S-Valine

Chiral amide and imide enolates are amongst the most effective reagents providing. yv -3-hy-droxycarboxylic acids in both high simple diastereoselectivity and induced stereoselectivity, e.g., the amides 1 and 2, and especially, the imides 3 and 4 (derived from (S(-valine and (l/ ,2S)-norephedrine, respectively)93 and the C2-symmetric amide 594 are highly effective systems ... 

Similar methodology has been applied in the syntheses of 2-amino-3-hydroxycarboxylic acids in high diastereomeric and enantiomeric purity. Two separate pathways give either the antt- or. WM-products. The first strategy relies on haloacetate precursors derived either from (S )-valine 17"- oi or from norephedrine 18102, which are converted into the boron enolates103 and subsequently reacted with aldehydes to deliver. ym-adducts99 102. The diastereomeric ratio, defined as the ratio of the desired diastereomer/the sum of all others, is 50 1 for the former and about 95 5 for the latter adducts. 

A decisive improvement in the stereoselective performance of the Ugi reaction was achieved by the use of 1-ferrocenylalkylamines, in particular, l-ferrocenyl-2-methylpropylamine. as the inducing chiral auxiliary 18, S7. The iminc formed from the (/ )-enantiomer and isobutyralde-hyde reacts at — 78 °C with tm-butyl isocyanidc and benzoic acid to give the (S )-valine derivative with a diastereoselectivity of about 100 1. 

An excellent method for the diastereoselective synthesis of substituted amino acids is based on optically active bislactim ethers of cyclodipeptides as Michael donors (Schollkopf method, see Section 1.5.2.4.2.2.4.). Thus, the lithium enolates of bislactim ethers, from amino acids add in a 1,4-fashion to various a,/i-unsaturated esters with high diastereofacial selectivity (syn/anti ratios > 99.3 0.7-99.5 0.5). For example, the enolate of the lactim ether derivative 6, prepared from (S)-valine and glycine, adds in a highly stereoselective manner to methyl ( )-3-phenyl-propenoate a cis/trans ratio of 99.6 0.4 and a syn/anti ratio of 91 9, with respect to the two new stereogenic centers, in the product 7 are found105, los. 

As an example the enolatc of (5,)-2,5-dihydro-5-isopiopyl-3,6-diinethoxypyrazine, prepared from (S>valine and glycine, reacts with methyl (2s)-3-phenylpropenoate and the (2/ ,/ S)-iso-mer is obtained as the major diastereomer. The diastereofacial selectivity is reflected by a 2R/2S ratio of 99.6 0.4, whereas the high simple diastereoselectivity is shown by the diastereomeric ratio (syn/ami) of 91 9. Using methyl (Z)-3-phenylpropenoate the (2R, R)-isomer is formed... 

The (S )-valine based bislacdm ether adds regioselectively in a 1,6-fashion to a,/ -y,<5-unsat-urated -substituted esters with both simple and induced diastereoselectivity exceeding 99 1. This provides, after hydrolysis, virtually enantiomerically pure dimethyl ( )-2-amino-3-hep-tene-l,7-dioates 206. 

Michael reaction of enamines of u-alkyl- -keto esters. The chiral lithioen-amine (1), prepared from (S)-valine /-butyl ester, does not react with methyl vinyl ketone or ethyl acrylate unless these Michael acceptors are activated by ClSi(CH3)3... 

The iminium salt 132, generated from benzylamine hydrochloride and aqueous formaldehyde, reacts with cyclopentadiene during 3 h at room temperature to give, after basification, the cycloadduct 133 in nearly quantitative yield (equation 70). Other examples of this reaction are shown in equations 71-75. The separable diastereomers 134 and 135 are formed in the ratio 4 1 from cyclopentadiene, (—)-a-methylbenzylamine hydrochloride and aqueous formaldehyde in a combined yield of 86% (equation 75)62. Hydrochlorides 136 of methyl esters of natural amino acids [(S )-valine, (S )-isoleucine] react with cyclopentadiene and formaldehyde in aqueous THF to produce mixtures of the diastereomers 137 and 138, in which the former predominate (equation 76)63. 

