(1R,2S)-N-Methylephedrine1

(1; R = Me)

[552-79-4]  · C11H17NO  · (1R,2S)-N-Methylephedrine  · (MW 179.29) (2; R = n-Bu)

[115651-77-9]  · C17H29NO  · (1R,2S)-N,N-Dibutylnorephedrine  · (MW 263.47) (3; R = CH2=CHCH2-)

[150296-38-1]  · C15H21NO  · (1R,2S)-N,N-Diallylnorephedrine  · (MW 231.37) (4; R = Ph(CH2)4)

[132284-82-3]  · C29H37NO  · (1R,2S)-N,N-Bis(4-phenylbutyl)norephedrine  · (MW 415.67) (5; R = -(CH2)5-)

[133576-76-8]  · C14H21NO  · (1R,2S)-N-Piperidinonorephedrine  · (MW 219.36)

(chiral ligand for the enantioselective reduction of ketones with lithium aluminum hydride; chiral auxiliary for the diastereoselective aldol condensation; chiral catalyst for the enantioselective Darzens reaction; chiral catalyst for the enantioselective alkylation of aldehydes with dialkylzincs; chiral catalyst for the enantioselective conjugate addition of dialkylzincs to enones; chiral catalyst for the enantioselective alkylation of imines with dialkylzincs; chiral catalyst for the enantioselective Michael addition of nitromethane to a,b-unsaturated ketones)

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

Physical Data: (1) mp 86-88 °C; [a]21D -29.2° (c 5, MeOH). (2) bp 170 °C/2 mmHg; [a]25D + 24.4° (c 2, hexane).

Solubility: sol many organic solvents.

Form Supplied in: (1) colorless crystals; (2) colorless oil; (1) and (2) are commercially available.

Enantioselective Reduction of Ketones with Lithium Aluminum Hydride-N-Methylephedrine.

Aryl alkyl ketones and a-alkynic ketones are reduced enantioselectively by a chiral complex of Lithium Aluminum Hydride, N-methylephedrine (1), and 3,5-dimethylphenol (molar ratio, 1:1:2) to afford optically active alcohols with 75-90% ee (eq 1).2

The optically active alkynyl alcohols are converted into the corresponding optically active 4-alkyl-g-butyrolactones3 and 4-alkylbutenolides.4

A chiral complex of (1), LiAlH4, and N-ethylaniline (molar ratio, 1:1:2) reduces aryl alkyl ketones to optically active alcohols in high ee.5 a,b-Unsaturated ketones are reduced enantioselectively to afford optically active (S)-allylic alcohols with 80-98% ee. An intermediate in an anthracyclinone synthesis is prepared in 92% ee by the enantioselective reduction of a cyclic a,b-unsaturated ketone (eq 2).6

A chiral complex of (1), LiAlH4, and 2-ethylaminopyridine (molar ratio, 1:1:2), prepared in refluxing ether for 3 h, reduces cyclic ketones to (R)-alcohols in 75-96% ee.7 Advantages of the enantioselective reduction of ketones with LiAlH4 modified with (1) and additives are the ready availability of (1) in either enantiomeric form and easy removal of (1) from the reaction mixture by washing with dilute acid.

anti-Selective Aldol Condensation and Related Reactions.

Silyl ketene acetals react with aldehydes in the presence of Titanium(IV) Chloride to give b-hydroxy esters.8 The silyl ketene acetal derived from (1R,2S)-(1)-O-propionate reacts with benzaldehyde in the presence of TiCl4 and Triphenylphosphine to afford the anti-a-methyl-b-hydroxy ester in 94% de (eq 3).9

When the same silyl ketene acetal is reacted with benzylideneaniline in the presence of TiCl4, the anti-b-amino ester is obtained (anti/syn > 10/1). Cyclization of the b-amino ester affords the trans-b-lactam in 95% ee (eq 4).10

The reaction of this silyl ketene acetal with Di-t-butyl Azodicarboxylate in the presence of TiCl4 affords the adduct in 45-70% yield with ca. 90% de. The subsequent treatment of the adduct with Trifluoroacetic Acid and Lithium Hydroxide affords (R)-a-hydrazo acids (eq 5).11

Enantioselective Butylation of Carbonyl Compounds with Lithium Tetra-n-butylaluminate Modified with (1).

The reaction between lithium tetra-n-butylaluminate and (1) forms the chiral lithium alkoxytri-n-butylaluminate. This chiral ate complex reduces carbonyl compounds to form secondary and tertiary alcohols in 8-31% ee (eq 6).12

Enantioselective Darzens Reaction.

