Hydroxycarboxylic acids, enantioselective

Dochnahl M, Fu GC (2009) Catalytic asymmetric cycloaddition of ketenes and nitroso compounds enantioselective synthesis of a-hydroxycarboxylic acid derivatives. Angew Chem Int Ed 48 2391-2393... 

Lewis acid-promoted asymmetric addition of dialkylzincs to aldehydes is also an acceptable procedure for the preparation of chiral secondary alcohol. Various chiral titanium complexes are highly enantioselective catalysts [4]. C2-Symmet-ric disulfonamide, chiral diol (TADDOL) derived from tartaric acid, and chiral thiophosphoramidate are efficient chiral ligands. C2-Symmetric chiral diol 10, readily prepared from 1-indene by Brown s asymmetric hydroboration, is also a good chiral source (Scheme 2) [17], Even a simple a-hydroxycarboxylic acid 11 can achieve a good enantioselectivity [18]. 

Interest in the synthesis of enantiopure 2-hydroxycarboxylic acids via asymmetric enzymatic transformations is still increasing and two pathways have risen into prominence recently. The first is based on enantioselective hydrocyanation of the appropriate aldehyde in the presence of an oxynitrilase (hydroxynitrile lyase, EC 4.1.2.10), which gives rise to the corresponding enantiomerically pure cyanohydrin, followed by chemical hydrolysis in the presence of strong acid (Figure 16.1, route a). This latter step generates copious quantities of salt and is not compatible with sensitive functional groups, which is a serious limitation. 

Alternatively, enantiopure 2-hydroxycarboxylic acids can be obtained via a dynamic kinetic resolution of the (chemically synthesized) cyanohydrin in the presence of an enantioselective nitrilase (EC 3.5.5.1) (see Figure 16.1, route b). Racemization of the cyanohydrin, via reversible dehydrocyanation, takes place readily at pH 7 or above. The methodology [1] is attractive on account of the mild reaction conditions and is industrially applied in the multiton-scale synthesis of (R)-mandehc acid [2]. 

Figure 16.1 Synthetic routes to enantiomerically pure 2-hydroxycarboxylic acids, via oxynitrilase (hydroxynitrile lyase) catalysed enantioselective hydrocyanation (route A) and (R)-nitrilase (nitrilase) mediated dynamic kinetic resolution (route B).

The bienzymatic approach described above could also be advantageously applied to the synthesis of (R)-2-hydroxycarboxylic acids in cases where no satisfactorily enantioselective nitrilase is available (Figure 16.5). The best enantioselectivity in the hydrolysis of lb, for example, was 92% ee. The enantioselectivity of the hydroxynitrile lyase from ahnonds (PaHnL) in the synthesis of lb is also less then perfect [13], but we found that a combiCLEA of PaHnL and NIT-106 quantitatively converted 2b (O.IM starting concentration) into 3b with ee>99% R (reaction in 90 10 DlPE-buffer pH 5.5, as before) with very little (>3%) amide formation. 

Zirconium enolates of chiral amido derivatives (6) have been were employed to achieve an asymmetric aldol reaction. Hydrolysis of the aldol products (7) gave /3-hydroxycarboxylic acids (8) with high enantioselectivity (Eq. 3). 

The regioselective process is suitable for the synthesis of protected (3-amino-a-hydroxycarboxylic acid derivatives (racemic, no chiral ligand added) from the corresponding acrylic acid substrates. On the other hand, 1,4-bis(dihydroquininoxy)-anthraquinone mediates enantioselective formation of A-benzyloxycarbonylphenylserine. ... 

The same concept was used for sensing a-hydroxycarboxylic acids and diols using chiral boronate 56 (Fig. 17a) containing a displaceable fluorescent group [144]. Formation of the boronate resulted in an increased fluorescence of a couma-rin derived fluorophore, while displacement by the hydroxy acid restored the weaker emission of the free fluorophore. The enantioselective fluorescent response was sufficient for the determination of the enantiomeric excess of phenyllactic acid with a 0.13 (13%) maximum deviation from the actual values. A mathematical algorithm has recently been proposed for the calculation of both stability constants and enantiomeric excess in these indicator-displacement assays [145]. 

Liu HL, Peng Q, Wu YD et al (2010) Highly enantioselective recognition of structurally diverse a-hydroxycarboxylic acids using a fluorescent sensor. Angew Chem Int Ed 49 602-606... 

Figure 11.77 Enantioselective reduction of an aryl f CIalkyl ketone using stoichiometric amounts of (+ )-lpc2BCI synthesis of an e.p. substituted y-hydroxycarboxylic acid derivative...

The hydration of C-C multiple bonds is a reaction with prevalent industrial interest due to the usefulness of the products as chemical intermediates. The wool-Pd complex is an economical and highly active catalyst for hydration of olefins. It is very stable and can be reused several times without any remarkable change in the catalytic activity [73, 74]. In particular, to convert alkenes to the corresponding alcohols in excellent enantioselectivity, a new biopolymer-metal complex constituted of wool-supported palladium-iron or palladium-cobalt was prepared and used, such as allylamine to amino-2-propanoI, acrylonitrile to lactonitrile and unsaturated acids to a-hydroxycarboxylic acids [75-77]. The same catalytic system was also used for hydration of substituted styrenes to produce chiral benzyl alcohols. The simple and cleaner procedure, mild reaction conditions, high stability and recovery rate of catalyst made these catalytic systems an attractive and useful alternative to the existing methods (Scheme 37). 

When /V-arenesulfonyl-a-amino acid derived boranes 13 and 14 are used in substoichiometric amounts in order to mediate enantioselective aldol additions of a,a-dimethyl substituted ketcnc acetal 15, /J-hydroxycarboxylic esters 16 are obtained in enantiomeric excess of 84 to > 99 %3fi. 

Our first elDA was developed for chiral or-hydroxy-carboxylates (Figure 35) and vicinal diols using chiral aryl-boronic acids as receptors. The reversible interaction between arylboronic acids and a-hydroxycarboxylates or diols has been described in the previons section. Our original design is based on the hypothesis that the incorporated stereocenters near the postulated B-N dative bond in the receptors would induce enantioselectivity for the binding between the receptor and two enantiomers of the analyte. However, extensive studies reveal that the proposed B-N dative bond does not exist to an appropriate extent in protic sol vents.A small library of achiral and chiral phenylboronic acids (66, 78-80) was synthesized, and... 

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