N-Methylephedrine

Another possibility for asymmetric reduction is the use of chiral complex hydrides derived from LiAlH. and chiral alcohols, e.g. N-methylephedrine (I. Jacquet, 1974), or 1,4-bis(dimethylamino)butanediol (D. Seebach, 1974). But stereoselectivities are mostly below 50%. At the present time attempts to form chiral alcohols from ketones are less successful than the asymmetric reduction of C = C double bonds via hydroboration or hydrogenation with Wilkinson type catalysts (G. Zweifel, 1963 H.B. Kagan, 1978 see p. 102f.). 

Tab. 3.7 N-Methylephedrine reagent modification in Simmons-Smith cyclopropanation...

Enantioselective addition of CjH zZn to aldehydes.1 Addition of diethylzinc to either aromatic or aliphatic aldehydes catalyzed by 1 (6 mole %) results in (S)-secondary alcohols in generally 90-95% ee. Although several chiral amino alcohols are known to effect enantioselective addition of R2Zn to aromatic aldehydes, this one is the first catalyst to be effective for aliphatic aldehydes. The dibutylamino group of 1 is essential for the high enantioselectivity the dimethylamino analog of 1, (lS,2R)-N-methylephedrine, effects this addition in only about 60% ee. 

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. 

Chiral trms-fi-lactams. The silyl ketene acetal (1), derived from (1S,2R)-N-methylephedrine, reacts in the presence of TiCl, with benzylideneaniline (2) to give as the major products anti- and syn-3 in the ratio >10 1. Cyclization of the mixture gives the trans-p-lactam (4) in 95% ee. 

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. 

A chiral hydride complex, tentatively assumed to be 86, prepared by partially reacting LAH with (- )-N-methylephedrine (1 equivalent) and /V-ethylaniline (2 equivalents) was found to reduce 2-acetyl-5,8-dimethoxy-3,4-dihydronaphtha-lene (87) quantitatively to the (- )-carbinol (88) with 92% e.e. (94,95). Carbinol 88, which was obtained optically pure by recrystallization, could be converted to (/ )-(-)-2-acetyl-5,8-dimethoxy-l,2,3,4-tetrahydro-2-naphthol (89). The lat-... 

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). 

ASYMMETRIC REDUCTIONS 2,2 -Di-hydroxy-1,1 -binaphthyl-Eithium aluminum hydride. (2S,3RH+)-4-Dimethyl-ainino-3-methyl-l, 2-diphenyl-2-butanol. Lithium aluminum hydride-(-)-N-Methylephedrine. B-(3)-a-Pinanyl-9-borabicyclo[3.3.11nonane. (S)-2-(2.6-Xylidinomethyl)pyrrolidine. 

ALKYL-y-BUTYROLACTONES N-Methylephedrine-Lithium aluminum hydride-3,5-Dimethylphenol. 

Methoxy-1,3-bis( trimethylsilyloxy) -1,3-butadiene, 178 (1 R,2S)-N-Methylephedrine-0-pro-pionate, 308 Norephedrine, 200 Organotitanium reagents, 213 2-Oxazolidones, chiral, 225 (2R,4R)-Pentanediol, 237 Tin(II) trifluoromethanesulfonate, 301 Alkylation... 

Recently Carreira reported the first catalytic and highly enantioselective alkynylation. Thus, in the presence of a catalytic amount of Zn(II) salt and N-methylephedrine (21), the reaction of aldehydes and terminal acetylenes proceeds to give various chiral propargyl alcohols with high ee (Scheme 8) [30]. A... 

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]. 

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. 

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. 

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