[299-42-3]  · C10H15NO  · (1R,2S)-Ephedrine  · (MW 165.23)

(chiral auxiliary for the following: diastereoselective alkylation and reduction of chiral hydrazones; diastereoselective alkylation of chiral amides; diastereoselective conjugate addition of organometallic reagents to unsaturated amides and imidazolidinones; diastereoselective alkylation and cyclopropanation of oxazepinediones and oxazolidines; diastereoselective homoaldol addition of N-allylimidazolidinone, and asymmetric coupling reaction of Grignard reagents; chiral ligand for enantioselective conjugate addition of organometallic reagents to enones; chiral ligand for enantioselective addition of dialkylzincs to aldehydes)

Alternate Name: [R-(R*,S*)]-a-[1-(Methylamino)ethyl]benzenemethanol

Physical Data: mp 37-39 °C; bp 255 °C; [a]21D -41° (c 5, 1M HCl). Hydrochloride, mp 216-220 °C; [a]20D -34° (c 4, H2O).

Solubility: sol alcohol, chloroform, ether, water.

Form Supplied in: waxy solid or crystals; also available as hydrochloride in either enantiomeric form.

General Features of Ephedrine.

Ephedrine is a chiral b-amino alcohol which is available in either enantiomeric form. It is often utilized as a chiral auxiliary in asymmetric synthesis. Via bond formation with the amino group of ephedrine, ephedrine can be derived into chiral hydrazones2,3 and amides.5,6 Highly diastereoselective asymmetric reactions are known using these chiral compounds. In reactions using organometallic reagents, the hydroxy groups of hydrazones and amides become metal alkoxides. Metal atoms of the alkoxide may chelate with nitrogen or oxygen atoms of chiral hydrazones and amides. This chelation may reduce the number of possible conformations of reactive species, and this may increase the diastereoselectivities.

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,12,13 oxazepinediones,14-18 and oxazolidines.20,21 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.

Ephedrine becomes a chiral ligand of metal atoms by the deprotonation of the hydroxy group and by the presence of the nitrogen atom.22-26 Highly enantioselective asymmetric reactions are known using chiral ephedrine-type ligands.

In addition, ephedrine is a chiral base catalyst because of the presence of the amine group.29-32 A highly enantioselective base-catalyzed reaction is known.

Diastereoselective Alkylation and Reduction of Chiral Hydrazones Derived from Ephedrine.2

Methylmagnesium Bromide adds to the chiral hydrazone derived from N-aminoephedrine and benzaldehyde to afford the optically active chiral hydrazine in almost 100% de. Hydrogenolysis of the chiral hydrazine gives (R)-a-phenylethylamine with more than 97% ee (eq 1). Ephedrine is recovered in good yield and without any loss of optical purity.

On the other hand, the diastereoselective reduction of the chiral hydrazone derived from N-aminoephedrine and acetophenone and subsequent hydrogenolysis affords (S)-a-phenylethylamine with 30% ee.3 Optically active a-phenylethylamine with high ee is obtained from the diastereoselective alkylation of chiral hydrazones derived from (R)- or (S)-1-amino-2-(methoxymethyl)pyrrolidine.4a

Diastereoselective Alkylation of Chiral Amides Derived from Ephedrine.

Chiral amides derived from ephedrine are converted to the corresponding dianion. The subsequent diastereoselective alkylation with alkyl iodides affords chiral a-substituted amides with >90% de.5 Acid hydrolysis affords optically active a-substituted acids with 78% ee as a result of racemization in the cleavage step (eq 2).

On the other hand, treatment with Methyllithium affords optically active methyl ketone in 44-74% ee, also as a result of racemization. a-Chiral ketones with higher ee (99% ee) are obtained from the diastereoselective alkylation of chiral hydrazones derived from (R)- or (S)-1-amino-2-methoxymethylproline.4b

Diastereoselective Conjugate Addition of Organometallic Reagents to Chiral a,b-Unsaturated Amides and Imidazolidinones Derived from Ephedrine.

Grignard reagents (2 equiv) add to chiral a,b-unsaturated amides derived from ephedrine in a 1,4-addition manner with high diastereoselectivities. Subsequent acidic hydrolysis affords optically active b-substituted carboxylic acids with 85-99% ee (eq 3).6

A seven-membered chelate intermediate is one of the reasons for the very high diastereoselectivities. The method is successfully applied to the asymmetric synthesis of malingolide.7 Similar results are obtained in diastereoselective conjugate addition of Grignard reagents to unsaturated amides derived from (S)-2-(1-hydroxy-1-methylethyl)pyrrolidine. The presence of a tertiary amine (e.g. 1,8-Diazabicyclo[5.4.0]undec-7-ene) increases the diastereoselectivity, and subsequent hydrolysis affords b-substituted carboxylic acids with up to 100% ee.8 Conjugate additions of alkyllithium or Grignard reagents to chiral N-crotonoylproline,9 imides,10 and N-enoyl sultams11 also afford b-substituted carboxylic acids with 60% ee, 96% ee, and 96% ee, respectively.

The chiral imidazolidinone12 derived from urea and ephedrine hydrochloride is utilized in a diastereoselective conjugate methylation.13 Subsequent hydrolysis affords optically pure (-)-citronellic acid (eq 4).

Diastereoselective Conjugate Additions to Chiral Oxazepinediones Derived from Ephedrine.

