Ephedrines, configuration

P-Nitro alcohols can be hydrogenated to the corresponding amino alcohols with retention of configuration the stereoselective Henry reaction is a useful tool in the elaboration of pharmacologically important P-amino alcohol derivatives including chloramphenicol, ephedrine, norephedrine, and others. Some important P-amino alcohols are listed in Scheme 3.11.107... 

It is of interest to note that in the case of oxaazaphosphospholidines 302 derived from (-)-ephedrine (42), some inversion at the benzylic carbon occurred giving a mixture of the P-epimeric derivatives 303 (Scheme 71) [108], Halide exchange with inversion of configuration in the intermediate was suggested as the most likely explanation for the loss of stereospecificity. 

The optically active thiones (4), readily obtainable from (—)-ephedrine, undergo P—N bond fission, with inversion of configuration at phosphorus, when treated with ethanolic HC1 this provides a highly recommendable method for the preparation of valuable amounts of optically active acyclic compounds (5), isolable as the 5-methyl esters (6).9... 

Despite the high sensitivity of the methods for chiral resolution described in Section IV.D.4, more direct methods are afforded by NMR spectroscopy, especially for the products of synthesis. Ephedrine (179), pseudoephedrine (180a) and its Me ether (180b) yield stable epimeric N — BH3 adducts on treatment with borane. The configuration of the nitrogen moiety was established by NMR, taking into account the conformational analysis of the molecule392. 

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. 

Clearly, upon using the enantiomeric catalyst [(S,S) instead of (R,R)] the opposite enantioselectivity of the overall process results. However, this effect is also seen with catalysts that are of analogous configuration, but not derived from trans-1,2-diaminocyclohexane (DACH). For example, the pseudo-ephedrine derived catalyst shown in Scheme 5, having (5)-configuration at the centers of chirality, shows some preference for the (5)-azlactone kinetically favors the (5)-azlactone in alcoholytic ring opening [37]. 

Substituted chiral aldehydes can be derivatized with naturally occurring (1/ ,2S)-ephedrine to give oxazolidines, UC- and H-NMR analysis allows determination of the enantiomeric excess and in simple cases the absolute configuration of the analyzed aldehyde6. Very mild reaction conditions are required. 

Acids and bases. These can be converted to various salts. For example, the absolute configuration of dimethyl (M)-5,6,8,10-tetramethyl-l,2-heptalenedicarboxylate (p 404) was determined by X-ray analysis of its (+)-ephedrine salt84, and the absolute configuration of Troger s base (p 404) by X-ray analysis of a salt with an acid of known configuration87. 

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. 

With benzaldehyde 144 or halogenated derivatives (Cl, F) as acceptors the yeast-PDC-catalyzed addition proceeds with almost complete stereoselectivity to furnish the corresponding (R)-configurated 1-hydroxy-1-phenylpropanones 145 [447]. For practical reasons, whole yeast cells are most often used as the catalyst, with only small loss of enantioselectivity [423,424]. The conversion of benzaldehyde in particular has gained industrial importance because the acyloin is an important precursor for the synthesis of L-(-)-ephedrine [448]. Otherwise, the substrate tolerance is remarkably broad for aromatic aldehydes on the laboratory scale, however, yields of acyloins are usually low because of the prior or consequent reductive metabolism of aldehyde substrate and product, giving rise to considerable quantities of alcohol 146 and vicinol diols 147, respectively [423,424,449], The range of structural variability covers both higher a-oxo-acids (e.g. -butyrate, -valerate) as the donor component, as well as a,/J-un-saturated aldehydes (e.g. cinnamaldehyde 148) as the acceptor [450]. 

Since allyl sulfoxides may quite easily undergo racemization at the sulfur atom via a reversible [2,3] sigmatropic process, the configurationally more stable chiral allylic phosphine oxides were also investigated.201 Compounds (184) and (185), prepared as a 1 1 mixture from allylphosphonyl dichloride and (-)-ephedrine, were shown to add to cycloalkenones with reasonably high diastereoselectivities. Ozono-lysis of the initially formed 1,4-adducts affords the respective optically active ketoaldehydes (Scheme 67). With a / /-isopropyl-substituted derivative even higher selectivities (88-98% ee) could be obtained. 

The change from the phenolic structure of epinephrine to the phenyl structure of ephedrine results in a marked difference in action. Unlike epinephrine, ephedrine is effective orally, has a prolonged action, exhibits tachyphylaxis, and is a potent corticomedullary stimulant. The oral effectiveness and prolonged action of ephedrine are apparently due to the presence of the methyl group on the a carbon atom, a configuration that renders the molecule refractory to deamination by the amine oxidase of the liver. 

The basic hydrolysis of acyclic phosphoramidates occurs with a mixture of C-0 and P-0 bond cleavage (l, 2) however similar treatment of l,3>2-oxazaphospholidines can result in substantial P-N cleavage ( 1, 3). 1,3,2-Oxazaphospholidines derived from (-)-ephedrine react with solutions of alkoxides in alcohol to give only the products of P-N cleavage and with inversion of configuration at phosphorus. Scheme I ( +, 5). ... 

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. 

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. 

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