The use of chiral auxiliaries has been developed into elegant three-step sequences to achieve high ee s (Figure 2). In the general scheme a ketone is derivatized with a chiral amine. Low temperature lithiation and alkylation followed by hydrolysis produces the alkylated ketone in moderate to excellent ee s. The auxiliaries most often used are (S)-valine tert-butyl ester (Koga), l-amino-2-methoxymethylpyrrolidine (Enders) and (S)-2-amino-1-... 

Racemic modifications may be resolved. There are very few examples of this approach having been employed successfully. The racemic cylic ether (RS)-36, which contains two CH2OCH2CO2H arms attached to the 3 and 3 positions on the axially chiral binaphthyl units, has been resolved (48-50, 93, 94) to optical purity in both its enantiomers by liquid-liquid chromatography using a chiral stationary phase of either (R)- or (S)-valine adsorbed on diatomaceous eaitii. Very recently, the optical resolution of crown ethers (/ S)-37 and (/ 5)-38, incorporating the elements of planar chirality in the form of a rron -doubly bridged ethylene unit, has been achieved (95) by HPLC on (+)-poly(triphenyl-methyl methacrylate). 

The commercially-available (S)-amino acids alanine, valine, leucine and isoleucine usually contained only negligible amounts (a few parts/thousand) of the (R)-antipode, but occasionally up to Z.5% of the (R)-enantiomer has been detected in (S)-alanine and (S)-valine. The (R)-enantiomer is almost completely removed by one recrystallization from water. 

The method described here illustrates the transformation of optically active 2-chlorocarboxylic acids, which are readily available from 2-amino acids, via 2-chloroalkan-l-ols to alkyloxiranes with inversion of configuration at the stereocenter. Thus (R)-methyloxirane is prepared from (S)-alanine, (R)-isopropyloxirane from (S)-valine, (R)-isobutyloxirane from... 

Auch der Versuch, die chirale Induktion durch optisch-aktive 2-Oxo-carbonsaure-Derivate zu erreichen, kann als minderwertige Methode betrachtet werden. (S)- Alanin6,7, (/ )- bzw. (S)-Valin und 1-Menthol wurden als chirale Hilfsreagentien verwendet6. Dabei harmo-nisiert nur das Imin aus (R)-1 -Phenyl-cthylamin mit dem 2-Oxo-propansaure-/-menthyl-ester6. 

The ot-amino acids (S)-alanine and (S)-valine can be converted into N,N-bis-(phosphinomethyl) derivatives (16) in a modified Mannich reaction42. ... 

The chiral ligands (R)-Val-Phos(17a) and (R)-Phe-Phos (17b) have been synthesized from (S)-valine and (S)-phenylalanine, respectively, in an industrial laboratory 43). 

As reported in 1983, the same group was able to improve the optical yield of the reduction of (24) to 25 %, while carrying out the electrochemical reduction at a poly-(S)-valine-coated graphite cathode63 . In the reduction of 4-methylcoumarin (25) on this cathode an optical yield of 43 % was achieved the (S)-configurational enantiomer (26) was formed in excess 63). 

High stereoselectivities (94-100 %) are attained in the reduction of aromatic ketones by use of a new chiral borane complex with (S)-2-amino-3-methyl-l,l-diphenylbutan-l-ol,(S-68) readily prepared in two steps from (S)-valine, in an experimentally convenient procedure961. (S)-Valine methyl ester hydrochloride was converted with excess of phenylmagnesium bromide into (S-68). The same treatment of (R)-valine gave (R-68). In a typical asymmetric reduction the reagent, prepared from (S-68) and borane, and the ketone (69) in tetrahydrofuran were kept at 30 °C for some hours. The corresponding alcohols were obtained in high optical purity. (S-68) could be recovered to more than 80% without racemization 96). 

