S -a-Methylbenzylamine

Rupaner, R. Justus Liebigs Ann. Chem./Liebigs Ann. Chem. 1987, 231. 

lycahashi, M. Taniguchi, N. Fukumoto, K. Kametani, T. Chem. Commun./J. Chem. Soc., Chem. Commun. 1987, 619. 

Kusumi, X Eukushima, X Ohtani, J. Kakisawa, H. Tetrahedron Lett. 1991, 32, 2939. 

Form Supplied in both enantiomers are commercially available. Analysis of Reagent Purity the enantiomeric purity of the reagent can be assessed by NMR analysis of the corresponding Mosher s amideChiral complexing reagents (such as 1,1 -binaphthyl-2,2 -diylphosphoric acid) have also been used in the direct NMR analysis of the reagent.  

Preparative Methods racemic a-methylbenzylamine has been resolved utilizing chiral acids such as tartaric acid and (S)-(—)-carbamalactic acid, among others. Several stereospecific syntheses have been reported.  

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The reaction of the imines, formed from 2-methylpropanal and (S )-a-methylbenzylamine with tert-butyl isocyanidc and benzoic acid under widely varied conditions, delivers the valine derivatives with only moderate diastcrcoselectivity (ratio of diastereomers less than 4 l)67. 

The very first investigations on this topic indicated that racemization can be monitored in micro reactors and that the degree of racemization seems not to be higher than in conventional organic synthesis. For dipeptide formation from the penta-fluorophenyl ester of (Ji)-2-phenylbutyric acid and (S)-a-methylbenzylamine, racemization of 4.2% was found [158]. At higher concentration (0.5 M instead of 0.1 M), a higher degree of racemization was found (7.8%). 

Organic synthesis 26 [OS 2 a-Dipeptide synthesis from (S)-a-methylbenzylamine... 

Boc-D-alanine and (S)-a-methylbenzylamine react to give the corresponding dipep tide via an EDCI [3-ethyl-l-(3-dimethylaminopropyl)-carbodiimid] coupling [86], control experiment, Boc-t-alanine and (S)-a-methylbenzylamine also reacted. 

OS 26] [R 4] [P 18] For dipeptide formation from the pentafluorophenyl ester of Boc-D-alanine and (S)-a-methylbenzylamine an extent of racemization of 5.6% was found [86]. This experiment also served to demonstrate monitoring of the racemization of an a-amino acid used in peptide synthesis. 

Figure 3. Separation of enantiomers using CSP-2. Left Separation of (a) R and (b) S a-methylbenzylamine run conditions 40/60 (v/v%) MeCN/5 mM citrate in H20, column pressure 16 bar. Right Separation of (a) R and (b) S ibuprofen (4-isobutyl-a-methylphenyl-acetic acid) run conditions 55/45 (v/v%) MeOH H20, column pressure 25 bar.

However, there are experiments which show that the anti mode can also take place. For instance, changing piperidine for sodium propanethiolate, the trans and cis mesitoates 1 and 93 (R,=CgH2(CH3)2 gave a mixture of syn and anti Sl products (30). Also, Oritani and Overton (34) showed that the reaction of dichlorobenzoates 98 (R=CH3 or C5H11, and X Cl2CeH3CO2 ) with (S)-a-methylbenzylamine gave a mixture of syn and anti 5N2 products (ratio =6 4). 

Salvadori, R, Uccello-Barretta, G. and Lazzaroni, R. (1990) A new method for the enantiomeric excess determination of chiral trisubstituted allenes by 195Pt NMR of traKi-dichloro[(S)-a-methylbenzylamine](allene)platinum(II) complexes. /. Chem. Soc. Chem. Commun., 1121-1123. 

Several reports have employed a more traditional approach where the use of enantio-pure chiral amino auxiliaries, that, after the successful Strecker reaction, can be chemically modified to yield the free amino acids. For example, Chakraborty and co-workers have reported the highly diastereoselective addition of trimethylsilyl cyanide to a variety of a-phenylglycinol-derived benzaldimines [16]. (S)-a-Methylbenzylamine has been used as a chiral auxiliary for the asymmetric Strecker reaction [17]. (R)-Phenylglycinol has been utilized as a chiral auxiliary from the asymmetric Strecker reaction products of aldehydes in the synthesis of a,a-disubstituted amino acids [18]. (R)- and (S)-2-Amino-2-phenylethanol were used as chiral auxiliaries in the synthesis of optically pure a-arylglycines [19]. 

Another classic resolution process developed by Ethyl Corp. for (S)-ibuprofen production uses (S)-(-)-a-methylbenzylamine (MAB) as the chiral base for diastereomeric salt formation 49 The difference in solubility between (S)- and (ft)-ibuprofen MAB salts is so substantial that only half an equivalent of MAB is used for each mole of racemic ibuprofen, and no seeding is needed. The process can also be performed in a wide range of solvents, and the unwanted (ft)-ibuprofen can be recycled conveniently by heating the mother liquor in sodium hydroxide or hydrochloric acid. Other designer amines have been developed for resolution of ibuprofen with good stereoselectivities,50 but these chiral amines were prepared specifically for ibuprofen resolution and are thus unlikely to be economical for industrial production. 

The imine of either R- or S-(a)-methylbenzylamine and ethylglyoxalate has been reacted with Danishefsky s diene to prepare a piperidine derivative.275 It is fortunate that the desired isomer crystallized out. This imine has also been reacted with cyclopentadiene to generate 2-azabicy-clo[2.2.1]heptane derivative at scale in moderate yields 276,277 In both cases the chiral auxiliary was removed by hydrogenation. 

The procedure has been applied to the gas-phase exchange equilibria of the N-protonated (/ )-(+)- and (S)-(—)a-methylbenzylamine ligands between chiral (.S, .Sr)-3 and the achiral 18-crown-6, as reference (Uref).437 The achiral crown ether Uref... 

The efficacy of the BINAP/Pd-system to mediate C-N bond formation without stereochemical erosion has been taken advantage of by several groups. Diver and co-workers described the double amination or orfho-di-bromobenzene with (S)-a-methylbenzylamine to yield the desired C2-sym-metric diamine in 61% yield, >99% ee, and 91% de, Eq. (69) [85]. Schmalz reported a similar coupling reaction to prepare new ligands for asymmetric catalysis [45]. 

Optically active a-amino nitriles.1 Optically active a-amino nitriles can be obtained by reaction of a-silyloxy nitriles with (R)- or (S)-a-methylbenzylamine in methanol (equation I). 

Reagent for the Resolution of Carboxylic Acids. Reagent (1) and its enantiomer have been used, although not as extensively as the more common (S)-a-Methylbenzylamine, as resolving agents for carboxylic acids via fractional crystallization of the corresponding diastereomeric salts. Examples of acids resolved this way include (2)-(6). Additional examples, such as man-delic, hydratopic, and a-aryloxypropionic acids, can be found in the literature. ... 

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