Ephedrine analog

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. 

Acids and lactones Alkaloids (brucine, strychnine, quinidine, quinine, chinchonine, chinchonidine, dehydroabietylamine, quinotoxine, cinchotoxine), terpene derivatives (endo-bomylamine, 1 R-3-endo-aminobomeol, pinelylamines, (+)-3-aminomethylpinane) ephedrine and ephedrine analogs, synthetic amines (d-methyl-benzylamine and its derivatives, d-l-naphthylethyl-amine, 2-amino-l,2-diphenylethanol), amino acids and bases derived thereof [15-19] [20-23] [24,25-27] [28-31]... 

According to Camus, hordenine is of low toxicity, but in large doses it causes death by arrest of respiration. It is less active than adrenaline but analogous in its action, resembling ephedrine rather than adrenaline. Barger and Dale found that the methiodide had a marked nicotine-... 

Addition of a hydroxyl group to the aromatic ring of ephedrine as well as changing the substitution on nitrogen leads to a compound whose main activity is to raise blood pressure. Thus, lormation of the Shiff base of the m-hydroxy analog of 30 with bcnzylamine (34), followed by catalytic reduction, yields metar- uiiinol (35). When optically active hydroxyketone is employed in... 

The oxazaborolidines are easily prepared by heating ephedrine with borane dimethyl sulfide or the appropriate boronate ester. The aluminum reagent C is obtained by mixing ephedrine and trimethylaluminum. Borolidinc A is superior to its methyl derivative B and to the aluminum analog C. The diastereomeric borolidine obtained from borane and (S,S)-pseu-doephedrine failed to show any cnantioselectivity25. A variety of aromatic aldehydes can be enantioselectively alkylated in the presence of A, however, with heptanal the enantioselectivity is poor25. 

Chemical Structures. Figure 1 shows the chemical structures for 14 phenylethylamine compounds. Nine of these compounds are used clinically as anorectics (ii-amphetamine, phentermine, diethylpropion, phenmetrazine, phendimetrazine, clotermine, chlorphentermine, benzphetamine, and fenfluramine). Four of these compounds are not approved for clinical use and are reported to have hallucinogenic properties (MDA, PMA, DOM, and DOET). The final compound ( /-ephedrine) is used clinically for bronchial muscle relaxation, cardiovascular, and mydriatic effects. Figure 2 shows the chemical structure for MDMA, the methyl analog of MDA. MDMA is not approved for clinical use and has been reported to produce both LSD-like and cocaine-like effects. 

Ephedrine, for example, produces weak AMPH-like activity (Huang and Ho 1974b). (+)Norpseudoephedrine (cathine) also produces AMPH-like stimulus effects. The oxidized analogs of norephedrine and ephedrine, cathinone and methcathinone, respectively, however, are potent AMPH-like agents (table 2). 

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]. 

Analogous to the use of chiral enoates (see previous section), a, -unsaturated carboxylic amides, prepared from chiral amines, may be utilized in asymmetric 1,4-additions. When Grignard reagents are added to unsaturated amides (21), derived from (-)-ephedrine (20),25 highly optically active fi-sub-stituted alkanoic acids (22 R and R = alkyl or phenyl) are obtained in a variety of cases, after hydrolysis of the initially formed adducts (Scheme 7). This method was used for the synthesis of the antibiotic (-) malyngolide and its stereoisomers.26 Recrystallization of the intermediate (saturated) amide was necess-... 

Analogous to the use of chiral acetals one can employ chiral N,O-acetals, accessible from a, -unsatu-rated aldehydes and certain chiral amino alcohols, to prepare optically active -substituted aldehydes via subsequent Sn2 addition and hydrolysis. However, the situation is more complicated in this case, since the N,0-acetal center constitutes a new stereogenic center which has to be selectively established. The addition of organocopper compounds to a, -ethylenic oxazolidine derivatives prepared from unsaturated aldehydes and ephedrine was studied.70-78 The (diastereo) selectivities were rather low (<50% ee after hydrolysis) in most cases, the highest value being 80% ee in a single case.73 There is a strong solvent effect in these reactions, e.g. in the addition of lithium dimethylcuprate to the ( )-cinnamaldehyde-derived oxazolidine (70 Scheme 28) 73 the (fl)-aldehyde (71) is formed preferentially in polar solvents, while the (S)-enantiomer [ent-71) is the major product in nonpolar solvents like hexane. This approach was utilized in the preparation of citronellal (80% ee) from crotonaldehyde (40% overall yield).78... 