An enantioselective Darzens reaction between ethyl methyl ketone and chloromethyl p-tolyl sulfone in the presence of a chiral ammonium salt derived from (1) and chloromethylpolystyrene affords an optically active a,b-epoxy sulfone in 23% ee.13

Catalytic Enantioselective Alkylation of Aldehydes with Dialkylzincs.1

The chiral N,N-dialkylnorephedrines, analogs of (1), are highly efficient catalysts for the enantioselective addition of dialkylzincs to aliphatic and aromatic aldehydes.14,15 Optically active aliphatic and aromatic secondary alcohols with high ee are obtained using N,N-dialkylnorephedrines (4-6 mol%) as chiral catalyst precursors. When (1S,2R)-N,N-dialkylnorephedrine is used as a chiral catalyst precursor, prochiral aldehydes are attacked at the si face to afford (S)-alcohols (when the priority order is R1 > R2) (eq 7).

N-Alkyl substituents on the (1S,2R)-N,N-di-n-alkylnorephedrines have a significant effect on the enantioselectivity of the addition of diethylzinc to aldehydes (3-methylbutanal). As shown in Table 1, the optical purity of the product [(S)-5-methylhexane-3-ol] increases as the chain length of the N-n-alkyl substituent increases and reaches a peak of 93% ee at a chain length of four carbons (Table 1, entry 4). Thus, among N,N-di-n-alkylnorephedrines examined, (1S,2R)-N,N-di-n-butylnorephedrine (DBNE) (2) is the best chiral catalyst precursor.14,15

As shown in Table 2 (eq 7), the advantages of N,N-di-n-alkylnorephedrines (most typically DBNE) over other chiral catalysts for the enantioselective addition of dialkylzincs to aldehydes are as follows:

  • 1)DBNE is highly enantioselective for the alkylation of aliphatic aldehydes (Table 2, entries 5-11) as well as for the alkylation of aromatic aldehydes (Table 2, entries 1-4). Most of other types of chiral catalysts are effective only for the alkylation of aromatic aldehydes. Thus, various types of optically active aliphatic alcohols are first synthesized using DBNE (Table 2, entries 5-11). (It should be noted that the structures of aliphatic alcohols synthesized by asymmetric reduction of ketones or by asymmetric hydroboration of alkenes have been somewhat limited.)
  • 2)The structures of dialkylzincs catalyzed by N,N-di-n-alkylnorephedrines (most typically DBNE) are not limited to primary ones. Diisopropylzinc (with a secondary alkyl substituent) adds to benzaldehyde in the presence of a catalytic amount of DBNE to afford the corresponding alcohol with high ee (entry 4).15 The reaction of diisopropylzinc in the presence of other types of catalysts may result in the reduction of aldehydes.
  • 3)N,N-Di-n-alkylnorephedrines are readily synthesized in a one-pot reaction between norephedrine and alkyl iodide in the presence of potassium carbonate.14,15 (DBNE is commercially available.)
  • 4)Either enantiomer of the N,N-di-n-alkylnorephedrines are available. Therefore by using the appropriate enantiomer of N,N-di-n-alkylnorephedrine as a chiral catalyst precursor, the optically active alcohol of the desired configuration with the same ee can be synthesized (entries 8 and 9).

    Optically active fluorine-containing alcohols (91-93% ee) (entries 12 and 13)16 and deuterio alcohols (84-94% ee) (entries 14 and 15)17 are synthesized, respectively, by the enantioselective alkylation of fluorine-containing aldehyde and deuterio aldehyde using DBNE.

    (1S,2R)-1-phenyl-2-(1-pyrrolidinyl)propan-1-ol (6) (entry 10) and (1S,2R)-N,N-diallylnorephedrine (3) (entry 11) are also highly enantioselective catalyst precursors.15

    Enantioselective Addition of Various Organozinc Reagents to Aldehydes.

    Catalytic enantioselective addition of dialkynylzinc reagents to aldehydes using (1S,2R)-DBNE (20 mol %) affords optically active (R)-alkynyl alcohols with 43% ee in 99% yield.18 When an alkylalkynylzinc is used with (1S,2R)-DBNE (5 mol %), an alkynyl alcohol with 40% ee is obtained.18 When 2-phenylzinc bromide is reacted with an aldehyde in the presence of 1 equiv of the lithium salt of (1R,2S)-(1), the corresponding alkynyl alcohol is obtained in 88% ee (eq 8).19

    Alkenylzinc bromides add to aldehydes to afford optically active allyl alcohols with 88% ee in 80% yield using a stoichiometric amount of the lithium salt of (1S,2R)-(1) (eq 9).20