The asymmetric hydrogenation of the phenylhydrazone of methyl-N-(3,3-dimethyl-2-oxobutanoyl)-(S)-valinate (83) was investigated using palladium catalysts105). The absolute configuration of the newly formed t-leucine moiety in (84) was found to be (S). The diastereoselectivity in the hydrogenation step was shown to be as high as 56%. 

The chiral auxiliaries H-A developed by Evans et al. 176) were derivatives of naturally occurring amino acids. The (S)-proline-derived amide enolates (164) as well as the (S)-valine-derived amide enolates (166) and imide enolates (165) have proven to be exceptionally versatile chiral nucleophiles. 

Not surprinsingly, the aldol addition of the lithium enolates derived from these systems proved to be unsatisfactory. However, the derived zirkonium enolates in these and related systems have proven to be exceptional 176). The amides (171) and (172), each of which is readily derived from (S)-proline and (S)-valine respectively, exhibit good stereoselectivity with a range of aldehydes. The optical purity of the P-hydroxy amides (173) was very good (>95% e.e.). However, this method has a limitation which has been associated with the acidic conditions that are required to hydrolize these chiral amides (173) to their derived carboxylic acids (174). While... 

Due to these limitations Evans et al. focussed on the exploration of imide-derived enolates (165). They expected these systems to react stereoselective in carbon-carbon bond formation and that the derived imides might be readily hydrolized or reduced under the mild conditions required for the construction of complex products, One of the two chiral 2-oxazolidones (175) chosen for study by Evans et al.179) is derived from (S)-valine and was readily prepared from this inexpensive commercially available a-amino acid having an optical purity exceeding 99 %. The preparation of the related imide-derived enolate (165) is shown in the next scheme. Alkylation reactions employing (175) resulted in excellent diastereoface selection, as summarized in Table 4 179). 

Symmetrical hw-Iactim ethers of type (187) — built up from two identical amino acids — do have one disadvantage, inherent in the system only 50% of the chiral auxiliary — in this case (S)-alanine — is recovered the other 50 % is first racemized via (188) and finally incorporated in the product (189). To avoid this disadvantage Schollkopf et al. have developed methods to synthesize mixed bw-lactim ethers, starting from two different amino acids, e.g. (S)-valine and (R,S)-alanine. Thus, the authors obtained cyclo [(S)-val-(R,S)-ala] and prepared the related h/.s-lactim ether... 

Strikingly high stereoselectivities have been achieved in asymmetric syntheses with optically pure proline or proline derivatives, probably due to the rigidity of the five-membered ring. Other preferably used chiral auxiliaries include (S)-phenyl-alanine, (S)-valine and tert.-(S)-leucine. 

Fig. 6. Effect of modifying temperature on EDA with the following modifying reagent and conditions ( ) (+)-erythro-2-methyltartaric acid, pH 5.0 5.2, 0°C (O) (S.S)-tartaric acid, pH 5.0-5.2, 0°C (A) ( + )-2-methyl glutamic acid, pH 5.0, 0°C (O) (S)-valine, isoelectric point, 0 C ( ) (S)-glutamic acid, pH 5.2, 0 C. Reaction conditions MAA (neat), 60"C, 80 100 kg/cm2.

S)-Valine, 66, 153 Vilsmeier-Haack reagent, 66, 121 Vibro-mixer, 65, 52... 

The utility of the method was demonstrated with a variety of electron-rich and electron-poor aryl aldehydes, but the method was not suitable for aliphatic aldehydes. No racemization was observed in the copper-catalyzed oxidative amidation reaction when an optically active amine, (S)-valine methyl ester, was employed. 

R)-phenylglycine Rj = Ph, (S)-phenylalanine R=PhCH2(S)-Methionine R]= CH2CH2Sl-le, (S)-valine Ri = (CH3)2CH, etc. The activated azide compounds(2) were prepared as generally described via hydrazides... 

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