To improve supercritical C02 solubilities of target alkaloidal salts, an appropriate modifier to raise the polarity of C02 had to be used. As previously mentioned, the most common modifier used in SFE is methanol because of its high solvation parameters, which can greatly increase the resultant polarity of C02. Water has been chosen as another modifier because some alkaloidal salts are freely soluble in water as well as methanol. Moreover, the addition of water into C02 has been reported to improve the extraction yield of some alkaloids [29]. Methanol or water as a modifier was added into the extractor at the concentration levels of 1, 5 and 10% (v/v), respectively. The effect of methanol and water on the solubilities of hyoscyamine (1) and scopolamine (2) is shown in Figure 5. Analogous information on ephedrine derivatives such as methylephedrine (3), norephedrine (4), ephedrine (5), and pseudopehedrine is illustrated in Figure 6. 

The reaction of racemic A-phthalimido-S-p-tolyl-S-vinylsulfoximine with a deficiency (0.5 molar equiv) of enantiomerically pure (-)-ephedrine resulted in a kinetic resolution of the vinyl sulfoximine.113 When the reaction was conducted at -30 °C the unreacted vinyl sulfoximine could be recovered with an enantiomeric purity of 46%. (-)-Amphetamine and (+)-l-phenylethylamine were not effective for kinetic resolution. The analogous (Z)-propenyl sulfoximine also underwent kinetic resolution with (-)-ephedrine, but the extent of kinetic resolution was not determined. 

The subsequent steps in the French and Czech modifications follow the Woodward synthesis in its broad lines, but it should be noted that Velluz already resolves Woodward s XXXV into optical isomers with the help of either brucine or ephedrine (185). In an analogous study, the Czech investigators resolve a hydroxy acid (XXXVIII), obtained by hydrolysis of the Velluz compound (XXXVII) (185), with the help of brucine (187). Also, another dihydroxy acid (XXXIX), obtained from Woodward s lactone acid (XXXVI), has been resolved, again by use of... 

The use of CDs with bile salt micelles has been also successful for enantiomer separations. For example, Dns-DL-AAs, baclofen and its analogs, mephenytoin and fenoldopam, naphthalene-2,3-dicarboxaldehyde derivatized dl-AAs (CBI-dl-AAs), diclofensine, ephedrine, nadolol, and other j8-blockers, and binaphthyl-related compounds were enantioseparated by CD-MEKC with bile salts. 

Analogous additions were later reported by Ito and co-workers (Scheme 9) (20). The enamines for these additions were prepared from the corresponding aminals using a mild base in the presence of trimethylsilyl chloride. In turn, the aminals used are available from (— )-ephedrine and (S)-prolinol. The byproduct amine hydrochloride was removed either by distillation or by precipitation from a benzene solution. Enamines prepared by this method were found to be unreactive toward unsaturated carbonyl compounds in a variety of solvents. Importantly, it was found that use of a mild Lewis acid such as anhydrous MgCl2 or ZnCl2 in THF promoted the reactions. Thus, the addition of enamines 9.1 and 9.2 to methyl acrylate is achieved. Of the two enamines, the proline-derived 9.1 is the more effective auxiliary. The... 

The enolates of //-acylimidazolidinones derived from 1.131 generated from ephedrine 1.61 (R = H) are useful in asymmetric alkylations [447, 448] and aldol reactions [449, 450] and cuprate additions to the a,p-unsaturated acyl analogs have recently been described [451], These chiral auxiliaries are cleaved by MeONa/MeOH or LiEtBHj. Recently, Davies and coworkers have suggested the use of symmetrical AyV-diacyl-1,3-imidazolidin-2-ones 1.132, formed from diamines having a C2 axis of symmetry [452], for asymmetric aldol reactions [449]. Juaristi [453] has used peihydropyrimidin-4-ones for related purposes. 

Additional catalysts have also been proposed for the reaction of Et2Zn with aromatic aldehydes, including (proline derivative 2.13 (R = CPh2OH) [110] and a four-membered analog [646], (1S,2R)-1.61 (R = S02Tol), 2.47, and pyridine-derived aminoalcohols [110, 644, 651, 1173]. Other catalysts include sulfur derivatives of ephedra alkaloids [645, 728], the Li diamide of piperazine 2.46, diamines 1.64 (R = 2-Py) and other related 2-aminopyridines [367, 648, 649, 1174], p-Hydroxysulfoximines have also been used as catalysts in these reactions [1175], as has an oxazaborolidine derived from ephedrine [1176],... 

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