Norephedrine yields

The synthesis of ephedrine shown in Method H is of commercial interest (316). Condensation of benzaldehyde with nitroethane gives a diastereomeric mixture of nitro alcohols. Reduction yields a separable mixture of ( )-norephedrine and ( )-norpseudoephedrine. Methylation of ( )-norephedrine yields ( )-ephe-drine, which can be resolved into optical antipodes by chemical methods. 

The reduction of ketoxime ethers by borane in the presence of (—)-norephedrine yields (S)-amines from a/ i-kctoximcs and (/ )-isomers from. s i/ -ketoximes, e.g. from phenyl-4-tolyl-methyl ketoxime methyl ether40. 

Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

Chiral oxazolidines 6, or mixtures with their corresponding imines 7, are obtained in quantitative yield from acid-catalyzed condensation of methyl ketones and ( + )- or ( )-2-amino-l-phcnylpropanol (norephedrine, 5) with azeotropic removal of water. Metalation of these chiral oxazolidines (or their imine mixtures) using lithium diisopropylamide generates lithioazaeno-lates which, upon treatment with tin(II) chloride, are converted to cyclic tin(II) azaenolates. After enantioselective reaction with a variety of aldehydes at 0°C and hydrolysis, ft-hydroxy ketones 8 are obtained in 58-86% op4. 

These reactions were also performed by Jin et al. in the presence of chiral amino thioaeetate ligands derived from (-i-)-norephedrine." As shown in Scheme 3.5, quantitative yields and excellent enantioselectivities of up to >99% ee were obtained in almost all eases of aldehydes, even when using 1.1 equivalent of ZnEt2 instead of 2 equivalents as usually employed. More recently, these authors developed eorresponding chiral amino thiocyanate derivatives from (-)-norephedrine and tested these new aprotic ligands for... 

In another context, Soai et al. have described the enantioselective cyclo-propanation of various aldehydes using dicyclopropylzinc in the presence of a catalytic amount of a chiral thiophosphoramidate ligand derived from norephedrine and Ti(Oi-Pr)4, providing the corresponding cyclopropyl alkanols with high yields and enantioselectivities of up to 97% ee (Scheme 6.24). ... 

In their efforts to construct a library of norephedrine aminothiol ligand analogues, Pericas and co-workers treated spiroaziridinium salts with sulfur nucleophiles to give /3-aminothioacetates (Equations 11 and 12) <2001SL1155>. The yield was not reported for thioacetate 38. The acetyl group was easily reduced with DIBAL-H resulting in the desired compounds. 

It is well known that bakers yeast is capable of reducing a wide range of ketones to optically active secondary alcohols. A recent example involves the preparation of the (R)-alcohol (7) (97 % ee) (a key intermediate to ( norephedrine) from the corresponding ketone in 79 % yield1281. Other less well-known organisms are capable of performing similar tasks for instance, reduction of 5-oxohexanoic acid with Yamadazyma farinosa furnishes (R)-5-hydroxyhexanoic acid in 98 % yield and 97 % ee[29]. 

The first study was performed by Milne and Murphy, who found that the rearrangement of substituted cyclopentene oxide 69 into 70 by a stoichiometric amount of the dilithiated homochiral base 71 derived from norephedrine occurred in excellent yield and good ee... 

PREPARATION OF N-ALKYLATED NOREPHEDRINE ANALOGS Ephedine Alkyl Halide Product Yield (%)... 

Enantioselective reduction of acetophenone was achieved in a ruthenium-catalysed hydrogen transfer reaction using isopropanol as the hydrogen source in the presence of mono-tosylated (R, R)-diphenylethylenediamine, ephedrine or norephedrine as chiral auxiliary ligands. Under optimised conditions, ( R)-l-phenylethanol was obtained in 90% yield and 82% enantiomeric excess (ee) within 9 min. f-Butylphenylketone was reduced under similar conditions in almost quantitative yield but in moderate ee... 

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. 

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.

