids (78-91% ee),22 a-methyl-d-oxoesters (72-75% ee),20b cis- and trans-l1-lactams (70-96% ee),23 and carbapenem antibiotics.24... 

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. 

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. 

Scheme 5.13 The PDC-catalyzed synthesis of (R)-phenylacetyl-carbinol induces the stereochemistry in the industrial synthesis of (-)-ephedrine.

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. 

During the isolation of cathinone, 3,6-dimethyl-2,5-diphenyl pyrazine (3) was also found (14). This is doubtless an artifact, the product of oxidative dimerization of cathinone which involves the formation of condensation product 4 as an intermediate (18). Also found was the diketone (5) and the cinnamoyl compound (6) (14), later shown to have the (S) stereochemistry illustrated and named merucathinone (6,19,20). Merucathine (7) has also been isolated (6,21,22), and this and merucathinone are minor components. (-)-Norephedrine (8) also occurs in khat (14), and its iV-formyl derivative (9) has been found in plant material of South Arabian origin (23). Despite earlier positive reports, ephedrine and pseudoephedrine have not been verified as components of khat (14). HPLC has been employed to separate and quantify mixtures of the khatamines cathinone, (+)-norpseudoephedrine, and (—)-norephedrine in connection with a study of their distribution in different parts of the khat plant and in specimens of different geographical origin (20,21). 

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). 

The fT-alkylidene derived from furfural undergoes cycloaddition to form a major diastcrcomer with the opposite absolute configuration at the (3-carbon. However, it is found that the extent of diastereofacial selectivity in addition to -acceptor is around 90%, so a more efficient method to reverse the sense of induction is to employ <7-ephedrine as the source of chirality. In each example, the stereochemistry of addition to the /i-carbon of the acceptor is the result of attack syn to the phenyl and methyl groups and explained by a conformational effect69. 

Mechanism of action of /-ephedrine Drudi-Baraceo et al. Compt. Rend. Soc. Biol 158 259 (1964). Toxicity M. D. Fairchild, G. A. Alles, J. Pharmacol. Exp Ther. 158, 135 (1967). Review of new methods and developments in stereochemistry Fodor, Recent Develop. Chem. Nat. Carbon... 

The bicyclic 1,3,2-dioxaphosphorinanes have lost their popularity and have been replaced, both for mechanistic studies and for synthetic purposes, by the monocyclic and yet diastereoisomeric 3,4-dimethyl-5-phenyl-l,3,2-oxazaphospholidines . The most widely employed of these compounds have been those derived from (-)-ephedrine and of 4S,5R geometry (79), from (+)-ephedrine, and so of 4R,5S geometry, and from (+)-pseudoephedrine, which are of structure 83 with 4S,5R stereochemistry. Their syntheses with a dichloride RP(Z)Cl2 in the presence of an appropriate HCl acceptor yield mixtures of products, epimeric at phosphorus, and generally separable. A few other compounds have been derived from norephedrine. The stereochemistries of several such compounds have been determined by X-ray crystallography, and reference has just been made to some... 

In the last section several oxazaphospholidine oxides, obtained by oxidation of the P(III) precursor with t-BuOOH, have already been described. There is also one report by Juge and co-workers in which they prepare oxazaphospholidine oxides and sulfides by in situ deboronation/oxidation of oxazaphospholidine boranes. This section illustrates some more derivatives, prepared directly from P(V) species and ephedrine. Chronologically, these types of compounds were studied earlier than the corresponding P(III) counterparts. Nowadays oxazaphospholidine boranes, not oxides, are the most important precursors used to prepare enantiopure phosphorus ligands. However, apart from historic interest, ephedrine-derived oxazaphospholidine oxides, sulfides and selenides occupy an important place in the study of phosphorus stereochemistry and conformational analysis. Only a few examples are described here. 

The low vapor pressure and high thermal stability of CILs render them suitable for enantioseparations in gas chromatography (GC). Recently, CILs have been used as chiral stationary phases (CSPs) in GC [40]. Armstrong and coworkers carried out enantiomeric separation of chiral alcohols and diols, chiral sulfoxides, some chiral epoxides and acetamides using a CIL based on ephedrinium salt. Using an ephedrinium CIL (4) as the CSP, enantiomeric separation of alcohols and diols was achieved (Fig. 1). The presence of both enantiomeric forms of ephedrine makes it possible to produce CSPs of opposite stereochemistry, which could reverse the enantiomeric elution order of the analytes. This offers an additional advantage that may not be easily achieved with common and widely used chiral selectors in GC such as the cyclodextrins. However, there was a decrease in enantiomeric recognition ability of the CSP after a week which the authors attributed to dehydration-induced... 

Results are shown in Table VI and they appear rather complex. For example, the ephedrine polymers gave products with optical purity comparable to or lower than that obtained with the monomer catalyst. The quinine polymer gave lower optical yield than the monomer at -78 °C, but higher at 0 and 25 °C, whereas XXXVIII shows an opposite trend. When a more detailed study was undertaken in order to determine the influence of temperature upon the optical purity of the product, the authors suggested that the mechanism of action of polymeric catalysts differed greatly from that of their corresponding monomeric models, particularly in the stereochemistry of the addition reaction. 

While GC/MS has traditionally been the screening method of choice for controlled substances, this approach does not provide molecular structural information and cannot be used as a principal means of identification for pseudoephedrine. GC/MS cannot distinguish pseudoephedrine from its sister compound ephedrine their GC retention times and mass spectra are essentially the same because the two compounds differ only in their stereochemistry. To achieve structural discrimination, scientists have combined infrared (IR) spectroscopy and GC/MS. The IR radiation provides structural information about the intact form of the molecules under study and is able to detect subtle variations in different structural forms. In this way, pseudoephedrine can be distinguished from ephedrine. However, while highly selective, this approach is still not as sensitive as GC/MS. 

Natural products of the general formula PhCH(OH)CH(NHMe)CH3 are isolated from Ephedra species and are called ephedrine and pseudoephedrine. They have various physiological effects, including uses as decongestants and appetite suppressants. Draw all four of the possible stereoisomers as Fischer projections, and assign the stereochemistry at each chiral center. Why do ephedrine and pseudoephedrine have different physiological effects Do the natural and unnatural isomers have different effects What is the relationship of these molecules to methamphetamine ... 

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