Derived from Ephedrine

Only few allyltitanium reagents bearing a removable chiral auxiliary at the allylic residue are known. The outstanding example is a metalated 1-alkyl-2-imidazolinone14, derived from (—)-ephedrine, representing a valuable homoenolate reagent. After deprotonation by butyllithium, metal exchange with chlorotris(diethylamino)titanium, and aldehyde or ketone addition, the homoaldol adducts are formed with 94 to 98% diastereoselectivity. 

The diastereoselectivity and the stereochemical outcome of the addition of 2,3,4,6-tetrahydro-3, 4-dimethyl-2-phenyl-1,4-oxazepine-5,7-dione, derived from ephedrine and methyl hydrogen malonate, to 1 -nitrocyclohexene was found to be dependent on the nature of the base and the solvent. The highest diastereoselectivity was obtained when potassium /tr/-butoxide in the presence of dicyclohcxyl-18-crown-6 was employed. In the absence of crown ether the diastereoselection was poor and the sense of the stereochemical outcome was reversed26. 

A Cp2ZrCl2-catalyzed addition of Bu2AlH to terminal alkynes has been applied in the synthesis of (E)-vinyl phosphonates [84]. 1-Hexyne and 1-octyne were hydroalu-minated at 0°C and the resulting vinylalanes transformed into the respective alumi-nate complexes by treatment with methyllithium. Subsequent addition of oxaza-phospholidinone 79, derived from (-)-ephedrine, lead to the homochiral vinyl phosphonates in yields of ca. 75% (Scheme 2-23). 

Scheme 1.59 Test reaction with diamino sulfides derived from ephedrine.

It is of interest to note that in the case of oxaazaphosphospholidines 302 derived from (-)-ephedrine (42), some inversion at the benzylic carbon occurred giving a mixture of the P-epimeric derivatives 303 (Scheme 71) [108], Halide exchange with inversion of configuration in the intermediate was suggested as the most likely explanation for the loss of stereospecificity. 

An alternative approach to hydroboration has utilized a chiral B-H source with either achiral or chiral rhodium complexes.58 The enantiomerically pure reagent (21) is derived from ephedrine. Notably in the reactions with BINAP, a higher enantiomeric excess is produced from (R)-BINAP (6) compared to the Y-form (Scheme 13). 

Taapken, T. and Biechert, S., Stereoselective synthesis of homochiral (E)-vinyl phosphonates derived from (-)-ephedrine, Tetrahedron Lett., 36, 6659, 1995. 

The quaternary ammonium salt 48 derived from (+)-ephedrine was utilized for the enantioselective addition of diethyl zinc to aldehydes.1421 The chiral ammonium fluorides 7 (R=4-CF3 or 2,4-(CF3)2, X=F) were also useful for the enantioselective trifluoro-methylation of aldehydes and ketones with moderate enantioselectivity,1431 shown in Scheme 17... 

Rh-H / -elimination step in step E gives the vinyl-borane which then dissociates to generate the first intermediate. This cycle explains the production of equimolar quantities of alkane and -vinylborane with unreactive R2BH derived from ephedrines with catecholborane there is an additional shunt pathway — step C in competition with step E leading to the primary regio-isomer of alkylborane. 

The (2 S)-diastcrcomer is the major isomer starting material is derived from ( + )-ephedrine. 

Analogous to the use of chiral enoates (see previous section), a, -unsaturated carboxylic amides, prepared from chiral amines, may be utilized in asymmetric 1,4-additions. When Grignard reagents are added to unsaturated amides (21), derived from (-)-ephedrine (20),25 highly optically active fi-sub-stituted alkanoic acids (22 R and R = alkyl or phenyl) are obtained in a variety of cases, after hydrolysis of the initially formed adducts (Scheme 7). This method was used for the synthesis of the antibiotic (-) malyngolide and its stereoisomers.26 Recrystallization of the intermediate (saturated) amide was necess-... 

It should finally be mentioned that asymmetric reduction of prochiral ketones in chiral reverse micelles has also been attempted. Zhang et al. employed surfactants derived from ephedrine and achieved enantiomeric excesses up to 27% [25],... 

