Methylephedrine yields

The ( )-trimethylsilylenolates of A-methylephedrine propanoates are useful as chiral propanoate equivalents in the titanium(IV) chloride catalyzed addition to enones. Although diastereoselec-tivities are high, this method suffers from low yields due to excessive polymerization190. 

The third group4 used (1R,2S)-N methylephedrine as the chiral auxiliary. Thus the derived silylketene acetal (6) reacts with 1 in the presence of TiCl4 to give 7 in 45-70% yield with —90% stereoselectivity. The products are converted by TFA and LiOH to (R)-a-hydrazino acids (8), which are obtained in 5=98% ee after one crystallization. 

Carreira and co-workers developed a highly efficient enantioselective addition of terminal alkynes to aldehydes giving propargyl alcohols by the mediation of zinc tri-flate and N-methylephedrine [17]. This reaction serves as a convenient and powerful synthetic route to a wide variety of enantioenriched allenes via propargyl alcohols. Dieter and Yu applied this alkynylation to the asymmetric synthesis of allenes (Scheme 4.12) [18]. Reaction of phenylacetylene with isobutyraldehyde afforded the propargyl alcohol in 80% yield with 99% ee, which was mesylated to 49 in quantitative yield. Reaction of 49 with the cyanocuprate 50 afforded the desired allene 51 with 83% ee. 

In a synthesis of optically active allethrolone and prostaglandin intermediates, Yamada and co-workers (92) studied the reduction of certain 2-alkyl-1,3,4-cyclopentanetriones (82) with a reagent prepared by the reaction of LAH with 3 equivalents of (- )-A-methylephedrine in THF. Reduction of the cyclopen-tanetriones 82 with this reagent gave (/ )-83 in 55 to 58% e.e. (Scheme 12). Thus (/ )-83b (R2 = Ac, after acetylation) was obtained in 48% yield and 55% e.e. from 82b. The steric course and enantiomeric excess in the reduction were... 

Commercial samples containing approximately 400 mg of ephedra per capsule yield roughly 5 mg of ephedrine, 1 mg of pseudoephedrine, and less than 1 mg of methylephedrine (White et al. 1997). For a dose of four capsules, yielding approximately 20 mg of ephedrine, the elimination half-life is 5.2 hours. The time to reach maxium concentration is 3.9 hours. Compared to pure ephedrine tablets, the elimination kinetics of ephedra are comparable. However, ephedra showed somewhat different absorption kinetics (e.g., lag time, area under the concentration-time curve, and maximum plasma concentration). So, ephedra tablets may vary from pure ephedrine in the onset of action, but the durations of action are grossly equivalent. 

Metal alkyl peroxides can be used for the epoxidation of electron-deficient alkenes such as enones. The use of a combination of diethylzinc, oxygen, and A-methylephedrine gave epoxides in very high yield and generally high enantio-selectivity (Figure 11.8). " ... 

An alternative method for the epoxidation of enones was developed by Jackson and coworkers in 1997 , who utilized metal peroxides that are modified by chiral ligands such as diethyl tartrate (DET), (5,5)-diphenylethanediol, (—)-ephedrine, ( )-N-methylephedrine and various simple chiral alcohols. The best results were achieved with DET as chiral inductor in toluene. In the stoichiometric version, DET and lithium tert-butyl peroxide, which was generated in situ from TBHP and n-butyllithium, were used as catalyst for the epoxidation of enones. Use of 1.1 equivalent of (-l-)-DET in toluene as solvent afforded (2/f,35 )-chalcone epoxide in 71-75% yield and 62% ee. In the substo-ichiometric method n-butyllithium was replaced by dibutylmagnesium. With this system (10 mol% Bu2Mg and 11 mol% DET), a variety of chalcone-type enones could be oxidized in moderate to good yields (36-61%) and high asymmetric induction (81-94%), giving exactly the other enantiomeric epoxide than obtained with the stoichiometric system (equation 37). 

Of greater synthetic interest is asymmetric induction by the use of chiral catalysis. Grigg was the first to report chiral catalysis of 1,3-dipolar cycloadditions in 1991 (101). A study of metal salts and chiral ligands revealed that 358 underwent cycloaddition with methyl acrylate to furnish adduct 359 in the presence of C0CI2 and (IR, 25)-A-methylephedrine as the chiral ligand. The pyrrolidine product was isolated in 55% yield with an ee of 84%. The use of methyl acrylate as solvent led to an improved yield of 84% with an excellent ee of 96% (Scheme 3.121). 

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. 

While increasing the concentration of water did not show any significant influence, the addition of a greater proportion of methanol yielded great enhancements in the resultant solubilities of the alkaloids, except for methylephedrine (3). These observations may be due to the fact that water is not so miscible as methanol in CO, (Figure 7). Therefore, water was less effective than methanol in terms of the enhancement of the SFE efficiency. Even though the addition of methanol in CO, resulted in slight improvements in solubilities, they were still poor, hence another modifier to enhance the solubilities of the alkaloidal salts was required. 

Table 4. Yields of methylephedrine (ME), norephedrine (NE), ephedrine (E), and pseudoephedrine (PE) obtained by organic solvent extraction and SFE. Results are mg/g [41].u Reproduced with permission from Vieweg Publishing 1999.