    A mixture of phenyl Grignard and zinc halide adds to aldehydes in the presence of a stoichiometric amount of (1R,2S)-DBNE to afford optically active phenyl alcohols with 82% ee in 90% yield (eq 10).21

    Difurylzinc adds to aldehydes in the presence of a stoichiometric amount of the lithium salt of (1S,2R)-N,N-bis(4-phenylbutyl)norephedrine (4) to afford optically active furylalcohols with 73% ee in 58% yield (eq 11).22a

    Enantioselective addition of a Reformatsky reagent to aldehydes22b and ketones22c in the presence of DBNE or N,N-diallylnorephedrine (3) affords the corresponding b-hydroxy esters in up to 75% ee (eq 12).

    Enantioselective Addition of Dialkylzincs to Aldehydes with Functional Groups.

    Enantioselective and chemoselective addition of dialkylzincs to formyl esters using (1S,2R)-DBNE as a catalyst affords optically active hydroxy esters. The subsequent hydrolysis of the esters afford the corresponding optically active alkyl substituted lactones with up to 95% ee (eq 13).23

    Enantio- and chemoselective addition of diethylzinc to keto aldehydes using DBNE as a chiral ligand affords optically active hydroxy ketones with 91% ee in 84% yield (eq 14).24 This reaction cannot be realized by Grignard reagents or alkyllithium reagents because of the strong reactivity towards both aldehydes and ketones.

    Enantioselective addition of dialkylzinc to furyl aldehydes using DBNE as a chiral catalyst affords optically active furyl alcohols in up to 94% ee (eqs 15 and 16).25

    Enantioselective additions of dialkylzincs to 4-(diethoxymethyl)benzaldehyde,26 3-pyridinecarbaldehyde,27 terephthalyl aldehyde,28 and 2-bromobenzaldehyde29 using DBNE as a chiral catalyst afford, after appropriate treatment, optically active hydroxy aldehydes,26 pyridyl alcohols (eq 17),27 diols (eq 18),28 and 3-alkylphthalides (eq 19),29 respectively, with high ee.

    A highly functionalized chiral aldehyde when treated with Et2Zn using (1R,2S)-DBNE as a chiral catalyst affords the optically active alcohol with 82% de in 98% yield (eq 20).30 The alcohol has been further elaborated into (+)-lepicidin.

    Stereoselective Addition of Dialkylzincs to Chiral Aldehydes.

    Stereoselective addition of dibutylzinc to racemic 2-phenylpropanal using (1S,2R)-DBNE as a chiral catalyst affords optically active alcohols (84% ee, 92% ee) as a result of the si face attack of the aldehyde regardless of its configuration (eq 21).31

    By changing the configuration of the chiral catalyst precursor (DBNE), stereoselective synthesis of optically active syn (78% de) and anti (91% de) 1,3-diols has been reported in the addition of diethylzinc to optically active b-alkoxyaldehyde (eq 22).32 The method has an advantage over the R2Zn-TiCl4 method,33 which is only anti selective.

    Catalytic Enantioselective Conjugate Addition of Dialkylzincs to Enones.

    A chiral nickel complex modified with DBNE and an achiral ligand such as 2,2-bipyridyl in acetonitrile/toluene is an highly enantioselective catalyst for the addition of dialkylzincs to enones.34 b-Substituted ketones with up to 90% ee are obtained (eq 23).34c The method is the first highly enantioselective catalytic conjugate addition of an organometallic reagent to an enone.

    In addition, a chiral amino alcohol [1-phenyl-2-(1-piperidinyl)propan-1-ol] mediates the reaction without using any nickel compound to afford the adduct in 94% ee (eq 24).34d

    Enantioselective Addition of Dialkylzincs to Imines.

    Enantioselective addition of dialkylzincs to N-diphenylphosphinoylimines in the presence of DBNE or its analog affords optically active phosphoramides. Subsequent hydrolysis affords optically active amines in up to 91% ee (eq 25).35 When the amount of DBNE is catalytic (10 mol %), the enantioselectivity is 75% ee. One of the advantages of this method over the alkyllithium method36 is the use of a lesser amount of chiral ligand.

    Diethylzinc also adds to N-(amidobenzyl)benzotriazoles (masked N-acylimines) in the presence of DBNE to afford an optically active amide with 76% ee (eq 26).37

    Asymmetric Michael Addition of Nitromethane to Enone.

    N-Methylephedrinium fluoride catalyzes the Michael addition of nitromethane to chalcone to afford the adduct with 23% ee in 50% yield (eq 27).38


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    Kenso Soai

    Science University of Tokyo, Japan



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