Diastereomer pseudoephedrine

The first report on the reaction of D-pseudoephedrine 66 with phosphoryl chloride appeared as early as 1962 [49], More recently it was found that this condensation gave 2-chloro-l,3,2-oxazaphospholidine 2-oxides 67 as a single diastereomer which was subsequently esterified with racemic aldehyde cyanohydrins 68 without racemization at the phosphorus atom. The prepared diastereomeric esters 69 were used as substrates for the asymmetric synthesis of optically active cyanohydrins 72, which involves the intermediate formation of the tertiary esters 70, as shown in Scheme 22 [50],... 

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. 

Limits of detection for many amino acids were enhanced considerably by pre-column derivatization with the achiral reagent dansyl chloride whose function it was to increase their specific rotation [17]. Determinations of the enantiomeric purities for mixtures of D-and L-tryptophan [18] and of isomeric ratios for mixtures of pseudoephedrine and its diastereomer ephedrine [19], were effected using diode-laser polarimetry and using OR detection in series with UV absorbance detection respectively. 

The six optically active alkaloids ephedrine, pseudoephedrine, norephedrine, norpseudoephedrine, and the N-methylated N-methylephedrine and N-methylpseudoephedrine are described in detail in Reti s review (2). Two new alkaloids of related structure have since been identified in Ephedra species, namely, (9-benzoylpseudoephedrine (271) and the oxazolidine derivative ephe-droxane (272). The 4-quinolone derivative ephedralone, recently isolated from Ephedra alata (273), may be of similar biogenetic origin as the ephedrines. Ephedra species also contain macrocyclic alkaloids of more complex structure (275). The two major Ephedra alkaloids (—)-ephedrine and (+)-pseudoephedrine are diastereomers. (—)-Ephedrine has the erythro and (+)-pseudoephedrine has the threo configuration. 

The natural enantiomers of the two diastereomers are (-)-ephedrine and (+)-pseudoephedrine, which does not tell you which is which, or (lR,2S)-(-)-ephedrine and (lS,2S)-(+)-pseudoephedrine, which does. From that you should be able to deduce the corresponding structures. 

Moderate asymmetric induction and low yields are observed when the compound 5, prepared from (A, )-hexadienal and (15,25)-pseudoephedrine, undergoes cycloaddition with the nitroso derivative 6. The major cycloadduct 7 is obtained together with minor amounts of diastereomers (d.r. 62 24 11 3) and after chromatography is isolated in 32% yield. Its configuration is first assigned by H NMR, and then by conversion into the known (+ )-(S)-2-methyl-l-(4-toluenesulfonyl)piperidine. Compound 7 is the key intermediate for the total synthesis of an amino allose derivative135. 

A useful mnemonic for deriving the preferred diastereomer formed in the alkylation reaction of pseudoephedrine amide eno-lates with alkyl halides is as follows the alkyl halide enters from the same face as the methyl group of the pseudoephedrine auxiliary when the (putative) ( -enolate is drawn in a planar, extended conformation (eq 1). ... 

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-... 

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). 

Several amino alcohols have been isolated from Ephedra species ephedrine (3), norephedrine (1), pseudoephedrine (or t/ -ephedrine, 4), and norpseudoephedrine (2). The pseudocompounds are diastereomers of the corresponding alkaloids. 

Compounds containing more than one chiral center probably are the most common type of diastereoisomer used as drugs. The classic example of compounds of this type is the diastereoisomers ephedrine and pseudoephedrine (Fig. 2.21). When a molecule contains two chiral centers, there can be as many as four possible stereoisomers consisting of two sets of enantiomeric pairs. For each enantiomeric pair, there is inversion of both chiral centers, whereas the difference between diastereomers is inversion of only one chiral center (Problem 9 at the end of this chapter helps to illustrate this point). 

Pseudoephedrine, as previously discussed, is the three diastereomer of ephedrine, with virtually no direct activity and fewer CNS side effects than ephedrine. (+)-Pseudoephedrine is widely used as a nasal decongestant. 

One of the older syntheses of ephedrine originates from Aladar Skita (1876-1953) in 1929 (Fig. 6.44). Methyl phenyl diketone is catalytically hydrogenated in presence of methylamine. Thus, ephedrine is produced in a single step, devoid of the other diastereomers of pseudoephedrine (the R,R- and S,S- enantiomers). [100]... 

In spite of the mentioned stereochemical complexities, in all cases the major diastereomer has the substituent at the P atom and the Ph and Me groups of the ephedrine backbone in trans disposition. This has been confirmed by X-ray crystallography and can be easily rationalised in terms of thermodynamic preference. The result in entry 27 by Hansen and co-workers, who used pseudoephedrine, sheds more light on this issue. They demonstrated that the phenyl groups at the P atom and in the ephedrine have a trans relationship and concluded that the absolute configuration of the P atom is controlled by the carbon atom bearing the phenyl group in the ephedrine or pseudoephedrine. 

Notably, pseudoephedrine is a diastereomer of ephedrine and considerably racemic ephedrine (dl-ephedrine) has not been found naturally, however, it is prepared synthetically and is inactive for commercial purposes. Ephedrine and pseudoephedrine are completely stable compounds under changing temperature conditions, but they are quite unstable when exposed to sunlight or in the presence of oxygen pressure [2]. The unique molecular structure of ephedrine causes its different stereoisomers to be valuable for pharmaceutical applications such as nasal decongestant, pupil dilator, bronchodilator, and central nervous system stimulant. Ephedrine is a sympathomimetic substance and the principle mechanism of ephedrine activity is its influence, by enhancing the activity of noradren-alin, on post-synaptic a- and (3-receptors in the nervous system. Stimulation of a 1-adrenergic receptors produces contraction of vascular smooth muscle. 

Ephedrine and pseudoephedrine are diastereomers (one stereogenic center is the same one is different). 

Two other alkylations were based on readily-available chiral auxiharies. PhUippe Karoyan of the Universite Pierre et Marie Curie observed Tetrahedron Lett. 2008, 49, 4704) that the acylated Oppolzer camphor sultam 20 condensed with the Mannich reagent 21 to give 22 as a single diastereomer. Andrew G. Myers of Harvard University developed the pseudoephedrine chiral auxiliary of 23 to direct the construction of ternary alkylated centers. He has now established J. Am. Chem. Soc. 2008,130, 13231) that further alkylation gave 24, having a quaternary alkylated center, in high diastereomeric excess. 

Furstner et al. used Myers et al. s pseudoephedrine-based alkylation twice in the preparation of different building blocks that were then further elaborated into amphidi-nolides B4 and G1 (Scheme 7.38). In one instance, t-butyl-(2-iodoethoxy)diphenylsilane was used as the alkylating agent, and in the second, 7 -propenoxide was employed. In the former case, a single diastereomer was generated in excellent yield. The epoxide-based alkylation also proceeded in excellent yield, but the diastereoselectivity was somewhat lower (92.5 7.5). In both cases, the alkylated amide product was transformed into the corresponding alcohol in excellent yield. 

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