Ephedrine conformations

With chiral enol species (/ )-silylketene acetal derived from (1 R,2S)-N-methyl ephedrine-O-propionate, both the aldehyde carbonyl and the ephedrine NMe2 group are expected to bind to TiCU, which usually chelates two electron-donating molecules to form ra-octahedral six-coordinated complexes.25 Conformational freedom is therefore reduced, and the C-C bond formation occurs on the six-coordinated metal in a highly stereoselective manner.18... 

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. 

From calculations of the preferred conformation of the ephedrine and pseudo ephedrine molecules the topography of the adrenergic receptor as a flat surface has been deduced (26). This view, however, does not explain the decisive effect of the additional methyl group its relative position should not influence the interaction with the proposed receptor to a large extent (Fig. 7a). However, as the differences in activities are especially high for the ephedrine and pseudo ephedrine isomers, we believe that the receptor must have an intercalated structure similar as projected for the "binding sites" of the silicones (Fig. 7b). ... 

From the 13C-NMR spectra of a series of 2-methylamino-l-phenyl-1 -propanol ephedrine analogs, it was established that the chemical shifts of C-l and C-3 are always 3-4 ppm smaller in the anti-than in the jvn-diastereomers363,364. This was explained by a greater number of gauche interactions in the energetically preferred anti conformation leading to a shielding of these two carbons. 

A number of methods for the synthesis of piperazic acid (7) and related derivatives are currently available as a result of growing interest in natural product chemistry and in their potential in medicinal chemistry. Their chemistry and conformational properties have been comprehensively reviewed. 2451 Racemic piperazic acid is obtained by condensation of penta-2,4-dienoic acid with phthalazinedione and subsequent reductive deprotection of the resulting A,A -bis(phthaloyl)-l,2,3,6-tetrahydropyridazine-3-carboxylic acid.12431 Resolution of racemic piperazic acid is achieved by fractional crystallization of the ephedrine salt of Nl-(benzyloxycarbonyl)piperazic acid from ethyl acetate. 246,2471 A typical route to enantiomerically pure (3S)-piperazic acid 56 starts from chiral 2-amino-5-hydroxyvaleric acid 55 as shown in Scheme 12.1248 Convenient stereoselective syntheses have been reported for 5-hydroxy- and 5-chloropiperazic acids as important constituents of natural cyclic peptides and depsipep-tides.1249,2521... 

Figure 12. Difference of chemical conformations of ephedrine (5) and pseudoephedrine ( ) and distance between hydrogen and nitrogen measured by molecular modeling (Sybyl 6.5, Tripos).

Various molecules were considered for studying the influence of the five-mem-bered ring conformations, and of the bulkiness of the ring substituents on the dia-stereomeric excess of the aminated products. Optically active (+)-ephedrine 89a and (—)-pseudo-ephedrine 89b were chosen as the chiral amino alcohols because of their relatively low cost and in view of the excellent results obtained in the similar asymmetric synthesis of a-amino carboxylic acids [13]. 

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. 

On the other hand, by bond formation with amino and hydroxy groups of ephedrine, ephedrine can be converted into chiral ring systems such as imidazolidinones, - oxazepinediones, and oxazolidines. - Diastereoselective reactions of derivatives of these chiral ring systems afford compounds with high de. The relatively rigid conformation of these ring systems is one of the reasons for high diastereoselectivities. 

While this approach has been applied primarily to nucleophilic reactions of carbonyl compounds, it can also be used to determine the primary direction of hydrogenation since adsorption on a catalyst surface is preferred from the less hindered side of the carbonyl group. The synthesis of dl ephedrine (20) was accomplished by the hydrogenation of the amino ketone, 19, one enantiomer of which is depicted in Eqn. 14.17.5 xhe hydrogen bond to the carbonyl oxygen helps fix the conformation with hydrogenation taking place from the side of the... 

Recently a systematic investigation of the conformational and electronic aspects of pharmacology has been launched in our laboratory, using the PCILO method. The compounds investigated for which results are already available are those which have been previously investigated by the EHT method acetylcholine, nicotine and muscarine 84>, serotonine 85 histamine 86), ephedrine, norephedrine and dopamine 87>, but also others tyramine, noradrenaline, ephedrine, amphetamine and privine 87), a number of barbiturates 88 and a number... 

FIGURE 26.4 Preferred conformations of D-(—)-ephedrine and of D-(—)-pseudo-ephedrine. 

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. 

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. 

Quantum mechanical calculations on the conformational properties of norepinephrine have also been reported. Interconversion of ephedrine and pseudo-ephedrine to a slight extent under y-irradiation has been observed. Absorption of carbon dioxide by cupric ephedrinates can be accounted for by carbamate formation rather than formation of metal-carbon dioxide bonds. -Acylation of /3-phenethylamines by protected amino-acids, e.g. N-CBZ-leucine, has been reported. ... 

A very large amount of NMR spectroscopic data has been collected during the year under review. The presentation of data in addition to data is now almost routine. NMR spectroscopic studies have now been presented for phosphonocarboxylic acids and their esters,some new phosphinic amides, and for Lawesson s reagent (solid and solution data). A spectroscopic study of the dimer of the nitrile oxide (401) suggested the structure (402). 1-(1-Naphthalenyl)ethylamine and ephedrine are recommended for the NMR spectroscopic determination of the enantiomeric composition of (1-aminoalkyl)-phosphonates, but of quinine and rert-butylphenylphosphinothioic acid, only the former was effective for the chiral resolution of the diethyl esters in the determination of e.e.s of (2-hydroxyalkyl)phosphonates. Conformational analyses, based on NMR spectroscopic data, have been carried out for dialkyl (2-hydroxyalkyl)phosphonates. ... 

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