Acid Halogenation, enantioselective

Procedures for enantioselective preparation of a-bromo acids based on reaction of NBS with enol derivatives 16A and 16B have been developed. Predict the absolute configuration of the halogenated compounds produced from both 16A and 16B. Explain the basis of your prediction. 

Burk et al. showed the enantioselective hydrogenation of a broad range of N-acylhydrazones 146 to occur readily with [Et-DuPhos Rh(COD)]OTf [14]. The reaction was found to be extremely chemoselective, with little or no reduction of alkenes, alkynes, ketones, aldehydes, esters, nitriles, imines, carbon-halogen, or nitro groups occurring. Excellent enantioselectivities were achieved (88-97% ee) at reasonable rates (TOF up to 500 h ) under very mild conditions (4 bar H2, 20°C). The products from these reactions could be easily converted into chiral amines or a-amino acids by cleavage of the N-N bond with samarium diiodide. 

Highly enantioselective atom transfer radical cydization reactions catalyzed by chiral Lewis acids have been reported by Yang et al. [80]. Two main advantages of these enantioselective cyclizations include installing multiple chiral centers and retaining a halogen atom in the product, which allows for further functionalization. 

Enantioselective halogenation is a powerful transformation, directly installing an efficient leaving group. Thomas Leckta of Johns Hopkins University has shown (7. Am. Chem. Soc. 2004,126, 4245) that benzoylquinine 11 catalyzes the a-chlorination of ketenes derived from acid chlorides such as 10, to give 12 in high . 

A similar chiral environment is given by inclusion to cyclodextrins (CDs), cyclic oligosaccharides (3). The outside of the host molecule is hydrophilic and the inside hydrophobic. The diameters of the cavities are approximately 6 (a), 7-8 (j3), and 9-10 A (7), respectively. Reduction of some prochiral ketone-j3-CD complexes with sodium boro-hydride in water gives the alcoholic products in modest ee (Scheme 2) (4). On the other hand, uncomplexed ketones are reduced with a crystalline CD complex of borane-pyridine complex dispersed in water to form the secondary alcohols in up to 90% ee, but in moderate chemical yields. Fair to excellent enantioselection has been achieved in gaseous hydrohalogenation or halogenation of a- or /3-CD complexes of crotonic or methacrylic acid. These reactions may seem attractive but currently require the use of stoichiometric amounts of the host CD molecules. 

With benzaldehyde 144 or halogenated derivatives (Cl, F) as acceptors the yeast-PDC-catalyzed addition proceeds with almost complete stereoselectivity to furnish the corresponding (R)-configurated 1-hydroxy-1-phenylpropanones 145 [447]. For practical reasons, whole yeast cells are most often used as the catalyst, with only small loss of enantioselectivity [423,424]. The conversion of benzaldehyde in particular has gained industrial importance because the acyloin is an important precursor for the synthesis of L-(-)-ephedrine [448]. Otherwise, the substrate tolerance is remarkably broad for aromatic aldehydes on the laboratory scale, however, yields of acyloins are usually low because of the prior or consequent reductive metabolism of aldehyde substrate and product, giving rise to considerable quantities of alcohol 146 and vicinol diols 147, respectively [423,424,449], The range of structural variability covers both higher a-oxo-acids (e.g. -butyrate, -valerate) as the donor component, as well as a,/J-un-saturated aldehydes (e.g. cinnamaldehyde 148) as the acceptor [450]. 

Asymmetric hydrohalogenation of fraws-2-butenoic acid has been achieved in a crystalline a-cyclodextrin complex using gaseous HBr at 20 °C and HC1 at 0 °C. The products were formed with 58% and 64% e.e., respectively, and were of (S )-configuration81. This contrasts with the low enantioselectivity of halogenation attempted in the same paper (vide supra). 

Novel approach for optically pure alcohol from racemic compounds is the use of dehalogenases.24 For example, L-2-halo acid dehalogenase Pseudomonas putida was used for the synthesis of D-3-chlorolactic acid from racemic 2,3-dichloropropionic acid (Figure 23(a)).24ad The enzyme catalyzed hydrolytic release of halogen from 2-halocarboxylic acids and produces 2-hydroxy acids with inversion of the configuration. L-2-Halo acid dehalogenase acted on the L-isomer of 2-halo acids and produces D-2-hydroxy acid with an excellent enantioselectivity. 

Many other electrophiles are able to react with metalated ferrocenylalkyl amines, e.g., trimethyl borate (Fig. 4-27 a), which gives, after hydrolytic workup, compounds like (S,S)-l-(iV,iV-dimethyl-l-aminoethyl)ferrocene-2-boronic acid [106]. Important intermediates for further derivatization are the halogens. For the lithiation technique, I2 (Fig. 4-27b) [151] and BrCN [106] lead to the desired compounds, but when BrCN is used, partial substitution of the dimethylamino group by cyanide occurs (see Sect. 4.3.3.2 and Fig. 4-17). For palladated amines, Brj is applicable [152]. (i ,S)-l-Iodo-2-(iV,iV-dimethyl-l-aminoethyl)ferrocene is the starting material for catalytically active zinc compounds for the enantioselective addition of zinc alkyls to carbonyl compounds [151] (see Chapter 3 for this topic). 

Asymmetric ene Reaction In 1988 Yamamoto and coworkers provided the first indication that asymmetry in ene-reactions could be induced by catalytic amounts of chiral Lewis acids in the presence of 4-A molecular sieves (Scheme 6.64) [88]. They described the first example of asymmetric ene-reaction between prochiral, halogenated aldehydes and alkenes catalyzed by chiral binaphthol-derived aluminum complexes. The hindered 3,3-silyl substituents in the chiral catalyst are essential to achieve good enantioselectivity and high yield. In fact, the use of a catalyst derived from MesAl and 3,3 -biphenylbinaphthol led to the racemic product in a low yield. 

Catalysts (25) are the Lewis acid-Lewis base bifunctional catalysts in which Lewis acid-Al(III) moiety activates acyl iminium ion and the Lewis base (oxygen of phosphine oxide) does TMSCN, simultaneously (Scheme 5.7). Halogen atoms at the 6-position enhanced both yields and enantioselectivity in Reissert-type cyanation of the imino part of 26. However, the order for the activation is not parallel to the electronegativity of the halogen atoms and, moreover, the strong electron-withdrawing trifluoromethyl group provided unexpectedly the worst result for the activation [13]. It is not simple to explain this phenomenon only in terms of the increased Lewis acidity of the metal center. Trifluoromethylated BINOL-zirconium catalysts (28) for asymmetric hetero Diels-Alder reaction (Scheme 5.8) [14], trifluoromethylated arylphosphine-palladium catalyst (32) for asymmetric hydrosilylation (Scheme 5.9) [15], and fluorinated BINOL-zinc catalyst (35) for asymmetric phenylation (Scheme 5.10) [16] are known. 

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