Novel norephedrine-based chiral ligands with multiple stereogenic centers have been conveniently prepared from norephedrine and. -substituted pyrrole.112 These novel chiral ligands have been used to catalyse the enantioselective addition of diethylzinc to aldehydes and to chalcone in high yields and with good to high enantioselectivities. 

Norephedrine 9 is alkylated with dibromide 26 to give pyrrolidine derivative 10.2 The hydroxy group of 9 is not alkylated under the conditions applied because of its lower basicity and nucleophilicity. First, the amino group of 9 is monoalkylated and the resulting ammonium salt 27 is deprotonated with NaHC03 as base. This yields secondary amine 28, which then undergoes intramolecular nucleophilic attack to furnish the desired A-pyrrolidinyl norephedrine 10 after deprotonation. Intermolecular nucleophilic substitution was not observed under these conditions. 

Chiral sulfoxides are useful intermediates in asymmetric synthesis. A number of methods for their preparation were developed in the last decade. An interesting displacement of dimethylphosphonylmethyl moiety, a carbon leaving group, from sulfur by Grignard reagents was used to obtain enantiomerically purep-tolyl sulfoxides.3 4 Optically pure methyl 4-bromophenyl sulfinate was subjected to a one-pot sequence yielding unsymmetrical dialkyl sulfoxides in 60-97% yield and >98% ee. A simple one-pot synthesis of chiral sulfoxides from norephedrine-derived... 

The norephedrine-derived Masamune asymmetric aldol reaction was utilized in the total synthesis of (+)-testudinariol A (12), a triterpene marine natural product that possesses a highly functionalized cyclopentanol framework with four contiguous stereocenters appended to a central 3-alkylidene tetrahydropyran6 (Scheme 2.2f). The norephedrine-derived ester 13 was enolized with dicyclo-hexylboron triflate and triethylamine in dichloromethane and then treated with 3-benzyloxypropanal to afford the aldol adduct (14) as a 97 3 mixture of anti/syn diastereomers in 72% yield. Diastereoselectivity within the anti -manifold was 90 10. Protection of alcohol as the methoxyethoxymethyl (MEM) ether followed by conversion of the ester to an aldehyde by LiAlELt reduction and subsequent Swem oxidation gave the aldehyde 16 in 64% yield over three steps. 

R-(R, S )]-p-Methyl-a-phenyl-1-pyrrolidineethanol is an important chiral mediator for the enantioselective addition of an acetylide to a prochiral ketone.2 3 This reaction has been successfully applied to the synthesis of the reverse transcriptase inhibitor efavirenz (DMP-266) (Scheme 1).3.4 Preparation of the enantiomer, (1S,2R)-N-pyrrolidinylnorephedrine, has been reported.2 The method used potassium carbonate (K2CO3) as base, but the yield of the product was only 33%. The submitters have extensively studied the formation of the pyrrolidinyl ring under various conditions as summarized in Table I. Eventually they found that the reaction was extremely efficient when it was run in toluene using sodium bicarbonate (NaHCC>3) as base (entry 8, Table I),5 which gave [R-(R, S )]-p-methyl-a-phenyl-1-pyrrolidineethanol quantitatively. Enantioselective (up to 99% ee) addition of cyclopropylacetylene to the ketoaniline 1 is achieved when the solution of [R-(R, S )]-p-methyl-a-phenyl-1-pyrrolidineethanol is used as a chiral additive.3 In addition, this method is also applicable to the preparation of a variety of alkylated norephedrines and other amino alcohols in excellent yields as Illustrated in Table II. These amino alcohols are potentially useful in asymmetric syntheses. 

Hoover and Hass hydrogenated 2-nitro-l-phenyl-l-propanol over Raney Ni in ethanol in the presence of sufficient carbon dioxide to produce a pressure of 2.1 MPa and obtained the corresponding amino alcohol (a mixture of /-norephedrine and dl-norisoephedrine) in 87% yield.18 The formation of /V-ethylbenzylamine, a byproduct, was depressed to 5% under these conditions (eq. 9.6). Without carbon dioxide the yield of /V-clhylbcnzylaminc was approximately 45%. 

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