The basic hydrolysis of acyclic phosphoramidates occurs with a mixture of C-0 and P-0 bond cleavage (l, 2) however similar treatment of l,3>2-oxazaphospholidines can result in substantial P-N cleavage ( 1, 3). 1,3,2-Oxazaphospholidines derived from (-)-ephedrine react with solutions of alkoxides in alcohol to give only the products of P-N cleavage and with inversion of configuration at phosphorus. Scheme I ( +, 5). ... 

The reaction of a chiral Grignard reagent derived from ephedrine with the oxathiane 2 was used to prepare the 8-hydroxy acid 5 in 34% overall yield. On standing, 5 lactonizes to (— )-malyngolide (6). ... 

This method was used to prepare an optically active alcohol in 60% ee from the chiral vinylsilane 3, derived from ( —)-ephedrine, as outlined in equation (111). 

The best results have been obtained with the cyclic silylated diamide 18, derived from ephedrine, which consists of practically one enantiomer (>98%)64. 

Asymmetric hydroboration of styrenes with the bo-ranes derived from ephedrine and pseudoephedrine catalyzed by [Rh(nbd)(dppb)]OTf gives excellent regioselectiv-... 

Diastereoselective Alkylation and Reduction of Chiral Hydrazones Derived from Ephedrine. Methylmagnesium Bromide adds to the chiral hydrazone derived from V-aminoephedrine and benzaldehyde to afford the optically active chiral hydrazine in almost 100% de. Hydrogenolysis of the chiral hydrazine gives (/ )-a-phenylethylamine with more than 97% ee (eq 1). Ephedrine is recovered in good yield and without any loss of enantiomeric purity. 

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. Acid hydrolysis affords optically active a-substituted acids with 78% ee as a result of racemization in the cleavage step (eq 2). 

Diastereoselective Conjugate Addition of Organometallic Reagents to Chiral a,P-Unsaturated Amides and Imidazolidi-nones Derived from Ephedrine. Grignard reagents (2 equiv) add to chiral a,P-unsaturated amides derived from ephedrine in a 1,4-addition manner with high diastereoselectivities. Subsequent acidic hydrolysis affords optically active p-substituted carboxylic acids with 85-99% ee (eq 3). ... 

Homoaldol Addition with Chiral A-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 y-lactones (eq 9). 4-Substituted -y-lactones with 92% ee can also be synthesized by catalytic enan-tioselective alkylation of 3-formyl esters. ... 

Diastereoselective Cy clopropanation and Alkylation of Chiral Oxazolidines Derived from Ephedrine. Ephedrine forms... 

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). ... 

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). ... 

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. When the cuprate is prepared from the lithium alkoxide of ephedrine, Phenyllithium, and Cul, 3-phenylcyclo-hexanone with 50% ee is obtained. The enantioselectivity reaches 92% ee in enantioselective ethylation when a chiral diamino alcohol derived from ephedrine is employed (eq 13). ... 

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 benzalde-hyde to afford l-phenylpropanol. When chiral amino alcohols possessing the appropriate stracture are used as a precatalyst, optically active secondary alcohols are obtained. Highly enantioselective chiral catalysts derived from ephedrine are known. (lR,25)-N-Isopropylephedrine functions as a precatalyst for the enantioselective addition of diethylzinc to benzaldehyde to afford (R)-l-phenylpropanol with 80% ee in 72% yield. The use of an excess amount of diethylzinc increases the enantioselectivity up to 97% ee (eq 17). ... 

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

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

Enantioselective Addition of Diethylzinc to Aldehydes. Oxazaborolidines derived from ephedrine have been used to catalyze the addition of Diethylzinc to aldehydes (eq 13). Both... 

Other Applications. Chiral oxazaborolidines derived from ephedrine have also been used in asymmetric hydroborations, and as reagents to determine the enantiomeric purity of secondary alcohols. Chiral l,3,2-oxazaborolidin-5-ones derived from amino acids have been used as asymmetric catalysts for the Diels-Alder reaction,and the aldol reaction. ... 

To explore the viability of chiral auxiliaries in the vinyl phosphate-p-ketophosphonate rearrangement, a series of vinyl phosphates derived from ephedrine, pseudoephedrine, (lR,2S,5R)-(-)-menthol, (15,25,35,57 )-(-i-)-isopinocampheol, (5)-(-)-2-methylbutanol, binaphtol, and (2R,4R)- or (25,45)-pentane-2,4-diol have been examined. (5)-(-)-2-methylbutanol and 2,4-pentane-2,4-diol derivatives appear as the most attractive chiral auxiliaries. 

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