A cheap and efficient enantioselective aza-Henry reaction of nitromethane with a variety of A-protected arylaldimines has been reported.73 Using zinc triflate and (-)-A-methylephedrine at -20 °C, yields and ees of up to 99% have been achieved with wide tolerance of aryl substituent in terms of both electronic nature and position. The auxiliary is also easily recycled. 

A catalytic version of the Zn( 11)-mediated enantioselective addition of alkynylides to aldehydes was documented after the stoichiometric process [19]. Initially, the reaction was reported to proceed using 22 mol % N-methylephedrine, 20 mol % Zn(OTf)2, and 50 mol % Et3N to furnish the product alcohols in yields and enantioselectivity only marginally lower than in the original stoichiometric version (Eq. 15). The key difference between the stoichiometric and the catalytic procedures is the elevated temperature (60 °C) for the catalytic process. Because the reaction can also be conducted under solvent-free conditions, ensuring a process with a high atom economy and volumetric efficiency (Eq. 16). Under these conditions, the reactions can be conducted with substantially lower catalyst loading (Eq. 17) [13]. 

A stereoselective synthesis of ( )-ephedrine and ( )-methylephedrine has been described (318). The method utilizes a carbanion, in which the negative charge is located a to the nitrogen, formed by deprotonation of 1. Subsequent reaction with benzaldehyde yields the 2-oxazolidone 2, and thermal removal of the diphenylphosphinyl group gives the 2-oxazolone 3. Hydrogenation of 3 proceeds with perfect stereoselectivity to yield the erythro isomer 4, which is easily converted to ( )-ephedrine or ( )-W-methylephedrine. 

Asymmetric reduction of cyclic ketones. Prochiral cyclic ketones arc reduced to (R)-alcohols in 75-96% ee by a chiral hydride obtained by refluxing a mixture of lithium aluminum hydride, (— )-N-methylephedrine (I equiv.), and 2-ethylaminopyridine (2 cquiv.) in ether for 3 hours. Reduction of prochiral acychc ketones with this hydride also results in (R)-alcohols, but only in moderate yield. 

Asymmetric reduction. The complex of L1A1H4, N-methylephedrine, and 3,5-dimethylphenol (1 1 2) reduces aryl alkyl ketones and a-acetylenic ketones to optically active alcohols with a purity of 75-90%. The optical yields are comparable to those observed with the structurally related darvon alcohol (8, 184-186). The reduction of benzoylacetylene, G HsCOC CH, results in a racemic alcohol. ... 

Modification of LAH with (-)-)V-methylephedrine (14) and )V-ethylaniline affords another chiral reducing agent (50). " A variety of aromatic ketones are reduced by (SO) to (S)-carbinols in high optical yields (Scheme 8). Acyclic a,3-unsaturated ketones are also reduced to (S)-carbinols with high selectivity (76-92% ee), but cyclic enones are reduced with only moderate selectivity. 

On the other hand, addition of diazomethane to the ester 18 [from (Z)-4-benzylidene-2-methyl-oxazolone and ( —)-iV-methylephedrine] and photolysis of the resultant 4,5-dihydro-3/f-pyr-azole gave a 57% yield of a mixture of diastereomers (66 34). Separation of the major dia-stereomer 19 by column chromatography and hydrolysis gave (— )-l-amino-2-phenylcycloprop-ane-1-carboxylic acid (-)-(17). ... 

Enders found that the use of diethylzinc, oxygen and N-methylephedrine converted enones into epoxides with enantiomeric excesses of up to 92% in excellent yields (Scheme 18) [53,54]. It is believed that the zinc peroxide 10 is the intermediate in the epoxidation process. Cyclic and s-trans-enones cannot be epox-idized under these conditions. 

The L-proline derived diketopiperazine 27 and diazomethane afford a 1-pyrazoline diastereo-mer which is photolyzed to give the cyclopropane derivative 28 in high yield. Acid hydrolysis then provides (+)-1-amino-2-phenylcyclopropanecarboxylic acid (29) [a] 5 +105 (c = 0.69, water) 81. The optical purity of this amino acid is not reported. Similarly the (—)-enantiomer of l-amino-2-phenylcyclopropanecarboxylic acid is available from a dehydroamino acid using (-)-Ar-methylephedrine as auxiliary81. 

An early intermediate (203) in the synthesis of paeoniflorigenin (204) by Corey was prepared from the silyl enol ether 202 and cyanoacetic acid under the Mn(III)-mediated radical addition conditions [133] (Scheme 69). Highly enantioselective synthesis of y-lactones was reported by Fukuzawa [134] (Scheme 70). The crotonate 205 derived from A-methylephedrine reacted with pentanal in the presence of Sml2 to yield the lactone 206 suggesting chelation control by samarium in the ketyl addition step. 

Quaternary ammonium salts derived from ephedrine have been used as catalysts for the addition of dialkylzinc to carbonyl compounds (Section D.1.3.1.4.) and are useful as phase-transfer catalysts for alkylation of carbonyl compounds17 and reductions18. N-Benzyl-A -methylephedri-nium salts 10 have found varied application they are easily prepared from A -methylephedrine 913 by reaction with benzyl halide in toluene1 or chloroform/methanol (1 1)18 in high yield. Ref 18 also gives the preparation of other ephedrinium and pseudoephedrinium salts. 

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