Ephedrine can form a chiral seven-membered relatively rigid oxazepinedione ring by condensation with malonic acid monoester. Alkylidene derivatives of chiral oxazepinediones undergo highly diastereoselective additions with nucleophilic reagents. Grignard reagents in the presence of a catalytic amount of Nickel(II) Chloride add to chiral alkylideneoxazepinediones. Acid hydrolysis affords optically active b-substituted acids with up to >99% ee (eq 5).14 The method is applied to the diastereoselective synthesis of (-)-indolmycin with 93% ee.15

Diastereoselective addition of sulfonium ylides affords enantiomerically pure cyclopropanedicarboxylic acid diesters after removal of the chiral auxiliary (eq 6).16

Diastereoselective addition of Phenylthiomethyllithium and subsequent treatment affords optically active lactones with >90% ee (eq 7).17

In addition, a chiral oxazepinedione plays the role of a nucleophile in the reaction with nitroalkenes in the presence of Potassium t-Butoxide and crown ether (eq 8).18

Homoaldol Addition with Chiral N-Allylimidazolidinone Derived from Ephedrine.

The chiral allyltitanium compound derived from ephedrine reacts with carbonyl compounds with very high (>200:1) de. Subsequent hydrolysis and oxidation affords optically pure 4-substituted g-lactones (eq 9).12 4-Substituted g-lactones with 92% ee can also be synthesized by catalytic enantioselective alkylation of 3-formyl esters.19

Diastereoselective Cyclopropanation and Alkylation of Chiral Oxazolidines Derived from Ephedrine.

Ephedrine forms oxazolidines upon reaction with aldehydes. Chiral unsaturated oxazolidines derived from ephedrine and unsaturated aldehydes are treated with diazomethane in the presence of Palladium(II) Acetate. Hydrolysis of the oxazolidine ring affords optically active formylcyclopropanes with >90% ee (eq 10).20

Diastereoselective addition of cuprate reagents to unsaturated oxazolidines and subsequent hydrolysis affords 3-substituted aldehydes with up to 81% ee (eq 11).21

Asymmetric Coupling Reactions of Chiral Grignard Reagents Derived from Ephedrine Derivatives.

Asymmetric coupling reactions of Allyl Bromide and chiral Grignard reagents derived from ephedrine methyl ether in the presence of Copper(I) Iodide (10 mol %) followed by oxidation affords optically active homoallyl alcohols with 60% ee (eq 12).22

Enantioselective Conjugate Addition to Prochiral Enones of Organometallic Reagents Modified with Ephedrine.

Enantioselective conjugate addition to 2-cyclohexenone with chiral organo(alkoxo)cuprates [MCu(OR*)R] has been studied.1a When the cuprate is prepared from the lithium alkoxide of ephedrine, Phenyllithium, and CuI, 3-phenylcyclohexanone with 50% ee is obtained.23 The enantioselectivity reaches 92% ee in enantioselective ethylation when a chiral diamino alcohol derived from ephedrine is employed (eq 13).24

On the other hand, enantioselective conjugate addition to 2-cyclohexenone with lithium dibutylcuprates (having a noncovalently bound chiral phosphorus ligand derived from ephedrine) affords 3-butylcyclohexanone with up to 76% ee (eq 14).25

Isopropylmagnesium chloride adds to 2-cyclohexenone in 17% ee in the presence of a catalytic amount of chiral alkoxyzinc chloride derived from ephedrine and Zinc Chloride (eq 15).26

Concerning the catalytic enantioselective conjugate addition reaction, conjugate addition of dialkylzinc to chalcone in the presence of a catalytic amount of the chiral nickel complex derived from norephedrine affords b-substituted ketones with up to 90% ee (eq 16).27

Enantioselective Addition of Dialkylzincs to Aldehydes Using Chiral Amino Alcohols Derived from Ephedrine.

Nucleophilic addition of dialkylzinc to aldehydes is usually very slow. Amino alcohols facilitate the addition of Diethylzinc to benzaldehyde to afford 1-phenylpropanol.1b,28 When chiral amino alcohols possessing the appropriate structure are used as a precatalyst, optically active secondary alcohols are obtained.1b Highly enantioselective chiral catalysts derived from ephedrine are known. (1R,2S)-N-Isopropylephedrine functions as a precatalyst for the enantioselective addition of diethylzinc to benzaldehyde to afford (R)-1-phenylpropanol with 80% ee in 72% yield.29 The use of an excess amount of diethylzinc increases the enantioselectivity up to 97% ee (eq 17).30

The lithium salt of (1R,2S)-N-[2-(dimethylamino)ethyl]ephedrine acts as a precatalyst for the addition of diethylzinc to afford the alcohol with 90% ee (eq 18).31

The dilithium salt of a chiral diaminodiol derived from ephedrine mediates the enantioselective addition of dialkylzinc to aldehydes to afford (R)-1-phenylethanol with 85% ee (eq 19).32

1. (a) Rossiter, B. E.; Swingle, N. M. CRV 1992, 92, 771. (b) Soai, K.; Niwa, S. CRV 1992, 92, 833.
2. Takahashi, H.; Tomita, K.; Noguchi, H. CPB 1981, 29, 3387.
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22. Tamao, K.; Kanatani, R.; Kumada, M. TL 1984, 25, 1913.
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27. Soai, K.; Hayasaka, T.; Ugajin, S. CC 1989, 516.
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29. Chaloner, P. A.; Perera, S. A. R. TL 1987, 28, 3013.
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Kenso Soai

Science University of Tokyo, Japan

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